Nrf2信号通路作为虾青素治疗新靶点的研究进展

doi:10.3760/cma.j.issn.1007-1245.2024.01.004

摘要/Abstract

摘要：

虾青素是一种多靶点脂溶性酮式类胡萝卜素，因其丰富的生物活性，特别是其强大的抗氧化能力而广受关注。虾青素具有抗氧化、抗炎、抗糖尿病、神经保护等多种生物活性作用，但虾青素这些治疗作用的分子机制尚不完全清楚。其中，核因子E2相关因子2（nuclear factor erythroid-2 related factor 2，Nrf2）信号通路是虾青素发挥作用的重要信号通路之一。Nrf2信号通路是细胞抗氧化应激的主要调节因子，它调节了氧化还原稳态以及细胞解毒相关基因的表达。本文综述了虾青素激活Nrf2信号通路的作用机制及其在各种疾病中的保护作用。

关键词:

虾青素, Nrf2信号通路, 氧化应激, 抗氧化应激, 作用机制, 进展

Abstract:

Astaxanthin is a multi-targeted fat-soluble ketocarotenoid, and has attracted much attention in recent years because of its abundant biological activity, especially its powerful antioxidant capacity. Astaxanthin has a variety of biological activities, such as antioxidant, anti-inflammatory, anti-diabetic, neuroprotective, and other effects. However, the molecular mechanisms of these therapeutic effects of astaxanthin are not fully understood, and the nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway is one of the important signaling pathways of astaxanthin. The Nrf2 signaling pathway is a major regulator of cellular resistance to oxidative stress, and it regulates redox homeostasis as well as the expression of genes involved in cellular detoxification. This article reviews the mechanism of astaxanthin activating the Nrf2 signaling pathway and its protective effect in various diseases.

Key words:

Astaxanthin, Nrf2 signaling pathway, Oxidative stress, Anti-oxidative stress, Action mechanism, Progress

商冠华田春梅.

Nrf2信号通路作为虾青素治疗新靶点的研究进展 [J]. 国际医药卫生导报, 2024, 30(1): 20-24.

Shang Guanhua, Tian Chunmei.

Research progress of Nrf2 signaling pathway as a new target for astaxanthin therapy [J]. International Medicine and Health Guidance News, 2024, 30(1): 20-24.

参考文献

[1] Ambati RR, Phang SM, Ravi S, et al. Astaxanthin: sources, extraction, stability, biological activities and its commercial applications--a review[J]. Mar Drugs, 2014,12(1):128-152. DOI: 10.3390/md12010128.
[2] Lorenz RT, Cysewski GR. Commercial potential for Haematococcus microalgae as a natural source of astaxanthin[J]. Trends Biotechnol, 2000,18(4):160-167. DOI: 10.1016/s0167-7799(00)01433-5.
[3] Chen Y, Tang J, Zhang Y, et al. Astaxanthin alleviates gestational diabetes mellitus in mice through suppression of oxidative stress[J]. Naunyn Schmiedebergs Arch Pharmacol, 2020,393(12):2517-2527. DOI: 10.1007/s00210-020-01861-x.
[4] Chen Q, Tao J, Li G, et al. Astaxanthin ameliorates experimental diabetes-induced renal oxidative stress and fibronectin by upregulating connexin43 in glomerular mesangial cells and diabetic mice[J]. Eur J Pharmacol, 2018,840:33-43. DOI: 10.1016/j.ejphar.2018.09.028.
[5] Farruggia C, Kim MB, Bae M, et al. Astaxanthin exerts anti-inflammatory and antioxidant effects in macrophages in NRF2-dependent and independent manners[J]. J Nutr Biochem, 2018,62:202-209. DOI: 10.1016/j.jnutbio.2018.09.005.
[6] Sajadimajd S, Khazaei M. Oxidative stress and cancer: the role of Nrf2[J]. Curr Cancer Drug Targets, 2018,18(6):538-557. DOI: 10.2174/1568009617666171002144228.
[7] Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress[J]. Antioxid Redox Signal, 2006,8(1-2):76-87. DOI: 10.1089/ars.2006.8.76.
[8] Kanwugu ON, Glukhareva TV. Activation of Nrf2 pathway as a protective mechanism against oxidative stress-induced diseases: potential of astaxanthin[J]. Arch Biochem Biophys, 2023,741:109601. DOI: 10.1016/j.abb.2023.109601.
[9] Zhou H, Wang Y, You Q, et al. Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present) [J]. Expert Opin Ther Pat, 2020,30(3):209-225. DOI: 10.1080/13543776.2020.1715365.
[10] Madden SK, Itzhaki LS. Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery[J]. Biochim Biophys Acta Proteins Proteom, 2020,1868(7):140405. DOI: 10.1016/j.bbapap.2020. 140405.
[11] Takagi Y, Kobayashi M, Li L, et al. MafT, a new member of the small Maf protein family in zebrafish[J]. Biochem Biophys Res Commun, 2004,320(1):62-69. DOI: 10.1016/j.bbrc.2004.05.131.
[12] Ooi BK, Chan KG, Goh BH, et al. The role of natural products in targeting cardiovascular diseases via Nrf2 pathway: novel molecular mechanisms and therapeutic approaches[J]. Front Pharmacol, 2018,9:1308. DOI: 10.3389/fphar.2018.01308.
[13] Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2[J]. Antioxid Redox Signal, 2018,29(17):1727-1745. DOI: 10.1089/ars.2017.7342.
[14] Nioi P, McMahon M, Itoh K, et al. Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence[J]. Biochem J, 2003,374(Pt 2):337-348. DOI: 10.1042/BJ20030754.
[15] Bellezza I, Giambanco I, Minelli A, et al. Nrf2-Keap1 signaling in oxidative and reductive stress[J]. Biochim Biophys Acta Mol Cell Res, 2018,1865(5):721-733. DOI: 10.1016/j.bbamcr.2018.02.010.
[16] Zenkov NK, Kozhin PM, Chechushkov AV, et al. Mazes of Nrf2 regulation[J]. Biochemistry (Mosc), 2017,82(5):556-564. DOI: 10.1134/S0006297917050030.
[17] Shaw P, Chattopadhyay A. Nrf2-ARE signaling in cellular protection: mechanism of action and the regulatory mechanisms[J]. J Cell Physiol, 2020,235(4):3119-3130. DOI: 10.1002/jcp.29219.
[18] McMahon M, Thomas N, Itoh K, et al. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron[J]. J Biol Chem, 2004,279(30):31556-31567. DOI: 10.1074/jbc.M403061200.
[19] Wang H, Liu K, Geng M, et al. RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2[J]. Cancer Res, 2013,73(10):3097-108. DOI: 10.1158/0008-5472.CAN-12-3386.
[20] Cleasby A, Yon J, Day PJ, et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO[J]. PLoS One, 2014,9(6):e98896. DOI: 10.1371/journal.pone.0098896.
[21] Namani A, Li Y, Wang XJ, et al Modulation of NRF2 signaling pathway by nuclear receptors: implications for cancer[J]. Biochim Biophys Acta, 2014,1843(9):1875-1885. DOI: 10.1016/j.bbamcr.2014.05.003.
[22] Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W. The Nrf2-ARE signaling pathway: an update on its regulation and possible role in cancer prevention and treatment[J]. Pharmacol Rep, 2017,69(3):393-402. DOI: 10.1016/j.pharep.2016.12.011.
[23] Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity[J]. J Biol Chem, 1991,266(18):11632-11639.
[24] Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway[J]. Trends Pharmacol Sci, 2013,34(6):340-346. DOI: 10.1016/j.tips.2013.04.005.
[25] Singh S, Vrishni S, Singh BK, et al. Nrf2-ARE stress response mechanism: a control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases[J]. Free Radic Res, 2010,44(11):1267-1288. DOI: 10.3109/10715762.2010.507670.
[26] Ying CJ, Zhang F, Zhou XY, et al. Anti-inflammatory effect of astaxanthin on the sickness behavior induced by diabetes mellitus[J]. Cell Mol Neurobiol, 2015,35(7):1027-1037. DOI: 10.1007/s10571-015-0197-3.
[27] Xie X, Chen Q, Tao J. Astaxanthin promotes Nrf2/ARE signaling to inhibit HG-induced renal fibrosis in GMCs[J]. Mar Drugs, 2018,16(4):117. DOI: 10.3390/md16040117.
[28] Liu G, Shi Y, Peng X, et al. Astaxanthin attenuates adriamycin-induced focal segmental glomerulosclerosis[J]. Pharmacology, 2015,95(3-4):193-200. DOI: 10.1159/000381314.
[29] Qiu X, Fu K, Zhao X, et al. Protective effects of astaxanthin against ischemia/reperfusion induced renal injury in mice[J]. J Transl Med, 2015,13:28. DOI: 10.1186/s12967-015-0388-1.
[30] Yang Y, Pham TX, Wegner CJ, et al. Astaxanthin lowers plasma TAG concentrations and increases hepatic antioxidant gene expression in diet-induced obesity mice[J]. Br J Nutr, 2014,112(11):1797-1804. DOI: 10.1017/S0007114514002554.
[31] Yang Y, Seo JM, Nguyen A, et al. Astaxanthin-rich extract from the green alga Haematococcus pluvialis lowers plasma lipid concentrations and enhances antioxidant defense in apolipoprotein E knockout mice[J]. J Nutr, 2011,141(9):1611-1617. DOI: 10.3945/jn.111.142109.
[32] El-Baz FK, Hussein RA, Abdel Jaleel GAR, et al. Astaxanthin-rich Haematococcus pluvialis algal hepatic modulation in D-Galactose-induced aging in rats: role of Nrf2[J]. Adv Pharm Bull, 2018,8(3):523-528. DOI: 10.15171/apb.2018.061.
[33] Xue Y, Sun C, Hao Q, et al. Astaxanthin ameliorates cardiomyocyte apoptosis after coronary microembolization by inhibiting oxidative stress via Nrf2/HO-1 pathway in rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2019,392(3):341-348. DOI: 10.1007/s00210-018-1595-0.
[34] Cui G, Li L, Xu W, et al. Astaxanthin protects ochratoxin a-induced oxidative stress and apoptosis in the heart via the Nrf2 pathway[J]. Oxid Med Cell Longev, 2020,2020:7639109. DOI: 10.1155/2020/7639109.
[35] Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease[J]. Annu Rev Pathol, 2009,4:435-459. DOI: 10.1146/annurev.pathol.4.110807.092145.
[36] Pryor WA, Stone K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite[J]. Ann N Y Acad Sci, 1993,686:12-27. DOI: 10.1111/j.1749-6632.1993.tb39148.x.
[37] Kubo H, Asai K, Kojima K, et al. Astaxanthin suppresses cigarette smoke-induced emphysema through Nrf2 activation in mice[J]. Mar Drugs, 2019,17(12):673. DOI: 10.3390/md17120673.
[38] Zhang XS, Zhang X, Zhou ML, et al. Amelioration of oxidative stress and protection against early brain injury by astaxanthin after experimental subarachnoid hemorrhage[J]. J Neurosurg, 2014,121(1):42-54. DOI: 10.3171/2014.2.JNS13730.
[39] Wu Q, Zhang XS, Wang HD, et al. Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury[J]. Mar Drugs, 2014,12(12):6125-6141. DOI: 10.3390/md12126125.