Network Pharmacology and Metabolomics Reveal Anti-Ferroptotic Effects of Curcumin in Acute Kidney Injury

Overview

Journal Drug Des Devel Ther

Specialty Pharmacology

Date 2024 Dec 26

PMID 39722679

Authors

Xi Liu

Yu Zhou

Ziyi Lu

Fenglin Yang

Yizhi Wang

Sijin Zhang

Jinwen Zhang

Hong Zou

Min Lin

Affiliations

Soon will be listed here.

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 , 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.

References

Li T, Zhang W, Hu E, Sun Z, Li P, Yu Z . Integrated metabolomics and network pharmacology to reveal the mechanisms of hydroxysafflor yellow A against acute traumatic brain injury. Comput Struct Biotechnol J. 2021; 19:1002-1013. PMC: 7868816. DOI: 10.1016/j.csbj.2021.01.033. View

Awad A, El-Sharif A . Curcumin immune-mediated and anti-apoptotic mechanisms protect against renal ischemia/reperfusion and distant organ induced injuries. Int Immunopharmacol. 2011; 11(8):992-6. DOI: 10.1016/j.intimp.2011.02.015. View

Konjevod M, Tudor L, Strac D, Nedic Erjavec G, Barbas C, Zarkovic N . Metabolomic and glycomic findings in posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 88:181-193. DOI: 10.1016/j.pnpbp.2018.07.014. View

Cao X, Li Y, Wang Y, Yu T, Zhu C, Zhang X . Curcumin suppresses tumorigenesis by ferroptosis in breast cancer. PLoS One. 2022; 17(1):e0261370. PMC: 8765616. DOI: 10.1371/journal.pone.0261370. View

Wei Z, Shaohuan Q, Pinfang K, Chao S . Curcumin Attenuates Ferroptosis-Induced Myocardial Injury in Diabetic Cardiomyopathy through the Nrf2 Pathway. Cardiovasc Ther. 2022; 2022:3159717. PMC: 9307414. DOI: 10.1155/2022/3159717. View

Wu T, Marakkath B, Ye Y, Khobahy E, Yan M, Hutcheson J . Curcumin Attenuates Both Acute and Chronic Immune Nephritis. Int J Mol Sci. 2020; 21(5). PMC: 7084772. DOI: 10.3390/ijms21051745. View

Tang X, Ding H, Liang M, Chen X, Yan Y, Wan N . Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy. Thorac Cancer. 2021; 12(8):1219-1230. PMC: 8046146. DOI: 10.1111/1759-7714.13904. View

Zhou J, Wu N, Lin L . Curcumin Suppresses Apoptosis and Inflammation in Hypoxia/Reperfusion-Exposed Neurons via Wnt Signaling Pathway. Med Sci Monit. 2020; 26:e920445. PMC: 7061587. DOI: 10.12659/MSM.920445. View

El-Gizawy M, Hosny E, Mourad H, Abd-El Razik A . Curcumin nanoparticles ameliorate hepatotoxicity and nephrotoxicity induced by cisplatin in rats. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393(10):1941-1953. DOI: 10.1007/s00210-020-01888-0. View

10.

Li W, Xiang Z, Xing Y, Li S, Shi S . Mitochondria bridge HIF signaling and ferroptosis blockage in acute kidney injury. Cell Death Dis. 2022; 13(4):308. PMC: 8986825. DOI: 10.1038/s41419-022-04770-4. View

11.

Wu L, Dong B, Chen Q, Wang Y, Han D, Zhu X . Effects of Curcumin on Oxidative Stress and Ferroptosis in Acute Ammonia Stress-Induced Liver Injury in Gibel Carp (). Int J Mol Sci. 2023; 24(7). PMC: 10094298. DOI: 10.3390/ijms24076441. View

12.

Chen Y, Lu T, Pettersson-Kymmer U, Stewart I, Butler-Laporte G, Nakanishi T . Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet. 2023; 55(1):44-53. PMC: 7614162. DOI: 10.1038/s41588-022-01270-1. View

13.

Tsuda T . Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives. Food Funct. 2017; 9(2):705-714. DOI: 10.1039/c7fo01242j. View

14.

Li H, Meng X, Huang C, Zhang L, Lv X, Li J . Application of Herbal Traditional Chinese Medicine in the Treatment of Acute Kidney Injury. Front Pharmacol. 2019; 10:376. PMC: 6482429. DOI: 10.3389/fphar.2019.00376. View

15.

Mao T, Xie L, Guo Y, Ji X, Wan J, Cui X . Mechanistic exploration of Yiqi Liangxue Shengji prescription on restenosis after balloon injury by integrating metabolomics with network pharmacology. Pharm Biol. 2023; 61(1):1260-1273. PMC: 10443980. DOI: 10.1080/13880209.2023.2244533. View

16.

Chen H, Busse L . Novel Therapies for Acute Kidney Injury. Kidney Int Rep. 2017; 2(5):785-799. PMC: 5733745. DOI: 10.1016/j.ekir.2017.06.020. View

17.

Kar F, Hacioglu C, Senturk H, Donmez D, Kanbak G, Uslu S . Curcumin and LOXblock-1 ameliorate ischemia-reperfusion induced inflammation and acute kidney injury by suppressing the semaphorin-plexin pathway. Life Sci. 2020; 256:118016. DOI: 10.1016/j.lfs.2020.118016. View

18.

Ghelani H, Razmovski-Naumovski V, Chang D, Nammi S . Chronic treatment of curcumin improves hepatic lipid metabolism and alleviates the renal damage in adenine-induced chronic kidney disease in Sprague-Dawley rats. BMC Nephrol. 2019; 20(1):431. PMC: 6873446. DOI: 10.1186/s12882-019-1621-6. View

19.

Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas P . Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998; 64(4):353-6. DOI: 10.1055/s-2006-957450. View

20.

Johnson C, Ivanisevic J, Siuzdak G . Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016; 17(7):451-9. PMC: 5729912. DOI: 10.1038/nrm.2016.25. View