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Various Insults (various + insult)
Selected AbstractsNeuronal protection by sirtuins in Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Thimmappa S. Anekonda Abstract Silent information regulator 2, a member of NAD+ -dependent histone deacetylase in yeast, and its homologs in mice and humans, participate in numerous important cell functions, including cell protection and cell cycle regulation. The sirtuin family members are highly conserved evolutionarily, and are predicted to have a role in cell survival. The science of sirtuins is an emerging field and is expected to contribute significantly to the role of sirtuins in healthy aging in humans. The role of sirtuins in neuronal protection has been studied in lower organisms, such as yeast, worms, flies and rodents. Both yeast Sir2 and mammalian sirtuin proteins are up-regulated under calorie-restricted and resveratrol treatments. Increased sirtuin expression protects cells from various insults. Caloric restriction and antioxidant treatments have shown useful effects in mouse models of aging and Alzheimer's disease (AD) and in limited human AD clinical trials. The role sirtuins may play in modifying and protecting neurons in patients with neurodegenerative diseases is still unknown. However, a recent report of Huntington's disease revealed that Sirtuin protects neurons in a Huntington's disease mouse model, suggesting that sirtuins may protect neurons in patients with neurodegenerative diseases, such as AD. In this review, we discuss the possible mechanisms of sirtuins involved in neuronal protection and the potential therapeutic value of sirtuins in healthy aging and AD. [source] Gene therapy approaches for Parkinson's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2003P. Aebischer The CNS delivery of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease constitutes one of the more promising clinical applications of neurotrophic factors. Crucial for clinical application will be the ability to deliver GDNF within the target structures, i.e. striatum and/or substantia nigra. We are developing both in vivo and ex vivo gene therapy approaches to reach this goal. We have shown in rodents that both lentiviral vectors coding for GDNF and polymer encapsulated cells genetically engineered to release GDNF are able to protect nigral dopaminergic neurons against various insults including axotomy and neurotoxins such as 6-hydroxydopamine. Even more important for clinical application is the ability to scale-up the technology to nonhuman primate application. Neurorestorative and/or neuroprotective properties of GDNF expression were demonstrated with both methods in various nonhuman primate models. [source] Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor ,,THE JOURNAL OF PATHOLOGY, Issue 4 2007F Fortunato Abstract Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber,DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNF,, IL-1,, IL-18, TGF,, and MCP-1. In addition, alcohol significantly increased the activity of PPAR,, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NF,B binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPAR,. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Disruption of gap junctions attenuates aminoglycoside-elicited renal tubular cell injuryBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2010Jian Yao BACKGROUND AND PURPOSE Gap junctions play important roles in the regulation of cell phenotype and in determining cell survival after various insults. Here, we investigated the role of gap junctions in aminoglycoside-induced injury to renal tubular cells. EXPERIMENTAL APPROACH Two tubular epithelial cell lines NRK-E52 and LLC-PK1 were compared for gap junction protein expression and function by immunofluorescent staining, Western blot and dye transfer assay. Cell viability after exposure to aminoglycosides was evaluated by WST assay. Gap junctions were modulated by transfection of the gap junction protein, connexin 43 (Cx43), use of Cx43 siRNA and gap junction inhibitors. KEY RESULTS NRK-E52 cells expressed abundant Cx43 and were functionally coupled by gap junctional intercellular communication (GJIC). Exposure of NRK-E52 cells to aminoglycosides, G418 and hygromycin, increased Cx43 phosphorylation and GJIC. The aminoglycosides also decreased cell viability that was prevented by gap junction inhibitors and Cx43 siRNA. LLC-PK1 cells were gap junction-deficient and resistant to aminoglycoside-induced cytotoxicity. Over-expression of a wild-type Cx43 converted LLC-PK1 cells to a drug-sensitive phenotype. The gap junction inhibitor ,-glycyrrhetinic acid (,-GA) activated Akt in NRK-E52 cells. Inhibition of the Akt pathway enhanced cell toxicity to G418 and abolished the protective effects of ,-GA. In addition, gentamycin-elicited cytotoxicity in NRK-E52 cells was also significantly attenuated by ,-GA. CONCLUSION AND IMPLICATIONS Gap junctions contributed to the cytotoxic effects of aminoglycosides. Modulation of gap junctions could be a promising approach for prevention and treatment of aminoglycoside-induced renal tubular cell injury. [source] | ||||||||||