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
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.
