Dissertation
Dissertation > Medicine, health > Chinese Medicine > Of Pharmacy > Pharmacology

Therapeutical Effect of5,7,3’-Triacetyl Hesperetin on Adejuvant Arthritis in Rats and Its Mechanisms

Author RenDanYang
Tutor LiJun
School Anhui Medical University,
Course Of Pharmacy
Keywords 5,7,3′-triacetyl hesperetin adjuvant-induced arthritis Jak2/Stat3 fibroblast-like synoviocytes Caspase-3 synovial tissue
CLC R285
Type Master's thesis
Year 2012
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Rheumatoid arthritis (RA) is a common chronic autoimmune disease,characterized by cytokine-mediated inflammation of the synovial lining of the jointsand destruction of cartilage and bone,which has high morbidity and is one of themajor diseases caused loss of labor crowd. But so far the pathogenesis of RA have notbeen completely cleared, numerous studies have confirmed that immune functiondisorder, synoviocyte extensive proliferation and articular cartilage or bone destroyare key etiological factors in RA development. Although there are a fewanti-rheumatic drugs showing effectiveness on treating RA, their side effects andtoxicity call for new and more effective natural drugs.Hesperidin, a flavanone glycoside comprising the hesperetin and the disacchatiderutinose, had been reported to have anti-rheumatic effects. However, its poor watersoluble ability and low biosvailability limited the application in medicine.With thedeep research on chemical modification od hesperidin, many hesperidin derivativesexerted better water soluble ability and bioavailability than hesperidin itself. In ourprevious studies, we aimed he structural feature of hesoeridin and synthesized a seriesof hesperidin derivatives. On the basis of our previous work, the aim of the currentstudy was first to screen the anti-inflammatory activity of hesperidin derivatives invivo and vivo. Then, the anti-rheumatic effect of hesperidin derivative (5,7,3′-triacetyl hesperetin, TAHP) with potent anti-inflammatory antivity was observed inAA rat model.We explored the possible mechanisms of TAHP on AA rat fromsynoviocyte proliferation or apoptosis. Therefore, this study provided experimentaldata for the development of new therapeutic interventions and targets of RA.The article is divided into three sections as follows: 1.5,7,3′-triacetyl hesperetin suppresses adjuvant-induced arthritis in ratsthrough modulating Jak2/Stat3pathwayObjectives:This work was designed to identify the effect of5,7,3′-triacetylhesperetin (TAHP) on rat adjuvant arthritis (AA) and further clarity the possible roleof TAHP on modulating Janus kinase signal transducers and activators (Jaks/Stats)pathway in this process. Methods:Freund’s complete adjuvant was used to induce AAin rats. TAHP (33,66,132mg/kg) was administered intragastrically. Secondary pawswelling, polyarthritis index, index of immune organs and histopathologicalassessment were used to evaluate the effects of TAHP on AA in rats. IL-6in serumwas examined with ELISA. In addition, Jak2/Stat3pathway-related key moleculeswere detected by RT-PCR and western blot respectively. Result: It was found thatTAHP (66,132mg/kg) could significantly inhibit secondary paw swelling, restore theindex of immune organs and reduce polyarthritis index. Results of histopathologicalassessment showed that TAHP clearly ameliorated the pathological changes in AA rats.TAHP could downregulate the level of IL-6in serum of AA rats. Besides, treatmentwith TAHP could decrease mRNA expressions of Stat3and Jak2, as well as the ratioof p-Jak2/Jak2protein and p-Stat3/Stat3protein from synovial tissues. Conclusions:The paper demonstrated that TAHP had a therapeutic effect on AA in rats and themechanisms were partly associated with inhibiting excessive activation of Jak2/Stat3signalling pathway which might play a crucial role in the pathogenesis of AA.2. The influence of5,7,3′-triacetyl hesperetin on Jak2/Stat3signalling pathwayand related apoptosis proteins of fibroblast-like synoviocytes in rats withadjuvant arthritisObjective: To investigate the effect of5,7,3′-triacetyl hesperetin (TAHP) onJak2/Stat3pathway and related apoptosis proteins of fibroblast-like synoviocytes(FLS) with adjuvant-induced arthritis in rats. Methods: Freund’s complete adjuvantwas used to induce AA in rats. FLS proliferation response was evaluated with MTTassay. The apoptosis of FLS was detected by Hoechst33258staining. The expressionsof Jak2、Stat3、Bcl-2、Bax and Caspase-3mRNA in FLS was detected by RT-PCR. The protein expressions of p-Stat3and Caspase-3were observed by Western blot.Results: The proliferation of FLS was inhibited by TAHP in a dose-and-timedependent manner. Hoechst33258staining indicated that TAHP could obviouslyincrease the AA FLS apoptosis. The results of RT-PCR showed that TAHP(50,250μmol/L)chould reduce the expressions of Jak2、Stat3and Bcl-2(P<0.05)butup-regulate the expressions of Bax and Caspase-3. The results of Western blot showedthat TAHP(50,250μmol/L)chould reduce the expression of p-Stat3and up-regulatethe expression of Caspase-3. Conclusions: TAHP chould inhibit the of theproliferation of FLS. The mechanism might be associated with inhibiting Jak2/Stat3pathway, promoting the expressions of Bax and Caspase-3, decreasing the expressionof Bcl-2.

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