Background:G-protein coupled receptors(GPCRs)are recognized as attractive targets for drug therapy.However,it remains poorly understood how GPCRs,except for a few chemokine receptors,regulate the progression of liver ...Background:G-protein coupled receptors(GPCRs)are recognized as attractive targets for drug therapy.However,it remains poorly understood how GPCRs,except for a few chemokine receptors,regulate the progression of liver fibrosis.Here,we aimed to reveal the role of GPR65,a proton-sensing receptor,in liver fibrosis and to elucidate the underlying mechanism.Methods:The expression level of GPR65 was evaluated in both human and mouse fibrotic livers.Furthermore,Gpr65-deficient mice were treated with either bile duct ligation(BDL)for 21 d or carbon tetrachloride(CCl4)for 8 weeks to investigate the role of GPR65 in liver fibrosis.A combination of experimental approaches,including Western blotting,quantitative real-time reverse transcription-polymerase chain reaction(qRT-PCR),and enzyme-linked immunosorbent assay(ELISA),confocal microscopy and rescue studies,were used to explore the underlying mechanisms of GPR65’s action in liver fibrosis.Additionally,the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated.Results:We found that hepatic macrophage(HM)-enriched GPR65 was upregulated in both human and mouse fibrotic livers.Moreover,knockout of Gpr65 significantly alleviated BDL-and CCl4-induced liver inflammation,injury and fibrosis in vivo,and mouse bone marrow transplantation(BMT)experiments further demonstrated that the protective effect of Gpr65knockout is primarily mediated by bone marrow-derived macrophages(BMMs).Additionally,in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited,while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and transforming growth factor-β(TGF-β),all of which subsequently promoted the activation of hepatic stellate cells(HSCs)and the damage of hepatocytes(HCs).Mechanistically,GPR65 overexpression,the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-αand IL-6 via the Gαq-Ca^(2+)-JNK/NF-κB pathways,while promoted the expression of TGF-βthrough the Gαq-Ca^(2+)-MLK3-MKK7-JNK pathway.Notably,pharmacological GPR65 inhibition retarded the development of inflammation,HCs injury and fibrosis invivo.Conclusions:GPR65 is a major regulator that modulates the progression of liver fibrosis.Thus,targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.展开更多
Van der Waals heterostructures(vdWHs)realized by vertically stacking of different two-dimensional(2D)materials are a promising candidate for tunneling devices because of their atomically clean and lattice mismatch-fre...Van der Waals heterostructures(vdWHs)realized by vertically stacking of different two-dimensional(2D)materials are a promising candidate for tunneling devices because of their atomically clean and lattice mismatch-free interfaces in which different layers are separated by the vdW gaps.The gaps can provide an ideal electric modulation environment on the vdWH band structures and,on the other hand,can also impede the electron tunneling behavior because of large tunneling widths.Here,through first-principles calculations,we find that the electrically modulated tunneling behavior is immune to the interlayer interaction,keeping a direct band-to-band tunneling manner even the vdWHs have been varied to the indirect semiconductor,which means that the tunneling probability can be promoted through the vdW gap shrinking.Using transition metal dichalcogenide heterostructures as examples and normal strains as the gap reducing strategy,a maximum shrinking of 33%is achieved without changing the direct tunneling manner,resulting in a tunneling probability promotion of more than 45 times.Furthermore,the enhanced interlayer interaction by the strains will boost the stability of the vdWHs at the lateral direction,preventing the interlayer displacement effectively.It is expected that our findings provide perspectives in improving the electric behaviors of the vdWH devices.展开更多
基金This work was supported by the National Natural Science Foundation of China(32171125,81971331 and 82170630).
文摘Background:G-protein coupled receptors(GPCRs)are recognized as attractive targets for drug therapy.However,it remains poorly understood how GPCRs,except for a few chemokine receptors,regulate the progression of liver fibrosis.Here,we aimed to reveal the role of GPR65,a proton-sensing receptor,in liver fibrosis and to elucidate the underlying mechanism.Methods:The expression level of GPR65 was evaluated in both human and mouse fibrotic livers.Furthermore,Gpr65-deficient mice were treated with either bile duct ligation(BDL)for 21 d or carbon tetrachloride(CCl4)for 8 weeks to investigate the role of GPR65 in liver fibrosis.A combination of experimental approaches,including Western blotting,quantitative real-time reverse transcription-polymerase chain reaction(qRT-PCR),and enzyme-linked immunosorbent assay(ELISA),confocal microscopy and rescue studies,were used to explore the underlying mechanisms of GPR65’s action in liver fibrosis.Additionally,the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated.Results:We found that hepatic macrophage(HM)-enriched GPR65 was upregulated in both human and mouse fibrotic livers.Moreover,knockout of Gpr65 significantly alleviated BDL-and CCl4-induced liver inflammation,injury and fibrosis in vivo,and mouse bone marrow transplantation(BMT)experiments further demonstrated that the protective effect of Gpr65knockout is primarily mediated by bone marrow-derived macrophages(BMMs).Additionally,in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited,while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and transforming growth factor-β(TGF-β),all of which subsequently promoted the activation of hepatic stellate cells(HSCs)and the damage of hepatocytes(HCs).Mechanistically,GPR65 overexpression,the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-αand IL-6 via the Gαq-Ca^(2+)-JNK/NF-κB pathways,while promoted the expression of TGF-βthrough the Gαq-Ca^(2+)-MLK3-MKK7-JNK pathway.Notably,pharmacological GPR65 inhibition retarded the development of inflammation,HCs injury and fibrosis invivo.Conclusions:GPR65 is a major regulator that modulates the progression of liver fibrosis.Thus,targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.
基金Supported by the National Key Research and Development Program of China(Grant Nos.2018YFB0406603 and 2018YFA0703704)the National Natural Science Foundation of China(Grant Nos.51991341,61904052,61851403 and 61704051)+1 种基金the Key Research and Development Plan of Hunan Province(Grant No.2018GK2064)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB30000000).
文摘Van der Waals heterostructures(vdWHs)realized by vertically stacking of different two-dimensional(2D)materials are a promising candidate for tunneling devices because of their atomically clean and lattice mismatch-free interfaces in which different layers are separated by the vdW gaps.The gaps can provide an ideal electric modulation environment on the vdWH band structures and,on the other hand,can also impede the electron tunneling behavior because of large tunneling widths.Here,through first-principles calculations,we find that the electrically modulated tunneling behavior is immune to the interlayer interaction,keeping a direct band-to-band tunneling manner even the vdWHs have been varied to the indirect semiconductor,which means that the tunneling probability can be promoted through the vdW gap shrinking.Using transition metal dichalcogenide heterostructures as examples and normal strains as the gap reducing strategy,a maximum shrinking of 33%is achieved without changing the direct tunneling manner,resulting in a tunneling probability promotion of more than 45 times.Furthermore,the enhanced interlayer interaction by the strains will boost the stability of the vdWHs at the lateral direction,preventing the interlayer displacement effectively.It is expected that our findings provide perspectives in improving the electric behaviors of the vdWH devices.
