Xi Liu, Yu Zhou, Ziyi Lu, Fenglin Yang, Yizhi Wang, Sijin Zhang, Jinwen Zhang, Hong Zou, Min Lin
{"title":"Network Pharmacology and Metabolomics Reveal Anti-Ferroptotic Effects of Curcumin in Acute Kidney Injury.","authors":"Xi Liu, Yu Zhou, Ziyi Lu, Fenglin Yang, Yizhi Wang, Sijin Zhang, Jinwen Zhang, Hong Zou, Min Lin","doi":"10.2147/DDDT.S486286","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Acute kidney injury (AKI) is linked to high rates of mortality and morbidity worldwide thereby posing a major public health problem. Evidences suggest that ferroptosis is the primary cause of AKI, while inhibition of monoamine oxidase A(MAOA) and 5-hydroxytryptamine were recognized as the defender of ferroptosis. Curcumin (Cur) is a natural polyphenol and the main bioactive compound of <i>Curcuma longa</i>, which has been found nephroprotection in AKI. However, the potential mechanism of Cur in alleviating AKI ferroptosis remains unknown.</p><p><strong>Objective: </strong>This study aims to investigate the effects of Cur on AKI ferroptosis.</p><p><strong>Methods: </strong>Folic acid (FA)-induced AKI mouse model and erastin/(rsl-3)-induced HK-2 model were constructed to assess the renoprotection of Cur. The nuclear magnetic resonance (NMR)-based metabolomics coupled network pharmacology approach was used to explore the metabolic regulation and potential targets of Cur. Molecular docking and enzyme activity assay was carried out to evaluate the effects of Cur on MAOA.</p><p><strong>Results: </strong>Our results showed that in vivo Cur preserved renal functions in AKI mice by lowering levels of serum creatinine, blood urea nitrogen, while in vitro ameliorated the cell viability of HK-2 cells damaged by ferroptosis. Mechanistic studies indicated that Cur protected AKI against ferroptosis via inhibition of MAOA thereby regulating 5-hydroxy-L-tryptophan metabolism.</p><p><strong>Conclusion: </strong>Our study for the first time clarified that Cur might acts as a MAOA inhibitor and alleviates ferroptosis in AKI mice, laying a scientific foundation for new insights of clinical therapy on AKI.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"6223-6241"},"PeriodicalIF":4.7000,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669278/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S486286","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: Acute kidney injury (AKI) is linked to high rates of mortality and morbidity worldwide thereby posing a major public health problem. Evidences suggest that ferroptosis is the primary cause of AKI, while inhibition of monoamine oxidase A(MAOA) and 5-hydroxytryptamine were recognized as the defender of ferroptosis. Curcumin (Cur) is a natural polyphenol and the main bioactive compound of Curcuma longa, which has been found nephroprotection in AKI. However, the potential mechanism of Cur in alleviating AKI ferroptosis remains unknown.
Objective: This study aims to investigate the effects of Cur on AKI ferroptosis.
Methods: Folic acid (FA)-induced AKI mouse model and erastin/(rsl-3)-induced HK-2 model were constructed to assess the renoprotection of Cur. The nuclear magnetic resonance (NMR)-based metabolomics coupled network pharmacology approach was used to explore the metabolic regulation and potential targets of Cur. Molecular docking and enzyme activity assay was carried out to evaluate the effects of Cur on MAOA.
Results: Our results showed that in vivo Cur preserved renal functions in AKI mice by lowering levels of serum creatinine, blood urea nitrogen, while in vitro ameliorated the cell viability of HK-2 cells damaged by ferroptosis. Mechanistic studies indicated that Cur protected AKI against ferroptosis via inhibition of MAOA thereby regulating 5-hydroxy-L-tryptophan metabolism.
Conclusion: Our study for the first time clarified that Cur might acts as a MAOA inhibitor and alleviates ferroptosis in AKI mice, laying a scientific foundation for new insights of clinical therapy on AKI.
简介：急性肾损伤（AKI）与世界范围内的高死亡率和发病率相关，因此构成了一个重大的公共卫生问题。有证据表明，铁下垂是AKI的主要原因，而单胺氧化酶A（MAOA）和5-羟色胺的抑制被认为是铁下垂的防御者。姜黄素（Curcumin, Cur）是一种天然多酚，是姜黄的主要生物活性化合物，在AKI中被发现具有肾保护作用。然而，Cur缓解AKI铁下垂的潜在机制尚不清楚。目的：探讨Cur对AKI铁下垂的影响。方法：建立叶酸（FA）诱导的AKI小鼠模型和erastin/(rsl-3)诱导的HK-2模型，评估Cur的肾保护作用，采用核磁共振（NMR）代谢组学耦合网络药理学方法探讨Cur的代谢调控和潜在靶点，通过分子对接和酶活性实验评价Cur对MAOA的影响。结果：我们的研究结果表明，在体内，Cur通过降低血清肌酐、血尿素氮水平来维持AKI小鼠的肾功能，而在体外，Cur可以改善铁下垂损伤的HK-2细胞的细胞活力。机制研究表明，Cur通过抑制MAOA从而调节5-羟基- l -色氨酸代谢来保护AKI免受铁下垂。结论：我们的研究首次阐明了Cur可能具有MAOA抑制剂的作用，可减轻AKI小鼠的铁下垂，为AKI临床治疗的新认识奠定了科学基础。
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
