Objective Ticagrelor is a widely used anti-platelet drug.However,the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury(AKI)have not been clearly demonstrated.We designed this study to ...Objective Ticagrelor is a widely used anti-platelet drug.However,the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury(AKI)have not been clearly demonstrated.We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.Methods C57BL6J mice received oral ticagrelor(20 mg/kg and 50 mg/kg)for 7 days,and then caecal ligation and puncture(CLP)were performed.An adenosine receptor antagonist,CGS15943,was administered(10 mg/kg,intraperitoneal injection)to block the adenosine pathway 2 h before CLP.After 24 h,serum creatinine levels were measured.Periodic acid-Schiff(PAS)staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)staining were employed to analyze pathological changes and cell apoptosis.Serum concentrations of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and mRNA expression of tissue TNF-αand IL-1βwere detected.Western blotting analysis was used to determine AKT and mammalian target of rapamycin(mTOR)protein expression in the kidney.Results PAS staining showed less swelling of renal tubules,and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group.Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group.Moreover,significantly lower serum and kidney levels of TNF-αand IL-1βwere observed in the ticagrelor group.CGS15943 blocked the effects of ticagrelor.Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group.The adenosine receptor antagonist inhibited the activation of AKT and mTOR.Conclusion This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.展开更多
Recently,the films of the Ruddlesden-Popper(RP) nickelate superconductors,in which the(La,Pr)_(3) Ni_(2)O_(7) system exhibits a remarkable transition temperature T_(c) exceeding 40 K,were synthesized at ambient pressu...Recently,the films of the Ruddlesden-Popper(RP) nickelate superconductors,in which the(La,Pr)_(3) Ni_(2)O_(7) system exhibits a remarkable transition temperature T_(c) exceeding 40 K,were synthesized at ambient pressure.We systematically investigate the band structures and electronic correlation effects to identify the key factors controlling superconductivity and pathways to enhance T_(c).Based on density functional theory(DFT) calculations,we construct a bilayer two-orbital(3d_(3_(z^(2))-r^(2)) and 3d_(x^(2)-y^(2))) tight-binding model for a series of in-plane compression mimicking the substrate effect.We find the band energy at the M point drops with the compression,leading to an increase in the density of states at the Fermi level,in stark contrast to the behavior of the bulk under pressure.We then apply the functional renormalization group(FRG) method to study the electronic correlation effect on the superconductivity.We find the s_(±)-wave pairing symmetry remains robust in the films,the same as the bulk.But somewhat surprisingly,for the films,we find T_(c) can be enhanced by reducing the in-plane lattice constant,increasing the out-of-plane lattice constant,or further electron-doping.These findings are consistent with the itinerant picture of the superconductivity induced by spin-fluctuations and provide theoretical support for further boosting T_(c) in future experiments.展开更多
基金the National Natural Science Foundation of China(No.81700265 to Cong FU and No.81702092 to Yu-han CAO).
文摘Objective Ticagrelor is a widely used anti-platelet drug.However,the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury(AKI)have not been clearly demonstrated.We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.Methods C57BL6J mice received oral ticagrelor(20 mg/kg and 50 mg/kg)for 7 days,and then caecal ligation and puncture(CLP)were performed.An adenosine receptor antagonist,CGS15943,was administered(10 mg/kg,intraperitoneal injection)to block the adenosine pathway 2 h before CLP.After 24 h,serum creatinine levels were measured.Periodic acid-Schiff(PAS)staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)staining were employed to analyze pathological changes and cell apoptosis.Serum concentrations of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and mRNA expression of tissue TNF-αand IL-1βwere detected.Western blotting analysis was used to determine AKT and mammalian target of rapamycin(mTOR)protein expression in the kidney.Results PAS staining showed less swelling of renal tubules,and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group.Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group.Moreover,significantly lower serum and kidney levels of TNF-αand IL-1βwere observed in the ticagrelor group.CGS15943 blocked the effects of ticagrelor.Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group.The adenosine receptor antagonist inhibited the activation of AKT and mTOR.Conclusion This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.
基金supported by the National Key Research and Development Program of China (Grant Nos.2024YFA1408100,and 2022YFA1403201)the National Natural Science Foundation of China (Grant Nos.12074213,12374147,12274205,and 92365203)the Major Basic Program of Natural Science Foundation of Shandong Province (Grant No.ZR2021ZD01)。
文摘Recently,the films of the Ruddlesden-Popper(RP) nickelate superconductors,in which the(La,Pr)_(3) Ni_(2)O_(7) system exhibits a remarkable transition temperature T_(c) exceeding 40 K,were synthesized at ambient pressure.We systematically investigate the band structures and electronic correlation effects to identify the key factors controlling superconductivity and pathways to enhance T_(c).Based on density functional theory(DFT) calculations,we construct a bilayer two-orbital(3d_(3_(z^(2))-r^(2)) and 3d_(x^(2)-y^(2))) tight-binding model for a series of in-plane compression mimicking the substrate effect.We find the band energy at the M point drops with the compression,leading to an increase in the density of states at the Fermi level,in stark contrast to the behavior of the bulk under pressure.We then apply the functional renormalization group(FRG) method to study the electronic correlation effect on the superconductivity.We find the s_(±)-wave pairing symmetry remains robust in the films,the same as the bulk.But somewhat surprisingly,for the films,we find T_(c) can be enhanced by reducing the in-plane lattice constant,increasing the out-of-plane lattice constant,or further electron-doping.These findings are consistent with the itinerant picture of the superconductivity induced by spin-fluctuations and provide theoretical support for further boosting T_(c) in future experiments.
