Tetrahydroxystilbene Glycoside Improves Microvascular Endothelial Dysfunction and Ameliorates Obesity-Associated Hypertension in Obese ZDF Rats Via Inhibition of Endothelial Autophagy.

AIMS: Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension. METHODS: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP-RFP-LC3. RESULTS: Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins. CONCLUSION: Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.

Tetrahydroxystilbene glycoside improves endothelial dysfunction and hypertension in obese rats: The role of omentin-1.

RATIONALE: Hypertension in obesity has become a major threat for public health. Omentin-1, a novel adipokine, is down-regulated in obesity. Tetrahydroxystilbene glycoside (TSG) is the main ingredient extracted from Polygonum multiflorum Thunb (PMT), a traditional Chinese medicinal herb safely used for protecting cardiovascular systems over bimillennium. This study aims to examine (i) the impact of omentin-1 downregulation on obesity-related hypertension in murine models and the underlying mechanisms; (ii) whether tetrahydroxystilbene glycoside (TSG) improved endothelial dysfunction and obesity-associated hypertension via the increase of omentin-1. METHODS: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT-/-) mice were used. In vitro, human umbilical vein endothelial cells (HUVECs) and mature adipocytes differentiated from human visceral preadipocyte (HPA-v) were maintained in a co-culture system. RESULTS: TSG was the main active component of PMT reducing systolic blood pressure and improving endothelial vasodilation. Fortnight-TSG treatment (100 mg/kg/day) increased serum omentin-1 level, also activated Akt/eNOS signaling and enhanced NO bioactivity; decreased expression of NOX2 and p22phox, suppressed production of superoxide and peroxynitrite anion. OMT-/- mice showed elevated blood pressure and impaired endothelial vasorelaxation, whereas hypotensive effect of TSG was blunted. In co-culture system, TSG incubation promoted binding of peroxisome proliferator-activated receptor-γ (PPAR-γ) and Itln-1 promoter in adipocytes, activated Akt/eNOS/NO signaling and attenuated oxidative/nitrative stress in HUVECs. Suppression of Itln-1 with siRNA significantly blocked the protective effect of TSG in vitro. CONCLUSIONS: Down-regulation of omentin-1 induces endothelial dysfunction and hypertension in obesity. TSG treatment (at least partially) increases omentin-1 via promoting binding of PPAR-γ and Itln-1 promoter in adipose tissues, subsequently exerts protective effects on endothelial function via activating Akt/eNOS/NO signaling and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.

Anti-amyloidgenic and neurotrophic effects of tetrahydroxystilbene glucoside on a chronic mitochondrial dysfunction rat model induced by sodium azide.

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. Emerging evidence indicates that there is a tight relationship between mitochondrial dysfunction and ß-amyloid (Aß) formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on Aß production and neurotrophins in the brains of rats by using a mitochondrial dysfunction rat model induced by sodium azide (NaN3), an inhibitor of mitochondrial cytochrome c oxidase (COX). NaN3 was administered to rats by continuous subcutaneous infusion for 28 days via implanted osmotic minipumps to establish the animal model. TSG was intragastrically administered starting 24 h after the operation. The activity of mitochondrial COX was measured by a biochemical method. The content of Aß 1-42 was detected by ELISA. The expression of neurotrophic factors was determined by Western blot and immunohistochemistry. The results showed that NaN3 infusion for 28 days induced a decrease in mitochondrial COX activity, an increase in Aß 1-42 content and the expression of amyloidogenic ß-amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1) and presenilin 1 (PS1), and a decline in the expression of neurotrophins in the hippocampus of rats. Intragastrical administration of TSG elevated mitochondrial COX activity, decreased Aß 1-42 content and the expression of APP, BACE1 and PS1, and enhanced the expression of nerve growth factor, brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of NaN3-infused rats. These findings suggest that TSG may be beneficial in blocking or slowing the progression of AD by enhancing mitochondrial function, decreasing Aß production and increasing neurotrophic factors at some extent.

Anti-diabetic activities of cis- and trans-2,3,5,4'-tetrahydroxystilbene 2-O-ß-glucopyranoside from Polygonum multiflorum.

SCOPE: Functional foods can be used alone or in combination with existing therapies in preventing and treating type 2 diabetes (T2D). Trans-2,3,5,4'-tetrahydroxystilbene 2-O-ß-glucopyranoside (trans-THSG), a dominant bioactive compound from Polygonum multiflorum (PM)-a popular medicinal food in Asia, has attracted increasing research interests due to its strong antioxidant activity. The content of naturally occurring cis-THSG (cis-2,3,5,4'-tetrahydroxystilbene 2-O-ß-glucopyranoside) was very low in PM root, but was prepared in this study by mimicking the traditional process of PM. The anti-diabetic effects of trans- and cis-THSG were evaluated in T2D to search for more efficacious food ingredient(s). METHODS AND RESULTS: Trans-THSG was chromatographically purified from PM roots and cis-THSG was prepared with our innovative process via exposure of trans-THSG to UV-light. The anti-diabetic effects of both THSGs were tested with HFD-induced male CF-1 diabetic mice. Cis-THSG was found more effective than trans-THSG in hypoglycemic effect and in ameliorating glucose intolerance and insulin resistance. In HepG2 cells, cis-THSG also demonstrated more potent activity than trans-THSG in suppressing transcription of phosphoenopyruvate carboxykinase (PEPCK). CONCLUSION: Cis-THSG can be an enriched bioactive ingredient in PM roots from post-processing and is significantly more effective against hyperglycemia than trans-THSG. One of the effective pathways was through inhibition of PEPCK.