Anti-Atherosclerotic Effect of a Polyphenol-Rich Ingredient, Oleactiv®, in a Hypercholesterolemia-Induced Golden Syrian Hamster Model.

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv®, an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv® is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of fruit and vegetables commonly consumed within the Mediterranean diet. A total of 21 Golden Syrian hamsters were divided into three groups. The standard group (STD) was fed a normolipidemic diet for 12 weeks, while the control group (CTRL) and Oleactiv® goup (OLE) were fed a high-fat diet. After sacrifice, the aortic fatty streak area (AFSA), plasmatic total cholesterol (TC), high-density lipoproteins (HDL-C), non-HDL-C and triglycerides (TG), were assessed. The cholesterol efflux capacity (CEC) of hamster plasma was quantified using a radiolabeled technique in murine macrophages J774. OLE administration induced a significant reduction of AFSA (-69%, p < 0.0001). Hamsters of the OLE group showed a significant decrease of both non-HDL-C (-173 mmol/L, p < 0.05) and TG (-154 mmol/L, p < 0.05). Interestingly, OLE induced a significant increase of total CEC (+17,33%, p < 0,05). Oleactiv® supplementation prevented atheroma development and had positive effects on the lipid profile of hypercholesterolemic hamsters. The increased CEC underlines the anti-atherosclerotic mechanism at the root of the atheroma reduction observed.

Dietary silicon-enriched spirulina improves early atherosclerosis markers in hamsters on a high-fat diet.

OBJECTIVE: The aim of this study was to investigate the effects of dietary silicon-enriched spirulina (SES) on atherosclerosis. METHODS: Hamsters (six per group) on a high-fat (HF) diet received SES or non-enriched spirulina (both at 57 mg/kg body weight) daily. This corresponded to 0.57 mg silicon/kg body weight daily. RESULTS: The HF diet induced dyslipidemia, insulin resistance, oxidative stress, and vascular dysfunction. Compared with the HF group, SES attenuated increases of lipemia and prevented insulin resistance (IR) (P = 0.001). SES protected against oxidative stress through a reduction of heart (P = 0.006) and liver (P < 0.0001) nicotinamide adenine dinucleotide phosphate-oxidase activity and by sparing the activity of superoxide dismutase (P = 0.0017) and glutathione peroxidase (P = 0.01861). SES decreased inflammation, lowering tumor necrosis factor-α (P = 0.0006) and interleukin-6 levels (P = 0.0112), decreasing polymorphonuclear cells and preventing nuclear factor-κB activity (P = 0.0259). SES corrected plasma level of monocyte chemoattractant protein-1 (P = 0.0380), which was increased by the HF diet. Finally, SES supplementation prevented vascular and endothelial functions assessed respectively by the contractile response to the agonist phenylephrine and the relaxation induced by acetylcholine. CONCLUSION: SES protects against metabolic imbalance, inflammation, oxidative stress, and vascular dysfunction induced by an HF diet, and could prevent the atherogenic processes. Synergistic effects between spirulina and silicon were observed.

A 12-week randomized double-blind parallel pilot trial of Sinetrol XPur on body weight, abdominal fat, waist circumference, and muscle metabolism in overweight men.

Overweight and obesity are associated to increased risk of developing non-communicable diseases that might dramatically affect life expectancy according World Health Organization. Overweight, obesity, and decline in physical activity are correlated to a significant propensity to lose skeletal muscle mass as a result of prolonged inflammation and oxidative stress whereas cohort surveys and clinical investigations have demonstrated health benefits of Citrus-based polyphenols to reverse such regression. Overweight men were included in a double-blind, randomized, parallel pilot trial where they received daily for a 12-week period 900 mg of a Citrus-based polyphenol extract, Sinetrol® XPur. Body composition, anthropometric, and blood parameters were assessed before and at the end of the intervention period. After 12 weeks, while the silhouette slimmed down, metabolic parameters were significantly improved and skeletal muscle catabolism held back. These data suggest that over a 12-week period, the efficacy of the supplement improve both overweight process and correlated skeletal muscle mass metabolism.

Moderate chronic administration of Vineatrol-enriched red wines improves metabolic, oxidative, and inflammatory markers in hamsters fed a high-fat diet.

SCOPE: High-fat (HF) diets contribute to the development of cardiovascular diseases and the metabolic syndrome. This study was undertaken to investigate the beneficial effects of Vineatrol®-enriched red wines on blood lipids, oxidative stress and inflammation, and the role of some metabolic pathway regulatory proteins. METHODS AND RESULTS: Golden Syrian hamsters received an HF diet for 13 wk, in the presence or absence of red wines supplemented with Vineatrol® (RWV) or not. The HF diet increased plasma cholesterol, triglycerides, glucose, and insulin, which were attenuated by RWV treatment. RWV protected against the HF-induced increase in liver nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and spared antioxidant enzyme activities. RWV did not reduce either liver steatosis or increased plasma leptin due to the HF diet, but greatly improved adiponectinemia. In the liver, RWV affected the inflammatory response by decreasing polymorphonuclear cell number and lowering TNF-α and IL-6 levels. Moreover, the increase in NF-κB activity in the HF group liver was prevented by RWV. Finally, RWV partially corrected low SIRT1 levels due to the HF diet but had no influence on SIRT3 or p-AMPK protein levels. CONCLUSION: Our studies suggest that RWV is capable of reversing the atherogenic process induced by an HF diet in hamster tissues.

Endogenous antioxidant defense induction by melon superoxide dismutase reduces cardiac hypertrophy in spontaneously hypertensive rats.

We assessed the influence of SODB, a melon superoxide dismutase (SOD), on left ventricular (LV) hypertrophy in SHR. SODB (4 or 40U SOD) was given orally for 4 or 28 days to SHR. For each treatment period, LV weight index (LVWI) and cardiomyocytes size were measured. SOD, glutathione peroxidase (GPx) and catalase expressions, and LV production and presence of superoxide anion were determined. Pro-inflammatory markers were also measured. SODB reduced LVWI and cardiomyocytes size after 4 or 28 days. Cardiac SOD and GPx increased by 30-40% with SODB. The presence but not production of superoxide anion was significantly reduced by SODB. No effect of SODB was detected on inflammatory status in any group. The beneficial effect of SODB on cardiac hypertrophy seems to be related to the stimulation of endogenous antioxidant defense, suggesting that SODB may be of interest as a dietary supplementation during conventional antihypertensive therapy.

Superoxide dismutase administration, a potential therapy against oxidative stress related diseases: several routes of supplementation and proposal of an original mechanism of action.

Oxidative stress, involved in many diseases, is defined as an impaired balance between reactive oxygen species (ROS) production and antioxidant defences. Antioxidant enzymes such as superoxide dismutase (SOD) play a key role in diminishing oxidative stress. Thus, the removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. The poor bioavailability of exogenous SODs has been criticized. However, improvements in SOD formulation may overcome this limitation and boost interest in its therapeutic properties. Here, we provide a review of animal and human studies about SODs supplementation in order to evaluate their therapeutic value. Protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration has also been reported to alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders, raising the question of its mechanism of action in these diverse situations. Some authors have shown an increase in endogenous antioxidant enzymes after exogenous SODs administration. The induction of endogenous antioxidant defence and, consequently, a decrease in oxidative stress, could explain all the effects observed. Further investigations need to be carried out to test the hypothesis that SODs supplementation acts by inducing an endogenous antioxidant defence.

Vineatrol and cardiovascular disease: beneficial effects of a vine-shoot phenolic extract in a hamster atherosclerosis model.

We evaluated the effect of the intake of a grapevine-shoot phenolic extract (Vineatrol 30) on early atherosclerosis in hamsters fed a hyperlipidic diet. Golden Syrian hamsters received for 13 weeks either a standard diet, a high-fat (HF) diet, or the HF diet plus Vineatrol 30 at 0.04, 0.2, or 1.0 mg/(kg body weight/d). We measured plasma lipids and glucose, insulin, leptin and adiponectin, as well as liver TNF-α and IL-6 levels. Oxidative stress was assessed by measuring plasma paraoxonase activity (PON) and liver superoxide anion production (O(2)(•-)). The aortic fatty streak area (AFSA) was also determined. In comparison with HF group, we demonstrated that the highest dose of Vineatrol 30 was capable of decreasing AFSA (67%), insulinemia (40%), and leptinemia (8.7%), which were increased by the HF diet. We also showed increased O(2)(•-) production (35%) and a rise in levels of the liver proinflammatory cytokines TNF-α (22%) and IL-6 (21%), accompanied by a fall in PON activity (56%) due to the HF diet versus the standard diet. In contrast, except plasma adiponectin levels that are not changed, Vineatrol 30 treatment lowered AFSA (67%), O(2)(•-) production (36%), insulin resistance (42%), leptinemia (9%), liver TNF-α (18%) and IL-6 (15%), while it rose PON activity (29%). These findings demonstrate the preventive effects of polyphenols present in Vineatrol 30 in managing cardiovascular, metabolic, and inflammatory risk factors.

Antioxidant capacity and angiotensin I converting enzyme inhibitory activity of a melon concentrate rich in superoxide dismutase.

Antioxidant capacity and angiotensin 1-converting enzyme (ACE) inhibitory activity of a melon concentrate rich in superoxide dismutase (SOD-MC) were investigated in vitro. The total antioxidant capacity (TAC) was measured by the Trolox equivalent antioxidant capacity assay (TEAC), the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay, and the ferric reducing antioxidant power assay (FRAP). The ability of the extract to scavenge three specific reactive oxygen species (superoxide radical anion (O(2)(-)), hydroxyl radical (HO()) and hydrogen peroxide (H(2)O(2))) was also investigated in order to better evaluate its antioxidant properties. Even if the measures of TAC were relatively low, results clearly established an antioxidant potential of SOD-MC that exhibited the highest radical-scavenging activity towards O(2)(-), with a IC(50) 12-fold lower than that of H(2)O(2) or HO(). This lets hypothesis that the antioxidant potential of SOD-MC could be mainly due to its high level of SOD. Moreover, for the first time, an ACE inhibitory activity of SOD-MC (IC(50)=2.4±0.1mg/mL) was demonstrated, showing that its use as a functional food ingredient with potential preventive benefits in the context of hypertension may have important public health implications and should be carefully considered.

Validation of a surgical technique for rat intestinal irradiation: potential side effects prevention by dietary grape phenolics.

AIMS: This study evaluates and defines the histological and biochemical consequences of irradiation on the Hauer-Jensen intestinal model and investigates the potential effects of dietary polyphenols. MAIN METHODS: Sprague-Dawley rats were orchiectomized, and an ileal loop was transposed to the left part of the scrotum, then irradiated 2 weeks after surgery with a single dose of 21 Gy (4.49 Gy/min). Four groups of rats received either phenolic extracts from grape seeds (EGS) and from red wine (ACYS, EGT), or pure quercetin 3-O-ß-glucoside (Q3G), for 5 days before the irradiation and were sacrificed 2 weeks after. Antioxidant enzyme activities, i.e. superoxide dismutase (SOD) and glutathione peroxidase activity (GSHPx), and oxidative markers such as myeloperoxidase activity (MPO) and thiobarbituric acid reactive substances (MDA) were measured as well as cytokine-induced neutrophil chemoattractant level (CINC-1), a chemokine involved in inflammation. KEY FINDINGS: Irradiated rats exhibited a high radiation injury score (RIS) with a thickened serosa, mucosal loss and ulceration, and epithelial atypicality. Intestinal MPO activity and CINC-1 concentration were significantly increased in irradiated animals (60 and 66 %, respectively). Higher plasma MDA levels (58 %) and SOD activity (32 %) were accompanied by a reduced GSHPx activity (79 %). However, feeding phenolic extracts remarkably reduced levels of blood SOD activity (34 % on average), intestinal CINC-1 (25-75 % range) and MPO activity (36-84 %). Except for Q3G, phenolics preserved the intestinal structure. SIGNIFICANCE: These findings show that irradiation triggers an inflammation, and an oxidative stress by disturbing the pro-oxidant/antioxidant balance and indicate that phenolics supply exerts preventive effects against radio-induced intestinal impairment.

Polyphenols prevent lipid abnormalities and arterial dysfunction in hamsters on a high-fat diet: a comparative study of red grape and white persimmon wines.

SCOPE: We compared the effects of two dealcoholized wines, persimmon (P) and Merlot (M), in hypercholesterolemic hamsters. METHODS AND RESULTS: Four groups of hamsters received a standard (ST) or an atherogenic diet (AT) for 12 weeks. AT animals received either dealcoholized persimmon wine (AT + P) or Merlot wine (AT + M) by gavage, while controls received water (AT and ST). Plasma cholesterol, triglycerides and glucose and paraoxonase activity were measured. Oxidative stress was assessed by aortic O(2)°(-) production, and vascular function was evaluated in aortic rings. The atherogenic diet led to higher plasma triglycerides (246%), total cholesterol (142%), LDL-cholesterol (91%) and HDL-cholesterol (49%). Aortic production of O(2)°(-) also increased (207%) and vascular reactivity was modified with altered endothelial function as assessed by acetylcholine-dependent vasorelaxation. The two wines partially prevented these alterations, reducing O(2)°(-) production and improving vascular reactivity without altering endothelial function. There was no difference between the P and M groups, although the procyanidin composition of the two dealcoholized fractions differed significantly, and only dimer concentrations were similar. CONCLUSION: These findings indicate that polyphenols are responsible, at least in part, for the antiatherogenic/antioxidant effects of wines.

Raspberry juice consumption, oxidative stress and reduction of atherosclerosis risk factors in hypercholesterolemic golden Syrian hamsters.

The effects of raspberries on early atherosclerosis in Syrian hamsters were investigated using three juices prepared from var. Cardinal, Glen Ample and Tulameen berries. The hamsters received an atherogenic diet for 12 weeks and at the same time a juice at a daily dose corresponding to the consumption of 275 ml by a 70 kg human. A control group received the same diet with water instead juice. The principal polyphenolic compounds in the juices were anthocyanins and ellagitannins, which were present at concentrations of 218-305 µg mL(-1) and 45-72 µg mL(-1), respectively. The three juices had similar but not identical effects. They all inhibited cardiac and aortic production of superoxide anion and increased hepatic glutathione peroxidase activity although only Tulameen juice brought about a significant increase in superoxide dismutase activity. Glen Ample was the only juice to significantly increase plasma paraoxonase activity. All the juices lowered plasma triglyceride level while consumption of Tulameen and Cardinal, but not Glen Ample, significantly lowered plasma total cholesterol and LDL-cholesterol. Cardinal was the sole juice to significantly increase HDL-cholesterol and likewise it also significantly reduced body weight. These findings suggest that moderate consumption of raspberry juices can help to prevent the development of early atherosclerosis, with the underlying mechanisms related to improved antioxidant status and serum lipid profiles.

Chardonnay grape seed procyanidin extract supplementation prevents high-fat diet-induced obesity in hamsters by improving adipokine imbalance and oxidative stress markers.

Studies reported the effects of polyphenols but not for grape polyphenols towards obesity. We analysed the effects of a polyphenolic grape seed extract (GSE) on obesity and oxidative stress in hamsters receiving a high-fat diet (HFD). Three groups of hamsters received a standard diet (STD), or a HFD plus a daily gavage with water (Control, HFD) or a solution of GSE (HFD + GSE) for 12 wk. Plasma glucose, triglycerides (TG), insulin, leptin and adiponectin were measured. Oxidative stress was assessed by cardiac production of superoxide anion and NAD(P)H oxidase expression. After 12 wk, HFD increased abdominal fat as compared with standards. GSE avoided this feature. HFD led to higher plasma glucose, TG, insulin and greater insulin resistance (HOMA-IR) values. GSE prevented in part these effects, reducing insulinemia and leptinemia by 16.5 and 45%, respectively, whereas adiponectin level increased by 61% compared with obese controls. GSE lowered glycemia and HOMA-IR and strongly prevented cardiac production of superoxide by 74% and NAD(P)H oxidase expression by 30%. This is the first time that chronic consumption of grape phenolics is shown to reduce obesity development and related metabolic pathways including adipokine secretion and oxidative stress.

Polyphenols-enriched Chardonnay white wine and sparkling Pinot Noir red wine identically prevent early atherosclerosis in hamsters.

The effects of a white wine enriched with polyphenols (PEWW) from Chardonnay grapes and of a sparkling red wine (SRW) from Pinot Noir and Chardonnay grapes were studied for the first time on early atherosclerosis in hamsters. Animals were fed an atherogenic diet for 12 weeks. They received by force-feeding PEWW, SRW, ethanol 12% (ETH), or water as control (mimicking a moderate consumption of approximately 2 red wine glasses per meal for a 70 kg human). Plasma cholesterol concentrations were lower in groups that consumed PEWW and SRW accompanied by an increase in the ratio apo A-1/apo B. Liver-specific activities of superoxide dismutase and catalase were significantly increased by PEWW (38 and 16%, respectively) and by SRW (48 and 15%, respectively). PEWW and ETH significantly increased plasma antioxidant capacity and vitamin A concentrations. Aortic fatty streak area (AFSA) was significantly strongly reduced in the groups receiving PEWW (85%) and SRW (89%) in comparison with the control. AFSA was reduced by ethanol to a lesser extent (58%). These data suggest that tannins from the phenolics-enriched white wine induce a protective effect against early atherosclerosis comparable to that produced by sparkling red wine containing tanins and anthocyanins and dissociated from the antioxidant action of these compounds.

Phenolics from commercialized grape extracts prevent early atherosclerotic lesions in hamsters by mechanisms other than antioxidant effect.

The aim of this study was to evaluate the antiatherosclerotic effect of commercially available phenolic-rich extracts from grape seeds (ExGrape seeds, EGS; grape seed extract, GSE) and marc (ExGrape total, EGT) in cholesterol-fed hamsters and to investigate possible operating mechanisms. These extracts fed at a moderate dose mimicking two glasses of red wine per meal reduced plasma cholesterol (-11% on average) but did not affect plasma antioxidant capacity of hamsters. The extracts prevented the development of aortic atherosclerosis by 68% (EGS), 63% (EGT), and 34% (GSE). Elsewhere, in an ex vivo experiment using rat aortic rings, EGS (7 microg/mL) induced 77% endothelium-dependent relaxation, whereas EGT and GSE (30 microg/mL) induced 84 and 72%, respectively. These results suggests that phenolic extracts from grape seeds and marc are beneficial in inhibiting atherosclerosis by indirect mechanism(s).

Hydroxycinnamic acids do not prevent aortic atherosclerosis in hypercholesterolemic golden Syrian hamsters.

The protective effect of hydroxycinnamic acids, i.e. caffeic acid (CA) and sinapic acid (SA) present in wine, and chlorogenic acid (CHA) present in apple, compared to a red wine phenolic extract (RWPE) was investigated in hamsters fed an atherogenic diet for 12 weeks. Five groups of 8 hamsters fed such a diet received by force-feeding RWPE, CA or SA in water, mimicking a moderate consumption of alcohol-free red wine. Controls received water and CHA force-feeding was extrapolated from apple consumption. Plasma cholesterol concentration was lower in group that received RWPE (-22%) and hydroxycinnamic acids had no effect. Plasma apolipoprotein Apo-A1 concentration was not affected; consumption of RWPE only decreased Apo-B concentration (-46%). Liver superoxide dismutase activity was 33% lower and glutathione peroxidase activity was 67% greater in the group receiving RWPE compared to controls; there was no effect when CA, SA or CHA were given. All the phenolic compounds significantly increased plasma antioxidant capacity (about 28% on average) compared with controls. Aortic fatty streak area was significantly reduced in the group receiving RWPE (-30%) in comparison with controls and hydroxycinnamic acids. Our findings demonstrate that chronic ingestion of the nonalcoholic components of red wine, mainly polyphenols, prevent the development of atherosclerosis in hamster and that wine hydroxycinnamic acids are not the phenolic compounds involved in such a beneficial effect.

Antidiabetic activity of red wine polyphenolic extract, ethanol, or both in streptozotocin-treated rats.

A polyphenol extract from a Corbières (France) red wine (P, 200 mg/kg), ethanol (E, 1 mL/kg), or a combination of both (PE) was administered by daily gavage for 6 weeks to healthy control or streptozotocin (60 mg/kg i.v.)-induced diabetic rats (180-200 g). Treatment groups included C or D (untreated control or diabetic) and CP, CE, or CPE (treated control) or DP, DE, or DPE (treated diabetic). P treatment induced a reduction in body growth, food intake, and glycemia in both CP and DP groups. In DP, hyperglycemia was reduced when measured 1 h after daily treatment but not at sacrifice (no treatment on that day). The hyperglycemic response to the oral glucose tolerance test (OGTT) and plasma insulin at sacrifice were impaired similarly in DP and D groups. In contrast, in DE or DPE, body growth was partially restored while hyperglycemia was reduced both during treatment and at sacrifice. In addition, hyperglycemia response to OGTT was reduced and plasma insulin was higher in DE or DPE than in D animals, indicating a long-term correction of diabetes in ethanol-treated animals. Morphometric studies showed that ethanol partially reversed the enlarging effect of diabetes on the mesenteric arterial system while the polyphenolic treatment enhanced it in the absence of ethanol. In summary, our study shows that (i). a polyphenol extract from red wine ("used at a pharmacological" dose) reduces glycemia and decreases food intake and body growth in diabetic and nondiabetic animals and (ii). ethanol ("nutritional" dose) administered alone or in combination with polyphenols is able to correct the diabetic state. Some of the effects of polyphenols were masked by the effects of ethanol, notably in diabetic animals. Further studies will determine the effect of "nutritional" doses of polyphenols as well as their mechanism of action.