The new coumarin compound Bis 3 ameliorates cognitive disorder and suppresses brain-intestine-liver systematic oxidative stress in high-fat diet mice.
High-fat diet (HFD)-induced systemic oxidative damage is critical to the pathological process of obesity and is associated with energy metabolism and cognitive disorders. In our previous research, the coumarin derivative Bis 3 was shown to improve neurological disorders as a potent free radical scavenger. In this study, a 12-week high-fat diet model was established, and mice were randomly divided into 3 groups: standard diet, high-fat diet, and high-fat diet with Bis 3 treatment. Our results demonstrated that Bis 3 attenuated body weight gain and inhibited the development of insulin resistance in high-fat diet-fed mice. Bis 3 protected against high fat-induced intestinal barrier integrity damage and lipid content disorder. HFD-induced hepatocyte lipid metabolism disorder and hepatocyte damage were also alleviated by Bis 3. Moreover, the results of cognitive tests indicated that Bis 3 attenuated high fat-induced cerebral dysfunction, such as cognitive disorders. Importantly, Bis 3 simultaneously ameliorated oxidative stress in the digestive and central nervous systems. These findings suggest that Bis 3 protects against systematic oxidative stress in HFD-induced obese mice, balancing insulin resistance, lipid metabolic disorders, and cognitive disorders through its antioxidative effects, indicating that Bis 3, a novel free radical scavenger, might represent a new therapeutic strategy for high fat-induced chronic systemic redox imbalance.


Stroke rehabilitation: evidence-based or evidence-tinged?
The evidence to support stroke rehabilitation has expanded dramatically in the last decade. In order to ensure that the resultant research findings can be generalized to all patients after stroke, research in the next decade must shift to multicentre trial activity. Published evidence from the stroke unit, early supported discharge and out-patient trials is strong and supports the beneficial effects of these stroke rehabilitation services. Evidence for individual therapeutic practices is continuing to develop, but in many areas further research is required. The benefits of task-specific interventions and the need to practise these with intensity are core findings from the current research literature. Technological and capacity-building advances, along with newly developing stroke research networks, will ensure that the future of stroke rehabilitation is strong and progressing towards becoming truly evidence-based.


NOS3 is involved in the increased protein and arginine metabolic response in muscle during early endotoxemia in mice.
Sepsis is a severe catabolic condition. The loss of skeletal muscle protein mass is characterized by enhanced release of the amino acids glutamine and arginine, which (in)directly affects interorgan arginine and the related nitric oxide (NO) synthesis. To establish whether changes in muscle amino acid and protein kinetics are regulated by NO synthesized by nitric oxide synthase-2 or -3 (NOS2 or NOS3), we studied C57BL6/J wild-type (WT), NOS2-deficient (NOS2-/-), and NOS3-deficient (NOS3-/-) mice under control (unstimulated) and lipopolysaccharide (LPS)-treated conditions. Muscle amino acid metabolism was studied across the hindquarter by infusing the stable isotopes L-[ring-2H5]phenylalanine, L-[ring-2H2]tyrosine, L-[guanidino-15N2]arginine, and L-[ureido-13C,2H2]citrulline. Muscle blood flow was measured using radioactive p-aminohippuric acid dilution. Under baseline conditions, muscle blood flow was halved in NOS2-/- mice (P < 0.1), with simultaneous reductions in muscle glutamine, glycine, alanine, arginine release and glutamic acid, citrulline, valine, and leucine uptake (P < 0.1). After LPS treatment, (net) muscle protein synthesis increased in WT and NOS2-/- mice [LPS vs. control: 13 +/- 3 vs. 8 +/- 1 (SE) nmol.10 g(-1).min(-1) (WT), 18 +/- 5 vs. 7 +/- 2 nmol.10 g(-1).min(-1) (NOS2-/-); P < 0.05 for LPS vs. control]. This response was absent in NOS3-/- mice (LPS vs. control: 11 +/- 4 vs. 10 +/- 2 nmol.10 g(-1).min(-1)). In agreement, the increase in muscle arginine turnover after LPS was also absent in NOS3-/- mice. In conclusion, disruption of the NOS2 gene compromises muscle glutamine release and muscle blood flow in control mice, but had only minor effects after LPS. NOS3 activity is crucial for the increase in muscle arginine and protein turnover during early endotoxemia.


Cancer stem cells in sarcomas: Getting to the stemness core.
Sarcomas are rare tumors but represent the third most common malignancy in children. The cancer stem cell (CSC) paradigm is well established, and CSCs have been intensively studied in sarcomas in the past decade. This review summarizes current knowledge on CSCs in sarcomas and provides new perspectives on the role of a deregulated stemness program in sarcomagenesis. Cell surface markers have so far failed to specifically target sarcoma CSCs. Sarcomas likely arise from immature cells that undergo pathological reprogramming. Transcription factor Sox2, which is frequently upregulated in sarcomas, is directly involved in this process, and its crucial role in the acquisition and maintenance of the CSC phenotype has been demonstrated in various sarcomas. Sox2 is a core functional regulator of the stem-like state and is an outstanding marker of sarcoma CSCs. Fluorescence protein-based reporters of Sox2 expression might provide useful tools for subsequent studies of sarcoma CSCs.


Brain-enriched microRNAs circulating in plasma as novel biomarkers for Rett syndrome.
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Minimally invasive and accurate biomarkers of disease progression and treatment response could facilitate screening of therapeutic compounds in animal models, enrollment of better-defined participants into clinical trials, and treatment monitoring. In this study, we used a targeted approach based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma to identify miRNA biomarkers of RTT using Mecp2-mutant mice as a model system and human plasma samples. An "miRNA pair" approach, i.e. the ratio between two miRNAs, was used for data normalization. Specific miRNA pairs and their combinations (classifiers) analyzed in plasma differentiated wild-type from Mecp2 male and female mice with >90% accuracy. Individual miRNA pairs were more effective in distinguishing male (homozygous) animals than female (heterozygous) animals, suggesting that disease severity correlated with the levels of the miRNA biomarkers. In the human study, 30 RTT patients were compared with age-matched controls. The results of this study showed that miRNA classifiers were able to differentiate RTT patients from controls with 85-100% sensitivity. In addition, a comparison of various age groups demonstrated that the dynamics in levels of miRNAs appear to be associated with disease development (involvement of liver, muscle and lipid metabolism in the pathology). Importantly, certain miRNA biomarker pairs were common to both the animal models and human subjects, indicating the similarity between the underlying pathological processes. The data generated in this feasibility study suggest that circulating miRNAs have the potential to be developed as markers of RTT progression and treatment response. Larger clinical studies are needed to further evaluate the findings presented here.