Cytological Studies On The Mechanism Of Pseudolaric Acids Preventing And Curing Type 2 Diabetes Mellitus

Insulin resistance is one of the main pathogenesis of type 2 diabetes mellitus(T2DM).Previous studies have shown that insulin resistance will lead to endoplasmic reticulum stress and mitochondrial damage,and all of them are the main factors inducing T2 DM.Previous studies of our group have found that pseudolaric acid B(PAB)has the function of preventing and treating T2 DM in mice.In the paper,the mechanism of pseudolaric acid A(PAA)and PAB preventing and treating T2 DM was elucidated from cytological level,based on the studies of the regulation of PAA and PAB to insulin resistance,endoplasmic reticulum stress.mitochondrial damage and related proteins of human hepatocellular carcinoma cells(HepG2),the studies of the inhibition of PAA and PAB to the release of nitric oxide(NO)from macrophages(RAW 264.7)and microglial cells(BV2),and the protection of PAA and PAB to islet ? cells(min6).It was shown that PAA and PAB can significantly alleviate human hepatocellular carcinoma cells' insulin resistance,endoplasmic reticulum stress induced by tunicamycin and mitochondrial damage induced by oligomycin,and the effect of PAB is stronger than that of PAA,and the effect of 10?M PAB is close to that of 10?M rosiglitazone.PAA and PAB could reduce the ROS level and increase the ATP level in the mitochondrial damage model cells.Both of PAA and PAB could upregulate the expression of PPAR-?,IRS-1 and P-Akt proteins and down-regulate the expression of GRP-78 in hepatocellular carcinoma cells.The NO release from macrophages and microglial cells was significantly reduced after the treatment of PAA or PAB.PAA and PAB could also decrease the apoptotic degree of ? islet cells,and the protective effect of PAB on ? islet cells was significantly better than that of PAA.The following conclusions could be drawn from the above experiments:(1)Pseudolaric diterpenoid acid compounds,PAA or PAB,can significantly relieve insulin resistance,endoplasmic reticulum stress and mitochondrial damage of human hepatocellular carcinoma cells,and the effect of PAB is stronger than that of PAA.(2)PAA or PAB,as a PPAR-? agonist,can allivate endoplasmic reticulum stress and mitochondrial damage by upregulating the expression of IRS-1 and p-Akt,and down-regulate the expression of GRP-78.And PAA and PAB inhibit endoplasmic reticulum stress and mitochondrial damage of human hepatocellular carcinoma cells through the above effects.(3)PAA or PAB can inhibit the inflammation of macrophages and microglial cells by decreasing the NO production.(4)Pseudolaric acid compouds have the protecting functions for ? islet cells.Through the above effects,pseudolaric diterpenoid acids play the functions of anti-T2 DM.