At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Therapeutic potential of resveratrol: the in vivo evidence.

I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

Methods in Enzymology.

The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration

The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics

There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the β-oxidation of long-chain fatty acids. The control of fatty acid β-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via β-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and β-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid β-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid β-oxidation and how alterations in fatty acid β-oxidation can contribute to heart disease. The implications of inhibiting fatty acid β-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.

Myocardial Fatty Acid Metabolism in Health and Disease

Epidemiological studies suggest that the consumption of wine, particularly of red wine, reduces the incidence of mortality and morbidity from coronary heart disease. This has given rise to what is now popularly termed the "French paradox". The cardioprotective effect has been attributed to antioxidants present in the polyphenol fraction of red wine. Grapes contain a variety of antioxidants, including resveratrol, catechin, epicatechin and proanthocyanidins. Of these, resveratrol is present mainly in grape skin while proanthocyanidin is present in the seeds. In this report, we provide evidence that red wine extract as well as resveratrol and proanthocyanidins are equally effective in reducing myocardial ischemic reperfusion injury, which suggests that these red wine polyphenolic antioxidants play a crucial role in cardioprotection.

Cardioprotection of red wine: role of polyphenolic antioxidants.

Background—Reperfusion of ischemic myocardium causes cardiomyocyte apoptosis in concert with downregulation of Bcl-2 gene. Ischemic preconditioning (PC) mediated by cyclic episodes of short-term ischemia and reperfusion reduces apoptotic cell death. PC also triggers a signaling pathway by potentiating tyrosine kinase phosphorylation leading to the activation of p38 MAP kinase and MAPKAP kinase 2. The nuclear transcription factor, NFκB, plays a crucial role in this signaling process. Because NFκB is a target of oxygen free radicals and Bcl-2 is an antioxidant gene, we hypothesized that reactive oxygen species might play a role in the signaling process. Methods and Results—Isolated rat hearts were perfused in the absence or presence of either dimethyl thiourea (DMTU), a hydroxyl radical scavenger, or SN50 peptide, a NFκB blocker. Hearts were then subjected to PC by 4 repeated episodes of 5-minute ischemia, each followed by 10 minutes reperfusion. All hearts were then made globally ischemic at normothermia f...

Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2.

This review describes the dose-dependent health benefits of resveratrol, a polyphenolic antioxidant that is found in a variety of foods, especially grape skin and red wine. Resveratrol provides diverse health benefits including cardioprotection, inhibition of low-density lipoprotein, activation of nitric oxide (NO) production, hindering of platelet aggregation [32] A.A.E. Bertelli, D.E. Giovannini, R.L. Caterina, W. Bernini, M. Migliori and M. Fregoni et al., Antiplatelet activity of cis-resveratrol, Drugs Exp Clin Res 22 (1996), pp. 61-63. View Record in Scopus | Cited By in Scopus (111) and promotion of anti-inflammatory effects. Studies have shown that at a lower dose, resveratrol acts as an anti-apoptotic agent, providing cardioprotection as evidenced by increased expression in cell survival proteins, improved postischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis and maintains a stable redox environment compared to control. At higher dose, resveratrol acts as a pro-apoptotic compound, inducing apoptosis in cancer cells by exerting a death signal. At higher doses, resveratrol depresses cardiac function, elevates levels of apoptotic protein expressions, results in an unstable redox environment, increases myocardial infarct size and number of apoptotic cells. At high dose, resveratrol not only hinders tumor growth but also inhibits the synthesis of RNA, DNA and protein, causes structural chromosome aberrations, chromatin breaks, chromatin exchanges, weak aneuploidy, higher S-phase arrest, blocks cell proliferation, decreases wound healing, endothelial cell growth by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor, and angiogenesis in healthy tissue cells leading to cell death. Thus, at lower dose, resveratrol can be very useful in maintaining the human health whereas at higher dose, resveratrol has pro-apoptotic actions on healthy cells, but can kill tumor cells.

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Dose-Dependency of Resveratrol in Providing Health Benefits:

Objective: The molecular mechanism of preconditioning the heart by repeated ischaemia was investigated by examining the expression of stress related and antioxidative genes and proteins. Methods: Isolated buffer-perfused rat hearts were made ischaemic for 5 min followed by 10 min of reperfusion (1×PC). Another group of experiments was performed by repeating the ischaemia/reperfusion episode four times (4×PC). Both 1×PC and 4×PC groups were reperfused for 60 min. Control experiments were performed by perfusing the hearts with buffer using the same time frame, but without ischaemia/reperfusion. The induction of the expression of two oncogenes (c-fos and c-myc), three heat shock protein (HSP) genes (HSP 27, HSP 70, and HSP 89 mRNAs) and two antioxidative enzyme genes (Mn-superoxide dismutase (SOD) and catalase mRNAs) by northern hybridisation, as well as the activities of four major antioxidative enzymes (SOD, catalase, glutathione peroxidase, and glutathione reductase) were examined in control and 1×PC and 4×PC hearts. In addition, 2-D gel electrophoresis of the proteins in all groups was performed to examine the induction of any new protein. Myocardial preservation was studied by examining left ventricular functions. Results: Northern hybridisation detected enhanced level of c-fos 2.2 kb mRNA and c-myc 2.4 kb mRNA in 4XPC hearts after 60 min of reperfusion, induction being stronger for c-fos. I× PC hearts showed minimal expression of c-fos mRNA, but not c-myc mRNA. 4×PC hearts also showed the induction of HSP 27, HSP 70, and HSP 89 mRNAs as well as catalase and Mn-SOD mRNAs, whereas 1×PC hearts showed some induction of HSP 70 mRNA and catalase mRNA only. 2-D gel electrophoresis revealed the expression of 15-20 new proteins in 4×PC hearts only. The activities of three major antioxidative enzymes, Mn-SOD, peroxisomal catalase, and glutathione peroxidase, but not Cu/Zn-SOD, cytosolic catalase, and glutathione reductase, were enhanced after 60 min of reperfusion in 4×PC hearts only compared to both 1×PC and baseline values. 4×PC hearts, but not 1×PC hearts, showed reduction of subsequent myocardial ischaemic and reperfusion injury. Conclusions: Repeated ischaemia and reperfusion (4×PC), and not 1×PC, caused the induction of several stress related and antioxidant genes including HSP 27, 70, and 89 genes, Mn-SOD and catalase genes, and proto-oncogenes (c-fos and c-myc), as well as the expression of several stress inducible proteins and stimulation of three antioxidative enzymes, Mn-SOD, peroxisomal catalase, and glutathione peroxidase, simultaneously protecting the heart from subsequent ischaemia-reperfusion injury. The expression of stress inducible and antioxidant genes and stimulation of antioxidant enzyme activities may reflect the heart's response enabling it to survive against ischaemic stress by eliminating the oxidative assault.

Cardiovascular Research 1993; 27 :578-584

Dipak K. Das

Papers

Cardioprotection of red wine: role of polyphenolic antioxidants.

Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2.

Dose-Dependency of Resveratrol in Providing Health Benefits:

Molecular adaptation of cellular defences following preconditioning of the heart by repeated ischaemia

Role of STAT3 in Ischemic Preconditioning