Milagros Galisteo

Quercetin Ameliorates Metabolic Syndrome and Improves the Inflammatory Status in Obese Zucker Rats

The aim of this study was to analyze the effects of chronic administration of high doses of quercetin on metabolic syndrome abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance. For this purpose, obese Zucker rats and their lean littermates were used. The rats received a daily dose of quercetin (2 or 10 mg/kg of body weight) or vehicle for 10 weeks. Body weight and systolic blood pressure (SBP) were recorded weekly. At the end of the treatment, plasma concentrations of triglycerides, total cholesterol, free‐fatty acids (FFAs), glucose, insulin, adiponectin, and nitrate plus nitrite (NOx) were determined. Tumor necrosis factor‐α (TNF‐α) production, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) protein expression were analyzed in visceral adipose tissue (VAT). The raised SBP and high plasma concentrations of triglycerides, total cholesterol, FFA, and insulin found in obese Zucker rats were reduced in obese rats that received either of the doses of quercetin assayed. The higher dose also improved the inflammatory status peculiar to this model, as it increased the plasma concentration of adiponectin, reduced NOx levels in plasma, and lowered VAT TNF‐α production in obese Zucker rats. Furthermore, chronic intake of the higher dose of quercetin enhanced VAT eNOS expression among obese Zucker rats, whereas it downregulated VAT iNOS expression. In conclusion, both doses of quercetin improved dyslipidemia, hypertension, and hyperinsulinemia in obese Zucker rats, but only the high dose produced antiinflammatory effects in VAT together with a reduction in body weight gain.

Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats.

Background and objective Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in sponataneously hypertensive rats (SHR). Design and methods Male SHR and Wistar–Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47phox were analysed by Western blot, eNOS activity by conversion of [3H]arginine to L-[3H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin. Results In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47phox protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed. Conclusions Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2−) generation associated with reduced p47phox expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.

Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats

Objectives The present study analysed, for the first time, the effects of the flavonoid quercetin in rats after chronic inhibition of nitric oxide (NO) synthesis with Nω-nitro-l-arginine methyl ester (l-NAME). Design Rats were divided randomly into five different treatment groups for 6 weeks: (1) vehicle (control, 1 ml of 1% methylcellulose once daily); (2) vehicle plus l-NAME (75 mg/100 ml in drinking water); (3) quercetin (10 mg/kg p.o. once daily); (4) quercetin (5 mg/kg p.o.) plus l-NAME; and (5) quercetin (10 mg/kg p.o.) plus l-NAME. Methods The evolution of systolic blood pressure, morphological variables, proteinuria, plasma malondialdehyde and nitrite and nitrate concentrations, hepatic glutathione and malondialdehyde content, glutathione enzymes activity and vascular reactivity at the end of the experiment were analysed. Results Quercetin markedly inhibited the development of l-NAME-induced hypertension. This effect was accompanied by a partial or full prevention of most of the effects induced by l-NAME, such as: (1) increases in the left ventricular and kidney weight indices; (2) proteinuria; (3) renal histological lesions, including hyaline arteriopathy and thickening of the vascular wall with moderate decrease of the lumen; (4) increased endothelium-dependent contraction; (5) increased vascular thromboxane B2 (TXB2) synthesis; (6) reduced plasma concentrations of nitrites plus nitrates (NOx); (7) increased plasma and hepatic malondialdehyde (MDA) concentrations; and (8) reduced glutathione peroxidase activity. In most cases these effects were dose dependent, but none of them were observed in normotensive animals. Conclusions This study confirms and extends the previous evidence about the antihypertensive effects and end-organ protection of the flavonoid quercetin in animal models of hypertension.

Effects of chronic quercetin treatment in experimental renovascular hypertension.

The aims of the present study were to analyse the effects of an oral daily dose (10 mg/kg) of the dietary flavonoid quercetin for five weeks in two-kidney, one-clip (2K1C) Goldblatt (GB) hypertensive rats. The evolution of systolic blood pressure was followed by weekly measurements, and morphological variables, proteinuria, plasma nitrates plus nitrites (NOx) and thiobarbituric acid reactive substances (TBARS), liver oxidative stress markers and endothelial function were determined at the end of the experimental period. Quercetin treatment reduced systolic blood pressure of GB rats, producing no effect in control animals. It also reduced cardiac hypertrophy and proteinuria developed in GB hypertensive rats. Decreased endothelium-dependent relaxation to acetylcholine of aortic rings from GB rats was improved by chronic quercetin treatment, as well as increased endothelium-dependent vasoconstrictor response to acetylcholine and overproduction of TXB2 by aortic vessels of GB rats, being without effect in normotensive animals. Increased plasma NOx and TBARS, and decreased liver total glutathione (GSH) levels and glutathione peroxidase (GPX) activity were observed in GB hypertensive rats compared to the control animals. Normalisation of plasma NOx and TBARS concentrations and improvement of the antioxidant defences system in liver accompanied the antihypertensive effect of quercetin. We conclude that chronic oral treatment with quercetin shows both antihypertensive and antioxidant effects in this model of renovascular hypertension. (Mol Cell Biochem 270: 147–155, 2005)

Effects of chronic quercetin treatment on hepatic oxidative status of spontaneously hypertensive rats

The effects of chronic administration of an oral daily dose of quercetin (10 mg Kg−1), the most abundant dietary flavonoid, were investigated on hepatic oxidative status in spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Decreased liver glutathione peroxidase activity, increased liver total glutathione levels and increased both hepatic and plasmatic malondialdehyde concentrations were observed in spontaneously hypertensive rats when compared to Wistar Kyoto rats. In spontaneously hypertensive rats, treatment with quercetin for 5 weeks reduced blood pressure, increased glutathione peroxidase activity and reduced both plasma and hepatic malondialdehyde levels. However, none of these effects were observed in Wistar Kyoto rats. In conclusion, quercetin shows both antihypertensive and antioxidant properties in this model of genetic hypertension.

Chronic administration of genistein improves endothelial dysfunction in spontaneously hypertensive rats: involvement of eNOS, caveolin and calmodulin expression and NADPH oxidase activity.

The soya-derived phytoestrogen genistein has been suggested to be protective in cardiovascular diseases. In the present study, we have analysed whether chronic oral genistein might influence endothelial function in male SHRs (spontaneously hypertensive rats) via ERs (oestrogen receptors), changes in eNOS (endothelial NO synthase) activity and vascular O(2)(-) (superoxide) production. Rats (23-weeks old) were divided into the following groups: WKY (Wistar-Kyoto)-vehicle, SHR-vehicle, WKY-genistein (10 mg.kg(-1) of body weight.day(-1)); SHR-genistein; SHR-genistein-faslodex (ICI 182780; 2.5 mg.kg(-1) of body weight.day(-1)). Vascular expression of eNOS, caveolin-1 and calmodulin-1 were analysed by Western blotting, eNOS activity by conversion of [(3)H]arginine into L-[(3)H]citrulline and O(2)(-) production by chemoluminescence of lucigenin. In SHRs, after 5 weeks of treatment, genistein reduced systolic blood pressure and enhanced endothelium-dependent aortic relaxation to acetylcholine, but had no effect on the vasodilator responses to sodium nitroprusside. Compared with WKY rats, SHRs had up-regulated eNOS and down-regulated caveolin-1 and calmodulin-1 expression, increased NADPH-induced O(2)(-) production, but reduced eNOS activity. Genistein increased aortic calmodulin-1 protein abundance and eNOS activity, and reduced NADPH-induced O(2)(-) production in SHRs. The pure ERalpha and ERbeta antagonist faslodex did not modify any of the changes induced by genistein in SHRs, suggesting that these effects are unrelated to ER stimulation. In conclusion, genistein reduced the elevated blood pressure and endothelial dysfunction in SHRs. This latter effect appears to be related to increased eNOS activity associated with increased calmodulin-1 expression and decreased O(2)(-) generation.

Effects of chronic quercetin treatment on antioxidant defence system and oxidative status of deoxycorticosterone acetate-salt-hypertensive rats

We investigated the potential of chronic administration of an oral daily dose (10 mg/kg) of the dietary flavonoid quercetin to prevent hypertension and oxidative stress induced by deoxycorticosterone acetate (DOCA)-salt in rats. We have compared its effects to those produced by the well-known anti-hypertensive drug verapamil, administered orally (20 mg/kg/day). Quercetin and verapamil treatments reduced systolic blood pressure of DOCA-salt rats in approximately 67.6 and 63.3% respectively, producing no effect in control animals. Both drugs reduced significantly hepatic and renal hypertrophy induced by DOCA-salt administration, while only quercetin prevented cardiac hypertrophy. Decreased endothelium-dependent relaxation to acetylcholine of aortic rings from DOCA-salt-treated rats was improved by quercetin, but verapamil only enhanced it in the presence of superoxide dismutase (SOD) plus catalase. Increased plasma and heart thiobarbituric acid reactive substances (TBARS) and total glutathione (GSH) levels in liver and heart, decreased liver glutathione peroxidase (GPX) and liver and kidney glutathione transferase (GST) activities were observed in DOCA-salt-treated rats compared to the control animals. The antihypertensive effect of quercetin was accompanied by normalisation of plasma TBARS values, improvement of the antioxidant defences system in heart and liver, restoring total GSH levels in both organs and altered liver GST and GPX activities, and improving kidney GST activity. Verapamil treatment only restored GSH levels in heart, having no effect on other alterations induced by DOCA-salt chronic administration in the antioxidant defences analysed. In conclusion, quercetin shows both antihypertensive and antioxidant properties in this model of mineralocorticoid hypertension, while verapamil exhibits only antihypertensive effects.

Plantago ovata husks-supplemented diet ameliorates metabolic alterations in obese Zucker rats through activation of AMP-activated protein kinase. Comparative study with other dietary fibers

BACKGROUND & AIMS Our aim was to compare the effects of intake of diets supplemented with different dietary fibers, namely cellulose, methylcellulose or Plantago ovata husks, (insoluble, soluble non-fermentable, and soluble fermentable fiber, respectively), on the abnormalities clustered in the metabolic syndrome. METHODS Adult obese Zucker rats were distributed in four groups which were fed respectively a standard, a cellulose-supplemented, a methylcellulose-supplemented or a P. ovata husks-supplemented diet, for ten weeks. RESULTS Increased body weight, hyperlipidemia, hyperinsulinemia and hyperleptinemia, increased TNF-alpha and reduced adiponectin secretion by adipose tissue found in obese Zucker rats were significantly improved in obese rats fed the P. ovata husks-supplemented diet, together with a lower hepatic lipid content which parallels activation of the signaling pathway of AMP-protein kinase in the liver. The methylcellulose-supplemented diet reduced body weight, hyperlipidemia, circulating free fatty acids concentration and ameliorated adipose tissue secretion of adiponectin and TNF-alpha. Feeding with the cellulose-supplemented diet only reduced free fatty acids circulating levels. CONCLUSIONS The soluble dietary fibers essayed are more beneficial than insoluble fiber in the treatment of metabolic syndrome, being the soluble and fermentable the more efficient to improve metabolic alterations. Fermentation products of P. ovata husks must play an important role in such effects.

Improvement of the antioxidant and hypolipidaemic effects of cowpea flours (Vigna unguiculata) by fermentation: results of in vitro and in vivo experiments

BACKGROUND The antioxidant capacity and hypolipidaemic effects of Vigna unguiculata, as well as their potential improvement by different fermentation and thermal processes were studied using in vitro and in vivo methods. RESULTS Phenolic content and reducing capacity of legume acetone extract were significantly increased by different fermentation processes, and by the thermal treatment of fermented legume flours. TBARS inhibiting capacity was increased by fermentation but not by thermal treatment. A higher ability to decrease Cu(2+)/H2O2-induced electrophoretic mobility of LDL was found in fermented when compared to raw legume extracts, and a higher protective effect on short term metabolic status of HT-29 cells was found for raw and lactobacillus-fermented Vigna followed by naturally fermented Vigna extracts. Significant improvements in plasma antioxidant capacity and hepatic activity of antioxidant enzymes were observed in rats that consumed fermented legume flours when compared to the untreated legume or a casein-methionine control diet. In addition, liver weight and plasma levels of cholesterol and triglycerides were also positively affected by untreated or naturally fermented Vigna. CONCLUSION V. unguiculata has demonstrated its potential as a functional food with interesting antioxidant and lipid lowering properties, which can be further augmented by fermentation processes associated or not to thermal processing.

Antihepatotoxic activity of Rosmarinus tomentosus in a model of acute hepatic damage induced by thioacetamide

R. tomentosus is a vegetal species closely related to the culinary rosemary (R. officinalis), a plant reported to contain antihepatotoxic agents. A dried ethanol extract of the aerial parts of Rosmarinus tomentosus (Lamiaceae) and its major fraction separated by column chromatography (fraction F19) were evaluated for antihepatotoxic activity in rats with acute liver damage induced by a single oral dose of thioacetamide. Silymarin was used as a reference antihepatotoxic substance.