			Home About us Contact

Pleiotropic Mechanism (pleiotropic + mechanism)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Epigenetic gambling and epigenetic drift as an antagonistic pleiotropic mechanism of aging

AGING CELL, Issue 6 2009
George M. Martin
Summary Generations of biogerontologists have been puzzled by the marked intraspecific variations in lifespan of their experimental model organisms despite all efforts to control both genotype and environment. The most cogent example comes from life table studies of wild-type Caenorhabditis elegans when grown in suspension cultures using axenic media. While nuclear and mitochondrial somatic mutations and ,thermodynamic noise' likely contribute to such lifespan variegations, I raise an additional hypothetical mechanism, one that may have evolved as a mechanism of phenotypic variation which could have preceded the evolution of meiotic recombination. I suggest that random changes in cellular gene expression (cellular epigenetic gambling or bet hedging) evolved as an adaptive mechanism to ensure survival of members of a group in the face of unpredictable environmental challenges. Once activated, it could lead to progressive epigenetic variegation (epigenetic drift) amongst all members of the group. Thus, while particular patterns of gene expression would be adaptive for a subset of reproductive individuals within a population early in life, once initiated, I predict that continued epigenetic drift will result in variable onsets and patterns of pathophysiology , perhaps yet another example of antagonistic pleiotropic gene action in the genesis of senescent phenotypes. The weakness of this hypothesis is that we do not currently have a plausible molecular mechanism for the putative genetic ,randomizer' of epigenetic expression, particularly one whose ,setting' may be responsive to the ecology in which a given species evolves. I offer experimental approaches, however, to search for the elusive epigenetic gambler(s). [source]

Re-assessing the relationship between cholesterol, statins and Alzheimer's disease

ACTA NEUROLOGICA SCANDINAVICA, Issue 2006
B. Wolozin
This communication integrates the purported role of cholesterol and statins in Alzheimer's disease (AD) with recent data. Meta-analysis of association studies relevant to AD indicates that apolipoprotein (apo)E4 is the only cholesterol-related polymorphism that shows clear association with AD. This suggests that the effect of apoE4 on the pathophysiology of AD occurs via a mechanism that is not directly related to cholesterol, such as fibrillization of A,. Despite the lack of genetic association, cholesterol and statins clearly modulate amyloid precursor protein (APP) processing in cell culture and animal models. Statins appear to act by a pleiotropic mechanism, involving both cholesterol (via lipid rafts) and isoprenylation. The pleiotropic mechanism of statin action clarifies conflicting data from clinical studies, where statins exert an action on A, and AD that might be dose dependent because of actions on both cholesterol and isoprenylation. Reduced isoprenylation can also inhibit inflammation. Our own studies of brains from Alzheimer subjects ± statins indicate that statins inhibit inflammation in humans but might not reduce cerebral A, load. These results suggest that the primary action of statins in humans with AD might be to reduce inflammation rather than decrease A, load. [source]

Therapeutic effect of statin on aortic stenosis: a review with meta-analysis

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2010
H. Ge MD
Background:, Aortic stenosis (AS) is a common progressive disease. Statins have been hypothesized to delay its progression via pleiotropic mechanisms. However, results of clinical trials focusing on statin therapy in AS patients have been controversial. Objective:, To analyse and summarize the findings in recent statin trials and to discuss the rationale of statin usage in AS populations. Methods:, A comprehensive database search was conducted by two independent reviewers. Controlled trials that compared progression of AS between statin and non-statin therapy published before 31 December 2008 were included. Data were extracted for meta-analysis, to estimate overall effects, if available. Factors that contributed to heterogeneities among the trials were analysed. Results:, The meta-analysis included nine trials with a total of 2947 patients. Statin therapy displayed an overall statistically significant effect on delaying AS progression. The weighted mean difference (statin vs. control) of annual increase of peak aortic-jet velocity was ,0·12 m/s (95% confidence interval ,0·22 to ,0·03); the increase of mean transaortic pressure gradient was ,1·64 mmHg per year (,3·27 to ,0·01); Heterogeneity-analysis suggested that the baseline risk factors and characteristics of the patients, the use of different statins, and the time point to initiate statin therapy, may be important considerations when interpreting the result of individual studies. Conclusion:, Although the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial reported negative results in delaying AS progression in low-risk patients, the potential benefits of statins in those with multiple risk factors and their value in preventing future coronary events call for further investigation of different categories of AS patients. [source]

The Effect of Rosuvastatin on Insulin Sensitivity and Pancreatic Beta-Cell Function in Nondiabetic Renal Transplant Recipients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2009
A. Sharif
Interventions to attenuate abnormal glycemia posttransplantation are required. In addition, surrogate markers of declining glycemic control are valuable. Statins may have pleiotropic properties that attenuate abnormal glucose metabolism. We hypothesized statins would improve glucose metabolism and HbA1c would be advantageous as a surrogate for worsening glycemia. We conducted a prospective, randomized, placebo controlled, crossover study in 20 nondiabetic renal transplant recipients at low risk for NODAT and compared effects of rosuvastatin on insulin secretion/sensitivity. Mathematical model analysis of an intravenous glucose tolerance test determined first-phase insulin secretion, insulin sensitivity and disposition index. Second-phase insulin secretion was determined with a meal tolerance test. Biochemical/clinical parameters were also assessed. Rosuvastatin significantly improved total cholesterol (,30%, p < 0.001), LDL cholesterol (,44%, p < 0.001) and triglycerides (,19%, p = 0.013). C-reactive protein decreased but failed to achieve statistical significance (,31%, p = 0.097). Rosuvastatin failed to influence any glycemic physiological parameter, although an inadequate timeframe to allow pleiotropic mechanisms to clinically manifest raises the possibility of a type II statistical error. On multivariate analysis, glycated hemoglobin (HbA1c) correlated with disposition index (R2= 0.201, p = 0.006), first-phase insulin secretion (R2= 0.106, p = 0.049) and insulin sensitivity (R2= 0.136, p = 0.029). Rosuvastatin fails to modify glucose metabolism in low-risk patients posttransplantation but HbA1c is a useful surrogate for declining glycemic control. [source]