Drugs Under Experimental and Clinical Research 

About: Drugs Under Experimental and Clinical Research is an academic journal. The journal publishes majorly in the area(s): Antibacterial agent & Pharmacokinetics. It has an ISSN identifier of 0378-6501. Over the lifetime, 1388 publications have been published receiving 18931 citations.

Cancer chemopreventive activity of resveratrol.

Abstract: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit carcinogen-induced preneoplastic lesion formation in mouse mammary organ culture and tumorigenesis in the two-stage mouse skin model. Cancer chemopreventive potential was also suggested in various assays reflective of the three major stages of carcinogenesis. Anti-initiation activity was indicated by its antioxidant and antimutagenic effects, inhibition of the hydroperoxidase function of cyclooxygenase (COX), and induction of phase II drug-metabolizing enzymes. Antipromotion activity was indicated by antiinflammatory effects, inhibition of production of arachidonic acid metabolites catalyzed by either COX-1 or COX-2, and chemical carcinogen-induced neoplastic transformation of mouse embryo fibroblasts. Antiprogression activity was demonstrated by its ability to induce human promyelocytic leukemia (HL-60) cell differentiation. Moreover, pretreatment of mouse skin with resveratrol significantly counteracted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress, as evidenced by numerous biochemical responses. Resveratrol reduced the generation of hydrogen peroxide, and normalized levels of myeloperoxidase and oxidized-glutathione reductase activities. It also restored glutathione levels and superoxide dismutase activity. As judged by the reverse transcriptase-polymerase chain reaction, resveratrol selectively inhibited TPA-induced expression of c-fos and transforming growth factor-beta 1 (TGF-beta 1), but did not affect other TPA-induced gene products including COX-1, COX-2, c-myc, c-jun, and tumor necrosis factor-alpha. These data indicate that resveratrol may interfere with reactive oxidant pathways and/or modulate the expression of c-fos and TGF-beta 1 to inhibit tumorigenesis in mouse skin. As reported herein, in addition to the activities described above, resveratrol inhibited the de novo formation of inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated with lipopolysaccharide. This finding suggests an additional mechanism by which resveratrol may function as a cancer chemopreventive agent.

Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans

Abstract: The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.

Effects of resveratrol on the rat brain respiratory chain.

Abstract: The aim of this work was to investigate the possible effects of resveratrol on the mitochondrial respiratory chain in rat brains. Isolation of mitochondria was performed at 4 degrees C using differential centrifugation. Mitochondrial respiration rate (0.4 mg of protein/ml) was determined by measuring mitochondrial oxygen consumption with a Clark electrode at 37 degrees C. Respiratory control ratio (RCR) was evaluated as the state 3/state 4 ratio of oxidative phosphorylation with substrates adenosine 5'-diphosphate (ADP) and malate plus glutamate, respectively in the presence and in the absence of resveratrol. The rate of oxygen consumption by the different complexes was checked using rotenone (2 microM), malonate (10 mM), antimycin A (1 microM), potassium cyanide (KCN) (0.3 mM) and oligomycin (10 microM) to inhibit complexes II, III, IV, V and I, respectively. Moreover, enzyme activity determinations were checked as follows: the activities of complexes II-III were measured as the rate of cytochrome c reduction at 550 nm (37 degrees C) successively triggered either by succinate (complexes II and III) or by decylubiquinol (DUQH2) (complex III), in the presence and in the absence of resveratrol. Adenosine 5'-triphosphate (ATP) synthase activity was checked as ATP hydrolysis (ATPase) at 37 degrees C for 10 min from purified mitochondria on Percoll gradient. The inorganic phosphate (Pi) concentration was measured by the Fiske and Subbarow method. When complexes I to V were activated by glutamate plus malate, resveratrol (10(-11) - 10(-4) M) significantly decreased RC (p < 0.001) following a biphasic curve with two EC50 values, 0.162 +/- 0.072 microM and 24.5 +/- 4.0 microM, representing about 56% of total oxygen consumption inhibition. We also observed a concentration-dependent effect on state 3 with two EC50 values, 2.28 +/- 0.87 nM and 27 +/- 5 microM respectively. On the other hand, resveratrol inhibited state 4 following a concentration-dependent curve with an EC50 of 37 +/- 11 microM. When complex IV operated alone, resveratrol (100 microM) did not modify oxygen consumption compared with control, indicating that this molecule did not inhibit complex IV. Thus resveratrol inhibits the mitochondrial respiratory chain through complexes I to III. In order to confirm these data, we measured the enzymatic activity of ubiquinol cytochrome c reductase alone and in the presence of resveratrol. In the presence of disrupted mitochondria, after freeze thawing cycles (three times), resveratrol inhibited about 20% of complex III activity. These results suggest that resveratrol and DUQH2 could be competitive on complex III. Resveratrol significantly inhibited ATPase activity (p < 0.001) following a biphasic curve with two EC50 values, 0.39 +/- 0.15 nM and 23.1 +/- 6.4 microM, both representing about 80% of oligomycin-dependent ATPase total activity. Resveratrol was effective as a protecting agent on the three models of oxidation. On lipid peroxidation of brain synaptosomes induced by the Fenton reaction, it was three times more potent than DUQH2. Its effectiveness in reducing 1,1-diphenyl-2-picryl hydrazyl radical (DPPH degrees) showed a stoichiometry of two, indicating that two hydrogen atoms of resveratrol were abstracted by the process. Resveratrol was also able to scavenge the superoxide anion (O2 degrees) generated from rat forebrain mitochondria in a concentration dependent manner. In conclusion, resveratrol can decrease complex III activity by competition with coenzyme Q. This property is especially interesting as this complex is the site where reactive oxygen substances (ROS) are generated. By decreasing the activity of complex III, resveratrol cannot only oppose the production of ROS but can also scavenge them.

Cardioprotection of red wine: role of polyphenolic antioxidants.

Abstract: 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.

Plasma and tissue resveratrol concentrations and pharmacological activity.

Abstract: In this study a comparison was made between results obtained from resveratrol dosages which have been shown to be pharmacologically active, in vitro and in vivo, and the results of plasma and tissue concentrations obtained after a single administration or after prolonged administration of red wine with a known resveratrol content. The dosages used by different investigators in the tests are very different and, in general, rather high in relation to the concentrations which are found in wine or grapes. The results of our tests on platelet aggregation confirm that even with modest dosages of resveratrol, a pharmacological effect can be observed, and that these dosages can be compatible with the resveratrol concentrations obtained after oral administration. The data obtained from these tests on animals can lead to the conclusion that even an average drinker of wine can, particularly in the long term, absorb a sufficient quantity of resveratrol to explain the beneficial effect of red wine on health, which has been observed in epidemiological studies carried out in populations whose daily diet includes the drinking of wine.