https://staff.blog.ui.ac.id/hsuryadi/files/2012/02/ROS_RNS.pdf

Free radicals and antioxidants in normal physiological functions and human disease

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

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

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.

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

Generation of survival signal by differential interaction of p38MAPKα and p38MAPKβ with caveolin-1 and caveolin-3 in the adapted heart

The effect of different isomers of tocotrienol was tested on myocardial ischemia reperfusion injury. Although all of the tocotrienol isomers offered some degree of cardioprotection, gamma-tocotrienol was the most protective as evident from the result of myocardial apoptosis. To study the mechanism of tocotrienol mediated cardioprotection, we examined the interaction and/or translocation of different signaling components to caveolins and activity of proteasome. The results suggest that differential interaction of MAP kinases with caveolin 1/3 in conjuncture with proteasome stabilization play a unique role in tocotrienol mediated cardioprotection possibly by altering the availability of pro-survival and anti-survival proteins.

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Caveolin and proteasome in tocotrienol mediated myocardial protection.

Epidemiological studies strongly suggest an inverse correlation between plasma high-density lipoprotein (HDL) concentration and the risk of ischemic heart disease.1,2 Experimental evidence also exists to indicate cardioprotective effects of HDL.3 However, the mechanism for protective effect of HDL against ischemic heart disease is not completely understood. Although the widely accepted mechanism comprises the ability of HDL to enhance reverse cholesterol transport,4 cholesterol-independent mechanisms have also been postulated. For example, lower HDL is associated with endothelial cell injury, which is involved both in the progression of atherogenesis and myocardial ischemia-reperfusion injury. The ability of HDL to inhibit endothelial adhesion molecule expression5 and to potentiate prostacyclin release from the endothelial cells6 further supports cholesterol-independent mechanism of HDL.

Antiatherogenic property of HDL is mediated by its ability to release cholesterol from lipid-containing cells followed by esterification through lecithin:cholesterol acyltransferase and delivery to the liver and to steroidogenic organs for subsequent synthesis of bile acids and lipoproteins.7 Most importantly, HDL can inhibit oxidation of low-density lipoprotein (LDL) as well as the atherogenic effects of oxidized LDL by virtue of its antioxidant property.

Atherosclerosis is an inflammatory disease characterized by adhesion of circulating monocytes to activated endothelial cells followed by migration to the subendothelium with the help of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin.8 Consistent with these reports, there is an increased expression of adhesion molecules in atherosclerotic plaque9 and upregulation of adhesion molecules in the acute thrombotic process. …

Cardioprotection With High-Density Lipoproteins: Fact or Fiction?

Tocotrienols, a group of Vitamin E stereoisomers, offer many health benefits including their ability to lower cholesterol levels, and provide anticancer and tumor-suppressive activities. Several recent studies determined the cardioprotective abilities of tocotrienols, although the number is only 1% compared to the study with tocopherols. Both in acute perfusion experiments and in chronic models, tocotrienols attenuate myocardial ischemia-reperfusion injury, artherosclerosis, and reduced ventricular arrythmias. Apart from the antioxidative role of tocotrienols, it appears that tocotrienols mediated cardioprotection is also achieved through the preconditioning-like effect, the best yet devised method of cardioprotection. Hence, tocotrienols likely fulfills the definition of a pharmacological preconditioning agent and give a tremendous opportunity to place tocotrienols as an important therapeutic option in cardiovascular system.

Dipak K. Das

Papers

Generation of survival signal by differential interaction of p38MAPKα and p38MAPKβ with caveolin-1 and caveolin-3 in the adapted heart

Caveolin and proteasome in tocotrienol mediated myocardial protection.

Cardioprotection With High-Density Lipoproteins: Fact or Fiction?

Tocotrienols in cardioprotection.

Analysis of tissue free fatty acids isolated by aminopropyl bonded-phase columns