There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.
"Emerging evidence indicates that resveratrol increases mitochondrial biogenesis and reduces oxidative stress in a wide variety of age-associated disease models. It has been demonstrated that resveratrol induces mitochondrial biogenesis and ameliorates angiotensin II-induced cardiac remodeling through the activation of SIRT1, PGC-1α, and NRF . Csiszar et al.  demonstrated that resveratrol induced activation of PGC-1α and NRF, increased mitochondrial mass and mitochondrial DNA content, and upregulated protein expression of the ETC constituents in endothelial cells. "
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress has been implicated in pathophysiology of aging and age-associated disease. Antioxidative medicine has become a practice for prevention of atherosclerosis. However, limited success in preventing cardiovascular disease (CVD) in individuals with atherosclerosis using general antioxidants has prompted us to develop a novel antioxidative strategy to prevent atherosclerosis. Reducing visceral adipose tissue by calorie restriction (CR) and regular endurance exercise represents a causative therapy for ameliorating oxidative stress. Some of the recently emerging drugs used for the treatment of CVD may be assigned as site-specific antioxidants. CR and exercise mimetic agents are the choice for individuals who are difficult to continue CR and exercise. Better understanding of molecular and cellular biology of redox signaling will pave the way for more effective antioxidative medicine for prevention of CVD and prolongation of healthy life span.
Oxidative Medicine and Cellular Longevity 04/2013; 2013(8):936436. DOI:10.1155/2013/936436 · 3.36 Impact Factor
"Proteins in this system are thought as important regulators of blood pressure and are involved in the onset of hypertension [29-32]. Overexpression of REN leads to hypertension via chronic overproduction of AngII [33,34], and inhibiting the regulators of the RAS--such as REN--is a common treatment for hypertension . Adiponectin (ADIPOQ) is an adipocytokine synthesized by the adipose tissue. "
[Show abstract][Hide abstract] ABSTRACT: Background
Answering questions such as "Which genes are related to breast cancer?" usually requires retrieving relevant publications through the PubMed search engine, reading these publications, and creating gene lists. This process is not only time-consuming, but also prone to errors.
We report GLAD4U (Gene List Automatically Derived For You), a new, free web-based gene retrieval and prioritization tool. GLAD4U takes advantage of existing resources of the NCBI to ensure computational efficiency. The quality of gene lists created by GLAD4U for three Gene Ontology (GO) terms and three disease terms was assessed using corresponding "gold standard" lists curated in public databases. For all queries, GLAD4U gene lists showed very high recall but low precision, leading to low F-measure. As a comparison, EBIMed's recall was consistently lower than GLAD4U, but its precision was higher. To present the most relevant genes at the top of a list, we studied two prioritization methods based on publication count and the hypergeometric test, and compared the ranked lists and those generated by EBIMed to the gold standards. Both GLAD4U methods outperformed EBIMed for all queries based on a variety of quality metrics. Moreover, the hypergeometric method allowed for a better performance by thresholding genes with low scores. In addition, manual examination suggests that many false-positives could be explained by the incompleteness of the gold standards. The GLAD4U user interface accepts any valid queries for PubMed, and its output page displays the ranked gene list and information associated with each gene, chronologically-ordered supporting publications, along with a summary of the run and links for file export and functional enrichment and protein interaction network analysis.
GLAD4U has a high overall recall. Although precision is generally low, the prioritization methods successfully rank truly relevant genes at the top of the lists to facilitate efficient browsing. GLAD4U is simple to use, and its interface can be found at: http://bioinfo.vanderbilt.edu/glad4u.
"Mitochondrial fusion and biogenesis have also been implicated in neuroprotective strategies against acute neural injury. Calpain inhibition provided neuroprotection against NMDA-induced neurotoxicity and was dependent on Opa-1, an enzyme critical for mitochondrial fusion (Jahani-Asl et al, 2011) Furthermore , induction of core elements of mitochondrial biogenesis have been observed using multiple preconditioning stimuli in neurons, such as sublethal hypoxia or hypoxia/ischemia (Gutsaeva et al, 2008), hyperbaric oxygen (Gutsaeva et al, 2006), and resveratrol (Dasgupta and Milbrandt, 2007; Biala et al, 2010). These stimuli have been well documented as neuroprotective strategies against acute brain injury, including cerebral ischemia and glutamate excitotoxicity. "
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca(2+) overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O(2) and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca(2+)-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2012; 32(7):1362-76. DOI:10.1038/jcbfm.2012.32 · 5.41 Impact Factor
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