生物活性

• 描述SRT3025 is a Sirt1 inhibitor which showed effect on various fields including atheroprotection. Treatment with SRT3025 at concentration of 5μM and 10μM for 24h could attenuate Pcsk9 secretion and its binding to Ldlr in cultured AML12 hepatocytes. And this reduced Pcsk9-mediated Ldlr degradation and increased Ldlr expression and LDL uptake in vitro. This effect could also observed in vivo as administration of SRT3025 for 12 weeks through supplement in diet at 3.18g/kg diet could decrease plasma levels of LDL-cholesterol and total cholesterol and reduce atherosclerosis of Apoe^-/- mice fed a high-cholesterol diet (1.25% w/w). In addition, administration of SRT3025 increased deacetylation of hepatic p65 and skeletal muscle Foxo1. Exposure of SRT3025 at concentration below 5μM for 72h reduced viability of SU86.86 in a dose-dependent manner with IC50 of 0.98μM. Oral gavage with SRT3025 at dose of 50–200 mg/kg daily for 10 days prevented pancreatic tumor growth of mice subcutaneously xenograft Panc1 cells. The SRT3025-induced cell apoptosis in vitro was lysosomal dependent. Activation of Sirt1 by SRT3025 at concentration of 10μM inhibited murine osteoclast progenitor proliferation and reduced osteoclastogenesis, which was mediated by deacetylation of FoxOs. SRT3025 could increase the expression of the FoxO-target genes catalase and HO-1 in osteoclast progenitors in FoxO-dependent manner.

• 动物研究
  剂量	Mice: 50 mg/kg - 200 mg/kg[1] (p.o.)
  给药途径	p.o.