Hesperidin alleviates vascular dysfunction and remodelling in high-fat/high-fructose diet-fed rats by modulating oxidative stress, inflammation, AdipoR1, and eNOS expression.

Hesperidin, a flavanone glycoside, has shown antihypertensive, antioxidant, and anti-inflammatory effects. In the present study, the therapeutic effects of hesperidin on vascular function and remodelling, and possible underlying mechanisms involved in high-fat/high-fructose diet (HFFD)-fed rats were investigated. Male Sprague-Dawley rats were fed a high-fat diet plus 15% fructose in drinking water for 16 weeks. HFFD-fed rats were treated with hesperidin (30 mg/kg/day) or vehicle for the last 4 weeks. Treatment of HFFD-fed rats with hesperidin significantly attenuated metabolic alterations, vascular endothelial dysfunction and remodelling. Hesperidin markedly alleviated HFFD-induced oxidative stress and inflammation by decreasing plasma malondialdehyde level and aortic superoxide anion production, and by suppressing aortic tumor necrosis factor-α and interleukin-6 overexpression. Additionally, increased plasma levels of the adiponectin and nitric oxide metabolite, together with restoration of adiponectin receptor 1 (AdipoR1) and endothelial nitric oxide synthase (eNOS) protein expression, were also observed after treatment with hesperidin. These findings indicated that hesperidin alleviates HFFD-induced vascular dysfunction and remodelling in rats. The possible underlying mechanism may involve the reduction of oxidative stress and inflammation, and the restoration of AdipoR1and eNOS expression.

Cardiorenal dysfunction and hypertrophy induced by renal artery occlusion are normalized by galangin treatment in rats.

Galangin is a polyphenolic compound found in Alpinia officinarum and propolis. This study investigated the effect of galangin on blood pressure, the renin angiotensin system (RAS), cardiac and kidney alterations and oxidative stress in two-kidney one-clipped (2K-1C) hypertensive rats. Hypertension was induced in male Sprague Dawley rats (180-220 g), and the rats were given galangin (30 and 60 mg/kg) and losartan (10 mg/kg) for 4 weeks (n = 8/group). Galangin decreased hypertension and cardiac dysfunction and hypertrophy, which was related to the reducing circulation angiotensin converting enzyme (ACE) activity and angiotensin II concentration (p < 0.05). These effects were consistent with the reduced overexpression of angiotensin II receptor type 1 (AT1R), transforming growth factor beta 1 (TGF-ß1) and collagen type I (Col I) protein in cardiac tissue (p < 0.05). Additionally, renal artery occlusion, procedure-induced kidney dysfunction and fibrosis were attenuated in the galangin-treated group. Galangin treatment normalized the overexpression of AT1R and NADPH oxidase 4 (Nox-4) protein and normalized the downregulation of nuclear factor-erythroid Factor 2-related Factor 2 (Nrf-2) and haem oxygenase 1 (HO-1) in 2K-1C rats (p < 0.05). Galangin exhibited antioxidative effects, as it reduced systemic and tissue oxidative stress markers and increased catalase activity in 2K-1C rats (p < 0.05). In conclusion, galangin attenuated hypertension, renin-angiotensin system activation, cardiorenal damage and oxidative stress induced by renal artery stenosis in rats. These effects might be associated with modulation of the expression of AT1R, TGF-ß1 and Col I protein in the heart as well as AT1R/Nox-4 and Nrf-2/HO-1 protein in renal tissue in hypertensive rats.

Imperatorin attenuates cardiac remodelling and dysfunction in high-fat/high-fructose diet-fed rats by modulating oxidative stress, inflammation, and Nrf-2 expression.

Imperatorin, an active natural furocoumarin, exerts a wide range of biological activities. In the present study, the therapeutic effects of imperatorin on cardiac function and remodelling and the possible underlying mechanisms involved in high-fat/high-fructose diet (HFFD)-fed rats were investigated. Male Sprague-Dawley rats were fed a high-fat diet plus 15 % fructose in drinking water for 16 weeks. HFFD-fed rats were treated with imperatorin (15 or 30 mg/kg/day) for the last 4 weeks. Treatment of HFFD-fed rats with imperatorin significantly reduced dyslipidaemia, hyperinsulinaemia, and hypertension. Imperatorin markedly alleviated HFFD-induced cardiac morphology alterations and left ventricular (LV) dysfunction. Imperatorin also significantly decreased malondialdehyde concentration and increased catalase activity in plasma and cardiac tissue. Additionally, decreased plasma tumour necrosis factor-α and interleukin-6 concentrations, together with restoration of cardiac nuclear factor-erythroid 2-related factor 2 (Nrf-2) protein expression, were also observed after treatment with imperatorin. These findings indicated that imperatorin alleviates HFFD-induced cardiac remodelling and LV dysfunction in rats. The possible underlying mechanism may involve the reduction of oxidative stress and inflammation, and the restoration of Nrf-2 expression.

Genistein alleviates renin-angiotensin system mediated vascular and kidney alterations in renovascular hypertensive rats.

Genistein is a bioflavonoid mainly found in soybean. This study evaluated the effect of genistein on vascular dysfunction and kidney damage in two-kidney, one-clipped (2K1C) hypertensive rats. Male Sprague-Dawley-2K1C hypertensive rats were treated with genistein (40 or 80 mg/kg) or losartan 10 mg/kg (n = 8/group). Genistein reduced blood pressure, attenuated the increase in sympathetic nerve-mediated contractile response and endothelial dysfunction in the mesenteric vascular beds and aorta of 2K1C rats. Increases in the intensity of tyrosine hydroxylase (TH) in the mesentery and plasma norepinephrine (NE) were alleviated in the genistein-treated group. Genistein also improved renal dysfunction, hypertrophy of the non-clipped kidney (NCK) and atrophy of the clipped kidney (CK) in 2K1C rats. Upregulation of angiotensin II receptor type I (AT1R), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 4 (Nox4) and Bcl2-associated X protein (BAX) and downregulation of B-cell lymphoma 2 (Bcl2) protein found in CK were restored by genistein. It also suppressed the overexpression of AT1R, transforming growth factor beta I (TGF-ß1), smad2/3 and p-smad3 in NCK. Genistein reduced serum angiotensin converting enzyme (ACE) activity and plasma angiotensin II (Ang II) in 2K1C rats. Low levels of catalase activity as well as high levels of superoxide generation and malondialdehyde (MDA) in 2K1C rats were restored by genistein treatment. In conclusion, genistein suppressed renin-angiotensin system-mediated sympathetic activation and oxidative stress in 2K1C rats. It alleviated renal atrophy in CK via modulation of AT1R/NADPH oxidase/Bcl-2/BAX pathways and hypertrophy in NCK via AT1R/TGF-ß1/smad-dependent signalling pathways.

Galangin alleviates vascular dysfunction and remodelling through modulation of the TNF-R1, p-NF-κB and VCAM-1 pathways in hypertensive rats.

Galangin is a natural flavonoid isolated from ginger, honey and propolis. AIMS: To investigate the effect of galangin on blood pressure, vascular changes, sympathoexcitation, oxidative stress and inflammation in rats treated with NG-nitro-l-arginine methyl ester (l-NAME). MATERIALS AND METHODS: Male Wistar rats (220-250 g) were given l-NAME (0.5 mg/mL in drinking water) to induce hypertension for 5 weeks. They were treated with vehicle, galangin (30 or 60 mg/kg), or amlodipine (10 mg/kg) for the final two weeks (n = 6/group). KEY FINDINGS: Galangin significantly reduced blood pressure and improved the impairment of endothelium-dependent vasodilation in hypertensive rats. Sympathoexcitation, including enhancement of contractile responses to electrical field stimulation, increases in intensity of tyrosine hydroxylase and plasma norepinephrine concentration in hypertensive rats, was attenuated by galangin treatment. Galangin also reduced systemic and vascular oxidative damage and increased plasma nitric oxide levels in the hypertensive groups. Aortic remodelling accompanied by aortic wall hypertrophy and fibrosis observed in hypertensive rats were alleviated by galangin treatment. Furthermore, galangin exhibited an anti-inflammatory effect by suppressing the upregulation of tumour necrosis factor receptor 1 (TNF-R1), phospho-nuclear factor kappa B (p-NF-κB) and vascular cell adhesion protein 1 (VCAM-1) in aortic tissue and reducing plasma tumour necrosis factor alpha (TNF-α) in l-NAME rats. In conclusion, galangin had antihypertensive effects that were relevant to attenuating endothelial dysfunction, sympathoexcitation and vascular remodelling. These effects might be contributed by antioxidant and anti-inflammatory capacities and modulation of the TNF-R1, p-NF-κB and VCAM-1 pathways in hypertensive rats.

Galangin Resolves Cardiometabolic Disorders through Modulation of AdipoR1, COX-2, and NF-κB Expression in Rats Fed a High-Fat Diet.

Galangin is a natural flavonoid. In this study, we evaluated whether galangin could alleviate signs of metabolic syndrome (MS) and cardiac abnormalities in rats receiving a high-fat (HF) diet. Male Sprague-Dawley rats were given an HF diet plus 15% fructose for four months, and they were fed with galangin (25 or 50 mg/kg), metformin (100 mg/kg), or a vehicle for the last four weeks. The MS rats exhibited signs of MS, hypertrophy of adipocytes, impaired liver function, and cardiac dysfunction and remodeling. These abnormalities were alleviated by galangin (p < 0.05). Interleukin-6 and tumor necrosis factor-α concentrations and expression were high in the plasma and cardiac tissue in the MS rats, and these markers were suppressed by galangin (p < 0.05). These treatments also alleviated the low levels of adiponectin and oxidative stress induced by an HF diet in rats. The downregulation of adiponectin receptor 1 (AdipoR1) and cyclooxygenase-2 (COX-2) and the upregulation of nuclear factor kappa B (NF-κB) expression were recovered in the galangin-treated groups. Metformin produced similar effects to galangin. In conclusion, galangin reduced cardiometabolic disorders in MS rats. These effects might be linked to the suppression of inflammation and oxidative stress and the restoration of AdipoR1, COX-2, and NF-κB expression.

Butterfly Pea Flower (Clitoria ternatea Linn.) Extract Ameliorates Cardiovascular Dysfunction and Oxidative Stress in Nitric Oxide-Deficient Hypertensive Rats.

In this study, we examine whether Clitoria ternatea Linn. (CT) can prevent Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced cardiac and vascular dysfunction in rats. Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) and orally administered with CT extract (300 mg/kg/day) or lisinopril (2.5 mg/kg/day) for 5 weeks. The main phytochemical components of the CT extract were found to be flavonoids. The CT extract alleviated the high blood pressure in rats receiving L-NAME. Decreased vasorelaxation responses to acetylcholine and enhanced contractile responses to sympathetic nerve stimulation in aortic rings and mesenteric vascular beds of L-NAME treated rats were ameliorated by CT extract supplementation. Left ventricular hypertrophy and dysfunction were developed in L-NAME rats, which were partially prevented by CT extract treatment. The CT extract alleviated upregulated endothelial nitric oxide synthase expression, decreased plasma nitrate/nitrite levels, and increased oxidative stress in L-NAME rats. It suppressed high levels of serum angiotensin-converting enzyme activity, plasma angiotensin II, and cardiac angiotensin II type 1 receptor, NADPH oxidases 2, nuclear factor-kappa B, and tumor necrosis factor-alpha expression. The CT extract, therefore, partially prevented L-NAME-induced hypertension and cardiovascular alterations in rats. These effects might be related to a reduction in the oxidative stress and renin-angiotensin system activation due to L-NAME in rats.

Hesperidin ameliorates signs of the metabolic syndrome and cardiac dysfunction via IRS/Akt/GLUT4 signaling pathway in a rat model of diet-induced metabolic syndrome.

BACKGROUND: Hesperidin has been reported to have biological activities such as antihypertensive, hypoglycemic, and antioxidant effects. This study investigated whether hesperidin could improve signs of the metabolic syndrome and cardiac function in a high-fat diet (HFD) induced metabolic syndrome (MS) in rats. METHODS: Male Sprague-Dawley rats were fed HFD and 15% fructose for 16 weeks and treated with hesperidin (15 or 30 mg/kg, based on signs of MS from a preliminary study) or metformin, a positive control agent, (100 mg/kg) for the final four weeks. Cardiac function, blood pressure, fasting blood glucose, oral glucose tolerance, serum insulin, and lipid profiles were measured. Histomorphometrics of left ventricles, epidydimal fat pads and liver were evaluated. Expressions of phosphorylate insulin receptor substrate1(p-IRS1), p-Akt and GLUT4 in cardiac tissue were determined. RESULTS: Hesperidin and metformin attenuated MS in HFD rats (p < 0.05). The accumulation of visceral fat pads and fatty liver associated with increases in liver lipid contents and liver enzymes were found in MS rats that were alleviated in hesperidin or metformin-treated groups (p < 0.05). Hesperidin and metformin improved cardiac dysfunction and hypertrophy observed in MS rats (p < 0.05). Restoration of the insulin signaling pathway, IRS/Akt/GLUT4 protein expression, was demonstrated in hesperidin and metformin-treated groups (p < 0.05). Hesperidin (30 mg/kg) was more effective than the lower dose. CONCLUSION: Hesperidin was effective in reducing signs of MS and alterations of LV hypertrophy and function. These beneficial effects on the heart were associated with the restoration of the cardiac insulin signaling pathway in MS rats.

Nobiletin alleviates high-fat diet-induced nonalcoholic fatty liver disease by modulating AdipoR1 and gp91phox expression in rats.

Nobiletin, one of the polymethoxylated flavonoids isolated from citrus peels, is reported to possess various biological activities. The current study investigates the effect and possible mechanisms of nobiletin on nonalcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-fed rats. Male Sprague-Dawley rats were administrated with HFD and fructose (15%) in drinking water for 16 weeks to induce NAFLD. HFD-fed rats were treated with nobiletin (20 or 40 mg/kg/day) or vehicle for the last 4 weeks. Treatment of HFD-fed rats with nobiletin significantly reduced systolic blood pressure, adiposity, hyperlipidemia, insulin resistance, hepatic lipids content, NAFLD activity score and liver fibrosis. Nobiletin significantly increased plasma adiponectin levels, together with up-regulation of liver adiponectin receptor 1 (AdipoR1) expression. Additionally, decreased malondialdehyde levels and increased superoxide dismutase activity in plasma and hepatic tissue, consistent with down-regulation of liver NADPH oxidase subunit gp91phox expression, were also observed after nobiletin treatment. Furthermore, high dose of nobiletin exhibited higher therapeutic effect as a compared to low dose. These findings suggest that nobiletin alleviates HFD-induced NAFLD and metabolic dysfunction in rats. There might be an association between the observed inhibitory effect of nobiletin on NAFLD and modulation of AdipoR1 and gp91phox.

Nobiletin ameliorates high-fat diet-induced vascular and renal changes by reducing inflammation with modulating AdipoR1 and TGF-ß1 expression in rats.

AIMS: We investigate the effect of nobiletin on vascular and renal alterations and possible mechanisms involved in high-fat diet (HFD)-fed rats. MAIN METHODS: Male Sprague-Dawley rats were fed a HFD with fructose 15% in drinking water for 16 weeks. HFD-fed rats were treated with nobiletin (20 or 40 mg/kg/day) or vehicle for the last 4 weeks. KEY FINDINGS: HFD-fed rats treated with nobiletin was significantly reduced obesity, hypertension, dyslipidemia and hyperinsulinemia. Nobiletin improved vascular endothelial function, restored creatinine clearance, and reduced plasma urea and creatinine levels, as well as urinary protein excretion. Nobiletin markedly alleviated vascular medial cross-sectional area (CSA) and collagen deposition, glomerular extracellular matrix (ECM) accumulation, and renal fibrosis. Nobiletin significantly elevated plasma adiponectin levels, together with upregulated adiponectin receptor 1 (AdipoR1) and suppressed transforming growth factor-ß1 (TGF-ß1) expression in kidney. In addition, an increase of plasma tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was significantly attenuated after nobiletin treatment. SIGNIFICANCE: Our results suggest that nobiletin attenuates HFD-induced vascular and renal alterations in rats, which is possibly related to the modulation of AdipoR1 and TGF-ß1expression, and suppression of inflammation.

Hesperidin Prevents Nitric Oxide Deficiency-Induced Cardiovascular Remodeling in Rats via Suppressing TGF-ß1 and MMPs Protein Expression.

Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by n-nitro l-arginine methyl ester (l-NAME) in rats. Male Sprague-Dawley rats were treated with l-NAME (40 mg/kg), l-NAME plus hesperidin (15 mg/kg), hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in l-NAME rats. l-NAME-induced cardiac remodeling, i.e., increases in wall thickness, cross-sectional area (CSA), and fibrosis in the left ventricular and vascular remodeling, i.e., increases in wall thickness, CSA, vascular smooth muscle cells, and collagen deposition in the aorta were attenuated by hesperidin or captopril. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-ß1), and enhancing plasma nitric oxide metabolite (NOx) in l-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF- ß1 protein expression and the overexpression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was suppressed in l-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in l-NAME hypertensive rats. The possible mechanism may involve antioxidant and anti-inflammatory effects.

Hesperidin Suppresses Renin-Angiotensin System Mediated NOX2 Over-Expression and Sympathoexcitation in 2K-1C Hypertensive Rats.

Hesperidin, a flavonoid derived from citrus fruits, possesses several beneficial effects including anti-oxidation and anti-inflammation. The aim of this study was to investigate the effects of hesperidin on the renin-angiotensin system (RAS) cascade that mediated oxidative stress and sympathoexcitation in two-kidney, one-clipped (2K-1C) hypertensive rats. 2K-1C hypertension was induced in male Sprague-Dawley rats. Hypertensive rats were treated with hesperidin at 20[Formula: see text]mg/kg or 40[Formula: see text]mg/kg or losartan at 10[Formula: see text]mg/kg beginning at three weeks after surgery and then continued for four weeks ([Formula: see text]/group). Hesperidin reduced blood pressure in a dose-dependent manner in hypertensive rats compared to untreated rats ([Formula: see text]). Increased plasma angiotensin converting enzyme (ACE) activity and angiotensin II levels, as well as, upregulated AT1 receptor protein expression in aortic tissues were attenuated in hypertensive rats treated with hesperidin. Hesperidin suppressed oxidative stress markers and NADPH oxidase over-expression, and restored plasma nitric oxide metabolites in 2K-1C rats. This was associated with improvement of the vascular response to acetylcholine in isolated mesenteric vascular beds and aortic rings from 2K-1C rats treated with hesperidin ([Formula: see text]). Enhancement of nerve-mediated vasoconstriction related to high plasma noradrenaline in the 2K-1C group was alleviated by hesperidin treatment ([Formula: see text]). Furthermore, losartan exhibited antihypertensive effects by suppressing the RAS cascade and oxidative stress and improved vascular dysfunction observed in 2K-1C rats ([Formula: see text]). Based on these results, it can be presumed that hesperidin is an antihypertensive agent. Its antihypertensive action might be associated with reducing RAS cascade-induced NOX2 over-expression and sympathoexcitation in 2K-1C hypertensive rats.

Asiatic acid alleviates cardiovascular remodelling in rats with L-NAME-induced hypertension.

A previous study demonstrated the antihypertensive effect of asiatic acid. The current study investigates the effect of asiatic acid on cardiovascular remodelling and possible mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg per day) for 3 weeks in order to induce hypertension. Hypertensive rats were administered asiatic acid (20 mg/kg per day) or vehicle for a further 2 weeks. It was found that hypertensive rats showed high systolic blood pressure, left ventricular (LV) hypertrophy, increases in LV fibrosis, aortic wall thickness and aortic collagen deposition (P < 0.05). Moreover, decreased plasma nitrate and nitrite (NOx) and increased plasma tumor necrosis factor alpha (TNF-α) were observed in hypertensive rats (P < 0.05). This was consistent with downregulation of endothelial nitric oxide synthase (eNOS) expression and upregulation of inducible nitric oxide synthase (iNOS) expression in heart and aortic tissues (P < 0.05). Levels of malondialdehyde (MDA) in plasma, aortic and heart tissues were significantly increased in hypertensive rats (P < 0.05). Asiatic acid markedly reduced blood pressure, alleviated cardiovascular remodelling, and restored plasma NOx and TNF-α as well as eNOS/iNOS expression in heart and aortic tissues (P < 0.05). Additionally, there was a significant reduction of MDA levels in the tissues of treated hypertensive rats. In conclusion, this study demonstrates the therapeutic effects of asiatic acid on blood pressure and cardiovascular remodelling, which is possibly related to the restoration of eNOS/iNOS expression, and the resulting anti-inflammatory and antioxidant activities.

Asiatic acid alleviates hemodynamic and metabolic alterations via restoring eNOS/iNOS expression, oxidative stress, and inflammation in diet-induced metabolic syndrome rats.

Asiatic acid is a triterpenoid isolated from Centella asiatica. The present study aimed to investigate whether asiatic acid could lessen the metabolic, cardiovascular complications in rats with metabolic syndrome (MS) induced by a high-carbohydrate, high-fat (HCHF) diet. Male Sprague-Dawley rats were fed with HCHF diet with 15% fructose in drinking water for 12 weeks to induce MS. MS rats were treated with asiatic acid (10 or 20 mg/kg/day) or vehicle for a further three weeks. MS rats had an impairment of oral glucose tolerance, increases in fasting blood glucose, serum insulin, total cholesterol, triglycerides, mean arterial blood pressure, heart rate, and hindlimb vascular resistance; these were related to the augmentation of vascular superoxide anion production, plasma malondialdehyde and tumor necrosis factor-alpha (TNF-α) levels (p<0.05). Plasma nitrate and nitrite (NOx) were markedly high with upregulation of inducible nitric oxide synthase (iNOS) expression, but dowregulation of endothelial nitric oxide synthase (eNOS) expression (p<0.05). Asiatic acid significantly improved insulin sensitivity, lipid profiles, hemodynamic parameters, oxidative stress markers, plasma TNF-α, NOx, and recovered abnormality of eNOS/iNOS expressions in MS rats (p<0.05). In conclusion, asiatic acid improved metabolic, hemodynamic abnormalities in MS rats that could be associated with its antioxidant, anti-inflammatory effects and recovering regulation of eNOS/iNOS expression.