Effects Of Alginate Derivatives And Fucoidans On Diabetes And Its Complications

In this thesis, the effects of marine carbohydrates on diabetes and its complications were investigated, and the regulation mechanisms were also clarified. Sulfated low molecular weight guluronate (SLMG) was found to down-regulate lipid synthesis for the first time. Moreover, the fucoidans extracts of Fucus vesiculosus (FNF) had better a-glucosidase inhibitory activity than acarbose, and it was also found to be potent therapy drug for diabetic nephropathy, the mechanism of which was further discussed.Low molecular weight and sulfated low molecular weight guluronate (LMG and SLMG) were prepared and the hypolipidemia effects on a human hepatocellular carcinoma HepG2 cell line were investigated. Both compounds decreased total cholesterol (TC) and triglyceride (TG) and increased apolipoprotein AI (apo AI) contents in HepG2 cells. In general, SLMG had better activities than that of LMG. Activations of Sterol regulatory element-binding protein 2 (SREBP-2), LDLR, AMP-activated protein kinase (AMPK) and AMPK’s downstream targets were, evidenced by increased phosphorylations of AMPK,3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and acetyl-CoA-carboxylase (ACC), which resulted in decreased activities of HMGRC and ACC. We further demonstrated that the activated AMPK was linked to down-regulated SREBP-1 and up-regulated cholesterol 7a-hydroxylase (CYP7A1).Kinds of extracts of seaweeds for a-glucosidase inhibitory effects was evaluated, and the results showed fucoidans from F. vesiaulosus (FNF) had good inhibitory activity (IC50=39 μg/mL), which was better than acarbose (IC5o=387 μg/mL). Degradation of FNF by simulated gastric acid did not reduce its activity. Results of acid degradation and ultrafiltration of FNF indicated the activity was associated with the high molecular weight. The content of Polyphenol in FNF was only 0.43%, which indicated that polyphenol was not the active ingredient. The effect of inhibition of α-glucosidase was reduced after deproteinization indicated the proteinbinding to glycan has a certain contribution to the inhibitory activity, but it was not the main active unit. The results above indicated that fucoidans is the main active substances in FNF. IEC-6 cells toxicity tests showed FNF had no significant cytotoxicity; db/db mice experiment showed FNF could decrease random blood glucose, postprandial blood glucose and glycated hemoglobin.Fucoidans were found to inhibit renal cell proliferation on HBZY-1 cell lines in a dose-dependent manner, which could slow the kidney fibrosis. Among 11 kinds of fucoidans, FNF showed the best ability to inhibit the cell proliferation. We observed no toxicity up to 200 μM in that FNF did not influence the proliferation of IEC-6 and HBZY-1 cells. The results of Western blotting indicated FNF could reduce the synthesis of cytoskeletal protein a-SMA by inhibiting the expression of TGF-β1R and TGF-β1, and could promote the degradation of the extracellular matrix by inhibiting the expression of TIMP-1.In summary, SLMG was found to regulate the liqid metabolic of liver by activating AMPK. FNF had good a-glucosidase inhibitory effects in vitro and could decrease random blood glucose, postprandial blood glucose and glycated hemoglobin in db/db mice. Moreover, FNF could slow the kidney fibrosis. Results showed both of them could be developed as potential adjuvant in the prevention and treatment of diabetes and its complications.