Polyguluronate Sulfate and Its Oligosaccharides but not Heparin Promotes FGF19/FGFR1c Signaling

Fibroblast growth factor 19(FGF19) functions as a hormone by affecting glucose metabolism. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. A functional cellular FGF19 receptor consists of FGF receptor(FGFR) and glycosaminoglycan complexed with either α Klotho or β Klotho. Interestingly, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar levels to a healthy range. FGF1 binds heparin with high affinity whereas FGF19 does not, indicating that polysaccharides other than heparin might enhance FGF19/FGFR signaling. Using a FGFs/FGFR1 c signaling-dependent Ba F3 cell proliferation assay, we discovered that polyguluronate sulfate(PGS) and its oligosaccharides, PGS12 and PGS25, but not polyguluronate(PG), a natural marine polysaccharide, enhanced FGF19/FGFR1 c signaling better than that of heparin based on ~3H-thymidine incorporation. Interestingly, PGS6, PGS8, PGS10, PGS12, PGS25, and PGS, but not PG, had comparable FGF1/FGFR1 c signal-stimulating activity compared to that of heparin. These results indicated that PGS and its oligosaccharides were excellent FGF1/FGFR1 c and FGF19/FGFR1 c signaling enhancers at cellular level. Since the inexpensive PGS and PGS oligosaccharides can be absorbed through oral route, these seaweed-derived compounds merit further investigation as novel agents for the treatment of type 2 diabetes through enhancing FGF1/FGFR1 c and FGF19/FGFR1 c signaling in future.

Polyguluronate Sulfate,Polymannuronate Sulfate,and Their Oligosaccharides Have AntithrombinⅢ-and Heparin CofactorⅡ-independent Anticoagulant Activity

Cardiovascular disease is the leading causes of death.However,the complications can be treated with heparin and heparinoids,such as heparin pentasaccharide Fondaparinux,dermatan sulfate,and PSS made from alginate extracted from brown seaweeds by chemical sulfation.Alginate is composed of a linear backbone of polymannuronate(PM),polyguluronate(PG),and alternate residues of mannuronic acid and guluronic acid.It is unknown if heparin and sulfated PG(PGS)/PM(PMS) have the same or different anticoagulant molecular targets.In the current study,the anticoagulant activities of PGS,PMS,and their oligosaccharides were directly compared to that of heparin,Fondaparinux,and dermatan sulfate by the activated partial thrombinplastin time(aP TT) assay using normal,antithrombin III(ATIII)-deficient,heparin co-factor II(HCII)-deficient,and ATIII-and HCII-double deficient human plasmas.Our results showed that PGS,PMS,and their oligosaccharides had better anticoagulant activity than that of Fondaparinux in all four human plasmas tested.As expected,heparin was the best anticoagulant in normal plasma.Moreover,PGS,PGS6,PGS12,PGS25,PMS6,PMS12,and PMS25 were better anticoagulants than dermatan sulfate in HCII-deficient plasma.Most strikingly,PGS,PGS12,PGS25,PMS6,PMS12,and PMS25 were better anticoagulants than that of heparin in ATIII-and HCII-double deficient human plasma.The results revealed for the first time that sulfated alginate had ATIII-and HCII-independent anticoagulant activities.Therefore,developing PGS and PMS-based anticoagulants might require to discover their major molecular targets and to develop target-specific anticoagulant assays.