关键词:

"> 白芍总苷, 脂质过氧化, 糖尿病肝损伤, NRF2 / SLC7A11 / GPX4 通路, 铁死亡

Abstract:

This study aimed to investigate the protective effect of total glucosides from Paeoniae Radix Alba (TGP) against liver injury in rats with type 2 diabetes mellitus (T2DM) by regulating of the nuclear factor erythroid 2-related factor 2 (NRF2) / solute carrier family 7 member 11 (SLC7A11) / glutathione peroxidase 4 (GPX4) signaling pathway to inhibit hepatocyte ferroptosis. Using T2DM model rats as experimental subjects,and the animals were randomly divided into control group,model group,metformin group,and TGP (50,100,and 200 mg/ kg) groups. They were treated with the corresponding drugs or distilled water by oral gavage for four weeks. Fasting blood glucose (FBG) and liver indexs were tested,and the biochemical method is used to detect alanine aminotransferase (ALT),aspartate aminotransferase (AST),triglycerides (TG), total cholesterol ( TC), low-density lipoprotein cholesterol ( LDL-C), and high-density lipoprotein cholesterol ( HDL-C) . Histopathological changes were evaluated. Superoxide dismutase (SOD),malondialdehyde (MDA),glutathione (GSH),and Fe^{2 +} levels were detected by colorimetric assay. The protein expressions of transferrin receptor 1 ( TFR1), ferroportin 1 (FPN1) ,NRF2,SLC7A11,and GPX4 were assessed with Western blot,and their gene expressions were checked by RTqPCR. Compared with the control group,the model group showed significantly elevated levels of FBG,liver index,ALT,AST, TG,TC,LDL-C and MDA (P < 0. 01),and significantly decreased levels of HDL-C,SOD and GSH (P < 0. 01). Lipid deposition and lipotoxic inflammatory injury were observed in liver tissue. The hepatic Fe^{2 +} content and TFR1 expression were increased (P < 0. 01),while the protein expressions of FPN1,NRF2,SLC7A11 and GPX4 were significantly down-regulated (P < 0. 01),and the mRNA expression levels of NRF2,SLC7A11 and GPX4 were markedly reduced (P < 0. 01). Compared with the model group,High-dose TGP markedly reduced FBG levels in model rats (P < 0. 05). In the medium- and high-dose TGP groups,the liver index and levels of ALT,AST,TG,TC,and LDL-C were significantly decreased (P < 0. 05,P < 0. 01),while HDL-C was notably increased (P < 0. 01). Hepatic pathological injury and steatosis were alleviated to varying degrees;MDA expression was significantly decreased (P < 0. 01),and SOD and GSH expressions were markedly elevated (P < 0. 01). The protein levels of NRF2,SLC7A11,and GPX4 were significantly upregulated ( P < 0. 01) . High-dose TGP significantly increased the mRNA expressions of NRF2, SLC7A11,and GPX4 (P < 0. 01). In all TGP-treated groups,Fe^{2 +} content were significantly reduced (P < 0. 01) and FPN1 expression was markedly increased (P < 0. 01);TFR1 was significantly decreased in the medium- and high-dose groups (P < 0. 01). TGP can improve hyperglycemia and liver injury in T2DM rats,and the mechanism may involve in activating the NRF2 / SLC7A11 / GPX4 signaling pathway and therefore to inhibit ferroptosis.

Key words:

"> total glucosides from Paeoniae Radix Alba, lipid peroxidation, diabetic liver injury, NRF2 / SLC7A11 / GPX4 pathway, ferroptosis