{"title":"代谢组学和蛋白质组学的综合分析揭示了小檗碱诱导肾毒性的机制","authors":"Jinqiu Rao , Tianwang Wang , Kai Wang , Feng Qiu","doi":"10.1016/j.taap.2024.116992","DOIUrl":null,"url":null,"abstract":"<div><p>Berberrubine (BRB), a main metabolite of berberine, has stronger hypoglycemic and lipid-lowering activity than its parent form. We previously found that BRB could cause obvious nephrotoxicity, but the molecular mechanism involved remains unknown. In this study, we systematically integrated metabolomics and quantitative proteomics to reveal the potential mechanism of nephrotoxicity caused by BRB. Metabolomic analysis revealed that 103 significant— differentially metabolites were changed. Among the mentioned compounds, significantly upregulated metabolites were observed for phosphorylcholine, sn-glycerol-3-phosphoethanolamine, and phosphatidylcholine. The top three enriched KEGG pathways were the mTOR signaling pathway, central carbon metabolism in cancer, and choline metabolism in cancer. ERK1/2 plays key roles in all three metabolic pathways. To further confirm the main signaling pathways involved, a proteomic analysis was conducted to screen for key proteins (such as Mapk1, Mapk14, and Caspase), indicating the potential involvement of cellular growth and apoptosis. Moreover, combined metabolomics and proteomics analyses revealed the participation of ERK1/2 in multiple metabolic pathways. These findings indicated that ERK1/2 regulated the significant— differentially abundant metabolites determined via metabolomics analysis. Notably, through a cellular thermal shift assay (CETSA) and molecular docking, ERK1/2 were revealed to be the direct binding target involved in BRB-induced nephrotoxicity. To summarize, this study sheds light on the understanding of severe nephrotoxicity caused by BRB and provides scientific basis for its safe use and rational development.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Integrative analysis of metabolomics and proteomics reveals mechanism of berberrubine-induced nephrotoxicity\",\"authors\":\"Jinqiu Rao , Tianwang Wang , Kai Wang , Feng Qiu\",\"doi\":\"10.1016/j.taap.2024.116992\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Berberrubine (BRB), a main metabolite of berberine, has stronger hypoglycemic and lipid-lowering activity than its parent form. We previously found that BRB could cause obvious nephrotoxicity, but the molecular mechanism involved remains unknown. In this study, we systematically integrated metabolomics and quantitative proteomics to reveal the potential mechanism of nephrotoxicity caused by BRB. Metabolomic analysis revealed that 103 significant— differentially metabolites were changed. Among the mentioned compounds, significantly upregulated metabolites were observed for phosphorylcholine, sn-glycerol-3-phosphoethanolamine, and phosphatidylcholine. The top three enriched KEGG pathways were the mTOR signaling pathway, central carbon metabolism in cancer, and choline metabolism in cancer. ERK1/2 plays key roles in all three metabolic pathways. To further confirm the main signaling pathways involved, a proteomic analysis was conducted to screen for key proteins (such as Mapk1, Mapk14, and Caspase), indicating the potential involvement of cellular growth and apoptosis. Moreover, combined metabolomics and proteomics analyses revealed the participation of ERK1/2 in multiple metabolic pathways. These findings indicated that ERK1/2 regulated the significant— differentially abundant metabolites determined via metabolomics analysis. Notably, through a cellular thermal shift assay (CETSA) and molecular docking, ERK1/2 were revealed to be the direct binding target involved in BRB-induced nephrotoxicity. To summarize, this study sheds light on the understanding of severe nephrotoxicity caused by BRB and provides scientific basis for its safe use and rational development.</p></div>\",\"PeriodicalId\":23174,\"journal\":{\"name\":\"Toxicology and applied pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-06-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology and applied pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0041008X2400190X\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X2400190X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Integrative analysis of metabolomics and proteomics reveals mechanism of berberrubine-induced nephrotoxicity
Berberrubine (BRB), a main metabolite of berberine, has stronger hypoglycemic and lipid-lowering activity than its parent form. We previously found that BRB could cause obvious nephrotoxicity, but the molecular mechanism involved remains unknown. In this study, we systematically integrated metabolomics and quantitative proteomics to reveal the potential mechanism of nephrotoxicity caused by BRB. Metabolomic analysis revealed that 103 significant— differentially metabolites were changed. Among the mentioned compounds, significantly upregulated metabolites were observed for phosphorylcholine, sn-glycerol-3-phosphoethanolamine, and phosphatidylcholine. The top three enriched KEGG pathways were the mTOR signaling pathway, central carbon metabolism in cancer, and choline metabolism in cancer. ERK1/2 plays key roles in all three metabolic pathways. To further confirm the main signaling pathways involved, a proteomic analysis was conducted to screen for key proteins (such as Mapk1, Mapk14, and Caspase), indicating the potential involvement of cellular growth and apoptosis. Moreover, combined metabolomics and proteomics analyses revealed the participation of ERK1/2 in multiple metabolic pathways. These findings indicated that ERK1/2 regulated the significant— differentially abundant metabolites determined via metabolomics analysis. Notably, through a cellular thermal shift assay (CETSA) and molecular docking, ERK1/2 were revealed to be the direct binding target involved in BRB-induced nephrotoxicity. To summarize, this study sheds light on the understanding of severe nephrotoxicity caused by BRB and provides scientific basis for its safe use and rational development.
期刊介绍:
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.