Ezzedine Aouani

Grape Seed and Skin Extract Prevents High-Fat Diet-Induced Brain Lipotoxicity in Rat

Obesity is related to an elevated risk of dementia and the physiologic mechanisms whereby fat adversely affects the brain are poorly understood. The present investigation analyzed the effect of a high fat diet (HFD) on brain steatosis and oxidative stress and the intracellular mediators involved in signal transduction, as well as the protection offered by grape seed and skin extract (GSSE). HFD induced ectopic deposition of cholesterol and phospholipid but not triglyceride. Moreover brain lipotoxicity is linked to an oxidative stress characterized by increased lipoperoxidation and carbonylation, inhibition of glutathione peroxidase and superoxide dismutase activities, depletion of manganese and a concomitant increase in ionizable calcium and acetylcholinesterase activity. Importantly GSSE alleviated all the deleterious effects of HFD treatment. Altogether our data indicated that HFD could find some potential application in the treatment of manganism and that GSSE should be used as a safe anti-lipotoxic agent in the prevention and treatment of fat-induced brain injury.

High-fat diet induced an oxidative stress in white adipose tissue and disturbed plasma transition metals in rat: prevention by grape seed and skin extract

Obesity is a public health problem characterized by increased accumulation of fat into adipose tissues leading to oxidative stress, dyslipidemia, and chronic inflammatory status. We used an experimental model of high-fat diet-induced obesity to analyze the link between dyslipidemia, oxidative stress, and fat accumulation into adipose tissue of rats, as well as the involvement of intracellular mediators such as transition metals on signal transduction. We also looked at the ability of a grape seed and skin extract (GSSE) from a Tunisian cultivar to prevent fat-induced disturbances. Data showed that a high-fat diet (HFD) provoked dyslipidemia into plasma which is linked to an oxidative stress, an accumulation of transition metals such as manganese, copper, and zinc and a depletion of iron. GSSE prevented dyslipidemia by modulating lipase activity, together with increased antioxidant capacity and depletion of transition metals as well as of free radicals such as O2− and OH. These data indicated that GSSE has important preventive effects on HFD-induced obesity and oxidative stress whose transduction seems to involve transition metals. GSSE should be used as a safe anti-obesity agent that could find potential applications in metabolic disorders involving transition metals dyshomeostasis.

Cardioprotective effect of resveratrol on lipopolysaccharide-induced oxidative stress in rat

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces a deleterious effect on several organs, including the heart, eventually leading to septic shock and death. Endotoxemia-induced cardiotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation, inducing DNA, protein, and membrane lipid damage. Resveratrol (trans-3,5,4′ trihydroxystilbene; RVT) is a phytoalexin polyphenol that exhibits antioxidant and -inflammatory properties. We investigated the putative effect of a subacute treatment with this natural compound on LPS-induced cardiotoxicity in the rat. We found that resveratrol counteracted LPS-induced lipoperoxidation and decreased superoxide dismutase (SOD) activity, but had no effect on the LPS-induced decrease in catalase (CAT) nor on the increase in peroxidase (POD) activity. Resveratrol also reversed LPS-induced myocardial nitric oxide (NO) elevation. More important, LPS-induced iron depletion from plasma to the myocardial compartment was abolished upon resveratrol treatment. All these data suggest that resveratrol is capable of alleviating LPS-induced cardiotoxicity, and that its mode of action may involve iron-shuttling proteins.

Protective effect of resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent signaling pathway

Lipopolysaccharides (LPS) are major components of the cell wall of Gram negative bacteria implicated in the pathogenesis of bacterial infection. Resveratrol is a polyphenolic phytoalexin exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effects of this natural compound on LPS-induced proinflammatory effect using non-myeloid AR42J pancreatic cells. We found that LPS dose-dependently increased extracellular malondialdehyde (MDA) and nitric oxide without affecting their intracellular level whereas resveratrol abolished all these deleterious effects. LPS increased CD14 expression; IRAK1 and a phosphorylated form of p38 MAPK protein. Resveratrol counteracted LPS effect by decreasing CD14 and IRAK1 expression but unexpectedly increased the p38 MAPK protein phosphorylation. Altogether, our data highlighted the functionality of the TLR4-Myd88 signaling pathway in LPS pro-oxidant effect using non-myeloid cells. They further suggested that resveratrol exerted antioxidant properties either by a Myd88-dependent way not involving IRAK1 or by a TRIF dependent pathway.

Grape seed and skin extract mitigates heart and liver oxidative damage induced by a high-fat diet in the rat: gender dependency

Obesity is a public health problem contributing to morbidity and mortality from metabolic syndrome. It has long been recognized that there is a gender dependency in several obesity-related health risks. Using a high fat diet (HFD) to induce obesity in Wistar rats, we studied the gender dependency of fat-induced oxidative stress in the heart and liver, with a special emphasis on the distribution of transition metals, as well as the protective effects of grape seed and skin extract (GSSE). HFD induced obesity in both male and female rats, characterized by increased body weight as well as relative liver mass in both genders, and increased relative heart mass in the males only. HFD also provoked the accumulation of triglycerides and total cholesterol into the male hearts, and into the livers of both genders. HFD induced oxidative stress in the male hearts and also in the livers of both genders. Furthermore, HFD affected cardiac levels of copper in the males, and hepatic levels of copper and zinc in both genders, whereas HFD affected free iron in the male hearts and female livers, specifically. In conclusion, HFD treatment altered transition metal homeostasis more drastically in the male heart than in the female liver, and GSSE efficiently protected these organs against fat-induced disturbances, regardless of gender.

Grape seed and skin extract protects against bleomycin-induced oxidative stress in rat lung.

INTRODUCTION Lung fibrosis is a common side effect of the chemotherapeutic agent bleomycin and current evidence suggests that reactive oxygen species play a key role in the development of lung injury. We examined whether grape seed and skin extract (GSSE), a polyphenolic mixture exhibiting antioxidant properties, is able to protect against bleomycin-induced lung oxidative stress and injury. METHODS Rats were pre-treated during three weeks either with vehicle (ethanol 10% control) or GSSE (4g/kg), then administered with a single high dose bleomycin (15mg/kg) at the 7th day. RESULTS Bleomycin increased lung lipoperoxidation, carbonylation and decreased antioxidant enzyme activities as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Bleomycin also induced copper depletion from the lung and iron accumulation within the lung, but had no effect on either zinc nor manganese. Correlatively bleomycin decreased the copper associated enzyme tyrosinase, increased the zinc dependent lactate dehydrogenase (LDH) and did not affect the manganese dependent glutamine synthetase. GSSE efficiently counteracted almost all bleomycin-induced oxidative stress, biochemical and morphological changes of lung tissue. CONCLUSION Data suggest that GSSE exerts potent antioxidant properties that could find potential application in the protection against bleomycin-induced lung fibrosis.

Effect of garlic's mode of administration on erythrocytes and plasma parameters in Wistar rat

Garlic preparations are recognized as hypolipidemic, cardioprotective and antihypertensive agents. However, there are some discrepancies about the beneficial effects of garlic according to dosage and mode of administration. We aimed to determine the ability of high dosage garlic (5 g/kg bw ) to modulate erythrocytes and plasma parameters when administered orally (p.o.) or via intraperitoneal (i.p.) route. With regard to erythrocytes parameters, p.o. garlic treatment was found to have beneficial effects as it increased hemoglobin and hematocrit levels. Garlic i.p. treatment showed detrimental activity as it decreased these parameters. Our results reveal that garlic administered by p.o. does not involve any significant variation on mean cell volume (MCV), mean cell hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC). Nevertheless, garlic i.p. increased MCV but reduced the MCH. The MCHC remained invariable even in intraperitoneal way. Concerning plasma parameters, our data show that garlic did not induce any variation on glycaemia and plasma electrolytes whatever its mode of administration. High garlic dosage was found to be relatively safe when administered orally. Keywords: Garlic, erythrocytes, hemoglobin, hematocrit, glycaemia, plasmatic electrolytes, administration mode

Dietary supplementation of grape seed and skin flour mitigates brain oxidative damage induced by a high-fat diet in rat: Gender dependency

It is unknown whether gender has an impact on brain injury in obesity, and, if so, whether treatment with grape seed and skin flour could exert a protective effect. Both male and female rats were fed a standard diet (SD) or a high fat diet (HFD) during eight weeks and treated with high dosage grape seed and skin flour (GSSF). Fat-induced oxidative stress was evaluated into the brain with a special emphasis on transition metals determination. HFD induced male-cholesterol overload (+78.12%) and an oxidative stress status characterized by increased lipoperoxidation (+68.97%), carbonylation (+40.28%), decreased antioxidant enzyme activities as glutathione peroxidase (-61.07%) and manganese-superoxide dismutase (-35.47%) but not catalase. Additionally HFD depleted the brain from manganese (-71.31%) and dropped glutamine synthetase activity (-36.16%), without affecting copper nor iron nor their associated enzymes. HFD also altered intracellular mediators as superoxide anion (+36.12%), calcium (+44.41%) and also calpain (+76.54%) a calcium dependent protease. Importantly all these alterations were detected exclusively in male brain and were efficiently corrected upon GSSF treatment. In conclusion, GSSF has the potential to alleviate the deleterious lipotoxic effect of HFD treatment that occurred in male brain and perhaps in post-menauposal female brain.

Protective effect of grape seed and skin extract against diabetes-induced oxidative stress and renal dysfunction in virgin and pregnant rat.

The present work deal with the effect of alloxan-induced diabetes on kidney oxidative stress and dysfunction of virgin and pregnant rat as well as the protection that may be afforded by high dosage GSSE (4g/kg) treatment. Diabetes affected negatively several kidney function parameters as creatinemia, uremia, uricemia and proteinuria without affecting kidney index. Diabetes also induced an oxidative stress characterized by increased lipid and protein oxidation, a drop in antioxidant enzyme defenses as catalase, superoxide-dismutase, glutathione-peroxidase, an alteration in transition metals as free iron, copper, selenium and associated enzymes and an increase in calpain and acetyl-cholinesterase activities. Tremendously, GSSE treatment protected efficiently against all the deleterious effects of diabetes-induced kidney dysfunction in both virgin and pregnant animals. High dosage GSSE is a safe and potent anti-oxidant that may be further tested in clinical trials for the long-term preservation of kidney function especially in multiple pregnancies.

Grape seed and skin extract as an adjunct to xenical therapy reduces obesity, brain lipotoxicity and oxidative stress in high fat diet fed rats

BACKGROUND Obesity is a public health problem and a major risk factor for metabolic syndrome. This study was designed to assess the effectiveness of grape seed and skin extract (GSSE) and Xenical (Xe) on high fat diet (HFD)-induced obesity and brain lipotoxicity. METHOD Rats were rendered obese and then treated either with vehicle (control) or GSSE (4g/kg bw) or Xe (1, 2, 4 or 8mg/kg bw) or (GSSE+Xe) and monitored for weight loss during 3 months. Animals were then sacrificed and their brain utilised for the evaluation of lipotoxicity-induced oxidative stress as well as the putative protection offered by GSSE and Xe treatment. RESULTS As expected HFD-induced body and adipose tissue weight gain, dyslipidemia, accumulation of lipid into the brain, a drop in adiponectin, increased oxidative stress and disruption of Mn, Ca2+ and of related enzyme activities as glutamine synthetase and calpain. Xe alone exerted anti-obesity effect during the first 2 months and became inefficient thereafter. GSSE per se exhibited potent anti-obesity effect whereas the combination (GSSE+Xe), by acting in concert, was the most efficient against obesity and brain lipotoxicity. GSSE acted partially through its anti-oxidative properties, whereas Xe did not. CONCLUSION Combining GSSE with Xe improved outcomes in body weight and fat reduction as well as in brain lipotoxicity.