Studies On The Antidiabetic Activities And Mechanisms Of Novel Flavonoid Derivatives Of Potentilla Chinensis

Objective:The present study was to screen of novel flavonoid derivatives of potentilla chinensis with anti-diabetes activities,using alloxan-induced diabetic mice.Observing the effects of anti-diabetic.candiadate compound on regulating glucose,lipid metabolism and insulin resistance,antioxidant and anti-inflammatory on type 2 diabetes model,to explore the anti-diabetic mechanisms of Fla-CN and provide a theoretical basis for further drug candidate compounds derived systhesis.Method:1.Mice were initated with intervenous injection 80mg/kg alloxan to establish diabetic model mice,the alloxan-diabetic mice and normal mice were randomly divided into the model group,novel flavonoid derivatives of potentilla chinensis with different dosage and normal control group.Each goup were given derivates for 15 days,once a time.Mouse weight and fasting blood glucose level were measuremented once a week,serum TG and TC were also tested at the end of the experiment.2.C57BL/Ksj-db/db mice were randomly divided into 5 groups,positive control group,db/db control group,Fla-CN high,medium and low dose group.After 4 weeks drug administration,OGTT,ITT,INS,serum TG,TC,NEFA,LDL,HDL,TNF?,MDA and SOD activity were detected on each group.3.The phosphorylation levels of AMPK,Akt and ACC in liver and adipose tissue of db/db mice were detected by WB,the gene transcription levels of miRNA29b,miRNA29c.miRNA33a and miRNA33b were also detected in liver and adipose tissue by RT-PCR.Results:1.After injected with alloxan for three days,alloxan diabetic mice were selected,which's fasting blood glucose amounted to over 11.1mmol/L.Typical symptoms of diabetes were appeared on the diabetic mice,which means the the diabetic mice model was successful and reliable.After administration for 15 days,compared with the model group,the FBG level was decreased in different degree with the novel flavonoid derivatives of potentilla chinensis in mice,while the TG and TC levels could be decreased significantly by Fla-CN,Fla-OEt,Fla-Me,Fla-Cl.2.Compared with the model group,the levels of FBG and lipids decreased significantly and the glucose tolerance was significantly improved in Fla-CN and Fla-OEt treated groups.In addition,the external signs and weight were also significantly improved in Fla-CN treated groups.The experimental results showed that the derivative Fla-CN had more potential.3.The obse polydipsia symptom was existed before test in db/db mice,there were no obvious changes on body weight and food intake in db/db mice after treated with Fla-CN for 4 weeks.After 4 weeks Fla-CN administration,compared with db/db control group,the levels of FBG,INS,serum TC,TG,LDL,NEFA,MDA and TNF-a were decreased,the serum HDL level and SOD activity were increased,the tolerance of glucose and insulin was improved in db/db mice.And there was a certain dose-effect relationship among these Fla-CN groups.4.Compare to db/db control group,the phosphorylation levels of AMPK,Akt and ACC in liver and adipose tissue of db/db Fla-CN groups had been significantly increased,the gene expression levels of miRNA29b,miRNA29c in liver and adipose tissue of db/db Fla-CN groups had been obviously lowered,and the effects were better or equalily to melformin,there was a certain dose-effect relationship between Fla-CN groups too.Conclusion:These results suggested that novel flavonoid derivatives of potentilla chinensis possess hypolipidemic and hypoglycemic properties in alloxan induced diabetic mice,and derivative Fla-CN had more potential.Fla-CN can improve glycometabolism.lipid metabolism and IR,also has antioxidant,anti-inflammatory effect.Its mechanism might be relate to increase p-AMPK,p-ACC,p-Akt levels and decrease miRNA29b and miRNA29c both in liver and adipose tissue.