Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine(SAMC) from aged ga...Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine(SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model(the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC(300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis,insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor(INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3 b signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC(250 mmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC’s beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model.Long-term(90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3 b pathway.展开更多
Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 g...Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 group A member 1(NR4A1)was implicated in synaptic plasticity,long-term memory formation,suggesting that it may play a role in the pathophysiology of AD.Here,we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice.In addition,NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels,down-regulated ADAM10 expression,and promoted amyloidogenesis as indicated by decreased a-CTF levels and elevated b-CTF levels.Furthermore,a raised level of phospho-tau(p-tau,S396)was accompanied by p-GSK3b(S9)expression reducing,but total tau,p-tau(S262 and T231),CDK5 and ERK remained unchanged in NR4A1-overexpressing cells.Collectively,our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells;as well as NR4A1 accelerates tau hyperphosphorylation by GSK3b signal.Therefore,NR4A1 may play an important role in the pathogenesis of AD.展开更多
基金supported by National Natural Science Foundation of China (81970515)Guangdong Natural Science Funds for Distinguished Young Scholar (2019B151502013, China)。
文摘Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine(SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model(the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC(300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis,insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor(INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3 b signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC(250 mmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC’s beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model.Long-term(90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3 b pathway.
基金This study was supported by the National Natural Science Foundation of China(grant numbers:31500821).
文摘Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 group A member 1(NR4A1)was implicated in synaptic plasticity,long-term memory formation,suggesting that it may play a role in the pathophysiology of AD.Here,we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice.In addition,NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels,down-regulated ADAM10 expression,and promoted amyloidogenesis as indicated by decreased a-CTF levels and elevated b-CTF levels.Furthermore,a raised level of phospho-tau(p-tau,S396)was accompanied by p-GSK3b(S9)expression reducing,but total tau,p-tau(S262 and T231),CDK5 and ERK remained unchanged in NR4A1-overexpressing cells.Collectively,our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells;as well as NR4A1 accelerates tau hyperphosphorylation by GSK3b signal.Therefore,NR4A1 may play an important role in the pathogenesis of AD.
