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Secondary Metabolites from Higher Fungi: Discovery, Bioactivity, and Bioproduction
NASA Astrophysics Data System (ADS)
Zhong, Jian-Jiang; Xiao, Jian-Hui
Medicinal higher fungi such as Cordyceps sinensis and Ganoderma lucidum have been used as an alternative medicine remedy to promote health and longevity for people in China and other regions of the world since ancient times. Nowadays there is an increasing public interest in the secondary metabolites of those higher fungi for discovering new drugs or lead compounds. Current research in drug discovery from medicinal higher fungi involves a multifaceted approach combining mycological, biochemical, pharmacological, metabolic, biosynthetic and molecular techniques. In recent years, many new secondary metabolites from higher fungi have been isolated and are more likely to provide lead compounds for new drug discovery, which may include chemopreventive agents possessing the bioactivity of immunomodulatory, anticancer, etc. However, numerous challenges of secondary metabolites from higher fungi are encountered including bioseparation, identification, biosynthetic metabolism, and screening model issues, etc. Commercial production of secondary metabolites from medicinal mushrooms is still limited mainly due to less information about secondary metabolism and its regulation. Strategies for enhancing secondary metabolite production by medicinal mushroom fermentation include two-stage cultivation combining liquid fermentation and static culture, two-stage dissolved oxygen control, etc. Purification of bioactive secondary metabolites, such as ganoderic acids from G. lucidum, is also very important to pharmacological study and future pharmaceutical application. This review outlines typical examples of the discovery, bioactivity, and bioproduction of secondary metabolites of higher fungi origin.
Novel bioactive metabolites of dipyrone (metamizol).
Rogosch, Tobias; Sinning, Christian; Podlewski, Agnes; Watzer, Bernhard; Schlosburg, Joel; Lichtman, Aron H; Cascio, Maria G; Bisogno, Tiziana; Di Marzo, Vincenzo; Nüsing, Rolf; Imming, Peter
Dipyrone is a common antipyretic drug and the most popular non-opioid analgesic in many countries. In spite of its long and widespread use, molecular details of its fate in the body are not fully known. We administered dipyrone orally to mice. Two unknown metabolites were found, viz. the arachidonoyl amides of the known major dipyrone metabolites, 4-methylaminoantipyrine (2) and 4-aminoantipyrine (3). They were identified by ESI-LC-MS/MS after extraction from the CNS, and comparison with reference substances prepared synthetically. The arachidonoyl amides were positively tested for cannabis receptor binding (CB(1) and CB(2)) and cyclooxygenase inhibition (COX-1 and COX-2 in tissues and as isolated enzymes), suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain. PMID:22172309
Secondary metabolites and bioactivities of Albizia anthelmintica
Mohamed, Tahia K.; Nassar, Mahmoud I.; Gaara, Ahmed H.; El-Kashak, Walaa A.; Brouard, Iñaki; El-Toumy, Sayed A.
Background: Albizia species are rich in phenolics and terpenes in the different plant organs. They are widely used in traditional Chinese medicine. So this study investigated the phytochemical and biological activities of Albizia Anthelmintica. Materials and Methods: Column chromatography has been performed for the isolation of compounds. Bioactivity studies of A. anthelmintica leaves were carried out on aqueous ethanol extract and some pure compounds were tested for their antioxidant activities. Results: Eight compounds have been isolated for the first time from A. anthelmintica. The aqueous ethanol extract of A. anthelmintica showed moderate anti-inflammatory activity and significant for both analgesic and antioxidant activities. Quercetin-3-O-β-D-glucopyranoside, kaempferol-3-O-β-D-glucopyranoside, kaempferol-3-O-(6β-O-galloyl-β-D-glucopyranoside and quercetin-3-O-(6β-O-galloyl-β-D-glucopyranoside) exhibited potent antioxidant scavenging activity towards diphenyl-picrylhydrazine. PMID:23798881
Major bioactive metabolites from marine fungi: A Review
Hasan, Saba; Ansari, Mohammad Israil; Ahmad, Anis; Mishra, Maitreyi
Biologists and chemists of the world have been attracted towards marine natural products for the last five decades. Approximately 16,000 marine natural products have been isolated from marine organisms which have been reported in approximately 6,800 publications, proving marine microorganisms to be a invaluable source for the production of novel antibiotic, anti tumor, and anti inflammatory agents. The marine fungi particularly those associated with marine alga, sponge, invertebrates, and sediments appear to be a rich source for secondary metabolites, possessing Antibiotic, antiviral, antifungal and antiyeast activities. Besides, a few growth stimulant properties which may be useful in studies on wound healing, carcinogenic properties, and in the study of cancers are reported. Recent investigations on marine filamentous fungi looking for biologically active secondary metabolites indicate the tremendous potential of them as a source of new medicines. The present study reviews about some important bioactive metabolites reported from marine fungal strains which are anti bacterial, anti tumour and anti inflammatory in action. It highlights the chemistry and biological activity of the major bioactive alkaloids, polyketides, terpenoids, isoprenoid and non-isoprenoid compounds, quinones, isolated from marine fungi. PMID:26124556
Metabolites identification of bioactive licorice compounds in rats.
Wang, Qi; Qian, Yi; Wang, Qing; Yang, Yan-Fang; Ji, Shuai; Song, Wei; Qiao, Xue; Guo, De-An; Liang, Hong; Ye, Min
Licorice (Glycyrrhiza uralensis Fisch.) is one of the most popular herbal medicines worldwide. This study aims to identify the metabolites of seven representative bioactive licorice compounds in rats. These compounds include 22β-acetoxyl glycyrrhizin (1), licoflavonol (2), licoricidin (3), licoisoflavanone (4), isoglycycoumarin (5), semilicoisoflavone B (6), and 3-methoxy-9-hydroxy-pterocarpan (7). After oral administration of 250mg/kg of 1 or 40mg/kg of 2-7 to rats, a total of 16, 43 and 31 metabolites were detected in the plasma, urine and fecal samples, respectively. The metabolites were characterized by HPLC/DAD/ESI-MS(n) and LC/IT-TOF-MS analyses. Particularly, two metabolites of 1 were unambiguously identified by comparing with reference standards, and 22β-acetoxyl glycyrrhizin-6″-methyl ester (1-M2) is a new compound. Compound 1 could be readily hydrolyzed to eliminate the glucuronic acid residue. The phenolic compounds (4-7) mainly undertook phase II metabolism (glucuronidation or sulfation). Most phenolic compounds with an isoprenyl group (chain or cyclized, 2-5) could also undertake hydroxylation reaction. This is the first study on in vivo metabolism of these licorice compounds. PMID:26311472
Efficient total synthesis of novel bioactive microbial metabolites.
Sunazuka, Toshiaki; Hirose, Tomoyasu; Omura, Satoshi
Bioactive natural products produced by microbes have almost limitless potential in pharmaceutical applications, and the organic synthesis of such products as lead compounds will result in the creation of new and widely useful pharmaceutical products. A program of discovery of naturally occurring bioactive microbial metabolites has been ongoing at the Kitasato Institute. We have also developed efficient, rational, and highly flexible production methods for generation of target compounds, synthesis of related compounds, elucidation of their structure-activity relationships, and the possible creation of improved bioactive compounds. In this Account, the isolation and total synthesis of naturally occurring bioactive microbial metabolites in order to create novel medicines for specific illnesses is described. This covers diseases and conditions such as atherosclerosis, Alzheimer's disease, cancer, inflammation, and osteoporosis, among others, and focuses on six specific compounds. Pyripyropenes were discovered from Aspergillus fumigatus FO-1289 through our screening of microbial metabolites that strongly inhibit acyl-CoA cholesterol acyltransferase (ACAT) in order to develop a new class of cholesterol-lowering agents. These novel polyoxygenated mixed polyketide-terpenoid (meroterpenoid) metabolites contain a fused pyridyl alpha-pyrone moiety. We carried out the first total synthesis of (+)-pyripyropene A via a flexible, concise, and highly efficient route and also clarified the structure-activity relationships. Arisugacins were discovered from Penicillium sp. FO-4259 by our screening of microbial metabolites that strongly inhibit acetylcholinesterase (AChE) in order to create novel medicines for Alzheimer's disease (AD). Arisugacins are also meroterpenoids. We have achieved the first convergent total synthesis of arisugacins A and B. Lactacystin was isolated from Streptomyces sp. OM-6519 via our screening of microbial metabolites that promote the differentiation of the
Advancement into the Arctic Region for Bioactive Sponge Secondary Metabolites
Abbas, Samuel; Kelly, Michelle; Bowling, John; Sims, James; Waters, Amanda; Hamann, Mark
Porifera have long been a reservoir for the discovery of bioactive compounds and drug discovery. Most research in the area has focused on sponges from tropical and temperate waters, but more recently the focus has shifted to the less accessible colder waters of the Antarctic and, to a lesser extent, the Arctic. The Antarctic region in particular has been a more popular location for natural products discovery and has provided promising candidates for drug development. This article reviews groups of bioactive compounds that have been isolated and reported from the southern reaches of the Arctic Circle, surveys the known sponge diversity present in the Arctic waters, and details a recent sponge collection by our group in the Aleutian Islands, Alaska. The collection has yielded previously undescribed sponge species along with primary activity against opportunistic infectious diseases, malaria, and HCV. The discovery of new sponge species and bioactive crude extracts gives optimism for the isolation of new bioactive compounds from a relatively unexplored source. PMID:22163194
Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites
Frantz, C.E.; Chen, Hongwei; Eastmond, D.A.
Benzene is a clastogenic and carcinogenic agent that induces acute myelogenous leukemia in humans and multiple types of tumors in animals. Previous research has indicated that benzene must first be metabolized to one or more bioactive species to exert its myelotoxic and genotoxic effects. To better understand the possible role of individual benzene metabolites in the leukemogenic process, as well as to further investigate inhibition of topoisomerase 11 by benzene metabolites, a series of known and putative benzene metabolites, phenol, 4{prime}4-biphenol, 2,2{prime}-biphenol, hydroquinone, catechol, 1,2,4-benzenetriol, 1,4-benzoquinone, and trans-trans-muconaldehyde were tested for inhibitory effects in vitro on the human topoisomerase 11 enzyme. With minor modifications of the standard assay conditions, 1,4-benzoquinone and trans-trans-muconaldehyde were shown to be directly inhibitory, whereas all of the phenolic metabolites were shown to inhibit enzymatic activity following bioactivation using a peroxidase activation system. The majority of compounds tested inhibited topoisomerase 11 at concentrations at or below 10 pM. These results confirm and expand upon previous findings from our laboratory and indicate that many of the metabolites of benzene could potentially interfere with topoisomerase 11. Since other inhibitors of topoisomerase 11 have been shown to induce leukemia in humans, inhibition of this enzyme by benzene metabolites may also play a role in the carcinogenic effects of benzene. 48 refs., 4 tabs.
Chemotaxonomic Metabolite Profiling of 62 Indigenous Plant Species and Its Correlation with Bioactivities.
Lee, Sarah; Oh, Dong-Gu; Lee, Sunmin; Kim, Ga Ryun; Lee, Jong Seok; Son, Youn Kyoung; Bae, Chang-Hwan; Yeo, Joohong; Lee, Choong Hwan
Chemotaxonomic metabolite profiling of 62 indigenous Korean plant species was performed by ultrahigh performance liquid chromatography (UHPLC)-linear trap quadrupole-ion trap (LTQ-IT) mass spectrometry/mass spectrometry (MS/MS) combined with multivariate statistical analysis. In partial least squares discriminant analysis (PLS-DA), the 62 species clustered depending on their phylogenetic family, in particular, Aceraceae, Betulaceae, and Fagaceae were distinguished from Rosaceae, Fabaceae, and Asteraceae. Quinic acid, gallic acid, quercetin, quercetin derivatives, kaempferol, and kaempferol derivatives were identified as family-specific metabolites, and were found in relatively high concentrations in Aceraceae, Betulaceae, and Fagaceae. Fagaceae and Asteraceae were selected based on results of PLS-DA and bioactivities to determine the correlation between metabolic differences among plant families and bioactivities. Quinic acid, quercetin, kaempferol, quercetin derivatives, and kaempferol derivatives were found in higher concentrations in Fagaceae than in Asteraceae, and were positively correlated with antioxidant and tyrosinase inhibition activities. These results suggest that metabolite profiling was a useful tool for finding the different metabolic states of each plant family and understanding the correlation between metabolites and bioactivities in accordance with plant family. PMID:26540030
A Brief Review of Bioactive Metabolites Derived from Deep-Sea Fungi
Wang, Yan-Ting; Xue, Ya-Rong; Liu, Chang-Hong
Deep-sea fungi, the fungi that inhabit the sea and the sediment at depths of over 1000 m below the surface, have become an important source of industrial, agricultural, and nutraceutical compounds based on their diversities in both structure and function. Since the first study of deep-sea fungi in the Atlantic Ocean at a depth of 4450 m was conducted approximately 50 years ago, hundreds of isolates of deep-sea fungi have been reported based on culture-dependent methods. To date more than 180 bioactive secondary metabolites derived from deep-sea fungi have been documented in the literature. These include compounds with anticancer, antimicrobial, antifungal, antiprotozoal, and antiviral activities. In this review, we summarize the structures and bioactivities of these metabolites to provide help for novel drug development. PMID:26213949
A Brief Review of Bioactive Metabolites Derived from Deep-Sea Fungi.
Wang, Yan-Ting; Xue, Ya-Rong; Liu, Chang-Hong
Deep-sea fungi, the fungi that inhabit the sea and the sediment at depths of over 1000 m below the surface, have become an important source of industrial, agricultural, and nutraceutical compounds based on their diversities in both structure and function. Since the first study of deep-sea fungi in the Atlantic Ocean at a depth of 4450 m was conducted approximately 50 years ago, hundreds of isolates of deep-sea fungi have been reported based on culture-dependent methods. To date more than 180 bioactive secondary metabolites derived from deep-sea fungi have been documented in the literature. These include compounds with anticancer, antimicrobial, antifungal, antiprotozoal, and antiviral activities. In this review, we summarize the structures and bioactivities of these metabolites to provide help for novel drug development. PMID:26213949
Bioactive Secondary Metabolites Produced by the Oak Pathogen Diplodia corticola.
Masi, Marco; Maddau, Lucia; Linaldeddu, Benedetto Teodoro; Cimmino, Alessio; D'Amico, Wanda; Scanu, Bruno; Evidente, Marco; Tuzi, Angela; Evidente, Antonio
Three new lactones and a new fatty acid ester, named sapinofuranones C and D, diplopyrone B, and diplobifuranylone C, respectively, were isolated from Diplodia corticola, together with sphaeropsidins A and C, diplopyrone, diplobifuranylones A and B, diplofuranone A, and the (S,S)-enantiomer of sapinofuranone B. Sapinofuranones C and D, diplopyrone B, and diplobifuranylone C were characterized as (5S)-5-((1,S-1,6-dihydroxyhexa-2,4-dienyl)-dihydrofuran-2-one, 4,5-dihydroxy-deca-6,8-dienoic acid methyl ester, (5S)-5-hydroxy-6-(penta-1,3-dienyl)-5,6-dihydro-pyran-2-one, and 5'-((1R)-1-hydroxyethyl)-2',5'-dihydro-2H-[2,2']bifuranyl-5-one by spectroscopic and chemical methods, respectively. The relative configuration of sapinofuranone C was assigned by X-ray diffraction analysis, whereas its absolute configuration was determined by applying the advanced Mosher's method to its 11-O-p-bromobenzoyl derivative. The same method was used to assign the absolute configuration to C-5 of diplopyrone B and to that of the hydroxyethyl of the side chain of diplobifuranylone C, respectively. The metabolites isolated were tested at 1 mg/mL on leaves of cork oak, grapevine cv. 'Cannonau', and tomato using the leaf puncture assay. They were also tested on tomato cuttings at 0.2, 0.1, and 0.05 mg/mL. Each compound was tested for zootoxic activity on Artemia salina L. larvae. The efficacy of sapinofuranone C and diplopyrone B on three plant pathogens, namely, Athelia rolfsii, Fusarium avenaceum, and Phytophthora nicotianae was also evaluated. In all phytotoxic assays only diplopyrone B was found to be active. It also showed strong inhibition on the vegetative growth of A. rolfsii and P. nicotianae. All metabolites were inactive in the assay performed for the zootoxic activity (A. salina) even at the highest concentration used (200 μg/mL). Diplopyrone B showed a promising antioomycete activity for the control of Phytophthora spp. also taking into account the absence of zootoxic activity
Facilitated uptake of a bioactive metabolite of maritime pine bark extract (pycnogenol) into human erythrocytes.
Kurlbaum, Max; Mülek, Melanie; Högger, Petra
Many plant secondary metabolites exhibit some degree of biological activity in humans. It is a common observation that individual plant-derived compounds in vivo are present in the nanomolar concentration range at which they usually fail to display measurable activity in vitro. While it is debatable that compounds detected in plasma are not the key effectors of bioactivity, an alternative hypothesis may take into consideration that measurable concentrations also reside in compartments other than plasma. We analysed the binding of constituents and the metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone (M1), that had been previously detected in plasma samples of human consumers of pine bark extract Pycnogenol, to human erythrocytes. We found that caffeic acid, taxifolin, and ferulic acid passively bind to red blood cells, but only the bioactive metabolite M1 revealed pronounced accumulation. The partitioning of M1 into erythrocytes was significantly diminished at higher concentrations of M1 and in the presence of glucose, suggesting a facilitated transport of M1 via GLUT-1 transporter. This concept was further supported by structural similarities between the natural substrate α-D-glucose and the S-isomer of M1. After cellular uptake, M1 underwent further metabolism by conjugation with glutathione. We present strong indication for a transporter-mediated accumulation of a flavonoid metabolite in human erythrocytes and subsequent formation of a novel glutathione adduct. The physiologic role of the adduct remains to be elucidated. PMID:23646194
Discovery of Bioactive Metabolites in Biofuel Microalgae That Offer Protection against Predatory Bacteria
Bagwell, Christopher E.; Abernathy, Amanda; Barnwell, Remy; Milliken, Charles E.; Noble, Peter A.; Dale, Taraka; Beauchesne, Kevin R.; Moeller, Peter D. R.
Microalgae could become an important resource for addressing increasing global demand for food, energy, and commodities while helping to reduce atmospheric greenhouse gasses. Even though Chlorophytes are generally regarded safe for human consumption, there is still much we do not understand about the metabolic and biochemical potential of microscopic algae. The aim of this study was to evaluate biofuel candidate strains of Chlorella and Scenedesmus for the potential to produce bioactive metabolites when grown under nutrient depletion regimes intended to stimulate production of triacylglycerides. Strain specific combinations of macro- and micro-nutrient restricted growth media did stimulate neutral lipid accumulation by microalgal cultures. However, cultures that were restricted for iron consistently and reliably tested positive for cytotoxicity by in vivo bioassays. The addition of iron back to these cultures resulted in the disappearance of the bioactive components by LC/MS fingerprinting and loss of cytotoxicity by in vivo bioassay. Incomplete NMR characterization of the most abundant cytotoxic fractions suggested that small molecular weight peptides and glycosides could be responsible for Chlorella cytotoxicity. Experiments were conducted to determine if the bioactive metabolites induced by Fe-limitation in Chlorella sp. cultures would elicit protection against Vampirovibrio chlorellavorus, an obligate predator of Chlorella. Introduction of V. chlorellavorus resulted in a 72% decrease in algal biomass in the experimental controls after 7 days. Conversely, only slight losses of algal biomass were measured for the iron limited Chlorella cultures (0–9%). This study demonstrates a causal linkage between iron bioavailability and bioactive metabolite production in strains of Chlorella and Scenedesmus. Further study of this phenomenon could contribute to the development of new strategies to extend algal production cycles in open, outdoor systems while ensuring the
Discovery of Bioactive Metabolites in Biofuel Microalgae That Offer Protection against Predatory Bacteria.
Bagwell, Christopher E; Abernathy, Amanda; Barnwell, Remy; Milliken, Charles E; Noble, Peter A; Dale, Taraka; Beauchesne, Kevin R; Moeller, Peter D R
Microalgae could become an important resource for addressing increasing global demand for food, energy, and commodities while helping to reduce atmospheric greenhouse gasses. Even though Chlorophytes are generally regarded safe for human consumption, there is still much we do not understand about the metabolic and biochemical potential of microscopic algae. The aim of this study was to evaluate biofuel candidate strains of Chlorella and Scenedesmus for the potential to produce bioactive metabolites when grown under nutrient depletion regimes intended to stimulate production of triacylglycerides. Strain specific combinations of macro- and micro-nutrient restricted growth media did stimulate neutral lipid accumulation by microalgal cultures. However, cultures that were restricted for iron consistently and reliably tested positive for cytotoxicity by in vivo bioassays. The addition of iron back to these cultures resulted in the disappearance of the bioactive components by LC/MS fingerprinting and loss of cytotoxicity by in vivo bioassay. Incomplete NMR characterization of the most abundant cytotoxic fractions suggested that small molecular weight peptides and glycosides could be responsible for Chlorella cytotoxicity. Experiments were conducted to determine if the bioactive metabolites induced by Fe-limitation in Chlorella sp. cultures would elicit protection against Vampirovibrio chlorellavorus, an obligate predator of Chlorella. Introduction of V. chlorellavorus resulted in a 72% decrease in algal biomass in the experimental controls after 7 days. Conversely, only slight losses of algal biomass were measured for the iron limited Chlorella cultures (0-9%). This study demonstrates a causal linkage between iron bioavailability and bioactive metabolite production in strains of Chlorella and Scenedesmus. Further study of this phenomenon could contribute to the development of new strategies to extend algal production cycles in open, outdoor systems while ensuring the
Nanodiamonds coupled with plant bioactive metabolites: a nanotech approach for cancer therapy.
Gismondi, Angelo; Reina, Giacomo; Orlanducci, Silvia; Mizzoni, Francesca; Gay, Stefano; Terranova, Maria L; Canini, Antonella
Nanodiamond application in biotechnological and medical fields is nowadays in continuous progress. In fact, biocompatibility, reduced dimensions and high surface chemical interaction are specific features that make nanodiamonds perfect intracellular carriers of bioactive compounds. By confocal microscopy, we confirmed that nanodiamonds were able to penetrate in cell cytoplasm but we also demonstrated how they remained embedded in nuclear membrane just exposing some little portions into nuclear area, definitively clarifying this topic. In this work, for the first time, nanodiamonds were conjugated with plant secondary metabolites, ciproten and quercetin. Moreover, since drug-loading on nanoparticles was strongly conditioned by their chemical surface, different types of nanodiamonds (oxidized, wet chemical reduced and plasma reduced) were synthesized in this work and then functionalized with plant compounds. We found that ciproten and quercetin antiproliferative effects, on human (HeLa) and murine (B16F10) tumor cells, were improved after nanodiamond conjugation. Moreover, plant molecules highly reduced their in vitro pro-oxidant, cytotoxic and pro-apoptotic activity when associated with nanodiamond. We are led to suppose that natural drug-nanodiamond adducts would act at cellular level by different molecular mechanisms with respect to plant metabolite pure forms. Finally, our results showed that chemical and structural modifications of nanodiamond surfaces influenced the bioactivity of transported drugs. According to all these evidences, this work can be considered as a promotional research to favor the use of bioactive plant molecules associated with nanodiamonds for therapeutic purposes. PMID:25457980
Rice Bran Fermented with Saccharomyces boulardii Generates Novel Metabolite Profiles with Bioactivity
Emerging evidence supporting chronic disease fighting properties of rice bran has advanced the development of stabilized rice bran for human use as a functional food and dietary supplement. A global and targeted metabolomic investigation of stabilized rice bran fermented with Saccharomyces boulardii was performed in three rice varieties. Metabolites from S. boulardii-fermented rice bran were detected by gas chromatography−mass spectrometry (GC−MS) and assessed for bioactivity compared to nonfermented rice bran in normal and malignant lymphocytes. Global metabolite profiling revealed significant differences in the metabolome that led to discovery of candidate compounds modulated by S. boulardii fermentation. Fermented rice bran extracts from three rice varieties reduced growth of human B lymphomas compared to each variety's nonfermented control and revealed that fermentation differentially altered bioactive compounds. These data support that integration of global and targeted metabolite analysis can be utilized for assessing health properties of rice bran phytochemicals that are enhanced by yeast fermentation and that differ across rice varieties. PMID:21306106
Rare actinomycetes Nocardia caishijiensis and Pseudonocardia carboxydivorans as endophytes, their bioactivity and metabolites evaluation.
Tanvir, Rabia; Sajid, Imran; Hasnain, Shahida; Kulik, Andreas; Grond, Stephanie
Two strains identified as Nocardia caishijiensis (SORS 64b) and Pseudonocardia carboxydivorans (AGLS 2) were isolated as endophytes from Sonchus oleraceus and Ageratum conyzoides respectively. The analysis of their extracts revealed them to be strongly bioactive. The N. caishijiensis extract gave an LC50 of 570 μg/ml(-1) in the brine shrimp cytotoxicity assay and an EC50 of 0.552 μg/ml(-1) in the DPPH antioxidant assay. Antimicrobial activity was observed against Methicillin resistant Staphlococcus aureus (MRSA) and Escherichia coli ATCC 25922 (14 mm), Klebsiella pneumoniae ATCC 706003 (13 mm), S. aureus ATCC 25923 (11 mm) and Candida tropicalis (20 mm). For the extract of P. carboxydivorans the EC50 was 0.670 μg/ml(-1) and it was observed to be more bioactive against Bacillus subtilis DSM 10 ATCC 6051 (21 mm), C. tropicalis (20 mm), S. aureus ATCC 25923 (17 mm), MRSA (17 mm), E. coli K12 (W1130) (16 mm) and Chlorella vulgaris (10 mm). The genotoxicity testing revealed a 20 mm zone of inhibition against the polA mutant strain E. coli K-12 AB 3027 suggesting damage to the DNA and polA genes. The TLC and bioautography screening revealed a diversity of active bands of medium polar and nonpolar compounds. Metabolite analysis by HPLC-DAD via UV/vis spectral screening suggested the possibility of stenothricin and bagremycin A in the mycelium extract of N. caishijiensis respectively. In the broth and mycelium extract of P. carboxydivorans borrelidin was suggested along with α-pyrone. The HPLC-MS revealed bioactive long chained amide derivatives such as 7-Octadecenamide, 9, 12 octadecandienamide. This study reports the rare actinomycetes N. caishijiensis and P. carboxydivorans as endophytes and evaluates their bioactive metabolites. PMID:26946375
Bioactivation and bioinactivation of drugs and drug metabolites: Relevance to adverse drug reactions.
Park, B K; Pirmohamed, M; Tingle, M D; Madden, S; Kitteringham, N R
Adverse drug reactions that cannot be predicted from the pharmacological properties of the drug and which are not easily reproduced in laboratory animals are a major complication of drug therapy. It is necessary to investigate the mechanisms of such reactions in order to (1) define structural features within a given drug molecule which are responsible for causing toxicity and (2) to identify those individuals who are particularly sensitive to a given drug reaction. In theory, drug toxicity may arise by direct toxicity, genotoxicity or immune-mediated toxicity caused by either parent drug or chemical. In this respect chemically reactive metabolites are of particular importance and the balance between bioactivation and bioinactivation pathways of drug metabolism will be a critical factor in both the type and extent of toxicity. We have therefore developed in vitro techniques that incorporate human cells for the detection and characterization of stable, chemically reactive and cytotoxic metabolites. In such experiments bioactivation (by CYP1A, CYP2D6, CYP3A, etc.) can be investigated by use of a liver bank, while lymphocytes provide accessible human cells, which can be obtained from both patients and volunteers, genotyped and/or phenotyped for particular drug-metabolizing enzymes (eg. glutathione transferase mu). The relevance of in vitro experiments to drug toxicity observed in humans will be illustrated by reference to studies with anticonvulsants and antimalarials. PMID:20692973
Low water activity induces the production of bioactive metabolites in halophilic and halotolerant fungi.
Sepcic, Kristina; Zalar, Polona; Gunde-Cimerman, Nina
The aim of the present study was to investigate indigenous fungal communities isolated from extreme environments (hypersaline waters of solar salterns and subglacial ice), for the production of metabolic compounds with selected biological activities: hemolysis, antibacterial, and acetylcholinesterase inhibition. In their natural habitats, the selected fungi are exposed to environmental extremes, and therefore the production of bioactive metabolites was tested under both standard growth conditions for mesophilic microorganisms, and at high NaCl and sugar concentrations and low growth temperatures. The results indicate that selected halotolerant and halophilic species synthesize specific bioactive metabolites under conditions that represent stress for non-adapted species. Furthermore, adaptation at the level of the chemical nature of the solute lowering the water activity of the medium was observed. Increased salt concentrations resulted in higher hemolytic activity, particularly within species dominating the salterns. The appearance of antibacterial potential under stress conditions was seen in the similar pattern of fungal species as for hemolysis. The active extracts exclusively affected the growth of the Gram-positive bacterium tested, Bacillus subtilis. None of the extracts tested showed inhibition of acetylcholinesterase activity. PMID:21339946
Bioactive and Structural Metabolites of Pseudomonas and Burkholderia Species Causal Agents of Cultivated Mushrooms Diseases1
Andolfi, Anna; Cimmino, Alessio; Cantore, Pietro Lo; Iacobellis, Nicola Sante; Evidente, Antonio
Pseudomonas tolaasii, P. reactans and Burkholderia gladioli pv. agaricicola, are responsible of diseases on some species of cultivated mushrooms. The main bioactive metabolites produced by both Pseudomonas strains are the lipodepsipeptides (LDPs) tolaasin I and II and the so called White Line Inducing Principle (WLIP), respectively, LDPs which have been extensively studied for their role in the disease process and for their biological properties. In particular, their antimicrobial activity and the alteration of biological and model membranes (red blood cell and liposomes) was established. In the case of tolaasin I interaction with membranes was also related to the tridimensional structure in solution as determined by NMR combined with molecular dynamic calculation techniques. Recently, five news minor tolaasins, tolaasins A–E, were isolated from the culture filtrates of P. tolaasii and their chemical structure was determined by extensive use of NMR and MS spectroscopy. Furthermore, their antimicrobial activity was evaluated on target micro-organisms (fungi—including the cultivated mushrooms Agaricus bisporus, Lentinus edodes, and Pleurotus spp.—chromista, yeast and bacteria). The Gram positive bacteria resulted the most sensible and a significant structure-activity relationships was apparent. The isolation and structure determination of bioactive metabolites produced by B. gladioli pv. agaricicola are still in progress but preliminary results indicate their peptide nature. Furthermore, the exopolysaccharide (EPS) from the culture filtrates of B. gladioli pv. agaricicola, as well as the O-chain and lipid A, from the lipopolysaccharide (LPS) of the three bacteria, were isolated and the structures determined. PMID:19787100
Low Water Activity Induces the Production of Bioactive Metabolites in Halophilic and Halotolerant Fungi
Sepcic, Kristina; Zalar, Polona; Gunde-Cimerman, Nina
The aim of the present study was to investigate indigenous fungal communities isolated from extreme environments (hypersaline waters of solar salterns and subglacial ice), for the production of metabolic compounds with selected biological activities: hemolysis, antibacterial, and acetylcholinesterase inhibition. In their natural habitats, the selected fungi are exposed to environmental extremes, and therefore the production of bioactive metabolites was tested under both standard growth conditions for mesophilic microorganisms, and at high NaCl and sugar concentrations and low growth temperatures. The results indicate that selected halotolerant and halophilic species synthesize specific bioactive metabolites under conditions that represent stress for non-adapted species. Furthermore, adaptation at the level of the chemical nature of the solute lowering the water activity of the medium was observed. Increased salt concentrations resulted in higher hemolytic activity, particularly within species dominating the salterns. The appearance of antibacterial potential under stress conditions was seen in the similar pattern of fungal species as for hemolysis. The active extracts exclusively affected the growth of the Gram-positive bacterium tested, Bacillus subtilis. None of the extracts tested showed inhibition of acetylcholinesterase activity. PMID:21339946
Secondary metabolites of seagrasses (Alismatales and Potamogetonales; Alismatidae): Chemical diversity, bioactivity, and ecological function.
Zidorn, Christian
Seagrasses are the only higher plants living in fully marine environments; they play a significant role in coastal ecosystems. Seagrasses inhabit the coastal shelves of all continents except Antarctica and can grow in depths of up to 90m. Because of their eminent ecological importance, innumerous studies have been dedicated to seagrasses and their ecology. However, the phytochemistry has not been equally well investigated yet and many of the existing studies in chemical ecology are only investigating the chemistry at the level of compound classes, e.g. phenolics, and not at the level of chemically defined metabolites. In the present review, the existing literature on secondary metabolites of seagrasses, their known source seagrasses, their bioactivity, and ecological function are compiled and critically assessed. Moreover, research gaps are highlighted and avenues for future research are discussed. Currently, a total of 154 chemically defined natural products have been reported from the about 70 seagrass species known worldwide. Compounds reported include simple phenols derivatives (four compounds), phenylmethane derivatives (14 compounds), phenylethane derivatives (four compounds), phenylpropane derivatives including their esters and dimers (20 compounds), chalkones (four compounds), flavonoids including catechins (57 compounds), phenylheptanoids (four compounds), one monoterpene derivative, one sesquiterpene, diterpenoids (13 compounds), steroids (31 compounds), and one alkaloid. Most of the existing bioactivity studies of seagrass metabolites and extracts have been directed to potential cytotoxic, antimicrobial, or antimacrofouling activity. Antimicrobial studies have been performed towards panels of both human pathogens and ecologically relevant pathogens. In the antimacrofouling studies, investigations of the potential of zosteric acid from the genus Zostera are the most numerous and have yielded so far the most interesting results. Studies on the chemical
Molecular, chemical and biological screening of soil actinomycete isolates in seeking bioactive peptide metabolites
Imanparast, Somaye; Mohammadipanah, Fatemeh
Background and Objective: Due to the evolution of multidrug-resistant strains, screening of natural resources, especially actinomycetes, for new therapeutic agents discovery has become the interests of researchers. In this study, molecular, chemical and biological screening of soil actinomycetes was carried out in order to search for peptide-producing actinomycetes. Materials and Methods: 60 actinomycetes were isolated from soils of Iran. The isolates were subjected to molecular screening for detection NRPS (non-ribosomal peptide synthetases) gene. Phylogenic identification of NRPS containing isolates was performed. Chemical screening of the crude extracts was performed using chlorine o-dianisidine as peptide detector reagent and bioactivity of peptide producing strains was determined by antimicrobial bioassay. High pressure liquid chromatography- mass spectrometry (HPLC-MS) with UV-visible spectroscopy was performed for detection of the metabolite diversity in selected strain. Results: Amplified NRPS adenylation gene (700 bp) was detected among 30 strains. Phylogenic identification of these isolates showed presence of rare actinomycetes genera among the isolates and 10 out of 30 strains were subjected to chemical screening. Nocardia sp. UTMC 751 showed antimicrobial activity against bacterial and fungal test pathogens. HPLC-MS and UV-visible spectroscopy results from the crude extract showed that this strain has probably the ability to produce new metabolites. Conclusion: By application of a combined approach, including molecular, chemical and bioactivity analysis, a promising strain of Nocardia sp. UTMC 751 was obtained. This strain had significant activity against Staphylococcus aureus and Pseudomonas aeruginosa. Strain Nocardia sp. UTMC 751 produce five unknown and most probably new metabolites with molecular weights of 274.2, 390.3, 415.3, 598.4 and 772.5. This strain had showed 99% similarity to Nocardia ignorata DSM 44496 T. PMID:26644870
Synthesis of methylamino-2-phenyl-2-butyl-3,4,5-trimethoxybenzoate, the main bioactive metabolite of trimebutine maleate.
Martin, A; Figadère, B; Saivin, S; Houin, G; Chomard, J M; Cahiez, G
The first synthesis of the methylamino-2-phenyl-2-butyl-3,4,5-trimethoxybenzoate (desmethyltrimebutine) I is described. This compound is the main bioactive metabolite of trimebutine II (Debridat, CAS 39133-31-8), an antispasmodic widely used for intestinal diseases since 1969. It was used for pharmacokinetic and bioequivalence studies. PMID:10918948
Submerged cultivation of medicinal mushrooms for production of valuable bioactive metabolites.
Zhong, Jian-Jiang; Tang, Ya-Jie
Mushrooms are abundant sources of a wide range of useful natural products. Nowadays, commercial mushroom products are from mushrooms collected from field cultivation, which is a time-consuming and labor-intensive process. Submerged cultivation of mushrooms has significant industrial potential, but its success on a commercial scale depends on cost compared with existing technology. Increasing product yields and development of novel production systems that address the problems associated with this new technology will certainly facilitate expansion. This article outlines the major valuable metabolites produced by mushroom cultivation and advances in submerged culture of mushrooms, taking Ganoderma lucidum, a popular folk and an oriental medicine used to treat many diseases, as a typical example. Our latest data on mushroom cultivation for efficient production of bioactive ganoderic acids and Ganoderma polysaccharides in bioreactors are presented. PMID:15217103
Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites
Liu, Hao; Li, Wenjin; Rose, Marie E.; Pascoe, Jordan L.; Miller, Tricia M.; Ahmad, Muzamil; Poloyac, Samuel M.; Hickey, Robert W.; Graham, Steven H.
Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥ 10 μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture. PMID:23973622
Synthesis and bioactivity of secondary metabolites from marine sponges containing dibrominated indolic systems.
Mollica, Adriano; Locatelli, Marcello; Stefanucci, Azzurra; Pinnen, Francesco
Marine sponges. (e.g., Hyrtios sp., Dragmacidin sp., Aglophenia pleuma, Aplidium cyaneum, Aplidium meridianum.) produce bioactive secondary metabolites involved in their defence mechanisms. Recently it was demonstrated that several of those compounds show a large variety of biological activities against different human diseases with possible applications in medicinal chemistry and in pharmaceutical fields, especially related to the new drug development process. Researchers have focused their attention principally on secondary metabolites with anti-cancer and cytotoxic activities. A common target for these molecules is the cytoskeleton, which has a central role in cellular proliferation, motility, and profusion involved in the metastatic process associate with tumors. In particular, many substances containing brominated indolic rings such as 5,6-dibromotryptamine, 5,6-dibromo-N-methyltryptamine, 5,6-dibromo-N-methyltryptophan (dibromoabrine), 5,6-dibromo-N,N-dimethyltryptamine and 5,6-dibromo-L-hypaphorine isolated from different marine sources, have shown anti-cancer activity, as well as antibiotic and anti-inflammatory properties. Considering the structural correlation between endogenous monoamine serotonin with marine indolic alkaloids 5,6-dibromoabrine and 5,6-dibromotryptamine, a potential use of some dibrominated indolic metabolites in the treatment of depression-related pathologies has also been hypothesized. Due to the potential applications in the treatment of various diseases and the increasing demand of these compounds for biological assays and the difficult of their isolation from marine sources, we report in this review a series of recent syntheses of marine dibrominated indole-containing products. PMID:22614862
Bioactive metabolites from Phoma species, an endophytic fungus from the Chinese medicinal plant Arisaema erubescens.
Wang, Li-Wei; Xu, Bai-Ge; Wang, Jia-Ying; Su, Zhen-Zhu; Lin, Fu-Cheng; Zhang, Chu-Long; Kubicek, Christian P
Through bioassay-guided fractionation, the EtOAc extract of a culture broth of the endophytic fungus Phoma species ZJWCF006 in Arisaema erubescens afforded a new α-tetralone derivative, (3S)-3,6,7-trihydroxy-α-tetralone (1), together with cercosporamide (2), β-sitosterol (3), and trichodermin (4). The structures of compounds were established on the basis of spectroscopic analyses. Compounds 1, 2, and 3 were obtained from Phoma species for the first time. Additionally, the compounds were subjected to bioactivity assays, including antimicrobial activity, against four plant pathogenic fungi (Fusarium oxysporium, Rhizoctonia solani, Colletotrichum gloeosporioides, and Magnaporthe oryzae) and two plant pathogenic bacteria (Xanthomonas campestris and Xanthomonas oryzae), as well as in vitro antitumor activities against HT-29, SMMC-772, MCF-7, HL-60, MGC80-3, and P388 cell lines. Compound 1 showed growth inhibition against F. oxysporium and R. solani with EC₅₀ values of 413.22 and 48.5 μg/mL, respectively. Additionally, compound 1 showed no cytotoxicity, whereas compound 2 exhibited cytotoxic activity against the six tumor cell lines tested, with IC₅₀ values of 9.3 ± 2.8, 27.87 ± 1.78, 48.79 ± 2.56, 37.57 ± 1.65, 27.83 ± 0.48, and 30.37 ± 0.28 μM, respectively. We conclude that endophytic Phoma are promising sources of natural bioactive and novel metabolites. PMID:21814808
Bioactive metabolites from the endophytic fungus Ampelomyces sp. isolated from the medicinal plant Urospermum picroides.
Aly, Amal H; Edrada-Ebel, Ruangelie; Wray, Victor; Müller, Werner E G; Kozytska, Svitlana; Hentschel, Ute; Proksch, Peter; Ebel, Rainer
Extracts of cultures grown in liquid or on solid rice media of the fungal endophyte Ampelomyces sp. isolated from the medicinal plant Urospermum picroides exhibited considerable cytotoxic activity when tested in vitro against L5178Y cells. Chromatographic separation yielded 14 natural products that were unequivocally identified based on their 1H and 13C NMR as well as mass spectra and comparison with previously published data. Six compounds (2, 4, 5, 7, 9 and 11) were natural products. Both fungal extracts differed considerably in their secondary metabolites. The extract obtained from liquid cultures afforded a pyrone (2) and sulfated anthraquinones (7 and 9) along with the known compounds 1, 3, 6 and 8. When grown on solid rice medium the fungus yielded three compounds 4, 5 and 11 in addition to several known metabolites including 6, 8, 10, 12, 13 and 14. Compounds 4, 8 and 10 showed the strongest cytotoxic activity against L5178Y cells with EC50 values ranging from 0.2-7.3microg/ml. Furthermore, 8 and 10 displayed antimicrobial activity against the Gram-positive pathogens, Staphylococcus aureus, S. epidermidis and Enterococcus faecalis at minimal inhibitory concentrations (MIC) of 12.5microg/ml and 12.5-25microg/ml, respectively. Interestingly, 6 and 8 were also identified as constituents of an extract derived from a healthy plant sample of the host plant U. picroides thereby indicating that the production of bioactive natural products by the endophyte proceeds also under in situ conditions within the host plant. PMID:18400237
Isolation, characterization and biological evaluation of bioactive metabolites from Nocardia levis MK-VL_113.
Kavitha, Alapati; Prabhakar, Peddikotla; Narasimhulu, Manchala; Vijayalakshmi, Muvva; Venkateswarlu, Yenamandra; Rao, Karanam Venkateswara; Raju, Venkata Balaraju Subba
An Actinomycete isolate found to be prominent in the laterite soils of Acharya Nagarjuna University (ANU) Campus, Guntur was identified as Nocardia levis MK-VL_113 by 16S rRNA analysis. Cultural, morphological and physiological characteristics of the strain were recorded. Screening of secondary metabolites obtained from 4-day old culture broth of the strain led to the isolation of two fractions active against a wide variety of Gram-positive, Gram-negative bacteria and fungi. The structure of the first active fraction was elucidated using FT-IR, EI-MS, (1)H NMR and (13)C NMR spectra and identified as 1-phenylbut-3-ene-2-ol which is first time reported as a natural product. The compound exhibited good antimicrobial potential against the opportunistic and pathogenic bacteria and fungi. The antifungal activity of the strain and its metabolite were further confirmed with in vitro and in vivo studies. Evidence for the antagonism of the strain against Fusarium oxysporum, causing wilt disease in sorghum was demonstrated by the formation of inhibition zone in in vitro plate assay and reduction in the incidence of wilt of sorghum plants by using a green house trial. Analysis of the rhizosphere soil extracts by high performance liquid chromatography also demonstrated the production of the compound by the strain under in vivo conditions. As compared to the commercial fungicide mancozeb, the bioactive compound, 1-phenylbut-3-ene-2-ol was highly effective in controlling wilt of sorghum. Besides, the partially purified second fraction (PPF) subjected to gas chromatography-mass spectrometry revealed the presence of phenylethyl alcohol, dibutyl phthalate and 1,2-benzenedicarboxylic acid, 3-nitro. PMID:19577444
Efficient production of bioactive metabolites from Antrodia camphorata ATCC 200183 by asexual reproduction-based repeated batch fermentation.
Li, Hua-Xiang; Lu, Zhen-Ming; Geng, Yan; Gong, Jin-Song; Zhang, Xiao-Juan; Shi, Jin-Song; Xu, Zheng-Hong; Ma, Yan-He
Large-scale submerged fermentation (SmF) of Antrodia camphorata (A. camphorata) usually encounters challenges including tedious preparation of mycelial inoculum, long fermentation period (10-14 d), and poor repeatability. Here we developed an asexual reproduction-based repeated batch fermentation (RBF) process for bioactive metabolites production by A. camphorata ATCC 200183. Compared with traditional batch fermentation, production time was shortened to 58 d from 80 d (overall time for eight cycles) using the RBF process established in this study, and accordingly, the productivities of bioactive metabolites (including antrodins) were improved by 40-60%. Kinetic parameters (α is 2.1-18.7 times as β) indicated that the cell growth was the major contribution for bioactive metabolites production. The RBF shows excellent batch-repeatability (Pearson correlation coefficient of 0.998±0.001), together with advantages of energy-efficient, low cost, and labor-saving, RBF process can be implemented to SmF by other filamentous fungi. PMID:26210148
Biodegradation of multiple cyanobacterial metabolites in drinking water supplies.
Ho, Lionel; Tang, Tim; Monis, Paul T; Hoefel, Daniel
The fate of multiple cyanobacterial metabolites was assessed in two Australian source waters. The saxitoxins were the only metabolites shown to be non-biodegradable in Myponga Reservoir water, while microcystin-LR (MCLR) and geosmin were biodegradable in this water source. Likewise, cylindrospermopsin (CYN) was shown to be biodegradable in River Murray water. The order of ease of biodegradability followed the trend: MCLR>CYN>geosmin>saxitoxins. Biodegradation of the metabolites was affected by temperature and seasonal variations with more rapid degradation at 24°C and during autumn compared with 14°C and during winter. A microcystin-degrading bacterium was isolated and shown to degrade four microcystin variants within 4 h. This bacterium, designated as TT25, was shown to be 99% similar to a Sphingopyxis sp. based on a 16S rRNA gene fragment. Isolate TT25 was shown to contain a homologue of the mlrA gene; the sequence of which was 99% similar to that of a previously reported microcystin-degrader. Furthermore, isolate TT25 could degrade the microcystins in the presence of copper sulphate (0.5 mg L(-1) as Cu(2+)) which is advantageous for water authorities dosing such algicides into water bodies to control cyanobacterial blooms. PMID:22386459
Metabolism of 20(S)-Ginsenoside Rg₂ by Rat Liver Microsomes: Bioactivation to SIRT1-Activating Metabolites.
Ma, Li-Yuan; Zhou, Qi-Le; Yang, Xin-Bao; Wang, Hong-Ping; Yang, Xiu-Wei
20(S)-Ginsenoside Rg₂ (1) has recently become a hot research topic due to its potent bioactivities and abundance in natural sources such as the roots, rhizomes and stems-leaves of Panax ginseng. However, due to the lack of studies on systematic metabolic profiles, the prospects for new drug development of 1 are still difficult to predict, which has become a huge obstacle for its safe clinical use. To solve this problem, investigation of the metabolic profiles of 1 in rat liver microsomes was first carried out. To identify metabolites, a strategy of combined analyses based on prepared metabolites by column chromatography and ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was performed. As a result, four metabolites M1-M4, including a rare new compound named ginsenotransmetin A (M1), were isolated and the structures were confirmed by spectroscopic analyses. A series of metabolites of 1, MA-MG, were also tentatively identified by UPLC-Q-TOF/MS in rat liver microsomal incubate of 1. Partial metabolic pathways were proposed. Among them, 1 and its metabolites M1, M3 and M4 were discovered for the first time to be activators of SIRT1. The SIRT1 activating effects of the metabolite M1 was comparable to those of 1, while the most interesting SIRT1 activatory effects of M3 and M4 were higher than that of 1 and comparable with that of resveratrol, a positive SIRT1 activator. These results indicate that microsome-dependent metabolism may represent a bioactivation pathway for 1. This study is the first to report the metabolic profiles of 1 in vitro, and the results provide an experimental foundation to better understand the in vivo metabolic fate of 1. PMID:27294899
A Preliminary Study of the Algicidal Mechanism of Bioactive Metabolites of Brevibacillus laterosporus on Oscillatoria in Prawn Ponds
Jia, Wen; Huang, Xianghu; Li, Changling
The algae, Oscillatoria, is commonly found in prawn ponds and can lead to reduced productivity. We examined metabolites of the bacteria Brevibacillus laterosporus for algicidal qualities. To determine the possible algicidal mechanisms of these bioactive metabolites, different amounts of sterile filtrate of bacterial suspensions were added to cultures containing Oscillatoria. The dry weight, the concentrations of chlorophyll-a (chl-a), phycobiliprotein (PC, phycocyanin; APC, allophycocyanin; PE, phycoerythrin), and MDA (malondialdehyde) and the activities of SOD (superoxide dismutase), POD (peroxidase), and CAT (catalase) of algae were measured during the algicidal application. The results showed that lower concentrations of the sterile filtrate (addition ≤ 4 mL) accelerated the growth rate of Oscillatoria, but significant inhibition and lysis were observed with higher concentrations (addition ≥ 8 mL). In two trials (the additions were 8 mL and 10 mL, respectively), the algal dry weights were reduced by 26.02% and 45.30%, and the chl-a concentrations were decreased by 46.88% and 63.73%, respectively, after seven days. During the algicidal treatment, the concentrations of PC, APC, PE, and MDA and the activities of SOD, POD, and CAT were significantly increased in the early cultivation and declined quickly at later stages. Finally, the algae-lysing mechanism of the bioactive metabolites of the bacteria Brevibacillus laterosporus on Oscillatoria had been proposed. PMID:24744687
A preliminary study of the algicidal mechanism of bioactive metabolites of Brevibacillus laterosporus on Oscillatoria in prawn ponds.
Jia, Wen; Huang, Xianghu; Li, Changling
The algae, Oscillatoria, is commonly found in prawn ponds and can lead to reduced productivity. We examined metabolites of the bacteria Brevibacillus laterosporus for algicidal qualities. To determine the possible algicidal mechanisms of these bioactive metabolites, different amounts of sterile filtrate of bacterial suspensions were added to cultures containing Oscillatoria. The dry weight, the concentrations of chlorophyll-a (chl-a), phycobiliprotein (PC, phycocyanin; APC, allophycocyanin; PE, phycoerythrin), and MDA (malondialdehyde) and the activities of SOD (superoxide dismutase), POD (peroxidase), and CAT (catalase) of algae were measured during the algicidal application. The results showed that lower concentrations of the sterile filtrate (addition ≤ 4 mL) accelerated the growth rate of Oscillatoria, but significant inhibition and lysis were observed with higher concentrations (addition ≥ 8 mL). In two trials (the additions were 8 mL and 10 mL, respectively), the algal dry weights were reduced by 26.02% and 45.30%, and the chl-a concentrations were decreased by 46.88% and 63.73%, respectively, after seven days. During the algicidal treatment, the concentrations of PC, APC, PE, and MDA and the activities of SOD, POD, and CAT were significantly increased in the early cultivation and declined quickly at later stages. Finally, the algae-lysing mechanism of the bioactive metabolites of the bacteria Brevibacillus laterosporus on Oscillatoria had been proposed. PMID:24744687
A Review of Cyanobacterial Odorous and Bioactive Metabolites: Impacts and Management Alternatives in Aquaculture
Technology Transfer Automated Retrieval System (TEKTRAN)
An increased demand has pushed extensive aquaculture towards intensively operated production systems, commonly resulting in eutrophic conditions and cyanobacterial blooms. This review summarizes cyanobacterial secondary metabolites that can cause undesirable tastes and odors (odorous metabolites) o...
Optimization of cell disruption methods for efficient recovery of bioactive metabolites via NMR of three freshwater microalgae (chlorophyta).
Ma, Nyuk Ling; Teh, Kit Yinn; Lam, Su Shiung; Kaben, Anne Marie; Cha, Thye San
This study demonstrates the use of NMR techniques coupled with chemometric analysis as a high throughput data mining method to identify and examine the efficiency of different disruption techniques tested on microalgae (Chlorella variabilis, Scenedesmus regularis and Ankistrodesmus gracilis). The yield and chemical diversity from the disruptions together with the effects of pre-oven and pre-freeze drying prior to disruption techniques were discussed. HCl extraction showed the highest recovery of oil compounds from the disrupted microalgae (up to 90%). In contrast, NMR analysis showed the highest intensity of bioactive metabolites obtained for homogenized extracts pre-treated with freeze-drying, indicating that homogenizing is a more favorable approach to recover bioactive substances from the disrupted microalgae. The results show the potential of NMR as a useful metabolic fingerprinting tool for assessing compound diversity in complex microalgae extracts. PMID:25812996
Four butyrolactones and diverse bioactive secondary metabolites from terrestrial Aspergillus flavipes MM2: isolation and structure determination
The chemical constituents and biological activities of the terrestrial Aspergillus flavipes MM2 isolated from Egyptian rice hulls are reported. Seven bioactive compounds were obtained, of which one sterol: ergosterol (1), four butyrolactones: butyrolactone I (2), aspulvinone H (3), butyrolactone-V (6) and 4,4'-diydroxypulvinone (7), along with 6-methylsalicylic acid (4) and the cyclopentenone analogue; terrien (5). Structures of the isolated compounds were deduced by intensive studies of their 1D & 2D NMR, MS data and comparison with related structures. The strain extract and the isolated compounds (1-7) were biologically studied against number of microbial strains, and brine shrimp for cytotoxicity. In this article, the taxonomical characterization of A. flavipes MM2 along with its upscale fermentation, isolation and structural assignment of the obtained bioactive metabolites, and evaluate their antimicrobial and cytotoxic activities were described. PMID:22380482
Identifying and characterising regulatory metabolites with generalised supply-demand analysis.
Rohwer, Johann M; Hofmeyr, Jan-Hendrik S
We present the framework of generalised supply-demand analysis (SDA) of a kinetic model of a cellular system, which can be applied to networks of arbitrary complexity. By fixing the concentrations of each of the variable species in turn and varying them in a parameter scan, rate characteristics of supply-demand are constructed around each of these species. By inspecting the shapes of the rate characteristic patterns and comparing the flux-response coefficients of the supply and demand blocks with the elasticities of the enzymes that interact directly with the fixed metabolite, regulatory metabolites in the system can be identified and characterised. The analysis provides information on whether and where the system is functionally differentiated and which of its species are homeostatically buffered. The novelty in our proposed method lies in the fact that all metabolites are considered for SDA (hence the term "generalised"), which removes investigator bias. It supplies an entry point for the further analysis and detailed characterisation of large models of cellular systems, in which the choice of metabolite around which to perform a SDA is not always obvious. PMID:18068730
Influence of growing conditions on metabolite profile of Ammi visnaga umbels with special reference to bioactive furanochromones and pyranocoumarins.
Sellami, Hela Kallel; Napolitano, Assunta; Masullo, Milena; Smiti, Samira; Piacente, Sonia; Pizza, Cosimo
The medicinal plant Ammi visnaga is a valuable source of furanochromones and pyranocoumarins used as vasodilator agents. Its ability to germinate under unfavourable growth conditions, such as saline soil and hypoxia characterizing clay soils and marshes ecosystems, prompted us to qualitatively characterize secondary metabolites in umbels of A. visnaga plants grown under different conditions (in field, hydroponically controlled, and contrasted by salinity and/or hypoxia) by HPLC-ESI/IT/MS(n) analysis. Subsequently, the quantitative analysis of the bioactive compounds, above all furanochromones and pyranocoumarins, was carried out by HPLC-ESI/QqQ/MS/MS. The results show the influence of growing conditions on the quali-quantitative profile of A. visnaga secondary metabolites and evidence that hydroponic culture leads to increased level of A. visnaga active principles. Furthermore, two furanochromones never reported before were identified and characterized by 1D- and 2D-NMR analysis. PMID:23993295
Pharmacology and toxicology of pahayokolide A, a bioactive metabolite from a freshwater species of Lyngbya isolated from the Florida Everglades.
Berry, John P; Gantar, Miroslav; Gawley, Robert E; Wang, Minglei; Rein, Kathleen S
The genus of filamentous cyanobacteria, Lyngbya, has been found to be a rich source of bioactive metabolites. However, identification of such compounds from Lyngbya has largely focused on a few marine representatives. Here, we report on the pharmacology and toxicology of pahayokolide A from a freshwater isolate, Lyngbya sp. strain 15-2, from the Florida Everglades. Specifically, we investigated inhibition of microbial representatives and mammalian cell lines, as well as toxicity of the compound to both invertebrate and vertebrate models. Pahayokolide A inhibited representatives of Bacillus, as well as the yeast, Saccharomyces cerevisiae. Interestingly, the compound also inhibited several representatives of green algae that were also isolated from the Everglades. Pahayokolide A was shown to inhibit a number of cancer cell lines over a range of concentrations (IC50 varied from 2.13 to 44.57 microM) depending on the cell-type. When tested against brine shrimp, pahayokolide was only marginally toxic at the highest concentrations tested (1 mg/mL). The compound was, however, acutely toxic to zebrafish embryos (LC50=2.15 microM). Possible biomedical and environmental health aspects of the pahayokolides remain to be investigated; however, the identification of bioactive metabolites such as these demonstrates the potential of the Florida Everglades as source of new toxins and drugs. PMID:15683832
Marine Invertebrate Metabolites with Anticancer Activities: Solutions to the "Supply Problem".
Gomes, Nelson G M; Dasari, Ramesh; Chandra, Sunena; Kiss, Robert; Kornienko, Alexander
Marine invertebrates provide a rich source of metabolites with anticancer activities and several marine-derived agents have been approved for the treatment of cancer. However, the limited supply of promising anticancer metabolites from their natural sources is a major hurdle to their preclinical and clinical development. Thus, the lack of a sustainable large-scale supply has been an important challenge facing chemists and biologists involved in marine-based drug discovery. In the current review we describe the main strategies aimed to overcome the supply problem. These include: marine invertebrate aquaculture, invertebrate and symbiont cell culture, culture-independent strategies, total chemical synthesis, semi-synthesis, and a number of hybrid strategies. We provide examples illustrating the application of these strategies for the supply of marine invertebrate-derived anticancer agents. Finally, we encourage the scientific community to develop scalable methods to obtain selected metabolites, which in the authors' opinion should be pursued due to their most promising anticancer activities. PMID:27213412
Marine Invertebrate Metabolites with Anticancer Activities: Solutions to the "Supply Problem"
Gomes, Nelson G. M.; Dasari, Ramesh; Chandra, Sunena; Kiss, Robert; Kornienko, Alexander
Marine invertebrates provide a rich source of metabolites with anticancer activities and several marine-derived agents have been approved for the treatment of cancer. However, the limited supply of promising anticancer metabolites from their natural sources is a major hurdle to their preclinical and clinical development. Thus, the lack of a sustainable large-scale supply has been an important challenge facing chemists and biologists involved in marine-based drug discovery. In the current review we describe the main strategies aimed to overcome the supply problem. These include: marine invertebrate aquaculture, invertebrate and symbiont cell culture, culture-independent strategies, total chemical synthesis, semi-synthesis, and a number of hybrid strategies. We provide examples illustrating the application of these strategies for the supply of marine invertebrate-derived anticancer agents. Finally, we encourage the scientific community to develop scalable methods to obtain selected metabolites, which in the authors' opinion should be pursued due to their most promising anticancer activities. PMID:27213412
Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions.
Zhang, Linda S; Davies, Sean S
Mass spectrometry- and nuclear magnetic resonance-based metabolomic studies comparing diseased versus healthy individuals have shown that microbial metabolites are often the compounds most markedly altered in the disease state. Recent studies suggest that several of these metabolites that derive from microbial transformation of dietary components have significant effects on physiological processes such as gut and immune homeostasis, energy metabolism, vascular function, and neurological behavior. Here, we review several of the most intriguing diet-dependent metabolites that may impact host physiology and may therefore be appropriate targets for therapeutic interventions, such as short-chain fatty acids, trimethylamine N-oxide, tryptophan and tyrosine derivatives, and oxidized fatty acids. Such interventions will require modulating either bacterial species or the bacterial biosynthetic enzymes required to produce these metabolites, so we briefly describe the current understanding of the bacterial and enzymatic pathways involved in their biosynthesis and summarize their molecular mechanisms of action. We then discuss in more detail the impact of these metabolites on health and disease, and review current strategies to modulate levels of these metabolites to promote human health. We also suggest future studies that are needed to realize the full therapeutic potential of targeting the gut microbiota. PMID:27102537
A metabolite is any substance produced during metabolism (digestion or other bodily chemical processes). The term metabolite may also refer to the product that remains after a drug is broken down (metabolized) by the body.
Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling
Mace, Thomas A.; King, Samantha A.; Ameen, Zeenath; Elnaggar, Omar; Young, Gregory; Riedl, Kenneth M.; Schwartz, Steven J.; Clinton, Steven K.; Knobloch, Thomas J.; Weghorst, Christopher M.; Lesinski, Gregory B.
Bioactive phyotochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis) have direct anti-cancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation and viability of CD3/CD28 activated human CD4+ and CD8+ T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2 induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2 induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically-relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibit targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways. PMID:24893859
Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling.
Mace, Thomas A; King, Samantha A; Ameen, Zeenath; Elnaggar, Omar; Young, Gregory; Riedl, Kenneth M; Schwartz, Steven J; Clinton, Steven K; Knobloch, Thomas J; Weghorst, Christopher M; Lesinski, Gregory B
Bioactive phytochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis), have direct anticancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation, and viability of CD3/CD28 activated human CD4(+) and CD8(+) T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2-induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2-induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibits targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways. PMID:24893859
Assessing the Effectiveness of Functional Genetic Screens for the Identification of Bioactive Metabolites
Penesyan, Anahit; Ballestriero, Francesco; Daim, Malak; Kjelleberg, Staffan; Thomas, Torsten; Egan, Suhelen
A common limitation for the identification of novel activities from functional (meta) genomic screens is the low number of active clones detected relative to the number of clones screened. Here we demonstrate that constructing libraries with strains known to produce bioactives can greatly enhance the screening efficiency, by increasing the "hit-rate" and unmasking multiple activities from the same bacterial source. PMID:23271424
Bioactivation of clopidogrel and prasugrel: factors determining the stereochemistry of the thiol metabolite double bond.
Dansette, Patrick M; Levent, Dan; Hessani, Assia; Mansuy, Daniel
The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a further oxidation with the formation of a thiolactone sulfoxide whose hydrolytic opening leads to a sulfenic acid that is eventually reduced into the corresponding active cis thiol. Very few data were available on the formation of the isomer of the active cis thiol having a trans configuration of the double bond, the most striking result in that regard being that both cis and trans thiols were formed upon the metabolism of clopidogrel by human liver microsomes in the presence of glutathione (GSH), whereas only the cis thiol was detected in the sera of patients treated with this drug. This article shows that trans thiols are also formed upon the microsomal metabolism of prasugrel or its thiolactone metabolite in the presence of GSH and that metabolites having the trans configuration of the double bond are only formed when microsomal incubations are done in the presence of thiols, such as GSH, N-acetyl-cysteine, and mercaptoethanol. Intermediate formation of thioesters resulting from the reaction of GSH with the thiolactone sulfoxide metabolite appears to be responsible for trans thiol formation. Addition of human liver cytosol to the microsomal incubations led to a dramatic decrease of the formation of the trans thiol metabolites. These data suggest that cytosolic esterases would accelerate the hydrolytic opening of thiolactone sulfoxide intermediates and disfavor the formation of thioesters resulting from the reaction of these intermediates with GSH that is responsible for trans isomer formation. This would explain why trans thiols have not been detected in the sera of patients treated with clopidogrel. PMID:25970225
Bioactive metabolites produced by Penicillium sp. 1 and sp. 2, two endophytes associated with Alibertia macrophylla (Rubiaceae).
Oliveira, Camila M; Silva, Geraldo H; Regasini, Luis O; Zanardi, Lisinéia M; Evangelista, Alana H; Young, Maria C M; Bolzani, Vanderlan S; Araujo, Angela R
In the course of our continuous search for bioactive metabolites from endophytic fungi living in plants from the Brazilian flora, leaves of Alibertia macrophylla (Rubiaceae) were submitted to isolation of endophytes, and two species of Penicillium were isolated. The acetonitrile fraction obtained in corn from a culture of Penicillium sp. 1 afforded orcinol (1). On the other hand, Penicillium sp. 1 cultivated in potato-dextrose-broth furnished two different compounds, cyclo-(L-Pro-L-Val) (2) and uracil (3). The chromatographic fractionation of the acetonitrile fraction obtained from Penicillium sp. 2 led to three dihydroisocoumarins, 4-hydroxymellein (4), 8-methoxymellein (5) and 5-hydroxymellein (6). Compounds 5 and 6 were obtained from the Penicillium genus for the first time. Additionally, metabolites 1-6 were evaluated for their antifungal and acetylcholinesterase (AChE) inhibitory activities. The most active compounds 1 and 4 exhibited detection limits of 5.00 and 10.0 microg against Cladosporium cladosporioides and C. sphaerospermum, respectively. Compound 2 showed a detection limit of 10.0 microg, displaying potent AChE inhibitory activity. PMID:20158153
Bioactive natural products from fungicolous Hawaiian isolates: secondary metabolites from a Phialemoniopsis sp.
Kaur, Amninder; Rogers, Kristina D.; Swenson, Dale E.; Dowd, Patrick F.; Wicklow, Donald T.; Gloer, James B.
Chemical investigations of two fungal isolates initially identified as members of the genus Phialemonium are described. Both isolates were obtained as colonists of other fungi collected on the island of Hawaii and were later assigned as P. curvatum. However, P. curvatum has recently been reclassified as a member of a new genus (Phialemoniopsis) and renamed as Phialemoniopsis curvata. Studies of solid–substrate fermentation cultures of one of these isolates afforded an oxirapentyn analogue and destruxin A4 as major components, while analysis of the second strain led to the isolation of several simple aromatic metabolites and a compound of mixed biogenetic origin called gabusectin that had previously been reported only in a patent. Structures were assigned mainly by detailed nuclear magnetic resonance and mass spectrometry analysis, and those of two of the major components were confirmed by X-ray crystallography. This report constitutes the first description of secondary metabolites from a member of the genus Phialemoniopsis. PMID:25379336
Screening Reactive Metabolites Bioactivated by Multiple Enzyme Pathways Using a Multiplexed Microfluidic System
Wasalathanthri, Dhanuka P.; Faria, Ronaldo C.; Malla, Spundana; Joshi, Amit A.; Schenkman, John B.; Rusling, James F.
A multiplexed, microfluidic platform to detect reactive metabolites is described, and its performance is illustrated for compounds metabolized by oxidative and bioconjugation enzymes in multi-enzyme pathways to mimic natural human drug metabolism. The device features four 8-electrode screen printed carbon arrays coated with thin films of DNA, a ruthenium-polyvinylpyridine (RuPVP) catalyst, and multiple enzyme sources including human liver microsomes (HLM), cytochrome P450 (cyt P450) 1B1 supersomes, microsomal epoxide hydrolase (EH), human S9 liver fractions (Hs9) and N-acetyltransferase (NAT). Arrays are arranged in parallel to facilitate multiple compound screening, enabling up to 32 enzyme reactions and measurements in 20–30 min. In the first step of the assay, metabolic reactions are achieved under constant flow of oxygenated reactant solutions by electrode driven natural catalytic cycles of cyt P450s and cofactor-supported bioconjugation enzymes. Reactive metabolites formed in the enzyme reactions can react with DNA. Relative DNA damage is measuring in the second assay step using square wave voltammetry (SWV) with RuPVP as catalyst. Studies were done on chemicals known to require metabolic activation to induce genotoxicity, and results reproduced known features of metabolite DNA-reactivity for the test compounds. Metabolism of benzo[a]pyrene (B[a]P) by cyt P450s and epoxide hydrolase showed an enhanced relative DNA damage rate for DNA damage compared to cyt P450s alone. DNA damage rates for arylamines by pathways featuring both oxidative and conjugative enzymes at pH 7.4 gave better correlation with rodent genotoxicity metric TD50. Results illustrate the broad utility of the reactive metabolite screening device. PMID:23095952
Novel bioactive metabolites from a marine derived bacterium Nocardia sp. ALAA 2000.
El-Gendy, Mervat M A; Hawas, Usama W; Jaspars, Marcel
Extracts of the Egyptian marine actinomycete, Nocardia sp. ALAA 2000, were found to be highly bioactive. It was isolated from the marine red alga Laurenica spectabilis collected off the Ras-Gharib coast of the Red Sea, Egypt. According to detailed identification studies, the strain was classified as a member of the genus Nocardia. The cultivation and chemical analysis of this species yielded four structurally related compounds namely, chrysophanol 8-methyl ether (1), asphodelin; 4,7'-bichrysophanol (2) and justicidin B (3), in addition to a novel bioactive compound ayamycin; 1,1-dichloro-4-ethyl-5-(4-nitro-phenyl)-hexan-2-one (4) which is unique in contain both chlorination and a rarely observed nitro group. The compounds were isolated by a series of chromatographic steps and their structures of 1approximately 3 secured by detailed spectroscopic analysis of the MS and NMR data whereas that of 4 was elucidated by single crystal X-ray diffraction studies. These compounds displayed different potent antimicrobial activity against both Gram-positive and Gram-negative bacteria as well as fungi with MIC ranging from 0.1 to 10 microg/ml. PMID:18667786
Characterization and Optimization of Biosynthesis of Bioactive Secondary Metabolites Produced by Streptomyces sp. 8812.
Rajnisz, Aleksandra; Guśpiel, Adam; Postek, Magdalena; Ziemska, Joanna; Laskowska, Anna; Rabczenko, Daniel; Solecka, Jolanta
The nutritional requirements and environmental conditions for a submerged culture of Streptomyces sp. 8812 were determined. Batch and fed-batch Streptomyces sp. 8812 fermentations were conducted to obtain high activity of secondary metabolites. In the study several factors were examined for their influence on the biosynthesis of the active metabolites-7-hydroxy-6-oxo-2,3,4,6-tetrahydroisoquinoline-3-carboxy acid (C10H9NO4) and N-acetyl-3,4-dihydroxy-L-phenylalanine (C11H13NO5): changes in medium composition, pH of production medium, various growth phases of seed culture, amino acid supplementation and addition of anion exchange resin to the submerged culture. Biological activities of secondary metabolites were examined with the use of DD-carboxypeptidase 64-575 and horseradish peroxidase. Streptomyces sp. 8812 mycelium was evaluated under fluorescent microscopy and respiratory activity of the strain was analyzed. Moreover, the enzymatic profiles of the strain with the use of Api ZYM test were analyzed and genetic analysis made. Phylogenetic analysis of Streptomyces sp. 8812 revealed that its closest relative is Streptomyces capoamus JCM 4734 (98%), whereas sequence analysis for 16S rRNA gene using NCBI BLAST algorithm showed 100% homology between these two strains. Biosynthetic processes, mycelium growth and enzyme inhibitory activities of these two strains were also compared. PMID:27281994
Bioactivity of turmeric-derived curcuminoids and related metabolites in breast cancer.
Wright, Laura E; Frye, Jen B; Gorti, Bhavana; Timmermann, Barbara N; Funk, Janet L
While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurallyrelated metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10-16µg/mL) and secretion of osteolytic PTHrP (IC50=2-3µg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58µM), demethoxycurcumin did not have any effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22-31µM) to the same degree as the curcuminoid mixture (IC50=16µM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict
Bioactivity of Turmeric-Derived Curcuminoids and Related Metabolites in Breast Cancer
Wright, Laura E.; Frye, Jen B.; Gorti, Bhavana; Timmermann, Barbara N.; Funk, Janet L.
While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurally-related metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10–16μg/mL) and secretion of osteolytic PTHrP (IC50=2–3μg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58 μM), demethoxycurcumin was without effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22–31μM) to the same degree as the curcuminoid mixture (IC50=16 μM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict
Pesticides and their metabolites in selected surface-water public supplies in New York State, 1999
Phillips, Patrick J.; Eckhardt, D.A.; Smith, M.A.; Rosenmann, Larry
Sixteen different pesticides or their metabolites (degradations products) where detected in water samples collected in 1999 from three networks of lakes and reservoirs in upstate New York that are sources of public water supply. The networks sampled included the New York City network (10 reservoirs); the Finger Lakes-Great Lakes network (three Finger Lakes and two Great Lakes that supply large and small cities) and the western New York reservoir network (three reservoirs that supply small cities or towns). The concentrations of the compounds detected in the samples generally were low. Only a few of the compounds detected had a concentration exceeding 1 mg/L (microgram per liter), and no compounds detected in the New York City reservoirs network had concentrations exceeding 0.05 mg/L. None of the compounds detected exceeded any Federal or State water-quality standard. Compounds that were most frequently detected, and whose concentrations were highest, were the three herbicides atrazine, metolachlor, and simazine, and two herbicide metabolites (the atrazine metabolite deethylatrazine, and the metolachlor metabolite metolachlor ESA). Most of these compounds, or their parent compounds, are used on corn or other row crops. Median total pesticide and metabolite concentration for each network ranged from less than 0.02 mg/L for the New York City reservoirs network to more than 2 mg/L for the western New York reservoir network; the median for the Finger Lakes.Great Lakes network was about 0.1 mg/L. These differences reflect the amount of agricultural land use within each of the three networks, although other factors can affect pesticide and metabolite concentrations. The watersheds of the New York City reservoirs have the lowest percentage of agricultural land, and those of the western New York reservoirs have the highest. The highest herbicide or herbicide-metabolite concentrations among the New York City reservoirs were in the Cannonsville reservoir, whose watershed has
Aspergillus fumigatus CY018, an endophytic fungus in Cynodon dactylon as a versatile producer of new and bioactive metabolites.
Liu, J Y; Song, Y C; Zhang, Z; Wang, L; Guo, Z J; Zou, W X; Tan, R X
Aspergillus fumigatus CY018 was recognized as an endophytic fungus for the first time in the leaf of Cynodon dactylon. By bioassay-guided fractionation, the EtOAc extract of a solid-matrix steady culture of this fungus afforded two new metabolites, named asperfumoid (1) and asperfumin (2), together with six known bioactive compounds including monomethylsulochrin, fumigaclavine C, fumitremorgin C, physcion, helvolic acid and 5alpha,8alpha-epidioxy-ergosta-6,22-diene-3beta-ol as well as other four known compounds ergosta-4,22-diene-3beta-ol, ergosterol, cyclo(Ala-Leu) and cyclo(Ala-Ile). Through detailed spectroscopic analyses including HRESI-MS, homo- and hetero-nuclear correlation NMR experiments (HMQC, COSY, NOESY and HMBC), the structures of asperfumoid and asperfumin were established to be spiro-(3-hydroxyl-2,6-dimethoxyl-2,5-diene-4-cyclohexone-(1,3')-5'-methoxyl-7'-methyl-(1'H, 2'H, 4'H)-quinoline-2',4'-dione) and 5-hydroxyl-2-(6-hydroxyl-2-methoxyl-4-methylbenzoyl)-3,6-dimethoxyl-benzoic methyl ester, respectively. All of the 12 isolates were subjected to in vitro bioactive assays against three human pathogenic fungi Candida albicans, Tricophyton rubrum and Aspergillus niger. As a result, asperfumoid, fumigaclavine C, fumitremorgin C, physcion and helvolic acid were shown to inhibit C. albicans with MICs of 75.0, 31.5, 62.5, 125.0 and 31.5 microg/mL, respectively. PMID:15522437
Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: chemical synthesis and biological evaluation.
Zhu, Yingdong; Warin, Renaud F; Soroka, Dominique N; Chen, Huadong; Sang, Shengmin
Our previous study found that [6]-shogaol, a major bioactive component in ginger, is extensively metabolized in cancer cells and in mice. It is unclear whether these metabolites retain bioactivity. The aim of the current study is to synthesize the major metabolites of [6]-shogaol and evaluate their inhibition of growth and induction of apoptosis in human cancer cells. Twelve metabolites of [6]-shogaol (M1, M2, and M4-M13) were successfully synthesized using simple and easily accessible chemical methods. Growth inhibition assays showed that most metabolites of [6]-shogaol had measurable activities against human cancer cells HCT-116 and H-1299. In particular, metabolite M2 greatly retained the biological activities of [6]-shogaol, with an IC(50) of 24.43 µM in HCT-116 human colon cancer cells and an IC(50) of 25.82 µM in H-1299 human lung cancer cells. Also exhibiting a relatively high potency was thiol-conjugate M13, with IC(50) values of 45.47 and 47.77 µM toward HCT-116 and H-1299 cells, respectively. The toxicity evaluation of the synthetic metabolites (M1, M2, and M4-M13) against human normal fibroblast colon cells CCD-18Co and human normal lung cells IMR-90 demonstrated a detoxifying metabolic biotransformation of [6]-shogaol. The most active metabolite M2 had almost no toxicity to CCD-18Co and IMR-90 normal cells with IC(50)s of 99.18 and 98.30 µM, respectively. TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay indicated that apoptosis was triggered by metabolites M2, M13, and its two diastereomers M13-1 and M13-2. There was no significant difference between the apoptotic effect of [6]-shogaol and the effect of M2 and M13 after 6 hour treatment. PMID:23382939
Bioactive metabolites isolated from Penicillium sp. YY-20, the endophytic fungus from Ginkgo biloba.
Yuan, Yuan; Tian, Jun-Mian; Xiao, Jian; Shao, Qi; Gao, Jin-Ming
Six known metabolites, adenosine (1), methyl β-D-ribofuranoside (2), adenine (3), 2'-deoxyadenosine (4), 3-methylpiperazine-2,5-dione (5) and 2'-deoxyuridine (6), were isolated from the extracts of the endophytic fungus Penicillium sp. YY-20 isolated from the root of Ginkgo biloba, and their structures were elucidated by spectroscopic methods. The antioxidant and growth-promoting activities of these compounds were first evaluated. The results indicated that compounds 1, 3 and 4 exhibited potential DPPH-scavenging activities compared with positive control. In addition, all the compounds (except 5) stimulated seed germination of Raphanus sativus, Brassica napus and Brassica chinensis but had weak stimulating effect on their root and hypocotyl growth. PMID:24144081
Bioactive Metabolites from Chaetomium aureum: Structure Elucidation and Inhibition of the Hsp90 Machine Chaperoning Activity
Kabbaj, Fatima Zahra; Lu, Su; Faouzi, My El Abbés; Meddah, Bouchra; Proksch, Peter; Cherrah, Yahya; Altenbach, Hans-Josef; Aly, Amal H.; Chadli, Ahmed; Debbab, Abdessamad
Chemical investigation of the EtOAc extract of the fungus Chaetomium aureum, an endophyte of the Moroccan medicinal plant Thymelaea lythroides, afforded one new resorcinol derivative named chaetorcinol, together with five known metabolites. The structures of the isolated compounds were determined on the basis of one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry as well as by comparison with the literature. All compounds were tested for their activity towards the Hsp90 chaperoning machine in vitro using the progesterone receptor (PR) and rabbit reticulocyte lysate (RRL). Among the isolated compounds, only sclerotiorin efficiently inhibited the Hsp90 machine chaperoning activity. However, sclerotiorin showed no cytotoxic effect on breast cancer Hs578T, MDA-MB-231 and prostate cancer LNCaP cell lines. Interestingly, deacetylation of sclerotiorin increased its cytotoxicity toward the tested cell lines over a period of 48h. PMID:25482429
Screening for Bioactive Metabolites in Plant Extracts Modulating Glucose Uptake and Fat Accumulation
El-Houri, Rime B.; Kotowska, Dorota; Olsen, Louise C. B.; Bhattacharya, Sumangala; Christensen, Lars P.; Oksbjerg, Niels; Færgeman, Nils; Kristiansen, Karsten; Christensen, Kathrine B.
Dichloromethane and methanol extracts of seven different food and medicinal plants were tested in a screening platform for identification of extracts with potential bioactivity related to insulin-dependent glucose uptake and fat accumulation. The screening platform included a series of in vitro bioassays, peroxisome proliferator-activated receptor (PPAR) γ-mediated transactivation, adipocyte differentiation of 3T3-L1 cell cultures, and glucose uptake in both 3T3-L1 adipocytes and primary porcine myotubes, as well as one in vivo bioassay, fat accumulation in the nematode Caenorhabditis elegans. We found that dichloromethane extracts of aerial parts of golden root (Rhodiola rosea) and common elder (Sambucus nigra) as well as the dichloromethane extracts of thyme (Thymus vulgaris) and carrot (Daucus carota) were able to stimulate insulin-dependent glucose uptake in both adipocytes and myotubes while weekly activating PPARγ without promoting adipocyte differentiation. In addition, these extracts were able to decrease fat accumulation in C. elegans. Methanol extracts of summer savory (Satureja hortensis), common elder, and broccoli (Brassica oleracea) enhanced glucose uptake in myotubes but were not able to activate PPARγ, indicating a PPARγ-independent effect on glucose uptake. PMID:25254050
Bioactive Secondary Metabolites from the Red Sea Marine Verongid Sponge Suberea Species
Shaala, Lamiaa A.; Youssef, Diaa T. A.; Badr, Jihan M.; Sulaiman, Mansour; Khedr, Alaa
In a continuation of our efforts to identify bioactive compounds from Red Sea Verongid sponges, the organic extract of the sponge Suberea species afforded seven compounds including two new dibrominated alkaloids, subereamollines C and D (1 and 2), together with the known compounds aerothionin (3), homoaerothionin (4), aeroplysinin-1 (5), aeroplysinin-2 (6) and a revised subereaphenol C (7) as ethyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate. The structures of the isolated compounds were assigned by different spectral data including optical rotations, 1D (1H and 13C) and 2D (COSY, multiplicity-edited HSQC, and HMBC) NMR and high-resolution mass spectroscopy. Aerothionin (3) and subereaphenol C (7) displayed potent cytotoxic activity against HeLa cell line with IC50 values of 29 and 13.3 µM, respectively. In addition, aeroplysinin-2 (6) showed potent antimigratory activity against the human breast cancer cell line MDA-MB-231 with IC50 of 18 µM. Subereamollines C and D are new congeners of the previously reported compounds subereamollines A and B with methyl ester functionalities on the side chain. These findings provide further insight into the biosynthetic capabilities of members of the genus Suberea and the chemical diversity as well as the biological activity of these compounds. PMID:25812033
Screening for bioactive metabolites in plant extracts modulating glucose uptake and fat accumulation.
El-Houri, Rime B; Kotowska, Dorota; Olsen, Louise C B; Bhattacharya, Sumangala; Christensen, Lars P; Grevsen, Kai; Oksbjerg, Niels; Færgeman, Nils; Kristiansen, Karsten; Christensen, Kathrine B
Dichloromethane and methanol extracts of seven different food and medicinal plants were tested in a screening platform for identification of extracts with potential bioactivity related to insulin-dependent glucose uptake and fat accumulation. The screening platform included a series of in vitro bioassays, peroxisome proliferator-activated receptor (PPAR) γ-mediated transactivation, adipocyte differentiation of 3T3-L1 cell cultures, and glucose uptake in both 3T3-L1 adipocytes and primary porcine myotubes, as well as one in vivo bioassay, fat accumulation in the nematode Caenorhabditis elegans. We found that dichloromethane extracts of aerial parts of golden root (Rhodiola rosea) and common elder (Sambucus nigra) as well as the dichloromethane extracts of thyme (Thymus vulgaris) and carrot (Daucus carota) were able to stimulate insulin-dependent glucose uptake in both adipocytes and myotubes while weekly activating PPARγ without promoting adipocyte differentiation. In addition, these extracts were able to decrease fat accumulation in C. elegans. Methanol extracts of summer savory (Satureja hortensis), common elder, and broccoli (Brassica oleracea) enhanced glucose uptake in myotubes but were not able to activate PPARγ, indicating a PPARγ-independent effect on glucose uptake. PMID:25254050
Sonication-assisted Agrobacterium rhizogenes-mediated transformation of Verbascum xanthophoeniceum Griseb. for bioactive metabolite accumulation.
Georgiev, Milen I; Ludwig-Müller, Jutta; Alipieva, Kalina; Lippert, Annemarie
An efficient protocol for the establishment of transformed root culture of Verbascum xanthophoeniceum using sonication-assisted Agrobacterium rhizogenes-mediated transformation is reported. Only 10 days after the inoculation with A. rhizogenes ATCC 15834 and 45 s ultrasound exposure, hairy roots appeared on 75% of the Verbascum leaves. Ten hairy root lines were isolated, although only half of them were free of bacterial contamination and started growing when excised from mother explants. The transgenic nature of the most vigorously growing hairy root clones (VX1 and VX6) was confirmed by polymerase chain reaction. Under submerged cultivation both hairy root clones accumulated high biomass amounts (12.8 and 14.3 g L(-1), respectively) and significant amounts of bioactive phenylethanoid glycoside verbascoside (over 6-times more than in mother plant leaves). LC-APCI-MS analyses confirmed verbascoside accumulation in hairy root clones along with three other phenylethanoid glycosides (forsythoside B, leucosceptoside B and martynoside) and an iridoid glycoside aucubin. This is the first report on the induction of hairy roots of Verbascum plants. PMID:21184229
In vitro adrenal bioactivation and effects on steroid metabolism of DDT, PCBs and their metabolites in the gray seal (Halichoerus grypus)
Lund, B.O. . Dept. of Pharmacology and Toxicology)
The irreversible binding of the DDT metabolites o,p[prime]-DDD [2-(2-chlorophenyl)-2(4-chlorophenyl)-1,1-dichloroethane] and MeSO[sub 2]-DDE [3-methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene], as well as their potential to inhibit mitochondrial steroid 11[beta]-hydroxylation in the gray seal adrenal gland, was studied. The adrenal bioactivated both o,p[prime]-DDD and MeSO[sub 2[minus
Bioactive Metabolites from Mangrove Endophytic Fungus Aspergillus sp. 16-5B
Liu, Yayue; Chen, Senhua; Liu, Zhaoming; Lu, Yongjun; Xia, Guoping; Liu, Hongju; He, Lei; She, Zhigang
Chemical investigation of the endophytic fungus Aspergillus sp. 16-5B cultured on Czapek's medium led to the isolation of four new metabolites, aspergifuranone (1), isocoumarin derivatives (±) 2 and (±) 3, and (R)-3-demethylpurpurester A (4), together with the known purpurester B (5) and pestaphthalides A (6). Their structures were determined by analysis of 1D and 2D NMR spectroscopic data. The absolute configuration of Compound 1 was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra, and that of Compound 4 was revealed by comparing its optical rotation data and CD with those of the literature. The structure of Compound 6 was further confirmed by single-crystal X-ray diffraction experiment using CuKα radiation. All isolated compounds were evaluated for their α-glucosidase inhibitory activities, and Compound 1 showed significant inhibitory activity with IC50 value of 9.05 ± 0.60 μM. Kinetic analysis showed that Compound 1 was a noncompetitive inhibitor of α-glucosidase. Compounds 2 and 6 exhibited moderate inhibitory activities. PMID:25996099
A fast method using a new hydrophilic-lipophilic balanced sorbent in combination with ultra-high performance liquid chromatography for quantification of significant bioactive metabolites in wines.
Silva, Catarina L; Pereira, Jorge; Wouter, Van G; Giró, Carme; Câmara, José S
This manuscript describes the development and validation of an ultra-fast, efficient, and high throughput analytical method based on ultra-high performance liquid chromatography (UHPLC) equipped with a photodiode array (PDA) detection system, for the simultaneous analysis of fifteen bioactive metabolites: gallic acid, protocatechuic acid, (-)-catechin, gentisic acid, (-)-epicatechin, syringic acid, p-coumaric acid, ferulic acid, m-coumaric acid, rutin, trans-resveratrol, myricetin, quercetin, cinnamic acid and kaempferol, in wines. A 50-mm column packed with 1.7-μm particles operating at elevated pressure (UHPLC strategy) was selected to attain ultra-fast analysis and highly efficient separations. In order to reduce the complexity of wine extract and improve the recovery efficiency, a reverse-phase solid-phase extraction (SPE) procedure using as sorbent a new macroporous copolymer made from a balanced ratio of two monomers, the lipophilic divinylbenzene and the hydrophilic N-vinylpyrrolidone (Oasis™ HLB), was performed prior to UHPLC-PDA analysis. The calibration curves of bioactive metabolites showed good linearity within the established range. Limits of detection (LOD) and quantification (LOQ) ranged from 0.006 μg mL(-1) to 0.58 μg mL(-1), and from 0.019 μg mL(-1) to 1.94 μg mL(-1), for gallic and gentisic acids, respectively. The average recoveries ± SD for the three levels of concentration tested (n=9) in red and white wines were, respectively, 89 ± 3% and 90 ± 2%. The repeatability expressed as relative standard deviation (RSD) was below 10% for all the metabolites assayed. The validated method was then applied to red and white wines from different geographical origins (Azores, Canary and Madeira Islands). The most abundant component in the analysed red wines was (-)-epicatechin followed by (-)-catechin and rutin, whereas in white wines syringic and p-coumaric acids were found the major phenolic metabolites. The method was completely validated
Medium modification to enhance the formation of bioactive metabolites in shake flask cultures of Antrodia cinnamomea by adding citrus peel extract.
Yang, Fan-Chiang; Ma, Te-Wei; Chuang, Ya-Ting
Antrodia cinnamomea has recently become a well-known medicinal mushroom in Taiwan. Bioactive compounds found in A. cinnamomea include: polysaccharide, sesquiterpene lactone, steroids and triterpenoids. The aim of this study was to evaluate the feasibility of adding citrus peel extract to enhance the formation of bioactive metabolites in the submerged culture of A. cinnamomea. With the exception of grapefruit, citrus peel extracts tested were proved to be beneficial to mycelial growth and to the production of intracellular polysaccharide. Lemon was the most effective for enhancing bioactive metabolite production. With an addition of 2% (v/v), the mycelium biomass concentration and intracellular polysaccharide content rose from 11.96 g DW/L of the control and 123.6 mg/g DW to 21.96 g DW/L and 230.8 mg/g DW, respectively, on day 8. The production of triterpenoids also increased from 86.7 to 282.9 mg/L. Moreover, this study also demonstrates that although the addition of peel extract could cause the lengthening of the exponential phase and reduce the specific growth rate, the production rate of biomass, intracellular polysaccharide and triterpenoids was still enhanced significantly. PMID:22367480
Pesticides and their metabolites in three small public water-supply reservoir systems, western New York, 1998-99
Phillips, Patrick J.; Eckhardt, David A.; Rosenmann, Larry
Twenty five pesticides or pesticide metabolites were detected in samples collected from May, 1998 through January, 1999 in three small public- supply reservoirs in western New York.Samples were collected at tributaries and reservoir outlets for comparison with samples from the water-supply intakes. No samples from public-water-supply intakes exceeded any Federal or State water-quality standards, although some samples from tributaries did exceed a few standards. The maximum concentrations of the most frequently detected pesticides in water-supply intake samples were between 10 and 50 percent of the lowest applicable water quality standard. Pesticides that exceeded water-quality standards at the tributary sites were the herbicides atrazine, alachlor, and cyanazine, and the insecticide p,p?-DDE. Land use in the watersheds that surround these reservoirs is largely agricultural; thus, the results do not necessarily represent conditions in other water-supply reservoirs in New York State. The most frequently detected pesticides or pesticide metabolites were the corn herbicides atrazine and metolachlor, and two metabolites of metolachlor -metolachlor ethanesulfonic acid (ESA)and metolachlor oxanilic acid (OA). More than half of the samples from the three water-supply intake sites contained at least one of these compounds at concentrations greater than 0.2 ?g/L (micrograms per liter); the concentrations ranged from 0.01 to nearly 10 ?g/L. Many samples contained metabolites of other commonly used herbicides at concentrations greater than those of their parent compounds. Only two insecticides or insecticide metabolites were detected (carbofuran and p,p?-DDE and concentrations of these compounds were less than 0.1 ?g/L. The total concentration of pesticides and metabolites at the three water-supply intake sites are correlated with land use. The highest concentrations were in the watershed with the greatest percentage of row-crop land use,and the lowest concentrations were in
19,20-EpDPE, a bioactive CYP450 metabolite of DHA monoacyglyceride, decreases Ca²⁺ sensitivity in human pulmonary arteries.
Morin, Caroline; Fortin, Samuel; Rousseau, Eric
The aim of this study was to investigate the effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) on human pulmonary arterial tone. Tension measurements on pulmonary arterial tissues demonstrated that MAG-DHA reduced U-46619-induced tone, which is highly sensitive to the H-1152 inhibitor. Results also showed that MAG-DHA treatments decreased RhoA activity levels, which in turn inactivated the Rho-kinase pathway, leading to a reduction in U-46619-induced Ca(2+) sensitivity of permeabilized pulmonary artery smooth muscle cells. According to the mechanical responses assessing U-46619-induced Ca(2+) sensitivity in the absence or presence of 3 μM MAG-DHA, MAG-DHA plus 1 μM N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH, a cytochrome P-450 epoxygenase inhibitor) and 300 nM 19,20-epoxydocosapentaenoic acid (a cytochrome P-450 epoxygenase-dependent DHA metabolite), our data suggest that the MAG-DHA is metabolized in a bioactive epoxymetabolite. This epoxyeicosanoid in turn decreases active tone and Ca(2+) sensitivity of smooth muscles cells through an inhibition of the Rho-kinase pathway. Together, these data provide primary evidence regarding the mode of action of MAG-DHA in human pulmonary arteries and suggest that this compound may be of pharmacological interest in patients with pulmonary hypertension to generate intracellular bioactive metabolites. PMID:21821782
Bioactive Plant Metabolites in the Management of Non-Communicable Metabolic Diseases: Looking at Opportunities beyond the Horizon
Prasad, Chandan; Imrhan, Victorine; Juma, Shanil; Maziarz, Mindy; Prasad, Anand; Tiernan, Casey; Vijayagopal, Parakat
There has been an unprecedented worldwide rise in non-communicable metabolic diseases (NCDs), particularly cardiovascular diseases (CVD) and diabetes. While modern pharmacotherapy has decreased the mortality in the existing population, it has failed to stem the rise. Furthermore, a large segment of the world population cannot afford expensive pharmacotherapy. Therefore, there is an urgent need for inexpensive preventive measures to control the rise in CVD and diabetes and associated co-morbidities. The purpose of this review is to explore the role of food bioactives in prevention of NCDs. To this end, we have critically analyzed the possible utility of three classes of food bioactives: (a) resistant starch, a metabolically resistant carbohydrate known to favorably modulate insulin secretion and glucose metabolism; (b) cyclo (His-Pro), a food-derived cyclic dipeptides; and (c) polyphenol-rich berries. Finally, we have also briefly outlined the strategies needed to prepare these food-bioactives for human use. PMID:26703752
Bioactive Sulfur-Containing Sulochrin Dimers and Other Metabolites from an Alternaria sp. Isolate from a Hawaiian Soil Sample
Polluxochrin (1) and dioschrin (2), two new dimers of sulochrin linked by thioether bonds, were purified from an Alternaria sp. isolate obtained from a Hawaiian soil sample. The structures of the two metabolites were established by NMR, mass spectrometry data, and X-ray analysis. Metabolite 1 was determined to be susceptible to intramolecular cyclization under aqueous conditions, resulting in the generation of 2 as well as another dimeric compound, castochrin (3). An additional nine new metabolites were also obtained, including four new pyrenochaetic acid derivatives (8–11), one new asterric acid analogue (13), and four new secalonic acid analogues (14–17). Bioassay analysis of these compounds revealed 1–3 displayed antimicrobial and weak cytotoxic activities. PMID:25265160
Uptake and transport of roxarsone and its metabolites in water spinach as affected by phosphate supply.
Yao, Lixian; Li, Guoliang; Dang, Zhi; Yang, Baomei; He, Zhaohuan; Zhou, Changmin
Roxarsone (ROX) is widely used as a feed additive in intensive animal production. While an animal is fed with ROX, the As compounds in the manure primarily occur as ROX and its metabolites, including arsenate (As[V]), arsenite (As[III]), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA). Animal manure is commonly land applied with phosphorous fertilizers in China. A pot experiment was conducted to investigate the phytoavailability of ROX, As(V), As(III), MMA, and DMA in water spinach (Ipomoea aquatica), with the soil amended with 0, 0.25, 0.50, 1.0, and 2.0 g PO(4)/kg, respectively, plus 2% (w/w manure/soil) chicken manure (CM) bearing ROX and its metabolites. The results indicate that this species of water spinach cannot accumulate ROX and MMA at detectable levels, but As(V), As(III), and DMA were present in all plant samples. Increased phosphorous decreased the shoot As(V) and As(III) in water spinach but did not affect the root As(V). The shoot DMA and root As(III) and DMA were decreased/increased and then increased/decreased by elevated phosphorous. The total phosphorous content (P) in plant tissue did not correlate with the total As or the three As species in tissues. Arsenate, As(III), and DMA were more easily accumulated in the roots, and phosphate considerably inhibited their upward transport. Dimethylarsinic acid had higher transport efficiency than As(V) and As(III), but As(III) was dominant in tissues. Conclusively, phosphate had multiple effects on the accumulation and transport of ROX metabolites, which depended on their levels. However, proper utilization of phosphate fertilizer can decrease the accumulation of ROX metabolites in water spinach when treated with CM containing ROX and its metabolites. PMID:20821525
Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction
Umbrello, Michele; Dyson, Alex; Pinto, Bernardo Bollen; Fernandez, Bernadette O; Simon, Verena; Feelisch, Martin; Singer, Mervyn
Local increases in blood flow – 'hypoxic vasodilation' – confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from preformed stores and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NO synthase inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite. PMID:24396056
Pesticides and their metabolites in community water-supply wells of central and western New York, August 1999
Eckhardt, David A.V.; Hetcher, Kari K.; Phillips, Patrick J.; Miller, Todd S.
Ten pesticides and pesticide metabolites were detected in ground-water samples collected from each of 32 community water-supply (CWS) systems in central and west ern New York in August 1999. The sampling sites consisted of 30 wells that ranged from 23 to 120 feet in depth, and 2 springwater infiltration galleries. All wells tapped unconfined sand and gravel aquifers except one, wh ich was completed in karstic limestone. These systems were selected because they were deemed vulnerable to pesticide contamination; accordingly, the results are not considered representative of all CWS systems in New York. The samples were analyzed for 60 pesticides. Twenty-four of the 32 samples contained at least one pesticide, and one sample contained eight pesticides or pesticide metabolites. New York State and Federal water-quality standards were not exceeded in any sample collected in this study. All pesticides detected in the CWS wells are a specific class of herbicides that are used to control broadleaf weeds and undesirable grasses in agricultural fields, lawns, and other areas that require control of vegetation. The four compounds detected most frequently were the herbicides atrazine and metolachlor and their metabolites--deethylatrazine and metolachlor ESA. Maximum concentrations of the four compounds ranged from 0.088 micrograms per liter (?g/L) for deethylatrazine to 3.58 ?g/L for metolachlor ESA.
Bioactive brominated metabolites from the natural habitat and tank-maintained cuttings of the Jamaican sponge Aplysina fistularis.
Gallimore, Winklet A
Cut specimens of the common reef sponge of the Verongid family, Aplysina fistularis, were retained in flow-through seawater tanks over a six-week period to assess the metabolite profile of the sponge when subjected to stress, compare the profile with the source material, and assess the preliminary feasibility of the protocol for sponge culture. The living specimens were harvested, extracted with MeOH/CH₂Cl₂ 1:1, and subjected to column chromatography to identify metabolites. The brominated isoxazoline compounds, aerothionin (1) and 11-oxoaerothionin (2), along with aeroplysinin 2 (3) and 2-(3,5-dibromo-4-hydroxyphenol)acetamide (4), were detected in the cuttings from the tank-maintained sponge. An examination of the metabolite profile of the sponge from the natural habitat showed that the compounds 1 and 2 were present. The identities of all the compounds were ascertained by analysis of the mass-spectral data and NMR spectra (¹H, ¹³C, HMBC, and HSQC) of the compounds, which were compared with reported data. The survival rate was 44% with limited necrosis or exposed skeletal tissue being observed in eight of the 18 cuttings, suggesting that protocol modifications would be required for culturing the sponge. PMID:23776020
Isolation and Characterization of Bioactive Metabolites from Fruiting Bodies and Mycelial Culture of Ganoderma oerstedii (Higher Basidiomycetes) from Mexico.
Mendoza, Guillermo; Suárez-Medellín, Jorge; Espinoza, César; Ramos-Ligonio, Angel; Fernández, José J; Norte, Manuel; Trigos, Ángel
Various species of the genus Ganoderma have been used for centuries according to oriental tradition as a source of medicines and nutrients. A chemical study of the fruiting bodies and mycelial culture of G. oerstedii was carried out with the idea of isolating and characterizing active natural components present to make use of their potential pharmaceutical application in Mexico. The fruiting bodies and mycelial culture of G. oesrtedii were lyophylized and extracted one after the other with hexane, chloroform, and methanol. Following this process, each substance was extracted separately by using column chromatography. From fruiting bodies eight metabolites, five sterols (ergosta-7,22-dien-3β-ol, ergosterol peroxide, ergosterol, cerevisterol, and ergosta-7,22-dien-3-one) as well as three terpene compounds (ganodermanondiol, ganoderic acid Sz, and ganoderitriol M) were obtained from fruiting bodies. From the mycelial culture three metabolites, two sterols (ergosterol and cerevisterol), and a new terpene compound (ganoderic acetate from the acid) were obtained. These structures were established based on a spectroscopic analysis mainly using nuclear magnetic resonance and a comparison with data already established. PMID:26349508
Medium optimization for enhanced co-production of two bioactive metabolites in the same fermentation by a statistical approach.
Wu, Qi; Song, Yong-Chun; Xu, Hao; Guo, Ye; Li, Jing; Tan, Ren-Xiang
This paper describes improved optimization method that combines the one-factor-at-a-time method (OFAT), Plackett-Burman design, and the response surface method (RSM), which were used to optimize the medium for the production of fumigaclavine C (FC) and helvolic acid (HA) from endophytic Aspergillus fumigatus CY018 simultaneously. The ideal carbon and nitrogen sources for the two compounds were assessed initially via the one-factor-at-a-time method. Three key cultivation factors (pH, phosphate, and inoculum size) were chosen based on the results of Plackett-Burman design, and subsequently optimized by the central composite design. The two metabolites were amply afforded when the cultivation was carried out with the inoculum size of 2.45% at pH 4.2 and 28°C for 19 days in the medium containing (g/l): mannitol 50, sodium succinate 5.4, NaNO₃ 2, MgSO₄·7H₂O 0.3, FeSO₄·7H₂O 0.01, and KH₂PO₄ 0.67. The highest yields of FC and HA achieved herein were 17.26 and 16.88 mg/l. This work might be the first endeavor leading to the improved simultaneous production of two complex active metabolites with a single strain. PMID:22115035
Human prostaglandin H synthase (hPHS)-1- and hPHS-2-dependent bioactivation, oxidative macromolecular damage, and cytotoxicity of dopamine, its precursor, and its metabolites.
Ramkissoon, Annmarie; Wells, Peter G
The dopamine (DA) precursor l-dihydroxyphenylalanine (L-DOPA) and metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine may serve as substrates for prostaglandin H synthase (PHS)-catalyzed bioactivation to free radical intermediates. We used CHO-K1 cells expressing human (h) PHS-1 or hPHS-2 to investigate hPHS isozyme-dependent oxidative damage and cytotoxicity. hPHS-1- and hPHS-2-expressing cells incubated with DA, L-DOPA, DOPAC, or HVA exhibited increased cytotoxicity compared to untransfected cells, and cytotoxicity was increased further by exogenous arachidonic acid (AA), which increased hPHS activity. Preincubation with catalase, which detoxifies reactive oxygen species, or acetylsalicylic acid, an inhibitor of hPHS-1 and -2, reduced the cytotoxicity caused by DA, L-DOPA, DOPAC, and HVA in hPHS-1 and -2 cells both with and without AA. Protein oxidation was increased in hPHS-1 and -2 cells exposed to DA or L-DOPA and further increased by AA addition. DNA oxidation was enhanced earlier and at lower substrate concentrations than protein oxidation in both hPHS-1 and -2 cells by DA, L-DOPA, DOPAC, and HVA and further enhanced by AA addition. hPHS-2 cells seemed more susceptible than hPHS-1 cells, whereas untransfected CHO-K1 cells were less susceptible. Thus, isozyme-specific, hPHS-dependent oxidative damage and cytotoxicity caused by neurotransmitters, their precursors, and their metabolites may contribute to neurodegeneration associated with aging. PMID:21078384
Secondary metabolites of a deep sea derived fungus Aspergillus versicolor CXCTD-06-6a and their bioactivity
NASA Astrophysics Data System (ADS)
Kong, Xianglan; Cai, Shengxin; Zhu, Tianjiao; Gu, Qianqun; Li, Dehai; Luan, Yepeng
In order to obtain novel secondary metabolites, a deep sea inhabiting fungus Aspergillus versicolor CXCTD-06-6a was investigated. One new diketopiperazine brevianamide W ( 1a), as well as five known diketopiperazine alkaloids, diketopiperazine V ( 1b), brevianamide Q ( 2), brevianamide R ( 3), brevianamide K ( 4), and brevianamide E ( 5), were isolated from the EtOAc extract of the fermentation broth. Their structures were elucidated by spectroscopy techniques (NMR, MS). The six compounds exhibited moderate radical scavenging activity against DPPH with clearance ratio of 55.0% ( 1a and 1b), 53.7% ( 2), 46.2% ( 3), 61.4% ( 4) and 19.3% ( 5) at a concentration of 13.9 μmol L-1, respectively; while the positive control ascorbic acid showed a ratio of 70.3% at the concentration of 28.4 μmol L-1.
Characterization of leaf apoplastic peroxidases and metabolites in Vigna unguiculata in response to toxic manganese supply and silicon.
Führs, Hendrik; Götze, Stefanie; Specht, André; Erban, Alexander; Gallien, Sébastien; Heintz, Dimitri; Van Dorsselaer, Alain; Kopka, Joachim; Braun, Hans-Peter; Horst, Walter J
Previous work suggested that the apoplastic phenol composition and its interaction with apoplastic class III peroxidases (PODs) are decisive in the development or avoidance of manganese (Mn) toxicity in cowpea (Vigna unguiculata L.). This study characterizes apoplastic PODs with particular emphasis on the activities of specific isoenzymes and their modulation by phenols in the Mn-sensitive cowpea cultivar TVu 91 as affected by Mn and silicon (Si) supply. Si reduced Mn-induced toxicity symptoms without affecting the Mn uptake. Blue Native-PAGE combined with Nano-LC-MS/MS allowed identification of a range of POD isoenzymes in the apoplastic washing fluid (AWF). In Si-treated plants Mn-mediated induction of POD activity was delayed. Four POD isoenzymes eluted from the BN gels catalysed both H(2)O(2)-consuming and H(2)O(2)-producing activity with pH optima at 6.5 and 5.5, respectively. Four phenols enhanced NADH-peroxidase activity of these isoenzymes in the presence of Mn(2+) (p-coumaric=vanillic>benzoic>ferulic acid). p-Coumaric acid-enhanced NADH-peroxidase activity was inhibited by ferulic acid (50%) and five other phenols (50-90%). An independent component analysis (ICA) of the total and apoplastic GC-MS-based metabolome profile showed that Mn, Si supply, and the AWF fraction (AWF(H(2)O), AWF(NaCl)) significantly changed the metabolite composition. Extracting non-polar metabolites from the AWF allowed the identification of phenols. Predominantly NADH-peroxidase activity-inhibiting ferulic acid appeared to be down-regulated in Mn-sensitive (+Mn, -Si) and up-regulated in Mn-tolerant (+Si) leaf tissue. The results presented here support the previously hypothesized role of apoplastic NADH-peroxidase and its activity-modulating phenols in Mn toxicity and Si-enhanced Mn tolerance. PMID:19286915
A novel stereo bioactive metabolite isolated from an endophytic fungus induces caspase dependent apoptosis and STAT-3 inhibition in human leukemia cells.
Pathania, Anup Singh; Guru, Santosh Kumar; Ul Ashraf, Nissar; Riyaz-Ul-Hassan, Syed; Ali, Asif; Abdullah Tasduq, Sheikh; Malik, Fayaz; Bhushan, Shashi
The present study describes the anti-leukemic potential of a novel stereo bioactive secondary metabolite, (R)-5-hydroxy-2-methylchroman-4-one (HMC) isolated from a novel endophytic fungus source (Cryptosporiopsis sp. H2-1, NFCCI-2856), associated with Clidemia hirta. HMC inhibited cell proliferation of different cancer cell lines with IC50 values in the range of 8-55 µg/ml. The cytotoxicity window of HMC was 6-12 times lower in normal cells as compared to susceptible leukemic HL-60, MOLT-4 and K-562 cells. It persuades apoptosis through both intrinsic and extrinsic pathways in above leukemic cell lines, which was evident through Hoechst staining, Annexin-V binding, cell cycle analysis, loss of mitochondrial membrane potential (Δψm), release of cytochrome c, Bax, Bid, over-expression of apical death receptors, activation of caspase-3,-8,-9 and PARP (poly ADP ribose polymerase) cleavage. HMC induced caspase dependent apoptosis and robustly attenuate transcription factor, p-STAT-3 in myeloid and lymphoid leukemia cells. The mechanism of HMC arbitrated inhibition of p-STAT-3 was due to the activation of ubiquitin dependent degradation of p-STAT-3. Therefore, our study not only describes the anti-leukemic potential of HMC but also provides insights into how endophytes can be useful in discovery and development of novel anticancer therapeutics. PMID:26291658
Optimization and pharmacological validation of a leukocyte migration assay in zebrafish larvae for the rapid in vivo bioactivity analysis of anti-inflammatory secondary metabolites.
Cordero-Maldonado, María Lorena; Siverio-Mota, Dany; Vicet-Muro, Liliana; Wilches-Arizábala, Isabel María; Esguerra, Camila V; de Witte, Peter A M; Crawford, Alexander D
Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. PMID:24124487
Bioactive secondary metabolites of a marine Bacillus sp. inhibit superoxide generation and elastase release in human neutrophils by blocking formyl peptide receptor 1.
Yang, Shun-Chin; Lin, Chwan-Fwu; Chang, Wen-Yi; Kuo, Jimmy; Huang, Yin-Ting; Chung, Pei-Jen; Hwang, Tsong-Long
It is well known that overwhelming neutrophil activation is closely related to acute and chronic inflammatory injuries. Formyl peptide receptor 1 (FPR1) plays an important role in activation of neutrophils and may represent a potent therapeutic target in inflammatory diseases. In the present study, we demonstrated that IA-LBI07-1 (IA), an extract of bioactive secondary metabolites from a marine Bacillus sp., has anti-inflammatory effects in human neutrophils. IA significantly inhibited superoxide generation and elastase release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated neutrophils, but failed to suppress the cell responses activated by non-FPR1 agonists. IA did not alter superoxide production and elastase activity in cell-free systems. IA also attenuated the downstream signaling from FPR1, such as the Ca2+, MAP kinases and AKT pathways. In addition, IA inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analogue of FMLP, to FPR1 in human neutrophils and FPR1-transfected HEK293 cells. Taken together, these results show that the anti-inflammatory effects of IA in human neutrophils are through the inhibition of FPR1. Also, our data suggest that IA may have therapeutic potential to decrease tissue damage induced by human neutrophils. PMID:23736784
Oxidized Metabolites of 20-Hydroxyecdysone and Their Activity on Skeletal Muscle Cells: Preparation of a Pair of Desmotropes with Opposite Bioactivities.
Csábi, József; Hsieh, Tusty-Jiuan; Hasanpour, Feria; Martins, Ana; Kele, Zoltán; Gáti, Tamás; Simon, András; Tóth, Gábor; Hunyadi, Attila
Increasing the activation of protein kinase B (Akt) has been suggested as a key signaling step in the nonhormonal anabolic activity of the phytoecdysteroid 20-hydroxyecdysone (20E) in mammals. Base-catalyzed autoxidation of this compound was shown previously to yield interesting B-ring-modified analogues. Herein is reported a thorough study on this reaction, resulting in the preparation and complete NMR spectroscopic assignments of calonysterone (5) and its previously overlooked desmotropic pair (7), along with two new sensitive metabolites of 20E. The two isomers showed considerable stability in solution. Time dependency of the reaction for yield optimization is also presented; by means of analytical HPLC, the two desmotropes can reach a maximum combined yield of >90%. The activity of these compounds on Akt phosphorylation was tested in murine skeletal muscle cells. Compounds 2 and 5 showed more potent activity than 20E in increasing Akt activation, while compound 7 exerted an opposite effect. As such, the present study provides the first direct evidence for a pair of desmotropes exerting significantly different bioactivities. PMID:26465254
Characterization of the bioactive metabolites from a plant growth-promoting rhizobacteria and their exploitation as antimicrobial and plant growth-promoting agents.
George, Emrin; Kumar, S Nishanth; Jacob, Jubi; Bommasani, Bhaskara; Lankalapalli, Ravi S; Morang, P; Kumar, B S Dileep
A plant growth-promoting bacterial strain, PM 105, isolated from a tea plantation soil from the North Eastern region of India was identified as Pseudomonas aeruginosa through classical and 16S ribosomal DNA (rDNA) gene sequencing. Further studies with this strain confirmed broad spectrum antifungal activity against ten human and plant pathogenic fungal pathogens viz. Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus tubingensis, Candida albicans, Colletotrichum gloeosporioides, Fusarium oxysporum, Pencillium expansum, Rhizoctonia solani, Trichophyton rubrum besides growth-promoting property in cowpea (Vigna unguiculata) and pigeon pea (Cajanus cajan). However, no antibacterial property was exhibited by this strain against the four test bacterial pathogens tested in agar overlay method. The crude bioactive metabolites produced by this strain were isolated with three different solvents that exhibited significant antimicrobial and plant growth-promoting activity. Chloroform extract recorded significant antimicrobial and plant growth-promoting activity. Three major compounds viz. 1-hydroxyphenazine, pyocyanin, and phenazine-1-carboxamide were purified and characterized from crude extracts of this strain by various spectral data. The purified compounds recorded prominent antimicrobial activity but failed to establish the plant growth promotion activity in test crop plants under gnotobiotic conditions. Pyocyanin recorded significant antimicrobial activity, and best activity was recorded against T. rubrum (29 mm), followed by P. expansum (28 mm). These results suggest the use of PM 105 as plant growth-promoting agent in crop plants after successful field trials. PMID:25832181
Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites
Vicet-Muro, Liliana; Wilches-Arizábala, Isabel María; Esguerra, Camila V.; de Witte, Peter A. M.; Crawford, Alexander D.
Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. PMID:24124487
Bioactivity-guided identification of antimicrobial metabolites in Alnus glutinosa bark and optimization of oregonin purification by Centrifugal Partition Chromatography.
Abedini, Amin; Chollet, Sébastien; Angelis, Apostolis; Borie, Nicolas; Nuzillard, Jean-Marc; Skaltsounis, Alexios-Leandros; Reynaud, Romain; Gangloff, Sophie C; Renault, Jean-Hugues; Hubert, Jane
Barks from conifers and broadleaved trees constitute abundant wastes generated from wood harvesting and logging activities. Extracts of such residues obtained from Alnus trees have been reported as interesting resources with potent antibacterial activities. The present study aims to determine the antimicrobial activity of a crude methanol extract prepared from the bark of Alnus glutinosa against a panel of 22 bacteria and yeasts and to optimize a purification method enabling the high production of the most active substances. Fractionation of the crude extract was performed by Centrifugal Partition Chromatography (CPC) using a three-phase solvent system composed of n-heptane, methyl-ter-butyl ether, acetonitrile and water. The major known compounds contained in the fractions produced by CPC were chemically profiled by (13)C NMR dereplication, resulting in the unambiguous identification of oregonin, hirsutanonol, betulinic acid, and alusenone 1a. The antibacterial evaluation of the fractions by bioautography on Staphylococcus aureus revealed that oregonin, in addition to being the major metabolite of the crude extract (∼32% w/w), was the most active with an antibacterial inhibitory effect comparable to antibiotics. The purification of oregonin was optimized at the laboratory-scale by CPC. A single injection of 3.7g of crude extract resulted in a recovery of 72% (850mg) of the available oregonin at purity higher than 94%. PMID:27428455
UPLC-Q-TOF/MS-based screening and identification of two major bioactive components and their metabolites in normal and CKD rat plasma, urine and feces after oral administration of Rehmannia glutinosa Libosch extract.
Tao, Jin-hua; Zhao, Min; Wang, Dong-geng; Yang, Chi; Chen, Guang-tong; Zhao, Xi; Pu, Xu-lian; Jiang, Shu
Rehmannia glutinosa is a widely used traditional Chinese medicine (TCM) in clinical practice to tackle chronic kidney disease for thousands of years. However, the in vivo metabolism of its two major bioactive components (catalpol and acteoside) remains unknown. In this paper, a highly sensitive, rapid and robust ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with MetaboLynx™ software combined with mass defect filtering (MDF) method was established. This validated analysis method was successfully applied to investigate the in vivo metabolic profiles of R. glutinosa extract in normal and chronic kidney disease (CKD) rats. The results showed that a total of 17 metabolites of two parent compounds in normal rats in vivo were tentatively detected and identified according to the characteristics of their protonated ions and relevant literature. While 11 of the metabolites were observed in the CKD rat samples. These metabolites suggested that catalpol was firstly deglycosylated to its aglycone and subsequently to two main metabolites (M1 and M4) by conjugation and hydrogenation respectively and acteoside was mainly metabolized by O-glucuronide conjugation and O-sulphate conjugation. In conclusion, this study showed an insight into the metabolism of R. glutinosa extract in vivo and the proposed metabolic pathways of bioactive components might play a key role in further pharmacokinetic experiments evaluations. PMID:26262601
Development of a new high-performance liquid chromatography method with diode array and electrospray ionization-mass spectrometry detection for the metabolite fingerprinting of bioactive compounds in Humulus lupulus L.
Prencipe, Francesco Pio; Brighenti, Virginia; Rodolfi, Margherita; Mongelli, Andrea; dall'Asta, Chiara; Ganino, Tommaso; Bruni, Renato; Pellati, Federica
The study was aimed at developing a new analytical method for the metabolite fingerprinting of bioactive compounds in Humulus lupulus L. (hop), together with a simple extraction procedure. Different extraction techniques, including maceration, heat reflux extraction (HRE), ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE), were compared in order to obtain a high yield of the target analytes. Dynamic maceration for 30min with MeOH-HCOOH (99:1, v/v) as the extraction solvent provided the best result in terms of recovery of secondary metabolites. The analysis of hop constituents, including prenylflavonoids and prenylphloroglucinols (bitter acids), was carried out by means of HPLC-UV/DAD, HPLC-ESI-MS and MS(2), using an ion trap mass analyzer. An Ascentis Express C18 column (150mm×3.0mm I.D., 2.7μm) was used for the HPLC analysis, with a mobile phase composed of 0.25% formic acid in both water and acetonitrile, under gradient elution. The method validation was performed to show compliance with ICH guidelines. The validated technique was successfully applied to the phytochemical analysis of ten commercial cultivars and twenty-three wild Italian hop genotypes, thus demonstrating to be a reliable and useful tool for the comprehensive multi-component analysis of hop secondary metabolites. PMID:24857039
Antifeedant, larvicidal and growth inhibitory bioactivities of novel polyketide metabolite isolated from Streptomyces sp. AP-123 against Helicoverpa armigera and Spodoptera litura
Background Considerable attention has been paid to actinomycetes, especially the secondary metabolites obtained from Streptomyces species, as the best alternatives to chemicals as biological control agents for polyphagous pests such as Helicoverpa armigera and Spodoptera litura. On the basis of their novel biocontrol attributes, novel polyketide metabolite isolated from marine Streptomyces sp. AP-123 exhibited significant antifeedant, larvicidal and growth inhibitory activities against polyphagous pests. Results Leaf disc no-choice method was used for the insect bioassay. The polyketide metabolite presented significant antifeedant activities against H. armigera (78.51%) and S. litura (70.75%) at 1000 ppm concentration. The metabolite also exhibited high larvicidal activities against H. armigera (63.11%) and S. litura (58.22%) and the LC50 values were 645.25 ppm for H. armigera and 806.54 ppm for S. litura. The metabolite also prolonged the larval–pupal duration of the insects at all the tested concentrations. Conclusions The activities of the polyketide metabolite were concentration dependent for both the insects therefore it could be used as an agent to prepare new pesticidal formulations. PMID:23668716
Ultra-performance liquid chromatography tandem mass spectrometry combined with automated MetaboLynx analysis approach to screen the bioactive components and their metabolites in Wen-Xin-Formula.
Cao, Hongxin; Zhang, Aihua; Zhang, Fang-mei; Wang, Qin-qin; Zhang, He; Song, Yan-hua; Zhou, Ying; Sun, Hui; Yan, Guang-li; Han, Ying; Wang, Xijun
Wen-Xin-Formula (WXF), a famous traditional prescription, has been widely used to treat myocardial ischemia syndrome for thousands of years. However, the constituents absorbed into blood after oral administration of WXF remain unknown. Here, an integrative ultra performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) combined with the MetaboLynx approach was established to investigate the absorbed constituents in rats after oral administration of WXF. A hyphenated electrospray ionization and quadrupole-time-of-flight analyzer was used for the determination of accurate mass of the molecule and fragment ions. With this rapid and automated analysis method, a total of 32 peaks were tentatively characterized in vivo based on MS and MS/MS data and comparison with available databasess, 26 of which were parent components and six metabolites. These components mainly were ginsenosides, paeoniflorin, galloyl glucose, berberis alkaloids, phenolic, phenolic glycosides and unsaturated fatty acids, glucuronide products of original berberis alkaloids. The present study demonstrates that integrative UPLC-ESI-Q-TOF-MS technique and MetaboLynx data processing method were successfully applied for the rapid discovery of potentially bioactive components and metabolites from WXF, and proved that the established method could help to explore the effective substances for further research into WXF. PMID:24853889
Studies on bioactivity and secondary metabolites of crude extracts of Bidens pilosa L. (Asteraceae): A medicinal plant used in the Transkei region of South Africa.
Njume, Collise; Gqaza, Bomkazi M; Rozani, Carina; Goduka, Nomalungelo I
Whole plant-parts of Bidens pilosa were powdered and extracted in concentrated hexane, acetone, ethanol, methanol and water. The extracts were tested for antimicrobial activity against Escherichia coli (25922), Bacillus subtilis (ATCC 6051), Enterococcus faecalis (51299) Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (ATCC127853), using standard microbiological techniques. Active crude extracts were macerated in concentrated methanol and tested for secondary metabolites including tannins, saponins, alkaloids, cardiac glycosides, anthraquinones, steroids and flavonoids using standard phytochemical procedures. Hexane and methanol extracts demonstrated similar activity producing 8-17 mm and 11-18 mm inhibition zone-diameter ranges respectively. Further analysis for minimum inhibitory concentrations (MIC(50)) recorded 1.25-20mg/mL and 2.5-20mg/mL for hexane and methanol extracts respectively. The highest zones of inhibition diameters (22-36mm) and lowest MIC(50) values (0.0002-0.0006mg/mL) were recorded for Gentamicin, the positive control. Minimum bactericidal concentration (MBC) ranges were between 10-80mg/mL and 0.001-0.005mg/mL for extracts and control antibiotic respectively. With the exception of anthraquinones, the plant crude extracts tested positive for all secondary metabolites analyzed. These results provide scientific basis for the use of B. pilosa in South African traditional medicine. The antibacterial activity reported herein may be attributed to one or more of the 6 secondary metabolites detected in the plant crude extracts. PMID:27166532
Accurate Dereplication of Bioactive Secondary Metabolites from Marine-Derived Fungi by UHPLC-DAD-QTOFMS and a MS/HRMS Library
Kildgaard, Sara; Mansson, Maria; Dosen, Ina; Klitgaard, Andreas; Frisvad, Jens C.; Larsen, Thomas O.; Nielsen, Kristian F.
In drug discovery, reliable and fast dereplication of known compounds is essential for identification of novel bioactive compounds. Here, we show an integrated approach using ultra-high performance liquid chromatography-diode array detection-quadrupole time of flight mass spectrometry (UHPLC-DAD-QTOFMS) providing both accurate mass full-scan mass spectrometry (MS) and tandem high resolution MS (MS/HRMS) data. The methodology was demonstrated on compounds from bioactive marine-derived strains of Aspergillus, Penicillium, and Emericellopsis, including small polyketides, non-ribosomal peptides, terpenes, and meroterpenoids. The MS/HRMS data were then searched against an in-house MS/HRMS library of ~1300 compounds for unambiguous identification. The full scan MS data was used for dereplication of compounds not in the MS/HRMS library, combined with ultraviolet/visual (UV/Vis) and MS/HRMS data for faster exclusion of database search results. This led to the identification of four novel isomers of the known anticancer compound, asperphenamate. Except for very low intensity peaks, no false negatives were found using the MS/HRMS approach, which proved to be robust against poor data quality caused by system overload or loss of lock-mass. Only for small polyketides, like patulin, were both retention time and UV/Vis spectra necessary for unambiguous identification. For the ophiobolin family with many structurally similar analogues partly co-eluting, the peaks could be assigned correctly by combining MS/HRMS data and m/z of the [M + Na]+ ions. PMID:24955556
Advances in Marine Microbial Symbionts in the China Sea and Related Pharmaceutical Metabolites
Li, Zhiyong
Marine animals and plants such as sponges, sea squirts, corals, worms and algae host diverse and abundant symbiotic microorganisms. Marine microbial symbionts are possible the true producers or take part in the biosynthesis of some bioactive marine natural products isolated from the marine organism hosts. Investigation of the pharmaceutical metabolites may reveal the biosynthesis mechanisms of related natural products and solve the current problem of supply limitation in marine drug development. This paper reviews the advances in diversity revelation, biological activity and related pharmaceutical metabolites, and functional genes of marine microbial symbionts from the China Sea. PMID:19597576
Gene identification in black cohosh (Actaea racemosa L.): expressed sequence tag profiling and genetic screening yields candidate genes for production of bioactive secondary metabolites.
Spiering, Martin J; Urban, Lori A; Nuss, Donald L; Gopalan, Vivek; Stoltzfus, Arlin; Eisenstein, Edward
Black cohosh (Actaea racemosa L., syn. Cimicifuga racemosa, Nutt., Ranunculaceae) is a popular herb used for relieving menopausal discomforts. A variety of secondary metabolites, including triterpenoids, phenolic dimers, and serotonin derivatives have been associated with its biological activity, but the genes and metabolic pathways as well as the tissue distribution of their production in this plant are unknown. A gene discovery effort was initiated in A. racemosa by partial sequencing of cDNA libraries constructed from young leaf, rhizome, and root tissues. In total, 2,066 expressed sequence tags (ESTs) were assembled into 1,590 unique genes (unigenes). Most of the unigenes were predicted to encode primary metabolism genes, but about 70 were identified as putative secondary metabolism genes. Several of these candidates were analyzed further and full-length cDNA and genomic sequences for a putative 2,3 oxidosqualene cyclase (CAS1) and two BAHD-type acyltransferases (ACT1 and HCT1) were obtained. Homology-based PCR screening for the central gene in plant serotonin biosynthesis, tryptophan decarboxylase (TDC), identified two TDC-related sequences in A. racemosa. CAS1, ACT1, and HCT1 were expressed in most plant tissues, whereas expression of TDC genes was detected only sporadically in immature flower heads and some very young leaf tissues. The cDNA libraries described and assorted genes identified provide initial insight into gene content and diversity in black cohosh, and provide tools and resources for detailed investigations of secondary metabolite genes and enzymes in this important medicinal plant. PMID:21188383
High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation.
Kotapati, Srikanth; Esades, Amanda; Matter, Brock; Le, Chap; Tretyakova, Natalia
1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-L-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI(-)-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI(-)-MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA+DHBMA+THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers. PMID:25727266
Healthy and Adverse Effects of Plant-Derived Functional Metabolites: The Need of Revealing their Content and Bioactivity in a Complex Food Matrix
Lavecchia, Teresa; Rea, Giuseppina; Antonacci, Amina; Giardi, Maria T.
In recent years, both food quality and its effect on human health have become a fundamental issue all over the world. As a consequence of this new and increased awareness, American, European, and Asian policymakers have strongly encouraged the research programs on food quality and safety thematic. Attempts to improve human health and to satisfy people's desire for healthcare without intake of pharmaceuticals, has led the food industry to focus attention on functional or nutraceutical food. For a long time, compounds with nutraceutical activity have been produced chemically, but the new demands for a sustainable life have gradually led the food industry to move towards natural compounds, mainly those derived from plants. Many phytochemicals are known to promote good health, but, sometimes, undesirable effects are also reported. Furthermore, several products present on the market show few benefits and sometimes even the reverse – unhealthy effects; the evidence of efficacy is often unconvincing and epidemiological studies are necessary to prove the truth of their claims. Therefore, there is a need for reliable analytical control systems to measure the bioactivity, content, and quality of these additives in the complex food matrix. This review describes the most widespread nutraceutics and an analytical control of the same using recently developed biosensors which are promising candidates for routine control of functional foods. PMID:23072533
Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites.
Lian, Jiazhang; Zhao, Huimin
Fatty acids or their activated forms, fatty acyl-CoAs and fatty acyl-ACPs, are important precursors to synthesize a wide variety of fuels and chemicals, including but not limited to free fatty acids (FFAs), fatty alcohols (FALs), fatty acid ethyl esters (FAEEs), and alkanes. However, Saccharomyces cerevisiae, an important cell factory, does not naturally accumulate fatty acids in large quantities. Therefore, metabolic engineering strategies were carried out to increase the glycolytic fluxes to fatty acid biosynthesis in yeast, specifically to enhance the supply of precursors, eliminate competing pathways, and bypass the host regulatory network. This review will focus on the genetic manipulation of both structural and regulatory genes in each step for fatty acids overproduction in S. cerevisiae, including from sugar to acetyl-CoA, from acetyl-CoA to malonyl-CoA, and from malonyl-CoA to fatty acyl-CoAs. The downstream pathways for the conversion of fatty acyl-CoAs to the desired products will also be discussed. PMID:25306882
Bioactive Terpenes from Marine-Derived Fungi
Elissawy, Ahmed M.; El-Shazly, Mohamed; Ebada, Sherif S.; Singab, AbdelNasser B.; Proksch, Peter
Marine-derived fungi continue to be a prolific source of secondary metabolites showing diverse bioactivities. Terpenoids from marine-derived fungi exhibit wide structural diversity including numerous compounds with pronounced biological activities. In this review, we survey the last five years' reports on terpenoidal metabolites from marine-derived fungi with particular attention on those showing marked biological activities. PMID:25854644
Nanodiamonds coupled with 5,7-dimethoxycoumarin, a plant bioactive metabolite, interfere with the mitotic process in B16F10 cells altering the actin organization
Gismondi, Angelo; Nanni, Valentina; Reina, Giacomo; Orlanducci, Silvia; Terranova, Maria Letizia; Canini, Antonella
For the first time, we coupled reduced detonation nanodiamonds (NDs) with a plant secondary metabolite, citropten (5,7-dimethoxycoumarin), and demonstrated how this complex was able to reduce B16F10 tumor cell growth more effectively than treatment with the pure molecule. These results encouraged us to find out the specific mechanism underlying this phenomenon. Internalization kinetics and quantification of citropten in cells after treatment with its pure or ND-conjugated form were measured, and it was revealed that the coupling between NDs and citropten was essential for the biological properties of the complex. We showed that the adduct was not able to induce apoptosis, senescence, or differentiation, but it determined cell cycle arrest, morphological changes, and alteration of mRNA levels of the cytoskeletal-related genes. The identification of metaphasic nuclei and irregular disposition of β-actin in the cell cytoplasm supported the hypothesis that citropten conjugated with NDs showed antimitotic properties in B16F10 cells. This work can be considered a pioneering piece of research that could promote and support the biomedical use of plant drug-functionalized NDs in cancer therapy. PMID:26893562
Nanodiamonds coupled with 5,7-dimethoxycoumarin, a plant bioactive metabolite, interfere with the mitotic process in B16F10 cells altering the actin organization.
Gismondi, Angelo; Nanni, Valentina; Reina, Giacomo; Orlanducci, Silvia; Terranova, Maria Letizia; Canini, Antonella
For the first time, we coupled reduced detonation nanodiamonds (NDs) with a plant secondary metabolite, citropten (5,7-dimethoxycoumarin), and demonstrated how this complex was able to reduce B16F10 tumor cell growth more effectively than treatment with the pure molecule. These results encouraged us to find out the specific mechanism underlying this phenomenon. Internalization kinetics and quantification of citropten in cells after treatment with its pure or ND-conjugated form were measured, and it was revealed that the coupling between NDs and citropten was essential for the biological properties of the complex. We showed that the adduct was not able to induce apoptosis, senescence, or differentiation, but it determined cell cycle arrest, morphological changes, and alteration of mRNA levels of the cytoskeletal-related genes. The identification of metaphasic nuclei and irregular disposition of β-actin in the cell cytoplasm supported the hypothesis that citropten conjugated with NDs showed antimitotic properties in B16F10 cells. This work can be considered a pioneering piece of research that could promote and support the biomedical use of plant drug-functionalized NDs in cancer therapy. PMID:26893562
Bioactive secondary metabolites from Salix tetrasperma Roxb.
El-Shazly, Assem; El-Sayed, Afaf; Fikrey, Eman
Column chromatography of the light petroleum fraction from the methanolic extract of the stem bark of Salix tetrasperma Roxb. (Salicaceae) resulted in the isolation of beta-sitosterol acetate, friedelin, 3beta-friedelinol, beta-amyrin, beta-sitosterol, beta-sitosterol-O-glucoside in addition to palmitic acid. From the dichloromethane fraction of the leaves, catechol and tremulacin were isolated. Salicin and its derivatives tremuloidin and 2'-O-p-(E)-coumaroyl salicin were isolated from the ethyl acetate fraction of the leaves. The isolated compounds were identified by MS, and 1D NMR (1H and 13C) and 2D NMR (H-H COSY, HSQC, and HMBC) spectral analyses. The total methanolic extract exhibited significant anti-inflammatory activity (rat hind paw oedema). The extract with a content of 120 mg/kg body weight produced 52% inhibition equivalent to the standard diclofenac sodium (54% inhibition). The antioxidant (DPPH free radical scavenging) and analgesic activities, respectively, were also evaluated. PMID:23016273
Planctomycetes as Novel Source of Bioactive Molecules.
Graça, Ana P; Calisto, Rita; Lage, Olga M
Marine environments are a fruitful source of bioactive compounds some of which are the newest leading drugs in medicinal therapeutics. Of particular importance are organisms like sponges and macroalgae and their associated microbiome. Planctomycetes, abundant in macroalgae biofilms, are promising producers of bioactive compounds since they share characteristics, like large genomes and complex life cycles, with the most bioactive bacteria, the Actinobacteria. Furthermore, genome mining revealed the presence of secondary metabolite pathway genes or clusters in 13 analyzed Planctomycetes genomes. In order to assess the antimicrobial production of a large and diverse collection of Planctomycetes isolated from macroalgae from the Portuguese coast, molecular, and bioactivity assays were performed in 40 bacteria from several taxa. Two genes commonly associated with the production of bioactive compounds, nonribosomal peptide synthetases (NRPS), and polyketide synthases (PKS) genes were screened. Molecular analysis revealed that 95% of the planctomycetes potentially have one or both secondary bioactive genes; 85% amplified with PKS-I primers and 55% with NRPS primers. Some of the amplified genes were confirmed to be involved in secondary metabolite pathways. Using bioinformatic tools their biosynthetic pathways were predicted. The secondary metabolite genomic potential of strains LF1, UC8, and FC18 was assessed using in silico analysis of their genomes. Aqueous and organic extracts of the Planctomycetes were evaluated for their antimicrobial activity against an environmental Escherichia coli, E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633, and a clinical isolate of Candida albicans. The screening assays showed a high number of planctomycetes with bioactive extracts revealing antifungal (43%) and antibacterial (54%) activity against C. albicans and B. subtilis, respectively. Bioactivity was observed in
Planctomycetes as Novel Source of Bioactive Molecules
Graça, Ana P.; Calisto, Rita; Lage, Olga M.
Marine environments are a fruitful source of bioactive compounds some of which are the newest leading drugs in medicinal therapeutics. Of particular importance are organisms like sponges and macroalgae and their associated microbiome. Planctomycetes, abundant in macroalgae biofilms, are promising producers of bioactive compounds since they share characteristics, like large genomes and complex life cycles, with the most bioactive bacteria, the Actinobacteria. Furthermore, genome mining revealed the presence of secondary metabolite pathway genes or clusters in 13 analyzed Planctomycetes genomes. In order to assess the antimicrobial production of a large and diverse collection of Planctomycetes isolated from macroalgae from the Portuguese coast, molecular, and bioactivity assays were performed in 40 bacteria from several taxa. Two genes commonly associated with the production of bioactive compounds, nonribosomal peptide synthetases (NRPS), and polyketide synthases (PKS) genes were screened. Molecular analysis revealed that 95% of the planctomycetes potentially have one or both secondary bioactive genes; 85% amplified with PKS-I primers and 55% with NRPS primers. Some of the amplified genes were confirmed to be involved in secondary metabolite pathways. Using bioinformatic tools their biosynthetic pathways were predicted. The secondary metabolite genomic potential of strains LF1, UC8, and FC18 was assessed using in silico analysis of their genomes. Aqueous and organic extracts of the Planctomycetes were evaluated for their antimicrobial activity against an environmental Escherichia coli, E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633, and a clinical isolate of Candida albicans. The screening assays showed a high number of planctomycetes with bioactive extracts revealing antifungal (43%) and antibacterial (54%) activity against C. albicans and B. subtilis, respectively. Bioactivity was observed in
Deleterious effects of reactive metabolites
A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected toxicities that become apparent only after the launch of new drug entities. Circumstantial evidence suggests that, in most cases, reactive metabolites are responsible for these unexpected toxicities. In this review, a general overview of the types of reactive metabolites and the consequences of their formation are presented. The current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these procedures will be discussed. Reasonable reasons for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development. This will, in turn, help us to design and bring safer drugs to the market. PMID:20972370
Bioactive alkaloids in vertically transmitted fungal endophytes
Technology Transfer Automated Retrieval System (TEKTRAN)
Plants form mutualistic symbioses with a variety of microorganisms, including endophytic fungi that live inside the plant and cause no symptoms of infection. Some endophytic fungi form defensive mutualisms based on the production of bioactive metabolites that protect the plant from herbivores in exc...
Metabolites of arachidonic acid ("eicosanoids") and platelet activating factor are important bioactive lipids that may be involved in the pathobiological alterations in animals induced by pollutant exposure. nalysis of these substances in biological tissue and fluids is important...
Amphiregulin co-operates with bone morphogenetic protein 15 to increase bovine oocyte developmental competence: effects on gap junction-mediated metabolite supply.
Sugimura, Satoshi; Ritter, Lesley J; Sutton-McDowall, Melanie L; Mottershead, David G; Thompson, Jeremy G; Gilchrist, Robert B
This study assessed the participation of amphiregulin (AREG) and bone morphogenetic protein 15 (BMP15) during maturation of bovine cumulus-oocyte complexes (COCs) on cumulus cell function and their impact on subsequent embryo development. AREG treatment of COCs enhanced blastocyst formation and quality only when in the presence of BMP15. Expression of hyaluronan synthase 2 was enhanced by follicle-stimulating hormone (FSH) but not by AREG, which was reflected in the level of cumulus expansion. Although both FSH and AREG stimulated glycolysis, AREG-treated COCs had higher glucose consumption, lactate production and ratio of lactate production to glucose uptake. Autofluorescence levels in oocytes, indicative of NAD(P)H and FAD(++), were increased with combined AREG and BMP15 treatment of COCs. In contrast, these treatments did not alter autofluorescence levels when cumulus cells were removed from oocytes, even in the presence of other COCs, suggesting that oocyte-cumulus gap-junctional communication (GJC) is required. FSH contributed to maintaining GJC for an extended period of time. Remarkably, BMP15 was equally effective at maintaining GJC even in the presence of AREG. Hence, AREG stimulation of COC glycolysis and BMP15 preservation of GJC may facilitate efficient transfer of metabolites from cumulus cells to the oocyte thereby enhancing oocyte developmental competence. These results have implications for improving in vitro oocyte maturation systems. PMID:24557840
Analyzing cranberry bioactive compounds.
Côté, J; Caillet, S; Doyon, G; Sylvain, J-F; Lacroix, M
There is a growing public interest for the North American cranberry (Vaccinium macrocarpon) as a functional food because of the potential health benefits linked to phytochemical compounds present in the fruit--the anthocyanin pigments, responsible for its brilliant red color, and other secondary plant metabolites (flavonols, flavan-3-ols, proanthocyanidins, and phenolic acid derivatives). Isolation of these phenolic compounds and flavonoids from a sample matrix is a prerequisite to any comprehensive analysis scheme. By far the most widely employed analytical technique for the characterization of these compounds has been high-performance liquid chromatography(HPLC) coupled with ultraviolet-visible(UV/Vis) and mass spectrometer(MS) detection. This review covers the cranberry major bioactive compounds, the extraction and purification methods, and the analytical conditions for HPLC used to characterize them. Extraction, chromatographic separation and detection strategies, analyte determinations, and applications in HPLC are discussed and the information regarding methods of specific cranberry analyte analyses has been summarized in tabular form to provide a means of rapid access to information pertinent to the reader. PMID:20924868
A Simple Approach for Obtaining High Resolution, High Sensitivity ¹H NMR Metabolite Spectra of Biofluids with Limited Mass Supply
Hu, Jian Zhi; Rommereim, Donald N.; Wind, Robert A.; Minard, Kevin R.; Sears, Jesse A.
A simple approach is reported that yields high resolution, high sensitivity ¹H NMR spectra of biofluids with limited mass supply. This is achieved by spinning a capillary sample tube containing a biofluid at the magic angle at a frequency of about 80Hz. A 2D pulse sequence called ¹H PASS is then used to produce a high-resolution ¹H NMR spectrum that is free from magnetic susceptibility induced line broadening. With this new approach a high resolution ¹H NMR spectrum of biofluids with a volume less than 1.0 µl can be easily achieved at a magnetic field strength as low as 7.05T. Furthermore, the methodology facilitates easy sample handling, i.e., the samples can be directly collected into inexpensive and disposable capillary tubes at the site of collection and subsequently used for NMR measurements. In addition, slow magic angle spinning improves magnetic field shimming and is especially suitable for high throughput investigations. In this paper first results are shown obtained in a magnetic field of 7.05T on urine samples collected from mice using a modified commercial NMR probe.
Identification of Epoxide-Derived Metabolite(s) of Benzbromarone.
Wang, Kai; Wang, Hui; Peng, Ying; Zheng, Jiang
Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR. PMID:26792818
Bioactivation of myelotoxic xenobiotics by human neutrophil myeloperoxidase
Roy, R.R.
Many environmental pollutants and drugs are toxic to the bone marrow. Some of these xenobiotics may initiate toxicity after undergoing bioactivation to free radicals and/or other reactive electrophiles. Peroxidases are a group of enzymes that catalyze the one-electron oxidative bioactivation of a variety of xenobiotics in vitro. Myeloperoxidase (MPO) is a peroxidative enzyme found in very high concentration in the neutrophils of human bone marrow. In this study, human MPO was evaluated to determine its ability to catalyze the in vitro bioactivation of known bone marrow toxicants that contain the aromatic hydroxyl (Ar-OH), aromatic amine (Ar-N-R{sub 2}), or heterocyclic tertiary amine ({double bond}N-R) moieties. The formation of free radical metabolites during the MPO-catalyzed bioactivation of hydroquinone and catechol (benzene metabolites), mitoxantrone and ametantrone (antitumor drugs), and chlorpromazine and promazine (antipsychotic drugs) was demonstrated by EPR spectroscopy. The reactivity of the products formed during the MPO catalyzed bioactivation of ({sup 14}C)hydroquinone and ({sup 14}C)catechol was shown by their covalent binding to protein and DNA in vitro. The covalently binding metabolite in each case is postulated to be the quinone form of the xenobiotic. In addition, both GSH and NADH were oxidized by the reactive intermediate(s) formed during the MPO-catalyzed bioactivation of many of the bone marrow toxicants tested. It was also shown that p,p-biphenol stimulated the MPO catalyzed bioactivation of both hydroquinone and catechol, while p-cresol stimulated the MPO-catalyzed bioactivation of catechol.
Immense Essence of Excellence: Marine Microbial Bioactive Compounds
Bhatnagar, Ira; Kim, Se-Kwon
Oceans have borne most of the biological activities on our planet. A number of biologically active compounds with varying degrees of action, such as anti-tumor, anti-cancer, anti-microtubule, anti-proliferative, cytotoxic, photo protective, as well as antibiotic and antifouling properties, have been isolated to date from marine sources. The marine environment also represents a largely unexplored source for isolation of new microbes (bacteria, fungi, actinomycetes, microalgae-cyanobacteria and diatoms) that are potent producers of bioactive secondary metabolites. Extensive research has been done to unveil the bioactive potential of marine microbes (free living and symbiotic) and the results are amazingly diverse and productive. Some of these bioactive secondary metabolites of microbial origin with strong antibacterial and antifungal activities are being intensely used as antibiotics and may be effective against infectious diseases such as HIV, conditions of multiple bacterial infections (penicillin, cephalosporines, streptomycin, and vancomycin) or neuropsychiatric sequelae. Research is also being conducted on the general aspects of biophysical and biochemical properties, chemical structures and biotechnological applications of the bioactive substances derived from marine microorganisms, and their potential use as cosmeceuticals and nutraceuticals. This review is an attempt to consolidate the latest studies and critical research in this field, and to showcase the immense competence of marine microbial flora as bioactive metabolite producers. In addition, the present review addresses some effective and novel approaches of procuring marine microbial compounds utilizing the latest screening strategies of drug discovery. PMID:21116414
Immense essence of excellence: marine microbial bioactive compounds.
Bhatnagar, Ira; Kim, Se-Kwon
Oceans have borne most of the biological activities on our planet. A number of biologically active compounds with varying degrees of action, such as anti-tumor, anti-cancer, anti-microtubule, anti-proliferative, cytotoxic, photo protective, as well as antibiotic and antifouling properties, have been isolated to date from marine sources. The marine environment also represents a largely unexplored source for isolation of new microbes (bacteria, fungi, actinomycetes, microalgae-cyanobacteria and diatoms) that are potent producers of bioactive secondary metabolites. Extensive research has been done to unveil the bioactive potential of marine microbes (free living and symbiotic) and the results are amazingly diverse and productive. Some of these bioactive secondary metabolites of microbial origin with strong antibacterial and antifungal activities are being intensely used as antibiotics and may be effective against infectious diseases such as HIV, conditions of multiple bacterial infections (penicillin, cephalosporines, streptomycin, and vancomycin) or neuropsychiatric sequelae. Research is also being conducted on the general aspects of biophysical and biochemical properties, chemical structures and biotechnological applications of the bioactive substances derived from marine microorganisms, and their potential use as cosmeceuticals and nutraceuticals. This review is an attempt to consolidate the latest studies and critical research in this field, and to showcase the immense competence of marine microbial flora as bioactive metabolite producers. In addition, the present review addresses some effective and novel approaches of procuring marine microbial compounds utilizing the latest screening strategies of drug discovery. PMID:21116414
Metabolomic screening and identification of bioactivation pathways of ritonavir
Li, Feng; Lu, Jie; Ma, Xiaochao
Ritonavir-boosted protease inhibitor regimens are widely used for HIV chemotherapy. However, ritonavir causes multiple side effects, and the mechanisms are not fully understood. The current study was designed to explore the metabolic pathways of ritonavir that may be related to its toxicity. Metabolomic analysis screened out 26 ritonavir metabolites in mice, and half of them are novel. These novel ritonavir metabolites include two glycine conjugated, two N-acetylcysteine conjugated and three ring-open products. Accompanied with the generation of ritonavir ring-open metabolites, the formation of methanethioamide and 2-methylpropanethioamide were expected. Based upon the structures of these novel metabolites, five bioactivation pathways are proposed, which may be associated with sulfation and epoxidation. By using Cyp3a-null mice, we confirmed that CYP3A is involved in four pathways of RTV bioactivation. In addition, all these five bioactivation pathways were recapitulated in the incubation of ritonavir in human liver microsomes. Further studies are suggested to determine the role of CYP3A and these bioactivation pathways in ritonavir toxicity. PMID:22040299
Pinaud, Fabien; King, David; Weiss, Shimon
Particles are bioactivated by attaching bioactivation peptides to the particle surface. The bioactivation peptides are peptide-based compounds that impart one or more biologically important functions to the particles. Each bioactivation peptide includes a molecular or surface recognition part that binds with the surface of the particle and one or more functional parts. The surface recognition part includes an amino-end and a carboxy-end and is composed of one or more hydrophobic spacers and one or more binding clusters. The functional part(s) is attached to the surface recognition part at the amino-end and/or said carboxy-end.
Construction of a metagenomic DNA library of sponge symbionts and screening of antibacterial metabolites
NASA Astrophysics Data System (ADS)
Chen, Juan; Zhu, Tianjiao; Li, Dehai; Cui, Chengbin; Fang, Yuchun; Liu, Hongbing; Liu, Peipei; Gu, Qianqun; Zhu, Weiming
To study the bioactive metabolites produced by sponge-derived uncultured symbionts, a metagenomic DNA library of the symbionts of sponge Gelliodes gracilis was constructed. The average size of DNA inserts in the library was 20 kb. This library was screened for antibiotic activity using paper dise assaying. Two clones displayed the antibacterial activity against Micrococcus tetragenus. The metabolites of these two clones were analyzed through HPLC. The result showed that their metabolites were quite different from those of the host E. coli DH5α and the host containing vector pHZ132. This study may present a new approach to exploring bioactive metabolites of sponge symbionts.
Biologically Active Metabolites Synthesized by Microalgae
de Morais, Michele Greque; Vaz, Bruna da Silva; de Morais, Etiele Greque; Costa, Jorge Alberto Vieira
Microalgae are microorganisms that have different morphological, physiological, and genetic traits that confer the ability to produce different biologically active metabolites. Microalgal biotechnology has become a subject of study for various fields, due to the varied bioproducts that can be obtained from these microorganisms. When microalgal cultivation processes are better understood, microalgae can become an environmentally friendly and economically viable source of compounds of interest, because production can be optimized in a controlled culture. The bioactive compounds derived from microalgae have anti-inflammatory, antimicrobial, and antioxidant activities, among others. Furthermore, these microorganisms have the ability to promote health and reduce the risk of the development of degenerative diseases. In this context, the aim of this review is to discuss bioactive metabolites produced by microalgae for possible applications in the life sciences. PMID:26339647
Rowan, Daryl D.
Volatile organic compounds (volatiles) comprise a chemically diverse class of low molecular weight organic compounds having an appreciable vapor pressure under ambient conditions. Volatiles produced by plants attract pollinators and seed dispersers, and provide defense against pests and pathogens. For insects, volatiles may act as pheromones directing social behavior or as cues for finding hosts or prey. For humans, volatiles are important as flavorants and as possible disease biomarkers. The marine environment is also a major source of halogenated and sulfur-containing volatiles which participate in the global cycling of these elements. While volatile analysis commonly measures a rather restricted set of analytes, the diverse and extreme physical properties of volatiles provide unique analytical challenges. Volatiles constitute only a small proportion of the total number of metabolites produced by living organisms, however, because of their roles as signaling molecules (semiochemicals) both within and between organisms, accurately measuring and determining the roles of these compounds is crucial to an integrated understanding of living systems. This review summarizes recent developments in volatile research from a metabolomics perspective with a focus on the role of recent technical innovation in developing new areas of volatile research and expanding the range of ecological interactions which may be mediated by volatile organic metabolites. PMID:24957243
Bioactive Compounds from Marine Bacteria and Fungi
Debbab, Abdessamad; Aly, Amal H.; Lin, Wen H.; Proksch, Peter
Summary Marine bacteria and fungi are of considerable importance as new promising sources of a huge number of biologically active products. Some of these marine species live in a stressful habitat, under cold, lightless and high pressure conditions. Surprisingly, a large number of species with high diversity survive under such conditions and produce fascinating and structurally complex natural products. Up till now, only a small number of microorganisms have been investigated for bioactive metabolites, yet a huge number of active substances with some of them featuring unique structural skeletons have been isolated. This review covers new biologically active natural products published recently (2007–09) and highlights the chemical potential of marine microorganisms, with focus on bioactive products as well as on their mechanisms of action. PMID:21255352
Littoral lichens as a novel source of potentially bioactive Actinobacteria
Parrot, Delphine; Antony-Babu, Sanjay; Intertaglia, Laurent; Grube, Martin; Tomasi, Sophie; Suzuki, Marcelino T.
Cultivable Actinobacteria are the largest source of microbially derived bioactive molecules. The high demand for novel antibiotics highlights the need for exploring novel sources of these bacteria. Microbial symbioses with sessile macro-organisms, known to contain bioactive compounds likely of bacterial origin, represent an interesting and underexplored source of Actinobacteria. We studied the diversity and potential for bioactive-metabolite production of Actinobacteria associated with two marine lichens (Lichina confinis and L. pygmaea; from intertidal and subtidal zones) and one littoral lichen (Roccella fuciformis; from supratidal zone) from the Brittany coast (France), as well as the terrestrial lichen Collema auriforme (from a riparian zone, Austria). A total of 247 bacterial strains were isolated using two selective media. Isolates were identified and clustered into 101 OTUs (98% identity) including 51 actinobacterial OTUs. The actinobacterial families observed were: Brevibacteriaceae, Cellulomonadaceae, Gordoniaceae, Micrococcaceae, Mycobacteriaceae, Nocardioidaceae, Promicromonosporaceae, Pseudonocardiaceae, Sanguibacteraceae and Streptomycetaceae. Interestingly, the diversity was most influenced by the selective media rather than lichen species or the level of lichen thallus association. The potential for bioactive-metabolite biosynthesis of the isolates was confirmed by screening genes coding for polyketide synthases types I and II. These results show that littoral lichens are a source of diverse potentially bioactive Actinobacteria. PMID:26514347
Littoral lichens as a novel source of potentially bioactive Actinobacteria.
Parrot, Delphine; Antony-Babu, Sanjay; Intertaglia, Laurent; Grube, Martin; Tomasi, Sophie; Suzuki, Marcelino T
Cultivable Actinobacteria are the largest source of microbially derived bioactive molecules. The high demand for novel antibiotics highlights the need for exploring novel sources of these bacteria. Microbial symbioses with sessile macro-organisms, known to contain bioactive compounds likely of bacterial origin, represent an interesting and underexplored source of Actinobacteria. We studied the diversity and potential for bioactive-metabolite production of Actinobacteria associated with two marine lichens (Lichina confinis and L. pygmaea; from intertidal and subtidal zones) and one littoral lichen (Roccella fuciformis; from supratidal zone) from the Brittany coast (France), as well as the terrestrial lichen Collema auriforme (from a riparian zone, Austria). A total of 247 bacterial strains were isolated using two selective media. Isolates were identified and clustered into 101 OTUs (98% identity) including 51 actinobacterial OTUs. The actinobacterial families observed were: Brevibacteriaceae, Cellulomonadaceae, Gordoniaceae, Micrococcaceae, Mycobacteriaceae, Nocardioidaceae, Promicromonosporaceae, Pseudonocardiaceae, Sanguibacteraceae and Streptomycetaceae. Interestingly, the diversity was most influenced by the selective media rather than lichen species or the level of lichen thallus association. The potential for bioactive-metabolite biosynthesis of the isolates was confirmed by screening genes coding for polyketide synthases types I and II. These results show that littoral lichens are a source of diverse potentially bioactive Actinobacteria. PMID:26514347
Effect of viroid infection on the dynamics of phenolic metabolites in the apoplast of tomato
Technology Transfer Automated Retrieval System (TEKTRAN)
Plants are capable of producing a wide array of secondary metabolites which serve many functions, due to their bioactive, redox or structural properties. Subtle changes in the external or internal environment can cause significant changes in the array of secondary metabolites presented in the tissu...
Using Molecular Networking for Microbial Secondary Metabolite Bioprospecting
Purves, Kevin; Macintyre, Lynsey; Brennan, Debra; Hreggviðsson, Guðmundur Ó.; Kuttner, Eva; Ásgeirsdóttir, Margrét E.; Young, Louise C.; Green, David H.; Edrada-Ebel, Ruangelie; Duncan, Katherine R.
The oceans represent an understudied resource for the isolation of bacteria with the potential to produce novel secondary metabolites. In particular, actinomyces are well known to produce chemically diverse metabolites with a wide range of biological activities. This study characterised spore-forming bacteria from both Scottish and Antarctic sediments to assess the influence of isolation location on secondary metabolite production. Due to the selective isolation method used, all 85 isolates belonged to the phyla Firmicutes and Actinobacteria, with the majority of isolates belonging to the genera Bacillus and Streptomyces. Based on morphology, thirty-eight isolates were chosen for chemical investigation. Molecular networking based on chemical profiles (HR-MS/MS) of fermentation extracts was used to compare complex metabolite extracts. The results revealed 40% and 42% of parent ions were produced by Antarctic and Scottish isolated bacteria, respectively, and only 8% of networked metabolites were shared between these locations, implying a high degree of biogeographic influence upon secondary metabolite production. The resulting molecular network contained over 3500 parent ions with a mass range of m/z 149–2558 illustrating the wealth of metabolites produced. Furthermore, seven fermentation extracts showed bioactivity against epithelial colon adenocarcinoma cells, demonstrating the potential for the discovery of novel bioactive compounds from these understudied locations. PMID:26761036
Bioactive metabolites from the mycelia of the basidiomycete Hericium erinaceum.
Lu, Qiang-Qiang; Tian, Jun-Mian; Wei, Jing; Gao, Jin-Ming
Seven known compounds, three diketopiperazine alkaloids, 12β-hydroxyverruculogen TR-2 (1), fumitremorgin C (2) and methylthiogliotoxin (5), two hetero-spirocyclic γ-lactam alkaloids, pseurotin A (3) and FD-838 (4), and cerevisterol (6) and herierin IV (7), were isolated from the mycelia of the basidiomycete Hericium erinaceum and identified by spectroscopic analyses. The antioxidant and antifungal activities of compounds 1-6 were evaluated. The results indicated that compounds 1, 3 and 6 exhibited potential antioxidant activity against DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical with their IC50 data of ca. 12 μM, compared with positive control tertiary butylhydroquinone. In addition, compound 4 significantly inhibited the growth of two plant fungal pathogens Botrytis cinerea and Glomerella cingulata with an minimum inhibitory concentration of 6.25 μM for each, similar to that of the positive fungicide, carbendazim. Compounds 1-5 were isolated from the genus Hericium for the first time. PMID:24635196
Phenolic plant metabolites as bioactive food and feed additives
Technology Transfer Automated Retrieval System (TEKTRAN)
Functional additives in food and animal feed formulations are gaining acceptance as consumers and producers recognize the health benefits associated with certain natural plant products. Phenolic compounds in particular have emerged as a class of compounds with antioxidant, antibacterial, and antifun...
Isothiocyanates: a class of bioactive metabolites with chemopreventive potential.
Kumar, Gaurav; Tuli, Hardeep Singh; Mittal, Sonam; Shandilya, Jitendra Kumar; Tiwari, Anil; Sandhu, Sardul Singh
In recent years, growing interest has been focused on the field of chemoprevention using natural therapies. The reason to turn toward "natural" remedies is associated with diverse beneficial pharmacological properties of natural compounds. Isothiocyanates (ITCs), the major pharmacological active constituents of cruciferous vegetables, are derived from the enzymatic hydrolysis of glucosinolates (GSLs). ITCs govern many intracellular targets including cytochrome P 450 (CYP) enzymes, proteins involved in antioxidant response, tumorigenesis, apoptosis, cell cycle, and metastasis. Investigation of the mechanisms of anti-cancer drugs has given important information regarding the use of natural chemopreventive compounds. This extensive review covers various molecular aspects of the interactions of ITCs with their recognized cellular targets involved in cancer treatment in order to enhance anti-tumor outcome with decreased toxicity to patients. PMID:25835976
Triterpenoidal saponins: bioactive secondary metabolites from Zygophyllum coccineum L
Technology Transfer Automated Retrieval System (TEKTRAN)
Phytochemical investigation of the aerial parts of Zygophyllum coccineum L., led to the isolation of nine ursane-type triterpene saponins (1-9) including one new: zygophylloside S (1), together with known flavonoid glycoside (10), and sterol glycoside (11). The isolated compounds were tested for ant...
Bioactive benzopyrone derivatives from new recombinant fusant of marine Streptomyces.
El-Gendy, Mervat M A; Shaaban, M; El-Bondkly, A M; Shaaban, K A
In our searching program for bioactive secondary metabolites from marine Streptomycetes, three microbial benzopyrone derivatives (1-3), 7-methylcoumarin (1) and two flavonoides, rhamnazin (2) and cirsimaritin (3), were obtained during the working up of the ethyl acetate fraction of a marine Streptomyces fusant obtained from protoplast fusion between Streptomyces strains Merv 1996 and Merv 7409. The structures of the three compounds (1-3) were established by nuclear magnetic resonance, mass, UV spectra, and by comparison with literature data. Marine Streptomyces strains were identified based on their phenotypic and chemotypic characteristics as two different bioactive strains of the genus Streptomyces. We described here the fermentation, isolation, as well as the biological activity of these bioactive compounds. The isolated compounds (1-3) are reported here as microbial products for the first time. PMID:18551256
Chemical constituents and bioactivities of Clinacanthus nutans aerial parts.
Tu, Shu-Fen; Liu, Rosa Huang; Cheng, Yuan-Bin; Hsu, Yu-Ming; Du, Ying-Chi; El-Shazly, Mohamed; Wu, Yang-Chang; Chang, Fang-Rong
Four new sulfur-containing compounds, named clinamides A-C (1-3), and 2-cis-entadamide A (4), were isolated together with three known compounds from the bioactive ethanol extract of the aerial parts of Clinacanthus nutans. These secondary metabolites possess sulfur atoms and acrylamide functionalities. The structures of the isolated components were established by interpretation of their spectroscopic data, especially 1D and 2D NMR. PMID:25490430
Electrostatic Control of Bioactivity
Goldberger, Joshua E.; Berns, Eric J.; Bitton, Ronit; Newcomb, Christina J.; Stupp, Samuel I.
The power of independence: When exhibited on the surface of self-assembling peptide-amphiphile nanofibers, the hydrophobic laminin-derived IKVAV epitope induced nanofiber bundling through interdigitation with neighboring fibers and thus decreased the bioactivity of the resulting materials. The inclusion of charged amino acids in the peptide amphiphiles disrupted the tendency to bundle and led to significantly enhanced neurite outgrowth.
Technology Transfer Automated Retrieval System (TEKTRAN)
Many oxygenated fatty acids are bioactive compounds. Nocardia cholesterolicum and Flavobacterium DS5 convert oleic acid to 10 hydroxy stearic acid and linoleic acid to 10-hydroxy-12(Z)-octadecanoic acid. Pseudomonas aeruginosa PR3 converts oleic acid to the new compounds, 7,10-dihydroxy-8(E)-octad...
Technology Transfer Automated Retrieval System (TEKTRAN)
Many oxygenated fatty acids are bioactive compounds. Nocardia cholesterolicum and Flavobacterium DS5 convert oleic acid to 10 hydroxy stearic acid and linoleic acid to 10-hydroxy-12(Z)-octadecanoic acid. Pseudomonas aeruginosa PR3 converts oleic acid to the new compounds, 7,10-dihydroxy-8(E)-octad...
Technology Transfer Automated Retrieval System (TEKTRAN)
Many oxygenated fatty acids are bioactive compounds. Nocardia cholesterolicum and Flavobacterium DS5 convert oleic acid to 10 hydroxy stearic acid and linoleic acid to 10-hydroxy-12(Z)-octadecanoic acid. Pseudomonas aeruginosa PR3 converts oleic acid to new compounds, 7,10-dihydroxy-8(E)-octadecen...
Bioactivity of degradable polymer sutures coated with bioactive glass.
Bretcanu, Oana; Verné, Enrica; Borello, Luisa; Boccaccini, Aldo R
Novel bioactive materials have been prepared by coating violet resorbable Vicryl sutures with a bioactive glass powder derived from a co-precipitation method. Two techniques have been chosen for the composite preparation: pressing the sutures in a bed of glass powder and slurry-dipping of sutures in liquid suspensions of bioactive glass powders. The uniformity and thickness of the coatings obtained by the two methods were compared. The bioactivity of the sutures with and without bioactive glass coating was tested by soaking in an inorganic acellular simulated body fluid (SBF). The composite sutures were characterised by XRD, SEM and FTIR analyses before and after soaking in SBF solution to assess the formation of hydroxyapatite on their surfaces, which is a qualitative measure of their bioactivity. The possible use of bioactive sutures to produce tissue engineering scaffolds and as reinforcement of resorbable calcium phosphates is discussed. PMID:15477741
NASA Astrophysics Data System (ADS)
Zhang, Kai
Bioactive materials chemically bond to tissues through the development of biologically active apatite. Porous structures in biomaterials are designed to enhance bioactivity, grow artificial tissues and achieve better integration with host tissues in the body. The goal of this research is to design, fabricate and characterize novel porous bioactive materials. 3D ordered macroporous bioactive glasses (3DOM-BGs, pore size: 200--1000 nm) were prepared using a sol-gel process and colloidal crystal templates. 3DOM-BGs are more bioactive and degradable than mesoporous (pore size <50 nm) sol-gel BGs in simulated body fluid (SBF). Apatite formation and 3DOM-BG degradation rates increased with the decrease of soaking ratio. Apatite induction time in SBF increased with 3DOM-BG calcination temperature (600--800°C). Apatite formation and 3DOMBG degradation were slightly enhanced for a phosphate containing composition. Large 3DOM-BG particles formed less apatite and degraded less completely as compared with small particles. An increase in macropore size slowed down 3DOM-BG degradation and apatite formation processes. After heating the converted apatite at a temperature higher than 700°C, highly crystalline hydroxyapatite and a minor tri-calcium phosphate phase formed. 3DOM-BGs have potential applications as bone/periodontal fillers, and drugs and biological factors delivery agents. Anchoring artificial soft tissues (e.g., cartilage) to native bone presents a challenge. Porous polymer/bioactive glass composites are candidate materials for engineering artificial soft tissue/bone interfaces. Porous composites consisting of polymer matrices (e.g., polysulfone, polylactide, and polyurethane) and bioactive glass particles were prepared by polymer phase separation techniques adapted to include ceramic particles. Composites (thickness: 200--500 mum) have asymmetric structures with dense top layers and porous structures beneath. Porous structures consist of large pores (>100 mum) in a
Non-nutrient bioactive substances of pulses.
Champ, Martine M-J
Pulses supply many bioactive substances found in minor amounts in food, but which may have significant metabolic and/or physiological effects. These compounds have long been classified as antinutritional factors, but many studies have reconsidered their impact on health. Some could play a role in the prevention of the major diseases of affluent societies. As these compounds can be beneficial or adverse, depending on conditions, an assessment of their various physiological effects is necessary to determine whether they should be preserved or eliminated in each main nutritional situation. PMID:12498631
Complete genome sequence of Streptomyces venezuelae ATCC 15439, a promising cell factory for production of secondary metabolites.
Song, Ju Yeon; Yoo, Young Ji; Lim, Si-Kyu; Cha, Sun Ho; Kim, Ji-Eun; Roe, Jung-Hye; Kim, Jihyun F; Yoon, Yeo Joon
Streptomyces venezuelae ATCC 15439, which produces 12- and 14-membered ring macrolide antibiotics, is a platform strain for heterologous expression of secondary metabolites. Its 9.05-Mb genome sequence revealed an abundance of genes involved in the biosynthesis of secondary metabolites and their precursors, which should be useful for the production of bioactive compounds. PMID:26718561
Mechanisms of Nitrite Bioactivation
Kim-Shapiro, Daniel B.; Gladwin, Mark T.
It is now accepted that the anion nitrite, once considered an inert oxidation product of nitric oxide (NO), contributes to hypoxic vasodilation, physiological blood pressure control, and redox signaling. As such, its application in therapeutics is being actively testing in pre-clinical models and in human phase I–II clinical trials. Major pathways for nitrite bioactivation involve its reduction to NO by members of the hemoglobin or molybdopterin family of proteins, or catalyzed dysproportionation. These conversions occur preferentially under hypoxic and acidic conditions. A number of enzymatic systems reduce nitrite to NO and their activity and importance are defined by oxygen tension, specific organ system and allosteric and redox effectors. In this work, we review different proposed mechanisms of nitrite bioactivation, focusing on analysis of kinetics and experimental evidence for the relevance of each mechanism under different conditions. PMID:24315961
Bioactive glass in tissue engineering
Rahaman, Mohamed N.; Day, Delbert E.; Bal, B. Sonny; Fu, Qiang; Jung, Steven B.; Bonewald, Lynda F.; Tomsia, Antoni P.
This review focuses on recent advances in the development and use of bioactive glass for tissue engineering applications. Despite its inherent brittleness, bioactive glass has several appealing characteristics as a scaffold material for bone tissue engineering. New bioactive glasses based on borate and borosilicate compositions have shown the ability to enhance new bone formation when compared to silicate bioactive glass. Borate-based bioactive glasses also have controllable degradation rates, so the degradation of the bioactive glass implant can be more closely matched to the rate of new bone formation. Bioactive glasses can be doped with trace quantities of elements such as Cu, Zn and Sr, which are known to be beneficial for healthy bone growth. In addition to the new bioactive glasses, recent advances in biomaterials processing have resulted in the creation of scaffold architectures with a range of mechanical properties suitable for the substitution of loaded as well as non-loaded bone. While bioactive glass has been extensively investigated for bone repair, there has been relatively little research on the application of bioactive glass to the repair of soft tissues. However, recent work has shown the ability of bioactive glass to promote angiogenesis, which is critical to numerous applications in tissue regeneration, such as neovascularization for bone regeneration and the healing of soft tissue wounds. Bioactive glass has also been shown to enhance neocartilage formation during in vitro culture of chondrocyte-seeded hydrogels, and to serve as a subchondral substrate for tissue-engineered osteochondral constructs. Methods used to manipulate the structure and performance of bioactive glass in these tissue engineering applications are analyzed. PMID:21421084
Enhanced production of phenazine-like metabolite produced by Streptomyces aurantiogriseus VSMGT1014 against rice pathogen, Rhizoctonia solani.
Harikrishnan, Hariharan; Shanmugaiah, Vellasamy; Nithya, Karmegham; Balasubramanian, Natesan; Sharma, Mahaveer P; Gachomo, Emma W; Kotchoni, Simeon O
The efficacy of a rhizobacterium Streptomyces aurantiogriseus VSMGT1014 for the production of bioactive metabolites with antifungal properties was evaluated under in vitro conditions. The production of bioactive metabolites by S. aurantiogriseus VSMGT1014 in International Streptomyces Project-2 (ISP-2) broth, supplemented with glucose and ammonium acetate was found to be the most suitable carbon and nitrogen sources for the maximum production of bioactive metabolites against rice pathogen, Rhizoctonia solani. The zone of inhibition range from 23.5 to 28.5 mm and 10.3 to 18.3 mm for glucose and ammonium acetate supplemented media, respectively. The culture filtrate of S. aurantiogriseus VSMGT1014 at pH 7.5, 37 °C at 120 rpm in 6 days of incubation showed the maximum production of bioactive metabolites with antagonistic potential. The crude metabolite was characterized by different spectral studies such as Ultraviolet spectrum, infrared-spectrum and based on the different analytical techniques, including thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) with the retention time 29.4 and the bioactive metabolite was identified as phenazine, which was confirmed by pure phenazine compound as positive control. PMID:26627705
ERIC Educational Resources Information Center
Marine Corps Inst., Washington, DC.
Developed as part of the Marine Corps Institute (MCI) correspondence training program, this course on supply management is designed to provide the supply chief with an understanding of the fundamental functions of supply management as it applies to a supply office. Introductory materials include specific information for MCI students, a course…
Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health.
Lv, Xinmiao; Zhao, Siyu; Ning, Zhangchi; Zeng, Honglian; Shu, Yisong; Tao, Ou; Xiao, Cheng; Lu, Cheng; Liu, Yuanyan
Citrus fruits, which are cultivated worldwide, have been recognized as some of the most high-consumption fruits in terms of energy, nutrients and health supplements. What is more, a number of these fruits have been used as traditional medicinal herbs to cure diseases in several Asian countries. Numerous studies have focused on Citrus secondary metabolites as well as bioactivities and have been intended to develop new chemotherapeutic or complementary medicine in recent decades. Citrus-derived secondary metabolites, including flavonoids, alkaloids, limonoids, coumarins, carotenoids, phenolic acids and essential oils, are of vital importance to human health due to their active properties. These characteristics include anti-oxidative, anti-inflammatory, anti-cancer, as well as cardiovascular protective effects, neuroprotective effects, etc. This review summarizes the global distribution and taxonomy, numerous secondary metabolites and bioactivities of Citrus fruits to provide a reference for further study. Flavonoids as characteristic bioactive metabolites in Citrus fruits are mainly introduced. PMID:26705419
An investigation of the bioactivation potential and metabolism profile of Zebrafish versus human.
Chng, Hui Ting; Ho, Han Kiat; Yap, Chun Wei; Lam, Siew Hong; Chan, Eric Chun Yong
The zebrafish model has been increasingly explored as an alternative model for toxicity screening of pharmaceutical drugs. However, little is understood about the bioactivation of drug to reactive metabolite and phase I and II metabolism of chemical in zebrafish as compared with human. The primary aim of our study was to establish the bioactivation potential of zebrafish using acetaminophen as a probe substrate. Our secondary aim was to perform metabolite profiling experiments on testosterone, a CYP3A probe substrate, in zebrafish and compare the metabolite profiles with that of human. The glutathione trapping assay of N-acetyl-p-benzoquinone imine demonstrated that zebrafish generates the same reactive metabolite as humans from the bioactivation of acetaminophen. Zebrafish possesses functional CYP3A4/5-like and UDP-glucuronosyltransferase metabolic activities on testosterone. Differential testosterone metabolism was observed among the two species. In silico docking studies suggested that the zebrafish CYP3A65 was responsible for the bioactivation of acetaminophen and phase I hydroxylation of testosterone. Our findings reinforce the need to further characterize the drug metabolism phenotype of zebrafish before the model can fully achieve its potential as an alternative toxicity screening model in drug research. PMID:22644267
Ursolic acid (UA): A metabolite with promising therapeutic potential.
Kashyap, Dharambir; Tuli, Hardeep Singh; Sharma, Anil K
Plants are known to produce a variety of bioactive metabolites which are being used to cure various life threatening and chronic diseases. The molecular mechanism of action of such bioactive molecules, may open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle dreadful diseases such as cancer and cardiovascular and neurodegenerative disorders. Ursolic acid (UA) is one among the categories of such plant-based therapeutic metabolites having multiple intracellular and extracellular targets that play role in apoptosis, metastasis, angiogenesis and inflammatory processes. Moreover, the synthetic derivatives of UA have also been seen to be involved in a range of pharmacological applications, which are associated with prevention of diseases. Evidences suggest that UA could be used as a potential candidate to develop a comprehensive competent strategy towards the treatment and prevention of health disorders. The review article herein describes the possible therapeutic effects of UA along with putative mechanism of action. PMID:26775565
Production of bioactive cyathane diterpenes by a bird's nest fungus Cyathus gansuensis growing on cooked rice.
Wang, Botao; Han, Junjie; Xu, Wei; Chen, Yuhui; Liu, Hongwei
Cyathane diterpenes are important bioactive substances produced by some edible and medicinal fungi. Seven new cyathane type diterpenes, named as cyathins J-P (1-7), together with two known diterpenes (8 and 9), were isolated from the solid culture of the bird's nest fungus Cyathus gansuensis growing on cooked rice. The structures of the new secondary metabolites were elucidated by NMR experiments. Bioactivity screening indicated that compounds 1, 2, 4, and 8 showed moderate inhibitory activity against NO production in lipopolysaccharide-activated macrophages with an IC50 value of 42, 78, 80, and 16 μM, respectively. The fungus C. gansuensis is a promising source of bioactive secondary metabolites and has application potential in preparing healthy food. PMID:24444922
Broad spectrum bioactive sunscreens.
Velasco, Maria Valéria Robles; Sarruf, Fernanda Daud; Salgado-Santos, Idalina Maria Nunes; Haroutiounian-Filho, Carlos Alberto; Kaneko, Telma Mary; Baby, André Rolim
The development of sunscreens containing reduced concentration of chemical UV filters, even though, possessing broad spectrum effectiveness with the use of natural raw materials that improve and infer UV absorption is of great interest. Due to the structural similarities between polyphenolic compounds and organic UV filters, they might exert photoprotection activity. The objective of the present research work was to develop bioactive sunscreen delivery systems containing rutin, Passiflora incarnata L. and Plantago lanceolata extracts associated or not with organic and inorganic UV filters. UV transmission of the sunscreen delivery system films was performed by using diffuse transmittance measurements coupling to an integrating sphere. In vitro photoprotection efficacy was evaluated according to the following parameters: estimated sun protection factor (SPF); Boot's Star Rating category; UVA/UVB ratio; and critical wavelength (lambda(c)). Sunscreen delivery systems obtained SPF values ranging from 0.972+/-0.004 to 28.064+/-2.429 and bioactive compounds interacted with the UV filters positive and negatively. This behavior may be attributed to: the composition of the delivery system; the presence of inorganic UV filter and quantitative composition of the organic UV filters; and the phytochemical composition of the P. incarnata L. and P. lanceolata extracts. Among all associations of bioactive compounds and UV filters, we found that the broad spectrum sunscreen was accomplished when 1.68% (w/w) P. incarnata L. dry extract was in the presence of 7.0% (w/w) ethylhexyl methoxycinnamate, 2.0% (w/w) benzophenone-3 and 2.0% (w/w) TiO(2). It was demonstrated that this association generated estimated SPF of 20.072+/-0.906 and it has improved the protective defense against UVA radiation accompanying augmentation of the UVA/UVB ratio from 0.49 to 0.52 and lambda(c) from 364 to 368.6nm. PMID:18662760
Bioactivity in Organic Chemistry Courses.
ERIC Educational Resources Information Center
Ferguson, Lloyd N.
Presented are three ways in which bioactivity of organic compounds has been introduced in organic chemistry courses. One is to point out a typical bioactivity of a given functional group. A second is to discuss biorganic mechanisms. A third is to draw structure-activity correlations (SAR). (Author/HM)
Bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant.
Bergström, Moa Andresen; Isin, Emre M; Castagnoli, Neal; Milne, Claire E
In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 because of a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins, and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3 position of the piperidinyl ring, and cleavage of the amide linkage. In coincubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol equivalents/mg protein). In coincubations with potassium cyanide and methoxylamine, the covalent binding was reduced by approximately 40 and 30%, respectively, whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time-dependent manner. In view of these findings, it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported. PMID:21733882
Tentative identification of new metabolites of epimedin C by liquid chromatography-mass spectrometry.
Liu, Minyan; Zhao, Shaohua; Wang, Zongquan; Wang, Hongtao; Shi, Xiaowei; Lü, Ziming; Xu, Honghui; Wang, Hairong; Du, Yingfeng; Zhang, Lantong
Epimedin C is one of the major bioactive constituents of Herba Epimedii. The aim of this study is to characterize and elucidate the structure of metabolites in the rat after administration of epimedin C. Metabolite identification was performed using a predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion (pMRM-IDA-EPI) scan in positive ion mode on a hybrid triple quadrupole-linear ion trap mass spectrometer. A total of 18 metabolites were characterized by the changes in their protonated molecular masses, their MS/MS spectrum and their retention times compared with those of the parent drug. The results reveal possible metabolite profiles of epimedin C in rats; the metabolic pathways including hydrolysis, hydroxylation, dehydrogenation, demethylation and conjugation with glucuronic acid and different sugars were observed. This study provides a practical approach for rapidly identifying complicated metabolites, a methodology that could be widely applied for the structural characterization of metabolites of other compounds. PMID:22012680
Reactive metabolites and agranulocytosis.
Uetrecht, J P
Central to most hypotheses of the mechanism of idiosyncratic drug-induced blood dyscrasias is the involvement of reactive metabolites. In view of the reactive nature of the majority of such metabolites, it is likely that they are formed by, or in close proximity to the blood cells affected. The major oxidative system of neutrophils generates hypochlorous acid. We have demonstrated that the drugs associated with the highest incidence of agranulocytosis are oxidized to reactive metabolites by hypochlorous acid and/or activated neutrophils. There are many mechanisms by which such reactive metabolites could induce agranulocytosis. In the case of aminopyrine-induced agranulocytosis, most cases appear to involve drug-dependent anti-neutrophil antibodies, and these are likely to be induced by cell membrane antigens modified by the reactive metabolite of aminopyrine. The target of agranulocytosis associated with many other drugs is usually neutrophil precursors and may involve cytotoxicity or a cell-mediated immune reaction induced by a reactive metabolite. In the case of aplastic anaemia, there is evidence in some cases for involvement of cytotoxic T cells, which could either be induced by metabolites generated by neutrophils, or more likely, by reactive metabolites generated by stem cells. PMID:8987247
Advances in metabolite identification.
Wishart, David S
One of the central challenges to metabolomics is metabolite identification. Regardless of whether one uses so-called 'targeted' or 'untargeted' metabolomics, eventually all paths lead to the requirement of identifying (and quantifying) certain key metabolites. Indeed, without metabolite identification, the results of any metabolomic analysis are biologically and chemically uninterpretable. Given the chemical diversity of most metabolomes and the character of most metabolomic data, metabolite identification is intrinsically difficult. Consequently a great deal of effort in metabolomics over the past decade has been focused on making metabolite identification better, faster and cheaper. This review describes some of the newly emerging techniques or technologies in metabolomics that are making metabolite identification easier and more robust. In particular, it focuses on advances in metabolite identification that have occurred over the past 2 to 3 years concerning the technologies, methodologies and software as applied to NMR, MS and separation science. The strengths and limitations of some of these approaches are discussed along with some of the important trends in metabolite identification. PMID:21827274
Study on bioactive compounds from Streptomyces sp. ANU 6277.
Narayana, Kolla J P; Prabhakar, Peddikotla; Vijayalakshmi, Muvva; Venkateswarlu, Yenamandra; Krishna, Palakodety S J
An attempt was made to study the bioactive compounds from a terrestrial Streptomyces sp. ANU 6277 isolated from laterite soil. Four active fractions were recovered from the solvent extracts obtained from the culture broth of five day-old strain. Three bioactive compounds were purified and identified as 3-phenylpropionic acid, anthracene-9,10-quinone and 8-hydroxyquinoline. The components of the partially purified fourth active fraction were analyzed by gas chromatography-mass spectrometry and identified as benzyl alcohol, phenylethyl alcohol and 2H-1, 4-benzoxazin-3 (4H)-one. Four active fractions were screened for antimicrobial activity against Gram-positive and Gram-negative bacteria, and fungi including phytopathogenic, toxigenic and dermatophytic genera. Among these metabolites, 8-hydroxyquinoline exhibited strong antibacterial and antifungal activity as compared to 3-phenylpropionic acid and anthracene-9,10-quinone. PMID:18610654
Marine microorganism-invertebrate assemblages: perspectives to solve the "supply problem" in the initial steps of drug discovery.
Leal, Miguel Costa; Sheridan, Christopher; Osinga, Ronald; Dionísio, Gisela; Rocha, Rui Jorge Miranda; Silva, Bruna; Rosa, Rui; Calado, Ricardo
The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the "blue gold" in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts. PMID:24983638
Marine Microorganism-Invertebrate Assemblages: Perspectives to Solve the "Supply Problem" in the Initial Steps of Drug Discovery
Leal, Miguel Costa; Sheridan, Christopher; Osinga, Ronald; Dionísio, Gisela; Rocha, Rui Jorge Miranda; Silva, Bruna; Rosa, Rui; Calado, Ricardo
The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the "blue gold" in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts. PMID:24983638
Bioactivity of Fungal Endophytes as a Function of Endophyte Taxonomy and the Taxonomy and Distribution of Their Host Plants
Higginbotham, Sarah J.; Arnold, A. Elizabeth; Ibañez, Alicia; Spadafora, Carmenza; Coley, Phyllis D.; Kursar, Thomas A.
Fungal endophytes – fungi that grow within plant tissues without causing immediate signs of disease – are abundant and diverse producers of bioactive secondary metabolites. Endophytes associated with leaves of tropical plants are an especially exciting and relatively untapped source of novel compounds. However, one major challenge in drug discovery lies in developing strategies to efficiently recover highly bioactive strains. As part of a 15-year drug discovery project, foliar endophytes were isolated from 3198 plant samples (51 orders, 105 families and at least 232 genera of angiosperms and ferns) collected in nine geographically distinct regions of Panama. Extracts from culture supernatants of >2700 isolates were tested for bioactivity (in vitro percent inhibition of growth, % IG) against a human breast cancer cell line (MCF-7) and the causative agents of malaria, leishmaniasis, and Chagas' disease. Overall, 32.7% of endophyte isolates were highly active in at least one bioassay, including representatives of diverse fungal lineages, host lineages, and collection sites. Up to 17% of isolates tested per assay were highly active. Most bioactive strains were active in only one assay. Fungal lineages differed in the incidence and degree of bioactivity, as did fungi from particular plant taxa, and greater bioactivity was observed in endophytes isolated from plants in cloud forests vs. lowland forests. Our results suggest that using host taxonomy and forest type to tailor plant collections, and selecting endophytes from specific orders or families for cultivation, will markedly increase the efficiency and efficacy of discovering bioactive metabolites for particular pharmaceutical targets. PMID:24066037
Bioactivities from Marine Algae of the Genus Gracilaria
de Almeida, Cynthia Layse F.; Falcão, Heloina de S.; Lima, Gedson R. de M.; Montenegro, Camila de A.; Lira, Narlize S.; de Athayde-Filho, Petrônio F.; Rodrigues, Luis C.; de Souza, Maria de Fátima V.; Barbosa-Filho, José M.; Batista, Leônia M.
Seaweeds are an important source of bioactive metabolites for the pharmaceutical industry in drug development. Many of these compounds are used to treat diseases like cancer, acquired immune-deficiency syndrome (AIDS), inflammation, pain, arthritis, as well as viral, bacterial, and fungal infections. This paper offers a survey of the literature for Gracilaria algae extracts with biological activity, and identifies avenues for future research. Nineteen species of this genus that were tested for antibacterial, antiviral, antifungal, antihypertensive, cytotoxic, spermicidal, embriotoxic, and anti-inflammatory activities are cited from the 121 references consulted. PMID:21845096
Metabolites of isocorynoxeine in rats after its oral administration.
Chen, Ya-Ping; Lu, Min-Nan; Hao, Jing-Chao; Li, Mei-Hong; Hattori, Masao; Wang, Wei
This work presents the metabolites of isocorynoxeine (ICOR), which is one of four bioactive tetracyclic oxindole alkaloids isolated from Uncaria hooks used commonly in the traditional Chinese medicines and Kampo medicines. After oral administration of 40 mg kg(-1) ICOR to rats, bile was drained and analyzed by LC-MS. Two phase I metabolites, namely 11-hydroxyisocorynoxeine (M1) and 10-hydroxyisocorynoxeine (M2), and two phase II metabolites, namely 11-hydroxyisocorynoxeine 11-O-β-D-glucuronide (M3) and 10-hydroxyisocorynoxeine 10-O-β-D-glucuronide (M4), were isolated from rat excreta and bile, respectively, whose structures were elucidated on the basis of CD, NMR, and MS. PMID:25633191
Boronic acid-containing proteasome inhibitors: alert to potential pharmaceutical bioactivation.
Li, Austin C; Yu, Erya; Ring, Steven C; Chovan, James P
Medicinal chemists try to avoid certain organic functional groups, summarized in an ever-growing list, in order to avoid the potential bioactivation to reactive metabolites. To add to that alert list, we report herein that boronic acid-containing compound structures, such as those found in proteasome inhibitors bortezomib and ixazomib, can become bioactivated to chemically reactive imine amide metabolites. Test compounds, ixazomib and bortezomib, were incubated in vitro using human liver fractions containing cytosol and microsomes (S9) under conventional conditions in the presence of GSH. Metabolites were then analyzed using LC-MS(n) with or without online hydrogen-deuterium exchange (HDX) liquid chromatography coupled with an LTQ-Orbitrap. The exact mass measurements of both the precursor and product ions were acquired through data dependent acquisition and compared with theoretical values of proposed fragment ions. Upon deboronation catalyzed by cytochrome P450 enzymes, both test compounds formed imine amide metabolites that were identified by high resolution exact mass measurements in both normal aqueous and HDX HPLC-MS analysis. GSH conjugates were also identified and were postulated as nucleophilic addition of GSH to the imine amide metabolites. All mass spectrometric and HDX measurements of these GSH conjugates proved that the GSH unit was added to the carbon atom of the imine amide partial structure, hence demonstrating the electrophilic property of these imine amide metabolites. The awareness of the formation of electrophilic imine amide metabolites from boronic acid-containing compounds, where the boron atom is bonded to a carbon atom adjacent to an amide nitrogen, should help in drug candidate design and optimization with regard to avoiding potential bioactivation. PMID:23514361
Elicitation: a tool for enriching the bioactive composition of foods.
Baenas, Nieves; García-Viguera, Cristina; Moreno, Diego A
Elicitation is a good strategy to induce physiological changes and stimulate defense or stress-induced responses in plants. The elicitor treatments trigger the synthesis of phytochemical compounds in fruits, vegetables and herbs. These metabolites have been widely investigated as bioactive compounds responsible of plant cell adaptation to the environment, specific organoleptic properties of foods, and protective effects in human cells against oxidative processes in the development of neurodegenerative and cardiovascular diseases and certain types of cancer. Biotic (biological origin), abiotic (chemical or physical origin) elicitors and phytohormones have been applied alone or in combinations, in hydroponic solutions or sprays, and in different selected time points of the plant growth or during post-harvest. Understanding how plant tissues and their specific secondary metabolic pathways respond to specific treatments with elicitors would be the basis for designing protocols to enhance the production of secondary metabolites, in order to produce quality and healthy fresh foods. PMID:25255755
Modulation of antimicrobial metabolites production by the fungus Aspergillus parasiticus
Bracarense, Adriana A.P.; Takahashi, Jacqueline A.
Biosynthesis of active secondary metabolites by fungi occurs as a specific response to the different growing environments. Changes in this environment alter the chemical and biological profiles leading to metabolites diversification and consequently to novel pharmacological applications. In this work, it was studied the influence of three parameters (fermentation length, medium composition and aeration) in the biosyntheses of antimicrobial metabolites by the fungus Aspergillus parasiticus in 10 distinct fermentation periods. Metabolism modulation in two culturing media, CYA and YES was evaluated by a 22 full factorial planning (ANOVA) and on a 23 factorial planning, role of aeration, medium composition and carbohydrate concentration were also evaluated. In overall, 120 different extracts were prepared, their HPLC profiles were obtained and the antimicrobial activity against A. flavus, C. albicans, E. coli and S. aureus of all extracts was evaluated by microdilution bioassay. Yield of kojic acid, a fine chemical produced by the fungus A. parasiticus was determined in all extracts. Statistical analyses pointed thirteen conditions able to modulate the production of bioactive metabolites by A. parasiticus. Effect of carbon source in metabolites diversification was significant as shown by the changes in the HPLC profiles of the extracts. Most of the extracts presented inhibition rates higher than that of kojic acid as for the extract obtained after 6 days of fermentation in YES medium under stirring. Kojic acid was not the only metabolite responsible for the activity since some highly active extracts showed to possess low amounts of this compound, as determined by HPLC. PMID:24948950
Richness and bioactivity of culturable soil fungi from the Fildes Peninsula, Antarctica.
Ding, Zhuang; Li, Liyuan; Che, Qian; Li, Dehai; Gu, Qianqun; Zhu, Tianjiao
Since the discovery of penicillin, fungi have been an important source of bioactive natural products. However, as a specific resource, the bioactive potentiality and specificity of fungal metabolites from the Antarctic region have had little attention. In this paper, we investigated the diversity patterns and biological activities of cultivable fungi isolated from soil samples in Fildes Peninsula, King George Island, Antarctica. Fungal communities showed low abundance and diversity; a total of 150 cultivable fungi were isolated from eight soil samples. After being dereplicated by morphological characteristics and chemical fingerprints, 47 fungal isolates were identified by ITS-rDNA sequencing. We confirmed that these isolates belonged to at least 11 different genera and clustered into nine groups corresponding to taxonomic orders in the phylogenetic analysis. Using two different fermentation conditions, 94 crude extracts acquired from the abovementioned different metabolite characteristic isolates were screened by bioactivity assay and 18 isolates produced biologically active compounds. Compared with HPLC-DAD-UV fingerprint analysis of culture extracts and standard compounds, two bioactive components secalonic acid and chetracins were identified. Our research suggests that the abundance and diversity of Antarctic cultivable fungal communities exhibit unique ecological characteristics and potential producers of novel natural bioactive products. PMID:27142030
Discovering new bioactive molecules from microbial sources
Monciardini, Paolo; Iorio, Marianna; Maffioli, Sonia; Sosio, Margherita; Donadio, Stefano
There is an increased need for new drug leads to treat diseases in humans, animals and plants. A dramatic example is represented by the need for novel and more effective antibiotics to combat multidrug-resistant microbial pathogens. Natural products represent a major source of approved drugs and still play an important role in supplying chemical diversity, despite a decreased interest by large pharmaceutical companies. Novel approaches must be implemented to decrease the chances of rediscovering the tens of thousands of known natural products. In this review, we present an overview of natural product screening, focusing particularly on microbial products. Different approaches can be implemented to increase the probability of finding new bioactive molecules. We thus present the rationale and selected examples of the use of hypersensitive assays; of accessing unexplored microorganisms, including the metagenome; and of genome mining. We then focus our attention on the technology platform that we are currently using, consisting of approximately 70 000 microbial strains, mostly actinomycetes and filamentous fungi, and discuss about high-quality screening in the search for bioactive molecules. Finally, two case studies are discussed, including the spark that arose interest in the compound: in the case of orthoformimycin, the novel mechanism of action predicted a novel structural class; in the case of NAI-112, structural similarity pointed out to a possible in vivo activity. Both predictions were then experimentally confirmed. PMID:24661414
Enhanced metabolite generation
Chidambaram, Devicharan
The present invention relates to the enhanced production of metabolites by a process whereby a carbon source is oxidized with a fermentative microbe in a compartment having a portal. An electron acceptor is added to the compartment to assist the microbe in the removal of excess electrons. The electron acceptor accepts electrons from the microbe after oxidation of the carbon source. Other transfers of electrons can take place to enhance the production of the metabolite, such as acids, biofuels or brewed beverages.
Bioactive Glasses: Frontiers and Challenges
Hench, Larry L.; Jones, Julian R.
Bioactive glasses were discovered in 1969 and provided for the first time an alternative to nearly inert implant materials. Bioglass formed a rapid, strong, and stable bond with host tissues. This article examines the frontiers of research crossed to achieve clinical use of bioactive glasses and glass–ceramics. In the 1980s, it was discovered that bioactive glasses could be used in particulate form to stimulate osteogenesis, which thereby led to the concept of regeneration of tissues. Later, it was discovered that the dissolution ions from the glasses behaved like growth factors, providing signals to the cells. This article summarizes the frontiers of knowledge crossed during four eras of development of bioactive glasses that have led from concept of bioactivity to widespread clinical and commercial use, with emphasis on the first composition, 45S5 Bioglass®. The four eras are (a) discovery, (b) clinical application, (c) tissue regeneration, and (d) innovation. Questions still to be answered for the fourth era are included to stimulate innovation in the field and exploration of new frontiers that can be the basis for a general theory of bioactive stimulation of regeneration of tissues and application to numerous clinical needs. PMID:26649290
Evaluating enzymes that generate genotoxic benzo[a]pyrene metabolites using sensor arrays.
Wang, Bingquan; Jansson, Ingela; Schenkman, John B; Rusling, James F
Arrays with individually addressable, demountable electrodes coated with ultrathin DNA/enzyme films were evaluated to estimate relative rates of genotoxic bioactivation of benzo[a]pyrene (BP) for several different enzymes simultaneously. Specifically, cytochrome (cyt) P450cam, cyt P40 1A2, and myoglobin in the array were activated with H2O2 to metabolize BP to genotoxic metabolites. DNA damage by the metabolites was detected by increases in square wave voltammetric oxidation peaks using Ru(bpy)3(2+) as catalyst. Cyt P450cam and cyt P450 1A2 showed 3-fold higher activity for genotoxic bioactivation of BP than myoglobin. The ability of the arrays to generate and detect metabolite-based DNA damage simultaneously for several enzymes is a rapid and promising approach to identify and characterize enzymes involved in genotoxicity of drugs and pollutants. PMID:15732919
Isolation and characterization of bioactive fungi from shark Carcharodon carcharias' gill with biopharmaceutical prospects
NASA Astrophysics Data System (ADS)
Zhang, Yi; Han, Jinyuan; Feng, Yan; Mu, Jun; Bao, Haiyan; Kulik, Andreas; Grond, Stephanie
Until recently, little was known about the fungi found in shark gills and their biomedicinal potential. In this article, we described the isolation, bioactivity, diversity, and secondary metabolites of bioactive fungi from the gill of a shark ( Carcharodon carcharias). A total of 115 isolates were obtained and grown in 12 culture media. Fifty-eight of these isolates demonstrated significant activity in four antimicrobial, pesticidal, and cytotoxic bioassay models. Four randomly selected bioactive isolates inhibited human cancer cell proliferation during re-screening. These active isolates were segregated into 6 genera using the internal transcribed spacer-large subunit (ITS-LSU) rDNA-sequence BLAST comparison. Four genera, Penicillium, Aspergillus, Mucor, and Chaetomium were the dominant taxa. A phylogenic tree illustrated their intergenera and intragenera genetic diversity. HPLC-DAD-HRMS analysis and subsequent database searching revealed that nine representative strains produced diverse bioactive compound profiles. These results detail the broad range of bioactive fungi found in a shark's gills, revealing their biopharmaceutical potential. To the best of our knowledge, this is the first study characterizing shark gill fungi and their bioactivity.
Regulation of cell proliferation and apoptosis by bioactive lipid mediators.
Clària, Joan
Bioactive lipid mediators are increasingly being recognized as important endogenous regulators of cell activation, signaling, apoptosis and proliferation. Most of these lipid mediators are originated from cleavage of constituents of cellular membranes under the activity of phospholipases and sphingomyelinases. One of the major cascades of bioactive lipid mediator production involves the release of arachidonic acid from membrane phospholipids followed by the formation of eicosanoids (i.e. prostaglandins, leukotrienes and lipoxins). These biologically active metabolites of arachidonic acid are emerging as key regulators of cell proliferation and neo-angiogenesis and agents that specifically target these lipid mediators are being investigated as potential anticancer drugs. On the other hand, the lysophospholipid family, which includes members of the sphingomyelin-ceramide-sphingosine-1-phosphate and lysophosphatidic acid subfamilies, has evolved as an important group of lipid signaling molecules implicated in cellular differentiation, cell growth and apoptosis. This article reviews the most recent patents in this field of research, covering the following strategies based on the modulation of bioactive lipid mediators: (1) prostaglandin H synthase-2 inhibitors, (2) lipoxin analogs and aspirin-triggered lipid mediators, and (3) lysophosphatidic acid and other lysophospholipids. PMID:18221047
Influence of abiotic stress signals on secondary metabolites in plants
Ramakrishna, Akula; Ravishankar, Gokare Aswathanarayana
Plant secondary metabolites are unique sources for pharmaceuticals, food additives, flavors, and industrially important biochemicals. Accumulation of such metabolites often occurs in plants subjected to stresses including various elicitors or signal molecules. Secondary metabolites play a major role in the adaptation of plants to the environment and in overcoming stress conditions. Environmental factors viz. temperature, humidity, light intensity, the supply of water, minerals, and CO2 influence the growth of a plant and secondary metabolite production. Drought, high salinity, and freezing temperatures are environmental conditions that cause adverse effects on the growth of plants and the productivity of crops. Plant cell culture technologies have been effective tools for both studying and producing plant secondary metabolites under in vitro conditions and for plant improvement. This brief review summarizes the influence of different abiotic factors include salt, drought, light, heavy metals, frost etc. on secondary metabolites in plants. The focus of the present review is the influence of abiotic factors on secondary metabolite production and some of important plant pharmaceuticals. Also, we describe the results of in vitro cultures and production of some important secondary metabolites obtained in our laboratory. PMID:22041989
Tissue distribution of berberine and its metabolites after oral administration in rats.
Tan, Xiang-Shan; Ma, Jing-Yi; Feng, Ru; Ma, Chao; Chen, Wen-Jing; Sun, Yu-Peng; Fu, Jie; Huang, Min; He, Chi-Yu; Shou, Jia-Wen; He, Wen-Yi; Wang, Yan; Jiang, Jian-Dong
Berberine (BBR) has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n)-IT-TOF) as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS) was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg). The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher) than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1), berberrubine (M2) and jatrorrhizine (M4), which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t) (area under the concentration-time curve) for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites) was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic. PMID:24205048
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NASA Technical Reports Server (NTRS)
Maxwell Laboratories capacitor charging power supply is the first commercial spinoff from the NASA CCDS program - a consortia of industries and government establishments to accelerate development of ground and space based commercial applications of NASA technology. The power supply transforms and conditions large voltages to charge capacitors used in x-ray sources, medical accelerators, etc. It is lighter, more reliable, more compact and efficient. Originally developed for space lasers, its commercial potential was soon recognized.
Drug bioactivation, covalent binding to target proteins and toxicity relevance.
Zhou, Shufeng; Chan, Eli; Duan, Wei; Huang, Min; Chen, Yu-Zong
A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients
Current approaches toward production of secondary plant metabolites
Hussain, Md. Sarfaraj; Fareed, Sheeba; Ansari, Saba; Rahman, Md. Akhlaquer; Ahmad, Iffat Zareen; Saeed, Mohd.
Plants are the tremendous source for the discovery of new products with medicinal importance in drug development. Today several distinct chemicals derived from plants are important drugs, which are currently used in one or more countries in the world. Secondary metabolites are economically important as drugs, flavor and fragrances, dye and pigments, pesticides, and food additives. Many of the drugs sold today are simple synthetic modifications or copies of the naturally obtained substances. The evolving commercial importance of secondary metabolites has in recent years resulted in a great interest in secondary metabolism, particularly in the possibility of altering the production of bioactive plant metabolites by means of tissue culture technology. Plant cell and tissue culture technologies can be established routinely under sterile conditions from explants, such as plant leaves, stems, roots, and meristems for both the ways for multiplication and extraction of secondary metabolites. In vitro production of secondary metabolite in plant cell suspension cultures has been reported from various medicinal plants, and bioreactors are the key step for their commercial production. Based on this lime light, the present review is aimed to cover phytotherapeutic application and recent advancement for the production of some important plant pharmaceuticals. PMID:22368394
Bioactive saponins from Dioscorea futschauensis.
Liu, H W; Hu, K; Zhao, Q C; Cui, C B; Kobayashi, H; Yao, X S
A new anti-neoplastic spirostanol saponin, (25S)-spirost-5-en-3 beta, 27-diol-3O-[alpha-L-rhamnopyranosyl(1-->2)-beta-D-glucopyranosyl (1-->3)]-beta-D-glucopyranoside and three known compounds viz. prosapogenin A of dioscin, dioscin and gracilin were isolated from Dioscorea futschauensis by bioactivity-guided fractionation. Their structures were elucidated mainly by means of spectroscopic analysis. Their bioactivity against Pyricularia oryzae and cytotoxic activity on ts-FT210 cell line was evaluated. PMID:12227201
Statistical Research on the Bioactivity of New Marine Natural Products Discovered during the 28 Years from 1985 to 2012
Hu, Yiwen; Chen, Jiahui; Hu, Guping; Yu, Jianchen; Zhu, Xun; Lin, Yongcheng; Chen, Shengping; Yuan, Jie
Every year, hundreds of new compounds are discovered from the metabolites of marine organisms. Finding new and useful compounds is one of the crucial drivers for this field of research. Here we describe the statistics of bioactive compounds discovered from marine organisms from 1985 to 2012. This work is based on our database, which contains information on more than 15,000 chemical substances including 4196 bioactive marine natural products. We performed a comprehensive statistical analysis to understand the characteristics of the novel bioactive compounds and detail temporal trends, chemical structures, species distribution, and research progress. We hope this meta-analysis will provide useful information for research into the bioactivity of marine natural products and drug development. PMID:25574736
The pharmacokinetics of anthocyanins and their metabolites in humans
de Ferrars, R M; Czank, C; Zhang, Q; Botting, N P; Kroon, P A; Cassidy, A; Kay, C D
BACKGROUND AND PURPOSE Anthocyanins are phytochemicals with reported vasoactive bioactivity. However, given their instability at neutral pH, they are presumed to undergo significant degradation and subsequent biotransformation. The aim of the present study was to establish the pharmacokinetics of the metabolites of cyanidin-3-glucoside (C3G), a widely consumed dietary phytochemical with potential cardioprotective properties. EXPERIMENTAL APPROACH A 500 mg oral bolus dose of 6,8,10,3′,5′-13C5-C3G was fed to eight healthy male participants, followed by a 48 h collection (0, 0.5, 1, 2, 4, 6, 24, 48 h) of blood, urine and faecal samples. Samples were analysed by HPLC-ESI-MS/MS with elimination kinetics established using non-compartmental pharmacokinetic modelling. KEY RESULTS Seventeen 13C-labelled compounds were identified in the serum, including 13C5-C3G, its degradation products, protocatechuic acid (PCA) and phloroglucinaldehyde (PGA), 13 metabolites of PCA and 1 metabolite derived from PGA. The maximal concentrations of the phenolic metabolites (Cmax) ranged from 10 to 2000 nM, between 2 and 30 h (tmax) post-consumption, with half-lives of elimination observed between 0.5 and 96 h. The major phenolic metabolites identified were hippuric acid and ferulic acid, which peaked in the serum at approximately 16 and 8 h respectively. CONCLUSIONS AND IMPLICATIONS Anthocyanins are metabolized to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. Understanding the elimination kinetics of these metabolites is key to the design of future studies examining their utility in dietary interventions or as therapeutics for disease risk reduction. PMID:24602005
Secondary metabolites from Ganoderma.
Baby, Sabulal; Johnson, Anil John; Govindan, Balaji
Ganoderma is a genus of medicinal mushrooms. This review deals with secondary metabolites isolated from Ganoderma and their biological significance. Phytochemical studies over the last 40years led to the isolation of 431 secondary metabolites from various Ganoderma species. The major secondary compounds isolated are (a) C30 lanostanes (ganoderic acids), (b) C30 lanostanes (aldehydes, alcohols, esters, glycosides, lactones, ketones), (c) C27 lanostanes (lucidenic acids), (d) C27 lanostanes (alcohols, lactones, esters), (e) C24, C25 lanostanes (f) C30 pentacyclic triterpenes, (g) meroterpenoids, (h) farnesyl hydroquinones (meroterpenoids), (i) C15 sesquiterpenoids, (j) steroids, (k) alkaloids, (l) prenyl hydroquinone (m) benzofurans, (n) benzopyran-4-one derivatives and (o) benzenoid derivatives. Ganoderma lucidum is the species extensively studied for its secondary metabolites and biological activities. Ganoderma applanatum, Ganoderma colossum, Ganoderma sinense, Ganoderma cochlear, Ganoderma tsugae, Ganoderma amboinense, Ganoderma orbiforme, Ganoderma resinaceum, Ganoderma hainanense, Ganoderma concinna, Ganoderma pfeifferi, Ganoderma neo-japonicum, Ganoderma tropicum, Ganoderma australe, Ganoderma carnosum, Ganoderma fornicatum, Ganoderma lipsiense (synonym G. applanatum), Ganoderma mastoporum, Ganoderma theaecolum, Ganoderma boninense, Ganoderma capense and Ganoderma annulare are the other Ganoderma species subjected to phytochemical studies. Further phytochemical studies on Ganoderma could lead to the discovery of hitherto unknown biologically active secondary metabolites. PMID:25975187
Human Colon Microbiota Transform Polycyclic Aromatic Hydrocarbons to Estrogenic Metabolites
Van de Wiele, Tom; Vanhaecke, Lynn; Boeckaert, Charlotte; Peru, Kerry; Headley, John; Verstraete, Willy; Siciliano, Steven
Ingestion is an important exposure route for polycyclic aromatic hydrocarbons (PAHs) to enter the human body. Although the formation of hazardous PAH metabolites by human biotransformation enzymes is well documented, nothing is known about the PAH transformation potency of human intestinal microbiota. Using a gastrointestinal simulator, we show that human intestinal microbiota can also bioactivate PAHs, more in particular to estrogenic metabolites. PAH compounds are not estrogenic, and indeed, stomach and small intestine digestions of 62.5 nmol naphthalene, phenanthrene, pyrene, and benzo(a)pyrene showed no estrogenic effects in the human estrogen receptor bioassay. In contrast, colon digests of these PAH compounds displayed estrogenicity, equivalent to 0.31, 2.14, 2.70, and 1.48 nmol 17α-ethynylestradiol (EE2), respectively. Inactivating the colon microbiota eliminated these estrogenic effects. Liquid chromatography–mass spectrometry analysis confirmed the microbial PAH transformation by the detection of PAH metabolites 1-hydroxypyrene and 7-hydroxybenzo(a)pyrene in colon digests of pyrene and benzo(a)pyrene. Furthermore, we show that colon digests of a PAH-contaminated soil (simulated ingestion dose of 5 g/day) displayed estrogenic activity equivalent to 0.58 nmol EE2, whereas stomach or small intestine digests did not. Although the matrix in which PAHs are ingested may result in lower exposure concentrations in the gut, our results imply that the PAH bioactivation potency of colon microbiota is not eliminated by the presence of soil. Moreover, because PAH toxicity is also linked to estrogenicity of the compounds, the PAH bioactivation potency of colon microbiota suggests that current risk assessment may underestimate the risk from ingested PAHs. PMID:15626640
Role of electrostatic potential in the in silico prediction of molecular bioactivation and mutagenesis.
Ford, Kevin A
Electrostatic potential (ESP) is a useful physicochemical property of a molecule that provides insights into inter- and intramolecular associations, as well as prediction of likely sites of electrophilic and nucleophilic metabolic attack. Knowledge of sites of metabolic attack is of paramount importance in DMPK research since drugs frequently fail in clinical trials due to the formation of bioactivated metabolites which are often difficult to measure experimentally due to their reactive nature and relatively short half-lives. Computational chemistry methods have proven invaluable in recent years as a means to predict and study bioactivated metabolites without the need for chemical syntheses, or testing on experimental animals. Additional molecular properties (heat of formation, heat of solvation and E(LUMO) - E(HOMO)) are discussed in this paper as complementary indicators of the behavior of metabolites in vivo. Five diverse examples are presented (acetaminophen, aniline/phenylamines, imidacloprid, nefazodone and vinyl chloride) which illustrate the utility of this multidimensional approach in predicting bioactivation, and in each case the predicted data agreed with experimental data described in the scientific literature. A further example of the usefulness of calculating ESP, in combination with the molecular properties mentioned above, is provided by an examination of the use of these parameters in providing an explanation for the sites of nucleophilic attack of the nucleic acid cytosine. Exploration of sites of nucleophilic attack of nucleic acids is important as adducts of DNA have the potential to result in mutagenesis. PMID:23323940
NASA Technical Reports Server (NTRS)
Paul Ducheyne, a principal investigator in the microgravity materials science program and head of the University of Pernsylvania's Center for Bioactive Materials and Tissue Engineering, is leading the trio as they use simulated microgravity to determine the optimal characteristics of tiny glass particles for growing bone tissue. The result could make possible a much broader range of synthetic bone-grafting applications. Even in normal gravity, bioactive glass particles enhance bone growth in laboratory tests with flat tissue cultures. Ducheyne and his team believe that using the bioactive microcarriers in a rotating bioreactor in microgravity will produce improved, three-dimensional tissue cultures. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Credit: NASA and University of Pennsylvania Center for Bioactive Materials and Tissue Engineering.
Understanding and Classifying Metabolite Space and Metabolite-Likeness
Peironcely, Julio E.; Reijmers, Theo; Coulier, Leon; Bender, Andreas; Hankemeier, Thomas
While the entirety of 'Chemical Space' is huge (and assumed to contain between 1063 and 10200 'small molecules'), distinct subsets of this space can nonetheless be defined according to certain structural parameters. An example of such a subspace is the chemical space spanned by endogenous metabolites, defined as 'naturally occurring' products of an organisms' metabolism. In order to understand this part of chemical space in more detail, we analyzed the chemical space populated by human metabolites in two ways. Firstly, in order to understand metabolite space better, we performed Principal Component Analysis (PCA), hierarchical clustering and scaffold analysis of metabolites and non-metabolites in order to analyze which chemical features are characteristic for both classes of compounds. Here we found that heteroatom (both oxygen and nitrogen) content, as well as the presence of particular ring systems was able to distinguish both groups of compounds. Secondly, we established which molecular descriptors and classifiers are capable of distinguishing metabolites from non-metabolites, by assigning a 'metabolite-likeness' score. It was found that the combination of MDL Public Keys and Random Forest exhibited best overall classification performance with an AUC value of 99.13%, a specificity of 99.84% and a selectivity of 88.79%. This performance is slightly better than previous classifiers; and interestingly we found that drugs occupy two distinct areas of metabolite-likeness, the one being more 'synthetic' and the other being more 'metabolite-like'. Also, on a truly prospective dataset of 457 compounds, 95.84% correct classification was achieved. Overall, we are confident that we contributed to the tasks of classifying metabolites, as well as to understanding metabolite chemical space better. This knowledge can now be used in the development of new drugs that need to resemble metabolites, and in our work particularly for assessing the metabolite
Yakymyshyn, Christopher Paul; Hamilton, Pamela Jane; Brubaker, Michael Allen
A modular, low weight impedance dropping power supply with battery backup is disclosed that can be connected to a high voltage AC source and provide electrical power at a lower voltage. The design can be scaled over a wide range of input voltages and over a wide range of output voltages and delivered power.
Microalgal metabolites: a new perspective.
Shimizu, Y
Occurrence of secondary metabolites in microalgae (protoctista) is discussed with respect to the phylogenic or taxonomic relationships of organisms. Biosynthetic mechanisms of certain metabolites such as paralytic shellfish poisoning toxins and polyether toxins are also discussed, and genetic aspects of the secondary metabolite production as well. PMID:8905087
Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery.
Moss, Nathan A; Bertin, Matthew J; Kleigrewe, Karin; Leão, Tiago F; Gerwick, Lena; Gerwick, William H
Filamentous marine cyanobacteria produce bioactive natural products with both potential therapeutic value and capacity to be harmful to human health. Genome sequencing has revealed that cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The biosynthetic pathways that encode cyanobacterial natural products are mostly uncharacterized, and lack of cyanobacterial genetic tools has largely prevented their heterologous expression. Hence, a combination of cutting edge and traditional techniques has been required to elucidate their secondary metabolite biosynthetic pathways. Here, we review the discovery and refined biochemical understanding of the olefin synthase and fatty acid ACP reductase/aldehyde deformylating oxygenase pathways to hydrocarbons, and the curacin A, jamaicamide A, lyngbyabellin, columbamide, and a trans-acyltransferase macrolactone pathway encoding phormidolide. We integrate into this discussion the use of genomics, mass spectrometric networking, biochemical characterization, and isolation and structure elucidation techniques. PMID:26578313
Identification of Microbial Metabolites Elevating Vitamin Contents in Barley Seeds.
Yousaf, Anam; Qadir, Abdul; Anjum, Tehmina; Ahmad, Aqeel
The current investigation analyzes metabolites of Acetobacter aceti to explore chemical compounds responsible for the induction of vitamins in barley seeds. A bioactivity guided assay of bacterial extracts and chromatographic analyses of barley produce revealed 13 chemical compounds, which were subjected to principal component analysis (PCA). PCA determined four chemical compounds (i.e., quinolinic acid, pyridoxic acid, p-aminobenzoate, and α-oxobutanoic acid) highly associated with increased quantities of vitamins. Further experimentations confirmed that quinolinic acid and p-aminobenzoate were the most efficient vitamin inducers. The results indicated chloroform/ethanol (4:1) as the best solvent system for the extraction of active compounds from crude metabolites of A. aceti. Significant quantities of mevalonic acid were detected in the extracted fraction, indicating the possible induction of the isoprenoid pathway. Altogether, the current investigation broadens the frontiers in plant-microbe interaction. PMID:26173019
Secondary metabolites in plants: transport and self-tolerance mechanisms.
Shitan, Nobukazu
Plants produce a host of secondary metabolites with a wide range of biological activities, including potential toxicity to eukaryotic cells. Plants generally manage these compounds by transport to the apoplast or specific organelles such as the vacuole, or other self-tolerance mechanisms. For efficient production of such bioactive compounds in plants or microbes, transport and self-tolerance mechanisms should function cooperatively with the corresponding biosynthetic enzymes. Intensive studies have identified and characterized the proteins responsible for transport and self-tolerance. In particular, many transporters have been isolated and their physiological functions have been proposed. This review describes recent progress in studies of transport and self-tolerance and provides an updated inventory of transporters according to their substrates. Application of such knowledge to synthetic biology might enable efficient production of valuable secondary metabolites in the future. PMID:26940949
Metabolite Damage and Metabolite Damage Control in Plants.
Hanson, Andrew D; Henry, Christopher S; Fiehn, Oliver; de Crécy-Lagard, Valérie
It is increasingly clear that (a) many metabolites undergo spontaneous or enzyme-catalyzed side reactions in vivo, (b) the damaged metabolites formed by these reactions can be harmful, and (c) organisms have biochemical systems that limit the buildup of damaged metabolites. These damage-control systems either return a damaged molecule to its pristine state (metabolite repair) or convert harmful molecules to harmless ones (damage preemption). Because all organisms share a core set of metabolites that suffer the same chemical and enzymatic damage reactions, certain damage-control systems are widely conserved across the kingdoms of life. Relatively few damage reactions and damage-control systems are well known. Uncovering new damage reactions and identifying the corresponding damaged metabolites, damage-control genes, and enzymes demands a coordinated mix of chemistry, metabolomics, cheminformatics, biochemistry, and comparative genomics. This review illustrates the above points using examples from plants, which are at least as prone to metabolite damage as other organisms. PMID:26667673
Dung-inhabiting fungi: a potential reservoir of novel secondary metabolites for the control of plant pathogens.
Sarrocco, Sabrina
Coprophilous fungi are a large group of saprotrophic fungi mostly found in herbivore dung. The number of these fungi undergoing investigation is continually increasing, and new species and genera continue to be described. Dung-inhabiting fungi play an important ecological role in decomposing and recycling nutrients from animal dung. They produce a large array of bioactive secondary metabolites and have a potent enzymatic arsenal able to utilise even complex molecules. Bioactive secondary metabolites are actively involved in interaction with and defence against other organisms whose growth can be inhibited, resulting in an enhanced ecological fitness of producer strains. Currently, these antibiotics and bioactive secondary metabolites are of interest in medicine in particular, while very little information is available concerning their potential use in agriculture. This review introduces the ecology of dung-inhabiting fungi, with particular emphasis on the production of antibiotic compounds as a means to compete with other microorganisms. Owing to the fast pace of technological progress, new approaches to predicting the biosynthesis of bioactive metabolites are proposed. Coprophilous fungi should be considered as elite candidate organisms for the discovery of novel antifungal compounds, above all in view of their exploitation for crop protection. PMID:26662623
Carbendazim (MBC), the bioactive metabolite of the fungicide benomyl, has been reported to induce a number of testicular alterations in male rats. In order to broaden an exploration of its effects on the reproductive system, the present study focused on the possible presence of c...
Comparative UPLC-QTOF-MS-based metabolomics and bioactivities analyses of Garcinia oblongifolia.
Li, Ping; AnandhiSenthilkumar, Harini; Wu, Shi-biao; Liu, Bo; Guo, Zhi-yong; Fata, Jimmie E; Kennelly, Edward J; Long, Chun-lin
Garcinia oblongifolia Champ. ex Benth. (Clusiaceae) is a well-known medicinal plant from southern China, with edible fruits. However, the phytochemistry and bioactivity of the different plant parts of G. oblongifolia have not been studied extensively. Comparative metabolic profiling and bioactivities of the leaf, branch, and fruit of G. oblongifolia were investigated. A total of 40 compounds such as biflavonoids, xanthones, and benzophenones were identified using UPLC-QTOF-MS and MS(E), including 15 compounds reported for the first time from this species. Heatmap analyses found that benzophenones, xanthones, and biflavonoids were predominately found in branches, with benzophenones present in relatively high concentrations in all three plant parts. Xanthones were found to have limited distribution in fruit while biflavonoids were present at only low levels in leaves. In addition, the cytotoxic (MCF-7 breast cancer cell line) and antioxidant (ABTS and DPPH chemical tests) activities of the crude extracts of G. oblongifolia indicate that the branch extract exhibits greater bioactivity than either the leaf or the fruit extracts. Orthogonal partial least squares discriminate analysis was used to find 12 marker compounds, mainly xanthones, from the branches, including well-known antioxidants and cytotoxic agents. These G. oblongifolia results revealed that the variation in metabolite profiles can be correlated to the differences in bioactivity of the three plant parts investigated. This UPLC-QTOF-MS strategy can be useful to identify bioactive constituents expressed differentially in the various plant parts of a single species. PMID:26773895
Emerging Strategies and Integrated Systems Microbiology Technologies for Biodiscovery of Marine Bioactive Compounds
Rocha-Martin, Javier; Harrington, Catriona; Dobson, Alan D.W.; O'Gara, Fergal
Marine microorganisms continue to be a source of structurally and biologically novel compounds with potential use in the biotechnology industry. The unique physiochemical properties of the marine environment (such as pH, pressure, temperature, osmolarity) and uncommon functional groups (such as isonitrile, dichloroimine, isocyanate, and halogenated functional groups) are frequently found in marine metabolites. These facts have resulted in the production of bioactive substances with different properties than those found in terrestrial habitats. In fact, the marine environment contains a relatively untapped reservoir of bioactivity. Recent advances in genomics, metagenomics, proteomics, combinatorial biosynthesis, synthetic biology, screening methods, expression systems, bioinformatics, and the ever increasing availability of sequenced genomes provides us with more opportunities than ever in the discovery of novel bioactive compounds and biocatalysts. The combination of these advanced techniques with traditional techniques, together with the use of dereplication strategies to eliminate known compounds, provides a powerful tool in the discovery of novel marine bioactive compounds. This review outlines and discusses the emerging strategies for the biodiscovery of these bioactive compounds. PMID:24918453
Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts
Bhaiya, Payal; Roychowdhury, Sanjoy; Vyas, Piyush M.; Doll, Mark A.; Hein, David W.; Svensson, Craig K. . E-mail: email@example.com
Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein was detected. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time- and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.
Hart, Edward J.; Leeman, James E.; MacDougall, Hugh R.; Marron, John J.; Smith, Calvin C.
An electric power supply employs a striking means to initiate ferroelectric elements which provide electrical energy output which subsequently initiates an explosive charge which initiates a second ferroelectric current generator to deliver current to the coil of a magnetic field current generator, creating a magnetic field around the coil. Continued detonation effects compression of the magnetic field and subsequent generation and delivery of a large output current to appropriate output loads.
Aeroplysinin-1, a Sponge-Derived Multi-Targeted Bioactive Marine Drug
García-Vilas, Javier A.; Martínez-Poveda, Beatriz; Quesada, Ana R.; Medina, Miguel Ángel
Organisms lacking external defense mechanisms have developed chemical defense strategies, particularly through the production of secondary metabolites with antibiotic or repellent effects. Secondary metabolites from marine organisms have proven to be an exceptionally rich source of small molecules with pharmacological activities potentially beneficial to human health. (+)-Aeroplysinin-1 is a secondary metabolite isolated from marine sponges with a wide spectrum of bio-activities. (+)-Aeroplysinin-1 has potent antibiotic effects on Gram-positive bacteria and several dinoflagellate microalgae causing toxic blooms. In preclinical studies, (+)-aeroplysinin-1 has been shown to have promising anti-inflammatory, anti-angiogenic and anti-tumor effects. Due to its versatility, (+)-aeroplysinin-1 might have a pharmaceutical interest for the treatment of different pathologies. PMID:26703630
Bioactive apocarotenoids from Tectona grandis.
Macías, Francisco A; Lacret, Rodney; Varela, Rosa M; Nogueiras, Clara; Molinillo, Jose M G
The bioactive fractions of Tectona grandis have yielded seven apocarotenoids, two of which have been isolated for the first time as natural products (tectoionols A and B). The chemical structures were determined through 1D and 2D nuclear magnetic resonance experiments. The absolute configuration of tectoionol A was determined using a modified Mosher methodology. Some NMR assignments for the compounds 9(S)-4-oxo-7,8-dihydro-beta-ionol and 3beta-hydroxy-7,8-dihydro-beta-ionone have been corrected on the basis of g-HSQC and g-HMBC experiments. The general bioactivities of isolated compounds have been studied using etiolated wheat coleoptiles. Those compounds that presented higher levels of activity were assayed on standard target species (Lactuca sativa, Lycopersicum esculentum, Lepidium sativum and Allium cepa). PMID:18834604
Marine Peptides: Bioactivities and Applications.
Cheung, Randy Chi Fai; Ng, Tzi Bun; Wong, Jack Ho
Peptides are important bioactive natural products which are present in many marine species. These marine peptides have high potential nutraceutical and medicinal values because of their broad spectra of bioactivities. Their antimicrobial, antiviral, antitumor, antioxidative, cardioprotective (antihypertensive, antiatherosclerotic and anticoagulant), immunomodulatory, analgesic, anxiolytic anti-diabetic, appetite suppressing and neuroprotective activities have attracted the attention of the pharmaceutical industry, which attempts to design them for use in the treatment or prevention of various diseases. Some marine peptides or their derivatives have high commercial values and had reached the pharmaceutical and nutraceutical markets. A large number of them are already in different phases of the clinical and preclinical pipeline. This review highlights the recent research in marine peptides and the trends and prospects for the future, with special emphasis on nutraceutical and pharmaceutical development into marketed products. PMID:26132844
Marine Peptides: Bioactivities and Applications
Cheung, Randy Chi Fai; Ng, Tzi Bun; Wong, Jack Ho
Peptides are important bioactive natural products which are present in many marine species. These marine peptides have high potential nutraceutical and medicinal values because of their broad spectra of bioactivities. Their antimicrobial, antiviral, antitumor, antioxidative, cardioprotective (antihypertensive, antiatherosclerotic and anticoagulant), immunomodulatory, analgesic, anxiolytic anti-diabetic, appetite suppressing and neuroprotective activities have attracted the attention of the pharmaceutical industry, which attempts to design them for use in the treatment or prevention of various diseases. Some marine peptides or their derivatives have high commercial values and had reached the pharmaceutical and nutraceutical markets. A large number of them are already in different phases of the clinical and preclinical pipeline. This review highlights the recent research in marine peptides and the trends and prospects for the future, with special emphasis on nutraceutical and pharmaceutical development into marketed products. PMID:26132844
NASA Technical Reports Server (NTRS)
Paul Ducheyne, a principal investigator in the microgravity materials science program and head of the University of Pernsylvania's Center for Bioactive Materials and Tissue Engineering, is leading the trio as they use simulated microgravity to determine the optimal characteristics of tiny glass particles for growing bone tissue. The result could make possible a much broader range of synthetic bone-grafting applications. Bioactive glass particles (left) with a microporous surface (right) are widely accepted as a synthetic material for periodontal procedures. Using the particles to grow three-dimensional tissue cultures may one day result in developing an improved, more rugged bone tissue that may be used to correct skeletal disorders and bone defects. The work is sponsored by NASA's Office of Biological and Physical Research.
Characterization of oxygenated metabolites of ginsenoside Rg1 in plasma and urine of rat.
Wang, Jing-Rong; Tong, Tian-Tian; Yau, Lee-Fong; Chen, Cheng-Yu; Bai, Li-Ping; Ma, Jing; Hu, Ming; Liu, Liang; Jiang, Zhi-Hong
This study describes the characterization of oxygenated metabolites of ginsenoside Rg1 in rat urine and plasma. These in vivo metabolites were profiled by using UHPLC-QTOF MS-based method. On the basis of high-resolution MS/MS data, and comparison with chemically synthesized authentic compounds, nine oxygenated metabolites of Rg1 were characterized as vinaginsenosides 21 and 22 (M1 and M2), vinaginsenoside R15 (M3), 6-O-(β-d-glucopyranosyl)-20-O-(β-d-glucopyranosyl) 3β, 6α, 12β, 20(S)-tetrahydroxy-24ξ-hydroxydammar-25-ene (M4 and M5), floralginsenoside A (M7 and M8), floralginsenoside B (M9) and epoxyginsenoside Rg1 (M13), respectively. Among these metabolites, M4, M5 and M13 are new ginsenosides and others were detected as in vivo metabolites of Rg1 for the first time. In addition, a series of oxygenated metabolites of Rh1 and deglycosylated metabolite of Rg1, were observed and characterized by comparing with compounds synthesized by us, which revealed an association between C-20 configuration and the extent of oxidation metabolism. Appearance of all these metabolites in blood stream and urine after i.v. dosing and oral administration of Rg1 was further examined, which clearly showed that mono-oxygenated metabolites of Rg1 were major circulating metabolites at the early stage after dosing. Characterization of exact chemical structures of these circulating metabolites contribute greatly to our understanding of chemical exposure after consumption of ginseng products, and provide valuable information for explaining multiple bioactivities of ginseng products. PMID:26809375
Production of antioxidant and antitumor metabolites by submerged cultures of Inonotus obliquus cocultured with Phellinus punctatus.
Zheng, Weifa; Zhao, Yanxia; Zheng, Xin; Liu, Yubing; Pan, Shenyuan; Dai, Yucheng; Liu, Fuming
While Inonotus obliquus produces a diverse range of bioactive metabolites in its natural habitats, it accumulates less in its submerged cultures. We show here that coculture of I. obliquus with Phellinus punctatus resulted in less production of mycelial biomass but an increased accumulation of phenolic compounds, melanins, and lanostane-type triterpenoids. Metabolites increased in production by coculture include phelligridin C, phelligridin H, methyl inoscavin A, inoscavin C, inoscavin B, davallialactone, methyl davallialactone, foscoparianol D, 21,24-cyclopentalanosta-3β,21,25-triol-8-en, lanosta-7,9(11),23-triene-3β,22,25-triol, and inotodisaccharide and melanins. Metabolites from coculture also showed an increased potential for scavenging free radicals and inhibiting the proliferation of HeLa 229 cells. Davallialactone, methyl davallialactone, and minor phenolic components are the major contributors for scavenging DPPH and hydroxyl radical in monoculture, and phelligridin C, phelligridin H, methyl inoscavin A, inoscavin C, methyl davallialactone, foscoparianol D, and inotodisaccharide are those for scavenging the tested radicals in coculture. Lanostane-type triterpenoids indicated limited roles in scavenging free radicals. Nearly all the detected metabolites correlate positively with inhibiting proliferation of HeLa 229 cells. Thus, coculture of I. obliquus with other fungi seems to be a cost-effective strategy for upregulating biosynthesis of bioactive metabolites. PMID:20830471
Identification of signatory secondary metabolites during mycoparasitism of Rhizoctonia solani by Stachybotrys elegans
Chamoun, Rony; Aliferis, Konstantinos A.; Jabaji, Suha
Stachybotrys elegans is able to parasitize the fungal plant pathogen Rhizoctonia solani AG-3 following a complex and intimate interaction, which, among others, includes the production of cell wall-degrading enzymes, intracellular colonization, and expression of pathogenic process encoding genes. However, information on the metabolome level is non-existent during mycoparasitism. Here, we performed a direct-infusion mass spectrometry (DIMS) metabolomics analysis using an LTQ Orbitrap analyzer in order to detect changes in the profiles of induced secondary metabolites of both partners during this mycoparasitic interaction 4 and 5 days following its establishment. The diketopiperazine(s) (DKPs) cyclo(S-Pro-S-Leu)/cyclo(S-Pro-S-Ile), ethyl 2-phenylacetate, and 3-nitro-4-hydroxybenzoic acid were detected as the primary response of Rhizoctonia 4 days following dual-culturing with Stachybotrys, whereas only the latter metabolite was up-regulated 1 day later. On the other hand, trichothecenes and atranones were mycoparasite-derived metabolites identified during mycoparasitism 4 and 5 days following dual-culturing. All the above secondary metabolites are known to exhibit bioactivity, including fungitoxicity, and represent key elements that determine the outcome of the interaction being studied. Results could be further exploited in programs for the evaluation of the bioactivity of these metabolites per se or their chemical analogs, and/or genetic engineering programs to obtain more efficient mycoparasite strains with improved efficacy and toxicological profiles. PMID:25972848
Development of a cell viability assay to assess drug metabolite structure-toxicity relationships.
Rana, Payal; Will, Yvonne; Nadanaciva, Sashi; Jones, Lyn H
Many adverse drug reactions are caused by the cytochrome P450 (CYP)-dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, we developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. We screened a series of drugs to explore structural motifs that may be responsible for CYP450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines. PMID:27397500
Bioactive Pigments from Marine Bacteria: Applications and Physiological Roles
Soliev, Azamjon B.; Hosokawa, Kakushi; Enomoto, Keiichi
Research into natural products from the marine environment, including microorganisms, has rapidly increased over the past two decades. Despite the enormous difficulty in isolating and harvesting marine bacteria, microbial metabolites are increasingly attractive to science because of their broad-ranging pharmacological activities, especially those with unique color pigments. This current review paper gives an overview of the pigmented natural compounds isolated from bacteria of marine origin, based on accumulated data in the literature. We review the biological activities of marine compounds, including recent advances in the study of pharmacological effects and other commercial applications, in addition to the biosynthesis and physiological roles of associated pigments. Chemical structures of the bioactive compounds discussed are also presented. PMID:21961023
Metabolomic Tools for Secondary Metabolite Discovery from Marine Microbial Symbionts
Macintyre, Lynsey; Zhang, Tong; Viegelmann, Christina; Juarez Martinez, Ignacio; Cheng, Cheng; Dowdells, Catherine; Abdelmohsen, Usama Ramadan; Gernert, Christine; Hentschel, Ute; Edrada-Ebel, RuAngelie
Marine invertebrate-associated symbiotic bacteria produce a plethora of novel secondary metabolites which may be structurally unique with interesting pharmacological properties. Selection of strains usually relies on literature searching, genetic screening and bioactivity results, often without considering the chemical novelty and abundance of secondary metabolites being produced by the microorganism until the time-consuming bioassay-guided isolation stages. To fast track the selection process, metabolomic tools were used to aid strain selection by investigating differences in the chemical profiles of 77 bacterial extracts isolated from cold water marine invertebrates from Orkney, Scotland using liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance (NMR) spectroscopy. Following mass spectrometric analysis and dereplication using an Excel macro developed in-house, principal component analysis (PCA) was employed to differentiate the bacterial strains based on their chemical profiles. NMR 1H and correlation spectroscopy (COSY) were also employed to obtain a chemical fingerprint of each bacterial strain and to confirm the presence of functional groups and spin systems. These results were then combined with taxonomic identification and bioassay screening data to identify three bacterial strains, namely Bacillus sp. 4117, Rhodococcus sp. ZS402 and Vibrio splendidus strain LGP32, to prioritize for scale-up based on their chemically interesting secondary metabolomes, established through dereplication and interesting bioactivities, determined from bioassay screening. PMID:24905482
Chemical investigation of metabolites produced by an endophytic Aspergillus sp. isolated from Limonia acidissima.
Siriwardane, A M D A; Kumar, N Savitri; Jayasinghe, Lalith; Fujimoto, Yoshinori
Endophytic fungi are considered as a good source to produce important secondary metabolites with interesting bioactivities. In a continuation of our studies towards the search for environmentally friendly bioactive compounds from Sri Lankan flora, we investigated the secondary metabolites produced by the endophytic fungi Aspergillus sp. isolated from the seeds of the popular edible fruit Limonia acidissima L. of the family Rutaceae. The pure culture of the Aspergillus sp. was grown on potato dextrose broth media. After 4 weeks fermentation, fungal media were extracted with organic solvents. Chromatographic separation of the fungal extracts over silica gel, Sephadex LH-20 and RP-HPLC furnished flavasperone (1), rubrofusarin B (2), aurasperone A (3), fonsecinone D (4) and aurasperone B (5). Compounds 1-4 showed moderate activities in brine shrimp toxicity assay. This is the first report of the (13)C NMR data of compounds 4 and 5. PMID:25809933
A genome-wide survey of the secondary metabolite biosynthesis genes in the wheat pathogen Parastagonospora nodorum
Chooi, Yit-Heng; Muria-Gonzalez, Mariano Jordi; Solomon, Peter S.
The model pathogen Parastagonospora nodorum is a necrotroph and the causal agent of the wheat disease Septoria nodorum blotch (SNB). The sequenced P. nodorum genome has revealed that the fungus harbours a large number of secondary metabolite genes. Secondary metabolites are known to play important roles in the virulence of plant pathogens, but limited knowledge is available about the SM repertoire of this wheat pathogen. Here, we review the secondary metabolites that have been isolated from P. nodorum and related species of the same genus and provide an in-depth genome-wide overview of the secondary metabolite gene clusters encoded in the P. nodorum genome. The secondary metabolite gene survey reveals that P. nodorum is capable of producing a diverse range of small molecules and exciting prospects exist for discovery of novel virulence factors and bioactive molecules. PMID:25379341
The morphology and bioactivity of the rice field cyanobacterium Leptolyngbya.
Ahmed, Mehboob; Stal, Lucas J; Hasnain, Shahida
The genus Leptolyngbya comprises filamentous cyanobacteria that are important in rice fields. In the rhizosphere, cyanobacteria produce a variety of secondary metabolites such as auxins that are important in agriculture soil performance. To assess this, Leptolyngbya strain MMG-1, was isolated from the rhizosphere of rice plants and described. For this, the morphology of this strain was studied by light microscopy as well as by confocal laser scanning microscopy. Besides, the ability of this strain to synthesize an auxin-like bioactive com- pound was demonstrated under various culture conditions (different amounts of tryptophan; pH; different alter- nating light:dark periods; duration of the incubation). The auxin-like compound was extracted from the culture of Leptolyngbya strain MMG-1 and identified as indole-3-acetic acid (IAA) by thin layer chromatography (TLC) as well as by high performance liquid chromatography (HPLC). Our results showed that the strain required the precursor L-tryptophan for the synthesis of IAA. Leptolyngbya strain MMG-1 accumulated IAA intracellularly. The IAA secreted by Leptolyngbya strain MMG-1 was significantly correlated with the initial concentration of L-tryptophan in the medium, as well as with the duration of the incubation. The bioactivity of the secreted IAA was determined by its effect on the rooting pattern of Pisum sativum seedlings. The culture supernatant of Leptolyngbya strain MMG-1 stimulated the seedling lateral rooting, while it decreased root length. Hence, rhizospheric Leptolyngbya produced auxin under different conditions and affected the plants rooting pattern. PMID:25412549
Mangrove rare actinobacteria: taxonomy, natural compound, and discovery of bioactivity
Azman, Adzzie-Shazleen; Othman, Iekhsan; Velu, Saraswati S.; Chan, Kok-Gan; Lee, Learn-Han
Actinobacteria are one of the most important and efficient groups of natural metabolite producers. The genus Streptomyces have been recognized as prolific producers of useful natural compounds as they produced more than half of the naturally-occurring antibiotics isolated to-date and continue as the primary source of new bioactive compounds. Lately, Streptomyces groups isolated from different environments produced the same types of compound, possibly due to frequent genetic exchanges between species. As a result, there is a dramatic increase in demand to look for new compounds which have pharmacological properties from another group of Actinobacteria, known as rare actinobacteria; which is isolated from special environments such as mangrove. Recently, mangrove ecosystem is becoming a hot spot for studies of bioactivities and the discovery of natural products. Many novel compounds discovered from the novel rare actinobacteria have been proven as potential new drugs in medical and pharmaceutical industries such as antibiotics, antimicrobials, antibacterials, anticancer, and antifungals. This review article highlights the latest studies on the discovery of natural compounds from the novel mangrove rare actinobacteria and provides insight on the impact of these findings. PMID:26347734
Screening botanical extracts for quinoid metabolites.
Johnson, B M; Bolton, J L; van Breemen, R B
Botanical dietary supplements represent a significant share of the growing market for alternative medicine in the USA, where current regulations do not require assessment of their safety. To help ensure the safety of such products, an in vitro assay using pulsed ultrafiltration and LC-MS-MS has been developed to screen botanical extracts for the formation of electrophilic and potentially toxic quinoid species upon bioactivation by hepatic cytochromes P450. Rat liver microsomes were trapped in a flow-through chamber by an ultrafiltration membrane, and samples containing botanical extracts, GSH and NADP(H), were flow-injected into the chamber. Botanical compounds that were metabolized to reactive intermediates formed stable GSH adducts mimicking a common in vivo detoxification pathway. If present in the ultrafiltrate, GSH conjugates were detected using LC-MS-MS with precursor ion scanning followed by additional characterization using product ion scanning and comparison to standard compounds. As expected, no GSH adducts of reactive metabolites were found in extracts of Trifolium pratense L. (red clover), which are under investigation as botanical dietary supplements for the management of menopause. However, extracts of Sassafras albidum (Nutt.) Nees (sassafras), Symphytum officinale L. (comfrey), and Rosmarinus officinalis L. (rosemary), all of which are known to contain compounds that are either carcinogenic or toxic to mammals, produced GSH adducts during this screening assay. Several compounds that formed GSH conjugates including novel metabolites of rosmarinic acid were identified using database searching and additional LC-MS-MS studies. This assay should be useful as a preliminary toxicity screen during the development of botanical dietary supplements. A positive test suggests that additional toxicological studies are warranted before human consumption of a botanical product. PMID:11712913
[Antiviral properties of basidiomycetes metabolites].
Avtonomova, A V; Krasnopolskaya, L M
The data on the antiviral action of the Ganoderma lucidum, Lentinus edodes, Grifola frondosa, Agaricus brasiliensis and other basidiomycetes metabolites are summurized. The metabolites of these species of basidiomycetes exhibit a direct antiviral effect on herpes simplex virus types I and II, human immunodeficiency virus (HIV), hepatitis B virus, vesicular stomatitis virus, influenza virus, Epstein-Barr virus, and others. Moreover, metabolites of basidiomycetes increased antiviral immunity. PMID:25975107
Quinone and Hydroquinone Metabolites from the Ascidians of the Genus Aplidium
Bertanha, Camila Spereta; Januário, Ana Helena; Alvarenga, Tavane Aparecida; Pimenta, Letícia Pereira; e Silva, Márcio Luis Andrade; Cunha, Wilson Roberto; Pauletti, Patrícia Mendonça
Ascidians of the genus Aplidium are recognized as an important source of chemical diversity and bioactive natural products. Among the compounds produced by this genus are non-nitrogenous metabolites, mainly prenylated quinones and hydroquinones. This review discusses the isolation, structural elucidation, and biological activities of quinones, hydroquinones, rossinones, longithorones, longithorols, floresolides, scabellones, conicaquinones, aplidinones, thiaplidiaquinones, and conithiaquinones. A compilation of the 13C-NMR spectral data of these compounds is also presented. PMID:24927227
Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using LC/MS/MS.
Jiang, Qing; Xu, Tianlin; Huang, Jianjie; Jannasch, Amber S; Cooper, Bruce; Yang, Chao
Tocopherols and tocotrienols are metabolized via hydroxylation and oxidation of their hydrophobic side chain to generate 13'-hydroxychromanols (13'-OHs) and various carboxychromanols, which can be further metabolized by conjugation including sulfation. Recent studies indicate that long-chain carboxychromanols, especially 13'-carboxychromanol (13'-COOH), appear to be more bioactive than tocopherols in anti-inflammatory and anticancer actions. To understand the potential contribution of metabolites to vitamin E-mediated effects, an accurate assay is needed to evaluate bioavailability of these metabolites. Here we describe an LC/MS/MS assay for quantifying vitamin E metabolites using negative polarity ESI. This assay includes a reliable sample extraction procedure with efficacy of ≥ 89% and interday/intraday variation of 3-11% for major metabolites. To ensure accurate quantification, short-chain, long-chain, and sulfated carboxychromanols are included as external/internal standards. Using this assay, we observed that sulfated carboxychromanols are the primary metabolites in the plasma of rodents fed with γ-tocopherol or δ-tocopherol. Although plasma levels of 13'-COOHs and 13'-OHs are low, high concentrations of these compounds are found in feces. Our study demonstrates an LC/MS/MS assay for quantitation of sulfated and unconjugated vitamin E metabolites, and this assay will be useful for evaluating the role of these metabolites in vivo. PMID:26351363
In situ label-free imaging for visualizing the biotransformation of a bioactive polyphenol
Kim, Yoon Hee; Fujimura, Yoshinori; Hagihara, Takatoki; Sasaki, Masako; Yukihira, Daichi; Nagao, Tatsuhiko; Miura, Daisuke; Yamaguchi, Shinichi; Saito, Kazunori; Tanaka, Hiroshi; Wariishi, Hiroyuki; Yamada, Koji; Tachibana, Hirofumi
Although understanding the high-resolution spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmacological effects, there has been no analytical technique that can easily detect the naïve molecular localization in mammalian tissues. We herein present a novel in situ label-free imaging technique for visualizing bioactive small molecules, using a polyphenol. We established a 1,5-diaminonaphthalene (1,5-DAN)-based matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) technique for visualizing epigallocatechin-3-O-gallate (EGCG), the major bioactive green tea polyphenol, within mammalian tissue micro-regions after oral dosing. Furthermore, the combination of this label-free MALDI-MSI method and a standard-independent metabolite identification method, an isotopic fine structure analysis using ultrahigh-resolution mass spectrometer, allows for the visualization of spatially-resolved biotransformation based on simultaneous mapping of EGCG and its phase II metabolites. Although this approach has limitations of the detection sensitivity, it will overcome the drawbacks associated with conventional molecular imaging techniques, and could contribute to biological discovery. PMID:24076623
In situ label-free imaging for visualizing the biotransformation of a bioactive polyphenol.
Kim, Yoon Hee; Fujimura, Yoshinori; Hagihara, Takatoki; Sasaki, Masako; Yukihira, Daichi; Nagao, Tatsuhiko; Miura, Daisuke; Yamaguchi, Shinichi; Saito, Kazunori; Tanaka, Hiroshi; Wariishi, Hiroyuki; Yamada, Koji; Tachibana, Hirofumi
Although understanding the high-resolution spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmacological effects, there has been no analytical technique that can easily detect the naïve molecular localization in mammalian tissues. We herein present a novel in situ label-free imaging technique for visualizing bioactive small molecules, using a polyphenol. We established a 1,5-diaminonaphthalene (1,5-DAN)-based matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) technique for visualizing epigallocatechin-3-O-gallate (EGCG), the major bioactive green tea polyphenol, within mammalian tissue micro-regions after oral dosing. Furthermore, the combination of this label-free MALDI-MSI method and a standard-independent metabolite identification method, an isotopic fine structure analysis using ultrahigh-resolution mass spectrometer, allows for the visualization of spatially-resolved biotransformation based on simultaneous mapping of EGCG and its phase II metabolites. Although this approach has limitations of the detection sensitivity, it will overcome the drawbacks associated with conventional molecular imaging techniques, and could contribute to biological discovery. PMID:24076623
Human Carboxymethylenebutenolidase as a Bioactivating Hydrolase of Olmesartan Medoxomil in Liver and Intestine
Ishizuka, Tomoko; Fujimori, Izumi; Kato, Mitsunori; Noji-Sakikawa, Chisa; Saito, Motoko; Yoshigae, Yasushi; Kubota, Kazuishi; Kurihara, Atsushi; Izumi, Takashi; Ikeda, Toshihiko; Okazaki, Osamu
Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the identification and characterization of the OM bioactivating enzyme that hydrolyzes the prodrug and converts to its pharmacologically active metabolite olmesartan in human liver and intestine. The protein was purified from human liver cytosol by successive column chromatography and was identified by mass spectrometry to be a carboxymethylenebutenolidase (CMBL) homolog. Human CMBL, whose endogenous function has still not been reported, is a human homolog of Pseudomonas dienelactone hydrolase involved in the bacterial halocatechol degradation pathway. The ubiquitous expression of human CMBL gene transcript in various tissues was observed. The recombinant human CMBL expressed in mammalian cells was clearly shown to activate OM. By comparing the enzyme kinetics and chemical inhibition properties between the recombinant protein and human tissue preparations, CMBL was demonstrated to be the primary OM bioactivating enzyme in the liver and intestine. The recombinant CMBL also converted other prodrugs having the same ester structure as OM, faropenem medoxomil and lenampicillin, to their active metabolites. CMBL exhibited a unique sensitivity to chemical inhibitors, thus, being distinguishable from other known esterases. Site-directed mutagenesis on the putative active residue Cys132 of the recombinant CMBL caused a drastic reduction of the OM-hydrolyzing activity. We report for the first time that CMBL serves as a key enzyme in the bioactivation of OM, hydrolyzing the ester bond of the prodrug type xenobiotics. PMID:20177059
Human carboxymethylenebutenolidase as a bioactivating hydrolase of olmesartan medoxomil in liver and intestine.
Ishizuka, Tomoko; Fujimori, Izumi; Kato, Mitsunori; Noji-Sakikawa, Chisa; Saito, Motoko; Yoshigae, Yasushi; Kubota, Kazuishi; Kurihara, Atsushi; Izumi, Takashi; Ikeda, Toshihiko; Okazaki, Osamu
Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the identification and characterization of the OM bioactivating enzyme that hydrolyzes the prodrug and converts to its pharmacologically active metabolite olmesartan in human liver and intestine. The protein was purified from human liver cytosol by successive column chromatography and was identified by mass spectrometry to be a carboxymethylenebutenolidase (CMBL) homolog. Human CMBL, whose endogenous function has still not been reported, is a human homolog of Pseudomonas dienelactone hydrolase involved in the bacterial halocatechol degradation pathway. The ubiquitous expression of human CMBL gene transcript in various tissues was observed. The recombinant human CMBL expressed in mammalian cells was clearly shown to activate OM. By comparing the enzyme kinetics and chemical inhibition properties between the recombinant protein and human tissue preparations, CMBL was demonstrated to be the primary OM bioactivating enzyme in the liver and intestine. The recombinant CMBL also converted other prodrugs having the same ester structure as OM, faropenem medoxomil and lenampicillin, to their active metabolites. CMBL exhibited a unique sensitivity to chemical inhibitors, thus, being distinguishable from other known esterases. Site-directed mutagenesis on the putative active residue Cys(132) of the recombinant CMBL caused a drastic reduction of the OM-hydrolyzing activity. We report for the first time that CMBL serves as a key enzyme in the bioactivation of OM, hydrolyzing the ester bond of the prodrug type xenobiotics. PMID:20177059
Bioactive properties and potentials cosmeceutical applications of phlorotannins isolated from brown seaweeds: A review.
Sanjeewa, Kalu Kapuge Asanka; Kim, Eun-A; Son, Kwang-Tae; Jeon, You-Jin
Currently, natural ingredients are becoming more attractive for the industries such as functional food, nutraceuticals, cosmeceutical and pharmaceutical industries as people starting to believe naturally occurring compounds are safer to humans than artificial compounds. Seaweeds are one of the most interesting organisms found in oceans around the earth, which are carrying great ecological importance and contribute to increase the biodiversity of ecosystems where they were originated and habitat. Within last few decades, discovery of secondary metabolites with biological activities from seaweeds has been significantly increased. Further, the unique secondary metabolites isolated from seaweeds including polysaccharides, carotenoids and polyphenols possess range of bioactive properties that make them potential ingredient for many industrial applications. Among those groups of compounds phlorotannins isolated from brown seaweeds have shown interesting bioactive properties including anti-cancer, anti-inflammation, anti-oxidant, anti-allergic, anti-wrinkling and hair growth promotion properties. Moreover, these properties associated with phlorotannins make them an ideal compounds to use as a functional ingredient in cosmeceutical products. Up to now no report has been reviewed about discuss properties of phlorotannins related to the cosmeceutical application. In the present review primary attention is given to the collect scientific data published about bioactive properties of brown algal phlorotannins related to the cosmeceutical industry. PMID:27362368
Quinazoline derivatives: synthesis and bioactivities
Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. This review summarizes the recent advances in the synthesis and biological activities investigations of quinazoline derivatives. According to the main method the authors adopted in their research design, those synthetic methods were divided into five main classifications, including Aza-reaction, Microwave-assisted reaction, Metal-mediated reaction, Ultrasound-promoted reaction and Phase-transfer catalysis reaction. The biological activities of the synthesized quinazoline derivatives also are discussed. PMID:23731671
Top-down Targeted Metabolomics Reveals a Sulfur-Containing Metabolite with Inhibitory Activity against Angiotensin-Converting Enzyme in Asparagus officinalis.
Nakabayashi, Ryo; Yang, Zhigang; Nishizawa, Tomoko; Mori, Tetsuya; Saito, Kazuki
The discovery of bioactive natural compounds containing sulfur, which is crucial for inhibitory activity against angiotensin-converting enzyme (ACE), is a challenging task in metabolomics. Herein, a new S-containing metabolite, asparaptine (1), was discovered in the spears of Asparagus officinalis by targeted metabolomics using mass spectrometry for S-containing metabolites. The contribution ratio (2.2%) to the IC50 value in the crude extract showed that asparaptine (1) is a new ACE inhibitor. PMID:25922884
Sun, shade, and secondary metabolites
Technology Transfer Automated Retrieval System (TEKTRAN)
My research program focuses on understanding plant primary and secondary metabolites. Grape secondary metabolites, such as phenolics, have long been valuable for the organoleptic properties they impart to fruit and wine, and, more recently, for their possible health benefits. These compounds develop...
Optimal Conditions for Antimicrobial Metabolites Production from a New Streptomyces sp. RUPA-08PR Isolated from Bangladeshi Soil
Ripa, F. A.; Nikkon, F.; Zaman, S.
An actinomycete strain was isolated from northern part of Bangladesh and identified as a new Streptomyces species on the basis of its morphological, biochemical, cultural characteristics and 16S rRNA data. Attempts were made to optimize the culture conditions for the production of antimicrobial metabolites by this strain. Antimicrobial metabolites production was started after 7 days of incubation of culture broth and reached its maximum levels after 10 days and thereafter gradually decreased. The maximum production of antimicrobial metabolites was obtained when the culture medium pH was adjusted to 8. The optimum temperature for antimicrobial metabolites production was 39℃, indicated the new strain as mesophilic organism. Basel medium supplemented with glucose and yeast extract as carbon and nitrogen sources, respectively, was proved to be the best for the production of bioactive metabolites. Maximum production of bioactive metabolites was when NaCl concentration was 1% and among different minerals tested, K2HPO4 and NaCl showed positive influence on antibiotic production by the strain. PMID:23983535
Improvement of hairy root cultures and plants by changing biosynthetic pathways leading to pharmaceutical metabolites: strategies and applications.
Ludwig-Müller, Jutta; Jahn, Linda; Lippert, Annemarie; Püschel, Joachim; Walter, Antje
A plethora of bioactive plant metabolites has been explored for pharmaceutical, food chemistry and agricultural applications. The chemical synthesis of these structures is often difficult, so plants are favorably used as producers. While whole plants can serve as a source for secondary metabolites and can be also improved by metabolic engineering, more often cell or organ cultures of relevant plant species are of interest. It should be noted that only in few cases the production for commercial application in such cultures has been achieved. Their genetic manipulation is sometimes faster and the production of a specific metabolite is more reliable, because of less environmental influences. In addition, upscaling in bioreactors is nowadays possible for many of these cultures, so some are already used in industry. There are approaches to alter the profile of metabolites not only by using plant genes, but also by using bacterial genes encoding modifying enzymes. Also, strategies to cope with unwanted or even toxic compounds are available. The need for metabolic engineering of plant secondary metabolite pathways is increasing with the rising demand for (novel) compounds with new bioactive properties. Here, we give some examples of recent developments for the metabolic engineering of plants and organ cultures, which can be used in the production of metabolites with interesting properties. PMID:24699436
Bioactive Components in Fish Venoms
Ziegman, Rebekah; Alewood, Paul
Animal venoms are widely recognized excellent resources for the discovery of novel drug leads and physiological tools. Most are comprised of a large number of components, of which the enzymes, small peptides, and proteins are studied for their important bioactivities. However, in spite of there being over 2000 venomous fish species, piscine venoms have been relatively underrepresented in the literature thus far. Most studies have explored whole or partially fractioned venom, revealing broad pharmacology, which includes cardiovascular, neuromuscular, cytotoxic, inflammatory, and nociceptive activities. Several large proteinaceous toxins, such as stonustoxin, verrucotoxin, and Sp-CTx, have been isolated from scorpaenoid fish. These form pores in cell membranes, resulting in cell death and creating a cascade of reactions that result in many, but not all, of the physiological symptoms observed from envenomation. Additionally, Natterins, a novel family of toxins possessing kininogenase activity have been found in toadfish venom. A variety of smaller protein toxins, as well as a small number of peptides, enzymes, and non-proteinaceous molecules have also been isolated from a range of fish venoms, but most remain poorly characterized. Many other bioactive fish venom components remain to be discovered and investigated. These represent an untapped treasure of potentially useful molecules. PMID:25941767
Bioactivity of plasma implanted biomaterials
NASA Astrophysics Data System (ADS)
Chu, Paul K.
Plasma immersion ion implantation and deposition (PIII&D) is an effective technique to enhance the surface bioactivity of materials. In this paper, recent progress made in our laboratory on plasma surface modification of biomedical materials is described. NiTi alloys have unique super-elastic and shape memory properties and are suitable for orthopedic implants but the leaching of toxic Ni may pose health hazards in humans. We have recently investigated the use of acetylene, oxygen and nitrogen PIII&D to prevent out-diffusion of nickel and good results have been obtained. Silicon is the most important material in the microelectronics industry but its surface biocompatibility has not been investigated in details. We have recently performed hydrogen PIII into silicon to improve the surface bioactivity and observed biomimetic growth of apatite on the surface in simulated body fluids. Diamond-like carbon (DLC) is widely used in the industry due to its excellent mechanical properties and chemical inertness and by incorporation of elements such as nitrogen and phosphorus, the surface blood compatibility can be improved. The properties as well as in vitro biological test results are discussed in this article.
Bioactive components in fish venoms.
Ziegman, Rebekah; Alewood, Paul
Animal venoms are widely recognized excellent resources for the discovery of novel drug leads and physiological tools. Most are comprised of a large number of components, of which the enzymes, small peptides, and proteins are studied for their important bioactivities. However, in spite of there being over 2000 venomous fish species, piscine venoms have been relatively underrepresented in the literature thus far. Most studies have explored whole or partially fractioned venom, revealing broad pharmacology, which includes cardiovascular, neuromuscular, cytotoxic, inflammatory, and nociceptive activities. Several large proteinaceous toxins, such as stonustoxin, verrucotoxin, and Sp-CTx, have been isolated from scorpaenoid fish. These form pores in cell membranes, resulting in cell death and creating a cascade of reactions that result in many, but not all, of the physiological symptoms observed from envenomation. Additionally, Natterins, a novel family of toxins possessing kininogenase activity have been found in toadfish venom. A variety of smaller protein toxins, as well as a small number of peptides, enzymes, and non-proteinaceous molecules have also been isolated from a range of fish venoms, but most remain poorly characterized. Many other bioactive fish venom components remain to be discovered and investigated. These represent an untapped treasure of potentially useful molecules. PMID:25941767
Bioactive Egg Components and Inflammation
Andersen, Catherine J.
Inflammation is a normal acute response of the immune system to pathogens and tissue injury. However, chronic inflammation is known to play a significant role in the pathophysiology of numerous chronic diseases, such as cardiovascular disease, type 2 diabetes mellitus, and cancer. Thus, the impact of dietary factors on inflammation may provide key insight into mitigating chronic disease risk. Eggs are recognized as a functional food that contain a variety of bioactive compounds that can influence pro- and anti-inflammatory pathways. Interestingly, the effects of egg consumption on inflammation varies across different populations, including those that are classified as healthy, overweight, metabolic syndrome, and type 2 diabetic. The following review will discuss the pro- and anti-inflammatory properties of egg components, with a focus on egg phospholipids, cholesterol, the carotenoids lutein and zeaxanthin, and bioactive proteins. The effects of egg consumption of inflammation across human populations will additionally be presented. Together, these findings have implications for population-specific dietary recommendations and chronic disease risk. PMID:26389951
Effect of grapefruit juice on the bioactivation of prasugrel
Holmberg, Mikko T; Tornio, Aleksi; Hyvärinen, Hanna; Neuvonen, Mikko; Neuvonen, Pertti J; Backman, Janne T; Niemi, Mikko
Aims The P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of grapefruit juice on prasugrel. Methods In a randomized crossover study, seven healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 4 days. On day 3, they ingested a single 10 mg dose of prasugrel with an additional 200 ml of grapefruit juice or water. Plasma concentrations of prasugrel metabolites and the antiplatelet effect were measured. Results Grapefruit juice increased the geometric mean area under the plasma concentration–time curve (AUC0–∞) of the primary, inactive metabolite of prasugrel to 164% of the control value (95% confidence interval 122–220%, P = 0.008), without a significant effect on its peak plasma concentration (Cmax). The Cmax and AUC0–∞ of the secondary, active metabolite were decreased to 51% (95% confidence interval 32–84%, P = 0.017) and 74% of the control value (95% confidence interval 60–91%, P = 0.014) by grapefruit juice (P < 0.05). The average platelet inhibition, assessed with the VerifyNow® method at 0–24 h after prasugrel intake, was 5 percentage points (95% confidence interval 1–10 percentage points) lower in the grapefruit juice phase than in the water phase (P = 0.034). Conclusions Grapefruit juice reduces the bioactivation of prasugrel, but this has only a limited effect on the antiplatelet effect of prasugrel. PMID:25557052
Surface modification of bioactive glasses and preparation of PDLLA/bioactive glass composite films.
Gao, Yuan; Chang, Jiang
In order to improve the homogeneous dispersion of particles in the polymeric matrix, 45S5, mesoporous 58S, and 58S bioactive glasses were surface modified by esterification reactions with dodecyl alcohol at reflux temperature of 260 degrees C (named as m-45S5, m-mesoporous 58S, and m-58S, respectively). The modified particles showed better hydrophobicity and longer time of suspension in organic matrix. The PDLLA/bioactive glass composite films were fabricated using surface modified bioactive glass particles through solvent casting-evaporation method. Surface morphology, mechanical property, and bioactivity were investigated. The results revealed that the inorganic particle distribution and tensile strength of the composite films with modified bioactive glass particles were significantly improved while great bioactive properties were maintained. Scanning electron microscopy (SEM) observation illustrated that the modified bioactive glass particles were homogeneously dispersed in the PDLLA matrix. The maximum tensile strengths of composite films with modified bioactive glass particles were higher than that of composite films with unmodified bioactive glass particles. The bioactivity of the composite films were evaluated by being soaked in the simulated body fluid (SBF) and the SEM observation of the films suggested that the modified composite films were still bioactive in that they could induce the formation of HAp on its surface and the distribution of HAp was even more homogeneous on the film. The results mentioned above indicated that the surface modification of bioactive glasses with dodecyl alcohol was an effective method to prepare PDLLA/bioactive glass composites with enhanced properties. By studying the comparisons of modification effects among the three types of bioactive glasses, we could get the conclusion that the size and morphology of the inorganic particles would greatly affect the modification effects and the properties of composites. PMID:18801895
The profiling and identification of the metabolites of (+)-catechin and study on their distribution in rats by HPLC-DAD-ESI-IT-TOF-MS(n) technique.
Liang, Jing; Xu, Feng; Zhang, Ya-Zhou; Zang, Xin-Yu; Wang, Dan; Shang, Ming-Ying; Wang, Xuan; Chui, De-Hua; Cai, Shao-Qing
(+)-Catechin, a potential beneficial compound to human health, is widely distributed in plants and foods. A high-performance liquid chromatography with diode array detector and combined with electrospray ionization ion trap time-of-flight multistage mass spectrometry method was applied to profile and identify the metabolites of (+)-catechin in rats and to study the distribution of these metabolites in rat organs for the first time. In total, 51 phase II metabolites (44 new) and three phase I metabolites were tentatively identified, comprising 16 (+)-catechin conjugates, 14 diarylpropan-2-ol metabolites, 6 phenyl valerolactone metabolites and 18 aromatic acid metabolites. Further, 19 phase II metabolites were new compounds. The in vivo metabolic reactions of (+)-catechin in rats were found to be ring-cleavage, sulfation, glucuronidation, methylation, dehydroxylation and dehydrogenation. The numbers of detected metabolites in urine, plasma, small intestine, kidney, liver, lung, heart, brain and spleen were 53, 23, 27, 9, 7, 5, 3, 2 and 1, respectively. This indicated that small intestine, kidney and liver were the major organs for the distribution of (+)-catechin metabolites. In addition, eight metabolites were found to possess bioactivities according to literature. These results are very helpful for better comprehension of the in vivo metabolism of (+)-catechin and its pharmacological actions, and also can give strong indications on the effective forms of (+)-catechin in vivo. PMID:24105958
Impacts of biotic and abiotic stress on major quality attributing metabolites of coffee beans.
Vaddadi, Sridevi; Parvatam, Giridhar
Biotic stress factors such as Rhizopus oligosporus and Aspergillus niger mycelial extracts and abiotic elements methyljasmonate (MJ) and salicylic acid (SA), when administered through floral spray to Coffea canephora, showed significant influence on major bioactive metabolites of beans. Up to 42% caffeine, 39% theobromine and 46% trigonelline, along with 32% cafestol and kahweol content elevation was evident under respective elicitor treatments. Over all, the surge in respective metabolites depends on elicitor stress type and concentration. Abiotic factors MJ and SA were found to be efficient at 1 to 5 microM concentration in augmenting all the metabolites, compared to R. oligosporus and A. niger spray at 0.5-2.0% wherein the response was moderate as compared to abiotic stress, however significant compared to control. Though this elevation in caffeine, theobromine, cafestol and kahweol is not warranted from quality point of view, increase in trigonelline improves coffee quality. Besides increase in metabolites, stress mediated augmentation of bioactive compounds in coffee has a wide scope for studying gene expression pattern. PMID:25895259
Extraction and purification of high-value metabolites from microalgae: essential lipids, astaxanthin and phycobiliproteins.
Cuellar-Bermudez, Sara P; Aguilar-Hernandez, Iris; Cardenas-Chavez, Diana L; Ornelas-Soto, Nancy; Romero-Ogawa, Miguel A; Parra-Saldivar, Roberto
The marked trend and consumers growing interest in natural and healthy products have forced researches and industry to develop novel products with functional ingredients. Microalgae have been recognized as source of functional ingredients with positive health effects since these microorganisms produce polyunsaturated fatty acids, polysaccharides, natural pigments, essential minerals, vitamins, enzymes and bioactive peptides. For this reason, the manuscript reviews two of the main high-value metabolites which can be obtained from microalgae: pigments and essential lipids. Therefore, the extraction and purification methods for polyunsaturated fatty acids, astaxanthin, phycoerythrin and phycocyanin are described. Also, the effect that environmental growth conditions have in the production of these metabolites is described. This review summarizes the existing methods to extract and purify such metabolites in order to develop a feasible and sustainable algae industry. PMID:25223877
Extraction and purification of high-value metabolites from microalgae: essential lipids, astaxanthin and phycobiliproteins
Cuellar-Bermudez, Sara P; Aguilar-Hernandez, Iris; Cardenas-Chavez, Diana L; Ornelas-Soto, Nancy; Romero-Ogawa, Miguel A; Parra-Saldivar, Roberto
The marked trend and consumers growing interest in natural and healthy products have forced researches and industry to develop novel products with functional ingredients. Microalgae have been recognized as source of functional ingredients with positive health effects since these microorganisms produce polyunsaturated fatty acids, polysaccharides, natural pigments, essential minerals, vitamins, enzymes and bioactive peptides. For this reason, the manuscript reviews two of the main high-value metabolites which can be obtained from microalgae: pigments and essential lipids. Therefore, the extraction and purification methods for polyunsaturated fatty acids, astaxanthin, phycoerythrin and phycocyanin are described. Also, the effect that environmental growth conditions have in the production of these metabolites is described. This review summarizes the existing methods to extract and purify such metabolites in order to develop a feasible and sustainable algae industry. PMID:25223877
Investigation of Secondary Metabolites in Plants. A General Protocol for Undergraduate Research in Natural Products
NASA Astrophysics Data System (ADS)
Cannon, Jonathan; Li, Du; Wood, Steven G.; Owen, Noel L.; Gromova, Alexandra; Lutsky, Vladislav
Many plants contain compounds known as metabolites that are believed to play important roles, such as attracting insects or defending the plants from predators. Some plant metabolites have medicinal properties, and a large percentage of currently used medicines were derived from plant extracts. A general procedure is outlined for extracting, isolating, and purifying metabolites from plant specimens. A number of simple bioassays are described that can be used to ascertain the bioactivity of the extracts, and the techniques most commonly used for determining the molecular structures of the compounds are described. One example of a plant (Astragalus danicus) that has been used for medicinal purposes by indigenous people is described in detail, and several of the compounds isolated and identified from this plant are described.
Extrahepatic targets and cellular reactivity of drug metabolites.
Orhan, Hilmi
Biotransformation is one of the key elements of chemically induced toxicity. Although organisms have an intrinsic tendency to diminish the harm posed by chemical exposure with or without structural modification and excretion of the agents (detoxification), this is not always the case; toxification may also occur. The liver has evolved to be the center of biotransformation from the anatomical, physiological and biochemical points of view; it is located alongside the stomach and intestine, it receives more than 25% of the cardiac output and it contains, in general, the richest quantity but also variety of drug metabolizing enzymes. That is why many orally taken drug-induced toxic effects are seen in the liver. Nevertheless, non-hepatic tissues in the organism are also subjected to toxic insult. Although several instances have suggested transport of liver-bioactivated reactive metabolites to the target tissue is responsible, such as monocrotaline-associated lung toxicity, tetraethyl lead- and n-hexane-associated nervous system toxicity and 2-methoxyethanol-associated testis toxicity, etc. [1], the vast majority of data show local bioactivation in the target tissue is responsible for the extrahepatic toxic outcome. The impact of extrahepatic bioactivation and toxicity of drugs can also be seen in cases of drug attrition due to unacceptable toxicity; adverse cardiovascular effects were the foremost reason for drug withdrawals between 1993 and 2006 [2]. On the other hand, the parent drug and/or its stable metabolite( s) may also cause adverse effects such as inhibition of transporters, occlusion of bile secretion (cholestasis) and accumulation in organelles such as mitochondria, causing steatosis in liver and possibly in other organs. However, this review attempts to summarize only extrahepatic bioactivation of drugs/chemicals and their effects at the cellular and tissue level. Specifically, it focuses on the two most perfused organs, lung and heart tissue, as well as
Diphenylthiourea, a common rubber chemical, is bioactivated to potent skin sensitizers.
Samuelsson, Kristin; Bergström, Moa Andresen; Jonsson, Charlotte A; Westman, Gunnar; Karlberg, Ann-Therese
Diphenylthiourea (DPTU) is a known skin sensitizer commonly used as a vulcanization accelerator in the production of synthetic rubber, for example, neoprene. The versatile usage of neoprene is due to the multifaceted properties of the material; for example, it is stretchable, waterproof, and chemical- and abrasion-resistant. The wide application of neoprene has resulted in numerous case reports of dermatitis patients allergic to DPTU. The mechanism by which DPTU works as a contact allergen has not been described; thus, the aim of the present study was to investigate if DPTU is a prohapten that can be activated by skin metabolism. The metabolic activation and covalent binding of (14)C-labeled DPTU to proteins were tested using a skinlike cytochrome P450 (P450) cocktail containing the five most abundant P450s found in human skin (CYP1A1, 1B1, 2B6, 2E1, and 3A5) and human liver microsomes. The incubations were carried out in the presence or absence of the metabolite trapping agents glutathione, methoxylamine, and benzylamine. The metabolism mixtures were analyzed by LC-radiochromatography, LC-MS, and LC-MS/MS. DPTU was mainly metabolically activated to reactive sulfoxides resulting in desulfurated adducts in both enzymatic systems used. Also, phenylisothiocyanate and phenylisocyanate were found to be metabolites of DPTU. The sensitizing capacity of the substrate (DPTU) and three metabolites was tested in the murine local lymph node assay. Two out of three metabolites tested were strong skin sensitizers, whereas DPTU itself, as previously known, was negative using this mouse model. In conclusion, DPTU forms highly reactive metabolites upon bioactivation by enzymes present in the skin. These metabolites are able to induce skin sensitization and are probable causes for DPTU allergy. To increase the possibilities of diagnosing contact allergy to DPTU-containing items, we suggest that suitable metabolites of DPTU should be used for screening testing. PMID:21073181
Endogenous cross-talk of fungal metabolites
Sheridan, Kevin J.; Dolan, Stephen K.; Doyle, Sean
Non-ribosomal peptide (NRP) synthesis in fungi requires a ready supply of proteogenic and non-proteogenic amino acids which are subsequently incorporated into the nascent NRP via a thiotemplate mechanism catalyzed by NRP synthetases. Substrate amino acids can be modified prior to or during incorporation into the NRP, or following incorporation into an early stage amino acid-containing biosynthetic intermediate. These post-incorporation modifications involve a range of additional enzymatic activities including but not exclusively, monooxygenases, methyltransferases, epimerases, oxidoreductases, and glutathione S-transferases which are essential to effect biosynthesis of the final NRP. Likewise, polyketide biosynthesis is directly by polyketide synthase megaenzymes and cluster-encoded ancillary decorating enzymes. Additionally, a suite of additional primary metabolites, for example: coenzyme A (CoA), acetyl CoA, S-adenosylmethionine, glutathione (GSH), NADPH, malonyl CoA, and molecular oxygen, amongst others are required for NRP and polyketide synthesis (PKS). Clearly these processes must involve exquisite orchestration to facilitate the simultaneous biosynthesis of different types of NRPs, polyketides, and related metabolites requiring identical or similar biosynthetic precursors or co-factors. Moreover, the near identical structures of many natural products within a given family (e.g., ergot alkaloids), along with localization to similar regions within fungi (e.g., conidia) suggests that cross-talk may exist, in terms of biosynthesis and functionality. Finally, we speculate if certain biosynthetic steps involved in NRP and PKS play a role in cellular protection or environmental adaptation, and wonder if these enzymatic reactions are of equivalent importance to the actual biosynthesis of the final metabolite. PMID:25601857
Bioactive lipids in pathological retinopathy.
Ma, Qi; Shen, Jun-Hui; Shen, Sheng-Rong; Das, Undurti N
Diabetic retinopathy is a common condition that occurs in patients with diabetes with long-standing hyperglycemia that is characterized by inappropriate angiogenesis. This pathological angiogenesis could be a sort of physiological proliferative response to injury by the endothelium. Recent studies suggested that reactive oxygen species (ROS) play a significant role in this angiogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that plays a significant role in diabetic retinopathy. The interaction between VEGF and ROS, and theirs in turn with pro- and anti-inflammatory cytokines and anti-inflammatory bioactive lipid molecules such as lipoxins, resolvins, protectins, and maresins is particularly relevant to understand the pathophysiology of diabetic retinopathy and develop future therapeutic interventions. PMID:24188230
Bioactive furanonaphthoquinones from Crescentia cujete.
Hetzel, C E; Gunatilaka, A A; Glass, T E; Kingston, D G; Hoffmann, G; Johnson, R K
Bioassay-directed fractionation of the MeCOEt extract of Crescentia cujete (Bignonaceae) resulted in the isolation of (2S,3S)-3-hydroxy-5,6-dimethoxydehydroiso-alpha-lapachone [1], (2R)-5,6-dimethoxydehydroiso-alpha-lapachone [2], (2R)-5-methoxydehydroiso-alpha-lapachone [3], 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [4], 5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [5], 2-isopropenylnaphtho[2,3-b]furan-4,9-dione [6], and 5-hydroxydehydroiso-alpha-lapachone [7]. Compounds 1-3 are new, and all compounds are bioactive, showing selective activity towards DNA-repair-deficient yeast mutants. The isolation, structure elucidation, and biological activities of these compounds are reported. PMID:8254347
Synthesis Of Labeled Metabolites
Martinez, Rodolfo A.; Silks, III, Louis A.; Unkefer, Clifford J.; Atcher, Robert
The present invention is directed to labeled compounds, for example, isotopically enriched mustard gas metabolites including: [1,1',2,2'-.sup.13 C.sub.4 ]ethane, 1,1'-sulfonylbis[2-(methylthio); [1,1',2,2'-.sup.13 C.sub.4 ]ethane, 1-[[2-(methylsulfinyl)ethyl]sulfonyl]-2-(methylthio); [1,1',2,2'-.sup.13 C.sub.4 ]ethane, 1,1'-sulfonylbis[2-(methylsulfinyl)]; and, 2,2'-sulfinylbis([1,2-.sup.13 C.sub.2 ]ethanol of the general formula ##STR1## where Q.sup.1 is selected from the group consisting of sulfide (--S--), sulfone (--S(O)--), sulfoxide (--S(O.sub.2)--) and oxide (--O--), at least one C* is .sup.13 C, X is selected from the group consisting of hydrogen and deuterium, and Z is selected from the group consisting of hydroxide (--OH), and --Q.sup.2 --R where Q.sup.2 is selected from the group consisting of sulfide (--S--), sulfone(--S(O)--), sulfoxide (--S(O.sub.2)--) and oxide (--O--), and R is selected from the group consisting of hydrogen, a C.sub.1 to C.sub.4 lower alkyl, and amino acid moieties, with the proviso that when Z is a hydroxide and Q.sup.1 is a sulfide, then at least one X is deuterium.
Towards microbial fermentation metabolites as markers for health benefits of prebiotics.
Verbeke, Kristin A; Boobis, Alan R; Chiodini, Alessandro; Edwards, Christine A; Franck, Anne; Kleerebezem, Michiel; Nauta, Arjen; Raes, Jeroen; van Tol, Eric A F; Tuohy, Kieran M
Available evidence on the bioactive, nutritional and putative detrimental properties of gut microbial metabolites has been evaluated to support a more integrated view of how prebiotics might affect host health throughout life. The present literature inventory targeted evidence for the physiological and nutritional effects of metabolites, for example, SCFA, the potential toxicity of other metabolites and attempted to determine normal concentration ranges. Furthermore, the biological relevance of more holistic approaches like faecal water toxicity assays and metabolomics and the limitations of faecal measurements were addressed. Existing literature indicates that protein fermentation metabolites (phenol, p-cresol, indole, ammonia), typically considered as potentially harmful, occur at concentration ranges in the colon such that no toxic effects are expected either locally or following systemic absorption. The endproducts of saccharolytic fermentation, SCFA, may have effects on colonic health, host physiology, immunity, lipid and protein metabolism and appetite control. However, measuring SCFA concentrations in faeces is insufficient to assess the dynamic processes of their nutrikinetics. Existing literature on the usefulness of faecal water toxicity measures as indicators of cancer risk seems limited. In conclusion, at present there is insufficient evidence to use changes in faecal bacterial metabolite concentrations as markers of prebiotic effectiveness. Integration of results from metabolomics and metagenomics holds promise for understanding the health implications of prebiotic microbiome modulation but adequate tools for data integration and interpretation are currently lacking. Similarly, studies measuring metabolite fluxes in different body compartments to provide a more accurate picture of their nutrikinetics are needed. PMID:26156216
Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites
Ahn, Jiyun; Chung, Woo-Jae; Jang, Young Jin; Seong, Ki-Seung; Moon, Jae-Hak; Ha, Tae Youl; Jung, Chang Hwa
Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis. PMID:26317351
Untargeted MS-based small metabolite identification from the plant leaves and stems of Impatiens balsamina.
Chua, Lee Suan
The identification of plant metabolites is very important for the understanding of plant physiology including plant growth, development and defense mechanism, particularly for herbal medicinal plants. The metabolite profile could possibly be used for future drug discovery since the pharmacological activities of the indigenous herbs have been proven for centuries. An untargeted mass spectrometric approach was used to identify metabolites from the leaves and stems of Impatiens balsamina using LC-DAD-MS/MS. The putative compounds are mostly from the groups of phenolic, organic and amino acids which are essential for plant growth and as intermediates for other compounds. Alanine appeared to be the main amino acid in the plant because many alanine derived metabolites were detected. There are also several secondary metabolites from the groups of benzopyrones, benzofuranones, naphthoquinones, alkaloids and flavonoids. The widely reported bioactive components such as kaempferol, quercetin and their glycosylated, lawsone and its derivatives were detected in this study. The results also revealed that aqueous methanol could extract flavonoids better than water, and mostly, flavonoids were detected from the leaf samples. The score plots of component analysis show that there is a minor variance in the metabolite profiles of water and aqueous methanolic extracts with 21.5 and 30.5% of the total variance for the first principal component at the positive and negative ion modes, respectively. PMID:27135814
Bioactive compounds from northern plants.
Hohtola, Anja
Northern conditions are characterised by long days with much light and low temperatures during the growing season. It has been chimed that herbs and berries grown in the north are stronger tasting compared to those of southern origin. The compounds imparting aroma and color to berries and herbs are secondary metabolites which in plants mostly act as chemical means of defense. Recently, the production of secondary metabolites using plant cells has been the subject of expanding research. Light intensity, photoperiod and temperature have been reported to influence the biosynthesis of many secondary metabolites. Native wild aromatic and medicinal plant species of different families are being studied to meet the needs of raw material for the expanding industry of e.g., health-promoting food products known as nutraceutics. There are already a large number of known secondary compounds produced by plants, but the recent advances in modern extraction and analysis should enable many more as yet unknown compounds to be found, characterised and utilised. Rose root (Rhodiola rosea) is a perennial herbaceous plant which inhabits mountain regions throughout Europe, Asia and east coastal regions of North America. The extract made from the rhizomes acts as a stimulant like the Ginseng root. Roseroot has been categorized as an adaptogen and is reported to have many pharmacological properties. The biologically active components of the extract are salitroside tyrosol and cinnamic acid glycosides (rosavin, rosarin, rosin). Round-leaved sundew (Drosera rotundifolia L.) has circumboreal distribution. It inhabits nutrient-poor, moist and sunny areas such as peat bogs and wetlands. Sundew leaves are collected from the wild-type for various medicinal preparations and can be utilized in treating e.g., as an important "cough-medicine" for different respiratory diseases. The antimicrobial activity of extracts of aerial parts against various bacteria has been investigated. Drosera produces
Potential Pharmacological Resources: Natural Bioactive Compounds from Marine-Derived Fungi
Jin, Liming; Quan, Chunshan; Hou, Xiyan; Fan, Shengdi
In recent years, a considerable number of structurally unique metabolites with biological and pharmacological activities have been isolated from the marine-derived fungi, such as polyketides, alkaloids, peptides, lactones, terpenoids and steroids. Some of these compounds have anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, antibiotic and cytotoxic properties. This review partially summarizes the new bioactive compounds from marine-derived fungi with classification according to the sources of fungi and their biological activities. Those fungi found from 2014 to the present are discussed. PMID:27110799
Natural Products from Plant-associated Microorganisms: Distribution, Structural Diversity, Bioactivity, and Implications of Their Occurrence⊥
Gunatilaka, A. A. Leslie
A growing body of evidence suggests that plant-associated microorganisms, especially endophytic and rhizosphere bacteria and fungi, represent a huge and largely untapped resource of natural products with chemical structures that have been optimized by evolution for biological and ecological relevance. A diverse array of bioactive small molecule natural products has been encountered in these microorganisms. The structures of over 230 metabolites isolated and characterized from over 70 plant-associated microbial strains during the past four years are presented with information on their hosts, culture conditions, and biological activities. Some significant biological and ecological implications of their occurrence are also reviewed. PMID:16562864
Bioactivities and Health Benefits of Wild Fruits
Li, Ya; Zhang, Jiao-Jiao; Xu, Dong-Ping; Zhou, Tong; Zhou, Yue; Li, Sha; Li, Hua-Bin
Wild fruits are exotic or underutilized. Wild fruits contain many bioactive compounds, such as anthocyanins and flavonoids. Many studies have shown that wild fruits possess various bioactivities and health benefits, such as free radical scavenging, antioxidant, anti-inflammatory, antimicrobial, and anticancer activity. Therefore, wild fruits have the potential to be developed into functional foods or pharmaceuticals to prevent and treat several chronic diseases. In the present article, we review current knowledge about the bioactivities and health benefits of wild fruits, which is valuable for the exploitation and utilization of wild fruits. PMID:27527154
Bioactivities and Health Benefits of Wild Fruits.
Li, Ya; Zhang, Jiao-Jiao; Xu, Dong-Ping; Zhou, Tong; Zhou, Yue; Li, Sha; Li, Hua-Bin
Wild fruits are exotic or underutilized. Wild fruits contain many bioactive compounds, such as anthocyanins and flavonoids. Many studies have shown that wild fruits possess various bioactivities and health benefits, such as free radical scavenging, antioxidant, anti-inflammatory, antimicrobial, and anticancer activity. Therefore, wild fruits have the potential to be developed into functional foods or pharmaceuticals to prevent and treat several chronic diseases. In the present article, we review current knowledge about the bioactivities and health benefits of wild fruits, which is valuable for the exploitation and utilization of wild fruits. PMID:27527154
Sol-gel derived porous bioactive nanocomposites: Synthesis and in vitro bioactivity
NASA Astrophysics Data System (ADS)
Shankhwar, Nisha; Kothiyal, G. P.; Srinivasan, A.
Porous bioactive composites consisting of SiO2-CaO-Na2O-P2O5 bioactive glass-ceramic and synthetic water soluble polymer Polyvinylpyrrolidone [PVP (C6H9NO)n, MW˜40000 g/mol] have been synthesized by sol-gel route. As-prepared polymeric composites were characterized by X-ray diffraction (XRD) technique. Two major bone mineral phases, viz., hydroxyapatite [Ca10(PO4)6(OH)2] and wollastonite [calcium silicate (CaSiO3)] have been identified in the XRD patterns of the composites. Presence of these bone minerals indicates the bioactive nature of the composites. In vitro bioactivity tests confirm bioactivity in the porous composites. The flexibility offered by these bioactive polymer composites is advantageous for its application as implant material.
Persistent and widespread occurrence of bioactive quinone pigments during post-Paleozoic crinoid diversification
Wolkenstein, Klaus
Secondary metabolites often play an important role in the adaptation of organisms to their environment. However, little is known about the secondary metabolites of ancient organisms and their evolutionary history. Chemical analysis of exceptionally well-preserved colored fossil crinoids and modern crinoids from the deep sea suggests that bioactive polycyclic quinones related to hypericin were, and still are, globally widespread in post-Paleozoic crinoids. The discovery of hypericinoid pigments both in fossil and in present-day representatives of the order Isocrinida indicates that the pigments remained almost unchanged since the Mesozoic, also suggesting that the original color of hypericinoid-containing ancient crinoids may have been analogous to that of their modern relatives. The persistent and widespread occurrence, spatially as well as taxonomically, of hypericinoid pigments in various orders during the adaptive radiation of post-Paleozoic crinoids suggests a general functional importance of the pigments, contributing to the evolutionary success of the Crinoidea. PMID:25730856
Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.
Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly
A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. PMID:26264839
Bioactive Compounds Derived from the Yeast Metabolism of Aromatic Amino Acids during Alcoholic Fermentation
Guillamon, Jose Manuel; Torija, Maria Jesus; Beltran, Gemma; Troncoso, Ana M.; Garcia-Parrilla, M. Carmen
Metabolites resulting from nitrogen metabolism in yeast are currently found in some fermented beverages such as wine and beer. Their study has recently attracted the attention of researchers. Some metabolites derived from aromatic amino acids are bioactive compounds that can behave as hormones or even mimic their role in humans and may also act as regulators in yeast. Although the metabolic pathways for their formation are well known, the physiological significance is still far from being understood. The understanding of this relevance will be a key element in managing the production of these compounds under controlled conditions, to offer fermented food with specific enrichment in these compounds or even to use the yeast as nutritional complements. PMID:24895623
Bioactive Carbohydrates and Peptides in Foods: An Overview of Sources, Downstream Processing Steps and Associated Bioactivities
Hayes, Maria; Tiwari, Brijesh K.
Bioactive peptides and carbohydrates are sourced from a myriad of plant, animal and insects and have huge potential for use as food ingredients and pharmaceuticals. However, downstream processing bottlenecks hinder the potential use of these natural bioactive compounds and add cost to production processes. This review discusses the health benefits and bioactivities associated with peptides and carbohydrates of natural origin and downstream processing methodologies and novel processes which may be used to overcome these. PMID:26393573
Bioactive Carbohydrates and Peptides in Foods: An Overview of Sources, Downstream Processing Steps and Associated Bioactivities.
Hayes, Maria; Tiwari, Brijesh K
Bioactive peptides and carbohydrates are sourced from a myriad of plant, animal and insects and have huge potential for use as food ingredients and pharmaceuticals. However, downstream processing bottlenecks hinder the potential use of these natural bioactive compounds and add cost to production processes. This review discusses the health benefits and bioactivities associated with peptides and carbohydrates of natural origin and downstream processing methodologies and novel processes which may be used to overcome these. PMID:26393573
Prospects and challenges for industrial production of seaweed bioactives.
Hafting, Jeff T; Craigie, James S; Stengel, Dagmar B; Loureiro, Rafael R; Buschmann, Alejandro H; Yarish, Charles; Edwards, Maeve D; Critchley, Alan T
Large-scale seaweed cultivation has been instrumental in globalizing the seaweed industry since the 1950s. The domestication of seaweed cultivars (begun in the 1940s) ended the reliance on natural cycles of raw material availability for some species, with efforts driven by consumer demands that far exceeded the available supplies. Currently, seaweed cultivation is unrivaled in mariculture with 94% of annual seaweed biomass utilized globally being derived from cultivated sources. In the last decade, research has confirmed seaweeds as rich sources of potentially valuable, health-promoting compounds. Most existing seaweed cultivars and current cultivation techniques have been developed for producing commoditized biomass, and may not necessarily be optimized for the production of valuable bioactive compounds. The future of the seaweed industry will include the development of high value markets for functional foods, cosmeceuticals, nutraceuticals, and pharmaceuticals. Entry into these markets will require a level of standardization, efficacy, and traceability that has not previously been demanded of seaweed products. Both internal concentrations and composition of bioactive compounds can fluctuate seasonally, geographically, bathymetrically, and according to genetic variability even within individual species, especially where life history stages can be important. History shows that successful expansion of seaweed products into new markets requires the cultivation of domesticated seaweed cultivars. Demands of an evolving new industry based upon efficacy and standardization will require the selection of improved cultivars, the domestication of new species, and a refinement of existing cultivation techniques to improve quality control and traceability of products. PMID:26986880
Green tea catechins and their metabolites in human skin before and after exposure to ultraviolet radiation.
Clarke, Kayleigh A; Dew, Tristan P; Watson, Rachel E B; Farrar, Mark D; Osman, Joanne E; Nicolaou, Anna; Rhodes, Lesley E; Williamson, Gary
Dietary flavonoids may protect against sunburn inflammation in skin. Preliminary reports using less complete analysis suggest that certain catechins and their metabolites are found in skin biopsies and blister fluid after consumption of green tea; however, it is not known if they are affected by solar-simulated ultraviolet radiation (UVR) or whether conjugated forms, with consequently altered bioactivity, are present. The present study tested the hypothesis that UVR affects the catechin levels in the skin of healthy volunteers after consumption of green tea and how catechins in the plasma are related to their presence in skin tissue samples. In an open oral intervention study, 11 subjects consumed green tea and vitamin C supplements daily for 3months. Presupplementation and postsupplementation plasma samples, suction blister fluid and skin biopsies were collected; the latter two samples were collected both before and after UVR. A sensitive high-performance liquid chromatography/mass spectrometric assay was used to measure the intact catechin metabolites, conjugates and free forms. Seven green tea catechins and their corresponding metabolites were identified postsupplementation in skin biopsies, 20 in blister fluid and 26 in plasma, with 15 green tea catechin metabolites present in both blister fluid and plasma. The valerolactone, O-methyl-M4-O-sulfate, a gut microbiota metabolite of catechins, was significantly increased 1.6-fold by UVR in blister fluid samples. In conclusion, there were some common catechin metabolites in the plasma and blister fluid, and the concentration was always higher in plasma. The results suggest that green tea catechins and metabolites are bioavailable in skin and provide a novel link between catechin metabolites derived from the skin and gut microbiota. PMID:26454512
Advances on Bioactive Polysaccharides from Medicinal Plants.
Xie, Jian-Hua; Jin, Ming-Liang; Morris, Gordon A; Zha, Xue-Qiang; Chen, Han-Qing; Yi, Yang; Li, Jing-En; Wang, Zhi-Jun; Gao, Jie; Nie, Shao-Ping; Shang, Peng; Xie, Ming-Yong
In recent decades, the polysaccharides from the medicinal plants have attracted a lot of attention due to their significant bioactivities, such as anti-tumor activity, antioxidant activity, anticoagulant activity, antidiabetic activity, radioprotection effect, anti-viral activity, hypolipidemic and immunomodulatory activities, which make them suitable for medicinal applications. Previous studies have also shown that medicinal plant polysaccharides are non-toxic and show no side effects. Based on these encouraging observations, most researches have been focusing on the isolation and identification of polysaccharides, as well as their bioactivities. A large number of bioactive polysaccharides with different structural features and biological effects from medicinal plants have been purified and characterized. This review provides a comprehensive summary of the most recent developments in physiochemical, structural features and biological activities of bioactive polysaccharides from a number of important medicinal plants, such as polysaccharides from Astragalus membranaceus, Dendrobium plants, Bupleurum, Cactus fruits, Acanthopanax senticosus, Angelica sinensis (Oliv.) Diels, Aloe barbadensis Miller, and Dimocarpus longan Lour. Moreover, the paper has also been focused on the applications of bioactive polysaccharides for medicinal applications. Recent studies have provided evidence that polysaccharides from medicinal plants can play a vital role in bioactivities. The contents and data will serve as a useful reference material for further investigation, production, and application of these polysaccharides in functional foods and therapeutic agents. PMID:26463231
Activation of the Silent Secondary Metabolite Production by Introducing Neomycin-Resistance in a Marine-Derived Penicillium purpurogenum G59
Wu, Chang-Jing; Yi, Le; Cui, Cheng-Bin; Li, Chang-Wei; Wang, Nan; Han, Xiao
Introduction of neomycin-resistance into a marine-derived, wild-type Penicillium purpurogenum G59 resulted in activation of silent biosynthetic pathways for the secondary metabolite production. Upon treatment of G59 spores with neomycin and dimethyl sulfoxide (DMSO), a total of 56 mutants were obtained by single colony isolation. The acquired resistance of mutants to neomycin was testified by the resistance test. In contrast to the G59 strain, the EtOAc extracts of 28 mutants inhibited the human cancer K562 cells, indicating that the 28 mutants have acquired the capability to produce bioactive metabolites. HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses further indicated that diverse secondary metabolites have been newly produced in the bioactive mutant extracts. Followed isolation and characterization demonstrated that five bioactive secondary metabolites, curvularin (1), citrinin (2), penicitrinone A (3), erythro-23-O-methylneocyclocitrinol (4) and 22E-7α-methoxy-5α,6α-epoxyergosta-8(14),22-dien-3β-ol (5), were newly produced by a mutant, 4-30, compared to the G59 strain. All 1–5 were also not yet found in the secondary metabolites of other wild type P. purpurogenum strains. Compounds 1–5 inhibited human cancer K562, HL-60, HeLa and BGC-823 cells to varying extents. Both present bioassays and chemical investigations demonstrated that the introduction of neomycin-resistance into the marine-derived fungal G59 strain could activate silent secondary metabolite production. The present work not only extended the previous DMSO-mediated method for introducing drug-resistance in fungi both in DMSO concentrations and antibiotics, but also additionally exemplified effectiveness of this method for activating silent fungal secondary metabolites. This method could be applied to other fungal isolates to elicit their metabolic potentials to investigate secondary metabolites from silent biosynthetic pathways. PMID:25913704
N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: strategies to eliminate reactive metabolites.
Nair, Sajiv K; Matthews, Jean J; Cripps, Stephan J; Cheng, Hengmiao; Hoffman, Jacqui E; Smith, Christopher; Kupchinsky, Stanley; Siu, Michael; Taylor, Wendy D; Wang, Yong; Johnson, Theodore O; Dress, Klaus R; Edwards, Martin P; Zhou, Sue; Hosea, Natilie A; Lapaglia, Amy; Kang, Ping; Castro, Arturo; Ermolieff, Jacques; Fanjul, Andrea; Vogel, Jennifer E; Rejto, Paul; Dalvie, Deepak
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay. PMID:23489629
Liver S9 Fraction-Derived Metabolites of Curcumin Analogue UBS109
To address the shortcomings of the natural product curcumin, many groups have created analogues that share similar structural features while displaying superior properties, particularly in anticancer drug discovery. Relatively unexplored have been the mechanisms by which such compounds are metabolized. A comprehensive in vitro study of a curcumin analogue (UBS109) in liver S9 fractions from five different species is presented. Further, we examine the cell-based bioactivity of the major metabolites. In spite of the fact that UBS109 reduces tumor growth in mice, it is quickly metabolized in vitro and 94% protein bound in mouse plasma. The primary monounsaturated metabolite is only modestly bioactive against MDA-MB-231 breast cancer cells. These observations suggest that while the α,β-unsaturated ketone common to curcumin analogues is important for bioactivity, protein binding and tissue distribution may serve to protect UBS109 from full metabolism in vivo while allowing it to exert a pharmacological effect by means of slow drug release. PMID:24900828
Pyrazoloquinazolines: Synthetic strategies and bioactivities.
Garg, Mansi; Chauhan, Monika; Singh, Pankaj Kumar; Alex, Jimi Marin; Kumar, Raj
Numerous N-heterocycles are indisputably evidenced to exhibit myriad biological activities. In the recent past, attempts made to condense the various heterocycles have resulted in derivatives possessing better bioactivities. Among many such condensed heterocycles, pyrazoloquinazolines have managed to hold the attention of many researchers, owing to the broad spectrum of activities they portray. This review is the first of its kind to congregate the various pyrazoloquinazolines reported until now and categorizes these structurally isomeric classes into eleven different groups based on the fusion pattern of the ring such as [1,5-c], [5,1-b], [4,3-h], etc. Furthermore, this review is a concerted effort to highlight design, synthetic strategies as well as biological activities of each class of this condensed heterocycle. Structure-activity relationship studies and in silico approaches wherever reported have also been discussed. In addition, manuscript also offers scope for design, synthesis and generation of libraries of unreported classes of pyrazoloquinazolines for the biological evaluation. PMID:25438709
The cilium secretes bioactive ectosomes.
Wood, Christopher R; Huang, Kaiyao; Diener, Dennis R; Rosenbaum, Joel L
The release of membrane vesicles from the surface of cells into their surrounding environment is now recognized as an important pathway for the delivery of proteins to extracellular sites of biological function. Membrane vesicles of this kind, termed exosomes and ectosomes, are the result of active processes and have been shown to carry a wide array of biological effector molecules that can play roles in cell-to-cell communication and remodeling of the extracellular space. Degradation of the extracellular matrix (ECM) through the regulated release of proteolytic enzymes is a key process for development, morphogenesis, and cell migration in animal and plant cells. Here we show that the unicellular alga Chlamydomonas achieves the timely degradation of its mother cell wall, a type of ECM, through the budding of ectosomes directly from the membranes of its flagella. Using a combination of immunoelectron microscopy, immunofluorescence microscopy, and functional analysis, we demonstrate that these vesicles, which we term ciliary ectosomes, act as carriers of the proteolytic enzyme necessary for the liberation of daughter cells following mitosis. Chlamydomonas has proven to be the key unicellular model for the highly conserved mechanisms of mammalian cilia, and our results suggest that cilia may be an underappreciated source of bioactive, extracellular membrane vesicles. PMID:23623554
Herbal bioactivation, molecular targets and the toxicity relevance.
Chen, Xiao-Wu; Serag, Erini S; Sneed, Kevin B; Zhou, Shu-Feng
There have been increasing reports on the adverse reactions associated with herbal consumption. For many of these adverse reactions, the underlying biochemical mechanisms are unknown, but bioactivation of herbal compounds to generate reactive intermediates have been implicated. This minireview updates our knowledge on metabolic activation of herbal compounds, molecular targets and the toxicity relevance. A number of studies have documented that some herbal compounds can be converted to toxic or even carcinogenic metabolites by Phase I [e.g. cytochrome P450s (CYPs)] and less frequently by Phase II enzymes. For example, aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras and myc oncogenes and gene mutation in renal cells and finally carcinogenesis of the kidneys. Teucrin A and teuchamaedryn A, two diterpenoids found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming herbal supplements that caused severe hepatotoxicity, are converted by CYP3A4 to reactive epoxide which reacts with proteins such as CYP3A and epoxide hydrolase and inactivate them. Some naturally occurring alkenylbenzenes (e.g. safrole, methyleugenol and estragole) and flavonoids (e.g. quercetin) can undergo bioactivation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts. Extensive pulegone metabolism generated p-cresol that is a glutathione depletory. The hepatotoxicity of kava is possibly due to intracellular glutathione depletion and/or quinone formation. Moreover, several herbal compounds including capsaicin from chili peppers, dially sulfone in garlic, methysticin and dihydromethysticin in kava, oleuropein in olive oil, and resveratrol found in grape seeds are mechanism-based (suicide
New secondary metabolites from bioactive extracts of the fungus Armillaria tabescens
Technology Transfer Automated Retrieval System (TEKTRAN)
Ethyl acetate extracts of Armillaria tabescens (strain JNB-OZ344) mycelium showed significant fungistatic and bacteristatic activities against several major human pathogens including Candida albicans, Cryptococcus neoformans, Escherichia coli and Mycobacterium intracellulare. Chemical analysis of th...
Vitamin D metabolites and bioactive parathyroid hormone levels during Spacelab 2
NASA Technical Reports Server (NTRS)
Morey-Holton, Emily R.; Schnoes, Heinrich K.; Deluca, Hector F.; Phelps, Mary E.; Klein, Robert F.
The effect of an 8-day space flight (Spacelab mission 2) on plasma levels of the vitamin D and parathyroid hormones is investigated experimentally in four crew members. The results are presented in tables and graphs and briefly characterized. Parathyroid hormone levels remained normal throughout the flight, whereas vitamin D hormone levels increased significantly on day 1 but returned to normal by day 7.
Microbial metabolism Part 14 Isolation and bioactivity evaluation of microbial metabolites of resveratrol
Technology Transfer Automated Retrieval System (TEKTRAN)
The fungi, Beauveria bassiana (ATCC 13144) and Penicillium chrysogenium (ATCC 9480) transformed resveratrol (1) to resveratrol-3-O-sulfate (4). The former, in addition, gave 5-methoxyresveratrol-3-O-ß-glucoside (2) with the latter yielding 5-methoxyresveratrol-3-O-sulfate (3). The structures were es...
Interpreting diplodiosis: bioactive metabolites in Stenocarpella maydis ear rot of maize
Technology Transfer Automated Retrieval System (TEKTRAN)
Stenocarpella maydis is a fungal pathogen of major importance that causes a dry-rot of maize ears and is associated with a neuromycotoxicosis in cattle grazing harvested maize fields in southern Africa and Argentina. Chemical investigations of S. maydis rotted kernels at harvest in Illinois led to t...
Bioactive natural products from fungicolous Hawaiian isolates: Secondary metabolites from a Phialemoniopsis sp.
Technology Transfer Automated Retrieval System (TEKTRAN)
Chemical investigations of two fungal isolates initially identified as members of the genus Phialemonium are described. Both isolates were obtained as colonists of other fungi collected on the island of Hawaii and were later assigned as P. curvatum. However, P. curvatum has recently been reclassifie...
Biological characterization of fusapyrone and deoxyfusapyrone, two bioactive secondary metabolites of Fusarium semitectum.
Altomare, C; Perrone, G; Zonno, M C; Evidente, A; Pengue, R; Fanti, F; Polonelli, L
Fusapyrone (1) and deoxyfusapyrone (2), two alpha-pyrones originally isolated from rice cultures of Fusarium semitectum, were tested in several biological assays. Compounds 1 and 2 showed considerable antifungal activity against several plant pathogenic and/or mycotoxigenic filamentous fungi, although they were inactive toward yeasts isolated from plants and the Gram-positive bacterium Bacillus megaterium in disk diffusion assays. Compound 1 was consistently more active than 2. Among the tested fungi, Fusarium species were the least sensitive to the two pyrones, while Alternaria alternata, Ascochyta rabiei, Aspergillusflavus, Botrytis cinerea, Cladosporium cucumerinum, Phoma tracheiphila, and Penicillium verrucosum were the most sensitive. Compounds 1 and 2 also showed good inhibitory activity toward agents of human mycoses. Aspergilli were the most sensitive, while some species-specific variability was found among the Candida spp. In an Artemia salina larvae bioassay, 1 was not toxic at the highest concentration tested (500 microM), whereas the LC(50) of 2 was 37.1 microM (21.8 microg/mL). Neither 1 nor 2 was phytotoxic in a panel of assays that monitored plant-cell toxicity, as well as wilt-, chlorosis-, and necrosis-inducing activity. Moreover, 2 stimulated the root elongation of tomato seedlings at doses of 10 and 100 microM. In consideration of the biological activities evidenced in this study, 1 and 2 appear to be potential candidates for biotechnological applications, as well as good models for studies on mechanism(s) of action and structure-activity relationships. PMID:10978211
HPLC-DAD-MS identification of bioactive secondary metabolites from Ferula communis roots.
Arnoldi, Lolita; Ballero, Mauro; Fuzzati, Nicola; Maxia, Andrea; Mercalli, Enrico; Pagni, Luca
A simple HPLC method was developed to distinguish between 'poisonous' and 'non-poisonous' chemotypes of Ferula communis. The method was performed on a C8 reverse phase analytical column using a binary eluent (aqueous TFA 0.01%-TFA 0.01% in acetonitrile) under gradient condition. The two chemotypes showed different fingerprints. The identification of five coumarins and eleven daucane derivatives by HPLC-diode array detection (HPLC-DAD) and HPLC-MS is described. A coumarin, not yet described, was detected. PMID:15158993
Microbial metabolism Part 12 isolation characterization and bioactivity evaluation of eighteen microbial metabolites of 4'-hydroxyflavanone
Technology Transfer Automated Retrieval System (TEKTRAN)
Fermentation of 4'-hydroxyflavanone (1) with fungal cultures, Beauveria bassiana (ATCC 13144 and ATCC 7159) yielded 6,3',4'-trihydroxyflavanone (2), 3',4'-dihydroxyflavanone 6-O-B-D-4-methoxyglucopyranoside (3), 4'-hydroxyflavanone 3'-sulfate (4), 6,4'-dihydroxyflavanone 3'-sulfate (5) and 4'-hydrox...
New compounds and secondary metabolites from bioactive extracts of the fungus Armillaria tabescens
Bandara Herath, H.M.T.; Jacob, Melissa; Wilson, A. Dan; Abbas, Hamed K.; Nanayakkara, N. P. Dhammika
Ethyl acetate extracts of Armillaria tabescens (strain JNB-OZ344) showed significant fungistatic and bacteristatic activities against several major human pathogens including Candida albicans, Cryptococcus neoformans, Escherichia coli and Mycobacterium intracellulare. Chemical analysis of these extracts led to the isolation and identification of four new compounds emestrin-F (1), emestrin-G (2), 6-O-(4-O-methyl-β-D-glucopyranosyl)-8-hydroxy-2,7-dimethyl-4H-benzopyran-4-one (3) and cephalosporolide-J (4) along with five other previously known compounds, emestrin (5), cephalosporolide-E (6), decarestrictine-C2 (7), ergosterol and brassicasterol. Structural elucidation of all compounds was carried out by NMR and MS analysis. Antimicrobial assays revealed that compounds 1 and 5 were responsible for the observed growth-inhibitory activities of the fungal extracts against the human pathogens tested. PMID:23140424
Mentha L. species (Lamiaceae) as promising sources of bioactive secondary metabolites.
Mimica-Dukic, N; Bozin, B
The use of mint species in traditional and conventional medicine is mostly due to the presence of two classes of secondary bimolecules: monoterpenoids in essential oils and different structural types of phenolic compounds. Essential oils are known to act as antimicrobial, antispasmodic, carminative, and antiviral agents. In addition, essential oils of several mint species have been recently qualified as natural antioxidants. However, since oil composition is highly variable, the pharmacological activity strongly depends on certain chemorace. On the contrary, composition of phenolic constituents is relatively stable within species. The most important phenolic compounds in Mentha species are flavonoids. Mints are characterized by the presence of specific lipophilic flavonoids. Phenolic compounds of mints are found to poses a wide range of pharmacological activity: antioxidant, antiulcer, cytoprotective, heptoprotective, cholagogue, chemopreventive, anti-inflammatory, antidiabetogenic etc. However, besides healing properties some mint species can exhibit an adverse effect on human health. Here we report on botany, chemistry and activity of Mentha species with special respect to their significance for the modern phytotherapy. PMID:19075696
Bioactive Secondary Metabolites from Schizogyne sericea (Asteraceae) Endemic to Canary Islands.
Venditti, Alessandro; Bianco, Armandodoriano; Muscolo, Camilla; Zorzetto, Christian; Sánchez-Mateo, Candelaria C; Rabanal, Rosa M; Quassinti, Luana; Bramucci, Massimo; Damiano, Silvia; Iannarelli, Romilde; Lupidi, Giulio; Papa, Fabrizio; Petrelli, Dezemona; Vitali, Luca A; Vittori, Sauro; Maggi, Filippo
Schizogyne sericea (Asteraceae) is a halophytic shrub endemic to the Canary Islands and traditionally employed as analgesic, astringent, anti-inflammatory, and vulnerary. A comprehensive phytochemical investigation was conducted on the flowering aerial parts by analyzing both essential oil constituents and polar compounds. The essential oil was dominated by p-cymene, with the noteworthy occurrence of β-pinene and thymol esters. From the EtOH extract, eight compounds were isolated and structurally elucidated. Essential oil, polar fractions, and isolates (2), (4), and (5) were separately in vitro assayed for antiproliferative activity on human tumor cell lines (A375, MDA-MB 231, and HCT116) by MTT assay, for antioxidant potential by DPPH, ABTS, and FRAP assays, and for antimicrobial activity by the agar disk diffusion method. Results revealed that essential oil and compounds 1 and 2 exert a strong inhibition on tumor cells, and in some cases, higher than that of cisplatin. Fractions containing thymol derivatives (1 and 2) and caffeoylquinic acid derivatives 4 and 5 displayed antioxidant activity comparable to that of Trolox, making S. sericea extract an interesting natural product with potential applications as preservative or in the treatment of diseases in which oxidative stress plays an important role. PMID:27272544
Technology Transfer Automated Retrieval System (TEKTRAN)
Hypericum perforatum, commonly known as St. John's Wort, is a popular herbal supplement today in the United States taken for its reported anti-depressant and anti-viral properties. A large amount of literature on St. John's Wort has amassed over the last half-century, however this species contains a...
Isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites.
Magarvey, Nathan A; Keller, Jessica M; Bernan, Valerie; Dworkin, Martin; Sherman, David H
A unique selective enrichment procedure has resulted in the isolation and identification of two new genera of marine-derived actinobacteria. Approximately 90% of the microorganisms cultured by using the presented method were from the prospective new genera, a result indicative of its high selectivity. In this study, 102 actinomycetes were isolated from subtidal marine sediments collected from the Bismarck Sea and the Solomon Sea off the coast of Papua New Guinea. A combination of physiological parameters, chemotaxonomic characteristics, distinguishing 16S rRNA gene sequences, and phylogenetic analysis based on 16S rRNA genes provided strong evidence for the two new genera (represented by strains of the PNG1 clade and strain UMM518) within the family Micromonosporaceae. Biological activity testing of fermentation products from the new marine-derived actinomycetes revealed that several had activities against multidrug-resistant gram-positive pathogens, malignant cells, and vaccinia virus replication. PMID:15574955
Antimicrobial metabolites from marine microorganisms.
Habbu, Prasanna; Warad, Vijayanand; Shastri, Rajesh; Madagundi, Smita; Kulkarni, Venkatrao H
Marine ecological niches have recently been described as "particularly promising" sources for search of new antimicrobials to combat antibiotic-resistant strains of pathogenic microorganisms. Marine organisms are excellent sources for many industrial products, but they are partly explored. Over 30 000 compounds have been isolated from marine sources. Bacteria, fungi, and cyanobacteria obtained from various marine sources secret several industrially useful bioactive compounds, possessing antibacterial, antifungal, and antimycobacterial activities. Sustainable cultivation methods for promising marine organisms and biotechnological processes for selected compounds can be developed, along with the establishment of biosensors for monitoring the target compounds. The semisynthetic modifications of marine-based bioactive compounds produce their new derivatives, structural analogs and mimetics that could serve as novel lead compounds against resistant pathogens. The present review focuses on promising antimicrobial compounds isolated from marine microbes from 1991-2013. PMID:26968676
Countercurrent assisted quantitative recovery of metabolites from plant-associated natural deep eutectic solvents.
Liu, Yang; Garzon, Jahir; Friesen, J Brent; Zhang, Yu; McAlpine, James B; Lankin, David C; Chen, Shao-Nong; Pauli, Guido F
NAtural Deep Eutectic Solvents (NADES) are chemically simple but physiologically important plant constituents that exhibit unique solubilizing properties of other metabolites, including bioactive constituents. The high polarity of NADES introduces a challenge in the ability of conventional solid-support based chromatography to recover potential bioactive metabolites. This complicates the systematic explanation of the NADES' functions in botanical extracts. The present study utilizes countercurrent separation (CCS) methodology to overcome the recovery challenge. To demonstrate its feasibility, Glucose-Choline chloride-Water (GCWat, 2:5:5, mole/mole) served as a model NADES, and four widely used marker flavonoids with different polarities (rutin, quercetin, kaempferol, and daidzein) were chosen as model target analytes. In order to prepare GCWat with high consistency, a water drying study was performed. The unique capabilities of the recently introduced CherryOne system, offering volumetric phase metering, were used to monitor the CCS operations. The collected fractions were analyzed using UHPLC and NMR/quantitative NMR. CCS was able to recover the analytes from the NADES matrix with quantitative recoveries of 95.7%, 94.6%, 97.0%, and 96.7% for rutin, quercetin, kaempferol, and daidzein respectively. The CCS strategy enables recovery of target metabolites from NADES-containing crude extracts as well as from other chemical mixtures, and moreover offers a means of using NADES as environmentally friendly extraction solvents. PMID:27118320
Toxicological significance of dihydrodiol metabolites
Hsia, M.T.
Dihydrodiols are often found as the major organic-extractable metabolites of various olefinic or aromatic xenobiotics in many biological samples. Studies on the chemistry of dihydrodiol metabolites have provided insight into the pharmacokinetic behavior and the mode of action of the parent compound. The toxicology of dihydrodiol is more complex than what can be deduced solely on the basis of diminished bioavailability of the epoxide precursor, and the increased hydrophilicity associated with the dihydrodiol moiety. Dihydrodiols can be intrinsically toxic and may even represent metabolically activated species. Some of the dihydrodiol metabolites may still retain sufficient lipophilic character to serve again as substrates for microsomal oxygenases. Because of the tremendous chemical and biological diversity that existed among the various dihydrodiols, more mechanistic studies are needed to examine the toxicological properties of these compounds. It may be premature to conclude dihydrodiol formation as purely a detoxification route for xenobioties.
Redundant synthesis of a conidial polyketide by two distinct secondary metabolite clusters in Aspergillus fumigatus
Throckmorton, Kurt; Lim, Fang Yun; Kontoyiannis, Dimitrios P.; Zheng, Weifa; Keller, Nancy P.
Summary Filamentous fungi are renowned for the production of bioactive secondary metabolites. Typically, one distinct metabolite is generated from a specific secondary metabolite cluster. Here, we characterize the newly described trypacidin (tpc) cluster in the opportunistic human pathogen Aspergillus fumigatus. We find that this cluster as well as the previously characterized endocrocin (enc) cluster both contribute to the production of the spore metabolite endocrocin. Whereas trypacidin is eliminated when only tpc cluster genes are deleted, endocrocin production is only eliminated when both the tpc and enc non-reducing polyketide synthase-encoding genes, tpcC and encA, respectively, are deleted. EncC, an anthrone oxidase, converts the product released from EncA to endocrocin as a final product. In contrast, endocrocin synthesis by the tpc cluster likely results from incomplete catalysis by TpcK (a putative decarboxylase), as its deletion results in a nearly 10-fold increase in endocrocin production. We suggest endocrocin is likely a shunt product in all related non-reducing polyketide synthase clusters containing homologues of TpcK and TpcL (a putative anthrone oxidase), e.g. geodin and monodictyphenone. This finding represents an unusual example of two physically discrete secondary metabolite clusters generating the same natural product in one fungal species by distinct routes. PMID:26242966
Health supply chain management.
Zimmerman, Rolf; Gallagher, Pat
This chapter gives an educational overview of: * The actual application of supply chain practice and disciplines required for service delivery improvement within the current health environment. * A rationale for the application of Supply Chain Management (SCM) approaches to the Health sector. * The tools and methods available for supply chain analysis and benchmarking. * Key supply chain success factors. PMID:20407173
Development of bioactive and biodegradable chitosan-based injectable systems containing bioactive glass nanoparticles.
Couto, Daniela S; Hong, Zhongkui; Mano, João F
There is increasing interest in the development of new tissue engineering strategies to deliver cells and bioactive agents encapsulated in a biodegradable matrix through minimally invasive procedures. The present work proposes to combine chitosan-beta-glycerophosphate salt formulations with bioactive glass nanoparticles in order to conceive novel injectable thermo-responsive hydrogels for orthopaedic reconstructive and regenerative medicine applications. The initial rheological properties and the gelation points of the developed organic-inorganic in situ thermosetting systems were revealed to be adequate for intracorporal injection. In vitro bioactivity tests, using incubation protocols in simulated body fluid (SBF), allowed the observation of bone-like apatite formation in the hydrogel formulations containing bioactive nanoparticles. The density of the apatite formed increased with increasing bioactive glass content and soaking time in SBF. These results indicate that the stimuli-responsive hydrogels could potentially be used as temporary injectable scaffolds in bone tissue engineering applications. PMID:18835230
Bioactive molecules from sea hares.
Kamiya, H; Sakai, R; Jimbo, M
Sea hares, belonging to the order Opisthobranchia, subclass Gastropoda, are mollusks that have attracted many researchers who are interested in the chemical defense mechanisms of these soft and "shell-less" snails. Numbers of small molecules of dietary origin have been isolated from sea hares and some have ecologically relevant activities, such as fish deterrent activity or toxicity. Recently, however, greater attention has been paid to biomedically interesting sea hare isolates such as dolastatins, a series of antitumor peptide/macrolides isolated from Dolabella auricularia. Another series of bioactive peptide/macrolides, as represented by aplyronines, have been isolated from sea hares in Japanese waters. Although earlier studies indicated the potent antitumor activity of aplyronines, their clinical development has never been conducted because of the minute amount of compound available from the natural source. Recent synthetic studies, however, have made it possible to prepare these compounds and analogs for a structure-activity relationship study, and started to uncover their unique action mechanism towards their putative targets, microfilaments. Here, recent findings of small antitumor molecules isolated from Japanese sea hares are reviewed. Sea hares are also known to produce cytotoxic and antimicrobial proteins. In contrast to the small molecules of dietary origin, proteins are the genetic products of sea hares and they are likely to have some primary physiological functions in addition to ecological roles in the sea hare. Based on the biochemical properties and phylogenetic analysis of these proteins, we propose that they belong to one family of molecule, the "Aplysianin A family," although their molecular weights are apparently divided into two groups. Interestingly, the active principles in Aplysia species and Dolabella auricularia were shown to be L-amino acid oxidase (LAAO), a flavin enzyme that oxidizes an alpha-amino group of the substrate with
Microbial production of primary metabolites
NASA Astrophysics Data System (ADS)
Demain, Arnold L.
Microbial production of primary metabolites contributes significantly to the quality of life. Through fermentation, microorganisms growing on inexpensive carbon sources can produce valuable products such as amino acids, nucleotides, organic acids, and vitamins which can be added to food to enhance its flavor or increase its nutritive value. The contribution of microorganisms will go well beyond the food industry with the renewed interest in solvent fermentations. Microorganisms have the potential to provide many petroleum-derived products as well as the ethanol necessary for liquid fuel. The role of primary metabolites and the microbes which produce them will certainly increase in importance.
Sphingolipid metabolites in inflammatory disease
Maceyka, Michael; Spiegel, Sarah
Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes. Progress in our understanding of sphingolipid metabolism, state-of-the-art sphingolipidomic approaches and animal models have generated a large body of evidence demonstrating that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate, are signalling molecules that regulate a diverse range of cellular processes that are important in immunity, inflammation and inflammatory disorders. Recent insights into the molecular mechanisms of action of sphingolipid metabolites and new perspectives on their roles in regulating chronic inflammation have been reported. The knowledge gained in this emerging field will aid in the development of new therapeutic options for inflammatory disorders. PMID:24899305
Profiling a gut microbiota-generated catechin metabolite's fate in human blood cells using a metabolomic approach.
Mülek, Melanie; Fekete, Agnes; Wiest, Johannes; Holzgrabe, Ulrike; Mueller, Martin J; Högger, Petra
The microbial catechin metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone (M1) has been found in human plasma samples after intake of maritime pine bark extract (Pycnogenol). M1 has been previously shown to accumulate in endothelial and blood cells in vitro after facilitated uptake and to exhibit anti-inflammatory activity. The purpose of the present research approach was to systematically and comprehensively analyze the metabolism of M1 in human blood cells in vitro and in vivo. A metabolomic approach that had been successfully applied for drug metabolite profiling was chosen to detect 19 metabolite peaks of M1 which were subsequently further analyzed and validated. The metabolites were categorized into three levels of identification according to the Metabolomics Standards Initiative with six compounds each confirmed at levels 1 and 2 and seven putative metabolites at level 3. The predominant metabolites were glutathione conjugates which were rapidly formed and revealed prolonged presence within the cells. Although a formation of an intracellular conjugate of M1 and glutathione (M1-GSH) was already known two GSH conjugate isomers, M1-S-GSH and M1-N-GSH were observed in the current study. Additionally detected organosulfur metabolites were conjugates with oxidized glutathione and cysteine. Other biotransformation products constituted the open-chained ester form of M1 and a methylated M1. Six of the metabolites determined in in vitro assays were also detected in blood cells in vivo after ingestion of the pine bark extract by two volunteers. The present study provides the first evidence that multiple and structurally heterogeneous polyphenol metabolites can be generated in human blood cells. The bioactivity of the M1 metabolites and their contribution to the previously determined anti-inflammatory effects of M1 now need to be elucidated. PMID:26025814
Integrative Approach to Analyze Biodiversity and Anti-Inflammatory Bioactivity of Wedelia Medicinal Plants
Chen, Yung-Hsiang; Hsiao, Pei-Wen; Liao, Jiunn-Wang; Peng, Ching-I; Yang, Ning-Sun
For the development of "medical foods" and/or botanical drugs as defined USA FDA, clear and systemic characterizations of the taxonomy, index phytochemical components, and the functional or medicinal bioactivities of the reputed or candidate medicinal plant are needed. In this study, we used an integrative approach, including macroscopic and microscopic examination, marker gene analysis, and chemical fingerprinting, to authenticate and validate various species/varieties of Wedelia, a reputed medicinal plant that grows naturally and commonly used in Asian countries. The anti-inflammatory bioactivities of Wedelia extracts were then evaluated in a DSS-induced murine colitis model. Different species/varieties of Wedelia exhibited distinguishable morphology and histological structures. Analysis of the ribosomal DNA internal transcribed spacer (ITS) region revealed significant differences among these plants. Chemical profiling of test Wedelia species demonstrated candidate index compounds and distinguishable secondary metabolites, such as caffeic acid derivatives, which may serve as phytochemical markers or index for quality control and identification of specific Wedelia species. In assessing their effect on treating DSS induced-murine colitis, we observed that only the phytoextract from W. chinensis species exhibited significant anti-inflammatory bioactivity on DSS-induced murine colitis among the various Wedelia species commonly found in Taiwan. Our results provide a translational research approach that may serve as a useful reference platform for biotechnological applications of traditional phytomedicines. Our findings indicate that specific Wedelia species warrant further investigation for potential treatment of human inflammatory bowel disease. PMID:26042672
Berry Leaves: An Alternative Source of Bioactive Natural Products of Nutritional and Medicinal Value†
Ferlemi, Anastasia-Varvara; Lamari, Fotini N.
Berry fruits are recognized, worldwide, as "superfoods" due to the high content of bioactive natural products and the health benefits deriving from their consumption. Berry leaves are byproducts of berry cultivation; their traditional therapeutic use against several diseases, such as the common cold, inflammation, diabetes, and ocular dysfunction, has been almost forgotten nowadays. Nevertheless, the scientific interest regarding the leaf composition and beneficial properties grows, documenting that berry leaves may be considered an alternative source of bioactives. The main bioactive compounds in berry leaves are similar as in berry fruits, i.e., phenolic acids and esters, flavonols, anthocyanins, and procyanidins. The leaves are one of the richest sources of chlorogenic acid. In various studies, these secondary metabolites have demonstrated antioxidant, anti-inflammatory, cardioprotective, and neuroprotective properties. This review focuses on the phytochemical composition of the leaves of the commonest berry species, i.e., blackcurrant, blackberry, raspberry, bilberry, blueberry, cranberry, and lingonberry leaves, and presents their traditional medicinal uses and their biological activities in vitro and in vivo. PMID:27258314
Bioactive Sesterterpenes and Triterpenes from Marine Sponges: Occurrence and Pharmacological Significance
Ebada, Sherif S.; Lin, WenHan; Proksch, Peter
Marine ecosystems (>70% of the planet's surface) comprise a continuous resource of immeasurable biological activities and immense chemical entities. This diversity has provided a unique source of chemical compounds with potential bioactivities that could lead to potential new drug candidates. Many marine-living organisms are soft bodied and/or sessile. Consequently, they have developed toxic secondary metabolites or obtained them from microorganisms to defend themselves against predators [1]. For the last 30–40 years, marine invertebrates have been an attractive research topic for scientists all over the world. A relatively small number of marine plants, animals and microbes have yielded more than 15,000 natural products including numerous compounds with potential pharmaceutical potential. Some of these have already been launched on the pharmaceutical market such as Prialt® (ziconotide; potent analgesic) and Yondelis® (trabectedin or ET-743; antitumor) while others have entered clinical trials, e.g., alpidin and kahalalide F. Amongst the vast array of marine natural products, the terpenoids are one of the more commonly reported and discovered to date. Sesterterpenoids (C25) and triterpenoids (C30) are of frequent occurrence, particularly in marine sponges, and they show prominent bioactivities. In this review, we survey sesterterpenoids and triterpenoids obtained from marine sponges and highlight their bioactivities. PMID:20390108
Bioactive Peptides and Depsipeptides with Anticancer Potential: Sources from Marine Animals
Suarez-Jimenez, Guadalupe-Miroslava; Burgos-Hernandez, Armando; Ezquerra-Brauer, Josafat-Marina
Biologically active compounds with different modes of action, such as, antiproliferative, antioxidant, antimicrotubule, have been isolated from marine sources, specifically algae and cyanobacteria. Recently research has been focused on peptides from marine animal sources, since they have been found as secondary metabolites from sponges, ascidians, tunicates, and mollusks. The structural characteristics of these peptides include various unusual amino acid residues which may be responsible for their bioactivity. Moreover, protein hydrolysates formed by the enzymatic digestion of aquatic and marine by-products are an important source of bioactive peptides. Purified peptides from these sources have been shown to have antioxidant activity and cytotoxic effect on several human cancer cell lines such as HeLa, AGS, and DLD-1. These characteristics imply that the use of peptides from marine sources has potential for the prevention and treatment of cancer, and that they might also be useful as molecular models in anticancer drug research. This review focuses on the latest studies and critical research in this field, and evidences the immense potential of marine animals as bioactive peptide sources. PMID:22822350
Interaction of bioactive glasses with peritoneal macrophages and monocytes in vitro.
Bosetti, M; Hench, L; Cannas, M
Macrophage activation was analyzed following exposure to pure, crystalline alpha-quartz powders, two bioactive gel-glass powders of different compositions, and a melt-derived glass, 45S5 Bioglass. The release of reactive oxygen metabolites (chemiluminescence test), modifications of cell morphology, the amount of tumor necrosis factor alpha (TNFalpha) secreted, and the amount of TNFalpha mRNA expression were evaluated. The 45S5 Bioglass powders elicited the highest chemiluminescence response while the two solgel glasses had a lower response with less of an oxidative burst difference between them. Particulate bioactive glasses are actively ingested by mouse peritoneal macrophages, and only the 58S solgel glass had a moderate toxic effect on the macrophages. Macrophage cell morphology showed increased size and cell spreading, consistent with the high level of cytokine secretion induced by 45S5 Bioglass. The 45S5 Bioglass powders led to an increased release of TNFalpha and expression of TNFalpha mRNA relative to unstimulated and control treated monocytes. Bioactive glasses (and particularly 45S5 Bioglass) that in vivo induce rapid bone growth appear to activate an autocrine-like process in which the response evoked by the material (for example monocyte and macrophage activation with cytokine production) enhances subsequent interactions with cells in contact with the material. PMID:11835162
Eco-taxonomic insights into actinomycete symbionts of termites for discovery of novel bioactive compounds.
Kurtböke, D Ipek; French, John R J; Hayes, R Andrew; Quinn, Ronald J
Termites play a major role in foraging and degradation of plant biomass as well as cultivating bioactive microorganisms for their defense. Current advances in "omics" sciences are revealing insights into function-related presence of these symbionts, and their related biosynthetic activities and genes identified in gut symbiotic bacteria might offer a significant potential for biotechnology and biodiscovery. Actinomycetes have been the major producers of bioactive compounds with an extraordinary range of biological activities. These metabolites have been in use as anticancer agents, immune suppressants, and most notably, as antibiotics. Insect-associated actinomycetes have also been reported to produce a range of antibiotics such as dentigerumycin and mycangimycin. Advances in genomics targeting a single species of the unculturable microbial members are currently aiding an improved understanding of the symbiotic interrelationships among the gut microorganisms as well as revealing the taxonomical identity and functions of the complex multilayered symbiotic actinofloral layers. If combined with target-directed approaches, these molecular advances can provide guidance towards the design of highly selective culturing methods to generate further information related to the physiology and growth requirements of these bioactive actinomycetes associated with the termite guts. This chapter provides an overview on the termite gut symbiotic actinoflora in the light of current advances in the "omics" science, with examples of their detection and selective isolation from the guts of the Sunshine Coast regional termite Coptotermes lacteus in Queensland, Australia. PMID:24817085
Integrative approach to analyze biodiversity and anti-inflammatory bioactivity of Wedelia medicinal plants.
Lin, Wen-Ching; Wen, Chih-Chun; Chen, Yung-Hsiang; Hsiao, Pei-Wen; Liao, Jiunn-Wang; Peng, Ching-I; Yang, Ning-Sun
For the development of "medical foods" and/or botanical drugs as defined USA FDA, clear and systemic characterizations of the taxonomy, index phytochemical components, and the functional or medicinal bioactivities of the reputed or candidate medicinal plant are needed. In this study, we used an integrative approach, including macroscopic and microscopic examination, marker gene analysis, and chemical fingerprinting, to authenticate and validate various species/varieties of Wedelia, a reputed medicinal plant that grows naturally and commonly used in Asian countries. The anti-inflammatory bioactivities of Wedelia extracts were then evaluated in a DSS-induced murine colitis model. Different species/varieties of Wedelia exhibited distinguishable morphology and histological structures. Analysis of the ribosomal DNA internal transcribed spacer (ITS) region revealed significant differences among these plants. Chemical profiling of test Wedelia species demonstrated candidate index compounds and distinguishable secondary metabolites, such as caffeic acid derivatives, which may serve as phytochemical markers or index for quality control and identification of specific Wedelia species. In assessing their effect on treating DSS induced-murine colitis, we observed that only the phytoextract from W. chinensis species exhibited significant anti-inflammatory bioactivity on DSS-induced murine colitis among the various Wedelia species commonly found in Taiwan. Our results provide a translational research approach that may serve as a useful reference platform for biotechnological applications of traditional phytomedicines. Our findings indicate that specific Wedelia species warrant further investigation for potential treatment of human inflammatory bowel disease. PMID:26042672
Berry Leaves: An Alternative Source of Bioactive Natural Products of Nutritional and Medicinal Value.
Ferlemi, Anastasia-Varvara; Lamari, Fotini N
Berry fruits are recognized, worldwide, as "superfoods" due to the high content of bioactive natural products and the health benefits deriving from their consumption. Berry leaves are byproducts of berry cultivation; their traditional therapeutic use against several diseases, such as the common cold, inflammation, diabetes, and ocular dysfunction, has been almost forgotten nowadays. Nevertheless, the scientific interest regarding the leaf composition and beneficial properties grows, documenting that berry leaves may be considered an alternative source of bioactives. The main bioactive compounds in berry leaves are similar as in berry fruits, i.e., phenolic acids and esters, flavonols, anthocyanins, and procyanidins. The leaves are one of the richest sources of chlorogenic acid. In various studies, these secondary metabolites have demonstrated antioxidant, anti-inflammatory, cardioprotective, and neuroprotective properties. This review focuses on the phytochemical composition of the leaves of the commonest berry species, i.e., blackcurrant, blackberry, raspberry, bilberry, blueberry, cranberry, and lingonberry leaves, and presents their traditional medicinal uses and their biological activities in vitro and in vivo. PMID:27258314
Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients
Xie, Cen; Zhou, Jialan; Guo, Zitao; Diao, Xingxing; Gao, Zhiwei; Zhong, Dafang; Jiang, Haoyuan; Zhang, Lijia; Chen, Xiaoyan
Background and Purpose Famitinib is a novel multi-targeted receptor tyrosine kinase inhibitor under development for cancer treatment. This study aims to characterize the metabolic and bioactivation pathways of famitinib. Experimental Approach The metabolites in human plasma, urine and feces were identified via ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometry and confirmed using synthetic standards. Biotransformation and bioactivation mechanisms were investigated using microsomes, recombinant metabolic enzymes and hepatocytes. Key Results Famitinib was extensively metabolized after repeated oral administrations. Unchanged famitinib was the major circulating material, followed by N-desethylfaminitib (M3), whose steady-state exposure represented 7.2 to 7.5% that of the parent drug. Metabolites in the excreta were mainly from oxidative deamination (M1), N-desethylation (M3), oxidative defluorination (M7), indolylidene hydroxylation (M9-1 and M9-5) and secondary phase-II conjugations. CYP3A4/5 was the major contributor to M3 formation, CYP3A4/5 and aldehyde dehydrogenase to M1 formation and CYP1A1/2 to M7, M9-1 and M9-5 formations. Minor cysteine conjugates were observed in the plasma, urine and feces, implying the formation of reactive intermediate(s). In vitro microsomal studies proved that famitinib was bioactivated through epoxidation at indolylidene by CYP1A1/2 and spontaneously defluorinated rearrangement to afford a quinone-imine species. A correlation between famitinib hepatotoxicity and its bioactivation was observed in the primary human hepatocytes. Conclusion and Implications Famitinib is well absorbed and extensively metabolized in cancer patients. Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. The quinone-imine intermediate formed through bioactivation may be associated with famitinib hepatotoxicity. Co-administered CYP1A1/2 inducers or inhibitors may potentiate or
Enriching screening libraries with bioactive fragment space.
Zhang, Na; Zhao, Hongtao
By deconvoluting 238,073 bioactive molecules in the ChEMBL library into extended Murcko ring systems, we identified a set of 2245 ring systems present in at least 10 molecules. These ring systems belong to 2221 clusters by ECFP4 fingerprints with a minimum intracluster similarity of 0.8. Their overlap with ring systems in commercial libraries was further quantified. Our findings suggest that success of a small fragment library is driven by the convergence of effective coverage of bioactive ring systems (e.g., 10% coverage by 1000 fragments vs. 40% by 2million HTS compounds), high enrichment of bioactive ring systems, and low molecular complexity enhancing the probability of a match with the protein targets. Reconciling with the previous studies, bioactive ring systems are underrepresented in screening libraries. As such, we propose a library of virtual fragments with key functionalities via fragmentation of bioactive molecules. Its utility is exemplified by a prospective application on protein kinase CK2, resulting in the discovery of a series of novel inhibitors with the most potent compound having an IC50 of 0.5μM and a ligand efficiency of 0.41kcal/mol per heavy atom. PMID:27311891
Bioactive Compounds from Vitex leptobotrys#
Pan, Wenhui; Liu, Kanglun; Guan, Yifu; Tan, Ghee Teng; Hung, Nguyen Van; Cuong, Nguyen Manh; Soejarto, D. Doel; Pezzuto, John M.; Fong, Harry H.S.; Zhang, Hongjie
A new lignan, vitexkarinol (1), as well as a known lignan, neopaulownin (2), a known chalcone, 3-(4-hydroxyphenyl)-1-(2,4,6-trimethoxyphenyl)-2-propen-1-one (3), two known dehydroflavones, tsugafolin (4) and alpinetin (5), two known dipeptides, aurantiamide and aurantiamide acetate, a known sesquiterpene, vemopolyanthofuran, and five known carotenoid metabolites, vomifoliol, dihydrovomifoliol, dehydrovomifoliol, loliolide and isololiolide, were isolated from the leaves and twigs of Vitex leptobotrys through bioassay-guided fractionation. The chalcone (3) was found to inhibit HIV-1 replication by 77% at 15.9 µM, and the two dehydroflavones (4 and 5) showed weak anti-HIV activity with IC50 values of 118 and 130 µM, respectively, while being devoid of cytotoxicity at 150 µM. A chlorophyll-enriched fraction of V. leptobotrys, containing pheophorbide a, was found to inhibit the replication of HIV-1 by 80% at a concentration of 10 µg/mL. Compounds 1 and 3 were further selected to be evaluated against 21 viral targets available at NIAID (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD). PMID:24404757
Bioactivity characterization of Lactobacillus strains isolated from dairy products
Haghshenas, Babak; Nami, Yousef; Haghshenas, Minoo; Abdullah, Norhafizah; Rosli, Rozita; Radiah, Dayang; Yari Khosroushahi, Ahmad
This study aimed to find candidate strains of Lactobacillus isolated from sheep dairy products (yogurt and ewe colostrum) with probiotic and anticancer activity. A total of 100 samples were randomly collected from yogurt and colostrum and 125 lactic acid bacteria were isolated. Of these, 17 Lactobacillus strains belonging to five species (L. delbrueckii, L. plantarum, L. rhamnosus, L. paracasei, and L. casei) were identified. L. plantarum 17C and 13C, which isolated from colostrums, demonstrated remarkable results such as resistant to low pH and high concentrations of bile salts, susceptible to some antibiotics and good antimicrobial activity that candidate them as potential probiotics. Seven strains (1C, 5C, 12C, 13C, 17C, 7M, and 40M), the most resistant to simulated digestion, were further investigated to evaluate their capability to adhere to human intestinal Caco-2 cells. L. plantarum 17C was the most adherent strain. The bioactivity assessment of L. plantarum 17C showed anticancer effects via the induction of apoptosis on HT-29 human cancer cells and negligible side effects on one human epithelial normal cell line (FHs 74). The metabolites produced by this strain can be used as alternative pharmaceutical compounds with promising therapeutic indices because they are not cytotoxic to normal mammalian cells. PMID:26219634
Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides
Grünewald, Jan; Marahiel, Mohamed A.
Non-ribosomally synthesized peptides have compelling biological activities ranging from antimicrobial to immunosuppressive and from cytostatic to antitumor. The broad spectrum of applications in modern medicine is reflected in the great structural diversity of these natural products. They contain unique building blocks, such as d-amino acids, fatty acids, sugar moieties, and heterocyclic elements, as well as halogenated, methylated, and formylated residues. In the past decades, significant progress has been made toward the understanding of the biosynthesis of these secondary metabolites by nonribosomal peptide synthetases (NRPSs) and their associated tailoring enzymes. Guided by this knowledge, researchers genetically redesigned the NRPS template to synthesize new peptide products. Moreover, chemoenzymatic strategies were developed to rationally engineer nonribosomal peptides products in order to increase or alter their bioactivities. Specifically, chemical synthesis combined with peptide cyclization mediated by nonribosomal thioesterase domains enabled the synthesis of glycosylated cyclopeptides, inhibitors of integrin receptors, peptide/polyketide hybrids, lipopeptide antibiotics, and streptogramin B antibiotics. In addition to the synthetic potential of these cyclization catalysts, which is the main focus of this review, different enzymes for tailoring of peptide scaffolds as well as the manipulation of carrier proteins with reporter-labeled coenzyme A analogs are discussed. PMID:16524919
Bioactive heterocycles containing endocyclic N-hydroxy groups
Rani, Reshma; Granchi, Carlotta
Drug-likeness rules consider N-O single bonds as "structural alerts" which should not be present in a perspective drug candidate. In most cases this concern is correct, since it is known that N-hydroxy metabolites of branded drugs produce reactive species that cause serious side effects. However, this dangerous reactivity of the N-OH species generally takes place when the nitrogen atom is not comprised in a cyclic moiety. In fact, the same type of metabolic behavior should not be expected when the nitrogen atom is included in the ring of an aromatic heterocyclic scaffold. Nevertheless, heterocycles bearing endocyclic N-hydroxy portions have so far been poorly studied as chemical classes that may provide new therapeutic agents. This review provides an overview of N-OH-containing heterocycles with reported bioactivities that may be considered as therapeutically relevant and, therefore, may extend the chemical space available for the future development of novel pharmaceuticals. A systematic treatment of the various chemical classes belonging to this particular family of molecules is described along with a discussion of the biological activities associated to the most important examples. PMID:25466924
P450 2C18 catalyzes the metabolic bioactivation of phenytoin.
Kinobe, Robert T; Parkinson, Oliver T; Mitchell, Deanne J; Gillam, Elizabeth M J
The safe clinical use of phenytoin (PHT) is compromised by a drug hypersensitivity reaction, hypothesized to be due to bioactivation of the drug to a protein-reactive metabolite. Previous studies have shown PHT is metabolized to the primary phenol metabolite, HPPH, then converted to a catechol which then autoxidizes to produce reactive quinone. PHT is known to be metabolized to HPPH by cytochromes P450 (P450s) 2C9 and 2C19 and then to the catechol by P450s 2C9, 2C19, 3A4, 3A5, and 3A7. However, the role of many poorly expressed or extrahepatic P450s in the metabolism and/or bioactivation of PHT is not known. The aim of this study was to assess the ability of other human P450s to catalyze PHT metabolism. P450 2C18 catalyzed the primary hydroxylation of PHT with a kcat (2.46 +/- 0.09 min-1) more than an order of magnitude higher than that of P450 2C9 (0.051 +/- 0.004 min-1) and P450 2C19 (0.054 +/- 0.002 min-1) and Km (45 +/- 5 microM) slightly greater than those of P450 2C9 (12 +/- 4 microM) and P450 2C19 (29 +/- 4 microM). P450 2C18 also efficiently catalyzed the secondary hydroxylation of PHT as well as covalent drug-protein adduct formation from both PHT and HPPH in vitro. While P450 2C18 is expressed poorly in the liver, significant expression has been reported in the skin. Thus, P450 2C18 may be important for the extrahepatic tissue-specific bioactivation of PHT in vivo. PMID:16359177
Anthocyanins and their physiologically relevant metabolites alter the expression of IL‐6 and VCAM‐1 in CD40L and oxidized LDL challenged vascular endothelial cells
Amin, Hiren P.; Czank, Charles; Raheem, Saki; Zhang, Qingzhi; Botting, Nigel P.; Cassidy, Aedín
Scope In vitro and in vivo studies suggest that dietary anthocyanins modulate cardiovascular disease risk; however, given anthocyanins extensive metabolism, it is likely that their degradation products and conjugated metabolites are responsible for this reported bioactivity. Methods and results Human vascular endothelial cells were stimulated with either oxidized LDL (oxLDL) or cluster of differentiation 40 ligand (CD40L) and cotreated with cyanidin‐3‐glucoside and 11 of its recently identified metabolites, at 0.1, 1, and 10 μM concentrations. Protein and gene expression of IL‐6 and VCAM‐1 was quantified by ELISA and RT‐qPCR. In oxLDL‐stimulated cells the parent anthocyanin had no effect on IL‐6 production, whereas numerous anthocyanin metabolites significantly reduced IL‐6 protein levels; phase II conjugates of protocatechuic acid produced the greatest effects (>75% reduction, p ≤ 0.05). In CD40L‐stimulated cells the anthocyanin and its phase II metabolites reduced IL‐6 protein production, where protocatechuic acid‐4‐sulfate induced the greatest reduction (>96% reduction, p ≤ 0.03). Similarly, the anthocyanin and its metabolites reduced VCAM‐1 protein production, with ferulic acid producing the greatest effect (>65% reduction, p ≤ 0.04). Conclusion These novel data provide evidence to suggest that anthocyanin metabolites are bioactive at physiologically relevant concentrations and have the potential to modulate cardiovascular disease progression by altering the expression of inflammatory mediators. PMID:25787755
Involvement of CYP 2E1 enzyme in ovotoxicity caused by 4-vinylcyclohexene and its metabolites.
Rajapaksa, Kathila S; Cannady, Ellen A; Sipes, I Glenn; Hoyer, Patricia B
4-Vinylcyclohexene (VCH) is bioactivated by hepatic CYP 2A and 2B to a monoepoxide (VCM) and subsequently to an ovotoxic diepoxide metabolite (VCD). Studies suggest that the ovary can directly bioactivate VCH via CYP 2E1. The current study was designed to evaluate the role of ovarian CYP 2E1 in VCM-induced ovotoxicity. Postnatal day 4 B6C3F(1) and CYP 2E1 wild-type (+/+) and null (-/-) mouse ovaries were cultured (15 days) with VCD (30 microM), 1,2-VCM (125-1000 microM), or vehicle. Twenty-eight days female CYP 2E1 +/+ and -/- mice were dosed daily (15 days; ip) with VCH, 1,2-VCM, VCD or vehicle. Following culture or in vivo dosing, ovaries were histologically evaluated. In culture, VCD decreased (p<0.05) primordial and primary follicles in ovaries from all three groups of mice. 1,2-VCM decreased (p<0.05) primordial follicles in B6C3F(1) and CYP 2E1 +/+ ovaries, but not in CYP 2E1 -/- ovaries in culture. 1,2-VCM did not affect primary follicles in any group of mouse ovaries. Conversely, following in vivo dosing, primordial and primary follicles were reduced (p<0.05) by VCD and VCM in CYP2E1 +/+ and -/-, and by VCH in +/+ mice. The data demonstrate that, whereas in vitro ovarian bioactivation of VCM requires CYP 2E1 enzyme, in vivo CYP 2E1 plays a minimal role. Thus, the findings support that hepatic metabolism dominates the contribution made by the ovary in bioactivation of VCM to its ovotoxic metabolite, VCD. This study also demonstrates the use of a novel ovarian culture system to evaluate ovary-specific metabolism of xenobiotics. PMID:17462685
Involvement of CYP 2E1 enzyme in ovotoxicity caused by 4-vinylcyclohexene and its metabolites
Rajapaksa, Kathila S.; Cannady, Ellen A.; Sipes, I. Glenn; Hoyer, Patricia B. . E-mail: email@example.com
4-Vinylcyclohexene (VCH) is bioactivated by hepatic CYP 2A and 2B to a monoepoxide (VCM) and subsequently to an ovotoxic diepoxide metabolite (VCD). Studies suggest that the ovary can directly bioactivate VCH via CYP 2E1. The current study was designed to evaluate the role of ovarian CYP 2E1 in VCM-induced ovotoxicity. Postnatal day 4 B6C3F{sub 1} and CYP 2E1 wild-type (+/+) and null (-/-) mouse ovaries were cultured (15 days) with VCD (30 {mu}M), 1,2-VCM (125-1000 {mu}M), or vehicle. Twenty-eight days female CYP 2E1 +/+ and -/- mice were dosed daily (15 days; ip) with VCH, 1,2-VCM, VCD or vehicle. Following culture or in vivo dosing, ovaries were histologically evaluated. In culture, VCD decreased (p < 0.05) primordial and primary follicles in ovaries from all three groups of mice. 1,2-VCM decreased (p < 0.05) primordial follicles in B6C3F{sub 1} and CYP 2E1 +/+ ovaries, but not in CYP 2E1 -/- ovaries in culture. 1,2-VCM did not affect primary follicles in any group of mouse ovaries. Conversely, following in vivo dosing, primordial and primary follicles were reduced (p < 0.05) by VCD and VCM in CYP2E1 +/+ and -/-, and by VCH in +/+ mice. The data demonstrate that, whereas in vitro ovarian bioactivation of VCM requires CYP 2E1 enzyme, in vivo CYP 2E1 plays a minimal role. Thus, the findings support that hepatic metabolism dominates the contribution made by the ovary in bioactivation of VCM to its ovotoxic metabolite, VCD. This study also demonstrates the use of a novel ovarian culture system to evaluate ovary-specific metabolism of xenobiotics.
Primary expectations of secondary metabolites
Technology Transfer Automated Retrieval System (TEKTRAN)
Plant secondary metabolites (e.g., phenolics) are important for human health, in addition to the organoleptic properties they impart to fresh and processed foods. Consumer expectations such as appearance, taste, or texture influence their purchasing decisions. Thorough identification of phenolic com...
Natural products: Hunting microbial metabolites
NASA Astrophysics Data System (ADS)
Schmidt, Eric W.
Symbiotic bacteria synthesize many specialized small molecules; however, establishing the role these chemicals play in human health and disease has been difficult. Now, the chemical structure and mechanism of the Escherichia coli product colibactin provides insight into the link between this secondary metabolite and colorectal cancer.
Automated analysis of oxidative metabolites
NASA Technical Reports Server (NTRS)
Furner, R. L. (Inventor)
An automated system for the study of drug metabolism is described. The system monitors the oxidative metabolites of aromatic amines and of compounds which produce formaldehyde on oxidative dealkylation. It includes color developing compositions suitable for detecting hyroxylated aromatic amines and formaldehyde.
Technology Transfer Automated Retrieval System (TEKTRAN)
Echinacea extracts have historically been used as herbal remedies to treat colds, coughs and snake bites. Echinacea products are currently sold as a popular herbal-remedy used for general enhancement of the immune system. However, the genetic variation in metabolites has not been systematically ch...
Marine Microbial Secondary Metabolites: Pathways, Evolution and Physiological Roles.
Giordano, Daniela; Coppola, Daniela; Russo, Roberta; Denaro, Renata; Giuliano, Laura; Lauro, Federico M; di Prisco, Guido; Verde, Cinzia
Microbes produce a huge array of secondary metabolites endowed with important ecological functions. These molecules, which can be catalogued as natural products, have long been exploited in medical fields as antibiotics, anticancer and anti-infective agents. Recent years have seen considerable advances in elucidating natural-product biosynthesis and many drugs used today are natural products or natural-product derivatives. The major contribution to recent knowledge came from application of genomics to secondary metabolism and was facilitated by all relevant genes being organised in a contiguous DNA segment known as gene cluster. Clustering of genes regulating biosynthesis in bacteria is virtually universal. Modular gene clusters can be mixed and matched during evolution to generate structural diversity in natural products. Biosynthesis of many natural products requires the participation of complex molecular machines known as polyketide synthases and non-ribosomal peptide synthetases. Discovery of new evolutionary links between the polyketide synthase and fatty acid synthase pathways may help to understand the selective advantages that led to evolution of secondary-metabolite biosynthesis within bacteria. Secondary metabolites confer selective advantages, either as antibiotics or by providing a chemical language that allows communication among species, with other organisms and their environment. Herewith, we discuss these aspects focusing on the most clinically relevant bioactive molecules, the thiotemplated modular systems that include polyketide synthases, non-ribosomal peptide synthetases and fatty acid synthases. We begin by describing the evolutionary and physiological role of marine natural products, their structural/functional features, mechanisms of action and biosynthesis, then turn to genomic and metagenomic approaches, highlighting how the growing body of information on microbial natural products can be used to address fundamental problems in
Trapping Methylglyoxal by Genistein and Its Metabolites in Mice.
Wang, Pei; Chen, Huadong; Sang, Shengmin
Increasing evidence supports dicarbonyl stress such as methylglyoxal (MGO) as one of the major pathogenic links between hyperglycemia and diabetic complications. In vitro studies have shown that dietary flavonoids can inhibit the formation of advanced glycation end products (AGEs) by trapping MGO. However, whether flavonoids can trap MGO in vivo and whether biotransformation limits the trapping capacity of flavonoids remain virtually unknown. In this study, we investigated whether genistein (GEN), the major soy isoflavone, could trap MGO in mice by promoting the formation of MGO adducts of GEN and its metabolites. Two different mouse studies were conducted. In the acute study, a single dose of MGO and GEN were administered to mice via oral gavage. In the chronic study, MGO was given to mice in drinking water for 1 month and then GEN was given to mice for 4 consecutive days via oral gavage. Two mono-MGO adducts of GEN and six mono-MGO adducts of GEN phase I and microbial metabolites were identified in mouse urine samples from these studies using liquid chromatography/electrospray ionization tandem mass spectrometry. The structures of these MGO adducts were confirmed by analyzing their MS(n) (n = 1-4) spectra as well as by comparing them with the tandem mass spectra of authentic standards. All of the MGO adducts presented in their phase II conjugated forms in mouse urine samples in the acute and chronic studies. To our knowledge, this is the first in vivo evidence to demonstrate the trapping efficacy of GEN in mice and to show that the metabolites of GEN remain bioactive. PMID:26881724
Exploring in vitro, in vivo metabolism of mogroside V and distribution of its metabolites in rats by HPLC-ESI-IT-TOF-MS(n).
Xu, Feng; Li, Dian-Peng; Huang, Zhen-Cong; Lu, Feng-Lai; Wang, Lei; Huang, Yong-Lin; Wang, Ru-Feng; Liu, Guang-Xue; Shang, Ming-Ying; Cai, Shao-Qing
Mogroside V, a cucurbitane-type saponin, is not only the major bioactive constituent of traditional Chinese medicine Siraitiae Fructus, but also a widely used sweetener. To clarify its biotransformation process and identify its effective forms in vivo, we studied its metabolism in a human intestinal bacteria incubation system, a rat hepatic 9000g supernatant (S9) incubation system, and rats. Meanwhile, the distribution of mogroside V and its metabolites was also reported firstly. Seventy-seven new metabolites, including 52 oxidation products formed by mono- to tetra- hydroxylation/dehydrogenation, were identified with the aid of HPLC in tandem with ESI ion trap (IT) TOF multistage mass spectrometry (HPLC-ESI-IT-TOF-MS(n)). Specifically, 14 metabolites were identified in human intestinal bacteria incubation system, 4 in hepatic S9 incubation system, 58 in faeces, 29 in urine, 14 in plasma, 34 in heart, 33 in liver, 39 in spleen, 39 in lungs, 42 in kidneys, 45 in stomach, and 51 in small intestine. The metabolic pathways of mogroside V were proposed and the identified metabolic reactions were deglycosylation, hydroxylation, dehydrogenation, isomerization, glucosylation, and methylation. Mogroside V and its metabolites were distributed unevenly in the organs of treated rats. Seven bioactive metabolites of mogroside V were identified, among which mogroside IIE was abundant in heart, liver, spleen and lung, suggesting that it may contribute to the bioactivities of mogroside V. Mogroside V was mainly excreted in urine, whereas its metabolites were mainly excreted in faeces. To our knowledge, this is the first report that a plant constituent can be biotransformed into more than 65 metabolites in vivo. These findings will improve understanding of the in vivo metabolism, distribution, and effective forms of mogroside V and congeneric molecules. PMID:26280925
Serum metabolites of proanthocyanidin-administered rats decrease lipid synthesis in HepG2 cells.
Guerrero, Ligia; Margalef, Maria; Pons, Zara; Quiñones, Mar; Arola, Lluis; Arola-Arnal, Anna; Muguerza, Begoña
The regular consumption of flavonoids has been associated with reduced mortality and a decreased risk of cardiovascular diseases. The proanthocyanidins found in plasma are very different from the original flavonoids in food sources. The use of physiologically appropriate conjugates of proanthocyanidins is essential for the in vitro analysis of flavonoid bioactivity. In this study, the effect of different proanthocyanidin-rich extracts, which were obtained from cocoa (CCX), French maritime pine bark (Pycnogenol extract, PYC) and grape seed (GSPE), on lipid homeostasis was evaluated. Hepatic human cells (HepG2 cells) were treated with 25 mg/L of CCX, PYC or GSPE. We also performed in vitro experiments to assess the effect on lipid synthesis that is induced by the bioactive GSPE proanthocyanidins using the physiological metabolites that are present in the serum of GSPE-administered rats. For this, Wistar rats were administered 1 g/kg of GSPE, and serum was collected after 2 h. The semipurified serum of GSPE-administered rats was fully characterized by liquid chromatography tandem triple quadrupole mass spectrometry (LC-QqQ/MS(2)). The lipids studied in the analyses were free cholesterol (FC), cholesterol ester (CE) and triglycerides (TG). All three proanthocyanidin-rich extracts induced a remarkable decrease in the de novo lipid synthesis in HepG2 cells. Moreover, GSPE rat serum metabolites reduced the total percentage of CE, FC and particularly TG; this reduction was significantly higher than that observed in the cells directly treated with GSPE. In conclusion, the bioactivity of the physiological metabolites that are present in the serum of rats after their ingestion of a proanthocyanidin-rich extract was demonstrated in Hep G2 cells. PMID:24231101
Regulating the cellular economy of supply and demand.
Hofmeyr, J S; Cornish-Bowden, A
Cellular metabolism is a molecular economy that is functionally organised into supply and demand blocks linked by metabolic products and cofactor cycles. Supply-demand analysis allows the behaviour, control and regulation of metabolism as a whole to be understood quantitatively in terms of the elasticities of supply and demand, which are experimentally measurable properties of the individual blocks. The kinetic and thermodynamic aspects of regulation are clearly distinguished. One important result is the demonstration that when flux is controlled by one block, the other block determines to which degree the concentration of the linking metabolite is homeostatically maintained. PMID:10878248
Microbial biotransformation of bioactive flavonoids.
Cao, Hui; Chen, Xiaoqing; Jassbi, Amir Reza; Xiao, Jianbo
The bioactive flavonoids are considered as the most important phytochemicals in food, which exert a wide range of biological benefits for human being. Microbial biotransformation strategies for production of flavonoids have attracted considerable interest because they allow yielding novel flavonoids, which do not exist in nature. In this review, we summarize the existing knowledge on the production and biotransformation of flavonoids by various microbes. The main reactions during microbial biotransformation are hydroxylation, dehydroxylation, O-methylation, O-demethylation, glycosylation, deglycosylation, dehydrogenation, hydrogenation, C ring cleavage of the benzo-γ-pyrone system, cyclization, and carbonyl reduction. Cunninghamella, Penicillium, and Aspergillus strains are very popular to biotransform flavonoids and they can perform almost all the reactions with excellent yields. Aspergillus niger is one of the most applied microorganisms in the flavonoids' biotransformation; for example, A. niger can transfer flavanone to flavan-4-ol, 2'-hydroxydihydrochalcone, flavone, 3-hydroxyflavone, 6-hydroxyflavanone, and 4'-hydroxyflavanone. The hydroxylation of flavones by microbes usually happens on the ortho position of hydroxyl group on the A ring and C-4' position of the B ring and microbes commonly hydroxylate flavonols at the C-8 position. The microorganisms tend to hydroxylate flavanones at the C-5, 6, and 4' positions; however, for prenylated flavanones, dihydroxylation often takes place on the C4α=C5α double bond on the prenyl group (the side chain of A ring). Isoflavones are usually hydroxylated at the C-3' position of the B ring by microorganisms. The microbes convert flavonoids to their 7-O-glycosides and 3-O-glycosides (when flavonoids have a hydroxyl moiety at the C-3 position). The demethylation of multimethoxyl flavonoids by microbes tends to happen at the C-3' and C-4' positions of the B ring. Multimethoxyl flavanones and isoflavone are demethylated at
Tantalum—A bioactive metal for implants
NASA Astrophysics Data System (ADS)
Balla, Vamsi Krishna; Bose, Susmita; Davies, Neal M.; Bandyopadhyay, Amit
Metallic biomaterials currently in use for load-bearing orthopedic applications are mostly bioinert and therefore lack sufficient osseointegration. Although bioactive ceramics such as hydroxyapatite (HA) can spontaneously bond to living bone tissue, low fracture toughness of HA limits their use as a bone substitute for load-bearing applications. Surface modification techniques such as HA coating on metals are current options to improve osseointegration in load-bearing metal implants. Over the last few decades researchers have attempted to find a bioactive metal with high mechanical strength and excellent fatigue resistance that can bond chemically with surrounding bone for orthopedic applications. Recent in vitro, in vivo, and clinical studies demonstrated that tantalum is a promising metal that is bioactive. However, tantalum applications in biomedical devices have been limited by processing challenges rather than biological performances. In this article, we provide an overview of processing aspects and biological properties of tantalum for load-bearing orthopedic applications.
Enhanced bioactivity, biocompatibility and mechanical behavior of strontium substituted bioactive glasses.
Arepalli, Sampath Kumar; Tripathi, Himanshu; Hira, Sumit Kumar; Manna, Partha Pratim; Pyare, Ram; S P Singh
Strontium contained biomaterials have been reported as a potential bioactive material for bone regeneration, as it reduces bone resorption and stimulates bone formation. In the present investigation, the bioactive glasses were designed to partially substitute SrO for SiO2 in Na2O-CaO-SrO-P2O5-SiO2 system. This work demonstrates that the substitution of SrO for SiO2 has got significant benefit than substitution for CaO in the bioactive glass. Bioactivity was assessed by the immersion of the samples in simulated body fluid for different intervals. The formation of hydroxy carbonate apatite layer was identified by X-ray diffractometry, scanning electron microscopy (SEM) and energy dispersive spectroscopy. The elastic modulus of the bioactive glasses was measured and found to increase with increasing SrO for SiO2. The blood compatibility of the samples was evaluated. In vitro cell culture studies of the samples were performed using human osteosarcoma U2-OS cell lines and found a significant improvement in cell viability and proliferation. The investigation showed enhancement in bioactivity, mechanical and biological properties of the strontia substituted for silica in glasses. Thus, these bioactive glasses would be highly potential for bone regeneration. PMID:27612694
Recent advances in genome mining of secondary metabolites in Aspergillus terreus
Guo, Chun-Jun; Wang, Clay C. C.
Filamentous fungi are rich resources of secondary metabolites (SMs) with a variety of interesting biological activities. Recent advances in genome sequencing and techniques in genetic manipulation have enabled researchers to study the biosynthetic genes of these SMs. Aspergillus terreus is the well-known producer of lovastatin, a cholesterol-lowering drug. This fungus also produces other SMs, including acetylaranotin, butyrolactones, and territram, with interesting bioactivities. This review will cover recent progress in genome mining of SMs identified in this fungus. The identification and characterization of the gene cluster for these SMs, as well as the proposed biosynthetic pathways, will be discussed in depth. PMID:25566227
Medicinal properties, in vitro protocols and secondary metabolite analyses of scots pine.
Häggman, Hely; Pirttilä, Anna Maria; Niemi, Karoliina; Sarjala, Tytti; Julkunen-Tiitto, Riitta
Scots pine (Pinus sylvestris L.) is known as an economically important forest tree with a wide distribution throughout the Northern hemisphere. Recently, the species has also become recognized as a novel source of functional food and bioactive compounds with medicinal properties. The present paper provides up-to-date information on protocols for somatic embryogenesis (i.e., the most promising in vitro method for vegetative propagation of Scots pine). Endophyte protocols cover the topics of endophyte isolation, identification and elimination from in vitro cultures. Moreover, the protocols for secondary metabolite analyses are described in order to emphasize the emerging role of Scots pine as a medicinal plant. PMID:19521833
Establishing high temperature gas chromatographic profiles of non-polar metabolites for quality assessment of African traditional herbal medicinal products.
Bony, Nicaise F; Libong, Danielle; Solgadi, Audrey; Bleton, Jean; Champy, Pierre; Malan, Anglade K; Chaminade, Pierre
The quality assessment of African traditional herbal medicinal products is a difficult challenge since they are complex mixtures of several herbal drug or herbal drug preparations. The plant source is also often unknown and/or highly variable. Plant metabolites chromatographic profiling is therefore an important tool for quality control of such herbal products. The objective of this work is to propose a protocol for sample preparation and gas chromatographic profiling of non-polar metabolites for quality control of African traditional herbal medicinal products. The methodology is based on the chemometric assessment of chromatographic profiles of non-polar metabolites issued from several batches of leaves of Combretum micranthum and Mitracarpus scaber by high temperature gas chromatography coupled to mass spectrometry, performed on extracts obtained in refluxed dichloromethane, after removal of chlorophyll pigments. The method using high temperature gas chromatography after dichloromethane extraction allows detection of most non-polar bioactive and non-bioactive metabolites already identified in leaves of both species. Chemometric data analysis using Principal Component Analysis and Partial Least Squares after Orthogonal Signal Correction applied to chromatographic profiles of leaves of Combretum micranthum and Mitracarpus scaber showed slight batch to batch differences, and allowed clear differentiation of the two herbal extracts. PMID:24211706
The Metabolite Transporters of the Plastid Envelope: An Update
Facchinelli, Fabio; Weber, Andreas P. M.
The engulfment of a photoautotrophic cyanobacterium by a primitive mitochondria-bearing eukaryote traces back to more than 1.2 billion years ago. This single endosymbiotic event not only provided the early petroalgae with the metabolic capacity to perform oxygenic photosynthesis, but also introduced a plethora of other metabolic routes ranging from fatty acids and amino acids biosynthesis, nitrogen and sulfur assimilation to secondary compounds synthesis. This implicated the integration and coordination of the newly acquired metabolic entity with the host metabolism. The interface between the host cytosol and the plastidic stroma became of crucial importance in sorting precursors and products between the plastid and other cellular compartments. The plastid envelope membranes fulfill different tasks: they perform important metabolic functions, as they are involved in the synthesis of carotenoids, chlorophylls, and galactolipids. In addition, since most genes of cyanobacterial origin have been transferred to the nucleus, plastidial proteins encoded by nuclear genes are post-translationally transported across the envelopes through the TIC–TOC import machinery. Most importantly, chloroplasts supply the photoautotrophic cell with photosynthates in form of reduced carbon. The innermost bilayer of the plastidic envelope represents the permeability barrier for the metabolites involved in the carbon cycle and is literally stuffed with transporter proteins facilitating their transfer. The intracellular metabolite transporters consist of polytopic proteins containing membrane spans usually in the number of four or more α-helices. Phylogenetic analyses revealed that connecting the plastid with the host metabolism was mainly a process driven by the host cell. In Arabidopsis, 58% of the metabolite transporters are of host origin, whereas only 12% are attributable to the cyanobacterial endosymbiont. This review focuses on the metabolite transporters of the inner envelope
A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat
Punt, Ans Freidig, Andreas P.; Delatour, Thierry; Scholz, Gabriele; Boersma, Marelle G.; Schilter, Benoit; Bladeren, Peter J. van; Rietjens, Ivonne M.C.M.
The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene estragole in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model consists of eight compartments including liver, lung and kidney as metabolizing compartments, and additional compartments for fat, arterial blood, venous blood, rapidly perfused tissue and slowly perfused tissue. Evaluation of the model was performed by comparing the PBBK predicted dose-dependent formation of the estragole metabolites 4-allylphenol and 1'-hydroxyestragole glucuronide to literature reported levels of these metabolites, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of estragole at different oral doses was examined. At low doses formation of 4-allylphenol, leading to detoxification, is observed to be the major metabolic pathway, occurring mainly in the lung and kidney due to formation of this metabolite with high affinity in these organs. Saturation of this metabolic pathway in the lung and kidney leads to a relative increase in formation of the proximate carcinogenic metabolite 1'-hydroxyestragole, occurring mainly in the liver. This relative increase in formation of 1'-hydroxyestragole leads to a relative increase in formation of 1'-hydroxyestragole glucuronide and 1'-sulfooxyestragole the latter being the ultimate carcinogenic metabolite of estragole. These results indicate that the relative importance of different metabolic pathways of estragole may vary in a dose-dependent way, leading to a relative increase in bioactiviation of estragole at higher doses.
Lin, Shunxin; Page, Nathaniel A.; Fung, Sun Mi; Fung, Ho-Leung
Organic nitrates (ORNs) are commonly used anti-ischemic and anti-anginal agents, which serve as an exogenous source of the potent vasodilator nitric oxide (NO). Recently, both mitochondrial aldehyde dehydrogenase-2 (ALDH2) and cytosolic aldehyde dehydrogenase-1a1 (ALDH1A1) have been shown to exhibit the ability to selectively bioactivate various ORNs in vitro. The objective of the present research was to examine the potential role of ALDH3A1, another major cytosolic isoform of ALDH, in the in vitro bioactivation of various ORNs, and to estimate the enzyme kinetic parameters toward ORNs through mechanistic modeling. The extent of bioactivation was assayed by exposing recombinant ALDH3A1 to various concentrations of ORNs, and measuring the concentration-time profiles of released NO via a NO-specific electrode. Metabolite formation kinetics was monitored for nitroglycerin (NTG) using LC/MS/MS. Our results showed that ALDH3A1 mRNA and protein were highly expressed in C57BL/6 mouse aortic, cardiac, and hepatic tissues, and it was able to release NO from several ORNs, including NTG, isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS-2-MN), and nicorandil with similar Vmax (0.175 – 0.503 nmol/min/mg of ALDH3A1), and Km values of 4.01, 46.5, 818 and 5.75 × 103 μM respectively. However, activation of isosorbide-5-mononitrate (IS-5-MN) by ALDH3A1 was undetectable in vitro. ALDH3A1 was also shown to denitrate NTG, producing primarily glyceryl 1, 2-dinitrate (1, 2-GDN) in preference to glyceryl 1, 3-dinitrate (1, 3-GDN). Therefore, ALDH3A1 may contribute to the bioactivation of ORNs in vivo. PMID:24126018
Global Perspectives of Fungal Secondary Metabolite Research
Technology Transfer Automated Retrieval System (TEKTRAN)
Fungi produce a wide range of unusual metabolites, termed secondary metabolites because they play no role in the normal, basic metabolic pathways used for growth and energy production, etc. Some of these secondary metabolites have antibiotic properties; others are potent toxins that are dangerous w...
Biochemometrics for Natural Products Research: Comparison of Data Analysis Approaches and Application to Identification of Bioactive Compounds.
Kellogg, Joshua J; Todd, Daniel A; Egan, Joseph M; Raja, Huzefa A; Oberlies, Nicholas H; Kvalheim, Olav M; Cech, Nadja B
A central challenge of natural products research is assigning bioactive compounds from complex mixtures. The gold standard approach to address this challenge, bioassay-guided fractionation, is often biased toward abundant, rather than bioactive, mixture components. This study evaluated the combination of bioassay-guided fractionation with untargeted metabolite profiling to improve active component identification early in the fractionation process. Key to this methodology was statistical modeling of the integrated biological and chemical data sets (biochemometric analysis). Three data analysis approaches for biochemometric analysis were compared, namely, partial least-squares loading vectors, S-plots, and the selectivity ratio. Extracts from the endophytic fungi Alternaria sp. and Pyrenochaeta sp. with antimicrobial activity against Staphylococcus aureus served as test cases. Biochemometric analysis incorporating the selectivity ratio performed best in identifying bioactive ions from these extracts early in the fractionation process, yielding altersetin (3, MIC 0.23 μg/mL) and macrosphelide A (4, MIC 75 μg/mL) as antibacterial constituents from Alternaria sp. and Pyrenochaeta sp., respectively. This study demonstrates the potential of biochemometrics coupled with bioassay-guided fractionation to identify bioactive mixture components. A benefit of this approach is the ability to integrate multiple stages of fractionation and bioassay data into a single analysis. PMID:26841051
Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material
NASA Technical Reports Server (NTRS)
Kentner, Kimberly A. (Inventor); Stuart, Katherine A. (Inventor); Janis, Abram D. (Inventor)
The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.
Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material
NASA Technical Reports Server (NTRS)
Kentner, Kimberly A. (Inventor); Stuart, Katherine A. (Inventor); Janis, Abram D. (Inventor)
The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.
Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material
NASA Technical Reports Server (NTRS)
Kentner, Kimberly A. (Inventor); Stuart, Katherine A. (Inventor); Janis, Abram D. (Inventor)
The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.
Oxidative stress and production of bioactive monoterpene indole alkaloids: biotechnological implications.
Matsuura, Hélio Nitta; Rau, Mariana Ritter; Fett-Neto, Arthur Germano
Monoterpene indole alkaloids (MIAs) encompass plant natural products with important pharmacological relevance. They include the anti-tumoral MIAs found in Catharanthus roseus and Camptotheca acuminata. The often low yields of bioactive alkaloids in plants has prompted research to identify the factors regulating MIA production. Oxidative stress is a general response associated with biotic and abiotic stresses leading to several secondary responses, including elicitation of MIA production. These changes in secondary metabolism may take place directly or via second messengers, such as Ca(2+) and reactive oxygen species (ROS). H2O2 is the main ROS that participates in MIA biosynthesis. This review analyzes the links between oxidative stress, elicitation of bioactive MIA production and their potential roles in antioxidant defense, as well as exploring the implications to developing biotechnological strategies relevant for alkaloid supply. PMID:24062135
Feedstock Supply System Logistics
Feedstock supply is a significant cost component in the production of biobased fuels, products, and power. The uncertainty of the biomass feedstock supply chain and associated risks are major barriers to procuring capital funding for start-up biorefineries.
Quantitative metabolite profiling of edible onion species by NMR and HPLC-MS.
Soininen, Tuula H; Jukarainen, Niko; Auriola, Seppo O K; Julkunen-Tiitto, Riitta; Karjalainen, Reijo; Vepsäläinen, Jouko J
Allium genus is a treasure trove of valuable bioactive compounds with potentially therapeutically important properties. This work utilises HPLC-MS and a constrained total-line-shape (CTLS) approach applied to (1)H NMR spectra to quantify metabolites present in onion species to reveal important inter-species differences. Extensive differences were detected between the sugar concentrations in onion species. Yellow onion contained the highest and red onion the lowest amounts of amino acids. The main flavonol-glucosides were quercetin 3,4'-diglucoside and quercetin 4'-glucoside. In general, the levels of flavonols were, higher in yellow onions than in red onions, and garlic and leek contained a lower amount of flavonols than the other Allium species. Our results highlight how (1)H NMR together with HPLC-MS can be useful in the quantification and the identification of the most abundant metabolites, representing an efficient means to pinpoint important functional food ingredients from Allium species. PMID:25038704
Secondary metabolites of plants from the genus chloranthus: chemistry and biological activities.
Wang, An-Ran; Song, Hong-Chuan; An, Hong-Mei; Huang, Qian; Luo, Xie; Dong, Jin-Yan
Chloranthus, a genus of the family Chloranthaceae, which is mainly distributed in eastern and southern Asia, has been used in Chinese folk medicine due to its antitumor, antifungal, and anti-inflammatory activities. This review compiles the research on isolation, structure elucidation, structural diversity, and bioactivities of Chloranthus secondary metabolites reported between 2007 and 2013. The metabolites listed encompass 82 sesquiterpenoids, 50 dimeric sesquiterpenoids, 15 diterpenoids, one coumarin, and five other compounds. Among them, dimeric sesquiterpenoids, the characteristic components of plants from the genus Chloranthus, have attracted considerable attention due to their complex structures and significant biological features, e.g., antitumor, antibacterial, antifungal, anti-inflammatory, and hepatoprotective activities, and potent and selective inhibition of the delayed rectifier (IK) K(+) current and tyrosinase. PMID:25879494
Investigation of bioactivity and cell effects of nano-porous sol-gel derived bioactive glass film
NASA Astrophysics Data System (ADS)
Ma, Zhijun; Ji, Huijiao; Hu, Xiaomeng; Teng, Yu; Zhao, Guiyun; Mo, Lijuan; Zhao, Xiaoli; Chen, Weibo; Qiu, Jianrong; Zhang, Ming
In orthopedic surgery, bioactive glass film coating is extensively studied to improve the synthetic performance of orthopedic implants. A lot of investigations have confirmed that nano-porous structure in bioactive glasses can remarkably improve their bioactivity. Nevertheless, researches on preparation of nano-porous bioactive glasses in the form of film coating and their cell response activities are scarce. Herein, we report the preparation of nano-porous bioactive glass film on commercial glass slide based on a sol-gel technique, together with the evaluation of its in vitro bioactivity through immersion in simulated body fluid and monitoring the precipitation of apatite-like layer. Cell responses of the samples, including attachment, proliferation and osteogenic differentiation, were also investigated using BMSCS (bone marrow derived mesenchymal stem cells) as a model. The results presented here provide some basic information on structural influence of bioactive glass film on the improvement of bioactivity and cellular effects.
Marine bioactives and potential application in sports.
Gammone, Maria Alessandra; Gemello, Eugenio; Riccioni, Graziano; D'Orazio, Nicolantonio
An enriched diet with antioxidants, such as vitamin E, vitamin C, β-carotene and phenolic compounds, has always been suggested to improve oxidative stress, preventing related diseases. In this respect, marine natural product (MNP), such as COX inhibitors, marine steroids, molecules interfering with factors involved in the modulation of gene expression (such as NF-κB), macrolides, many antioxidant agents, thermogenic substances and even substances that could help the immune system and that result in the protection of cartilage, have been recently gaining attention. The marine world represents a reserve of bioactive ingredients, with considerable potential as functional food. Substances, such as chitin, chitosan, n-3 oils, carotenoids, vitamins, minerals and bioactive peptides, can provide several health benefits, such as the reduction of cardiovascular diseases, anti-inflammatory and anticarcinogenic activities. In addition, new marine bioactive substances with potential anti-inflammatory, antioxidant and thermogenic capacity may provide health benefits and performance improvement, especially in those who practice physical activity, because of their increased free radical and Reacting Oxygen Species (ROS) production during exercise, and, particularly, in athletes. The aim of this review is to examine the potential pharmacological properties and application of many marine bioactive substances in sports. PMID:24796298
Marine Bioactives and Potential Application in Sports
Gammone, Maria Alessandra; Gemello, Eugenio; Riccioni, Graziano; D'Orazio, Nicolantonio
An enriched diet with antioxidants, such as vitamin E, vitamin C, β-carotene and phenolic compounds, has always been suggested to improve oxidative stress, preventing related diseases. In this respect, marine natural product (MNP), such as COX inhibitors, marine steroids, molecules interfering with factors involved in the modulation of gene expression (such as NF-κB), macrolides, many antioxidant agents, thermogenic substances and even substances that could help the immune system and that result in the protection of cartilage, have been recently gaining attention. The marine world represents a reserve of bioactive ingredients, with considerable potential as functional food. Substances, such as chitin, chitosan, n-3 oils, carotenoids, vitamins, minerals and bioactive peptides, can provide several health benefits, such as the reduction of cardiovascular diseases, anti-inflammatory and anticarcinogenic activities. In addition, new marine bioactive substances with potential anti-inflammatory, antioxidant and thermogenic capacity may provide health benefits and performance improvement, especially in those who practice physical activity, because of their increased free radical and Reacting Oxygen Species (ROS) production during exercise, and, particularly, in athletes. The aim of this review is to examine the potential pharmacological properties and application of many marine bioactive substances in sports. PMID:24796298
Modeling of the bioactivated nanopore devices.
Talasaz, AmirAli H; Liu, Yang; Ronaghi, Mostafa; Davis, Ronald W
This paper presents the modeling of the electrical properties of bioactivated nanopores, customized nanopore devices with a biological macromolecule attached in the pore as the probe. These devices are capable of detecting and analyzing interactions between the attached biomolecule and the molecules in the analyte at a single molecule level. PMID:17946483
Five new bioactive compounds from Chenopodium ambrosioides.
Song, Kun; Zhang, Jian; Zhang, Peng; Wang, Hong-Qing; Liu, Chao; Li, Bao-Ming; Kang, Jie; Chen, Ruo-Yun
Five new bioactive compounds, chenopodiumamines A-D (1-4) and chenopodiumoside A (5), were isolated from the ethanol extract of Chenopodium ambrosioides. The structures of these compounds were elucidated by various spectroscopic means (UV, IR, HR-ESI-MS, 1D and 2D NMR). Compounds 1-3 had moderate antioxidant and anti-inflammatory activities. PMID:26001043
Nanochemoprevention by Bioactive Food Components: A Perspective
Siddiqui, Imtiaz A.
Chemoprevention through the use of bioactive food components is a practical approach for cancer control. Despite abundant efficacy data under preclinical settings, this strategy has resulted in limited success for human cancer control. Amongst many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnect. We recently introduced a novel concept in which we utilized nanotechnology for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712–6) and termed it nanochemoprevention. To establish the proof-of-principle of nanotechnology for cancer management, we determined the efficacy of a well-known chemopreventive agent epigallocatechin-3-gallate (EGCG) encapsulated in polylactic acid (PLA)-polyethylene glycol (PEG) nanoparticles in preclinical settings and observed that, compared to non-encapsulated EGCG, nano-EGCG retained its biological efficacy with over 10-fold dose advantage both in cell culture system and in vivo settings in athymic nude mice implanted with human prostate cancer cells. This study laid the foundation of nanochemoprevention by bioactive food components. Since oral consumption is the most desirable and acceptable form of delivery of bioactive food components, it will be important to develop nanoparticles containing bioactive food components that are suitable for oral consumption for which experiments are underway in this laboratory. PMID:20221894
Technology Transfer Automated Retrieval System (TEKTRAN)
The Nutrient Data Laboratory (NDL), Agricultural Research Service (ARS), U.S. Department of Agriculture (USDA) is responsible for developing and maintaining composition databases for foods and supplements. Recent hypotheses concerning the possible roles of new bioactive dietary compounds in managing...
Citrus Limonoids: Analysis, Bioactivity, and Biomedical Prospects
Technology Transfer Automated Retrieval System (TEKTRAN)
This publication is a review of the chemistry, biochemistry and bioactivity of limonoids occurring in citrus. The review chronologically relates the evolution of research in citrus limonoids beginning with their association with bitterness development in citrus juices. The chemical and biochemical...
Antileishmanial Metabolites from Geosmithia langdonii
Antileishmanial bioassay guided fractionation of Geosmithia langdonii has resulted in the isolation and identification of two new compounds (1 and 2) together with 10 known compounds (3–12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as mass spectrometry. The absolute configuration at C4, C5, and C6 of 2 was determined as R using a modified Mosher esterification method and NOESY correlations. The extracts and the isolated metabolites were evaluated for their antileishmanial activities. Compounds 3, 9, 11, and 12 were found to be active against Leishmania donovani with IC50 values of 6.9, 3.3, 8.5, and 9.2 μM, respectively, while compounds 1, 5, and 10 showed lower activities against L. donovani with IC50 values of 13.0, 47.3, and 34.0 μM, respectively. PMID:25084548
Preparation and bioactive properties of nano bioactive glass and segmented polyurethane composites.
Aguilar-Pérez, Fernando J; Vargas-Coronado, Rossana F; Cervantes-Uc, Jose M; Cauich-Rodríguez, Juan V; Covarrubias, Cristian; Pedram-Yazdani, Merhdad
Composites of glutamine-based segmented polyurethanes with 5 to 25 wt.% bioactive glass nanoparticles were prepared, characterized, and their mineralization potential was evaluated in simulated body fluid. Biocompatibility with dental pulp stem cells was assessed by MTS to an extended range of compositions (1 to 25 wt.% of bioactive glass nanoparticles). Physicochemical characterization showed that composites retained many of the matrix properties, i.e. those corresponding to semicrystalline elastomeric polymers as they exhibited a glass transition temperature (Tg) between -41 and -36℃ and a melting temperature (Tm) between 46 and 49℃ in agreement with X-ray reflections at 23.6° and 21.3°. However, with bioactive glass nanoparticles addition, tensile strength and strain were reduced from 22.2 to 12.2 MPa and 667.2 to 457.8%, respectively with 25 wt.% of bioactive glass nanoparticles. Although Fourier transform infrared spectroscopy did not show evidence of mineralization after conditioning of these composites in simulated body fluid, X-ray diffraction, scanning electron microscopy, and energy dispersive X-ray microanalysis showed the formation of an apatite layer on the surface which increased with higher bioactive glass concentrations and longer conditioning time. Dental pulp stem cells proliferation at day 5 was improved in bioactive glass nanoparticles composites containing lower amounts of the filler (1-2.5 wt.%) but it was compromised at day 9 in composites containing high contents of nBG (5, 15, 25 wt.%). However, Runx2 gene expression was particularly upregulated for the dental pulp stem cells cultured with composites loaded with 15 and 25 wt.% of bioactive glass nanoparticles. In conclusion, low content bioactive glass nanoparticles and segmented polyurethanes composites deserve further investigation for applications such as guided bone regeneration membranes, where osteoconductivity is desirable but not a demanding mechanical performance. PMID
An integrated approach for profiling oxidative metabolites and glutathione adducts using liquid chromatography coupled with ultraviolet detection and triple quadrupole-linear ion trap mass spectrometry.
Chen, Guiying; Cheng, Zhongzhe; Zhang, Kerong; Jiang, Hongliang; Zhu, Mingshe
The use of liquid chromatography (LC) coupled with triple quadrupole linear ion trap (Qtrap) mass spectrometry (MS) for both quantitative and qualitative analysis in drug metabolism and pharmacokinetic studies is of great interest. Here, a new Qtrap-based analytical methodology for simultaneous detection, structural characterization and semi-quantitation of in vitro oxidative metabolites and glutathione trapped reactive metabolites was reported. In the current study, combined multiple ion monitoring and multiple reaction monitoring were served as surveying scans to trigger product ion spectral acquisition of oxidative metabolites and glutathione adduct, respectively. Then, detection of metabolites and recovery of their MS/MS spectra were accomplished using multiple data mining approaches. Additionally, on-line ultraviolet (UV) detection was employed to determine relative concentrations of major metabolites. Analyses of metabolites of clozapine and nomifensine in rat liver microsomes not only revealed multiple oxidative metabolites and glutathione adducts, but also identified their major oxidative metabolism and bioactivation pathways. The results demonstrated that the LC/UV/MS method enabled Qtrap to perform the comprehensive profiling of oxidative metabolites and glutathione adducts in vitro. PMID:27497649
Bioactive Organocopper Compound from Pseudomonas aeruginosa Inhibits the Growth of Xanthomonas citri subsp. citri
de Oliveira, Admilton G.; Spago, Flavia R.; Simionato, Ane S.; Navarro, Miguel O. P.; da Silva, Caroline S.; Barazetti, André R.; Cely, Martha V. T.; Tischer, Cesar A.; San Martin, Juca A. B.; de Jesus Andrade, Célia G. T.; Novello, Cláudio R.; Mello, João C. P.; Andrade, Galdino
Citrus canker is a very destructive disease of citrus species. The challenge is to find new compounds that show strong antibiotic activity and low toxicity to plants and the environment. The objectives of the present study were (1) to extract, purify and evaluate the secondary metabolites with antibiotic activity produced by Pseudomonas aeruginosa LV strain in vitro against Xanthomonas citri subsp. citri (strain 306), (2) to determine the potential of semi-purified secondary metabolites in foliar application to control citrus canker under greenhouse conditions, and (3) to identify antibiotic activity in orange leaf mesophyll infected with strain 306, by electron microscopy. Two pure bioactive compounds were isolated, an organocopper antibiotic compound (OAC) and phenazine-1-carboxamide. Phenazine-1-carboxamide did not show any antibiotic activity under the experimental conditions used in this study. The OAC showed a high level of antibiotic activity with a minimum inhibitory concentration of 0.12 μg mL-1. In greenhouse tests for control of citrus canker in orange trees, the semi-purified fraction F3d reduced lesion formation by about 97%. The concentration used was 500 times lower than that for the recommended commercial copper-based product. Electron microscopy showed that F3d altered the exopolysaccharide matrix and caused cell lysis of the pathogen inside the citrus canker lesions. These results suggest that secondary metabolites produced by inducing P. aeruginosa LV strain have a high potential to be used as a bioproduct to control citrus canker. PMID:26903992
Effect of nanoparticulate bioactive glass particles on bioactivity and cytocompatibility of poly(3-hydroxybutyrate) composites
Misra, Superb K.; Ansari, Tahera; Mohn, Dirk; Valappil, Sabeel P.; Brunner, Tobias J.; Stark, Wendelin J.; Roy, Ipsita; Knowles, Jonathan C.; Sibbons, Paul D.; Jones, Eugenia Valsami; Boccaccini, Aldo R.; Salih, Vehid
This work investigated the effect of adding nanoparticulate (29 nm) bioactive glass particles on the bioactivity, degradation and in vitro cytocompatibility of poly(3-hydroxybutyrate) (P(3HB)) composites/nano-sized bioactive glass (n-BG). Two different concentrations (10 and 20 wt %) of nanoscale bioactive glass particles of 45S5 Bioglass composition were used to prepare composite films. Several techniques (Raman spectroscopy, scanning electron microscopy, atomic force microscopy, energy dispersive X-ray) were used to monitor their surface and bioreactivity over a 45-day period of immersion in simulated body fluid (SBF). All results suggested the P(3HB)/n-BG composites to be highly bioactive, confirmed by the formation of hydroxyapatite on material surfaces upon immersion in SBF. The weight loss and water uptake were found to increase on increasing bioactive glass content. Cytocompatibility study (cell proliferation, cell attachment, alkaline phosphatase activity and osteocalcin production) using human MG-63 osteoblast-like cells in osteogenic and non-osteogenic medium showed that the composite substrates are suitable for cell attachment, proliferation and differentiation. PMID:19640877
Thermal analysis and in vitro bioactivity of bioactive glass-alumina composites
Chatzistavrou, Xanthippi; Kantiranis, Nikolaos; Kontonasaki, Eleana; Chrissafis, Konstantinos; Papadopoulou, Labrini; Koidis, Petros; Boccaccini, Aldo R.; Paraskevopoulos, Konstantinos M.
Bioactive glass-alumina composite (BA) pellets were fabricated in the range 95/5-60/40 wt.% respectively and were heat-treated under a specific thermal treatment up to 950 {sup o}C. Control (unheated) and heat-treated pellets were immersed in Simulated Body Fluid (SBF) for bioactivity testing. All pellets before and after immersion in SBF were studied by Fourier Transform Infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM-EDS) and X-ray Diffraction (XRD) analysis. All composite pellets presented bioactive response. On the surface of the heat-treated pellets the development of a rich biological hydroxyapatite (HAp) layer was delayed for one day, compared to the respective control pellets. Independent of the proportion of the two components, all composites of each group (control and heat-treated) presented the same bioactive response as a function of immersion time in SBF. It was found that by the applied methodology, Al{sub 2}O{sub 3} can be successfully applied in bioactive glass composites without obstructing their bioactive response. - Research Highlights: {yields} Isostatically pressed glass-alumina composites presented apatite-forming ability. {yields} The interaction with SBF resulted in an aluminium phosphate phase formation. {yields} The formation of an aluminium phosphate phase enhanced the in vitro apatite growth.
Bioactive macroporous titanium implants highly interconnected.
Caparrós, Cristina; Ortiz-Hernandez, Mónica; Molmeneu, Meritxell; Punset, Miguel; Calero, José Antonio; Aparicio, Conrado; Fernández-Fairén, Mariano; Perez, Román; Gil, Francisco Javier
Intervertebral implants should be designed with low load requirements, high friction coefficient and low elastic modulus in order to avoid the stress shielding effect on bone. Furthermore, the presence of a highly interconnected porous structure allows stimulating bone in-growth and enhancing implant-bone fixation. The aim of this study was to obtain bioactive porous titanium implants with highly interconnected pores with a total porosity of approximately 57 %. Porous Titanium implants were produced by powder sintering route using the space holder technique with a binder phase and were then evaluated in an in vivo study. The size of the interconnection diameter between the macropores was about 210 μm in order to guarantee bone in-growth through osteblastic cell penetration. Surface roughness and mechanical properties were analyzed. Stiffness was reduced as a result of the powder sintering technique which allowed the formation of a porous network. Compression and fatigue tests exhibited suitable properties in order to guarantee a proper compromise between mechanical properties and pore interconnectivity. Bioactivity treatment effect in novel sintered porous titanium materials was studied by thermo-chemical treatments and were compared with the same material that had undergone different bioactive treatments. Bioactive thermo-chemical treatment was confirmed by the presence of sodium titanates on the surface of the implants as well as inside the porous network. Raman spectroscopy results suggested that the identified titanate structures would enhance in vivo apatite formation by promoting ion exchange for the apatite formation process. In vivo results demonstrated that the bioactive titanium achieved over 75 % tissue colonization compared to the 40 % value for the untreated titanium. PMID:27582071
Simultaneous determination of arctiin and its metabolites in rat urine and feces by HPLC.
Wang, Wei; Pan, Qiang; Han, Xue-Ying; Wang, Jing; Tan, Ri-Qiu; He, Fan; Dou, De-Qiang; Kang, Ting-Guo
Arctiin, an important lignan compound in Fructus Arctii, has been reported to possess various kinds of bioactivities. Previous studies on the pharmacokinetic of arctiin after oral administration showed that it had a rapid absorption phase followed by a sharp but lasting disappearance. To gain deep insight into the action mechanism of arctiin, the excretion and metabolism of arctiin in vivo should be further studied. In this paper, three metabolites were isolated and identified in rat feces as (-)-enterolactone (M-1), (-)-arctigenin (M-2) and [(2R,3R)-2-(3'-hydroxybenzyl)-3-(3″,4″-dimethoxybenzyl)-butyrolactone] (M-3). Based on the structures of three metabolites, possible metabolic pathways of arctiin in rats are proposed. At the same time, the cumulative excretion rate of arctiin and its metabolites in rat urine and feces were determined, indicating that arctiin was excreted 19.84% in urine and 1.80% in feces, respectively, enterolactone, the most main metabolite, was excreted 35.80% in feces. These results provide very important information for understanding the metabolism and excretion of arctiin in vivo and speculating its action mechanism, they can provide useful information and reference for further metabolic investigations on arctiin in humans. PMID:23380537
Antibacterial metabolites synthesized by psychrotrophic bacteria isolated from cold-freshwater environments.
Barros, Javier; Becerra, José; González, Carlos; Martínez, Miguel
The ability of three psychrotrophic Gram-negative bacilli isolated from Chilean Patagonian cold freshwater rivers to produce bioactive metabolites was evaluated. The strains were isolated from cold waters rivers and identified by their biochemical properties and 16S rRNA gene analysis. The metabolites fractions showing antibacterial activity were obtained by solvent extraction and partially characterized by gas-mass chromatography (GC-MS). Antibacterial activity of the fractions was evaluated by an agar-well diffusion test upon 14 bacterial strains, both Gram positive and Gram negative. Thermal and proteolytic resistances of the antibacterial metabolites fractions were also evaluated. Molecular analysis allows the identification of the three Patagonian strains as Pseudomonas sp. RG-6 (Pseudomonas brenneri 99.6 % identity), Pseudomonas sp. RG-8 (Pseudomonas trivialis 99.6 % identity) and Yersinia sp. RP-3 (Yersinia aldovae 99.5 % identity). These extracts were able to inhibit both Gram-positive and Gram-negative bacteria but not Listeria monocytogenes. The antibacterial activity of the filtrated supernatants was lost at temperatures ≥60 °C, and was not affected by proteinase K treatment. The chemical structure of the active molecule remains to be elucidated, although the GC-MS analysis of the filtrates suggests that compounds like sesquiterpenes derivatives from β-maaliene or δ-selinene could be responsible of this antibacterial activity. Pristine cold freshwater streams showed to be interesting sources of metabolites-producing microorganisms with antibacterial activity. PMID:22886611
Significance of metabolite extraction method for evaluating sulfamethazine toxicity in adult zebrafish using metabolomics.
De Sotto, Ryan; Medriano, Carl; Cho, Yunchul; Seok, Kwang-Seol; Park, Youngja; Kim, Sungpyo
Recently, environmental metabolomics has been introduced as a next generation environmental toxicity method which helps in evaluating toxicity of bioactive compounds to non-target organisms. In general, efficient metabolite extraction from target cells is one of the keys to success to better understand the effects of toxic substances to organisms. In this regard, the aim of this study is (1) to compare two sample extraction methods in terms of abundance and quality of metabolites and (2) investigate how this could lead to difference in data interpretation using pathway analysis. For this purpose, the antibiotic sulfamethazine and zebrafish (Danio rerio) were selected as model toxic substance and target organism, respectively. The zebrafish was exposed to four different sulfamethazine concentrations (0, 10, 30, and 50mg/L) for 72h. Metabolites were extracted using two different methods (Bligh and Dyer and solid-phase extraction). A total of 13,538 and 12,469 features were detected using quadrupole time-of-flight liquid chromatography mass spectrometry (QTOF LC-MS). Of these metabolites, 4278 (Bligh and Dyer) and 332 (solid phase extraction) were found to be significant after false discovery rate adjustment at a significance threshold of 0.01. Metlin and KEGG pathway analysis showed comprehensive information from fish samples extracted using Bligh and Dyer compared to solid phase extraction. This study shows that proper selection of sample extraction method is critically important for interpreting and analyzing the toxicity data of organisms when metabolomics is applied. PMID:26827276
Endophytes as in vitro production platforms of high value plant secondary metabolites.
Venugopalan, Aarthi; Srivastava, Smita
Many reports have been published on bioprospecting of endophytic fungi capable of producing high value bioactive molecules like, paclitaxel, vincristine, vinblastine, camptothecin and podophyllotoxin. However, commercial exploitation of endophytes for high value-low volume plant secondary metabolites remains elusive due to widely reported genomic instability of endophytes in the axenic culture. While most of the endophyte research focuses on screening endophytes for novel or existing high value biomolecules, very few reports seek to explore the possible mechanisms of production of host-plant associated or novel secondary metabolites in these organisms. With an overview of host-endophyte relationship and its possible impact on the secondary metabolite production potential of endophytes, the review highlights the evidence reported for and against the presence of host-independent biosynthetic machinery in endophytes. The review aims to address the question, why should and how can endophytes be exploited for large scale in vitro production of high value phytochemicals? In this regard, various bioprocess optimization strategies that have been applied to sustain and enhance the product yield from the endophytes have also been described in detail. Further, techniques like mixed fermentation/co-cultivation and use of epigenetic modifiers have also been discussed as potential strategies to activate cryptic gene clusters in endophytes, thereby aiding in novel metabolite discovery and overcoming the limitations associated with axenic culture of endophytes. PMID:26225453
Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization
Yanai, Ryoji; Mulki, Lama; Hasegawa, Eiichi; Takeuchi, Kimio; Sweigard, Harry; Suzuki, Jun; Gaissert, Philipp; Vavvas, Demetrios G.; Sonoda, Koh-Hei; Rothe, Michael; Schunck, Wolf-Hagen; Miller, Joan W.; Connor, Kip M.
Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD. PMID:24979774
Metabolism of secondary metabolites isolated from Tartary buckwheat and its extract.
Ren, Qiang; Li, Yingfei; Wu, Caisheng; Wang, Caihong; Jin, Ying; Zhang, Jinlan
The metabolism of Tartary buckwheat was investigated using a strategy from single bioactive compounds to complex Tartary buckwheat extract. Firstly, the metabolites of different structural compounds were investigated by an in situ liver-intestinal perfusion model and the metabolic pathways were proposed. Furthermore, Tartary buckwheat extract in rats was elucidated on the basis of the metabolism information of single compounds. High-performance liquid chromatography coupled with high resolution mass and multiple-stage mass spectrometry (HPLC-HRMS/MS(n)) was performed to characterise and identify 19 metabolites in perfusate and intestinal content after administration of single compounds to an in situ liver/intestinal perfusion model and 16 metabolites and 6 components in rat faeces, urine, bile, and plasma after oral administration of Tartary buckwheat to rats. Five new metabolites were identified as the glucuronidation and sulfation products of N-trans-feruloyltyramine and the methylation product of quercetin-3-O-[β-d-xyloxyl-(1→2)-α-l-rhamnoside]. The metabolic pathways of phenylpropanoid glycosides and N-trans-feruloyltyramine were proposed for the first time. PMID:24518325
Characterization of human cytochrome P450s involved in the bioactivation of tri-ortho-cresyl phosphate (ToCP).
Reinen, Jelle; Nematollahi, Leyla; Fidder, Alex; Vermeulen, Nico P E; Noort, Daan; Commandeur, Jan N M
Tri-ortho-cresyl phosphate (ToCP) is a multipurpose organophosphorus compound that is neurotoxic and suspected to be involved in aerotoxic syndrome in humans. It has been reported that not ToCP itself but a metabolite of ToCP, namely, 2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP), may be responsible for this effect as it can irreversibly bind to human butyrylcholinesterase (BuChE) and human acetylcholinesterase (AChE). The bioactivation of ToCP into CBDP involves Cytochrome P450s (P450s). However, the individual human P450s responsible for this bioactivation have not been identified yet. In the present study, we aimed to investigate the metabolism of ToCP by different P450s and to determine the inhibitory effect of the in vitro generated ToCP-metabolites on human BuChE and AChE. Human liver microsomes, rat liver microsomes, and recombinant human P450s were used for that purpose. The recombinant P450s 2B6, 2C18, 2D6, 3A4 and 3A5 showed highest activity of ToCP-bioactivation to BuChE-inhibitory metabolites. Inhibition experiments using pooled human liver microsomes indicated that P450 3A4 and 3A5 were mainly involved in human hepatic bioactivation of ToCP. In addition, these experiments indicated a minor role for P450 1A2. Formation of CBDP by in-house expressed recombinant human P450s 1A2 and 3A4 was proven by both LC-MS and GC-MS analysis. When ToCP was incubated with P450 1A2 and 3A4 in the presence of human BuChE, CBDP-BuChE-adducts were detected by LC-MS/MS which were not present in the corresponding control incubations. These results confirmed the role of human P450s 1A2 and 3A4 in ToCP metabolism and demonstrated that CBDP is the metabolite responsible for the BuChE inactivation. Interindividual differences at the level of P450 1A2 and 3A4 might play an important role in the susceptibility of humans in developing neurotoxic effects, such as aerotoxic syndrome, after exposure to ToCP. PMID:25706813
Bioactivation of Heterocyclic Aromatic Amines by UDP Glucuronosyltransferases.
Cai, Tingting; Yao, Lihua; Turesky, Robert J
2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAA) that arise during the burning of tobacco and cooking of meats. UDP-glucuronosyltransferases (UGT) detoxicate many procarcinogens and their metabolites. The genotoxic N-hydroxylated metabolite of AαC, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC), undergoes glucuronidation to form the isomeric glucuronide (Gluc) conjugates N(2)-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON(2)-Gluc) and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN(2)-O-Gluc). AαC-HON(2)-Gluc is a stable metabolite but AαC-HN(2)-O-Gluc is a biologically reactive intermediate, which covalently adducts to DNA at levels that are 20-fold higher than HONH-AαC. We measured the rates of formation of AαC-HON(2)-Gluc and AαC-HN(2)-O-Gluc in human organs: highest activity occurred with liver and kidney microsomes, and lesser activity was found with colon and rectum microsomes. AαC-HN(2)-O-Gluc formation was largely diminished in liver and kidney microsomes, by niflumic acid, a selective inhibitor UGT1A9. In contrast, AαC-HON(2)-Gluc formation was less affected and other UGT contribute to N(2)-glucuronidation of HONH-AαC. UGT were reported to catalyze the formation of isomeric Gluc conjugates at the N(2) and N3 atoms of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), the genotoxic metabolite of PhIP. However, we found that the N3-Gluc of HONH-PhIP also covalently bound to DNA at higher levels than HONH-PhIP. The product ion spectra of this Gluc conjugate acquired by ion trap mass spectrometry revealed that the Gluc moiety was linked to the oxygen atom of HONH-PhIP and not the N3 imidazole atom of the oxime tautomer of HONH-PhIP as was originally proposed. UGT1A9, an abundant UGT isoform expressed in human liver and kidney, preferentially forms the O-linked Gluc conjugates of HONH
Metabolomic-Based Study of the Leafy Gall, the Ecological Niche of the Phytopathogen Rhodococcus Fascians, as a Potential Source of Bioactive Compounds
Nacoulma, Aminata P.; Vandeputte, Olivier M.; De Lorenzi, Manuella; El Jaziri, Mondher; Duez, Pierre
Leafy gall is a plant hyperplasia induced upon Rhodococcus fascians infection. Previously, by genomic and transcriptomic analysis, it has been reported that, at the early stage of symptom development, both primary and secondary metabolisms are modified. The present study is based on the hypothesis that fully developed leafy gall, could represent a potential source of new bioactive compounds. Therefore, non-targeted metabolomic analysis of aqueous and chloroform extracts of leafy gall and non-infected tobacco was carried out by 1H-NMR coupled to principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA). Polar metabolite profiling reflects modifications mainly in the primary metabolites and in some polyphenolics. In contrast, main modifications occurring in non-polar metabolites concern secondary metabolites, and gas chromatography and mass spectrometry (GC-MS) evidenced alterations in diterpenoids family. Analysis of crude extracts of leafy galls and non-infected tobacco leaves exhibited a distinct antiproliferative activity against all four tested human cancer cell lines. A bio-guided fractionation of chloroformic crude extract yield to semi-purified fractions, which inhibited proliferation of glioblastoma U373 cells with IC50 between 14.0 and 2.4 μg/mL. Discussion is focused on the consequence of these metabolic changes, with respect to plant defense mechanisms following infection. Considering the promising role of diterpenoid family as bioactive compounds, leafy gall may rather be a propitious source for drug discovery. PMID:23771021
Green tea catechins and their metabolites in human skin before and after exposure to ultraviolet radiation☆☆☆★
Clarke, Kayleigh A.; Dew, Tristan P.; Watson, Rachel E.B.; Farrar, Mark D.; Osman, Joanne E.; Nicolaou, Anna; Rhodes, Lesley E.; Williamson, Gary
Dietary flavonoids may protect against sunburn inflammation in skin. Preliminary reports using less complete analysis suggest that certain catechins and their metabolites are found in skin biopsies and blister fluid after consumption of green tea; however, it is not known if they are affected by solar-simulated ultraviolet radiation (UVR) or whether conjugated forms, with consequently altered bioactivity, are present. The present study tested the hypothesis that UVR affects the catechin levels in the skin of healthy volunteers after consumption of green tea and how catechins in the plasma are related to their presence in skin tissue samples. In an open oral intervention study, 11 subjects consumed green tea and vitamin C supplements daily for 3 months. Presupplementation and postsupplementation plasma samples, suction blister fluid and skin biopsies were collected; the latter two samples were collected both before and after UVR. A sensitive high-performance liquid chromatography/mass spectrometric assay was used to measure the intact catechin metabolites, conjugates and free forms. Seven green tea catechins and their corresponding metabolites were identified postsupplementation in skin biopsies, 20 in blister fluid and 26 in plasma, with 15 green tea catechin metabolites present in both blister fluid and plasma. The valerolactone, O-methyl-M4-O-sulfate, a gut microbiota metabolite of catechins, was significantly increased 1.6-fold by UVR in blister fluid samples. In conclusion, there were some common catechin metabolites in the plasma and blister fluid, and the concentration was always higher in plasma. The results suggest that green tea catechins and metabolites are bioavailable in skin and provide a novel link between catechin metabolites derived from the skin and gut microbiota. PMID:26454512
Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry.
Sleno, Lekha; Staack, Roland F; Varesio, Emmanuel; Hopfgartner, Gérard
The in vitro metabolism of the nootropic drug fipexide was studied using different liquid chromatography/mass spectrometry (LC/MS) techniques. This drug has been withdrawn from the market due to toxic effects. No previous reports have investigated the possible involvement of reactive metabolites in the toxicity of fipexide. The hydrolysis of this drug leads to the formation of two potentially toxic species, 3,4-methylenedioxybenzylpiperazine (MDBP) and 4-chlorophenoxyacetic acid (4-CPA). Here, we investigate the in vitro metabolism of fipexide in human, rat, mouse and dog, as well as of MDBP and 4-CPA in human and rat, while focusing on the formation of reactive metabolites. A combination of LC/MS analyses on a hybrid quadrupole-linear ion trap instrument and accurate mass data from QqTOF measurements was employed for the characterization of these metabolites. Microsomal metabolites of fipexide were MDBP, 4-CPA, fipexide N-oxide or hydroxyl, demethylenated fipexide and other minor ones, all of which were investigated by tandem mass spectrometry. Reactive metabolites were detected using several trapping procedures with small molecules such as glutathione, its ethyl ester derivative and N-acetylcysteine. The demethylenated metabolite, a catechol, formed its corresponding ortho-quinone, which readily reacts with these nucleophiles. MDBP was studied in a similar manner, due to its ability to form an analogous catechol. Because of its acidic nature, 4-CPA was assessed for possible acylglucuronide and acyl-CoA thioester metabolites, which could also be involved in bioactivation pathways. Several important metabolites were identified as potential mediators of toxicity via protein binding. PMID:17577876
Continuing hunt for endophytic actinomycetes as a source of novel biologically active metabolites.
Masand, Meeta; Jose, Polpass Arul; Menghani, Ekta; Jebakumar, Solomon Robinson David
Drug-resistant pathogens and persistent agrochemicals mount the detrimental threats against human health and welfare. Exploitation of beneficial microorganisms and their metabolic inventions is most promising way to tackle these two problems. Since the successive discoveries of penicillin and streptomycin in 1940s, numerous biologically active metabolites have been discovered from different microorganisms, especially actinomycetes. In recent years, actinomycetes that inhabit unexplored environments have received significant attention due to their broad diversity and distinctive metabolic potential with medical, agricultural and industrial importance. In this scenario, endophytic actinomycetes that inhabit living tissues of plants are emerging as a potential source of novel bioactive compounds for the discovery of drug leads. Also, endophytic actinomycetes are considered as bio-inoculants to improve crop performance through organic farming practices. Further efforts on exploring the endophytic actinomycetes associated with the plants warrant the likelihood of discovering new taxa and their metabolites with novel chemical structures and biotechnological importance. This mini-review highlights the recent achievements in isolation of endophytic actinomycetes and an assortment of bioactive compounds. PMID:26410426
Defensive Metabolites from Antarctic Invertebrates: Does Energetic Content Interfere with Feeding Repellence?
Núñez-Pons, Laura; Avila, Conxita
Many bioactive products from benthic invertebrates mediating ecological interactions have proved to reduce predation, but their mechanisms of action, and their molecular identities, are usually unknown. It was suggested, yet scarcely investigated, that nutritional quality interferes with defensive metabolites. This means that antifeedants would be less effective when combined with energetically rich prey, and that higher amounts of defensive compounds would be needed for predator avoidance. We evaluated the effects of five types of repellents obtained from Antarctic invertebrates, in combination with diets of different energetic values. The compounds came from soft corals, ascidians and hexactinellid sponges; they included wax esters, alkaloids, a meroterpenoid, a steroid, and the recently described organic acid, glassponsine. Feeding repellency was tested through preference assays by preparing diets (alginate pearls) combining different energetic content and inorganic material. Experimental diets contained various concentrations of each repellent product, and were offered along with control compound-free pearls, to the Antarctic omnivore amphipod Cheirimedon femoratus. Meridianin alkaloids were the most active repellents, and wax esters were the least active when combined with foods of distinct energetic content. Our data show that levels of repellency vary for each compound, and that they perform differently when mixed with distinct assay foods. The natural products that interacted the most with energetic content were those occurring in nature at higher concentrations. The bioactivity of the remaining metabolites tested was found to depend on a threshold concentration, enough to elicit feeding repellence, independently from nutritional quality. PMID:24962273
Structure-Activity Studies of Brassinosteroids and the Search for Novel Analogues and Mimetics with Improved Bioactivity.
Back, Thomas G.; Pharis, Richard P.
A number of novel brassinosteroid analogues were synthesized and subjected to the rice leaf lamina inclination bioassay. Modified B-ring analogues included lactam, thiolactone, cyclic ether, ketone, hydroxyl, and exocyclic methylene derivatives of brassinolide. Those derivatives containing polar functional groups retained considerable bioactivity, whereas the exocyclic methylene compounds were devoid of activity. Analogues containing normal alkyl and cycloalkyl substituents at C-24 (in place of the isopropyl group of brassinolide) showed an inverse relationship between activity and chain length or ring size, respectively. The corresponding cyclopropyl and cyclobutyl derivatives were significantly more active than brassinolide and appear to be the most potent brassinosteroids reported to date. When synergized with the auxin indole-3-acetic acid (IAA), their bioactivity can be further enhanced by 1-2 orders of magnitude. The cyclopropyl derivative, when coapplied with the auxin naphthaleneacetic acid, gave a significant increase in yield of wheat in a field trial. Certain 25- and 26-hydroxy derivatives are known metabolites of brassinosteroids. All of the C-25 stereoisomers of 25-hydroxy, 26-hydroxy, and 25,26-dihydroxy derivatives of brassinolide were prepared and shown to be much less active than brassinolide. This indicates that they are likely metabolic deactivation products of the parent phytohormone. A series of methyl ethers of brassinolide was synthesized to block deactivation by glucosylation of the free hydroxyl groups. The most significant finding was that the compound where three of the four hydroxyl groups (at C-3, C-22, and C-23) had been converted to methyl ethers retained substantial bioactivity. This type of modification could, in theory, allow brassinolide or 24-epibrassinolide to resist deactivation and thus offer greater persistence in field applications. A series of nonsteroidal mimetics of brassinolide was designed and synthesized. Two of the
NASA Technical Reports Server (NTRS)
Kumar, Prithvi R. (Inventor); Abare, Wayne (Inventor)
A filter for a switching power supply. The filter includes a common mode inductor with coil configurations allowing differential mode current from a dc source to pass through but attenuating common mode noise from the power supply so that the noise does not reach the dc source. The invention also includes the use of feed through capacitors at the switching power supply input terminals to provide further high-frequency noise attenuation.
NASA Technical Reports Server (NTRS)
Kramer, R. C.
Portable compressed air supply has two or more outputs at pressures from 20 to 100 psi. Applications include operating production equipment, spraying paint and lubricants, and pressurizing refrigeration systems. Supply filters air from standard high-pressure line, reduces it to working pressure, and adds lubricant when required. Regulator supplies low-pressure air to output channels. On channel lines, vernier-control valves select output pressures.
Absorption properties of micellar lipid metabolites into Caco2 cells.
Tsuzuki, Wakako
To elucidate the absorption characteristics of dietary lipids in the human intestine, we investigated the cellular uptake of lipid metabolites using a differential monolayer of the Caco2 cells. As lipid metabolites, several free fatty acids and 2-monoacylglycerols, were formed a mixed micelle by bile salts and lysophospholipids and they were supplied to the Caco2 cells. To estimate the effect of the mixed micelles on the permeability of cells' membranes during incubation with the mixed micelles, the transepitherial electrical resistance (TEER) value was monitored, and no pronounced changes of TEER was detected. This suggested that mixed micelles did not affect their cellular properties of the barrier measured by TEER. The lipid metabolites transferred from the mixed micelle into the Caco2 cells were determined quantitatively by an enzymatic colorimetric method and were done by thin layer chromatography (TLC) for a species of acylglycerols. These highly sensitive methods enabled us to monitor the transepithelial transports of various kinds of non-isotope-labeled various lipid metabolites. Newly re-synthesized triacylglycerols were accumulated in Caco2 cells after 30 min incubation with the mixed micelles, and their amounts increased gradually for 4 h. The secretion of re-esterified triacylglycerols into a basolateral medium from the Caco2 cells began at 2 h after the mixed micelles were added to the apical medium. The intake of external lipid metabolites by the Caco2 cells were evaluated by an initial 2-h incubation with the mixed micelles. For example, 2-monomyristin and 2-monopalmitin were more rapidly transferred into the Caco2 cells from the mixed micelles than 2-monocaprin was. On the other hand, the absorption rates of capric acid, lauric acid and myristic acid by the cells were larger than those of stearic acid and oleic acid. It revealed that the side-chain structure of these lipid metabolites affected their absorption by the Caco2 cells. The results of this
Polyphenols from wolfberry and their bioactivities.
Zhou, Zheng-Qun; Xiao, Jia; Fan, Hong-Xia; Yu, Yang; He, Rong-Rong; Feng, Xiao-Lin; Kurihara, Hiroshi; So, Kwok-Fai; Yao, Xin-Sheng; Gao, Hao
Nine new phenylpropanoids, one new coumarin, and 43 known polyphenols were isolated from wolfberry. Their structures were determined by spectroscopic analyses, chemical methods, and comparison of NMR data. Polyphenols, an important type of natural products, are notable constituents in wolfberry. 53 polyphenols, including 28 phenylpropanoids, four coumarins, eight lignans, five flavonoids, three isoflavonoids, two chlorogenic acid derivatives, and three other constituents, were identified from wolfberry. Lignans and isoflavonoids were firstly reported from wolfberry. 22 known polyphenols were the first isolates from the genus Lycium. This research presents a systematic study on wolfberry polyphenols, including their bioactivities. All these compounds exhibited oxygen radical absorbance capacity (ORAC), and some compounds displayed DPPH radical scavenging activity. One compound had acetylcholinesterase inhibitory activity. The discovery of new polyphenols and their bioactivities is beneficial for understanding the scientific basis of the effects of wolfberry. PMID:27507521
Microencapsulated Bioactive Agents and Method of Making
NASA Technical Reports Server (NTRS)
Morrison, Dennis R. (Inventor); Mosier, Benjamin (Inventor)
The invention is directed to microcapsules encapsulating an aqueous solution of a protein, drug or other bioactive substance inside a semi-permeable membrane. The microcapsules are formed by interfacial coacervation where shear forces are limited to 0-100 dynes per square centimeter. The resulting uniform microcapsules can then be subjected to dewatering in order to cause the internal solution to become supersaturated with the dissolved substance. This dewatering allows controlled nucleation and crystallization of the dissolved substance. The crystal-filled microcapsules can be stored, keeping the encapsulated crystals in good condition for further direct use in x-ray crystallography or as injectable formulations of the dissolved drug, protein or other bioactive substance.
Cameroonian medicinal plants: a bioactivity versus ethnobotanical survey and chemotaxonomic classification
Background In Cameroon herbs are traditionally used to meet health care needs and plans are on the way to integrate traditional medicine in the health care system, even though the plans have not been put into action yet. The country however has a rich biodiversity, with ~8,620 plant species, some of which are commonly used in the treatment of several microbial infections and a range of diseases (malaria, trypanosomiasis, leishmaniasis, diabetes and tuberculosis). Methods Our survey consisted in collecting published data from the literature sources, mainly from PhD theses in Cameroonian university libraries and also using the author queries in major natural product and medicinal chemistry journals. The collected data includes plant sources, uses of plant material in traditional medicine, plant families, region of collection of plant material, isolated metabolites and type (e.g. flavonoid, terpenoid, etc.), measured biological activities of isolated compounds, and any comments on significance of isolated metabolites on the chemotaxonomic classification of the plant species. This data was compiled on a excel sheet and analysed. Results In this study, a literature survey led to the collection of data on 2,700 secondary metabolites, which have been previously isolated or derived from Cameroonian medicinal plants. This represents distinct phytochemicals derived from 312 plant species belonging to 67 plant families. The plant species are investigated in terms of chemical composition with respect to the various plant families. A correlation between the known biological activities of isolated compounds and the ethnobotanical uses of the plants is also attempted. Insight into future direction for natural product search within the Cameroonian forest and Savanna is provided. Conclusions It can be verified that a phytochemical search of active secondary metabolites, which is inspired by knowledge from the ethnobotanical uses of medicinal plants could be very vital in a drug
Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention.
Shirode, Amit B; Bharali, Dhruba J; Nallanthighal, Sameera; Coon, Justin K; Mousa, Shaker A; Reliene, Ramune
Pomegranate polyphenols are potent antioxidants and chemopreventive agents but have low bioavailability and a short half-life. For example, punicalagin (PU), the major polyphenol in pomegranates, is not absorbed in its intact form but is hydrolyzed to ellagic acid (EA) moieties and rapidly metabolized into short-lived metabolites of EA. We hypothesized that encapsulation of pomegranate polyphenols into biodegradable sustained release nanoparticles (NPs) may circumvent these limitations. We describe here the development, characterization, and bioactivity assessment of novel formulations of poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs loaded with pomegranate extract (PE) or individual polyphenols such as PU or EA. Monodispersed, spherical 150-200 nm average diameter NPs were prepared by the double emulsion-solvent evaporation method. Uptake of Alexa Fluor-488-labeled NPs was evaluated in MCF-7 breast cancer cells over a 24-hour time course. Confocal fluorescent microscopy revealed that PLGA-PEG NPs were efficiently taken up, and the uptake reached the maximum at 24 hours. In addition, we examined the antiproliferative effects of PE-, PU-, and/or EA-loaded NPs in MCF-7 and Hs578T breast cancer cells. We found that PE, PU, and EA nanoprototypes had a 2- to 12-fold enhanced effect on cell growth inhibition compared to their free counterparts, while void NPs did not affect cell growth. PU-NPs were the most potent nanoprototype of pomegranates. Thus, PU may be the polyphenol of choice for further chemoprevention studies with pomegranate nanoprototypes. These data demonstrate that nanotechnology-enabled delivery of pomegranate polyphenols enhances their anticancer effects in breast cancer cells. Thus, pomegranate polyphenols are promising agents for nanochemoprevention of breast cancer. PMID:25624761
Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention
Shirode, Amit B; Bharali, Dhruba J; Nallanthighal, Sameera; Coon, Justin K; Mousa, Shaker A; Reliene, Ramune
Pomegranate polyphenols are potent antioxidants and chemopreventive agents but have low bioavailability and a short half-life. For example, punicalagin (PU), the major polyphenol in pomegranates, is not absorbed in its intact form but is hydrolyzed to ellagic acid (EA) moieties and rapidly metabolized into short-lived metabolites of EA. We hypothesized that encapsulation of pomegranate polyphenols into biodegradable sustained release nanoparticles (NPs) may circumvent these limitations. We describe here the development, characterization, and bioactivity assessment of novel formulations of poly(D,L-lactic-co-glycolic acid)–poly(ethylene glycol) (PLGA–PEG) NPs loaded with pomegranate extract (PE) or individual polyphenols such as PU or EA. Monodispersed, spherical 150–200 nm average diameter NPs were prepared by the double emulsion–solvent evaporation method. Uptake of Alexa Fluor-488-labeled NPs was evaluated in MCF-7 breast cancer cells over a 24-hour time course. Confocal fluorescent microscopy revealed that PLGA–PEG NPs were efficiently taken up, and the uptake reached the maximum at 24 hours. In addition, we examined the antiproliferative effects of PE-, PU-, and/or EA-loaded NPs in MCF-7 and Hs578T breast cancer cells. We found that PE, PU, and EA nanoprototypes had a 2- to 12-fold enhanced effect on cell growth inhibition compared to their free counterparts, while void NPs did not affect cell growth. PU-NPs were the most potent nanoprototype of pomegranates. Thus, PU may be the polyphenol of choice for further chemoprevention studies with pomegranate nanoprototypes. These data demonstrate that nanotechnology-enabled delivery of pomegranate polyphenols enhances their anticancer effects in breast cancer cells. Thus, pomegranate polyphenols are promising agents for nanochemoprevention of breast cancer. PMID:25624761
Fluoride-containing bioactive glasses: Glass design, structure, bioactivity, cellular interactions, and recent developments.
Shah, Furqan A
Bioactive glasses (BGs) are known to bond to both hard and soft tissues. Upon exposure to an aqueous environment, BG undergoes ion exchange, hydrolysis, selective dissolution and precipitation of an apatite layer on their surface, which elicits an interfacial biological response resulting in bioactive fixation, inhibiting further dissolution of the glass, and preventing complete resorption of the material. Fluorine is considered one of the most effective in-vivo bone anabolic factors. In low concentrations, fluoride ions (F(-)) increase bone mass and mineral density, improve the resistance of the apatite structure to acid attack, and have well documented antibacterial properties. F(-) ions may be incorporated into the glass in the form of calcium fluoride (CaF2) either by part-substitution of network modifier oxides, or by maintaining the ratios of the other constituents relatively constant. Fluoride-containing bioactive glasses (FBGs) enhance and control osteoblast proliferation, differentiation and mineralisation. And with their ability to release fluoride locally, FBGs make interesting candidates for various clinical applications, dentinal tubule occlusion in the treatment of dentin hypersensitivity. This paper reviews the chemistry of FBGs and the influence of F(-) incorporation on the thermal properties, bioactivity, and cytotoxicity; and novel glass compositions for improved mechanical properties, processing, and bioactive potential. PMID:26478431
Neuropeptides: metabolism to bioactive fragments and the pharmacology of their receptors.
Hallberg, Mathias
The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals
Formed and preformed metabolites: facts and comparisons.
Pang, K Sandy; Morris, Marilyn E; Sun, Huadong
The administration of metabolites arising from new drug entities is often employed in drug discovery to investigate their associated toxicity. It is expected that administration of metabolites can predict the exposure of metabolites originating from the administration of precursor drug. Whether exact and meaningful information can be obtained from this has been a topic of debate. This communication summarizes observations and theoretical relationships based on physiological modelling for the liver, kidney and intestine, three major eliminating organs/tissues. Theoretical solutions based on physiological modelling of organs were solved, and the results suggest that deviations are expected. Here, examples of metabolite kinetics observed mostly in perfused organs that did not match predictions are provided. For the liver, discrepancies in fate between formed and preformed metabolites may be explained by the heterogeneity of enzymes, the presence of membrane barriers and whether transporters are involved. For the kidney, differences have been attributed to glomerular filtration of the preformed but not the formed metabolite. For the intestine, the complexity of segregated flows to the enterocyte and serosal layers and differences in metabolism due to the route of administration are addressed. Administration of the metabolite may or may not directly reflect the toxicity associated with drug use. However, kinetic data on the preformed metabolite will be extremely useful to develop a sound model for modelling and simulations; in-vitro evidence on metabolite handling at the target organ is also paramount. Subsequent modelling and simulation of metabolite data arising from a combined model based on both drug and preformed metabolite data are needed to improve predictions on the behaviours of formed metabolites. PMID:18812018
Transfersomes: self-optimizing carriers for bioactives.
Rai, Kavita; Gupta, Yashwant; Jain, Anekant; Jain, Sanjay K
The transdermal route of drug delivery has gained great interest of pharmaceutical research, as it circumvents number of problems associated with oral route of drug administration. The major barrier in transdermal delivery of drug is the skin intrinsic barrier, the stratum corneum, the outermost envelop of the skin that offers the principal hurdle for diffusion of hydrophilic ionizable bioactives. Recently, various strategies have been used to augment the transdermal delivery of bioactives. Mainly, they include iontophoresis, electrophoresis, sonophoresis, chemical permeation enhancers, microneedles, and vesicular system (liposomes, niosomes, elastic liposomes such as ethosomes and transfersomes). Among these strategies transferosomes appear promising. Transport of this vesicular system through skin and epithelial hurdle depends upon the flexibility of their membrane, which can be attained using appropriate ratio of surfactant. Transfersomes have shown immense potential in drug delivery across the skin. Recent success also demonstrates the potential of transfersome in vaccine, steroid, protein, and peptide delivery across the skin. It is also used for transporting genetic material and achieving transfection. This review highlights the various aspects of the transferosomes in the effective delivery of drug/bioactives across the skin. PMID:19055232
Epitope topography controls bioactivity in supramolecular nanofibers
Sur, Shantanu; Tantakitti, Faifan; Matson, John B.; Stupp, Samuel I.
Incorporating bioactivity into artificial scaffolds using peptide epitopes present in the extracellular matrix (ECM) is a well-known approach. A common strategy has involved epitopes that provide cells with attachment points and external cues through interaction with integrin receptors. Although a variety of bioactive sequences have been identified so far, less is known about their optimal display in a scaffold. We report here on the use of self-assembled peptide amphiphile (PA) nanofiber matrices to investigate the impact of spatial presentation of the fibronectin derived epitope RGDS on cell response. Using one, three, or five glycine residues, RGDS epitopes were systematically spaced out from the surface of the rigid nanofibers. We found that cell morphology was strongly affected by the separation of the epitope from the nanofiber surface, with the longest distance yielding the most cell-spreading, bundling of actin filaments, and a round-to-polygonal transformation of cell shape. Cell response to this type of epitope display was also accompanied with activated integrin-mediated signaling and formation of stronger adhesions between cells and substrate. Interestingly, unlike length, changing the molecular flexibility of the linker had minimal influence on cell behavior on the substrate for reasons that remain poorly understood. The use in this study of high persistence length nanofibers rather than common flexible polymers allows us to conclude that epitope topography at the nanoscale structure of a scaffold influences its bioactive properties independent of epitope density and mechanical properties. PMID:25745558
Phenolic compounds and bioactivities of pigmented rice.
Deng, Gui-Fang; Xu, Xiang-Rong; Zhang, Yuan; Li, Dan; Gan, Ren-You; Li, Hua-Bin
The pigmented rice has been consumed in China, Japan, and Korea for a long time. It has been used for strengthening kidney function, treating anemia, promoting blood circulation, removing blood stasis, treating diabetes, and ameliorating sight in traditional Chinese medicine. The extracts from pigmented rice are used as natural food colorants in bread, ice cream, and liquor as well as functional food. The pigmented rice is mainly black, red, and dark purple rice, and contains a variety of flavones, tannin, phenolics, sterols, tocols, γ-oryzanols, amino acids, and essential oils. Anthocyanins are thought as major functional components of pigmented rice. Several anthocyanins have been isolated and identified from the pigmented rice, including cyanidin 3-glucoside, cyanidin 3-galactoside, cyanidin 3-rutinoside, cyanidin 3,5-diglucoside, malvidin 3-galactoside, peonidin 3-glucoside, and pelargonidin 3,5-diglucoside. This review provides up-to-date coverage of pigmented rice in regard to bioactive constituents, extraction and analytical methods, and bioactivities. Special attention is paid to the bioactivities including antioxidant and free radical scavenging, antitumor, antiatherosclerosis, hypoglycemic, and antiallergic activities. PMID:23216001
Novel sol-gel bioactive fibers.
Oréfice, R L; Hench, L L; Clark, A E; Brennan, A B
Bioactive fibers were produced using a sol-gel method. The rheological properties of two different sol compositions prepared from a mixture of TEOS, phosphorous alkoxide and calcium nitrate, or calcium chloride in a water-ethanol solution, are reported. The sols were extruded through a spinneret to produce continuous 10 microm-diameter fibers. Discontinuous fibers and fibrous mats were prepared by air-spraying the multicomponent sols. The sol-gel fibers were converted to the bioactive fibers by three different thermal treatments at either 600 degrees, 700 degrees, or 900 degrees C for 3 h. SEM, BET, EDX, and FTIR were used to characterize the morphology and structure of the fibers. The BET measured surface area of the fibers sintered at 900 degrees C was 0 m(2)/gm compared to a value of 200 m(2)/gm for a typical sol-gel-derived particle of similar composition. Both the continuous and discontinuous fibers exhibited in vitro bioactivity in a simulated body fluid. PMID:11288073
[Multiple emulsions; bioactive compounds and functional foods].
Jiménez-Colmenero, Francisco
The continued appearance of scientific evidence about the role of diet and/or its components in health and wellness, has favored the emergence of functional foods which currently constitute one of the chief factors driving the development of new products. The application of multiple emulsions opens new possibilities in the design and development of functional foods. Multiple emulsions can be used as an intermediate product (food ingredient) into technological strategies normally used in the optimization of the presence of bioactive compounds in healthy and functional foods. This paper presents a summary of the types, characteristics and formation of multiple emulsions, possible location of bioactive compounds and their potential application in the design and preparation of healthy and functional foods. Such applications are manifested particularly relevant in relation to quantitative and qualitative aspects of lipid material (reduced fat/calories and optimization of fatty acid profile), encapsulation of bioactive compounds mainly hydrophilic and sodium reduction. This strategy offers interesting possibilities regarding masking flavours and improving sensory characteristics of foods. PMID:24160194
Human Milk Composition: Nutrients and Bioactive Factors
Ballard, Olivia; Morrow, Ardythe L.
Synopsis The composition of human milk is the biologic norm for infant nutrition. Human milk also contains many hundreds to thousands of distinct bioactive molecules that protect against infection and inflammation and contribute to immune maturation, organ development, and healthy microbial colonization. Some of these molecules, e.g., lactoferrin, are being investigated as novel therapeutic agents. A dynamic, bioactive fluid, human milk changes in composition from colostrum to late lactation, and varies within feeds, diurnally, and between mothers. Feeding infants with expressed human milk is increasing. Pasteurized donor milk is now commonly provided to high risk infants and most mothers in the U.S. express and freeze their milk at some point in lactation for future infant feedings. Many milk proteins are degraded by heat treatment and freeze-thaw cycles may not have the same bioactivity after undergoing these treatments. This article provides an overview of the composition of human milk, sources of its variation, and its clinical relevance. PMID:23178060
Plant bioactives for ruminant health and productivity.
Rochfort, Simone; Parker, Anthony J; Dunshea, Frank R
Plants have been used throughout history for their medicinal properties. This use has often focused on human health but plants have also been, and still are, applied in ethnoveterinary practice and animal health management. In recent times, the use of synthetic chemicals has become prevalent. Public awareness of the potential environmental and health risks associated with heavy chemical use has also increased. This has put pressure on regulatory bodies to reduce the use of chemicals in agriculture. The most striking example is the 2006 banning of antibiotics in animal feed by the European Union. Moves such as this have increased the drive to find alternatives to synthetic chemicals and research has again turned to the use of plant bioactives as a means of improving animal health. Current scientific evidence suggests there is significant potential to use plants to enhance animal health in general and that of ruminants (cattle, deer, sheep, etc.) in particular. Active areas of research for plant bioactives (particularly saponin and tannin containing plants) include reproductive efficiency, milk and meat quality improvement, foam production/bloat control and methane production. Nematode control is also a significant area of research and the evidence suggests a much broader range of phytochemicals may be effective. This review presents a summary of the literature and examines international research efforts towards the development of plant bioactives for animal health. PMID:17919666
Are bioactive-rich fractions functionally richer?
Imam, Mustapha Umar; Ismail, Maznah; Ooi, Der Jiun; Azmi, Nur Hanisah; Sarega, Nadarajan; Chan, Kim Wei; Bhanger, Muhammad Iqbal
Plant bioresources are relied upon as natural, inexpensive, and sustainable remedies for the management of several chronic diseases worldwide. Plants have historically been consumed for medicinal purposes based on traditional belief, but this trend is currently changing. The growing interest in the medicinal properties of plant bioresources stems from concerns of side effects and other adverse effects caused by synthetic drugs. This interest has yielded a better understanding of the roles of plant bioactive compounds in health promotion and disease prevention, including the underlying mechanisms involved in such functional effects. The desire to maximize the potential of phytochemicals has led to the development of "rich fractions," in which extracts contain bioactive compounds in addition to elevated levels of the primary compound. Although a rich fraction effectively increases the bioactivity of the extract, the standardization and quality assurance process can be challenging. However, the supercritical fluid extraction (SFE) system is a promising green technology in this regard. Future clinical and pharmacological studies are needed to fully elucidate the implications of these preparations in the management of human diseases, thereby fostering a move toward evidence-based medicine. PMID:25641328
Simultaneous determination of six active metabolites in Astragalus mongholicus (Fisch.) Bge. under salt stress by ultra-pressure liquid chromatography with tandem mass spectrometry.
Liu, Yang; Liu, Jia; Wang, Yu; Abozeid, Ann; Tang, Zhong-Hua
Astragalus membranaceus Bge. var. mongholicus (Bge.) Hsiao (A. mongholicus, family Leguminosae) is one of the most important traditional Chinese herbs because it contains lots of bioactive metabolites, which have beneficial and pharmacological effects on health. Simultaneously, it has been proved to be a salt-tolerant plant-one of the potential species to control the soil salinization. Therefore, a sensitive and specific ultra-pressure liquid chromatography coupled with tandem mass spectrometric (UPLC-MS/MS) method was developed and validated for the simultaneous determination of six main bioactive metabolites, astragaloside IV, cycloastragenol, calycosin-7-O-β-d-glucoside, calycosin, ononin and formononetin in different organs of A. mongholicus. The detection was accomplished by multiple-reaction monitoring (MRM) scanning via electrospray ionization source operating in the positive ionization mode. Calibration curves offered linear ranges of two orders of magnitude with R(2) > 0.99. The method was fully validated for the linearity, intra-day and inter day precisions, accuracy, recovery, matrix effect and stability. Then this method was successfully applied to detect the content of major bioactive metabolites in different plant organs of A. mongholicus under salt stress. Significant variations in the content of six bioactive metabolites were observed after been processed by different levels of salinity in different part of plant. The results support for further exploration of the salt-tolerant mechanisms in A. mongholicus and its possibility as the species that control the soil salinization. Meanwhile, we established a UPLC-MS/MS assay of the trace components in seedling of A. mongholicus in this study. PMID:27386371
Aspirin metabolites are GPR35 agonists.
Deng, Huayun; Fang, Ye
Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472
The Use of Endophytes to Obtain Bioactive Compounds and Their Application in Biotransformation Process
Pimentel, Mariana Recco; Molina, Gustavo; Dionísio, Ana Paula; Maróstica Junior, Mário Roberto; Pastore, Gláucia Maria
Endophytes are microorganisms that reside asymptomatically in the tissues of higher plants and are a promising source of novel organic natural metabolites exhibiting a variety of biological activities. The laboratory of Bioaromas (Unicamp, Brazil) develops research in biotransformation processes and functional evaluation of natural products. With the intent to provide subsidies for studies on endophytic microbes related to areas cited before, this paper focuses particularly on the role of endophytes on the production of anticancer, antimicrobial, and antioxidant compounds and includes examples that illustrate their potential for human use. It also describes biotransformation as an auspicious method to obtain novel bioactive compounds from microbes. Biotransformation allows the production of regio- and stereoselective compounds under mild conditions that can be labeled as "natural," as discussed in this paper. PMID:21350663
Bioactive Compounds Produced by Strains of Penicillium and Talaromyces of Marine Origin
Nicoletti, Rosario; Trincone, Antonio
In recent years, the search for novel natural compounds with bioactive properties has received a remarkable boost in view of their possible pharmaceutical exploitation. In this respect the sea is entitled to hold a prominent place, considering the potential of the manifold animals and plants interacting in this ecological context, which becomes even greater when their associated microbes are considered for bioprospecting. This is the case particularly of fungi, which have only recently started to be considered for their fundamental contribution to the biosynthetic potential of other more valued marine organisms. Also in this regard, strains of species which were previously considered typical terrestrial fungi, such as Penicillium and Talaromyces, disclose foreground relevance. This paper offers an overview of data published over the past 25 years concerning the production and biological activities of secondary metabolites of marine strains belonging to these genera, and their relevance as prospective drugs. PMID:26901206
Isolation of Bioactive Compounds from Sunflower Leaves (Helianthus annuus L.) Extracted with Supercritical Carbon Dioxide.
El Marsni, Zouhir; Torres, Ascension; Varela, Rosa M; Molinillo, José M G; Casas, Lourdes; Mantell, Casimiro; Martinez de la Ossa, Enrique J; Macias, Francisco A
The work described herein is a continuation of our initial studies on the supercritical fluid extraction (SFE) with CO2 of bioactive substances from Helianthus annuus L. var. Arianna. The selected SFE extract showed high activity in the wheat coleoptile bioassay, in Petri dish phytotoxicity bioassays, and in the hydroponic culture of tomato seeds. Chromatographic fractionations of the extracts and a spectroscopic analysis of the isolated compounds showed 52 substances belonging to 10 different chemical classes, which were mainly sesquiterpene lactones, diterpenes, and flavonoids. Heliannuol M (31), helivypolides K and L (36, 37), and helieudesmanolide B (38) are described for the first time in the literature. Metabolites have been tested in the etiolated wheat coleoptile bioassay with good results in a noteworthy effect on germination. The most active compounds were also tested on tomato seeds, heliannuol A (30) and leptocarpin (45) being the most active, with values similar to those of the commercial herbicide. PMID:26151222
Humudifucol and Bioactive Prenylated Polyphenols from Hops (Humulus lupulus cv. "Cascade").
Forino, Martino; Pace, Simona; Chianese, Giuseppina; Santagostini, Laura; Werner, Markus; Weinigel, Christina; Rummler, Silke; Fico, Gelsomina; Werz, Oliver; Taglialatela-Scafati, Orazio
Humulus lupulus (hop plant) has long been used in traditional medicine as a sedative and antimicrobial agent. More recently, attention has been devoted to the phytoestrogenic activity of the plant extracts as well as to the anti-inflammatory and chemopreventive properties of the prenylated chalcones present. In this study, an Italian sample of H. lupulus cv. "Cascade" has been investigated and three new compounds [4-hydroxycolupulone (6), humudifucol (7) and cascadone (8)] have been purified and identified by means of NMR spectroscopy along with four known metabolites. Notably, humudifucol (7) is the first prenylated dimeric phlorotannin discovered in nature. Because structurally related phloroglucinols from natural sources were found previously to inhibit microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), the isolated compounds were evaluated for their bioactivity against these pro-inflammatory target proteins. The prenylated chalcone xanthohumol inhibited both enzymes at low μM concentrations. PMID:26918635
Nutrients and bioactive compounds content of Baillonella toxisperma, Trichoscypha abut and Pentaclethra macrophylla from Cameroon.
Fungo, Robert; Muyonga, John; Kaaya, Archileo; Okia, Clement; Tieguhong, Juius C; Baidu-Forson, Jojo J
Baillonella toxisperma, Pentaclethra macrophylla and Trichoscypha abut are important foods for communities living around forests in Cameroon. Information on the nutritional value and bioactive content of these foods is required to establish their contribution to the nutrition and health of the communities. Samples of the three foods were obtained from four villages in east and three villages in south Cameroon. The foods were analyzed for proximate composition, minerals and bioactive content using standard chemical analysis methods. T. abut was found to be an excellent source of bioactive compounds; flavonoids (306 mg/100 g), polyphenols (947 mg/100 g), proanthocyanins (61.2 mg/100 g), vitamin C (80.05 mg/100 g), and total oxalates (0.6 mg/100 g). P. macrophylla was found to be a rich source of total fat (38.71%), protein (15.82%) and total fiber (17.10%) and some bioactive compounds; vitamin E (19.4 mg/100 g) and proanthocyanins (65.0 mg/100 g). B. toxisperma, was found to have high content of carbohydrates (89.6%), potassium (27.5 mg/100 g) and calcium (37.5 mg/100 g). Flavonoids, polyphenols, vitamins C and E are the main bioactive compounds in these forest foods. The daily consumption of some of these fruits may coffer protection against some ailments and oxidative stress. Approximately 200 g of either B. toxisperma or P. macrophylla, can supply 100% iron and zinc RDAs for children aged 1-3 years, while 300 g of the two forest foods can supply about 85% iron and zinc RDAs for non-pregnant non-lactating women. The three foods provide 100% daily vitamins C and E requirements for both adults and children. The results of this study show that Baillonella toxisperma, Pentaclethra macrophylla and Trichoscypha abut can considerably contribute towards the human nutrient requirements. These forest foods also contain substantial levels of health promoting phytochemicals notably flavonoids, polyphenols, vitamins C and E. These foods therefore have
Nutrients and bioactive compounds content of Baillonella toxisperma, Trichoscypha abut and Pentaclethra macrophylla from Cameroon
Fungo, Robert; Muyonga, John; Kaaya, Archileo; Okia, Clement; Tieguhong, Juius C; Baidu-Forson, Jojo J
Baillonella toxisperma, Pentaclethra macrophylla and Trichoscypha abut are important foods for communities living around forests in Cameroon. Information on the nutritional value and bioactive content of these foods is required to establish their contribution to the nutrition and health of the communities. Samples of the three foods were obtained from four villages in east and three villages in south Cameroon. The foods were analyzed for proximate composition, minerals and bioactive content using standard chemical analysis methods. T. abut was found to be an excellent source of bioactive compounds; flavonoids (306 mg/100 g), polyphenols (947 mg/100 g), proanthocyanins (61.2 mg/100 g), vitamin C (80.05 mg/100 g), and total oxalates (0.6 mg/100 g). P. macrophylla was found to be a rich source of total fat (38.71%), protein (15.82%) and total fiber (17.10%) and some bioactive compounds; vitamin E (19.4 mg/100 g) and proanthocyanins (65.0 mg/100 g). B. toxisperma, was found to have high content of carbohydrates (89.6%), potassium (27.5 mg/100 g) and calcium (37.5 mg/100 g). Flavonoids, polyphenols, vitamins C and E are the main bioactive compounds in these forest foods. The daily consumption of some of these fruits may coffer protection against some ailments and oxidative stress. Approximately 200 g of either B. toxisperma or P. macrophylla, can supply 100% iron and zinc RDAs for children aged 1–3 years, while 300 g of the two forest foods can supply about 85% iron and zinc RDAs for non-pregnant non-lactating women. The three foods provide 100% daily vitamins C and E requirements for both adults and children. The results of this study show that Baillonella toxisperma, Pentaclethra macrophylla and Trichoscypha abut can considerably contribute towards the human nutrient requirements. These forest foods also contain substantial levels of health promoting phytochemicals notably flavonoids, polyphenols, vitamins C and E. These foods therefore have
Free and total urinary phthalate metabolite concentrations among pregnant women from the Healthy Baby Cohort (HBC), China.
Zhu, Yingshuang; Wan, Yanjian; Li, Yuanyuan; Zhang, Bin; Zhou, Aifen; Cai, Zongwei; Qian, Zhengmin; Zhang, Chuncao; Huo, Wenqian; Huang, Kai; Hu, Jie; Cheng, Lu; Chang, Huailong; Huang, Zheng; Xu, Bing; Xia, Wei; Xu, Shunqing
Total urinary phthalate metabolites (the free plus glucuronidated forms) have been frequently measured in the general population. However, data are limited on the free forms which may be more bioactive, especially for sensitive population such as pregnant women. Here the data gap was addressed by measuring concentrations of free and total forms of six phthalate metabolites in 293 urine samples from pregnant women at delivery, who were randomly selected from the prospective Healthy Baby Cohort (HBC), China. We observed detectable concentrations of the total amount of phthalate metabolites in all urine samples. The geometric mean (GM) urinary concentrations of free and total mono-butyl phthalate (MBP) (5.20, 54.49ng/mL) were the highest, followed by mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) (4.52, 7.27ng/mL). For most of phthalate metabolites, urinary concentrations were significantly higher in women who were nulliparous. Significantly higher concentrations of mono-ethyl phthalate (MEP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) were found in women who had higher educational level. To our knowledge, this is the first study to report the free and total forms of phthalate metabolites among pregnant women in China. The results suggest that exposure characteristics may be related to parity and education. PMID:26722670
Liquid Chromatography-Mass Spectrometry-Based Rapid Secondary-Metabolite Profiling of Marine Pseudoalteromonas sp. M2
Kim, Woo Jung; Kim, Young Ok; Kim, Jin Hee; Nam, Bo-Hye; Kim, Dong-Gyun; An, Cheul Min; Lee, Jun Sik; Kim, Pan Soo; Lee, Hye Min; Oh, Joa-Sup; Lee, Jong Suk
The ocean is a rich resource of flora, fauna, and food. A wild-type bacterial strain showing confluent growth on marine agar with antibacterial activity was isolated from marine water, identified using 16S rDNA sequence analysis as Pseudoalteromonas sp., and designated as strain M2. This strain was found to produce various secondary metabolites including quinolone alkaloids. Using high-resolution mass spectrometry (MS) and nuclear magnetic resonance (NMR) analysis, we identified nine secondary metabolites of 4-hydroxy-2-alkylquinoline (pseudane-III, IV, V, VI, VII, VIII, IX, X, and XI). Additionally, this strain produced two novel, closely related compounds, 2-isopentylqunoline-4-one and 2-(2,3-dimetylbutyl)qunoline-4-(1H)-one, which have not been previously reported from marine bacteria. From the metabolites produced by Pseudoalteromonas sp. M2, 2-(2,3-dimethylbutyl)quinolin-4-one, pseudane-VI, and pseudane-VII inhibited melanin synthesis in Melan-A cells by 23.0%, 28.2%, and 42.7%, respectively, wherein pseudane-VII showed the highest inhibition at 8 µg/mL. The results of this study suggest that liquid chromatography (LC)-MS/MS-based metabolite screening effectively improves the efficiency of novel metabolite discovery. Additionally, these compounds are promising candidates for further bioactivity development. PMID:26805856
Chemical diversity of biologically active metabolites in the sclerotia of Inonotus obliquus and submerged culture strategies for up-regulating their production.
Zheng, Weifa; Miao, Kangjie; Liu, Yubing; Zhao, Yanxia; Zhang, Meimei; Pan, Shenyuan; Dai, Yucheng
Inonotus obliquus (Fr.) Pilat is a white rot fungus belonging to the family Hymenochaetaceae in the Basidiomycota. In nature, this fungus rarely forms a fruiting body but usually an irregular shape of sclerotial conk called 'Chaga'. Characteristically, I. obliquus produces massive melanins released to the surface of Chaga. As early as in the sixteenth century, Chaga was used as an effective folk medicine in Russia and Northern Europe to treat several human malicious tumors and other diseases in the absence of any unacceptable toxic side effects. Chemical investigations show that I. obliquus produces a diverse range of secondary metabolites including phenolic compounds, melanins, and lanostane-type triterpenoids. Among these are the active components for antioxidant, antitumoral, and antiviral activities and for improving human immunity against infection of pathogenic microbes. Geographically, however, this fungus is restricted to very cold habitats and grows very slowly, suggesting that Chaga is not a reliable source of these bioactive compounds. Attempts for culturing this fungus axenically all resulted in a reduced production of bioactive metabolites. This review examines the current progress in the discovery of chemical diversity of Chaga and their biological activities and the strategies to modulate the expression of desired pathways to diversify and up-regulate the production of bioactive metabolites by the fungus grown in submerged cultures for possible drug discovery. PMID:20532760
NASA Astrophysics Data System (ADS)
Varadharajulu, P.; Azeem Saqiq, M.; Yu, F.; McMeekin, D. A.; West, G.; Arnold, L.; Moncrieff, S.
This paper describes current research into the supply of spatial data to the end user in as close to real time as possible via the World Wide Web. The Spatial Data Infrastructure paradigm has been discussed since the early 1990s. The concept has evolved significantly since then but has almost always examined data from the perspective of the supplier. It has been a supplier driven focus rather than a user driven focus. The current research being conducted is making a paradigm shift and looking at the supply of spatial data as a supply chain, similar to a manufacturing supply chain in which users play a significant part. A comprehensive consultation process took place within Australia and New Zealand incorporating a large number of stakeholders. Three research projects that have arisen from this consultation process are examining Spatial Data Supply Chains within Australia and New Zealand and are discussed within this paper.
Power supply conditioning circuit
NASA Technical Reports Server (NTRS)
Primas, L. E.; Loveland, R.
A power supply conditioning circuit that can reduce Periodic and Random Deviations (PARD) on the output voltages of dc power supplies to -150 dBV from dc to several KHz with no measurable periodic deviations is described. The PARD for a typical commercial low noise power supply is -74 dBV for frequencies above 20 Hz and is often much worse at frequencies below 20 Hz. The power supply conditioning circuit described here relies on the large differences in the dynamic impedances of a constant current diode and a zener diode to establish a dc voltage with low PARD. Power supplies with low PARD are especially important in circuitry involving ultrastable frequencies for the Deep Space Network.
Phytochemistry and bioactivity of aromatic and medicinal plants from the genus Agastache (Lamiaceae).
Zielińska, Sylwia; Matkowski, Adam
Agastache is a small genus of Lamiaceae, comprising 22 species of perennial aromatic medicinal herbs. In this article, we review recent advances in phytochemical, pharmacological, biotechnological and molecular research on Agastache. The phytochemical profile of all Agastache species studied to date is generally similar, consisted of two main metabolic classes-phenylpropanoids and terpenoids. In the relatively variable essential oils, most populations of different Agastache species contain over 50 % of a phenylallyl compound-estragole. Also, other volatile compounds (methyleugenol, pulegone, menthone, isomenthone and spathulenol) were reported in various proportions. Major non-volatile metabolites belong to phenolic compounds, such as caffeic acid derivatives, especially rosmarinic acid as well as several flavones and flavone glycosides like acacetin, tilianin, agastachoside, and a rare dimeric malonyl flavone (agastachin). Two unique lignans-agastenol and agastinol-were also isolated. Terpenoids include triterpenoids of oleanane-type (maslinic acid, oleanolic acid and β-amyrin), ursane-type (ursolic acid, corosolic acid and α-amyrin), and typical plant sterols, as well as abietane-type oxidized diterpenes (e.g., agastaquinone, agastol, and others). The bioactivity of various extracts or individual compounds in vitro and in vivo include antimicrobial, antiviral and anti-mutagenic activity, cytotoxic activity to cancer cell lines, and anti-nociceptive, anti-inflammatory, anti-atherogenic, antioxidant as well as biocidal activity to several foodstuff pests. Biotechnological and molecular studies have focused on in vitro propagation and enhancing the biosynthesis of bioactive metabolites in cell or organ cultures, as well as on the expression of genes involved in phenolic biosynthesis. PMID:24899872
Bioactive compounds from marine mussels and their effects on human health.
Grienke, Ulrike; Silke, Joe; Tasdemir, Deniz
The consumption of marine mussels as popular seafood has increased steadily over the past decades. Awareness of mussel derived molecules, that promote health, has contributed to extensive research efforts in that field. This review highlights the bioactive potential of mussel components from species of the genus Mytilus (e.g. M. edulis) and Perna (e.g. P. canaliculus). In particular, the bioactivity related to three major chemical classes of mussel primary metabolites, i.e. proteins, lipids, and carbohydrates, is evaluated. Within the group of proteins the focus is mainly on mussel peptides e.g. those obtained by bio-transformation processes, such as fermentation. In addition, mussel lipids, comprising polyunsaturated fatty acids (PUFAs), are discussed as compounds that are well known for prevention and treatment of rheumatoid arthritis (RA). Within the third group of carbohydrates, mussel polysaccharides are investigated. Furthermore, the importance of monitoring the mussel as food material in respect to contaminations with natural toxins produced by microalgae is discussed. PMID:24001811
Picocyanobacteria from a clade of marine Cyanobium revealed bioactive potential against microalgae, bacteria, and marine invertebrates.
Costa, Maria Sofia; Costa, Margarida; Ramos, Vítor; Leão, Pedro N; Barreiro, Aldo; Vasconcelos, Vítor; Martins, Rosário
The production of bioactive compounds either toxic or with pharmacological applications by cyanobacteria is well established. However, picoplanktonic forms within this group of organisms have rarely been studied in this context. In this study, the toxicological potential of picocyanobacteria from a clade of marine Cyanobium strains isolated from the Portuguese coast was examined using different biological models. First, strains were identified by applying morphological and molecular approaches and cultured under lab conditions. A crude extract and three fractions reflecting a preliminary segregation of lipophilic metabolites were tested for toxicity with the marine microalga Nannochloropsis sp., the bacteria Pseudomonas sp., the brine shrimp Artemia salina, and fertilized eggs of the sea urchin Paracentrotus lividus. No significant apparent adverse effects were noted against Artemia salina. However, significant adverse effects were found in all other assays, with an inhibition of Nannochloropsis sp. and Pseudomonas sp. growth and marked reduction in Paracentrotus lividus larvae length. The results obtained indicated that Cyanobium genus may serve as a potential source of interesting bioactive compounds and emphasize the importance of also studying smaller picoplanktonic fractions of marine cyanobacteria. PMID:25785557
Chemical characterization of bioactive compounds from the endophytic fungus Diaporthe helianthi isolated from Luehea divaricata.
Specian, Vânia; Sarragiotto, Maria Helena; Pamphile, João Alencar; Clemente, Edmar
Endophytic microorganisms, defined as fungi or bacteria that colonize the interior of plants without causing any immediate negative effects or damages, have reciprocal relationships with host plants. In some cases their presence is beneficial to the host due to the synthesis of bioactive compounds, among which several alcohols, esters, ketones and others that may react with other compounds and may be lethal to pathogenic microorganisms. Diaporthe helianthi (Phomopsis helianthi in its anamorphic phase) is available worldwide, especially in Europe, Asia and America. Isolated in Europe as an agent of the sunflower stem cancer, it has also been endophytically isolated from tropical and temperate plants. A D. helianthi strain isolated from Luehea divaricata has been employed in current research. An investigation of the secondary metabolite from D. helianthi by CC and NMR of (1)H and (13)C yielded the separation of 10 fractions and the identification of the phenolic compound 2(-4 hydroxyphenyl)-ethanol (Tyrosol). Its antimicrobial reaction was tested and the ensuing antagonistic effects on the human pathogenic bacteria Enterococcus hirae, Escherichia coli, Micrococcus luteus, Salmonella typhi, Staphylococcus aureus, phytopathogenic Xanthomonas asc. phaseoli and phytopathogenic fungi were demonstrated. Results show that bioactive compounds and Tyrosol produced by D. helianthi have a biotechnological potential. PMID:24031942
Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration.
Xu, Xueyu; Zhao, Xue; Yang, Zhichao; Wang, Hao; Meng, Xiangjun; Su, Chong; Liu, Mingyuan; Fawcett, John Paul; Yang, Yan; Gu, Jingkai
In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d₃ (8), 2-oxoclopidogrel-d₃ (9), vicagrel-d₃ (10a), and 12 vicagrel-d₃ analogs (10b-10m) with different alkyl groups in the thiophene ester moiety. The D₃C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H₃C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro. A study of the ability of the compounds to inhibit ADP-induced platelet aggregation in fresh rat whole blood collected 2 h after oral dosing of rats with the compounds (7.8 μmol/kg) showed that deuteration increased the activity of clopidogrel and that increasing the size of the alkyl group in the thiophene ester moiety reduced activity. A preliminary pharmacokinetic study comparing 10a with vicagrel administered simultaneously as single oral doses (72 μmol/kg of each drug) to male Wistar rats showed 10a generated more of its active metabolite than vicagrel. These results suggest that 10a is a potentially superior antiplatelet agent with improved metabolic characteristics and bioactivity, and less dose-related toxicity. PMID:27248988
High expression level of antioxidants and pharmaceutical bioactivities of endophytic fungus Chaetomium globosum JN711454.
Selim, Khaled A; El-Beih, Ahmed A; Abdel-Rahman, Tahany M; El-Diwany, Ahmed I
In order to maximize antioxidant activity of pharmaceutical bioactive endophytic fungus Chaetomium globosum JN711454 during fermentation process, designed fermentation experiments of culture media for three levels of eight culture factors were performed using a Taguchi orthogonal array (OA) design with layout L18 (2(1) × 3(7)). The agitation and the potato extract were the most significant affecting factors, and their interaction contributed significantly to fungus activity. The production of antioxidants was more favorable for static condition with 25 g potato extract/100 m. The remaining factors had no strong impact when considered individually. The validation of statistically optimized medium indicated the improvement of antioxidant activity to a level of twofold with approximately overall 40% enhancement in activity. The extract of optimized medium was investigated for various pharmaceutical bioactivities; it revealed a moderate antimicrobial activity, strong anticancer activity against HepG-2, UACC62 cell lines, an antiviral activity against HSV-2 virus, and strong inhibitory activity to butyrylcholinesterase enzyme, one of the neurohydrolase enzymes that play a major role in development of Alzheimer's disease. As a result of applying statistical fermentation designs, the optimized conditions of endophytic fungus C. globosum JN711454 developed a cost-effective production medium by using inexpensive commercial potato extracts statically, which can lower the energy requirement and could become an efficient, economic, and viable fermentation process for production of pharmaceutical secondary metabolites. PMID:25569373
Red Raspberries and Their Bioactive Polyphenols: Cardiometabolic and Neuronal Health Links.
Burton-Freeman, Britt M; Sandhu, Amandeep K; Edirisinghe, Indika
Diet is an essential factor that affects the risk of modern-day metabolic diseases, including cardiovascular disease, diabetes mellitus, obesity, and Alzheimer disease. The potential ability of certain foods and their bioactive compounds to reverse or prevent the progression of the pathogenic processes that underlie these diseases has attracted research attention. Red raspberries (Rubus idaeus L.) are unique berries with a rich history and nutrient and bioactive composition. They possess several essential micronutrients, dietary fibers, and polyphenolic components, especially ellagitannins and anthocyanins, the latter of which give them their distinctive red coloring. In vitro and in vivo studies have revealed various mechanisms through which anthocyanins and ellagitannins (via ellagic acid or their urolithin metabolites) and red raspberry extracts (or the entire fruit) could reduce the risk of or reverse metabolically associated pathophysiologies. To our knowledge, few studies in humans are available for evaluation. We review and summarize the available literature that assesses the health-promoting potential of red raspberries and select components in modulating metabolic disease risk, especially cardiovascular disease, diabetes mellitus, obesity, and Alzheimer disease-all of which share critical metabolic, oxidative, and inflammatory links. The body of research is growing and supports a potential role for red raspberries in reducing the risk of metabolically based chronic diseases. PMID:26773014
Chemical characterization of bioactive compounds from the endophytic fungus Diaporthe helianthi isolated from Luehea divaricata
Specian, Vânia; Sarragiotto, Maria Helena; Pamphile, João Alencar; Clemente, Edmar
Endophytic microorganisms, defined as fungi or bacteria that colonize the interior of plants without causing any immediate negative effects or damages, have reciprocal relationships with host plants. In some cases their presence is beneficial to the host due to the synthesis of bioactive compounds, among which several alcohols, esters, ketones and others that may react with other compounds and may be lethal to pathogenic microorganisms. Diaporthe helianthi (Phomopsis helianthi in its anamorphic phase) is available worldwide, especially in Europe, Asia and America. Isolated in Europe as an agent of the sunflower stem cancer, it has also been endophytically isolated from tropical and temperate plants. A D. helianthi strain isolated from Luehea divaricata has been employed in current research. An investigation of the secondary metabolite from D. helianthi by CC and NMR of 1H and 13C yielded the separation of 10 fractions and the identification of the phenolic compound 2(-4 hydroxyphenyl)-ethanol (Tyrosol). Its antimicrobial reaction was tested and the ensuing antagonistic effects on the human pathogenic bacteria Enterococcus hirae, Escherichia coli, Micrococcus luteus, Salmonella typhi, Staphylococcus aureus, phytopathogenic Xanthomonas asc. phaseoli and phytopathogenic fungi were demonstrated. Results show that bioactive compounds and Tyrosol produced by D. helianthi have a biotechnological potential. PMID:24031942
Identification of natural metabolites in mixture: a pattern recognition strategy based on (13)C NMR.
Hubert, Jane; Nuzillard, Jean-Marc; Purson, Sylvain; Hamzaoui, Mahmoud; Borie, Nicolas; Reynaud, Romain; Renault, Jean-Hugues
Because of their highly complex metabolite profile, the chemical characterization of bioactive natural extracts usually requires time-consuming multistep purification procedures to achieve the structural elucidation of pure individual metabolites. The aim of the present work was to develop a dereplication strategy for the identification of natural metabolites directly within mixtures. Exploiting the polarity range of metabolites, the principle was to rapidly fractionate a multigram quantity of a crude extract by centrifugal partition extraction (CPE). The obtained fractions of simplified chemical composition were subsequently analyzed by (13)C NMR. After automatic collection and alignment of (13)C signals across spectra, hierarchical clustering analysis (HCA) was performed for pattern recognition. As a result, strong correlations between (13)C signals of a single structure within the mixtures of the fraction series were visualized as chemical shift clusters. Each cluster was finally assigned to a molecular structure with the help of a locally built (13)C NMR chemical shift database. The proof of principle of this strategy was achieved on a simple model mixture of commercially available plant secondary metabolites and then applied to a bark extract of the African tree Anogeissus leiocarpus Guill. & Perr. (Combretaceae). Starting from 5 g of this genuine extract, the fraction series was generated by CPE in only 95 min. (13)C NMR analyses of all fractions followed by pattern recognition of (13)C chemical shifts resulted in the unambiguous identification of seven major compounds, namely, sericoside, trachelosperogenin E, ellagic acid, an epimer mixture of (+)-gallocatechin and (-)-epigallocatechin, 3,3'-di-O-methylellagic acid 4'-O-xylopyranoside, and 3,4,3'-tri-O-methylflavellagic acid 4'-O-glucopyranoside. PMID:24555703
Markers of electrophilic stress caused by chemically reactive metabolites in human hepatocytes.
Takakusa, Hideo; Masumoto, Hiroshi; Mitsuru, Ayako; Okazaki, Osamu; Sudo, Kenichi
The metabolic activation of a drug to an electrophilic reactive metabolite and its covalent binding to cellular macromolecules is considered to be involved in the occurrence of idiosyncratic drug toxicity (IDT). As a cellular defense system against oxidative and electrophilic stress, phase II enzymes are known to be induced through a Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2/antioxidant response element system. We presumed that it is important for the risk assessment of drug-induced hepatotoxicity and IDTs to observe the biological responses evoked by exposure to reactive metabolites, and then investigated the mRNA induction profiles of phase II enzymes in human hepatocytes after exposure to problematic drugs associated with IDTs, such as ticlopidine, diclofenac, clozapine, and tienilic acid, as well as safe drugs such as levofloxacin and caffeine. According to the results, the problematic drugs exhibited inductive effects on heme oxygenase 1 (HO-1), which contrasted with the safe drugs; therefore, the induction of HO-1 mRNA seems to be correlated with the occurrence of drug toxicity, including IDT caused by electrophilic reactive metabolites. Moreover, glutathione-depletion and cytochrome P450 (P450)-inhibition experiments have shown that the observed HO-1 induction was triggered by the electrophilic reactive metabolites produced from the problematic drugs through P450-mediated metabolic bioactivation. Taken together with our present study, this suggests that HO-1 induction in human hepatocytes would be a good marker of the occurrence of metabolism-based drug-induced hepatotoxicity and IDT caused by the formation of electrophilic reactive metabolites. PMID:18227147
Cyanobacterial Metabolite Calothrixins: Recent Advances in Synthesis and Biological Evaluation
Xu, Su; Nijampatnam, Bhavitavya; Dutta, Shilpa; Velu, Sadanandan E.
The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a plethora of diseases. Compounds that are extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotechnological traits. Calothrixins A and B are two cyanobacterial metabolites with a structural assembly of quinoline, quinone, and indole pharmacophores. This review surveys recent advances in the synthesis and evaluation of the biological activities of calothrixins. Due to the low isolation yields from the marine source and the promise this scaffold holds for anticancer and antimicrobial drugs, organic and medicinal chemists around the world have embarked on developing efficient synthetic routes to produce calothrixins. Since the first review appeared in 2009, 11 novel syntheses of calothrixins have been published in the efforts to develop methods that contain fewer steps and higher-yielding reactions. Calothrixins have shown their potential as topoisomerase I poisons for their cytotoxicity in cancer. They have also been observed to target various aspects of RNA synthesis in bacteria. Further investigation into the exact mechanism for their bioactivity is still required for many of its analogs. PMID:26771620
COX-2-derived endocannabinoid metabolites as novel inflammatory mediators.
Alhouayek, Mireille; Muccioli, Giulio G
Cyclooxygenase-2 (COX-2) is an enzyme that plays a key role in inflammatory processes. Classically, this enzyme is upregulated in inflammatory situations and is responsible for the generation of prostaglandins (PGs) from arachidonic acid (AA). One lesser-known property of COX-2 is its ability to metabolize the endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid metabolism by COX-2 is not merely a means to terminate their actions. On the contrary, it generates PG analogs, namely PG-glycerol esters (PG-G) for 2-AG and PG-ethanolamides (PG-EA or prostamides) for AEA. Although the formation of these COX-2-derived metabolites of the endocannabinoids has been known for a while, their biological effects remain to be fully elucidated. Recently, several studies have focused on the role of these PG-G or PG-EA in vivo. In this review we take a closer look at the literature concerning these novel bioactive lipids and their role in inflammation. PMID:24684963
Cyanobacterial Metabolite Calothrixins: Recent Advances in Synthesis and Biological Evaluation.
Xu, Su; Nijampatnam, Bhavitavya; Dutta, Shilpa; Velu, Sadanandan E
The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a plethora of diseases. Compounds that are extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotechnological traits. Calothrixins A and B are two cyanobacterial metabolites with a structural assembly of quinoline, quinone, and indole pharmacophores. This review surveys recent advances in the synthesis and evaluation of the biological activities of calothrixins. Due to the low isolation yields from the marine source and the promise this scaffold holds for anticancer and antimicrobial drugs, organic and medicinal chemists around the world have embarked on developing efficient synthetic routes to produce calothrixins. Since the first review appeared in 2009, 11 novel syntheses of calothrixins have been published in the efforts to develop methods that contain fewer steps and higher-yielding reactions. Calothrixins have shown their potential as topoisomerase I poisons for their cytotoxicity in cancer. They have also been observed to target various aspects of RNA synthesis in bacteria. Further investigation into the exact mechanism for their bioactivity is still required for many of its analogs. PMID:26771620
Antitumor Activity of Hierridin B, a Cyanobacterial Secondary Metabolite Found in both Filamentous and Unicellular Marine Strains
Ramos, Vitor; Pereira, Alban R.; Fernandes, Virgínia C.; Domingues, Valentina F.; Gerwick, William H.; Vasconcelos, Vitor M.; Martins, Rosário
Cyanobacteria are widely recognized as a valuable source of bioactive metabolites. The majority of such compounds have been isolated from so-called complex cyanobacteria, such as filamentous or colonial forms, which usually display a larger number of biosynthetic gene clusters in their genomes, when compared to free-living unicellular forms. Nevertheless, picocyanobacteria are also known to have potential to produce bioactive natural products. Here, we report the isolation of hierridin B from the marine picocyanobacterium Cyanobium sp. LEGE 06113. This compound had previously been isolated from the filamentous epiphytic cyanobacterium Phormidium ectocarpi SAG 60.90, and had been shown to possess antiplasmodial activity. A phylogenetic analysis of the 16S rRNA gene from both strains confirmed that these cyanobacteria derive from different evolutionary lineages. We further investigated the biological activity of hierridin B, and tested its cytotoxicity towards a panel of human cancer cell lines; it showed selective cytotoxicity towards HT-29 colon adenocarcinoma cells. PMID:23922738
Bioactive Peptides from Muscle Sources: Meat and Fish
Ryan, Joseph Thomas; Ross, Reynolds Paul; Bolton, Declan; Fitzgerald, Gerald F.; Stanton, Catherine
Bioactive peptides have been identified in a range of foods, including plant, milk and muscle, e.g., beef, chicken, pork and fish muscle proteins. Bioactive peptides from food proteins offer major potential for incorporation into functional foods and nutraceuticals. The aim of this paper is to present an outline of the bioactive peptides identified in the muscle protein of meat to date, with a focus on muscle protein from domestic animals and fish. The majority of research on bioactives from meat sources has focused on angiotensin-1-converting enzyme (ACE) inhibitory and antioxidant peptides. PMID:22254123
Automating power supply checkout
Laster, J.; Bruno, D.; D'Ottavio, T.; Drozd, J.; Marr, G.; Mi, C.
Power Supply checkout is a necessary, pre-beam, time-critical function. At odds are the desire to decrease the amount of time to perform the checkout while at the same time maximizing the number and types of checks that can be performed and analyzing the results quickly (in case any problems exist that must be addressed). Controls and Power Supply Group personnel have worked together to develop tools to accomplish these goals. Power Supply checkouts are now accomplished in a time-frame of hours rather than days, reducing the number of person-hours needed to accomplish the checkout and making the system available more quickly for beam development. The goal of the Collider-Accelerator Department (CAD) at Brookhaven National Laboratory is to provide experimenters with collisions of heavy-ions and polarized protons. The Relativistic Heavy-Ion Collider (RHIC) magnets are controlled by 100's of varying types of power supplies. There is a concentrated effort to perform routine maintenance on the supplies during shutdown periods. There is an effort at RHIC to streamline the time needed for system checkout in order to quickly arrive at a period of beam operations for RHIC. This time-critical period is when the checkout of the power supplies is performed as the RHIC ring becomes cold and the supplies are connected to their physical magnets. The checkout process is used to identify problems in voltage and current regulation by examining data signals related to each for problems in settling and regulation (ripple).
Microbial production of isoquinoline alkaloids as plant secondary metabolites based on metabolic engineering research
SATO, Fumihiko; KUMAGAI, Hidehiko
Plants produce a variety of secondary metabolites that possess strong physiological activities. Unfortunately, however, their production can suffer from a variety of serious problems, including low levels of productivity and heterogeneous quality, as well as difficulty in raw material supply. In contrast, microorganisms can be used to produce their primary and some of their secondary metabolites in a controlled environment, thus assuring high levels of efficiency and uniform quality. In an attempt to overcome the problems associated with secondary metabolite production in plants, we developed a microbial platform for the production of plant isoquinoline alkaloids involving the unification of the microbial and plant metabolic pathways into a single system. The potential applications of this system have also been discussed. PMID:23666088
Sarychev, Michael
This note describes BLS power supplies lifting techniques and provides stress calculations for lifting plate and handles bolts. BLS power supply weight is about 120 Lbs, with the center of gravity shifted toward the right front side. A lifting plate is used to attach a power supply to a crane or a hoist. Stress calculations show that safety factors for lifting plate are 12.9 (vs. 5 required) for ultimate stress and 5.7 (vs. 3 required) for yield stress. Safety factor for shackle bolt thread shear load is 37, and safety factor for bolts that attach handles is 12.8.
Biological control of toxigenic citrus and papaya-rotting fungi by Streptomyces violascens MT7 and its extracellular metabolites.
Choudhary, Bharti; Nagpure, Anand; Gupta, Rajinder K
An Indian indigenous, Loktak Lake soil isolate Streptomyces violascens MT7 was assessed for its biocontrol potential both in vitro and in vivo against toxigenic fruit-rotting fungi. Strain MT7 exhibited broad-spectrum antifungal activity against various pathogenic postharvest fungi of citrus and papaya. In shake-flask fermentation, antagonist S. violascens MT7 highly produced extracellular antifungal metabolites in early stationary growth phase in glucose-yeast extract-malt extract (M93) broth. Both extracellular culture fluid (ECF) and its n-butanol extract showed significant broad-spectrum fungal mycelial inhibition of several tested fruit-rotting fungi. Antifungal metabolite was found to be heat stable, nonpeptidic, and polyene type antibiotic. The lowest minimum inhibitory concentration (MIC) of n-butanol extract against Colletotrichum gloeosporioides MTCC 9664 and Aspergillus niger MTCC 281 was 0.0312 and 0.0625 mg/ml, respectively. Purification of n-butanol extract through silica gel chromatography resulted in partial purification of bioactive metabolite and the TLC autobiography revealed the presence of single antifungal metabolite with Rf value of 0.755. In vivo bioassays demonstrated the biocontrol potential of tested biocontrol agents on fruit-rotting fungi. Use of cell suspension of S. violascens MT7, extracellular metabolite(s), and n-butanol extract significantly (p < 0.05) reduced sour-rot development on Citrus reticulata Blanco (oranges) and soft-rot development on papaya fruits. Therefore, these results strongly suggest a high potential for application of S. violascens MT7 and its extracellular metabolites as an effective eco-friendly alternative to synthetic fungicides for controlling toxigenic citrus and papaya-rotting fungi. PMID:26214840
Antioxidant and anti-inflammatory potential of hesperetin metabolites obtained from hesperetin-administered rat serum: an ex vivo approach.
Yang, Hsin-Ling; Chen, Ssu-Ching; Senthil Kumar, K J; Yu, Kang-Ni; Lee Chao, Pei-Dawn; Tsai, Shang-Yuan; Hou, Yu-Chi; Hseu, You-Cheng
In recent years much attention has been focused on the pharmaceutical relevance of bioflavonoids, especially hesperidin and its aglycon hesperetin in terms of their antioxidant and anti-inflammatory actions. However, the bioactivity of their metabolites, the real molecules in vivo hesperetin glucuronides/sulfates produced after ingestion, has been poorly understood. Thus, the study using an ex vivo approach is aimed to compare the antioxidant and anti-inflammatory activities of hesperidin/hesperetin or hesperetin metabolites derived from hesperetin-administered rat serum. We found that hesperetin metabolites (2.5-20 μM) showed higher antioxidant activity against various oxidative systems, including superoxide anion scavenging, reducing power, and metal chelating effects, than that of hesperidin or hesperetin. The data also showed that pretreatment of hesperetin metabolites (1-10 μM) within the range of physiological concentrations, compared to hesperetin, significantly inhibited nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, as evidenced by the inhibition of their precursors, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels without appreciable cytotoxicity on LPS-activated RAW264.7 macrophages or A7r5 smooth muscle cells. Concomitantly, hesperetin metabolites dose-dependently inhibited LPS-induced intracellular reactive oxygen species (ROS). Furthermore, hesperetin metabolites significantly downregulate LPS-induced nuclear factor-κB (NF-κB) activation followed by the suppression of inhibitor-κB (I-κB) degradation and phosphorylation of c-Jun N-terminal kinase1/2 (JNK1/2) and p38 MAPKs after challenge with LPS. Hesperetin metabolites ex vivo showed potent antioxidant and anti-inflammatory activity in comparison with hesperidin/hesperetin. PMID:22098419
Complicating factors in safety testing of drug metabolites: Kinetic differences between generated and preformed metabolites
Prueksaritanont, Thomayant . E-mail: firstname.lastname@example.com; Lin, Jiunn H.; Baillie, Thomas A.
This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.
The effect of variation in physical properties of porous bioactive glass on the expression and maintenance of the osteoblastic phenotype
NASA Astrophysics Data System (ADS)
Effah Kaufmann, Elsie Akosua Biraa
Revision surgery to replace failed hip implants is a significant health care issue that is expected to escalate as life expectancy increases. A major goal of revision surgery is to reconstruct femoral intramedullary bone-stock loss. To address this problem of bone loss, grafting techniques are widely used. Although fresh autografts remain the optimal material for all forms of surgery seeking to restore structural integrity to the skeleton, it is evident that the supply of such tissue is limited. In recent years, calcium phosphate ceramics have been studied as alternatives to autografts and allografts. The significant limitations associated with the use of biological and synthetic grafts have led to a growing interest in the in vitro synthesis of bone tissue. The approach is to synthesize bone tissue in vitro with the patient's own cells, and use this tissue for the repair of bony defects. Various substrates including metals, polymers, calcium phosphate ceramics and bioactive glasses, have been seeded with osteogenic cells. The selection of bioactive glass in this study is based on the fact that this material has shown an intense beneficial biological effect which has not been reproduced by other biomaterials. Even though the literature provides extensive data on the effect of pore size and porosity on in vivo bone tissue ingrowth into porous materials for joint prosthesis fixation, the data from past studies cannot be applied to the use of bioactive glass as a substrate for the in vitro synthesis of bone tissue. First, unlike the in vivo studies in the literature, this research deals with the growth of bone tissue in vitro. Second, unlike the implants used in past studies, bioactive glass is a degradable and resorbable material. Thus, in order to establish optimal substrate characteristics (porosity and pore size) for bioactive glass, it was important to study these parameters in an in vitro model. We synthesized porous bioactive glass substrates (BG) with varying
A New Paradigm for Known Metabolite Identification in Metabonomics/Metabolomics: Metabolite Identification Efficiency
Everett, Jeremy R.
A new paradigm is proposed for assessing confidence in the identification of known metabolites in metabonomics studies using NMR spectroscopy approaches. This new paradigm is based upon the analysis of the amount of metabolite identification information retrieved from NMR spectra relative to the molecular size of the metabolite. Several new indices are proposed including: metabolite identification efficiency (MIE) and metabolite identification carbon efficiency (MICE), both of which can be easily calculated. These indices, together with some guidelines, can be used to provide a better indication of known metabolite identification confidence in metabonomics studies than existing methods. Since known metabolite identification in untargeted metabonomics studies is one of the key bottlenecks facing the science currently, it is hoped that these concepts based on molecular spectroscopic informatics, will find utility in the field. PMID:25750701
The Influence of Phase Separation on Bioactivity of Spray Pyrolyzed Bioactive Glass.
Shih, Shao-ju; Tzeng, Wei-lung; Chou, Yu-jen; Chen, Chin-yi; Chen, Yu-ju
In this study, bioactive glass (BG) particles were synthesized directly using spray pyrolysis (SP). Since the bioactivity of glass particles is well correlated with their chemical composition, how to obtain homogenous bioactive glass becomes an important issue. For SP, the main reason for chemical inhomogeneity was considered to be caused by the difference in the precipitation speed of each precursor. So, two Si-containing precursors of BG, namely tetraethyl orthosilicate (TEOS) and silicon acetate (SiA), have been applied to prepare BG particles. The bioglasses were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy and energy dispersive spectroscopy to examine their phase composition, and surface structures, inner morphologies and chemical compositions. It was observed that, under the calcination temperature of 700 degrees C, TEOS-derived powder contained Si-rich nanoparticles and Si-deficit submicron particles as inhomogeneity, whereas the SiA-derived powder was homogenous. The reason of inhomogeneity is that TEOS dissolves in "volatile" ethanol more readily than in water via the SP mechanism of "gas-to-particle-conversion" to form Si-rich nanoparticles. The presence of Si-rich nanoparticles causes Si-deficit "wollastonite submicron particles" to form, which impairs the bioactivity. Finally, BG particle formation mechanisms from different precursors have been proposed. PMID:26369098
Bioactive glass coupling with natural polyphenols: Surface modification, bioactivity and anti-oxidant ability
NASA Astrophysics Data System (ADS)
Cazzola, Martina; Corazzari, Ingrid; Prenesti, Enrico; Bertone, Elisa; Vernè, Enrica; Ferraris, Sara
Polyphenols are actually achieving an increasing interest due to their potential health benefits, such as antioxidant, anticancer, antibacterial and bone stimulation abilities. However their poor bioavailability and stability hamper an effective clinical application as therapeutic principles. The opportunity to couple these biomolecules with synthetic biomaterials, in order to obtain local delivery at the site of interest, improve their bioavailability and stability and combine their properties with the ones of the substrate, is a challenging opportunity for the biomedical research. A silica based bioactive glass, CEL2, has been successfully coupled with gallic acid and natural polyphenols extracted from red grape skins and green tea leaves. The effectiveness of grafting has been verified by means of XPS analyses and the Folin&Ciocalteu tests. In vitro bioactivity has been investigated by soaking in simulated body fluid (SBF). Surface modification after functionalization and early stage reactivity in SBF have been studied by means of zeta potential electrokinetic measurements in KCl and SBF. Finally the antioxidant properties of bare and modified bioactive glasses has been investigated by means of the evaluation of free radical scavenging activity by Electron Paramagnetic Resonance (EPR)/spin trapping technique after UV photolysis of H2O2 highlighting scavenging activity of the bioactive glass.
Preparation and Characterization of Bioactive Composites of Pcl/bioactive Fillers
NASA Astrophysics Data System (ADS)
Li, Ying; Cheah, Chi Mun; Chang, Hengky; Loh, Leonard; Kum, Adeline
A variety of bioactive composites have been invested over the last two decades as substitute materials for diseased or damaged tissues in the human body. In this paper, bioactive composites were prepared using polycaprolactone (PCL) and hydroxyapatite (HA). The influence of micro-sized and nano-sized HA on composite properties was investigated. The nano-HA was prepared by wet chemical co-precipitation reaction method. Studies of biocomposite specimen morphology were performed by Field-emission scanning electron microscopy (SEM). XRD (X-Ray Diffraction) and DSC (Differential scanning calorimetry) were used to assess the crystal structure of HA and thermal properties of the composites, respectively. The synthesized nano-HA is found to be of high purity HA structure. The relationship between composition, structure and properties was studied. Different methods to prepare uniform composites were tried, and the outcome of this work suggests that by proper manipulation of biodegradable polymers and bioactive ceramics through material design, bioactive composites with controlled properties might be achievable.
Physicochemical properties and bioactivity of freeze-cast chitosan nanocomposite scaffolds reinforced with bioactive glass.
Pourhaghgouy, Masoud; Zamanian, Ali; Shahrezaee, Mostafa; Masouleh, Milad Pourbaghi
Chitosan based nanocomposite scaffolds were prepared by freeze casting method through blending constant chitosan concentration with different portions of synthesized bioactive glass nanoparticles (BGNPs). Transmission Electron Microscopy (TEM) image showed that the particles size of bioactive glass (64SiO2.28CaO.8P2O5) prepared by sol-gel method was approximately less than 20 nm. Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Diffraction (XRD) analysis showed proper interfacial bonding between BGNPs and chitosan polymers. Scanning Electron Microscopy (SEM) images depicted a unidirectional structure with homogenous distribution of BGNPs among chitosan matrix associated with the absence of pure chitosan scaffold's wall pores after addition of only 10 wt.% BGNPs. As the BGNP content increased from 0 to 50 wt.%, the compressive strength and compressive module values increased from 0.034 to 0.419 MPa and 0.41 to 10.77 MPa, respectively. Biodegradation study showed that increase in BGNP content leads to growth of weight loss amount. The in vitro biomineralization studies confirmed the bioactive nature of all nanocomposites. Amount of 30 wt.% BGNPs represented the best concentration for absorption capacity and bioactivity behaviors. PMID:26478301
Discovery Strategies of Bioactive Compounds Synthesized by Nonribosomal Peptide Synthetases and Type-I Polyketide Synthases Derived from Marine Microbiomes.
Amoutzias, Grigoris D; Chaliotis, Anargyros; Mossialos, Dimitris
Considering that 70% of our planet's surface is covered by oceans, it is likely that undiscovered biodiversity is still enormous. A large portion of marine biodiversity consists of microbiomes. They are very attractive targets of bioprospecting because they are able to produce a vast repertoire of secondary metabolites in order to adapt in diverse environments. In many cases secondary metabolites of pharmaceutical and biotechnological interest such as nonribosomal peptides (NRPs) and polyketides (PKs) are synthesized by multimodular enzymes named nonribosomal peptide synthetases (NRPSes) and type-I polyketide synthases (PKSes-I), respectively. Novel findings regarding the mechanisms underlying NRPS and PKS evolution demonstrate how microorganisms could leverage their metabolic potential. Moreover, these findings could facilitate synthetic biology approaches leading to novel bioactive compounds. Ongoing advances in bioinformatics and next-generation sequencing (NGS) technologies are driving the discovery of NRPs and PKs derived from marine microbiomes mainly through two strategies: genome-mining and metagenomics. Microbial genomes are now sequenced at an unprecedented rate and this vast quantity of biological information can be analyzed through genome mining in order to identify gene clusters encoding NRPSes and PKSes of interest. On the other hand, metagenomics is a fast-growing research field which directly studies microbial genomes and their products present in marine environments using culture-independent approaches. The aim of this review is to examine recent developments regarding discovery strategies of bioactive compounds synthesized by NRPS and type-I PKS derived from marine microbiomes and to highlight the vast diversity of NRPSes and PKSes present in marine environments by giving examples of recently discovered bioactive compounds. PMID:27092515
Discovery Strategies of Bioactive Compounds Synthesized by Nonribosomal Peptide Synthetases and Type-I Polyketide Synthases Derived from Marine Microbiomes
Amoutzias, Grigoris D.; Chaliotis, Anargyros; Mossialos, Dimitris
Considering that 70% of our planet's surface is covered by oceans, it is likely that undiscovered biodiversity is still enormous. A large portion of marine biodiversity consists of microbiomes. They are very attractive targets of bioprospecting because they are able to produce a vast repertoire of secondary metabolites in order to adapt in diverse environments. In many cases secondary metabolites of pharmaceutical and biotechnological interest such as nonribosomal peptides (NRPs) and polyketides (PKs) are synthesized by multimodular enzymes named nonribosomal peptide synthetases (NRPSes) and type-I polyketide synthases (PKSes-I), respectively. Novel findings regarding the mechanisms underlying NRPS and PKS evolution demonstrate how microorganisms could leverage their metabolic potential. Moreover, these findings could facilitate synthetic biology approaches leading to novel bioactive compounds. Ongoing advances in bioinformatics and next-generation sequencing (NGS) technologies are driving the discovery of NRPs and PKs derived from marine microbiomes mainly through two strategies: genome-mining and metagenomics. Microbial genomes are now sequenced at an unprecedented rate and this vast quantity of biological information can be analyzed through genome mining in order to identify gene clusters encoding NRPSes and PKSes of interest. On the other hand, metagenomics is a fast-growing research field which directly studies microbial genomes and their products present in marine environments using culture-independent approaches. The aim of this review is to examine recent developments regarding discovery strategies of bioactive compounds synthesized by NRPS and type-I PKS derived from marine microbiomes and to highlight the vast diversity of NRPSes and PKSes present in marine environments by giving examples of recently discovered bioactive compounds. PMID:27092515
Bioactivities by a crude extract from the Greenlandic Pseudomonas sp. In5 involves the nonribosomal peptides, nunamycin and nunapeptin
Venditto, Vincent J.; Hennessy, Rosanna C.
Background. Bioactive microbial metabolites provide a successful source of novel compounds with pharmaceutical potentials. The bacterium Pseudomonas sp. In5 is a biocontrol strain isolated from a plant disease suppressive soil in Greenland, which produces two antimicrobial nonribosomal peptides (NRPs), nunapeptin and nunamycin. Methods. In this study, we used in vitro antimicrobial and anticancer bioassays to evaluate the potential bioactivities of both a crude extract derived from Pseudomonas sp. In5 and NRPs purified from the crude extract. Results. We verified that the crude extract derived from Pseudomonas sp. In5 showed suppressive activity against the basidiomycete Rhizoctonia solani by inducing a mitochondrial stress-response. Furthermore, we confirmed suppressive activity against the oomycete Pythium aphanidermatum by the Pseudomonas sp. In5 crude extract, and that the purified nunamycin and nunapeptin displayed distinct antimicrobial activities. In addition to the antimicrobial activity, we found that treatment of the cancer cell lines, Jurkat T-cells, Granta cells, and melanoma cells, with the Pseudomonas sp. In5 crude extract increased staining with the apoptotic marker Annexin V while no staining of healthy normal cells, i.e., naïve or activated CD4 T-cells, was observed. Treatment with either of the NRPs alone did not increase Annexin V staining of the Jurkat T-cells, despite individually showing robust antimicrobial activity, whereas an anticancer activity was detected when nunamycin and nunapeptin were used in combination. Discussion. Our results suggest that the bioactivity of a crude extract derived from Pseudomonas sp. In5 involves the presence of both nunamycin and nunapeptin and highlight the possibility of synergy between multiple microbial metabolites. PMID:26734508
Marine Nucleosides: Structure, Bioactivity, Synthesis and Biosynthesis
Huang, Ri-Ming; Chen, Yin-Ning; Zeng, Ziyu; Gao, Cheng-Hai; Su, Xiangdong; Peng, Yan
Nucleosides are glycosylamines that structurally form part of nucleotide molecules, the building block of DNA and RNA. Both nucleosides and nucleotides are vital components of all living cells and involved in several key biological processes. Some of these nucleosides have been obtained from a variety of marine resources. Because of the biological importance of these compounds, this review covers 68 marine originated nucleosides and their synthetic analogs published up to June 2014. The review will focus on the structures, bioactivities, synthesis and biosynthetic processes of these compounds. PMID:25474189
Effect of nitrogen and fluorine on mechanical properties and bioactivity in two series of bioactive glasses.
Bachar, Ahmed; Mercier, Cyrille; Tricoteaux, Arnaud; Hampshire, Stuart; Leriche, Anne; Follet, Claudine
Bioactive glasses are able to bond to bone through formation of carbonated hydroxyapatite in body fluids, and fluoride-releasing bioactive glasses are of interest for both orthopaedic and, in particular, dental applications for caries inhibition. However, because of their poor strength their use is restricted to non-load-bearing applications. In order to increase their mechanical properties, doping with nitrogen has been performed on two series of bioactive glasses: series (I) was a "bioglass" composition (without P2O5) within the quaternary system SiO2-Na2O-CaO-Si3N4 and series (II) was a simple substitution of CaF2 for CaO in series (I) glasses keeping the Na:Ca ratio constant. The objective of this work was to evaluate the effect of the variation in nitrogen and fluorine content on the properties of these glasses. The density, glass transition temperature, hardness and elastic modulus all increased linearly with nitrogen content which indicates that the incorporation of nitrogen stiffens the glass network because N is mainly in 3-fold coordination with Si atoms. Fluorine addition significantly decreases the thermal property values but the mechanical properties of these glasses remain unchanged with fluorine. The combination of both nitrogen and fluorine in oxyfluoronitride glasses gives better mechanical properties at much lower melting temperatures since fluorine reduces the melting point, allows higher solubility of nitrogen and does not affect the higher mechanical properties arising from incorporation of nitrogen. The characterization of these N and F substituted bioactive glasses using (29)Si MAS NMR has shown that the increase in rigidity of the glass network can be explained by the formation of SiO3N, SiO2N2 tetrahedra and Q(4) units with extra bridging anions at the expense of Q(3) units. Bioactivity of the glasses was investigated in vitro by examining apatite formation on the surface of glasses treated in acellular simulated body fluid (SBF) with ion
... a good breastfeeding rhythm with your baby. In reality, the efficient supply-and-demand rhythm of normal ... is one reason it's a good idea to alternate which breast you use to begin nursing. A ...
Supply options. [hydrogen market
NASA Technical Reports Server (NTRS)
The use of captive hydrogen (produced and consumed on site) and merchant hydrogen (externally supplied) is considered. A low-merchant-captive ratio market and a high-merchant-captive ratio market are described and compared.
Cleaning supplies and equipment
... on any object the person touched or on equipment that was used during their care. Some germs ... why it is important to disinfect supplies and equipment. To disinfect something means to clean it to ...
Han, B.M.; Karady, G.G.; Thiessen, H.A.
The particles in a Rapid Cycling Accelerator are accelerated by rf cavities, which are tuned by dc biased ferrite cores. The tuning is achieved by the regulation of bias current, which is produced by a power supply. The tuning magnet power supply utilizes a bridge circuit, supplied by a three phase rectifier. During the rise of the current, when the particles are accelerated, the current is controlled with precision by the bridge which operates a power amplifier. During the fall of the current, the bridge operates in a switching mode and recovers the energy stored in the ferrites. The recovered energy is stored in a capacitor bank. The bridge circuit is built with 150 power transistors. The drive, protection and control circuit were designed and built from commercial component. The system will be used for a rf cavity experiment in Los Alamos and will serve as a prototype tuning power supply for future accelerators. 1 ref., 7 figs.
MALDI Mass Spectrometry Imaging for Visualizing In Situ Metabolism of Endogenous Metabolites and Dietary Phytochemicals
Fujimura, Yoshinori; Miura, Daisuke
Understanding the spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmaceutical roles. Mass spectrometry imaging (MSI) enables determination of the distribution of ionizable molecules present in tissue sections of whole-body or single heterogeneous organ samples by direct ionization and detection. This emerging technique is now widely used for in situ label-free molecular imaging of endogenous or exogenous small molecules. MSI allows the simultaneous visualization of many types of molecules including a parent molecule and its metabolites. Thus, MSI has received much attention as a potential tool for pathological analysis, understanding pharmaceutical mechanisms, and biomarker discovery. On the other hand, several issues regarding the technical limitations of MSI are as of yet still unresolved. In this review, we describe the capabilities of the latest matrix-assisted laser desorption/ionization (MALDI)-MSI technology for visualizing in situ metabolism of endogenous metabolites or dietary phytochemicals (food factors), and also discuss the technical problems and new challenges, including MALDI matrix selection and metabolite identification, that need to be addressed for effective and widespread application of MSI in the diverse fields of biological, biomedical, and nutraceutical (food functionality) research. PMID:24957029
From covalent bonds to eco-physiological pharmacology of secondary plant metabolites.
Chatterjee, Shyam Sunder
Despite the availability of numerous drugs and other therapeutic modalities, the prevention and cure of over- and under-nutrition triggered metabolic and other disease states continues as a major challenge for modern medicine. Such silently progressing and eventually life-threatening diseases often accompany diverse spectrum of comorbid psychiatric disorders. Majority of the global population suffering from metabolic diseases live in economically developing or underdeveloped countries, where due to socioeconomic, cultural, and other reasons, therapies may be unavailable. Evidence from preclinical, clinical, and epidemiological studies of numerous structurally and functionally diverse secondary metabolites of plants suggest that many of these could be promising therapeutic leads for the treatment and prevention of malnutrition-associated diseases and mental health problems. The review discusses the potential therapeutic uses of secondary plant metabolites and their bacterial and mammalian catabolites based on their bioactivity profiles, with special emphasis on their modulating effects on gut microbial ecology and physiological stress responses. Based on concepts in medicinal chemistry and pharmacology considerations that evolved during the author's interactions with David Triggle, secondary plant metabolites may represent an alternative and economically feasible approach to new drugs. PMID:26253688
Composite bone cements loaded with a bioactive and ferrimagnetic glass-ceramic: Leaching, bioactivity and cytocompatibility.
Verné, Enrica; Bruno, Matteo; Miola, Marta; Maina, Giovanni; Bianco, Carlotta; Cochis, Andrea; Rimondini, Lia
In this work, composite bone cements, based on a commercial polymethylmethacrylate matrix (Palamed®) loaded with ferrimagnetic bioactive glass-ceramic particles (SC45), were produced and characterized in vitro. The ferrimagnetic bioactive glass-ceramic belongs to the system SiO2-Na2O-CaO-P2O5-FeO-Fe2O3 and contains magnetite (Fe3O4) crystals into a residual amorphous bioactive phase. Three different formulations (containing 10, 15 and 20 wt.% of glass-ceramic particles respectively) have been investigated. These materials are intended to be applied as bone fillers for the hyperthermic treatment of bone tumors. The morphological, compositional, calorimetric and mechanical properties of each formulation have been already discussed in a previous paper. The in vitro properties of the composite bone cements described in the present paper are related to iron ion leaching test (by graphite furnace atomic absorption spectrometer), bioactivity (i.e. the ability to stimulate the formation of a hydroxyapatite - HAp - layer on their surface after soaking in simulated body fluid SBF) and cytocompatibility toward human osteosarcoma cells (ATCC CRL-1427, Mg63). Morphological and chemical characterizations by scanning electron microscopy and energy dispersion spectrometry have been performed on the composite samples after each test. The iron release was negligible and all the tested samples showed the growth of HAp on their surface after 28 days of immersion in a simulated body fluid (SBF). Cells showed good viability, morphology, adhesion, density and the ability to develop bridge-like structures on all investigated samples. A synergistic effect between bioactivity and cell mineralization was also evidenced. PMID:26042695
Bioprospecting Chemical Diversity and Bioactivity in a Marine Derived Aspergillus terreus.
Adpressa, Donovon A; Loesgen, Sandra
A comparative metabolomic study of a marine derived fungus (Aspergillus terreus) grown under various culture conditions is presented. The fungus was grown in eleven different culture conditions using solid agar, broth cultures, or grain based media (OSMAC). Multivariate analysis of LC/MS data from the organic extracts revealed drastic differences in the metabolic profiles and guided our subsequent isolation efforts. The compound 7-desmethylcitreoviridin was isolated and identified, and is fully described for the first time. In addition, 16 known fungal metabolites were also isolated and identified. All compounds were elucidated by detailed spectroscopic analysis and tested for antibacterial activities against five human pathogens and tested for cytotoxicity. This study demonstrates that LC/MS based multivariate analysis provides a simple yet powerful tool to analyze the metabolome of a single fungal strain grown under various conditions. This approach allows environmentally-induced changes in metabolite expression to be rapidly visualized, and uses these differences to guide the discovery of new bioactive molecules. PMID:26880440
Bioactivation of bisphenol A and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes.
Schmidt, Jan; Kotnik, Petra; Trontelj, Jurij; Knez, Željko; Mašič, Lucija Peterlin
Bisphenol A analogs are a class of chemicals known as diphenylmethanes, which contain two benzene rings separated by one central carbon atom, usually with a para-hydroxy group on both benzene rings. Bisphenol A (BPA) can induce an uterotrophic response in immature CD-1 mice and elicits estrogenic responses in many other experimental systems. Besides highlighting endocrine effects, a number of metabolic studies provide strong support for the idea that reactive species of BPA are formed in vitro and in vivo that can form covalent adducts with nucleophilic macromolecules and/or produce oxidative stress. We used a liquid chromatography with a triple quadrupole tandem mass spectrometry (LC-MS/MS) for the detection of metabolites and glutathione conjugates of BPA and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes (HLM) or with recombinant CYP isozymes in the presence of NADPH and GSH as a trapping agent. We have confirmed that BPA and its structural analogs form hydroxylated metabolites and electrophilic species during bioactivation in HLM and CYP isozymes. These results provided important mechanistic insight into the metabolic fate of BPA structural analogs in vitro. PMID:23470418
Metabolism and Bioactivation of Fluorochloridone, a Novel Selective Herbicide, in Vivo and in Vitro.
Shi, Jingmin; Xie, Cen; Liu, Hongbing; Krausz, Kristopher W; Bewley, Carole A; Zhang, Suhui; Tang, Liming; Zhou, Zhijun; Gonzalez, Frank J
Fluorochloridone (FLC) is a herbicide used worldwide that is thought to be safe. However, due to its potential genotoxicity, cytotoxicity, and even systematic toxicity, there are increasing concerns about human exposure to this compound. Thus, the metabolism and bioactivation of FLC was investigated. After oral administration to mice, 27 metabolites were identified by ultrahigh performance liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry and with further structural identification by nuclear magnetic resonance spectroscopy. Hydroxylation and oxidative dechlorination were the major phase I pathways, while glutathione (GSH) and N-acetylcysteine conjugations were two major phase II pathways, indicating the formation of a reactive intermediate. In vitro microsomal and cytosolic studies revealed that a GSH conjugate (M13) was the predominant metabolite of FLC formed through a nucleophilic SN2 substitution of 3-Cl by GSH; this pathway is NADPH independent and accelerated by glutathione S-transferase (GST). Further, a kinetic study showed that M13 formation in both human liver microsomes and cytosols obeyed typical Michaelis-Menten kinetics. The maximum clearance (Vmax/Km) of GSH conjugation in human liver microsomes was approximately 5.5-fold higher than human liver cytosol, thus implying that microsomal GST was mainly responsible for M13 formation. These findings are important for understanding the potential hazard of human exposure to FLC. PMID:27443216
Bioactive compounds produced by gut microbial tannase: implications for colorectal cancer development
López de Felipe, Félix; de las Rivas, Blanca; Muñoz, Rosario
The microorganisms in the human gastrointestinal tract have a profound influence on the transformation of food into metabolites which can impact human health. Gallic acid (GA) and pyrogallol (PG) are bioactive compounds displaying diverse biological properties, including carcinogenic inhibiting activities. However, its concentration in fruits and vegetables is generally low. These metabolites can be also generated as final products of tannin metabolism by microbes endowed with tannase, which opens up the possibility of their anti-cancer potential being increased. Patients with colorectal cancer (CRC) display an imbalanced gut microbiota respect to healthy population. The recent use of next generation sequencing technologies has greatly improved knowledge of the identity of bacterial species that colonize non-tumorous and tumorous tissues of CRC patients. This information provides a unique opportunity to shed light on the role played by gut microorganisms in the different stages of this disease. We here review the recently published gut microbiome associated to CRC patients and highlight tannase as an underlying gene function of bacterial species that selectively colonize tumorous tissues, but not adjacent non-malignant tissues. Given the anti-carcinogenic roles of GA and PG produced by gut tannin-degrading bacteria, we provide an overview of the possible consequences of this intriguing coincidence for CRC development. PMID:25538697
Secondary metabolites produced by fungi derived from a microbial mat encountered in an iron-rich natural spring
Gerea, Alexandra L.; Branscum, Katie M.; King, Jarrod B.; You, Jianlan; Powell, Douglas R.; Miller, Andrew N.; Spear, John R.; Cichewicz, Robert H.
A collection of fungal isolates was obtained from a complex microbial mat, which occupied an iron-rich freshwater spring that feeds into Clear Creek, Golden, Colorado, USA. Two of the fungal isolates, a Glomeromycete (possible Entrophospora sp.) and a Dothideomycete (possible Phaeosphaeria sp.), were investigated for bioactive secondary metabolites. In total, six new compounds consisting of clearanols A–E (5, 6, 10–12) and disulochrin (7) were purified and their structures were determined. Disulochrin exhibited modest antibacterial activity against methicillin-resistant Staphylococcus aureus, whereas clearanol C showed weak inhibitory activity against Candida albicans biofilm formation. PMID:22844162
Urinary metabolites of diisodecyl phthalate in rats.
Kato, Kayoko; Silva, Manori J; Wolf, Cynthia; Gray, L Earl; Needham, Larry L; Calafat, Antonia M
Diisodecyl phthalate (DiDP) is an isomeric mixture of phthalates with predominantly 10-carbon branched-dialkyl chains, widely used as a plasticizer for polyvinyl chloride. The extent of human exposure to DiDP is unknown in part because adequate biomarkers of exposure to DiDP are not available. We identified several major metabolites of DiDP in urine of adult female Sprague-Dawley rats after a single oral administration of DiDP (300 mg/kg). These metabolites can potentially be used as biomarkers of exposure to DiDP. The metabolites extracted from urine were chromatographically resolved and identified by their chromatographic behavior and full scan negative ion electrospray ionization mass spectrum. The identity of metabolites with similar molecular weights was further examined in accurate mass mode. For some metabolites, unequivocal identification was done using authentic standards. Among these were the hydrolytic monoester of DiDP, monoisodecyl phthalate (MiDP), detected as a minor metabolite, and one omega oxidation product of MiDP, mono(carboxy-isononyl) phthalate (MCiNP), which was the most abundant urinary metabolite. We also tentatively identified other secondary metabolites of MiDP, mono(hydroxy-isodecyl) phthalate, mono(oxo-isodecyl) phthalate, mono(carboxy-isoheptyl) phthalate, mono(carboxy-isohexyl) phthalate, mono(carboxy-isopentyl) phthalate, mono(carboxy-isobutyl) phthalate, and mono(carboxy-ethyl) phthalate. Oxidative metabolites of diisoundecyl phthalate (DiUdP) and diisononyl phthalate (DiNP) were also detected suggesting the presence of DiUdP and DiNP in the DiDP formulation. The urinary concentrations of all these metabolites gradually decreased in the 4 days following the administration of DiDP. MCiNP and other DiDP secondary metabolites are more abundant in urine than MiDP, suggesting that these oxidative products are better biomarkers for DiDP exposure assessment than MiDP. Additional research on the toxicokinetics of these metabolites is needed
Screening and identification of the metabolites in rat urine and feces after oral administration of Lycopus lucidus Turcz extract by UHPLC-Q-TOF-MS mass spectrometry.
Ren, Qiang; Wang, Yun-Long; Wang, Mei-Ling; Wang, Hui-Yun
Lycopus lucidus Turcz has been used as a kind of edible and medicinal material in eastern Asian countries. It has various bioactivities, including treatment of menstrual disorder, amenorrhea, menstrual cramps, inflammation, and cardiovascular diseases. However, the in vivo metabolism of L. lucidus Turcz extract is still not well described. In this study, L. lucidus Turcz extracts were administered to rats. Urine and fecal samples were collected at the difference periods (0-12h, 12-24h, and 24-36h). Ultra-high performance liquid chromatography coupled with electrospray ionization tandem quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was developed to characterize and identify the metabolites. A total of 17 metabolites in feces and 19 metabolites in urine were tentatively identified by means of accurate mass and characteristic fragment ions. The results show that glucuronidation and sulfation are the major metabolic reactions. This study is the first reported analysis and characterization of the metabolites and the proposed metabolic pathways of bioactive components might provide further understanding of the metabolic fate of the chemical constituents after oral administration of L. lucidus Turcz extract in rats. PMID:27262082
40 CFR 159.179 - Metabolites, degradates, contaminants, and impurities.
Code of Federal Regulations, 2010 CFR
... chemical properties of the metabolite or degradate. (B) Data regarding structurally analogous chemicals. (C) Data regarding chemical reactivity of the metabolite or degradate and structurally analogous...
40 CFR 159.179 - Metabolites, degradates, contaminants, and impurities.
Code of Federal Regulations, 2012 CFR
... chemical properties of the metabolite or degradate. (B) Data regarding structurally analogous chemicals. (C) Data regarding chemical reactivity of the metabolite or degradate and structurally analogous...
40 CFR 159.179 - Metabolites, degradates, contaminants, and impurities.
Code of Federal Regulations, 2013 CFR
... chemical properties of the metabolite or degradate. (B) Data regarding structurally analogous chemicals. (C) Data regarding chemical reactivity of the metabolite or degradate and structurally analogous...
Application of mass spectrometry for metabolite identification.
Ma, Shuguang; Chowdhury, Swapan K; Alton, Kevin B
Metabolism studies play a pivotal role in drug discovery and development. Characterization of metabolic "hot-spots" as well as reactive and pharmacologically active metabolites is critical to designing new drug candidates with improved metabolic stability, toxicological profile and efficacy. Metabolite identification in the preclinical species used for safety evaluation is required in order to determine whether human metabolites have been adequately tested during non-clinical safety assessment. From an instrumental standpoint, high performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) dominates all analytical tools used for metabolite identification. The general strategies employed for metabolite identification in both drug discovery and drug development settings together with sample preparation techniques are reviewed herein. These include a discussion of the various ionization methods, mass analyzers, and tandem mass spectrometry (MS/MS) techniques that are used for structural characterization in a modern drug metabolism laboratory. Mass spectrometry-based techniques, such as stable isotope labeling, on-line H/D exchange, accurate mass measurement to enhance metabolite identification and recent improvements in data acquisition and processing for accelerating metabolite identification are also described. Rounding out this review, we offer additional thoughts about the potential of alternative and less frequently used techniques such as LC-NMR/MS, CRIMS and ICPMS. PMID:16787159
Mechanisms of human erythrocytic bioactivation of nitrite.
Liu, Chen; Wajih, Nadeem; Liu, Xiaohua; Basu, Swati; Janes, John; Marvel, Madison; Keggi, Christian; Helms, Christine C; Lee, Amber N; Belanger, Andrea M; Diz, Debra I; Laurienti, Paul J; Caudell, David L; Wang, Jun; Gladwin, Mark T; Kim-Shapiro, Daniel B
Nitrite signaling likely occurs through its reduction to nitric oxide (NO). Several reports support a role of erythrocytes and hemoglobin in nitrite reduction, but this remains controversial, and alternative reductive pathways have been proposed. In this work we determined whether the primary human erythrocytic nitrite reductase is hemoglobin as opposed to other erythrocytic proteins that have been suggested to be the major source of nitrite reduction. We employed several different assays to determine NO production from nitrite in erythrocytes including electron paramagnetic resonance detection of nitrosyl hemoglobin, chemiluminescent detection of NO, and inhibition of platelet activation and aggregation. Our studies show that NO is formed by red blood cells and inhibits platelet activation. Nitric oxide formation and signaling can be recapitulated with isolated deoxyhemoglobin. Importantly, there is limited NO production from erythrocytic xanthine oxidoreductase and nitric-oxide synthase. Under certain conditions we find dorzolamide (an inhibitor of carbonic anhydrase) results in diminished nitrite bioactivation, but the role of carbonic anhydrase is abrogated when physiological concentrations of CO2 are present. Importantly, carbon monoxide, which inhibits hemoglobin function as a nitrite reductase, abolishes nitrite bioactivation. Overall our data suggest that deoxyhemoglobin is the primary erythrocytic nitrite reductase operating under physiological conditions and accounts for nitrite-mediated NO signaling in blood. PMID:25471374
Quantification and bioaccessibility of california pistachio bioactives.
Liu, Yuntao; Blumberg, Jeffrey B; Chen, C-Y Oliver
The content of carotenoids, chlorophylls, phenolics, and tocols in pistachios ( Pistacia vera L.) has not been methodically quantified. The objective of this study was to first optimize extraction protocols for lipophilic nutrients and then quantify the content of two phenolic acids, nine flavonoids, four carotenoids, two chlorophylls, and three tocols in the skin, nutmeat, and whole nut of California pistachios. The dominant bioactives in whole pistachios are lutein [42.35 μg/g fresh weight (FW)], chlorophyll a (142.24 μg/g FW), γ-tocopherol (182.20 μg/g FW), flavan-3-ols (catechins) (199.18 μg/g FW), luteolin (217.89 μg/g FW), myricetin (135.18 μg/g FW), and cyanidin-3-galactose (38.34 μg/g FW) in each nutrient class. Most phenolics are present in the skin, while the lipophilic nutrients are dominantly present in the nutmeat. Digestion with a gastrointestinal mimic showed <10% of most hydrophilic compounds are released from pistachio matrices. In conclusion, 9 lipophilic and 11 hydrophilic bioactives in pistachios are systematically quantified. PMID:24460079
Bioavailability of bioactive food compounds: a challenging journey to bioefficacy
Rein, Maarit J.; Renouf, Mathieu; Cruz‐Hernandez, Cristina; Actis‐Goretta, Lucas; Thakkar, Sagar K.; da Silva Pinto, Marcia
Bioavailability is a key step in ensuring bioefficacy of bioactive food compounds or oral drugs. Bioavailability is a complex process involving several different stages: liberation, absorption, distribution, metabolism and elimination phases (LADME). Bioactive food compounds, whether derived from various plant or animal sources, need to be bioavailable in order to exert any beneficial effects. Through a better understanding of the digestive fate of bioactive food compounds we can impact the promotion of health and improvement of performance. Many varying factors affect bioavailability, such as bioaccessibility, food matrix effect, transporters, molecular structures and metabolizing enzymes. Bioefficacy may be improved through enhanced bioavailability. Therefore, several technologies have been developed to improve the bioavailability of xenobiotics, including structural modifications, nanotechnology and colloidal systems. Due to the complex nature of food bioactive compounds and also to the different mechanisms of absorption of hydrophilic and lipophilic bioactive compounds, unravelling the bioavailability of food constituents is challenging. Among the food sources discussed during this review, coffee, tea, citrus fruit and fish oil were included as sources of food bioactive compounds (e.g. (poly)phenols and polyunsaturated fatty acids (PUFAs)) since they are examples of important ingredients for the food industry. Although there are many studies reporting on bioavailability and bioefficacy of these bioactive food components, understanding their interactions, metabolism and mechanism of action still requires extensive work. This review focuses on some of the major factors affecting the bioavailability of the aforementioned bioactive food compounds. PMID:22897361
Flavonoid metabolites reduce tumor necrosis factor‐α secretion to a greater extent than their precursor compounds in human THP‐1 monocytes
di Gesso, Jessica L.; Kerr, Jason S.; Zhang, Qingzhi; Raheem, Saki; Yalamanchili, Sai Krishna; O'Hagan, David; Kay, Colin D.; O'Connell, Maria A.
1 Scope Flavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixtures of metabolites. Using a unique study design, we investigated the potential for singular or additive anti‐inflammatory effects of flavonoid metabolites relative to their precursor structures. 2 Methods and results Six flavonoids, 14 flavonoid metabolites, and 29 combinations of flavonoids and their metabolites (0.1–10 μM) were screened for their ability to reduce LPS‐induced tumor necrosis factor‐α (TNF‐α) secretion in THP‐1 monocytes. One micromolar peonidin‐3‐glucoside, cyanidin‐3‐glucoside, and the metabolites isovanillic acid (IVA), IVA‐glucuronide, vanillic acid‐glucuronide, protocatechuic acid‐3‐sulfate, and benzoic acid‐sulfate significantly reduced TNF‐α secretion when in isolation, while there was no effect on TNF‐α mRNA expression. Four combinations of metabolites that included 4‐hydroxybenzoic acid (4HBA) and/or protocatechuic acid also significantly reduced TNF‐α secretion to a greater extent than the precursors or metabolites alone. The effects on LPS‐induced IL‐1β and IL‐10 secretion and mRNA expression were also examined. 4HBA significantly reduced IL‐1β secretion but none of the flavonoids or metabolites significantly modified IL‐10 secretion. 3 Conclusion This study provides novel evidence suggesting flavonoid bioactivity results from cumulative or additive effects of circulating metabolites. PMID:25801720
Familial resemblance for serum metabolite concentrations.
Draisma, Harmen H M; Beekman, Marian; Pool, René; van Ommen, Gert-Jan B; Adamski, Jerzy; Prehn, Cornelia; Vaarhorst, Anika A M; de Craen, Anton J M; Willemsen, Gonneke; Slagboom, P Eline; Boomsma, Dorret I
Metabolomics is the comprehensive study of metabolites, which are the substrates, intermediate, and end products of cellular metabolism. The heritability of the concentrations of circulating metabolites bears relevance for evaluating their suitability as biomarkers for disease. We report aspects of familial resemblance for the concentrations in human serum of more than 100 metabolites, measured using a targeted metabolomics platform. Age- and sex-corrected monozygotic twin correlations, midparent-offspring regression coefficients, and spouse correlations in subjects from two independent cohorts (Netherlands Twin Register and Leiden Longevity Study) were estimated for each metabolite. In the Netherlands Twin Register subjects, who were largely fasting, we found significant monozygotic twin correlations for 121 out of 123 metabolites. Heritability was confirmed by midparent-offspring regression. For most detected metabolites, the correlations between spouses were considerably lower than those between twins, indicating a contribution of genetic effects to familial resemblance. Remarkably high heritability was observed for free carnitine (monozygotic twin correlation 0.66), for the amino acids serine (monozygotic twin correlation 0.77) and threonine (monozygotic twin correlation 0.64), and for phosphatidylcholine acyl-alkyl C40:3 (monozygotic twin correlation 0.77). For octenoylcarnitine, a consistent point estimate of approximately 0.50 was found for the spouse correlations in the two cohorts as well as for the monozygotic twin correlation, suggesting that familiality for this metabolite is explained by shared environment. We conclude that for the majority of metabolites targeted by the used metabolomics platform, the familial resemblance of serum concentrations is largely genetic. Our results contribute to the knowledge of the heritability of fasting serum metabolite concentrations, which is relevant for biomarker research. PMID:23985338
Zearalenone is bioactivated in the river Buffalo (Bubalus bubalis): hepatic biotransformation.
Hassan, Malekinejad; Fatemeh, Rahmani; Kobra, Bahrampour
Zearalenone (ZEA) as a mycoestrogen is found frequently in human foods and animal feeds. Its estrogenic effects depend on its biotransformation fate including both first- and second-phase reactions, which are predominantly governed by hydroxylation and glucuronidation, respectively. In this study, we investigate the hepatic biotransformation of ZEA in river buffalo. To evaluate the hepatic biotransformation of ZEA, both subcellular fractions of the liver were prepared. ZEA was incubated with intracellular subfractions in the presence of nicotinamide dinucleotide phosphate, and the products were determined by means of high-performance liquid chromatography. Moreover, in the same frame of experiment and in the presence of uridine diphosphate glucuronic acid, the rate of glucuronidation for substrate and products were estimated as well. We found that alpha-zearalenol (alpha-ZOL) is the major hydroxylated hepatic metabolite of ZEA produced by both studied subcellular fractions. The enzymatic kinetics analyses indicated that the alpha-ZOL and beta-ZOL production by microsomal fraction were two- and three-fold higher than those by postmitochondrial fraction, respectively. The calculated data showed that alpha-ZOL is conjugated with glucuronic acid more than ZEA and beta-ZOL, especially at the lower concentrations, which seems to be more applicable. Our data suggest that unlike other domestic ruminants including cattle and sheep, the hepatic biotransformation of ZEA in river buffalo results in bioactivation and formation of potent estrogenic metabolite. Moreover, at the relevant concentrations, the produced potent estrogenic metabolite is entirely conjugated with glucuronic acid and, consequently, may cause the prolongation of presence of the compound in the body due to enterohepatic cycle. PMID:20361255
Biomarkers of Flutamide-Bioactivation and Oxidative Stress In Vitro and In Vivo.
Teppner, Marieke; Boess, Franziska; Ernst, Beat; Pähler, Axel
The nonsteroidal androgen-receptor antagonist flutamide is associated with hepatic injury. Oxidative stress and reactive metabolite formation are considered contributing factors to liver toxicity. Here we have used flutamide as a model drug to study the generation of reactive drug metabolites that undergo redox cycling to induce oxidative stress (OS) in vitro and in vivo. Lipid peroxidation (LPO) markers, as well as genes regulated by the redox-sensitive Nrf2 pathway, have been identified as surrogates for the characterization of OS. These markers and metabolism biomarkers for drug bioactivation have been investigated to characterize drug-induced hepatic damage. Rat hepatocytes and in vivo studies showed that several LPO markers, namely the isoprostanes 15R-PD2, dihydro keto PE2, and iPF2 α-VI, as well as hydroxynonenal mercapturic acid metabolites, had increased significantly by 24 hours after flutamide treatment from 4.9 to 15.3-fold in hepatocytes and from 2.6 to 31.0-fold in rat plasma. Induction of mRNA expression levels for Nrf2-regulated genes was evident as well, with heme oxygenase 1, glutathione-S-transferase π1 and NAD(P)H dehydrogenase showing a 3.6-, 4.1-, and 1.9-fold increase in hepatocytes and 5.6-, 7.5-, and 94.1-fold in rat liver. All effects were observed at drug concentrations that did not show overt liver toxicity. Addition of an in situ hydrogen peroxide-generating system to in vitro experiments demonstrated the formation of a reactive di-imine intermediate as the responsible metabolic pathway for the generation of OS. The dataset suggests that hepatic oxidative stress conditions can be mediated via metabolic activation and can be monitored with suitable biomarkers preceding the terminal damage. PMID:26817949
Metabolism and metabolites of polychlorinated biphenyls (PCBs)
Grimm, FA; Hu, D; Kania-Korwel, I; Lehmler, HJ; Ludewig, G; Hornbuckle, KC; Duffel, MW; Bergman, A; Robertson, LW
The metabolism of polychlorinated biphenyls (PCBs) is complex and has an impact on toxicity and thereby assessment of PCB risks. A large number of reactive and stable metabolites are formed in the processes of biotransformation in biota in general and in humans in particular. The aim of this document is to provide an overview of PCB metabolism and to identify metabolites of concern and their occurrence. Emphasis is given to mammalian metabolism of PCBs and their hydroxyl, methylsulfonyl, and sulfated metabolites, especially those that persist in human blood. Potential intracellular targets and health risks are also discussed. PMID:25629923
A wood preservative metabolite in river water.
Khoroshko, Larisa O; Petrova, Varvara N; Viktorovskii, Igor V; Lahtiperä, Mirja; Sinkkonen, Seija; Paasivirta, Jaakko
A previously unknown pollutant in river water was identified to be 2-mercaptobenzothiazole (2-MBT) by interpretation and simulation of its GC/LRMS spectrum. Further GC/HRMS measurement of the isotope composition of the molecular ion verified this structure. 2-MBT is a well-known agent for corrosion inhibition and a stable metabolite of several other benzothiazoles. The present 2-MBT trace was most probably a metabolite of the wood preservative TCMTB which leaked from an upstream sawmill. The metabolite had been detected earlier in urine of the sawmill workers, but now was identified in the recipient water environment for the first time. PMID:15768735
Bioactive glasses: Importance of structure and properties in bone regeneration
NASA Astrophysics Data System (ADS)
Hench, Larry L.; Roki, Niksa; Fenn, Michael B.
This review provides a brief background on the applications, mechanisms and genetics involved with use of bioactive glass to stimulate regeneration of bone. The emphasis is on the role of structural changes of the bioactive glasses, in particular Bioglass, which result in controlled release of osteostimulative ions. The review also summarizes the use of Raman spectroscopy, referred to hereto forward as bio-Raman spectroscopy, to obtain rapid, real time in vitro analysis of human cells in contact with bioactive glasses, and the osteostimulative dissolution ions that lead to osteogenesis. The bio-Raman studies support the results obtained from in vivo studies of bioactive glasses, as well as extensive cell and molecular biology studies, and thus offers an innovative means for rapid screening of new bioactive materials while reducing the need for animal testing.
Secondary metabolites from Rubiaceae species.
Martins, Daiane; Nunez, Cecilia Veronica
This study describes some characteristics of the Rubiaceae family pertaining to the occurrence and distribution of secondary metabolites in the main genera of this family. It reports the review of phytochemical studies addressing all species of Rubiaceae, published between 1990 and 2014. Iridoids, anthraquinones, triterpenes, indole alkaloids as well as other varying alkaloid subclasses, have shown to be the most common. These compounds have been mostly isolated from the genera Uncaria, Psychotria, Hedyotis, Ophiorrhiza and Morinda. The occurrence and distribution of iridoids, alkaloids and anthraquinones point out their chemotaxonomic correlation among tribes and subfamilies. From an evolutionary point of view, Rubioideae is the most ancient subfamily, followed by Ixoroideae and finally Cinchonoideae. The chemical biosynthetic pathway, which is not so specific in Rubioideae, can explain this and large amounts of both iridoids and indole alkaloids are produced. In Ixoroideae, the most active biosysthetic pathway is the one that produces iridoids; while in Cinchonoideae, it produces indole alkaloids together with other alkaloids. The chemical biosynthetic pathway now supports this botanical conclusion. PMID:26205062
The Petroleum Supply Monthly (PSM) is one of a family of four publications produced by the Petroleum Supply Division within the Energy Information Administration (EIA) reflecting different levels of data timeliness and completeness. The other publications are the Weekly Petroleum Status Report (WPSR), the Winter Fuels Report, and the Petroleum Supply Annual (PSA). Data presented in the PSM describe the supply and disposition of petroleum products in the United States and major US geographic regions. The data series describe production, imports and exports, inter-Petroleum Administration for Defense (PAD) District movements, and inventories by the primary suppliers of petroleum products in the United States (50 States and the District of Columbia). The reporting universe includes those petroleum sectors in primary supply. Included are: petroleum refiners, motor gasoline blends, operators of natural gas processing plants and fractionators, inter-PAD transporters, importers, and major inventory holders of petroleum products and crude oil. When aggregated, the data reported by these sectors approximately represent the consumption of petroleum products in the United States.
The Petroleum Supply Monthly (PSM) is one of a family of four publications produced by the Petroleum Supply Division within the Energy Information Administration (EIA) reflecting different levels of data timeliness and completeness. The other publications are the Weekly Petroleum Status Report (WPSR), the Winter Fuels Report, and the Petroleum Supply Annual (PSA). Data presented in the PSM describe the supply and disposition of petroleum products in the United States and major U.S. geographic regions. The data series describe production, imports and exports, inter-Petroleum Administration for Defense (PAD) District movements, and inventories by the primary suppliers of petroleum products in the United States (50 States and the District of Columbia). The reporting universe includes those petroleum sectors in primary supply. Included are: petroleum refiners, motor gasoline blenders, operators of natural gas processing plants and fractionators, inter-PAD transporters, importers, and major inventory holders of petroleum products and crude oil. When aggregated, the data reported by these sectors approximately represent the consumption of petroleum products in the United States. Data presented in the PSM are divided into two sections: Summary Statistics and Detailed Statistics.
Effect of anodization and alkali-heat treatment on the bioactivity of titanium implant material (an in vitro study)
Abdelrahim, Ramy A.; Badr, Nadia A.; Baroudi, Kusai
Objective: This study was aimed to assess the effect of anodized and alkali-heat surface treatment on the bioactivity of titanium alloy (Ti-6Al-4V) after immersion in Hank's solution for 7 days. Materials and Methods: Fifteen titanium alloy samples were used in this study. The samples were divided into three groups (five for each), five samples were anodized in 1M H3PO4 at constant voltage value of 20 v and another five samples were alkali-treated in 5 M NaOH solution for 25 min at temperature 60°C followed by heat treatment at 600°C for 1 h. All samples were then immersed in Hank's solution for 7 days to assess the effect of surface modifications on the bioactivity of titanium alloy. The different treated surfaces and control one were characterized by X-ray diffraction, atomic force microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and Fourier transformation infra-red spectroscopy. Statistical analysis was performed with PASW Statistics 18.0® (Predictive Analytics Software). Results: Anodization of Ti-alloy samples (Group B) led to the formation of bioactive titanium oxide anatase phase and PO43− group on the surface. The alkali-heat treatment of titanium alloy samples (Group C) leads to the formation of bioactive titania hydrogel and supplied sodium ions. The reaction between the Ti sample and NaOH alkaline solution resulted in the formation of a layer of amorphous sodium titania on the Ti surface, and this layer can induce apatite deposition. Conclusions: The surface roughness and surface chemistry had an excellent ability to induce bioactivity of titanium alloy. The anodization in H3PO4 produced anatase titanium oxide on the surface with phosphate originated from electrolytes changed the surface topography and allowed formation of calcium-phosphate. PMID:27382532
Coping with shrub secondary metabolites by ruminants
Technology Transfer Automated Retrieval System (TEKTRAN)
Rangelands throughout the world contain varying but often substantial proportions of shrubs. Shrubs are generally heavily chemically defended, and herbivores must either contend with their plant secondary metabolites (PSM) or avoid a significant component of the available forage. Browsing ruminants ...
NASA Technical Reports Server (NTRS)
Yancik, J. J.
The potential sources and qualities of coals available for major utility and industrial consumers in California are examined and analyzed with respect to those factors that would affect the reliability of supplies. Other considerations, such as the requirements and assurances needed by the coal producers to enter into long-term contracts and dedicate large reserves of coal to these contracts are also discussed. Present and potential future mining contraints on coal mine operators are identified and analyzed with respect to their effect on availability of supply.
Alkylphenol Polyethoxylate Metabolite Behavior During Short-Term Soil Aquifer Treatment
NASA Astrophysics Data System (ADS)
Reinhard, M.
The attenuation of alkylphenol polyethoxylate (APEO) metabolites was studied at a soil aquifer treatment (SAT) facility located in Mesa, Arizona, USA. SAT is a technique commonly used in arid environments to augment groundwater supplies. In SAT, municipal wastewater is discharged into basins and allowed to infiltrate into the subsurface; the basins are most often filled for several days and then allowed to dry out. During SAT the quality of the recharged water is substantially improved. Because this water may eventually be used to augment drinking water supplies, there is a concern whether organic contaminants survive SAT. APEO metabolites are among the most frequently detected anthropogenic contaminants in the environment. The ubiquitous presence of these compounds may be of concern because they are relatively recalcitrant, can sorb and accumulate in soils and sediments, can bioaccumulate in plants and animals, and can be estrogenic to wildlife at low concentrations. In this study, two parcels of water were monitored during SAT -- one aerobic, the other anaerobic. During infiltration, under aerobic and anaerobic conditions, both alkylphenol ethoxycarboxylates (APECs) and carboxyalkylphenol ethoxycarboxylates (CAPECs) were substantially attenuated (> 90%) within 3 m. As expected, nonylphenol was removed under aerobic conditions, but produced under anaerobic conditions. Interestingly, no short-chained APEOs were detected. The rapid attenuation of CAPECs was surprising, as other researchers have found these metabolites to be very persistent. During infiltration, APEO metabolites with the longest ethoxycarboxylate side chain are attenuated fastest. Unlike several recent studies, alkylphenoxyacetic acids (AP1ECs) and carboxyalkylphenoxyacetic acids (CAP1ECs) were almost twice as abundant as alkylphenoxyethoxyacetic acids (AP2ECs) and carboxyalkylphenoxyethoxyacetic acids (CAP2ECs). Nonylphenol concentrations in both the wastewater and effluent SAT water were > 10 �
antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences
Medema, Marnix H.; Blin, Kai; Cimermancic, Peter; de Jager, Victor; Zakrzewski, Piotr; Fischbach, Michael A.; Weber, Tilmann; Takano, Eriko
Bacterial and fungal secondary metabolism is a rich source of novel bioactive compounds with potential pharmaceutical applications as antibiotics, anti-tumor drugs or cholesterol-lowering drugs. To find new drug candidates, microbiologists are increasingly relying on sequencing genomes of a wide variety of microbes. However, rapidly and reliably pinpointing all the potential gene clusters for secondary metabolites in dozens of newly sequenced genomes has been extremely challenging, due to their biochemical heterogeneity, the presence of unknown enzymes and the dispersed nature of the necessary specialized bioinformatics tools and resources. Here, we present antiSMASH (antibiotics & Secondary Metabolite Analysis Shell), the first comprehensive pipeline capable of identifying biosynthetic loci covering the whole range of known secondary metabolite compound classes (polyketides, non-ribosomal peptides, terpenes, aminoglycosides, aminocoumarins, indolocarbazoles, lantibiotics, bacteriocins, nucleosides, beta-lactams, butyrolactones, siderophores, melanins and others). It aligns the identified regions at the gene cluster level to their nearest relatives from a database containing all other known gene clusters, and integrates or cross-links all previously available secondary-metabolite specific gene analysis methods in one interactive view. antiSMASH is available at http://antismash.secondarymetabolites.org. PMID:21672958
Solvent Separating Secondary Metabolites Directly from Biosynthetic Tissue for Surface-Assisted Laser Desorption Ionisation Mass Spectrometry
Rudd, David; Benkendorff, Kirsten; Voelcker, Nicolas H.
Marine bioactive metabolites are often heterogeneously expressed in tissues both spatially and over time. Therefore, traditional solvent extraction methods benefit from an understanding of the in situ sites of biosynthesis and storage to deal with heterogeneity and maximize yield. Recently, surface-assisted mass spectrometry (MS) methods namely nanostructure-assisted laser desorption ionisation (NALDI) and desorption ionisation on porous silicon (DIOS) surfaces have been developed to enable the direct detection of low molecular weight metabolites. Since direct tissue NALDI-MS or DIOS-MS produce complex spectra due to the wide variety of other metabolites and fragments present in the low mass range, we report here the use of "on surface" solvent separation directly from mollusc tissue onto nanostructured surfaces for MS analysis, as a mechanism for simplifying data annotation and detecting possible artefacts from compound delocalization during the preparative steps. Water, ethanol, chloroform and hexane selectively extracted a range of choline esters, brominated indoles and lipids from Dicathais orbita hypobranchial tissue imprints. These compounds could be quantified on the nanostructured surfaces by comparison to standard curves generated from the pure compounds. Surface-assisted MS could have broad utility for detecting a broad range of secondary metabolites in complex marine tissue samples. PMID:25786067
The Significance of Lichens and Their Metabolites
NASA Astrophysics Data System (ADS)
Huneck, S.
Lichens, symbiontic organisms of fungi and algae, synthesize numerous metabolites, the "lichen substances," which comprise aliphatic, cycloaliphatic, aromatic, and terpenic compounds. Lichens and their metabolites have a manifold biological activity: antiviral, antibiotic, antitumor, allergenic, plant growth inhibitory, antiherbivore, and enzyme inhibitory. Usnic acid, a very active lichen substance is used in pharmaceutical preparations. Large amounts of Pseudevernia furfuracea and Evernia prunastri are processed in the perfume industry, and some lichens are sensitive reagents for the evaluation of air pollution.
Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity
Madden, Jill A.; Hoyer, Patricia B.; Devine, Patrick J.; Keating, Aileen F.
The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4 days before being exposed once to PM (10 or 30 μM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P < 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60 μM) exposure destroyed all stage follicles after 4 days (P < 0.05). VC from nearby wells depleted primordial follicles after 4 days (P < 0.05), temporarily reduced secondary follicle number after 2 days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors. - Highlights: • PM depletes all stage ovarian follicles in a temporal pattern. • A volatile ovotoxic compound is liberated from PM. • The volatile metabolite depletes primordial follicles.
Structural elucidation of rat biliary metabolites of corynoxeine and their quantification using LC-MS(n).
Wang, Wei; Li, Xinmei; Chen, Yaping; Hattori, Masao
Corynoxeine (COR) is one of 4 bioactive oxindole alkaloids in Uncaria species. In this work two phase I metabolites, namely 11-hydroxycorynoxeine (M1) and 10-hydroxycorynoxeine (M2), and two phase II metabolites, namely 11-hydroxycorynoxeine 11-O-β-d-glucuronide (M3) and 10-hydroxycorynoxeine 10-O-β-d-glucuronide (M4), were detected in rat bile after oral dose of COR (0.105 mmol/kg), by optimized high-performance liquid chromatography-tandem mass spectrometry (LC-MS(n) ) with electrospray ionization in positive ion mode. Structures of M1-4 were determined by LC-MS(n) , nuclear magnetic resonance, circular dichroism and high-resolution MS spectra. COR and its metabolites in rat bile were quantified by LC-MS(n) . The LC-MS(n) quantification methods for COR and its metabolites yielded a linearity with coefficient of determination ≥0.995 from 5.0 × 10(-10) to 5.0 × 10(-7) m. The recoveries of stability tests varied from 96.80 to 103.10%. Accuracy ranged from 91.00 to 105.20%. Relative standard deviation for intra-day and inter-day assay was <5.0%. After the oral dose 0.14% of COR was detected in rat bile from 0 to 8 h, in which in total 97.8% COR biotransformed into M1-4. M1 and M2 yielded 48.1 and 49.7%, which successively glucuronidated to M3 and M4 at 47.2 and 43.8%, respectively. PMID:24523045
Cellular toxicity of nicotinamide metabolites.
Rutkowski, Bolesław; Rutkowski, Przemysław; Słomińska, Ewa; Smolenski, Ryszard T; Swierczyński, Julian
There are almost 100 different substances called uremic toxins. Nicotinamide derivatives are known as new family of uremic toxins. These uremic compounds play a role in an increased oxidative stress and disturbances in cellular repair processes by inhibiting poly (ADP-ribose) polymerase activity. New members of this family were discovered and described. Their toxic properties were a subject of recent studies. This study evaluated the concentration of 4-pyridone-3-carboxamid-1-β-ribonucleoside-triphosphate (4PYTP) and 4-pyridone-3-carboxamid-1-β-ribonucleoside-monophosphate (4PYMP) in erythrocytes of patients with chronic renal failure. Serum and red blood cells were collected from chronic renal failure patients on conservative treatment, those treated with hemodialysis, and at different times from those who underwent kidney transplantation. Healthy volunteers served as a control group. Nicotinamide metabolites were determined using liquid chromatography with mass spectrometry based on originally discovered and described method. Three novel compounds were described: 4-pyridone-3-carboxamid-1-β-ribonucleoside (4PYR), 4PYMP, and 4PYTP. 4PYR concentration was elevated in the serum, whereas 4PYMP and 4PYTP concentrations were augmented in erythrocytes of dialysis patients. Interestingly, concentrations of these compounds were less elevated during the treatment with erythropoietin-stimulating agents (ESAs). After successful kidney transplantation, concentrations of 4PYR and 4PYMP normalized according to the graft function, whereas that of 4PYTP was still elevated. During the incubation of erythrocytes in the presence of 4PYR, concentration of 4PYMP rose very rapidly while that of 4PYTP increased slowly. Therefore, we hypothesized that 4PYR, as a toxic compound, was actively absorbed by erythrocytes and metabolized to the 4PYMP and 4PYTP, which may interfere with function and life span of these cells. PMID:22200423
Transplacental transport of netobimin metabolites in ewes.
Cristofol, C; Carretero, A; Fernandez, M; Navarro, M; Sautet, J; Ruberte, J; Arboix, M
Neither netobimin (NTB) nor its metabolite albendazole (ABZ) were found in plasma after an oral administration of 20 mg/kg of NTB to pregnant ewes during the last third of gestation. ABZ metabolites, albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) were found in plasma 30 min and 2 h, respectively, after administration. The maximal plasma concentration (Cmax) of ABZSO was detected at 11.6 +/- 1.0 h and for ABZSO2 at 16.5 +/- 2.3 h. The plasma levels of the latter remained constant for 36 h, and decreased as ABZSO was removed from the blood. Jugular plasma levels of both metabolites did not differ significantly from those observed in the ovarian vein, suggesting that there were no exchanges between foetal and placental tissues. Both metabolite concentrations were similar in the umbilical vein and artery and in the amniotic and allantoic fluids, their values were half the maternal plasma concentration, leading to the conclusion that there was transplacental movement of metabolites. Both metabolites reached the foetus and could be responsible for the teratogenicity of NTB in sheep. PMID:8751036
Metabolites of cannabidiol identified in human urine.
Harvey, D J; Mechoulam, R
1. Urine from a dystonic patient treated with cannabidiol (CBD) was examined by g.l.c.-mass spectrometry for CBD metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and methyl ester/TMS derivatives and as the TMS derivatives of the product of lithium aluminium deuteride reduction. 2. Thirty-three metabolites were identified in addition to unmetabolized CBD, and a further four metabolites were partially characterized. 3. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivatives of CBD-7-oic acid. Other metabolites, mainly acids, were formed by beta-oxidation and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was CBD-7-oic acid containing a hydroxyethyl side-chain. 4. Two 8,9-dihydroxy compounds, presumably derived from the corresponding epoxide were identified. 5. Also present were several cyclized cannabinoids including delta-6- and delta-1-tetrahydrocannabinol and cannabinol. 6. This is the first metabolic study of CBD in humans; most observed metabolic routes were typical of those found for CBD and related cannabinoids in other species. PMID:2336840
[Natural bioactive agents in liver therapy].
Blázovics, Anna
Medical science alongside with other sciences, aiming to preserve health and combat diseases, has evolved significantly since the late 1930s. It has reached incredible results and opened up unpredicted perspectives for future generations to come. From the 1980s significant results also emerged from researching natural plant active ingredients for the prevention of damage from free radicals which were discovered in different symptoms. One of the important areas of research is the recognition of significant bioactive molecules from the aspects of food consumption, alongside the detection of their effect in the context of their structure. It is also important that by possessing these data it is possible to develop correct food consumption habits, especially for people who are suffering from diseases. Through the decades we came a long way from folk medicine observations to molecular, biological justification of effect mechanisms. PMID:26568101
Bioactive glass coatings for orthopedic metallic implants
Lopez-Esteban, Sonia; Saiz, Eduardo; Fujino, Sigheru; Oku, Takeo; Suganuma, Katsuaki; Tomsia, Antoni P.
The objective of this work is to develop bioactive glass coatings for metallic orthopedic implants. A new family of glasses in the SiO2-Na2O-K2O-CaO-MgO-P2O5 system has been synthesized and characterized. The glass properties (thermal expansion, softening and transformation temperatures, density and hardness) are in line with the predictions of established empirical models. The optimized firing conditions to fabricate coatings on Ti-based and Co-Cr alloys have been determined and related to the glass properties and the interfacial reactions. Excellent adhesion to alloys has been achieved through the formation of 100-200 nm thick interfacial layers (Ti5Si3 on Ti-based alloys and CrOx on Co-Cr). Finally, glass coatings, approximately 100 mu m thick, have been fabricated onto commercial Ti alloy-based dental implants.
New Bioactive Compounds from Korean Native Mushrooms
Kim, Seong-Eun; Hwang, Byung Soon; Song, Ja-Gyeong; Lee, Seung Woong; Lee, In-Kyoung
Mushrooms are ubiquitous in nature and have high nutritional attributes. They have demonstrated diverse biological effects and therefore have been used in treatments of various diseases, including cancer, diabetes, bacterial and viral infections, and ulcer. In particular, polysaccharides, including β-glucan, are considered as the major constituents responsible for the biological activity of mushrooms. Although an overwhelming number of reports have been published on the importance of polysaccharides as immunomodulating agents, not all of the healing properties found in these mushrooms could be fully accounted for. Recently, many research groups have begun investigations on biologically active small-molecular weight compounds in wild mushrooms. In this mini-review, both structural diversity and biological activities of novel bioactive substances from Korean native mushrooms are described. PMID:24493936
Bioactive Compounds Found in Brazilian Cerrado Fruits.
Bailão, Elisa Flávia Luiz Cardoso; Devilla, Ivano Alessandro; da Conceição, Edemilson Cardoso; Borges, Leonardo Luiz
Functional foods include any natural product that presents health-promoting effects, thereby reducing the risk of chronic diseases. Cerrado fruits are considered a source of bioactive substances, mainly phenolic compounds, making them important functional foods. Despite this, the losses of natural vegetation in the Cerrado are progressive. Hence, the knowledge propagation about the importance of the species found in Cerrado could contribute to the preservation of this biome. This review provides information about Cerrado fruits and highlights the structures and pharmacologic potential of functional compounds found in these fruits. Compounds detected in Caryocar brasiliense Camb. (pequi), Dipteryx alata Vog. (baru), Eugenia dysenterica DC. (cagaita), Eugenia uniflora L. (pitanga), Genipa americana L. (jenipapo), Hancornia speciosa Gomes (mangaba), Mauritia flexuosa L.f. (buriti), Myrciaria cauliflora (DC) Berg (jabuticaba), Psidium guajava L. (goiaba), Psidium spp. (araçá), Solanum lycocarpum St. Hill (lobeira), Spondias mombin L. (cajá), Annona crassiflora Mart. (araticum), among others are reported here. PMID:26473827
Bioactive Compounds Found in Brazilian Cerrado Fruits
Bailão, Elisa Flávia Luiz Cardoso; Devilla, Ivano Alessandro; da Conceição, Edemilson Cardoso; Borges, Leonardo Luiz
Functional foods include any natural product that presents health-promoting effects, thereby reducing the risk of chronic diseases. Cerrado fruits are considered a source of bioactive substances, mainly phenolic compounds, making them important functional foods. Despite this, the losses of natural vegetation in the Cerrado are progressive. Hence, the knowledge propagation about the importance of the species found in Cerrado could contribute to the preservation of this biome. This review provides information about Cerrado fruits and highlights the structures and pharmacologic potential of functional compounds found in these fruits. Compounds detected in Caryocar brasiliense Camb. (pequi), Dipteryx alata Vog. (baru), Eugenia dysenterica DC. (cagaita), Eugenia uniflora L. (pitanga), Genipa americana L. (jenipapo), Hancornia speciosa Gomes (mangaba), Mauritia flexuosa L.f. (buriti), Myrciaria cauliflora (DC) Berg (jabuticaba), Psidium guajava L. (goiaba), Psidium spp. (araçá), Solanum lycocarpum St. Hill (lobeira), Spondias mombin L. (cajá), Annona crassiflora Mart. (araticum), among others are reported here. PMID:26473827
Bioactive properties of honey with propolis.
Osés, S M; Pascual-Maté, A; Fernández-Muiño, M A; López-Díaz, T M; Sancho, M T
Nowadays, propolis is used as an innovative preservative and as a bioactive food supplement. Due to its bitter and astringent flavour, propolis is hardly accepted by consumers. The aim of this study was to obtain a likeable food product made with honey and propolis, whose antimicrobial, antioxidant and anti-inflammatory properties were enhanced in comparison with those of the base honeys used. 0.1%, 0.3% and 0.5% soft propolis extracts were added to honeys and the products that most appealed to the users were subjected to further research. Total phenolics, flavonoids, ABTS free radical and hydroxyl radicals scavenging and anti-inflammatory activities increased in all mixtures. Antimicrobial activity of the combined products showed synergic effects, resulting in higher results than those of the base honeys and propolis extracts. Therefore, honeys enriched with small amounts of propolis extracts are promising functional foods. PMID:26593609
Fluorescent Bioactive Corrole Grafted-Chitosan Films.
Barata, Joana F B; Pinto, Ricardo J B; Vaz Serra, Vanda I R C; Silvestre, Armando J D; Trindade, Tito; Neves, Maria Graça P M S; Cavaleiro, José A S; Daina, Sara; Sadocco, Patrizia; Freire, Carmen S R
Transparent corrole grafted-chitosan films were prepared by chemical modification of chitosan with a corrole macrocycle, namely, 5,10,15-tris(pentafluorophenyl)corrole (TPFC), followed by solvent casting. The obtained films were characterized in terms of absorption spectra (UV-vis), FLIM (fluorescence lifetime imaging microscopy), structure (FTIR, XPS), thermal stability (TGA), thermomechanical properties (DMA), and antibacterial activity. The results showed that the chemical grafting of chitosan with corrole units did not affect its film-forming ability and that the grafting yield increased with the reaction time. The obtained transparent films presented fluorescence which increases with the amount of grafted corrole units. Additionally, all films showed bacteriostatic effect against S. aureus, as well as good thermomechanical properties and thermal stability. Considering these features, promising applications may be envisaged for these corrole-chitosan films, such as biosensors, bioimaging agents, and bioactive optical devices. PMID:26899016
Bioactivity improvement of poly(epsilon-caprolactone) membrane with the addition of nanofibrous bioactive glass.
Lee, Hae-Hyoung; Yu, Hye-Sun; Jang, Jun-Hyeog; Kim, Hae-Won
Nanofibrous glass with a bioactive composition was added to a degradable polymer poly(epsilon-caprolactone) (PCL) to produce a nanocomposite in thin membrane form ( approximately 260 microm). The bioactivity and osteoblastic responses of the nanocomposite membrane were examined and compared with those of a pure PCL membrane. Glass nanofibers with diameters in the range of hundreds of nanometers were added to a PCL solution at 20 wt.%, and the mixture was stirred vigorously and air dried. The obtained nanocomposite membrane showed that many chopped glass nanofibers formed by the mixing step were embedded uniformly into the PCL matrix. The nanocomposite membrane induced the rapid formation of apatite-like minerals on the surface when immersed in a simulated body fluid. Murine-derived osteoblastic cells (MC3T3-E1) grew actively over the nanocomposite membrane with cell viability significantly improved compared with those on the pure PCL membrane. Moreover, the osteoblastic activity, as assessed by the expression of alkaline phosphatase, was significantly higher on the nanocomposite membrane than on the pure PCL membrane. The currently developed nanocomposite of the bioactive glass-added PCL might find applications in the bone regeneration areas such as the guided bone regeneration (GBR) membrane. PMID:18171636
Supply-Chain Optimization Template
NASA Technical Reports Server (NTRS)
Quiett, William F.; Sealing, Scott L.
The Supply-Chain Optimization Template (SCOT) is an instructional guide for identifying, evaluating, and optimizing (including re-engineering) aerospace- oriented supply chains. The SCOT was derived from the Supply Chain Council s Supply-Chain Operations Reference (SCC SCOR) Model, which is more generic and more oriented toward achieving a competitive advantage in business.
A review of the bioactivity of hydraulic calcium silicate cements
Niu, Li-na; Jiao, Kai; Wang, Tian-da; Zhang, Wei; Camilleri, Josette; Bergeron, Brian E.; Feng, Hai-lan; Mao, Jing; Chen, Ji-hua; Pashley, David H.; Tay, Franklin R.
Objectives In tissue regeneration research, the term "bioactivity" was initially used to describe the resistance to removal of a biomaterial from host tissues after intraosseous implantation. Hydraulic calcium silicate cements (HCSCs) are putatively accepted as bioactive materials, as exemplified by the increasing number of publications reporting that these cements produce an apatite-rich surface layer after they contact simulated body fluids. Methods In this review, the same definitions employed for establishing in vitro and in vivo bioactivity in glass–ceramics, and the proposed mechanisms involved in these phenomena are used as blueprints for investigating whether HCSCs are bioactive. Results The literature abounds with evidence that HCSCs exhibit in vitro bioactivity; however, there is a general lack of stringent methodologies for characterizing the calcium phosphate phases precipitated on HCSCs. Although in vivo bioactivity has been demonstrated for some HCSCs, a fibrous connective tissue layer is frequently identified along the bone–cement interface that is reminiscent of the responses observed in bioinert materials, without accompanying clarifications to account for such observations. Conclusions As bone-bonding is not predictably achieved, there is insufficient scientific evidence to substantiate that HCSCs are indeed bioactive. Objective appraisal criteria should be developed for more accurately defining the bioactivity profiles of HCSCs designed for clinical use. PMID:24440449
ERIC Educational Resources Information Center
Oppenheim, Charles
This discussion of the ethics of the information process provides a brief review of the process of information supply and flow, primarily in science and technology; looks at various points in the flow of information; and highlights particular ethical concerns. Facets of the process discussed in more detail include ways in which some scientists…
Exploration Supply Chain Simulation
NASA Technical Reports Server (NTRS)
The Exploration Supply Chain Simulation project was chartered by the NASA Exploration Systems Mission Directorate to develop a software tool, with proper data, to quantitatively analyze supply chains for future program planning. This tool is a discrete-event simulation that uses the basic supply chain concepts of planning, sourcing, making, delivering, and returning. This supply chain perspective is combined with other discrete or continuous simulation factors. Discrete resource events (such as launch or delivery reviews) are represented as organizational functional units. Continuous resources (such as civil service or contractor program functions) are defined as enabling functional units. Concepts of fixed and variable costs are included in the model to allow the discrete events to interact with cost calculations. The definition file is intrinsic to the model, but a blank start can be initiated at any time. The current definition file is an Orion Ares I crew launch vehicle. Parameters stretch from Kennedy Space Center across and into other program entities (Michaud Assembly Facility, Aliant Techsystems, Stennis Space Center, Johnson Space Center, etc.) though these will only gain detail as the file continues to evolve. The Orion Ares I file definition in the tool continues to evolve, and analysis from this tool is expected in 2008. This is the first application of such business-driven modeling to a NASA/government-- aerospace contractor endeavor.
Lightweight Regulated Power Supply
NASA Technical Reports Server (NTRS)
Mclyman, C. W.
Power-supply circuit regulates output voltage by adjusting frequency of chopper circuit according to variations. Currently installed in battery charger for electric wheelchair, circuit is well suited to other uses in which light weight is important - for example, in portable computers, radios, and test instruments.
Maintenance and supply options
NASA Technical Reports Server (NTRS)
The object of the Maintenance and Supply Option was to develop a high level operational philosophy related to maintenance and supply operations and incorporate these concepts into the Lunar Base Study. Specific products to be generated during this task were three trade studies and a conceptual design of the Logistic Supply Module. The crew size study was performed to evaluate crew sizes from the baseline size of four to a crew size of eight and determine the preferred crew size. The second trade study was to determine the impact of extending surface stay times and recommend a preferred duration of stay time as a function of crew, consumables, and equipment support capabilities. The third trade study was an evaluation of packaging and storage methods to determine the preferred logistics approach to support the lunar base. A modified scenario was developed and served as the basis of the individual trade studies. Assumptions and guidelines were also developed from experience with Apollo programs, Space Shuttle operations, and Space Station studies. With this information, the trade studies were performed and a conceptual design for the Logistic Supply Module was developed.
Teleconnected food supply shocks
NASA Astrophysics Data System (ADS)
Bren d'Amour, Christopher; Wenz, Leonie; Kalkuhl, Matthias; Steckel, Jan Christoph; Creutzig, Felix
The 2008-2010 food crisis might have been a harbinger of fundamental climate-induced food crises with geopolitical implications. Heat-wave-induced yield losses in Russia and resulting export restrictions led to increases in market prices for wheat across the Middle East, likely contributing to the Arab Spring. With ongoing climate change, temperatures and temperature variability will rise, leading to higher uncertainty in yields for major nutritional crops. Here we investigate which countries are most vulnerable to teleconnected supply-shocks, i.e. where diets strongly rely on the import of wheat, maize, or rice, and where a large share of the population is living in poverty. We find that the Middle East is most sensitive to teleconnected supply shocks in wheat, Central America to supply shocks in maize, and Western Africa to supply shocks in rice. Weighing with poverty levels, Sub-Saharan Africa is most affected. Altogether, a simultaneous 10% reduction in exports of wheat, rice, and maize would reduce caloric intake of 55 million people living in poverty by about 5%. Export bans in major producing regions would put up to 200 million people below the poverty line at risk, 90% of which live in Sub-Saharan Africa. Our results suggest that a region-specific combination of national increases in agricultural productivity and diversification of trade partners and diets can effectively decrease future food security risks.
Teleconnected food supply shocks
NASA Astrophysics Data System (ADS)
Bren d'Amour, Christopher; Wenz, Leonie; Kalkuhl, Matthias; Steckel, Jan Christoph; Creutzig, Felix
The 2008–2010 food crisis might have been a harbinger of fundamental climate-induced food crises with geopolitical implications. Heat-wave-induced yield losses in Russia and resulting export restrictions led to increases in market prices for wheat across the Middle East, likely contributing to the Arab Spring. With ongoing climate change, temperatures and temperature variability will rise, leading to higher uncertainty in yields for major nutritional crops. Here we investigate which countries are most vulnerable to teleconnected supply-shocks, i.e. where diets strongly rely on the import of wheat, maize, or rice, and where a large share of the population is living in poverty. We find that the Middle East is most sensitive to teleconnected supply shocks in wheat, Central America to supply shocks in maize, and Western Africa to supply shocks in rice. Weighing with poverty levels, Sub-Saharan Africa is most affected. Altogether, a simultaneous 10% reduction in exports of wheat, rice, and maize would reduce caloric intake of 55 million people living in poverty by about 5%. Export bans in major producing regions would put up to 200 million people below the poverty line at risk, 90% of which live in Sub-Saharan Africa. Our results suggest that a region-specific combination of national increases in agricultural productivity and diversification of trade partners and diets can effectively decrease future food security risks.
Saunders, C.W.; Despe, O.D.
The purpose of this document is to provide comprehensive coverage of the APS power supply control design. This includes application software, embedded controller software, networks, and hardware. The basic components will be introduced first, followed by the requirements driving the overall design. Subsequent sections will address each component of the design one by one. Latter sections will address specific applications.
Power Supplies for Precooler Ring
Fuja, Raymond; Praeg, Walter
Eight power supplies will energize the antiproton Precooler ring. there will be two series connected supplies per quadrant. These supplies will power 32 dipole and 19 quadrupole magnets. The resistance and inductance per quadrant is R = 1.4045 Ohms and L = 0.466. Each powr supply will have 12-phase series bridge rectifiers and will be energized from the 480 V 3-phase grid. The total of eight power supplies are numbered IA, IIA, IIIA, IVA, and IB, IIB, IIIB, and IVB. Each quadrant will contain one A and one B supply. A block diagram of the Precooler ring with its power supplies is shown in Figure 1.
A chemical ecogenomics approach to understand the roles of secondary metabolites in fungal cereal pathogens
Chooi, Yit-Heng; Solomon, Peter S.
Secondary metabolites (SMs) are known to play important roles in the virulence and lifestyle of fungal plant pathogens. The increasing availability of fungal pathogen genome sequences and next-generation genomic tools have allowed us to survey the SM gene cluster inventory in individual fungi. Thus, there is immense opportunity for SM discovery in these plant pathogens. Comparative genomics and transcriptomics have been employed to obtain insights on the genetic features that enable fungal pathogens to adapt in individual ecological niches and to adopt the different pathogenic lifestyles. Here, we will discuss how we can use these tools to search for ecologically important SM gene clusters in fungi, using cereal pathogens as models. This ecological genomics approach, combined with genome mining and chemical ecology tools, is likely to advance our understanding of the natural functions of SMs and accelerate bioactive molecule discovery. PMID:25477876
Melatonin and Other Tryptophan Metabolites Produced by Yeasts: Implications in Cardiovascular and Neurodegenerative Diseases
Hornedo-Ortega, Ruth; Cerezo, Ana B.; Troncoso, Ana M.; Garcia-Parrilla, M. Carmen; Mas, Albert
Yeast metabolism produces compounds derived from tryptophan, which are found in fermented beverages, such as wine and beer. In particular, melatonin and serotonin, may be relevant due to their bioactivity in humans. Indeed, the former is a neurohormone related to circadian rhythms, which also has a putative protective effect against degenerative diseases. Moreover, serotonin is a neurotransmitter itself, in addition to being a precursor of melatonin synthesis. This paper summarizes data reported on fermented beverages, to evaluate dietary intake. Additionally, the article reviews observed effects of yeast amino acid metabolites on the prevention of neurodegenerative diseases (Alzheimer's and Parkinson's) and angiogenesis, focusing on evidence of the molecular mechanism involved and identification of molecular targets. PMID:26834716
Metabolite identification of seven active components of Huan-Nao-Yi-Cong-Fang in rat plasma using high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry.
Wang, Minchao; Lu, Yanzhen; Liu, Jiangang; Li, Hao; Wei, Yun
Huan-Nao-Yi-Cong-Fang (HNYCF) is a potential prescription in treating Alzheimer's disease. Seven constituents [ferulic acid (FA), 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside (THSG), berberine hydrochloride (BHCl), emodin, ginsenoside Rg1 (Rg1), ginsenoside Re (Re) and ginsenoside Rb1 (Rb1)] have been used as quality chemical markers of HNYCF owing to their biological significance and high contents in crude plant materials. This study explored the metabolites of the seven bioactive components in rat plasma to give useful data for further study of the action mechanism of HNYCF. LC/MS-IT-TOF was used to simultaneously characterize the metabolites of the seven components. Using the combination of MetID Solution 1.0 software and accurate mass measurements, the metabolites of HNYCF were reliably characterized. Their structures were elucidated based on the accurate MS(2) spectra and comparisons of their changes in accurate molecular masses and fragment ions with those of parent compounds. A total of five parent active compounds (BHCl, emodin, Rg1, Rb1 and Re) and 10 metabolites were found from the rat plasma 2 h after oral administration of HNYCF dosage, of which two metabolites of emodin were observed for the first time. The proposed metabolic pathways of the bioactive components in the rat plasma are helpful for further studies on the pharmacokinetics and real active compound forms of this drug. PMID:26138785
Vesicular system: Versatile carrier for transdermal delivery of bioactives.
Singh, Deependra; Pradhan, Madhulika; Nag, Mukesh; Singh, Manju Rawat
The transdermal route of drug delivery has gained immense interest for pharmaceutical researchers. The major hurdle for diffusion of drugs and bioactives through transdermal route is the stratum corneum, the outermost layer of the skin. Currently, various approaches such as physical approach, chemical approach, and delivery carriers have been used to augment the transdermal delivery of bioactives. This review provides a brief overview of mechanism of drug transport across skin, different lipid vesicular systems, with special emphasis on lipid vesicular systems including transfersomes, liposomes, niosomes, ethosomes, virosomes, and pharmacosomes and their application for the delivery of different bioactives. PMID:24564350
Reprint of: Review of bioactive glass: From Hench to hybrids.
Jones, Julian R
Bioactive glasses are reported to be able to stimulate more bone regeneration than other bioactive ceramics but they lag behind other bioactive ceramics in terms of commercial success. Bioactive glass has not yet reached its potential but research activity is growing. This paper reviews the current state of the art, starting with current products and moving onto recent developments. Larry Hench's 45S5 Bioglass® was the first artificial material that was found to form a chemical bond with bone, launching the field of bioactive ceramics. In vivo studies have shown that bioactive glasses bond with bone more rapidly than other bioceramics, and in vitro studies indicate that their osteogenic properties are due to their dissolution products stimulating osteoprogenitor cells at the genetic level. However, calcium phosphates such as tricalcium phosphate and synthetic hydroxyapatite are more widely used in the clinic. Some of the reasons are commercial, but others are due to the scientific limitations of the original Bioglass 45S5. An example is that it is difficult to produce porous bioactive glass templates (scaffolds) for bone regeneration from Bioglass 45S5 because it crystallizes during sintering. Recently, this has been overcome by understanding how the glass composition can be tailored to prevent crystallization. The sintering problems can also be avoided by synthesizing sol-gel glass, where the silica network is assembled at room temperature. Process developments in foaming, solid freeform fabrication and nanofibre spinning have now allowed the production of porous bioactive glass scaffolds from both melt- and sol-gel-derived glasses. An ideal scaffold for bone regeneration would share load with bone. Bioceramics cannot do this when the bone defect is subjected to cyclic loads, as they are brittle. To overcome this, bioactive glass polymer hybrids are being synthesized that have the potential to be tough, with congruent degradation of the bioactive inorganic and
In Vitro Bioactivity and Antimicrobial Tuning of Bioactive Glass Nanoparticles Added with Neem (Azadirachta indica) Leaf Powder
Prabhu, M.; Ruby Priscilla, S.; Kavitha, K.; Manivasakan, P.; Rajendran, V.; Kulandaivelu, P.
Silica and phosphate based bioactive glass nanoparticles (58SiO2-33CaO-9P2O5) with doping of neem (Azadirachta indica) leaf powder and silver nanoparticles were prepared and characterised. Bioactive glass nanoparticles were produced using sol-gel technique. In vitro bioactivity of the prepared samples was investigated using simulated body fluid. X-ray diffraction (XRD) pattern of prepared glass particles reveals amorphous phase and spherical morphology with a particle size of less than 50 nm. When compared to neem doped glass, better bioactivity was attained in silver doped glass through formation of hydroxyapatite layer on the surface, which was confirmed through XRD, Fourier transform infrared (FTIR), and scanning electron microscopy (SEM) analysis. However, neem leaf powder doped bioactive glass nanoparticles show good antimicrobial activity against Staphylococcus aureus and Escherichia coli and less bioactivity compared with silver doped glass particles. In addition, the biocompatibility of the prepared nanocomposites reveals better results for neem doped and silver doped glasses at lower concentration. Therefore, neem doped bioactive glass may act as a potent antimicrobial agent for preventing microbial infection in tissue engineering applications. PMID:25276834
Bioactive Molecules Released in Food by Lactic Acid Bacteria: Encrypted Peptides and Biogenic Amines
Pessione, Enrica; Cirrincione, Simona
Lactic acid bacteria (LAB) can produce a huge amount of bioactive compounds. Since their elective habitat is food, especially dairy but also vegetal food, it is frequent to find bioactive molecules in fermented products. Sometimes these compounds can have adverse effects on human health such as biogenic amines (tyramine and histamine), causing allergies, hypertensive crises, and headache. However, some LAB products also display benefits for the consumers. In the present review article, the main nitrogen compounds produced by LAB are considered. Besides biogenic amines derived from the amino acids tyrosine, histidine, phenylalanine, lysine, ornithine, and glutamate by decarboxylation, interesting peptides can be decrypted by the proteolytic activity of LAB. LAB proteolytic system is very efficient in releasing encrypted molecules from several proteins present in different food matrices. Alpha and beta-caseins, albumin and globulin from milk and dairy products, rubisco from spinach, beta-conglycinin from soy and gluten from cereals constitute a good source of important bioactive compounds. These encrypted peptides are able to control nutrition (mineral absorption and oxidative stress protection), metabolism (blood glucose and cholesterol lowering) cardiovascular function (antithrombotic and hypotensive action), infection (microbial inhibition and immunomodulation) and gut-brain axis (opioids and anti-opioids controlling mood and food intake). Very recent results underline the role of food-encrypted peptides in protein folding (chaperone-like molecules) as well as in cell cycle and apoptosis control, suggesting new and positive aspects of fermented food, still unexplored. In this context, the detailed (transcriptomic, proteomic, and metabolomic) characterization of LAB of food interest (as starters, biocontrol agents, nutraceuticals, and probiotics) can supply a solid evidence-based science to support beneficial effects and it is a promising approach as well to obtain
Bioactive Molecules Released in Food by Lactic Acid Bacteria: Encrypted Peptides and Biogenic Amines.
Pessione, Enrica; Cirrincione, Simona
Lactic acid bacteria (LAB) can produce a huge amount of bioactive compounds. Since their elective habitat is food, especially dairy but also vegetal food, it is frequent to find bioactive molecules in fermented products. Sometimes these compounds can have adverse effects on human health such as biogenic amines (tyramine and histamine), causing allergies, hypertensive crises, and headache. However, some LAB products also display benefits for the consumers. In the present review article, the main nitrogen compounds produced by LAB are considered. Besides biogenic amines derived from the amino acids tyrosine, histidine, phenylalanine, lysine, ornithine, and glutamate by decarboxylation, interesting peptides can be decrypted by the proteolytic activity of LAB. LAB proteolytic system is very efficient in releasing encrypted molecules from several proteins present in different food matrices. Alpha and beta-caseins, albumin and globulin from milk and dairy products, rubisco from spinach, beta-conglycinin from soy and gluten from cereals constitute a good source of important bioactive compounds. These encrypted peptides are able to control nutrition (mineral absorption and oxidative stress protection), metabolism (blood glucose and cholesterol lowering) cardiovascular function (antithrombotic and hypotensive action), infection (microbial inhibition and immunomodulation) and gut-brain axis (opioids and anti-opioids controlling mood and food intake). Very recent results underline the role of food-encrypted peptides in protein folding (chaperone-like molecules) as well as in cell cycle and apoptosis control, suggesting new and positive aspects of fermented food, still unexplored. In this context, the detailed (transcriptomic, proteomic, and metabolomic) characterization of LAB of food interest (as starters, biocontrol agents, nutraceuticals, and probiotics) can supply a solid evidence-based science to support beneficial effects and it is a promising approach as well to obtain
Spongionella Secondary Metabolites Protect Mitochondrial Function in Cortical Neurons against Oxidative Stress
Leirós, Marta; Sánchez, Jon A.; Alonso, Eva; Rateb, Mostafa E.; Houssen, Wael E.; Ebel, Rainer; Jaspars, Marcel; Alfonso, Amparo; Botana, Luis M.
The marine habitat provides a large number of structurally-diverse bioactive compounds for drug development. Marine sponges have been studied over many years and are found to be a rich source of these bioactive chemicals. This study is focused on the evaluation of the activity of six diterpene derivatives isolated from Spongionella sp. on mitochondrial function using an oxidative in vitro stress model. The test compounds include the Gracilins (A, H, K, J and L) and tetrahydroaplysulphurin-1. Compounds were co-incubated with hydrogen peroxide for 12 hours to determine their protective capacities and their effect on markers of apoptosis and Nrf2/ARE pathways was evaluated. Results conclude that Gracilins preserve neurons against oxidative damage, and that in particular, tetrahydroaplysulphurin-1 shows a complete neuroprotective activity. Oxidative stress is linked to mitochondrial dysfunction and consequently to neurodegenerative disorders like Parkinson and Alzheimer diseases, Friedreich ataxia or Amyotrophic lateral sclerosis. This neuroprotection against oxidation conditions suggest that these metabolites could be interesting lead candidates in drug development for neurodegenerative diseases. PMID:24473170
Antifungal activity of metabolites of the endophytic fungus Trichoderma brevicompactum from garlic
Shentu, Xuping; Zhan, Xiaohuan; Ma, Zheng; Yu, Xiaoping; Zhang, Chuanxi
The endophytic fungus strain 0248, isolated from garlic, was identified as Trichoderma brevicompactum based on morphological characteristics and the nucleotide sequences of ITS1-5.8S- ITS2 and tef1. The bioactive compound T2 was isolated from the culture extracts of this fungus by bioactivity-guided fractionation and identified as 4β-acetoxy-12,13- epoxy-Δ9-trichothecene (trichodermin) by spectral analysis and mass spectrometry. Trichodermin has a marked inhibitory activity on Rhizoctonia solani, with an EC50 of 0.25 μgmL−1. Strong inhibition by trichodermin was also found for Botrytis cinerea, with an EC50 of 2.02 μgmL−1. However, a relatively poor inhibitory effect was observed for trichodermin against Colletotrichum lindemuthianum (EC50 = 25.60 μgmL−1). Compared with the positive control Carbendazim, trichodermin showed a strong antifungal activity on the above phytopathogens. There is little known about endophytes from garlic. This paper studied in detail the identification of endophytic T. brevicompactum from garlic and the characterization of its active metabolite trichodermin. PMID:24948941
[Secondary Metabolites from Marine Microorganisms. I. Secondary Metabolites from Marine Actinomycetes].
Orlova, T I; Bulgakova, V G; Polin, A N
Review represents data on new active metabolites isolated from marine actinomycetes published in 2007 to 2014. Marine actinomycetes are an unlimited source of novel secondary metabolites with various biological activities. Among them there are antibiotics, anticancer compounds, inhibitors of biochemical processes. PMID:26863742
NASA Technical Reports Server (NTRS)
Ruitberg, A. P.; Young, K. M. (Inventor)
A high voltage power supply is formed by three discrete circuits energized by a battery to provide a plurality of concurrent output signals floating at a high output voltage on the order of several tens of kilovolts. In the first two circuits, the regulator stages are pulse width modulated and include adjustable ressistances for varying the duty cycles of pulse trains provided to corresponding oscillator stages while the third regulator stage includes an adjustable resistance for varying the amplitude of a steady signal provided to a third oscillator stage. In the first circuit, the oscillator, formed by a constant current drive network and a tuned resonant network included a step up transformer, is coupled to a second step up transformer which, in turn, supplies an amplified sinusoidal signal to a parallel pair of complementary poled rectifying, voltage multiplier stages to generate the high output voltage.