Objective:In traditional medicine,Asari Radix et Rhizoma(Xi Xin)is used to effectively treat respiratory diseases.However,the therapeutic portion of Xi Xin contains trace quantities of aristolochic acid I(AAI),which r...Objective:In traditional medicine,Asari Radix et Rhizoma(Xi Xin)is used to effectively treat respiratory diseases.However,the therapeutic portion of Xi Xin contains trace quantities of aristolochic acid I(AAI),which raises safety concerns.Furthermore,no compelling laboratory evidence confirms its safety.AAI-induced extensive renal tubular necrosis and inflammatory cell infiltration occurred primarily in the cortex and outer medulla.Accordingly,we examined the changes in metabolites within the aforementioned areas and thoroughly investigated the interactions between these differential metabolites and immune cells.Methods:We mapped the spatial distribution of the differential metabolites L-glutamic acid and glutamine in mouse kidneys and explored the underlying mechanisms using transcriptomics and flow cytometry,further validating these findings through co-culture experiments in vitro.Results:Administering 1 mg/kg AAI daily for 7 days(approximately 200 times the pharmacopeial Xi Xin dose)did not induce detectable levels of carcinogenic 7-(deoxyadenosin-N6-yl)-aristolactam I(dA-ALI)in mouse kidneys.However,dA-ALI was detected on the day after the administration of 10 mg/kg AAI.Mice with lipopolysaccharide-induced pneumonia exhibit increased tolerance to AAI-mediated nephrotoxicity.Based on integrated spatial metabolomics and renal transcriptomic analyses,increased tolerance to AAI-mediated nephrotoxicity may be related to glutamine-mediated oxidative stress regulation mechanisms.During pneumonia,mouse kidneys exhibit both immune and metabolic stress responses.Ly6C^(+)macrophages convert L-glutamic acid into glutamine,thereby reducing reactive oxygen species(ROS)levels in the extracellular matrix.This process,which is regulated by the ITGA5 receptor in renal tubular epithelial cells,modulates the pAkt/pNrf2/NQO1 pathway and reduces AAI-induced kidney damage.Conclusions:Collectively,our findings indicate that Xi Xin is safe at conventional clinical dosages,and its targeted use can further minimize potential risks.展开更多
This paper adopts free interface modal synthesis method to divide the whole automobile model into many sub-structures and establish dynamical equations of automobile nonlinear coupled system.The Monte Carlo method is ...This paper adopts free interface modal synthesis method to divide the whole automobile model into many sub-structures and establish dynamical equations of automobile nonlinear coupled system.The Monte Carlo method is used to simulate the spectrum of the random excitation of the road and the engine.Based on the automobile dynamical equations,a simulation is carried out within time domain and frequency domain on the characteristic of vibration due to the excitation of automobile wheel and the engine.The results are verified by bench experiment to make the research more practicable.In order to do research of rubber hysteresis’influence on automobile dynamic property,Poincare diagrams and amplitude frequency characteristic curves were drawn with automobile linear and nonlinear models.The results show that the nonlinear dynamical model concerning rubber hysteresis not only can improve the simulation accuracy,but also is beneficial to find some complex nonlinear dynamical behaviors of vehicles.展开更多
Objective:Neuronal ferroptosis has emerged as a promising therapeutic target for ischemic stroke.Tamarixetin,a natural dietary flavonoid,exerts protective effects against ischemic stroke by modulating neuroinflammator...Objective:Neuronal ferroptosis has emerged as a promising therapeutic target for ischemic stroke.Tamarixetin,a natural dietary flavonoid,exerts protective effects against ischemic stroke by modulating neuroinflammatory responses and mitigating oxidative stress.However,its potential role in regulating neuronal ferroptosis remains unclear.Methods:A rat model of middle cerebral artery occlusion and reperfusion and an erastin-treated SH-SY5Y cell model were used for in vivo and in vitro experiments,respectively.The neurological function of the rats was evaluated using a series of behavioral tests,the Garcia scoring system,and 2,3,5-triphenyltetrazolium chloride staining.Neuronal damage was detected via immunofluorescence staining and terminal deoxynucleotidyl transferase(TdT)-mediated deoxyuridine triphosphate(dUTP)nickend labeling.Commercial kits,western blotting,and coimmunoprecipitation were used to analyze neuronal ferroptosis and the activation of the Nuclear factor erythroid-2–related factor 2(Nrf2)signaling pathway.The direct target protein of tamarixetin was examined using the cellular thermal shift assay,drug affinity-responsive target stability assay,surface plasmon resonance,and molecular docking.Cellular Nrf2 was knocked down using small interfering RNA.Results:Tamarixetin mitigated the neurological dysfunctions of middle cerebral artery occlusion and reperfusion(MCAO/R)rats,including motor dysfunction,limb coordination impairment,neurological deficit,cerebral infarction,and reduced neuronal loss.Furthermore,it alleviated neuronal ferroptosis in vivo and in vitro by lowering the levels of iron ions,reactive oxygen species,malondialdehyde,and acyl-CoA synthetase long-chain family member 4 and upregulating the expression of superoxide dismutase,glutathione,glutathione peroxidase 4,heme oxygenase-1,and solute carrier family 7 member 11.Tamarixetin activated the Nrf2 signaling pathway by suppressing Keap1 protein expression,weakening the interaction between Keap1 and Nrf2,upregulating Nrf2 protein expression and nuclear translocation,and promoting antioxidant response element activity.Nrf2 is the direct binding protein of tamarixetin.It specifically interacts with amino acid residues at arginine 72,arginine 515,and lysine 518.The effects of tamarixetin on Nrf2 signaling pathway activation and neuronal ferroptosis inhibition were abrogated in Nrf2 knockdown cells challenged with erastin.Conclusions:Our findings not only identify tamarixetin as a novel ferroptosis inhibitor but also elucidate its mechanism of action via direct binding and Nrf2 pathway activation,providing a promising therapeutic candidate for ischemic stroke.展开更多
基金supported by the Consulting Project Funds of the Chinese Academy of Engineering(2023-XZ-88,China)Key Program of the National Natural Science Foundation of China(81721002 and 82230118,China)Key Program of the National Natural Science Foundation of China Regional Union Fund(U23A20519,China).
文摘Objective:In traditional medicine,Asari Radix et Rhizoma(Xi Xin)is used to effectively treat respiratory diseases.However,the therapeutic portion of Xi Xin contains trace quantities of aristolochic acid I(AAI),which raises safety concerns.Furthermore,no compelling laboratory evidence confirms its safety.AAI-induced extensive renal tubular necrosis and inflammatory cell infiltration occurred primarily in the cortex and outer medulla.Accordingly,we examined the changes in metabolites within the aforementioned areas and thoroughly investigated the interactions between these differential metabolites and immune cells.Methods:We mapped the spatial distribution of the differential metabolites L-glutamic acid and glutamine in mouse kidneys and explored the underlying mechanisms using transcriptomics and flow cytometry,further validating these findings through co-culture experiments in vitro.Results:Administering 1 mg/kg AAI daily for 7 days(approximately 200 times the pharmacopeial Xi Xin dose)did not induce detectable levels of carcinogenic 7-(deoxyadenosin-N6-yl)-aristolactam I(dA-ALI)in mouse kidneys.However,dA-ALI was detected on the day after the administration of 10 mg/kg AAI.Mice with lipopolysaccharide-induced pneumonia exhibit increased tolerance to AAI-mediated nephrotoxicity.Based on integrated spatial metabolomics and renal transcriptomic analyses,increased tolerance to AAI-mediated nephrotoxicity may be related to glutamine-mediated oxidative stress regulation mechanisms.During pneumonia,mouse kidneys exhibit both immune and metabolic stress responses.Ly6C^(+)macrophages convert L-glutamic acid into glutamine,thereby reducing reactive oxygen species(ROS)levels in the extracellular matrix.This process,which is regulated by the ITGA5 receptor in renal tubular epithelial cells,modulates the pAkt/pNrf2/NQO1 pathway and reduces AAI-induced kidney damage.Conclusions:Collectively,our findings indicate that Xi Xin is safe at conventional clinical dosages,and its targeted use can further minimize potential risks.
基金supported by the program of National Natural Science of China(No.51075303)
文摘This paper adopts free interface modal synthesis method to divide the whole automobile model into many sub-structures and establish dynamical equations of automobile nonlinear coupled system.The Monte Carlo method is used to simulate the spectrum of the random excitation of the road and the engine.Based on the automobile dynamical equations,a simulation is carried out within time domain and frequency domain on the characteristic of vibration due to the excitation of automobile wheel and the engine.The results are verified by bench experiment to make the research more practicable.In order to do research of rubber hysteresis’influence on automobile dynamic property,Poincare diagrams and amplitude frequency characteristic curves were drawn with automobile linear and nonlinear models.The results show that the nonlinear dynamical model concerning rubber hysteresis not only can improve the simulation accuracy,but also is beneficial to find some complex nonlinear dynamical behaviors of vehicles.
基金supported by the National Natural Science Foundation of China(82174076)the Construction Project of Liaoning Provincial Key Laboratory,China(2022JH13/10200026)+2 种基金the Natural Science Foundation of Hebei Province(H2024501002)the Fundamental Research Funds for the Central Universities(N2423006)the 111 Project(B16009).
文摘Objective:Neuronal ferroptosis has emerged as a promising therapeutic target for ischemic stroke.Tamarixetin,a natural dietary flavonoid,exerts protective effects against ischemic stroke by modulating neuroinflammatory responses and mitigating oxidative stress.However,its potential role in regulating neuronal ferroptosis remains unclear.Methods:A rat model of middle cerebral artery occlusion and reperfusion and an erastin-treated SH-SY5Y cell model were used for in vivo and in vitro experiments,respectively.The neurological function of the rats was evaluated using a series of behavioral tests,the Garcia scoring system,and 2,3,5-triphenyltetrazolium chloride staining.Neuronal damage was detected via immunofluorescence staining and terminal deoxynucleotidyl transferase(TdT)-mediated deoxyuridine triphosphate(dUTP)nickend labeling.Commercial kits,western blotting,and coimmunoprecipitation were used to analyze neuronal ferroptosis and the activation of the Nuclear factor erythroid-2–related factor 2(Nrf2)signaling pathway.The direct target protein of tamarixetin was examined using the cellular thermal shift assay,drug affinity-responsive target stability assay,surface plasmon resonance,and molecular docking.Cellular Nrf2 was knocked down using small interfering RNA.Results:Tamarixetin mitigated the neurological dysfunctions of middle cerebral artery occlusion and reperfusion(MCAO/R)rats,including motor dysfunction,limb coordination impairment,neurological deficit,cerebral infarction,and reduced neuronal loss.Furthermore,it alleviated neuronal ferroptosis in vivo and in vitro by lowering the levels of iron ions,reactive oxygen species,malondialdehyde,and acyl-CoA synthetase long-chain family member 4 and upregulating the expression of superoxide dismutase,glutathione,glutathione peroxidase 4,heme oxygenase-1,and solute carrier family 7 member 11.Tamarixetin activated the Nrf2 signaling pathway by suppressing Keap1 protein expression,weakening the interaction between Keap1 and Nrf2,upregulating Nrf2 protein expression and nuclear translocation,and promoting antioxidant response element activity.Nrf2 is the direct binding protein of tamarixetin.It specifically interacts with amino acid residues at arginine 72,arginine 515,and lysine 518.The effects of tamarixetin on Nrf2 signaling pathway activation and neuronal ferroptosis inhibition were abrogated in Nrf2 knockdown cells challenged with erastin.Conclusions:Our findings not only identify tamarixetin as a novel ferroptosis inhibitor but also elucidate its mechanism of action via direct binding and Nrf2 pathway activation,providing a promising therapeutic candidate for ischemic stroke.
