Mori fructus aqueous extracts attenuates liver injury by inhibiting ferroptosis via the Nrf2 pathway

Background Liver fibrosis and hepatocellular carcinogenesis secondary to liver fibrosis are serious liver diseases with no effective treatments.Mori fructus aqueous extracts(MFAEs)have served as successful treatments for many types of liver injury including fibrosis although the molecular mechanisms are unknown at present.Purpose To investigate the effect of MFAEs in alleviating acute and chronic liver injury and tried to decipher the underlying mechanism.Methods and results Mice were divided into 5 groups(n ps:contro=8)for acute(groups:control,0.3%CCl_(4),bifendate(BD),100 and 200 mg/kg MFAEs,7 d)and chronic(groul,10%CCl_(4),BD,100 and 200 mg/kg MFAEs,4 weeks)liver injury study.Each mouse was injected intraperitoneally with 10μL/g corn oil containing CCl_(4)expect the control group.HepG2 cells were used in vitro study.Eighteen communal components were identified by UPLC-LTQOrbitrap-MS.We utilized a mouse model for acute and chronic liver injury using CCl_(4)and MFAEs administration effectively blocked fibrosis and significantly inhibited inflammation in the liver.MFAEs activated the nuclear factor erythroid derived 2 like 2/heme oxygenase 1(Nrf2/HO-1)pathway and promoted the synthesis of the antioxidants glutathione(GSH),superoxidedismutase(SOD)and glutathione peroxidase(GSH-Px)that resulted in reduced levels of CCl_(4)-induced oxidative stress molecules including reactive oxygen species.These extracts administered to mice also inhibited ferroptosis in the liver by regulating the expression of Acyl-CoA synthetase long chain family member 4(ACSL4),solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),thus reducing the occurrence of liver fibrosis.Both in vivo and in vitro tests indicated that the mechanism of MFAEs protection against liver fibrosis was linked to activation of Nrf2 signaling.These effects were blocked in vitro by the addition of a specific Nrf2 inhibitor.Conclusion MFAEs inhibited oxidative stress,ferroptosis and inflammation of the liver by activating Nrf2 signal pathway and provided a significant protective effect against CCl_(4)-induced liver fibrosis.

桑椹氯仿部位化学成分研究

采用多种柱色谱手段对桑椹氯仿部位进行分离纯化,并采用磁共振、质谱及圆二色谱等波谱学技术鉴定分离得到化合物的结构。从桑椹70%乙醇提取物的氯仿萃取部位中分离得到15个化合物,分别为:(7R,8S)-赤式-7,9,9′-三羟基-3,3′-二甲氧基-8-O-4′-新木脂素-4-O-β-D-吡喃葡萄糖苷(1)、(7S,8R)-赤式-7,9,9′-三羟基-3,3′-二甲氧基-8-O-4′-新木脂素-4-O-β-D-吡喃葡萄糖苷(2)、(7S,8S)-苏式-7,9,9′-三羟基-3,3′-二甲氧基-8-O-4′新木脂素-4-O-β-D-吡喃葡萄糖苷(3)、丁香树脂醇4′-O-β-D-吡喃葡糖苷(4)、丁香酚-O-β-D-吡喃葡萄糖苷(5)、3,4-二羟基肉桂酸(6)、4-羟基-5-(2-氧代-1-吡咯烷基)-苯甲酸(7)、(6R)-5β-(6,7-二羟乙基)-4-(5′-羟甲基-呋喃-2-基-亚甲基)-2β-乙氧基-二氢呋喃-3-酮(8)、5-羟甲基糠醛(9)、2-脱氧-D-核糖-1,4-内酯(10)、4′-(3-甲基-2-丁烯基)-3′-甲氧基-5′,6-二羟基-2-苯基苯并呋喃(11)、4′-3-(甲基-2-丁烯基)-3′,5′,6-三羟基-2-苯基苯并呋喃(12)、7-(6-羟基-2-苯并呋喃基)-2,2-二甲基-2H-1-苯并吡喃-5-醇(13)、5-(6-羟基-2-苯并呋喃基)-2,2-二甲基-2H-1-苯并吡喃-7-醇(14)和β-D-吡喃葡萄糖,1-[2-(3,4-二羟基苯基)-4,6-二羟基-3-苯并呋喃甲酸酯](15)。化合物1~6为苯丙素类化合物,化合物11~15为苯并呋喃类化合物,化合物1~8和10~11为首次从该植物中分离得到。