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Exact Molecular Mechanisms (exact + molecular_mechanism)
Selected AbstractsWhen machines get stuck,obstructed RNA polymerase II: displacement, degradation or suicideBIOESSAYS, Issue 9 2002Vincent van den Boom The severe hereditary progeroid disorder Cockayne syndrome is a consequence of a defective transcription-coupled repair (TCR) pathway. This special mode of DNA repair aids a RNA polymerase that is stalled by a DNA lesion in the template and ensures efficient DNA repair to permit resumption of transcription and prevent cell death. Although some key players in TCR, such as the Cockayne syndrome A (CSA) and B (CSB) proteins have been identified, the exact molecular mechanism still remains illusive. A recent report provides new unexpected insights into TCR in yeast.1 The identification and characterisation of a novel protein co-purifying with the yeast homologue of CSB (Rad26) imposes reassessment of our current understanding of TCR in yeast. What about humans? BioEssays 24:780,784, 2002. © 2002 Wiley Periodicals, Inc. [source] Point of View: Could glucose be a proaging factor?JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2008Eva Kassi Abstract There is an ever-increasing scientific interest for the interplay between cell's environment and the aging process. Although it is known that calorie restriction affects longevity, the exact molecular mechanisms through which nutrients influence various cell signalling/modulators of lifespan remain a largely unresolved issue. Among nutrients, glucose constitutes an evolutionarily stable, precious metabolic fuel, which is catabolized through glycolytic pathway providing energy in the form of ATP and consuming NAD. Accumulating evidence shows that among the important regulators of aging process are autophagy, sirtuin activity and oxidative stress. In light of recent work indicating that glucose availability decreases lifespan whilst impaired glucose metabolism extends life expectancy, the present article deals with the potential role of glucose in the aging process by regulating , directly through its metabolism or indirectly through insulin secretion , autophagy, sirtuins as well as other modulators of aging like oxidative stress and advanced glycation end-products (AGEs). [source] The radical scavenger CR-6 protects SH-SY5Y neuroblastoma cells from oxidative stress-induced apoptosis: effect on survival pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Nuria Sanvicens Abstract Reactive oxygen species (ROS) and oxidative stress have long been linked to cell death of neurons in many neurodegenerative conditions. However, the exact molecular mechanisms triggered by oxidative stress in neurodegeneration are at present unclear. In the current work we have used the human neuroblastoma SH-SY5Y cell line as a model for studying the molecular events occurring after inducing apoptosis with H2O2. We show that treatment of SH-SY5Y cells with H2O2 up-regulates survival pathways during early stages of apoptosis. Subsequently, the decline of anti-apoptotic protein levels leads to the activation of the calcium-dependent proteases calpains and the cysteine proteases caspases. Additionally, we demonstrate that CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran) acts as a scavenger of ROS and prevents apoptosis by enhancing and prolonging up-regulation of survival pathways. Furthermore, we show that pre-treatment of SH-SY5Y cells with a cocktail containing CR-6, the pan-caspase inhibitor zVAD-fmk (zVal-Ala-Asp-fluoro-methylketone) and the calpain inhibitor SJA6017 confers almost total protection against apoptosis. In summary, the present work characterizes the molecular mechanisms involved in oxidative stress-induced apoptosis in SH-SY5Y cells. Our findings highlight the relevance of CR-6, alone or in combination with other drugs, as potential therapeutic strategy for the treatment of neurodegenerative diseases. [source] Alcohol-Induced Tolerance and Physical Dependence in Mice With Ethanol Insensitive ,1 GABAA ReceptorsALCOHOLISM, Issue 2 2009David F. Werner Background:, Although many people consume alcohol (ethanol), it remains unknown why some become addicted. Elucidating the molecular mechanisms of tolerance and physical dependence (withdrawal) may provide insight into alcohol addiction. While the exact molecular mechanisms of ethanol action are unclear, ,-aminobutyric acid type A receptors (GABAA -Rs) have been extensively implicated in ethanol action. The ,1 GABAA -R subunit is associated with tolerance and physical dependence, but its exact role remains unknown. In this report, we tested the hypothesis that ,1-GABAA -Rs mediate in part these effects of ethanol. Methods:, Ethanol-induced behavioral responses related to tolerance and physical dependence were investigated in knockin (KI) mice that have ethanol-insensitive ,1 GABAA -Rs and wildtype (WT) controls. Acute functional tolerance (AFT) was assessed using the stationary dowel and loss of righting reflex (LORR) assays. Chronic tolerance was assessed on the LORR, fixed speed rotarod, hypothermia, and radiant tail-flick assays following 10 consecutive days of ethanol exposure. Withdrawal-related hyperexcitability was assessed by handling-induced convulsions following 3 cycles of ethanol vapor exposure/withdrawal. Immunoblots were used to assess ,1 protein levels. Results:, Compared with controls, KI mice displayed decreased AFT and chronic tolerance to ethanol-induced motor ataxia, and also displayed heightened ethanol-withdrawal hyperexcitability. No differences between WT and KI mice were seen in other ethanol-induced behavioral measures. Following chronic exposure to ethanol, control mice displayed reductions in ,1 protein levels, but KIs did not. Conclusions:, We conclude that ,1-GABAA -Rs play a role in tolerance to ethanol-induced motor ataxia and withdrawal-related hyperexcitability. However, other aspects of behavioral tolerance and physical dependence do not rely on ,1-containing GABAA -Rs. [source] Influence of cigarette smoking on spermatozoa via seminal plasmaANDROLOGIA, Issue 4 2005M. Arabi Summary Numerous investigations have been conducted on the relationship between cigarette smoking and male infertility, however, the exact molecular mechanisms are not well understood in most of the cases. Few studies have indicated the direct effect of seminal plasma (SP) [in different dilutions with phosphate buffer solution (PBS)] from smokers (SM) on the sperm functional parameters from nonsmokers (non-SM). The aim of this study was to provide evidence that cigarette smoking affects male fertility via altering the sperm quality. Our results indicated that exposure of spermatozoa from the non-SM to the SP from the SM yielded a significant reduction in the sperm motility and acrosome reaction and an elevation in the amount of malondialdehyde (MDA), in a certain time course. Exposure of spermatozoa from the SM to the SP from the non-SM or with PBS resulted in the nonsignificant improvement in the altered sperm functional parameters indicating removal of SM's SP and then subsequent reconstitution with physiological media could be of clinical significance in the various assisted reproductive technologies applied for SM. However, the detrimental effect of SM's SP on non-SM's spermatozoa was prominent. In addition, as spermatozoa in SM's SP are susceptible to peroxidative damages, men with such cells who wish to have children should especially benefit from quitting smoking. 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