Background and Aims:Reducing reactive oxygen species(ROS)production has proven an effective way for allevi-ating oxidative stress during ischemia-reperfusion injury(IRI).Moreover,inhibition of Rac1 could reduce ROS pr...Background and Aims:Reducing reactive oxygen species(ROS)production has proven an effective way for allevi-ating oxidative stress during ischemia-reperfusion injury(IRI).Moreover,inhibition of Rac1 could reduce ROS pro-duction and prevent oxidative stress injury.Previous stud-ies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor(HIF)-1α,the latter being up-regulated early during ischemia.The posi-tive inter-activation between Rac1 and HIF-1αwould ag-gravate ROS production,thereby promoting IRI.This study was designed to verify the effects of Rac1 inhibition on he-patic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1αduring hepatic IRI.Methods:C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models.Rac1 inhibition was achieved by NSC23766(a specific Rac1 inhibitor).Lentiviral vectors were used for Rac1 knock-down.At designated time points,serum and liver tissues were collected from the mice and treated cells were col-lected for further analysis.Results:NSC23766 treatment significantly alleviated the hepatic IRI in mice,manifesting as lower vacuolation score and less apoptosis cells,lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels,and fewer activated inflammatory cells.IRI of AML-12 was also alleviated by 50μM NSC23766 or Rac1-knockdown,manifesting as reduced cell apoptosis,less extensive interruption of mitochondrial membrane po-tential,down-regulation of apoptosis,and effects on DNA damage-related proteins.Interestingly,Rac1 knockdown also down-regulated the expression level of HIF-1α.Con-clusions:Our study supports a protective effect of Rac1 inhibition on hepatic IRI.Aside from the classic topics of reducing ROS production and oxidative stress,our study showed an interaction between Rac1 and HIF-1αsignaling during hepatic IRI.展开更多
With the rapid application of nuclear energy and radiological technology in national economy and military field,the risk of nuclear accidents increases as well.Exposure to irradiation causes severe damages to the huma...With the rapid application of nuclear energy and radiological technology in national economy and military field,the risk of nuclear accidents increases as well.Exposure to irradiation causes severe damages to the human body,and radioprotective agents are required for medical protection.To find the safe and effective radioprotective agents is the key for nuclear emergency.Recently,Toll like receptors(TLRs)and PHD-HIF oxygen sensing signal pathway have been extensively studied for radioprotection.Great progress has been made in this field and a number of radioprotective agents have been found.In this review,we have summarized recent findings of radioprotective roles of TLRs signaling pathway and PHD-HIF signaling pathway and discussed the general principles of developing novel radioprotective agents.These findings will provide opportunities for developing new strategies to prevent IR-induced injuries in public health events.展开更多
基金This work was supported by the grants from the National Natural Science Foundation of China(No.81671576)the Shanghai Sailing Program(No.18YF1429200),and the Nat-ural Science Foundation of Shanghai(No.18ZR1449700).
文摘Background and Aims:Reducing reactive oxygen species(ROS)production has proven an effective way for allevi-ating oxidative stress during ischemia-reperfusion injury(IRI).Moreover,inhibition of Rac1 could reduce ROS pro-duction and prevent oxidative stress injury.Previous stud-ies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor(HIF)-1α,the latter being up-regulated early during ischemia.The posi-tive inter-activation between Rac1 and HIF-1αwould ag-gravate ROS production,thereby promoting IRI.This study was designed to verify the effects of Rac1 inhibition on he-patic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1αduring hepatic IRI.Methods:C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models.Rac1 inhibition was achieved by NSC23766(a specific Rac1 inhibitor).Lentiviral vectors were used for Rac1 knock-down.At designated time points,serum and liver tissues were collected from the mice and treated cells were col-lected for further analysis.Results:NSC23766 treatment significantly alleviated the hepatic IRI in mice,manifesting as lower vacuolation score and less apoptosis cells,lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels,and fewer activated inflammatory cells.IRI of AML-12 was also alleviated by 50μM NSC23766 or Rac1-knockdown,manifesting as reduced cell apoptosis,less extensive interruption of mitochondrial membrane po-tential,down-regulation of apoptosis,and effects on DNA damage-related proteins.Interestingly,Rac1 knockdown also down-regulated the expression level of HIF-1α.Con-clusions:Our study supports a protective effect of Rac1 inhibition on hepatic IRI.Aside from the classic topics of reducing ROS production and oxidative stress,our study showed an interaction between Rac1 and HIF-1αsignaling during hepatic IRI.
基金This work was sponsored by Major Projects(AWS17J007)and Shanghai Sailing Program(19YF1459100).
文摘With the rapid application of nuclear energy and radiological technology in national economy and military field,the risk of nuclear accidents increases as well.Exposure to irradiation causes severe damages to the human body,and radioprotective agents are required for medical protection.To find the safe and effective radioprotective agents is the key for nuclear emergency.Recently,Toll like receptors(TLRs)and PHD-HIF oxygen sensing signal pathway have been extensively studied for radioprotection.Great progress has been made in this field and a number of radioprotective agents have been found.In this review,we have summarized recent findings of radioprotective roles of TLRs signaling pathway and PHD-HIF signaling pathway and discussed the general principles of developing novel radioprotective agents.These findings will provide opportunities for developing new strategies to prevent IR-induced injuries in public health events.
