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|By Marketwired .
Article Rating:
|December 3, 2012 05:30 PM EST
NEW YORK, NY -- (Marketwire) -- 12/03/12 -- A quarterly dividend distribution of $0.065 per share was declared today by Global Income Fund, Inc. (PINKSHEETS: GIFD) (OTCBB: GIFD), payable December 28, 2012 to shareholders of record as of December 14, 2012.
As previously announced, the 1-for-4 reverse split of the issued and outstanding common shares of the Company is now anticipated to be effective as of the start of trading on December 10, 2012. The reverse stock split was approved by the Company's Board of Directors and is intended to enhance shareholder value. As a result of the reverse stock split, one new share will be issued for every four currently outstanding shares. The $0.065 per share represents the pre-split per share amount of the quarterly dividend distribution as of the date of this press release. Effective with the reverse share split, the amount of the per share dividend distribution restated to reflect post-split shares is anticipated to be $0.26.
This notice discloses information on the sources of the distribution as required by SEC Rule 19(a) of the Investment Company Act of 1940. As of the date of this press release and based on the Company's results and estimates for the current quarter, the current distribution of $0.065 per pre-split share and the anticipated restated distribution of $0.26 per post-split share would include approximately 19%, 0%, and 81% from net investment income, capital gains, and return of capital, respectively. The Company's fixed distributions are not tied to its investment income and realized capital gains and do not represent yield or investment return.
The amounts and sources of distributions reported in this press release are only estimates and are not being provided for tax reporting purposes. The actual amounts and sources of the amounts for tax reporting purposes will depend upon the Company's investment experience during the entirety of its fiscal year and may be subject to changes based on tax regulations. In early 2013, the Company intends to send a Form 1099-DIV for the calendar year concerning the tax treatment of the dividend distributions that were paid to shareholders of record during the 12 months ended December 31, 2012.
Safe Harbor Note
This release contains certain "forward looking statements" made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements involve known and unknown risks, uncertainties and other factors, many of which are beyond the control of the Company, which may cause the Company's actual results to be materially different from those expressed or implied by such statements. The forward looking statements made herein are only made as of the date of this release, and the Company undertakes no obligation to publicly update such forward looking statements to reflect subsequent events or circumstances.
Thomas O'Malley
E-mail: Email Contact
1-212-344-6310, ext. 267
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Pot culture experiments were established to determine the effects of arbuscular mycorrhizal fungus (AMF) (Glomus fasciculatum) on tropical gum tree (Sterculia setigera Del.) grown in Copper contaminated soils. AMF and non-AMF inoculated plants were grown in sterilized substrates and subjected to different copper level (0, 200, 400,600, 800 mg kg-1) concentrations. Root and shoot biomasses of inoculated plants were significantly higher than those of non-inoculated. Copper concentrations in roots were significantly higher than those in shoots in both the inoculated and non-inoculated plants, indicating this heavy metal mostly accumulated in the roots of plants. Copper translocation efficiency from root to shoot was lower in mycorrhizal plants than in nonmycorrhizal ones at any Copper addition levels. However, at high soil Copper concentrations, shoot Copper concentration of inoculated plant were significantly reduced by about 50% compared to non-inoculated plants. These results indicated that AMF could promote tropical gum tree growth and decrease the uptake of Cu at higher soil concentrations, thus protecting their hosts from the toxicity of Copper contaminated soils.
Article Citation:
Malick Ndiaye, Cavalli Eric, Diouf Adama, Diop Tahir Abdoulaye.
Uptake and translocation of copper by mycorrhized seedlings Sterculia setigera (Del.) under Copper-contamined soil.
Journal of Research in Agriculture (2012) 1(1): 022-028.
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ambient air Companies in Delaware
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ENSEPATEC is a specialist for mechanical fluid separation technology. We provide design, engineering and manufacturing of fluid separation equipment aiming at the separation of solids from continuous gas flows. liquids from continuous gas flows. 2- and 3-Phase separation. ENSEPATEC has a long term experience among a large number of industrial applications and utilizes ...
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inVentures Technologies incorporated (iTi) develops, manufactures and markets world-class technologies that are based on a membrane-like polymer matrix barrier of microporous hollow fibre. iTi's Gas inFusion technology, infuses ultra-high levels of nascent dissolved gas into liquids. Environmental applications include the in-situ Submerged Oxygen Curtain (iSOC) and the ...
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CMS membrane contactors provide a nonporous but highly gas transmissive barrier to liquids. Examples of typical applications include: deoxygenation or degassing of oils and solvents, ozonation of aqueous solutions, and dewatering of solvents, oils, or fluids that would otherwise be damaged by water evaporation through heating.
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JAS specializes in innovative systems and customized solutions for a wide range of applications in any field of analytic. We currently manufacture a broad range of GC and LC based products as well as lab automation and process equipment. With headquarters in Germany and in the USA as well as subsidiaries in China and Singapore we can, together with our partners, serve our ...
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Supercritical Fluid Technologies, Inc. (SFT) has worked to advance research in supercritical fluid extraction and reaction chemistry. SFT's core expertise center around the design and construction of equipment for supercritical fluid extraction (SFE), supercritical fluid reaction chemistry (SFR), and related, high pressure applications. Supercritical Fluid Technologies is ...
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Modern Water's Monitoring division has developed some of the world's most advanced systems for monitoring water quality. We provide market-leading toxicity monitoring systems, trace metal and environmental monitoring systems. The range includes systems for portable, online, and laboratory use. Our toxicity monitoring products, Microtox and Microtox CTM, detect toxins in ...
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Dajak, in conjunction with the companies it represents, provides technical solutions to challenges faced by the environmental consulting community. Dajak can be a valuable partner to consultants and providers of site characterization and remediation technologies, as we have intimate knowledge of leading edge technologies, their appropriate applicability and their ...


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Crazy Substitute Teachers
Enjoy, NG4.03 / 5.00 2,646 Views
Vacuum Salesman
This dude and his Megazord vacuum cleaner4.01 / 5.00 2,908 Views
Markiplier Animated | Mark Of The Survey Corps
This took far too long to make...3.96 / 5.00 7,565 Views
Sounds like me...
this was great animation...it was funny i never thought i could see an emo robot...but good job great animation just work on the lip sink a little bit and you got a perfect flash..
christ never saved a robot
well maybe they did not exist lol good job
i know i already gave a review but . . .
That was almost exactly like a friend of mine, no exaggerations, I've been trying to get him out of his loop of pointless self pity for years but every time I get somewhere I'm at the drawing board once again next time we talk. That was great, very funny, well voiced, well animated. Really great
like d movie
but really did you have to put the puertorican line??? ):-(


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The Crime of Padre AmaroDirector: Carlos Carrera
Cast: Carlos Carrera, Gael García Bernal, Sancho Gracia, Ana Claudia Talancón
View All Available Formats & Editions
- Overview
- Editorial Reviews
- Product Details
- Special Features
- Related Subjects
- Cast & Crew
- Scene Index
- Menu
- Videos
Oscar-nominated and controversial, The Crime of Padre Amaro comes to DVD in a decent, though far from flashy, package. The image, framed at 1.85:1 and anamorphic, is a fine representation. Colors are well balanced, but not showy, portraying the Mexican locations in a very realistic fashion. Detail is also quite good, as is skin tone, which stands out strongly. The 5.1 Dolby Digital tracks, both in Spanish and English, are basically centered up front, with a moment or two of separation at appropriate times. Dialogue is clear and distinguishable. This disc hardly has a wealth of supplements. On the positive side, it does have a commentary track (in Spanish, with English subtitles, which is something that can't be said for the DVD of Y Tu Mamá También) by director Carlos Carrera and star Gael García Bernal. Both men ramble on and on, and do offer some interesting tidbits, but often it's difficult to distinguish the two, and Bernal certainly doesn't contribute as much as the director. Beyond that is a press kit featurette about the film that doesn't offer much, a very brief poster gallery, and two trailers for this film and Talk to Her.
Editorial Reviews
The film is directed in a straightforward way by Carlos Carrera, who makes it direct and heartfelt, like a soap opera.
Product Details
- Release Date:
- 04/22/2003
- 0043396004672
- Original Release:
- 2002
- Rating:
- Source:
- Sony Pictures
- Region Code:
- 1
- Presentation:
- [Wide Screen]
- Sound:
- [Dolby Digital 5.1 Surround]
- Time:
- 1:59:00
- Sales rank:
- 57,546
Special Features
Cast & Crew
|Gael García Bernal
|Padre Amaro
|Sancho Gracia
|Father Benito
|Ana Claudia Talancón
|Damián Alcázar
|Father Natalio
|Angélica Aragón
|La Sanjuanera
|Ernesto Gómez Cruz
|Luisa Huertas
|Pedro Armendariz
|Presidente Municipal
|Gaston Melo
|Veronica Langer
|Jorge Zárate
|Father Mauro
|Andres Montiel
|Roger Nevares
|Father Galvan
Technical Credits
|Carlos Carrera
|Nerio Barberis
|Sound/Sound Designer
|Sandra Leon Becker
|Carmen Gimenez Cacho
|Production Designer
|Maria Estela Fernandez
|Costumes/Costume Designer
|Oscar Fuigueroa
|Guillermo Granillo
|Laura Imperiale
|Executive Producer
|Vicente Leñero
|Miguel Lima
|Asst. Director
|Jose Maria Morales
|Arturo Ripstein
|Alfredo Ripstein
|Daniel Birman Ripstein
|Rosino Serrano
|Score Composer
Scene Index
1. Start [1:08]
2. Padre Amaro [3:43]
3. Amelia & Ruben [1:42]
4. Padre Benito [3:50]
5. Sanjuanera [:41]
6. First Mass [8:38]
7. Amelia's Touching Confession [1:43]
8. Getsemani [1:10]
9. Padre Natalio's Liberation Theology [7:13]
10. Baptism at Chato's Hacienda [4:14]
11. Ruben's Assignment [7:30]
12. A Meeting With the Bishop [3:18]
13. The Church's Rebuttal [1:52]
14. The Devil's Lair [3:27]
15. Amaro's Sermon [3:06]
16. A Touching Moment [5:21]
17. Assault & Battery [1:07]
18. People Wouldn't Understand [4:51]
19. Securing a Trysting Place [4:44]
20. Song of Songs [3:04]
21. Ten Commandments of Love [7:19]
22. Blackmailing a Hypocrite [1:34]
23. "I'm Pregnant." [6:15]
24. "Maybe Ruben Will Marry Me." [4:43]
25. Dionisia [2:01]
26. Excommunicated [10:22]
27. "She's Bleeding to Death!" [5:29]
28. A Prayer for Amelia's Soul [8:24]
Play Movie
Audio Set Up
Subtitles Off
Scene Selections
Special Features
Director Carlos Carrera and Actor Commentary: On
Director Carlos Carrera and Actor Commentary: Off
Making-Of: The Crime of Padre Amaro - English
Making-Of: El Crimen del Padre Amaro - Spanish/Español
Poster Explorations
Carlos Carrera
Alfredo Ripstein
Daniel Birman Ripstein
Vicente Leñero
Gael García Bernal
Interview 1
Interview 2
Ana Claudia Talancón
The Crime of Padre Amaro
The Crime of Padre Amaro (International Version)
Talk to Her
Customer Reviews
Average Review:
and post it to your social network
Most Helpful Customer Reviews
See all customer reviews >
El Crimen del Padre Amaro, i believe, is a very good movie to watch. It is a well crafted film in every aspect. The film's story unfolded smoothly. The subplots were interwoven in a manner that each of them contributed to the development of the characters and the story as a whole. The scenes provided perfect examples of how visuals can be cunningly used to convey socially-relevant messages. On the whole, the movie is a rare piece of art.
Two Latin actors, Natasha Perez and Carlos W. Jimenez, were selected to dub the starring roles of this controversial Mexican film. The dubbing of ''El Crimen del Padre Amaro'' was carried out at Media Concept studios, North Hollywood, using Protools software. This non-linear technique is not too commonly used in the Spanish dubbing industry. Carlos Jimenez dubs Gael García Bernal (Padre Amaro). He has been dubbing from English to Spanish for fourteen years. According to Jimenez ''switching was the most difficult part. When I record from other languages to Spanish it comes out natural but now I had to do the opposite. And although Gael is an excellent actor, he speaks very fast. Adaptation, that was the most difficult thing to do'' El Crimen del Padre Amaro (The Crime of Father Amaro) is one of the privileged six feature films that have been nominated at the Foreign Language category of the 75th Oscar awards. After it's nomination at the Golden Globe Awards¿ Foreign Language category, nobody should be surprised at Sony Pictures¿ initiative of launching a DVD that includes a version dubbed in English. Perez says she was really lucky. ''Although I don¿t have as much dubbing experience as him, I¿ve been performing in English for quite some time. Carlos and I didn¿t get to be in the recording booth together, but his professionalism and human quality helped a lot. He had access to the material and he shared it with me. We were both able to rehearse before recording, allowing us to deliver a top-quality work''. Perez thinks it would be a step forward to see computers and rehearsals becoming the standard in the Spanish dubbing industry ''you are able to give a good performance, you get precise synchronization, and the audience gets to hear the remainder of the original soundtrack ¿intact- because basically, the only sounds removed are the voices in Spanish''.
A great movie overall, you have to see it, I can't tell you how good it is!!!
I really recommened this movie to everyone!! the setting and the plot is excelent and will keep you at the edge of your seat. TWO THUMBS UP!!!!!!!!!!
''El Crimen del Padre Amaro'' is truly the gem of current Mexican cinema. However, it began with the movie ''Sexo, Pudor, y Lagrimas'' (1999) then followed by ''Amores Perros'', and ''Y Tu Mama Tambien.'' Be sure to see many more movies coming from Mexico that will leave you amazed. Its a shame that Mexico didn't win the Academy Award for ''Best Foreign Film''back in March. Not to worry there's still more to come!!!
Excellent movie! Gael Garcia Bernal is fantastic in this movie! Very contraversial!


text:
Season 6, Episode 26 Things Ain't Goin' Too Good at Southfork
First Aired: April 15, 1983
J.R.'s betrayal drives Sue Ellen back to the bottle and away from Southfork; Ellie confronts Clayton about his involvement with Sue Ellen. Larry Hagman, Linda Gray, Barbara Bel Geddes, Howard Keel.
Cast & Details See all »
- Premiered: April 2, 1978
- Rating: None
- Premise: Power, passion and duplicity drive this landmark saga set at the Southfork ranch, home of the oil-rich Ewing clan and ground zero for prime-time soaps in the late '70s and through the '80s. The most successful prime-time soap in TV history, `Dallas' spawne… (more)
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Vt. power line vandalism cost utilities $1.25mAP PHOTO
In this photo released by Vermont Electric Power Company, a worker repairs a power line in Concord on Tuesday.
CONCORD Gunshot damage to insulators on a major electric transmission line that runs from Quebec to Massachusetts cost New England ratepayers about $1 million for the replacement power that had to be purchased while the line was being repaired, according to an official with the Vermont company that owns the states electrical transmission grid.
Vermont Electric Power Company Vice President Kerrick Johnson said replacing the shot-out insulators cost about $250,000.
The damage posed a serious threat to anyone in the area, he said.
We hadnt before seen this level of damage before or consequences this high, he said.
The transmission line is capable of carrying 10 percent of the electricity used throughout New England.
The damage was discovered last Friday by a crew inspecting the line after the passage of Superstorm Sandy. It took crews two days to repair the damage.
The Caledonian Record reported that 167 insulators were shot out. The case was reviewed by state and federal authorities to determine if it was terrorist-related, but its being treated as vandalism.MORE IN Vermont NewsPHILADELPHIA With his presidential campaign officially over, independent Sen. Full StoryMONTPELIER Millions of dollars are at stake as the Vermont Public Service Board considers a new... Full StoryPHILADELPHIA Vermonts delegation to the Democratic National Convention took center stage... Full Story
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NEW YORK Dec 28 U.S. stocks extended their losses on Friday, with the Dow falling 1 percent as President Barack Obama and top lawmakers met in a last-ditch attempt at a budget deal to prevent the United States from going over the "fiscal cliff."
The Dow Jones industrial average tumbled 125.33 points, or 0.96 percent, to 12,970.98. The Standard & Poor's 500 Index fell 11.66 points, or 0.82 percent, to 1,406.44. The Nasdaq Composite Index lost 16.81 points, or 0.56 percent, to 2,969.09.
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Raj Malhotra (Raj Mahal is his stage name) is a former Wall Street trader-turned-stand-up-comedian. By day, he works as a senior trading mentor at the Institute of Trading and Portfolio Management (ITPM). He has worked at Wall Street firms covering three continents, including at Bank of America, BNP Paribas and Nomura. By night, he is a comedian who draws from his unique ethnic background and Wall Street career to entertain audiences, highlighting the struggles of the 1 percent. He can be seen at Gotham Comedy Club, Broadway Comedy Club, NY Comedy Club, Greenwich Village Comedy Club, and the Tribeca Comedy Lounge. Follow him on Twitter @RajMahalTweets and @RajWSGuru.
How to become a great trader? Avoid these six classic mistakes, says trading mentor Raj Malhotra.
Veteran trader Raj Malhotra offers up some key advice for the summer interns if they want a full-time job on Wall Street.
How did that UK trader allegedly cause the "flash crash?" Ex-trader Raj Malhotra breaks it down.
If you were casting the Wall Street edition of "Mad Men," who would play Don Draper? Peggy Olson?
This ex-trader has run the analysis and he's predicting NCAA top seed Kentucky will get shut down in the final dance. Here's his pick.
Raj Malhotra was a former star trader on Wall Street. So who's his money on for the Oscars?
Raj Malhotra was a former star trader on Wall Street. So how's he betting on this year's Super Bowl between the Seahawks and the Patriots?
Key indicators — including steak, strippers and sweet rides — suggest 2015 could be the year Wall Street and its big spender ways comes back!
Wall Street is a dog-eat-dog world. Here are four dirty secrets for making friends from ex-trader Raj Mahal.
Whoa! This is not the time to hit on your office crush. Plus other nuggets of wisdom to make sure you don't screw up your office holiday party. #yourewelcome
Julissa Arce says if Donald Trump were president while she was a young, undocumented immigrant, he probably would've deported her. And after his hate-filled speech, it's time to stop Trump.
In fact, says "Make It Work" co-founder Vivien Labaton, Trump has shown himself time and time again to be the opposite of a champion for women.
Critics who blasted Trump for excessive fearmongering in his GOP convention speech are being ridiculous, says Jake Novak. Here's why.
Donald Trump "spent nearly 77 minutes running down my beloved country and I don't take kindly to it," says Commentary magazine editor John Podhoretz.


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Impaired perfusion after myocardial infarction is due to reperfusion-induced δPKC-mediated myocardial damage
Ikeno, Fumiaki
Inagaki, Koichi
Rezaee, Mehrdad
Mochly-Rosen, Daria
Cardiovascular research
To improve myocardial flow during reperfusion after acute myocardial infarction and to elucidate the molecular and cellular basis that impedes it. According to the AHA/ACC recommendation, an ideal reperfusion treatment in patients with acute myocardial infarction (AMI) should not only focus on restoring flow in the occluded artery, but should aim to reduce microvascular damage to improve blood flow in the infarcted myocardium.
Transgenic mouse hearts expressing the δPKC (protein kinase C) inhibitor, δV1-1, in their myocytes only were treated with or without the δPKC inhibitor after ischemia in an ex vivo AMI model. δV1-1 or vehicle was also delivered at reperfusion in an in vivo porcine model of AMI. Microvascular dysfunction was assessed by physiological and histological measurements.
δPKC inhibition in the endothelial cells improved myocardial perfusion in the transgenic mice. In the porcine in vivo AMI model, coronary flow reserve (CFR), which is impaired for 6 days following infarction, was improved immediately following a one-minute treatment at the end of the ischemic period with the δPKC-selective inhibitor, δV1-1 (∼250 ng/Kg), and was completely corrected by 24 hrs. Myocardial contrast echocardiography, electron microscopy studies, and TUNEL staining demonstrated δPKC-mediated microvascular damage. δPKC-induced preconditioning, which also reduces infarct size by >60%, did not improve microvascular function.
These data suggest that δPKC activation in the microvasculature impairs blood flow in the infarcted tissue after restoring flow in the occluded artery and that AMI patients with no-reflow may therefore benefit from treatment with a δPKC inhibitor given in conjunction with removal of the coronary occlusion.
Related Articles
Activation of Protein Kinase C Delta following Cerebral Ischemia Leads to Release of Cytochrome C from the Mitochondria via Bad Pathway
Dave, Kunjan R.
Bhattacharya, Sanjoy K.
Saul, Isabel
DeFazio, R. Anthony
Dezfulian, Cameron
Lin, Hung Wen
Raval, Ami P.
Perez-Pinzon, Miguel A.
PLoS ONE
The release of cytochrome c from the mitochondria following cerebral ischemia is a key event leading to cell death. The goal of the present study was to determine the mechanisms involved in post-ischemic activation of protein kinase c delta (δPKC) that lead to cytochrome c release.
We used a rat model of cardiac arrest as an in vivo model, and an in vitro analog, oxygen glucose deprivation (OGD) in rat hippocampal synaptosomes. Cardiac arrest triggered translocation of δPKC to the mitochondrial fraction at 1 h reperfusion. In synaptosomes, the peptide inhibitor of δPKC blocked OGD-induced translocation to the mitochondria. We tested two potential pathways by which δPKC activation could lead to cytochrome c release: phosphorylation of phospholipid scramblase-3 (PLSCR3) and/or protein phosphatase 2A (PP2A). Cardiac arrest increased levels of phosphorlyated PLSCR3; however, inhibition of δPKC translocation failed to affect the OGD-induced increase in PLSCR3 in synaptosomal mitochondria suggesting the post-ischemic phosphorylation of PLSCR3 is not mediated by δPKC. Inhibition of either δPKC or PP2A decreased cytochrome c release from synaptosomal mitochondria. Cardiac arrest results in the dephosphorylation of Bad and Bax, both downstream targets of PP2A promoting apoptosis. Inhibition of δPKC or PP2A prevented OGD-induced Bad, but not Bax, dephosphorylation. To complement these studies, we used proteomics to identify novel mitochondrial substrates of δPKC.
We conclude that δPKC initiates cytochrome c release via phosphorylation of PP2A and subsequent dephosphorylation of Bad and identified δPKC, PP2A and additional mitochondrial proteins as potential therapeutic targets for ischemic neuroprotection.
Related Articles
δPKC Participates in the Endoplasmic Reticulum Stress-Induced Response in Cultured Cardiac Myocytes and Ischemic Heart
Qi, Xin
Vallentin, Alice
Churchill, Eric
Mochly-Rosen, Daria
Journal of molecular and cellular cardiology
The cellular response to excessive endoplasmic reticulum (ER) stress includes the activation of signaling pathways, which lead to apoptotic cell death. Here we show that treatment of cultured cardiac myocytes with tunicamycin, an agent that induces ER stress, causes the rapid translocation of δPKC to the ER. We further demonstrate that inhibition of δPKC using the δPKC-specific antagonist peptide, δV1-1, reduces tunicamycin-induced apoptotic cell death, and inhibits expression of specific ER stress response markers such as CHOP, GRP78 and phosphorylation of JNK. The physiological importance of δPKC in this event is further supported by our findings that the ER stress response is also induced in hearts subjected to ischemia and reperfusion injury and that this response also involves δPKC translocation to the ER. We found that the levels of the ER chaperone, GRP78, the spliced XBP-1 and the phosphorylation of JNK are all increased following ischemia and reperfusion and that δPKC inhibition by δV1-1 blocks these events. Therefore, ischemia-reperfusion injury induces ER stress in the myocardium in a mechanism that requires δPKC activity. Taken together, our data show for the first time that δPKC activation plays a critical role in the ER stress-mediated response and the resultant cell death.
Related Articles
The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways
Gao, Xuwen
Zhang, Hanfeng
Takahashi, Tetsuya
Hsieh, Jason
Liao, Janette
Steinberg, Gary K.
Zhao, Heng
Journal of neurochemistry
We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide-dependent protein kinase-1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3β, an Akt effector. In addition, postconditioning blocked β-catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non-phosphorylated active β-catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death-promoting δPKC cleavage and attenuated reduction in phosphorylation of survival-promoting εPKC. In conclusion, our data suggest that postconditioning provides long-term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning's protection; furthermore, increases in εPKC activity, a survival-promoting pathway, and reductions in MAPK and δPKC activity; two putative death-promoting pathways correlate with postconditioning's protection.
Akt; cerebral ischemia; mitogen-activated protein kinase; postconditioning; protein kinase C; β-catenin
Related Articles
δPKC inhibition or εPKC activation repairs endothelial vascular dysfunction by regulating eNOS post-translational modification
Monti, Martina
Donnini, Sandra
Giachettia, Antonio
Mochly-Rosen, Daria
Zichea, Marina
Journal of molecular and cellular cardiology
The balance between endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) and reactive oxygen species (ROS) production determines endothelial-mediated vascular homeostasis. Activation of protein kinase C (PKC) has been linked to imbalance of the eNOS/ROS system, which leads to endothelial dysfunction. We previously found that selective inhibition of delta PKC (δPKC) or selective activation of epsilon PKC (εPKC) reduces oxidative damage in the heart following myocardial infarction. In this study we determined the effect of these PKC isozymes in the survival of coronary endothelial cells (CVEC). We demonstrate here that serum deprivation of CVEC increased eNOS-mediated ROS levels, activated caspase-3, reduced Akt phosphorylation and cell number. Treatment with either the δPKC inhibitor, δV1-1, or the εPKC activator, ψεRACK, inhibited these effects, restoring cell survival through inhibition of eNOS activity. The decrease in eNOS activity coincided with specific de-phosphorylation of eNOS at Ser1179, and eNOS phosphorylation at Thr497 and Ser116. Furthermore, δV1-1 or ψεRACK induced physical association of eNOS with caveolin-1, an additional marker of eNOS inhibition, and restored Akt activation by inhibiting its nitration. Together our data demonstrate that 1) in endothelial dysfunction, ROS and reactive nitrogen species (RNS) formation result from uncontrolled eNOS activity mediated by activation of δPKC or inhibition of εPKC 2) inhibition of δPKC or activation of εePKC correct the perturbed phosphorylation state of eNOS, thus increasing cell survival. Since endothelial health ensures better tissue perfusion and oxygenation, treatment with a δPKC inhibitor and/or an εPKC activator in diseases of endothelial dysfunction should be considered.
Related Articles
Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway
Maddahi, Aida
Edvinsson, Lars
Journal of Neuroinflammation
Cerebral ischemia from middle cerebral artery wall (MCA) occlusion results in increased expression of cerebrovascular endothelin and angiotensin receptors and activation of the mitogen-activated protein kinase (MAPK) pathway, as well as reduced local cerebral blood flow and increased levels of pro-inflammatory mediators in the infarct region. In this study, we hypothesised that inhibition of the cerebrovascular inflammatory reaction with a specific MEK1/2 inhibitor (U0126) to block transcription or a combined receptor blockade would reduce infarct size and improve neurological score.
Rats were subjected to a 2-hours middle cerebral artery occlusion (MCAO) followed by reperfusion for 48 hours. Two groups of treated animals were studied; (i) one group received intraperitoneal administration of a specific MEK1/2 inhibitor (U0126) starting at 0, 6, or 12 hours after the occlusion, and (ii) a second group received two specific receptor antagonists (a combination of the angiotensin AT1 receptor inhibitor Candesartan and the endothelin ETA receptor antagonist ZD1611), given immediately after occlusion. The middle cerebral arteries, microvessels and brain tissue were harvested; and the expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and phosphorylated ERK1/2, p38 and JNK were analysed using immunohistochemistry.
We observed an infarct volume of 25 ± 2% of total brain volume, and reduced neurological function 2 days after MCAO followed by 48 hours of recirculation. Immunohistochemistry revealed enhanced expression of TNF-α, IL-1ß, IL-6 and iNOS, as well as elevated levels of phosphorylated ERK1/2 in smooth muscle cells of ischemic MCA and in associated intracerebral microvessels. U0126, given intraperitoneal at zero or 6 hours after the ischemic event, but not at 12 hours, reduced the infarct volume (11.7 ± 2% and 15 ± 3%, respectively), normalized pERK1/2, and prevented elevation of the expressions of TNF-α IL-1ß, IL-6 and iNOS. Combined inhibition of angiotensin AT1 and endothelin ETA receptors decreased the volume of brain damaged (12.3 ± 3; P < 0.05) but only slightly reduced MCAO-induced enhanced expression of iNOS and cytokines
The present study shows elevated microvascular expression of TNF-α, IL-1ß, IL-6 and iNOS following focal ischemia, and shows that this expression is transcriptionally regulated via the MEK/ERK pathway.
Related Articles
Subtype-Specific Translocation of the δ Subtype of Protein Kinase C and Its Activation by Tyrosine Phosphorylation Induced by Ceramide in HeLa Cells
Kajimoto, Taketoshi
Ohmori, Shiho
Shirai, Yasuhito
Sakai, Norio
Saito, Naoaki
Molecular and Cellular Biology
We investigated the functional roles of ceramide, an intracellular lipid mediator, in cell signaling pathways by monitoring the intracellular movement of protein kinase C (PKC) subtypes fused to green fluorescent protein (GFP) in HeLa living cells. C2-ceramide but not C2-dihydroceramide induced translocation of δPKC-GFP to the Golgi complex, while αPKC- and ζPKC-GFP did not respond to ceramide. The Golgi-associated δPKC-GFP induced by ceramide was further translocated to the plasma membrane by phorbol ester treatment. Ceramide itself accumulated to the Golgi complex where δPKC was translocated by ceramide. Gamma interferon also induced the δPKC-specific translocation from the cytoplasm to the Golgi complex via the activation of Janus kinase and Mg2+-dependent neutral sphingomyelinase. Photobleaching studies showed that ceramide does not evoke tight binding of δPKC-GFP to the Golgi complex but induces the continuous association and dissociation of δPKC with the Golgi complex. Ceramide inhibited the kinase activity of δPKC-GFP in the presence of phosphatidylserine and diolein in vitro, while the kinase activity of δPKC-GFP immunoprecipitated from ceramide-treated cells was increased. The immunoprecipitated δPKC-GFP was tyrosine phosphorylated after ceramide treatment. Tyrosine kinase inhibitor abolished the ceramide-induced activation and tyrosine phosphorylation of δPKC-GFP. These results suggested that gamma interferon stimulation followed by ceramide generation through Mg2+-dependent sphingomyelinase induced δPKC-specific translocation to the Golgi complex and that translocation results in δPKC activation through tyrosine phosphorylation of the enzyme.
Related Articles
Ischaemic preconditioning improves proteasomal activity and increases the degradation of δPKC during reperfusion
Churchill, Eric N.
Ferreira, Julio C.
Brum, Patricia C.
Szweda, Luke I.
Mochly-Rosen, Daria
Cardiovascular Research
The response of the myocardium to an ischaemic insult is regulated by two highly homologous protein kinase C (PKC) isozymes, δ and εPKC. Here, we determined the spatial and temporal relationships between these two isozymes in the context of ischaemia/reperfusion (I/R) and ischaemic preconditioning (IPC) to better understand their roles in cardioprotection.
Methods and results
Using an ex vivo rat model of myocardial infarction, we found that short bouts of ischaemia and reperfusion prior to the prolonged ischaemic event (IPC) diminished δPKC translocation by 3.8-fold and increased εPKC accumulation at mitochondria by 16-fold during reperfusion. In addition, total cellular levels of δPKC decreased by 60 ± 2.7% in response to IPC, whereas the levels of εPKC did not significantly change. Prolonged ischaemia induced a 48 ± 11% decline in the ATP-dependent proteasomal activity and increased the accumulation of misfolded proteins during reperfusion by 192 ± 32%; both of these events were completely prevented by IPC. Pharmacological inhibition of the proteasome or selective inhibition of εPKC during IPC restored δPKC levels at the mitochondria while decreasing εPKC levels, resulting in a loss of IPC-induced protection from I/R. Importantly, increased myocardial injury was the result, in part, of restoring a δPKC-mediated I/R pro-apoptotic phenotype by decreasing pro-survival signalling and increasing cytochrome c release into the cytosol.
Taken together, our findings indicate that IPC prevents I/R injury at reperfusion by protecting ATP-dependent 26S proteasomal function. This decreases the accumulation of the pro-apoptotic kinase, δPKC, at cardiac mitochondria, resulting in the accumulation of the pro-survival kinase, εPKC.
Cardioprotection; Ischaemia/reperfusion; Apoptosis; Proteasome; PKC; Ischaemic preconditioning
Related Articles
Preserved Coronary Endothelial Function by Inhibition of δ Protein Kinase C in a Porcine Acute Myocardial Infarction Model
Kaneda, Hideaki
Inagaki, Koichi
Ikeno, Fumiaki
Mochly-Rosen, Daria
International journal of cardiology
Previous studies demonstrate impairment of endothelial-dependent vasodilation after ischemia/reperfusion (I/R). Though we have demonstrated that inhibition of δ protein kinase C (δPKC) at reperfusion reduces myocyte damage and improves cardiac function in a porcine acute myocardial infarction (AMI) model, impact of the selective δPKC inhibitor on epicardial coronary endothelial function remains unknown.
Either δPKC inhibitor (δV1-1, n=5) or saline (n=5) was infused into the left anterior descending artery at the last 1 minute of the 30-minute ischemia by balloon occlusion. In vivo responses to bradykinin (endothelium-dependent vasodilator) or nitroglycerin (endothelium-independent vasodilator) were analyzed at 24 h after I/R using intravascular ultrasound. Vascular responses were calculated as the ratio of vessel area at each time point (30, 60, 90 and 120 seconds after the infusion), divided by values at baseline (before the infusion).
In control pigs, endothelial-dependent vasodilation following bradykinin infusion in infarct-related epicardial coronary artery was impaired, whereas in δPKC inhibitor treated-pigs the endothelial-dependent vasodilation was preserved. Nitroglycerin infusion caused similar vasodilatory responses in the both groups.
This is the first demonstration that a δPKC inhibitor preserves vasodilator capacity in epicardial coronary arteries in an in vivo porcine AMI model. Because endothelial dysfunction correlates with worse outcome in patients with AMI, this preserved endothelial function in epicardial coronary arteries might result in a better clinical outcome.
ultrasonography; angioplasty; myocardial infarction; protein kinases; endothelium
Related Articles
Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway
Maddahi, Aida
Edvinsson, Lars
BMC Neuroscience
MEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the role of the MEK/ERK pathway in receptor expression following ischemic brain injury using the specific MEK1 inhibitor U0126.
Methods and result
Rats were subjected to a 2-h middle cerebral artery occlusion (MCAO) followed by reperfusion for 48-h and the ischemic area was calculated. The expression of phosphorylated ERK1/2 and Elk-1, and of endothelin ETA and ETB, angiotensin AT1, and 5-hydroxytryptamine 5-HT1B receptors were analyzed with immunohistochemistry using confocal microscopy in cerebral arteries, microvessels and in brain tissue. The expression of endothelin ETB receptor was analyzed by quantitative Western blot. We demonstrate that there is an increase in the number of contractile smooth muscle receptors in the MCA and in micro- vessels within the ischemic region. The enhanced expression occurs in the smooth muscle cells as verified by co-localization studies. This receptor upregulation is furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the enhanced vascular receptor expression, and attenuated the cerebral infarct and improved neurology score.
Our results show that MCAO results in upregulation of cerebrovascular ETB, AT1 and 5-HT1B receptors. Blockade of this event with a MEK1 inhibitor as late as 6 h after the insult reduced the enhanced vascular receptor expression and the associated cerebral infarction.
Related Articles
Pharmacological Postconditioning Treatment of Myocardial Infarction with Netrin-1
Bouhidel, Jalaleddinne Omar
Wang, Ping
Li, Qiang
Cai, Hua
Frontiers in bioscience (Landmark edition)
The present study investigated whether pharmacological postconditoning with netrin-1 is cardioprotective against ischemia reperfusion (I/R) injury, and the underlying signaling mechanisms. Langendorff perfused hearts isolated from wild-type (WT) C57BL/6 or DCC+/− mice underwent a 20 min of ischemia, followed by a 60 min of reperfusion, in the presence or absence of netrin-1, or netrin-1 in combination with U0126 (MEK1/2 inhibitor), or PTIO (nitric oxide/NO scavenger). In WT mice, netrin-1 postconditioning dramatically reduced infarct size to 17.0±2.5%, from 40.5±4.2% in the untreated I/R group. U0126 or PTIO alone had no effect on infarct size but abolished the effects of netrin-1. The protective effect of netrin-1 was markedly diminished in DCC+/− mice (44.5±2% vs. 15±2.6 % for infract size in DCC+/− vs. DCC+/+ group). Our results indicate that netrin-1, given as a pharmacological postconditioning agent, induces cardioprotection via a DCC-dependent mechanism that involves ERK1/2 activation and NO production. Combined with our previous findings, netrin-1 treatment proves to be extremely and consistently beneficial whenever delivered to the heart, establishing its substantial promises for being developed into a robust therapeutic strategy for acute myocardial infarction.
Netrin-1; Pharmacological postconditioning; Cardioprotection; Ischemia reperfusion (I/R) injury; deleted in colorectal cancer (DCC); ERK1/2; nitric oxide (NO)
Related Articles
Electroacupuncture-like stimulation at Baihui and Dazhui acupoints exerts neuroprotective effects through activation of the brain-derived neurotrophic factor-mediated MEK1/2/ERK1/2/p90RSK/bad signaling pathway in mild transient focal cerebral ischemia in rats
Cheng, Chin Yi
Lin, Jaung Geng
Su, Shan Yu
Tang, Nou Ying
Kao, Shung Te
Hsieh, Ching Liang
BMC Complementary and Alternative Medicine
This study was designed to evaluate the effects of electroacupuncture-like stimulation at Baihui (GV20) and Dazhui (GV14) acupoints (EA at acupoints) following mild cerebral ischemia-reperfusion (I/R) injury. Furthermore, we investigated whether brain-derived neurotrophic factor (BDNF)-mediated activation of extracellular signal-regulated kinase (ERK)1/2 signaling pathway is involved in the neuroprotection induced by EA at acupoints.
Rats were subjected to middle cerebral artery occlusion (MCAo) for 15 min followed by reperfusion for 3 d. EA at acupoints was applied 1 d postreperfusion then once daily for 2 consecutive days.
Following the application of EA at acupoints, initiated 1 d postreperfusion, we observed significant reductions in the cerebral infarct area, neurological deficit scores, active caspase-3 protein expression, and apoptosis in the ischemic cortex after 3 d of reperfusion. We also observed markedly upregulated BDNF, phospho-Raf-1 (pRaf-1), phospho-MEK1/2 (pMEK1/2), phospho-ERK1/2 (pERK1/2), phospho-90 kDa ribosomal S6 kinase (pp90RSK), and phospho-Bad (pBad) expression, and restored neuronal nuclear antigen (NeuN) expression. Pretreatment with the MEK1/2 inhibitor U0126 abrogated the effects of EA at acupoints on cerebral infarct size, neurological deficits, active caspase-3 protein, and apoptosis in the ischemic cortex after 3 d of reperfusion. Pretreatment with U0126 also abrogated the effects of EA at acupoints on pMEK1/2, pERK1/2, pp90RSK, pBad, and NeuN expression, but did not influence BDNF and pRaf-1 expression.
Overall, our study results indicated that EA at acupoints, initiated 1 d postreperfusion, upregulates BDNF expression to provide BDNF-mediated neuroprotection against caspase-3-dependent neuronal apoptosis through activation of the Raf-1/MEK1/2/ERK1/2/p90RSK/Bad signaling cascade after 3 d of reperfusion in mild MCAo.
Electroacupuncture; Brain-derived neurotrophic factor; Phospho-ERK1/2; Phospho-p90RSK; Phospho-Bad; Apoptosis
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ERK1/2-Egr-1 Signaling Pathway-Mediated Protective Effects of Electroacupuncture in a Mouse Model of Myocardial Ischemia-Reperfusion
Zhang, Juan
Song, Jiangang
Xu, Jin
Chen, Xuemei
Yin, Peihao
Lv, Xin
Wang, Xiangrui
Evidence-based Complementary and Alternative Medicine : eCAM
Early growth response- (Egr-) 1 is an upstream master switch in controlling inflammatory responses following myocardial ischemia-reperfusion (I/R). Activation of extracellular signal-regulated protein kinase-1 and kinase-2 (ERK1/2) signaling is known to upregulate Egr-1. ERK1/2 pathway has been previously shown to mediate the therapeutic action of electroacupucture (EA). Thus, we hypothesized that EA would reduce myocardial I/R injury and inflammatory responses through inhibiting Egr-1 expression via the ERK1/2 pathway. Mice were pretreated with EA, U0126, or combination of EA and U0126 and then underwent 1 h myocardial ischemia and 3 h reperfusion. We investigated that EA significantly attenuated the I/R-induced upregulation of both Egr-1 and phosporylated-ERK1/2 (p-ERK1/2), decreased myocardial inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and reduced the infarct size and the release of cardiac troponin I (cTnI). U0126 treatment also exhibited the same effect as EA on Egr-1 level and subsequent cardioprotective effects. There was no additive effect of cotreatment with EA and U0126 on the expression of Egr-1 and its downstream target genes (TNF-α, IL-1β) or serum cTnI level. Collectively, these observations suggested that EA attenuates myocardial I/R injury, possibly through inhibiting the ERK1/2-Egr-1 signaling pathway and reducing the release of proinflammatory cytokines.
Related Articles
N-n-butyl haloperidol iodide inhibits H2O2-induced Na+/Ca2+-exchanger activation via the Na+/H+ exchanger in rat ventricular myocytes
Huang, Yong-Pan
Gao, Fen-Fei
Wang, Bin
Zheng, Fu-Chun
Zhang, Yan-Mei
Chen, Yi-Cun
Huang, Zhan-Qin
Zheng, Yan-Shan
Zhong, Shu-Ping
Shi, Gang-Gang
Drug Design, Development and Therapy
N-n-butyl haloperidol iodide (F2), a novel compound, has shown palliative effects in myocardial ischemia/reperfusion (I/R) injury. In this study, we investigated the effects of F2 on the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/Na+/H+ exchanger (NHE)/Na+/Ca2+ exchanger (NCX) signal-transduction pathway involved in H2O2-induced Ca2+ overload, in order to probe the underlying molecular mechanism by which F2 antagonizes myocardial I/R injury. Acute exposure of rat cardiac myocytes to 100 μM H2O2 increased both NHE and NCX activities, as well as levels of phosphorylated MEK and ERK. The H2O2-induced increase in NCX current (INCX) was nearly completely inhibited by the MEK inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[o-aminophenylmercapto] butadiene), but only partly by the NHE inhibitor 5-(N,N-dimethyl)-amiloride (DMA), indicating the INCX increase was primarily mediated by the MEK/mitogen-activated protein kinase (MAPK) pathway, and partially through activation of NHE. F2 attenuated the H2O2-induced INCX increase in a concentration-dependent manner. To determine whether pathway inhibition was H2O2-specific, we examined the ability of F2 to inhibit MEK/ERK activation by epidermal growth factor (EGF), and NHE activation by angiotensin II. F2 not only inhibited H2O2-induced and EGF-induced MEK/ERK activation, but also completely blocked both H2O2-induced and angiotensin II-induced increases in NHE activity, suggesting that F2 directly inhibits MEK/ERK and NHE activation. These results show that F2 exerts multiple inhibitions on the signal-transduction pathway involved in H2O2-induced INCX increase, providing an additional mechanism for F2 alleviating intracellular Ca2+ overload to protect against myocardial I/R injury.
N-n-butyl haloperidol; hydrogen peroxide; Na+/Ca2+ exchanger; Na+/H+ exchanger
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An Inhibitor of the δPKC Interaction with the d Subunit of F1Fo ATP Synthase Reduces Cardiac Troponin I Release from Ischemic Rat Hearts: Utility of a Novel Ammonium Sulfate Precipitation Technique
Ogbi, Mourad
Obi, Ijeoma
Johnson, John A.
PLoS ONE
We have previously reported protection against hypoxic injury by a cell-permeable, mitochondrially-targeted δPKC-d subunit of F1Fo ATPase (dF1Fo) interaction inhibitor [NH2-YGRKKRRQRRRMLA TRALSLIGKRAISTSVCAGRKLALKTIDWVSFDYKDDDDK-COOH] in neonatal cardiac myo-cytes. In the present work we demonstrate the partitioning of this peptide to the inner membrane and matrix of mitochondria when it is perfused into isolated rat hearts. We also used ammonium sulfate ((NH4)2SO4) and chloroform/methanol precipitation of heart effluents to demonstrate reduced card-iac troponin I (cTnI) release from ischemic rat hearts perfused with this inhibitor. 50% (NH4)2SO4 saturation of perfusates collected from Langendorff rat heart preparations optimally precipitated cTnI, allowing its detection in Western blots. In hearts receiving 20 min of ischemia followed by 30, or 60 min of reperfusion, the Mean±S.E. (n = 5) percentage of maximal cTnI release was 30±7 and 60±17, respectively, with additional cTnI release occurring after 150 min of reperfusion. Perfusion of hearts with the δPKC-dF1Fo interaction inhibitor, prior to 20 min of ischemia and 60–150 min of reperfusion, reduced cTnI release by 80%. Additionally, we found that when soybean trypsin inhibitor (SBTI), was added to rat heart effluents, it could also be precipitated using (NH4)2SO4 and detected in western blots. This provided a convenient method for normalizing protein recoveries between groups. Our results support the further development of the δPKC-dF1Fo inhibitor as a potential therapeutic for combating cardiac ischemic injury. In addition, we have developed an improved method for the detection of cTnI release from perfused rat hearts.
Related Articles
Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway
Maddahi, Aida
Povlsen, Gro
Edvinsson, Lars
Journal of Neuroinflammation
Subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. It is suggested that the associated inflammation is mediated through activation of the mitogen-activated protein kinase (MAPK) pathway which plays a crucial role in the pathogenesis of delayed cerebral ischemia after SAH. The aim of this study was first to investigate the timecourse of altered expression of proinflammatory cytokines and matrix metalloproteinase in the cerebral arteries walls following SAH. Secondly, we investigated whether administration of a specific mitogen-activated protein kinase kinase (MEK)1/2 inhibitor, U0126, given at 6 h after SAH prevents activation of the MEK/extracellular signal-regulated kinase 1/2 pathway and the upregulation of cerebrovascular inflammatory mediators and improves neurological function.
SAH was induced in rats by injection of 250 μl of autologous blood into basal cisterns. U0126 was given intracisternally using two treatment regimens: (A) treatments at 6, 12, 24 and 36 h after SAH and experiments terminated at 48 h after SAH, or (B) treatments at 6, 12, and 24 h after SAH and terminated at 72 h after SAH. Cerebral arteries were harvested and interleukin (IL)-6, IL-1β, tumor necrosis factor α (TNF)α, matrix metalloproteinase (MMP)-9 and phosphorylated ERK1/2 (pERK1/2) levels investigated by immunohistochemistry. Early activation of pERK1/2 was measured by western blot. Functional neurological outcome after SAH was also analyzed.
Expression levels of IL-1β, IL-6, MMP-9 and pERK1/2 proteins were elevated over time with an early increase at around 6 h and a late peak at 48 to 72 h post-SAH in cerebral arteries. Enhanced expression of TNFα in cerebral arteries started at 24 h and increased until 96 h. In addition, SAH induced sensorimotor and spontaneous behavior deficits in the animals. Treatment with U0126 starting at 6 h after SAH prevented activation of MEK-ERK1/2 signaling. Further, U0126 significantly decreased the upregulation of inflammation proteins at 48 and 72 h following SAH and improved neurological function. We found no differences between treatment regimens A and B.
These results show that SAH induces early activation of the MEK-ERK1/2 pathway in cerebral artery walls, which is associated with upregulation of proinflammatory cytokines and MMP-9. Inhibition of the MEK-ERK1/2 pathway by U0126 starting at 6 h post-SAH prevented upregulation of cytokines and MMP-9 in cerebral vessels, and improved neurological outcome.
Subarachnoid hemorrhage; TNFα; IL-1β; IL-6; MMP-9; Phosphorylated ERK1/2
Related Articles
δPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo
Bright, Rachel
Steinberg, Gary K.
Mochly-Rosen, Daria
Brain research
Maintaining cerebrovascular function is a priority for reducing damage following acute ischemic events such as stroke, and under chronic stress in diseases such as hypertension. Ischemic episodes lead to endothelial cell damage, deleterious inflammatory responses, and altered neuronal and astrocyte regulation of vascular function. These, in turn, can lead to impaired cerebral blood flow and compromised blood–brain barrier function, promoting microvascular collapse, edema, hemorrhagic transformation, and worsened neurological recovery. Multiple studies demonstrate that protein kinase C (PKC), a widely expressed serine/threonine kinase, is involved in mediating arterial tone and microvascular function. However, there is no clear understanding about the role of individual PKC isozymes. We show that intraperitoneal injection of δV1-1–TAT47–57 (0.2 mg/kg in 1 mL), an isozymespecific peptide inhibitor of δPKC, improved microvascular pathology, increased the number of patent microvessels by 92% compared to control-treated animals, and increased cerebral blood flow by 26% following acute focal ischemia induced by middle cerebral artery occlusion in normotensive rats. In addition, acute delivery of δV1-1–TAT47–57 in hypertensive Dahl rats increased cerebral blood flow by 12%, and sustained delivery δV1-1–TAT47–57 (5 uL/h, 1 mM), reduced infarct size by 25% following an acute stroke induced by MCA occlusion for 90 min. Together, these findings demonstrate that δPKC is an important therapeutic target for protection of microvascular structure and function under both acute and chronic conditions of cerebrovascular stress.
Cerebral blood flow; Hypertension; Microvasculature; Protein kinase C; Stroke; Vasculature
Related Articles
Protein Kinase C Protects Preconditioned Rabbit Hearts by Increasing Sensitivity of Adenosine A2b-Dependent Signaling During Early Reperfusion
Kuno, Atsushi
Critz, Stuart D.
Cui, Lin
Solodushko, Victoriya
Yang, Xi-Ming
Krahn, Thomas
Albrecht, Barbara
Philipp, Sebastian
Cohen, Michael V.
Downey, James M.
Journal of molecular and cellular cardiology
Although protein kinase C (PKC) plays a key role in ischemic preconditioning (IPC), the actual mechanism of that protection is unknown. We recently found that protection from IPC requires activation of adenosine receptors during early reperfusion. We, therefore, hypothesized PKC might act to increase the heart's sensitivity to adenosine. IPC limited infarct size in isolated rabbit hearts subjected to 30-min regional ischemia/2-h reperfusion and IPC's protection was blocked by the PKC inhibitor chelerythrine given during early reperfusion revealing involvement of PKC at reperfusion. Similarly chelerythrine infused in the early reperfusion period blocked the increased phosphorylation of the protective kinases Akt and ERK1/2 observed after IPC. Infusing phorbol 12-myristate 13-acetate (PMA), a PKC activator, during early reperfusion mimicked IPC's protection. As expected, the protection triggered by PMA at reperfusion was blocked by chelerythrine, but surprisingly it was also blocked by MRS1754, an adenosine A2b receptor–selective antagonist, suggesting that PKC was somehow facilitating signaling from the A2b receptors. NECA [5′-(N-ethylcarboxamido) adenosine], a potent but not selective A2b receptor agonist, increased phosphorylation of Akt and ERK1/2 in a dose-dependent manner. Pretreating hearts with PMA or brief preconditioning ischemia had no effect on phosphorylation of Akt or ERK1/2 per se, but markedly lowered the threshold for NECA to induce their phosphorylation. BAY 60-6583, a highly selective A2b agonist, also caused phosphorylation of ERK 1/2 and Akt. MRS1754 prevented phosphorylation induced by BAY 60-6583. BAY 60-6583 limited infarct size when given to ischemic hearts at reperfusion. These results suggest that activation of cardiac A2b receptors at reperfusion is protective, but because of the very low affinity of the receptors endogenous cardiac adenosine is unable to trigger their signaling. We propose that the key protective event in IPC occurs when PKC increases the heart's sensitivity to adenosine so that endogenous adenosine can activate A2b-dependent signaling.
adenosine A2b receptors; BAY 60-6583; NECA; preconditioning; protein kinase C
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Ischemia-reperfusion injury of the retina is linked to necroptosis via the ERK1/2-RIP3 pathway
Gao, Sheng
Andreeva, Kalina
Cooper, Nigel G. F.
Molecular Vision
Ischemia-reperfusion (IR) injury is involved in the pathology of many retinal disorders since it contributes to the death of retinal neurons and the subsequent decline in vision. We determined the molecular patterns of some of the principal molecules involved in necroptosis and investigated whether IR retinal injury is associated with the extracellular signal-regulated kinase-1/2- receptor-interacting protein kinase 3 (ERK1/2-RIP3) pathway.
The cellular and subcellular localization of molecules involved in the cell death pathway, including RAGE, ERK1/2, FLIP, and RIP3, was determined with immunohistochemistry of cryosections of IR-injured retina from 2-month-old Long Evans rats. The total and phosphorylated protein levels were analyzed with quantitative western blots. ERK1/2 activity was inhibited by intravitreal injection of U0126, a highly selective inhibitor of mitogen-activated protein kinase 1/2 (MEK1/2).
The IR-injured rat retinas expressed two RAGE isoforms with different intracellular localizations at early time points after injury. At that time point, frame inhibition of ERK activation decreased RIP3 accumulation and cell death. FLIP was detected in the IR-injured rat retinas at early time points after ischemia reperfusion.
We report that the necroptotic cell death mechanism is executed by an ERK1/2-RIP3 pathway in the retinal ganglion cells in early stages after IR injury. Inhibition of ERK1/2 activity increased retinal ganglion cell (RGC) survival indicating that targeting of this pathway within the initial 12 h after IR injury can be used to inhibit the necroptosis pathway. We also provide evidence that a novel RAGE isoform is expressed in the early stages in rat retinal RGCs.
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Differential Effects of Delta and Epsilon Protein Kinase C in Modulation of Postischemic Cerebral Blood Flow
Lin, Hung Wen
Della-Morte, David
Thompson, John W.
Gresia, Victoria L.
Narayanan, Srinivasan V.
DeFazio, R. Anthony
Raval, Ami P.
Saul, Isabel
Dave, Kunjan R.
Morris, Kahlilia C.
Si, Min-Liang
Perez-Pinzon, Miguel
Advances in experimental medicine and biology
Cerebral ischemia causes cerebral blood flow (CBF) derangements resulting in neuronal damage by enhanced protein kinase C delta (δPKC) levels leading to hippocampal and cortical neuronal death after ischemia. Contrarily, activation of εPKC mediates ischemic tolerance by decreasing vascular tone providing neuroprotection. However, whether part of this protection is due to the role of differential isozymes of PKCs on CBF following cerebral ischemia remains poorly understood. Rats pretreated with a δPKC specific inhibitor (δV1-1, 0.5 mg/kg) exhibited attenuation of hyperemia and latent hypoperfusion characterized by vasoconstriction followed by vasodilation of microvessels after two-vessel occlusion plus hypotension. In an asphyxial cardiac arrest (ACA) model, rats treated with δ V1-1 (pre- and postischemia) exhibited improved perfusion after 24 h and less hippocampal CA1 and cortical neuronal death 7 days after ACA. On the contrary, εPKC-selective peptide activator, conferred neuroprotection in the CA1 region of the rat hippocampus 30 min before induction of global cerebral ischemia and decreased regional CBF during the reperfusion phase. These opposing effects of δ v. εPKC suggest a possible therapeutic potential by modulating CBF preventing neuronal damage after cerebral ischemia.
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p90RSK activation contributes to cerebral ischemic damage via phosphorylation of Na+/H+ exchanger isoform 1
Manhas, Namratta
Shi, Yejie
Taunton, Jack
Sun, Dandan
Journal of neurochemistry
Excessive activation of Na+/H+ exchanger isoform 1 (NHE-1) plays a role in cerebral ischemic injury. The current study investigated whether NHE-1 protein in ischemic brains is regulated by extracellular signal-regulated kinase (ERK)/90-kDa ribosomal S6 kinase (p90RSK) signaling pathways. A transient focal ischemia in mice was induced by a 60 min-occlusion of the middle cerebral artery followed by reperfusion for 3, 10, or 60 min (Rp). Expression of phosphorylated ERK 1/2 was significantly elevated in the ipsilateral hemispheres at 3 – 10 min Rp and reduced by 60 min Rp. An increase in phosphorylation of p90RSK, a known NHE-1 kinase, was also detected at 3 – 10 min Rp, which was accompanied with a transient elevation of NHE-1 phosphorylation (p-NHE-1). Stimulation of p90RSK in ischemic neurons was downstream of ERK activation because inhibition of MEK1 (MAP kinase/ERK kinase) with its inhibitor U0126 blocked phosphorylation of p90RSK. Moreover, direct inhibition of p90RSK by its selective inhibitor FMK not only reduced p-NHE-1 expression but also ischemic infarct volume. Taken together, our study revealed that reperfusion triggers a transient stimulation of the ERK/p90RSK pathway. p90RSK activation contributes to cerebral ischemic damage in part via activation of NHE-1 protein.
brain damage; transient cerebral ischemia; reperfusion; U0126; FMK
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Nociceptive-induced Myocardial Remote Conditioning Is Mediated By Neuronal Gamma Protein Kinase C
Gross, Eric R.
Hsu, Anna K.
Urban, Travis J.
Mochly-Rosen, Daria
Gross, Garrett J.
Basic research in cardiology
Deciphering the remote conditioning molecular mechanism may provide targets to develop therapeutics that can broaden the clinical application. To further investigate this, we tested whether two protein kinase C isozymes, the ubiquitously expressed epsilon PKC (εPKC) and the neuronal specific gamma PKC (γPKC), mediate nociceptive-induced remote myocardial conditioning.
Male Sprague-Dawley rats were used for both in vivo and ex vivo myocardial ischemia-reperfusion protocols. For the in vivo studies, using a surgical abdominal incision for comparison, applying only to the abdomen either bradykinin or the εPKC activator (ψεRACK) reduced myocardial infarct size (45±1%, 44±2%, respectively, versus incision: 43±2%, and control: 63±2%, P < 0.001). Western blot showed only εPKC, and not γPKC, is highly expressed in the myocardium. However, applying a selective γPKC inhibitor (γV5-3) to the abdominal skin blocked remote protection by any of these strategies.
Using an ex vivo isolated heart model without an intact nervous system, only selective εPKC activation, unlike a selective classical PKC isozyme activator (activating α, β, βII and γ), reduced myocardial injury. Importantly, the classical PKC isozyme activator given to the abdomen in vivo (with an intact nervous system including γPKC) during myocardial ischemia reduced infarct size as effectively as an abdominal incision or ψεRACK (45±1% versus 45±2% and 47±1%, respectively). The classical PKC activator-induced protection was also blocked by spinal cord surgical transection.
These findings identified potential remote conditioning mimetics, with these strategies effective even during myocardial ischemia. A novel mechanism of nociceptive-induced remote conditioning, involving γPKC, was also identified.
infarct size; remote; incision; protein kinase C; gamma; epsilon
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Activation of εPKC Reduces Reperfusion Arrhythmias and Improves Recovery from Ischemia: Optical Mapping of Activation Patterns in the Isolated Guinea-pig Heart
Restivo, Mark
Kozhevnikov, Dmitry O.
Qu, Yongxia
Yue, Yuankun
Rosen, Daria-Mochly
El-Sherif, Nabil
Boutjdir, Mohamed
Biochemical and biophysical research communications
Pervious biochemical and hemodymanic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias.
Protein transduction domain from HIV- TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30 min stabilization period, 15 min of no-flow ischemia, followed by 20 min reperfusion. Peptides (0.5 μM) were infused as follows: a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); b) εPKC agonist (TAT-ψεRACK); c) εPKC antagonist (TAT-εV1).
Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, p<0.05) and (VF, 70%, P<0.05). However, the highest incidence of VT (100%, P<0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20 min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (p<0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P<0.5) of hearts in control. At 20 min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2±9 ms) compared to exacerbated dispersion (115.4±42 ms, P<0.05) in εPKC antagonist and control (67±20 ms, P<0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control.
In conclusion
the results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents.
cardiac electrophysiology; Protein Kinase C; reperfusion arrhythmia; optical mapping
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Derangements of Post-ischemic Cerebral Blood Flow by Protein Kinase C Delta
Lin, Hung Wen
DeFazio, R. Anthony
DellaMorte, David
Thompson, John W.
Narayanan, Srinivasan V.
Raval, Ami P.
Saul, Isabel
Dave, Kunjan R.
Perez-Pinzon, Miguel A.
Cerebral ischemia causes blood flow derangements characterized by hyperemia (increased cerebral blood flow, CBF) and subsequent hypoperfusion (decreased CBF). We previously demonstrated that protein kinase C delta (δPKC) plays an important role in hippocampal neuronal death after ischemia. However, whether part of this protection is due to the role of δPKC on CBF following cerebral ischemia remains poorly understood. We hypothesized that δPKC exacerbates hyperemia and subsequent hypoperfusion resulting in CBF derangements following ischemia. Sprague-Dawley (SD) rats pretreated with a δPKC specific inhibitor (δV1-1, 0.5 mg/kg) exhibited attenuation of hyperemia and latent hypoperfusion characterized by vasoconstriction followed by vasodilation of microvessels after 2-vessel occlusion plus hypotension measured by 2-photon microscopy. In an asphyxial cardiac arrest model (ACA), SD rats treated with δV1-1 (pre- and post-ischemia) exhibited improved perfusion after 24 hrs and less hippocampal CA1 neuronal death 7 days after ACA. These results suggest possible therapeutic potential of δPKC in modulating CBF and neuronal damage after cerebral ischemia.
Protein Kinase C Delta; Asphyxial Cardiac Arrest; Neuroprotection; Two-vessel Occlusion; Two-photon Microscopy; Cerebral Ischemia
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Hypercholesterolemic Myocardium Is Vulnerable to Ischemia-Reperfusion Injury and Refractory to Sevoflurane-Induced Protection
Xu, Yong
Ma, Lei-Lei
Zhou, Chen
Zhang, Fei-Jiang
Kong, Fei-Juan
Wang, Wen-Na
Qian, Ling-Bo
Wang, Can-Can
Liu, Xian-Bao
Yan, Min
Wang, Jian-An
PLoS ONE
Recent studies have demonstrated that volatile anesthetic postconditioning confers myocardial protection against ischemia-reperfusion (IR) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been shown to be impaired in hypercholesterolemia. Therefore, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats. In the present study, normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane for 5 min or 3 cycles of 10-s ischemia/10-s reperfusion. The hemodynamic parameters, including left ventricular developed pressure, left ventricular end-diastolic pressure and heart rate, were continuously monitored. The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined. We found that both sevoflurane and ischemic postconditioning significantly improved heart pump function, reduced infarct size and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β in the healthy rats. In the hypercholesterolemic rats, neither sevoflurane nor ischemic postconditioning improved left ventricular hemodynamics, reduced infarct size and increased the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts. In conclusions, hyperchoesterolemia abrogated sevoflurane-induced cardioprotection against IR injury by alteration of upstream signaling of GSK3β and acute GSK inhibition may provide a novel therapeutic strategy to protect hypercholesterolemic hearts against IR injury.
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text:
Hi, am looking for some good stores to buy some frocks and other clothes. Which one you ladies recommend?
girls outfits
Posted 02/11/2013
Hey Aysha where are you from.your name sounds familiar.
Chk macys too they got some good dresses.
Chk macys too they got some good dresses.
Ayeshahassankhan · Original Poster
Posted 02/11/2013
Thank you. I am going to check these places.
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text:
Looking for apartment to stay in from july6th for 4 nights somewhere on Italian Lakes. Finishing up a 6week trip and coming from Venice after a 7 night cruise. Thinking of spending 1 night in Verona, 4 in lakes and 1 im Milan as we fly out of there 12.00 lunch time. Spent hours trolling through sites. Found some in Aregegna, lake como. Would this be a good spot to base ourselves?We won't have a car so need to be somewhere close to ferries, train etc. Has anyone stayed here before and can recommend a good place to stay with beautiful views or anywhere that's better?
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Bellagio...www.residencelalimonera.com. Or Residence L'Ulivo, with access to the luxury hotel property Villa Serbelloni.
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We stayed in Arona on Lake Maggiore because it is very close to Malpensa Airport which is quite a ways from Milan city center and actually closer to Arona. If you were to do Verona, Milan etc. first then make the lakes your last stay, it's an easy train/bus ride from Arona to Malpensa esp. as it's a mid-day flight.
I can't speak for Lake Como as I've not been there and many may prefer it for scenery but for ease of getting to Malpensa, somewhere on the southern end of Lake Maggiore is a good choice.
We did a lake cruise from Arona to Locarno Switzerland which was quite long but relaxing and full of great scenery then a train ride back through Domodossola. It was a very nice relaxing way to end our Italy stay. And we were so close to our flight home at Malpensa.
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text: Home > Regions Plane crashlands at Loakan ABS-CBN News Posted at Aug 05 2010 11:15 AM | Updated as of Aug 06 2010 01:28 AM Share Facebook Twitter GPlus LinkedIn Pinterest MANILA, Philippines (2nd UPDATE) - A training aircraft crash-landed at the Loakan Airport in Baguio City on Thursday morning. An initial report from the Civil Aviation Authority of the Philippines (CAAP) said an RPC 8864 Cessna 152 training aircraft crash-landed at the airport at 9:27 a.m.. It said that its occupants, Captain Glen Pedraha and student pilot Paul Burns, sustained minor injuries. They were rushed to the PMA General Hospital. The training aircraft is reportedly owned by the Omni Aviation School based in Clark, Pampanga. -- with a report from Dhobbie de Guzman, ABS-CBN Baguio Share Facebook Share on Twitter GPlus LinkedIn Pinterest Read More: crash plane crash loakan airport /news/07/26/16/look-drug-surrenderees-play-basketball-with-prisoners/news/07/26/16/pope-francis-appoints-new-bishop-of-kidapawan/life/07/26/16/kailan-dapat-pa-operahan-ang-bingot/life/07/26/16/women-more-prone-to-acl-injuries-than-men-studies/video/news/07/26/16/curfew-sa-3-lungsod-ipinatitigil-ng-korte-suprema


text:
At the moment, I'm not - 0.4.1.5 Windows, 0.4.13 Ubuntu. But I had the
same problem with 0.4.14 Windows and 0.4.13 Windows. This suggests
there's something actually wrong.
On 30 November 2013 20:17, Tres Finocchiaro <firstname.lastname@example.com> wrote:
> Sorry, I completely misunderstood your problem.
> Yes, I've had issues similar to that, where it forgot the patch number the
> sound was on. ĀHave you confirmed you are on the exact same version of LMMS
> on both computers?
> If you deffinitely are, this is almost deffinitely a bug and one I've seen
> before. ĀThe reason few people complain is that many soundfonts only have a
> few patches. ĀYou are using one with many many patches, so it's frustrating.
> Can you confirm that a project created with windows fails to work in linux
> as well?
> -Tres