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Beneficial Effects of THSG on Acetic Acid-induced Experimental Colitis: Involvement of Upregulating PPAR-γ and Inhibiting NF-κB Inflammatory Pathway

Author: ZengCheng
Tutor: WangJiaLing
School: Huazhong University of Science and Technology
Course: Pharmacology
Keywords: THSG IBD MPO MDA 2,3,5,4’-tetrahydroxystilbene-2-O-beta-D-glucoside Inflammatory bowel disease Peroxisome proliferator-activated receptor-γ Nuclear factor-кB
CLC: R285
Type: PhD thesis
Year: 2011
Downloads: 89
Quote: 0
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Abstract


PartⅠ:Determination of THSG and study of the time-effect and dose-effect relationship of THSGBackground and Objective:Polygonum multiflorum Thunb (PM) is a typically traditional Chinese medicinal herb. PM has been used for thousands of years as a tonic and anti-aging agent and been used effectively to prevent graying, treat skin depigmentation diseases and lubricate the intestine.2,3,5,4’-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG), extracted from PM, has been demonstrated to possess the protective effects on anti-oxygen and anti-inflammation. Here we examine the content of THSG extracted from PM and explore the time-effect and dose-effect relationship of THSG against experimental colitis induced by acetic acid.Methods:Content of THSG extracted from PM was tested by using high performance liquid chromatography (HPLC). Staining method of HE was used to assess the inflamm-atory degree of colonic tissues. MPO and MDA were examined by a biochemical method.Results:By screening, the best chromatographic conditions were to employ Hypersil ODS-C18 (5um,4.6×250 mm) as the stable phase, methanol-water (4:6) as mobile phase, 310nm as the detective wavelength. Within the range from 4.224~132μg/mL, there was a good linearity with the regression equation of Y=19087X-19466, r=0.970.5,7 and 10 days after model preparation, the mice deceased gradually in the body weight, compared with the normal mice. Mesalazine, a positive drug control, significantly reversed the loss of the body weight. THSG 10,30,60 mg/kg could dose-dependently improve the loss of body weight. THSG 60 and 120 mg/kg could enhance the body weight similar to the mice in normal and 5-ASA group. After acetic acid administration, treatment with THSG for 5,7 and 10 days, at doses of 10,30,60 and 120 mg/kg, could reduce edema, ulcer and adhesions to adjacent bowel wall comparing with the acetic acid control group. HE staining showed that treatment with THSG could obviously attenuate granulocytes infiltrating, mucosal edema and also improve necrosis of epithelial cells and ulcer. The elevation of MDA was also attenuated by THSG in a dose dependent manner at the doses of 10,30 and 60 mg/kg; but there was no difference between 60 and 120 mg/kg THSG. The increase of MPO was also lowered by THSG in a dose dependent manner at the doses of 10,30 and 60 mg/kg; and there was no difference between 60 and 120 mg/kg THSG.Conclusion:The content of self-produced THSG was up to 99.90%, which tallied with the monomer quality standard. At the doses of 10 to 60 mg/kg, the protective effect of THSG was in a dose-dependent manner; but there was no difference at the doses of 60 to 120 mg/kg, due to THSG 60 mg/kg has already had the maximum effect and they were at the platform period of pharmacological effect.Part II:Protective effects of THSG on inflammatory bowel disease and the underlying mechanismBackground and Objective:Inflammatory bowel disease (IBD) is a disease that has not only reduced the quality of life for patient, but also brought great economic pressure on society. Cumulative studies have shown that significant association between IBD and the deficiency of PPAR-y. Among the inflammatory cascade reaction, activated NF-κB induces the target inflammatory genes such as TNF-a, IL-6 and COX-2 expression which leads to over-expression of reactive oxygen/nitrogen species (ROS/RNS) and at last completes the positive feedback loop between inflammation and oxidation.2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside (THS-G), an active component of the Polygonum multiflorum Thunb (PM), exhibits anti-oxidative and anti-inflammatory effects. Our previous studies have shown that THSG exerts protective effects on experimental colitis through alleviating oxygen and nitrogen free radicals level and down-regulating iNOS expression. In the paper, we investigated the anti-inflammatory effects of THSG on experimental colitis as well as the underlying mechanisms.Methods:Acetic acid-induced experimental colitis was established. RT-PCR was used to determine the Peroxisome proliferator-activated receptor gamma (PPAR-γ) expression at the mRNA level. Western blot analysis was used to assess the express-ion of TNF-α, IL-6, COX-2, NF-κB and PPAR-y protein.Results:After acetic acid administration, treatment with THSG for 7 days, at doses of 10, 30 and 60 mg/kg, could attenuate the increased protein expression of inflammato -ry mediator TNF-a, IL-6 and COX-2 in a dose dependent manner; THSG 60 mg/kg could decreased TNF-a expression to 120.88±4.45% of normal group; THSG 60 mg/kg could lower IL-6 protein expression and the decreased extent was better than that of mesalazine; at the doses of 10,30 and 60 mg/kg, THSG could also inhibit expression of COX-2 in a dose dependent manner; and the COX-2 expression were decreased to 200.3±6.67%, 142.28±7.46% and 118.56±5.59% of normal group. THSG 10,30 and 60 mg/kg could attenuate NF-κB expression to 186.57±4.12%,171.3±6.94% and 91.51±3.67% of normal group, respectively. THSG could dramatically increase PPAR-y expression at both the mRNA level and protein level. The effect of THSG 60 mg/kg was better than that of mesalazine.Conclusion:Our study indicated that THSG protected against acetic acid-experime-ntal colitis through broken positive feedback loop between inflammation and oxidation including upregulation of PPAR-y expression, down regulation of NF-κB expression, inhibition of TNF-α, IL-6, COX-2 expression.

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