氧化应激在急性肝损伤中的作用
DOI: 10.3969/j.issn.1001-5256.2022.10.039
利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:廖月负责查阅文献及撰写文章;何毅怀、罗亚文参与修改文章的关键内容。
-
摘要: 急性肝损伤常由病毒感染、酒精、药物、毒物、代谢异常等原因引起。氧化应激是急性肝损伤及其他肝病发生发展的共同病理生理机制。急性肝损伤发生后,肝细胞功能受损,引起氧化应激;而持续或高强度的氧化应激将增加肝细胞死亡的风险,导致一系列肝脏疾病。氧化应激主要与Nrf2、NF-κB等信号通路相关。因此,了解氧化应激参与肝损伤的发生发展机制及相关通路至关重要。本文介绍了氧化系统及抗氧化系统、氧化应激与损伤因素、氧化应激与肝损伤相关通路,以期为急性肝损伤的治疗靶点选择及相关临床研究提供参考。
-
关键词:
- 性肝损伤 /
- 氧化应激 /
- NF-E2相关因子2 /
- NF-κB
Abstract: Acute liver injury (ALI) is often caused by virus infection, alcohol, drugs, toxin, and metabolic disorder, and oxidative stress is a common pathophysiological mechanism in the development and progression of ALI and other liver diseases. Hepatocyte function is impaired after ALI, which further causes oxidative stress, and persistent or high-intensive oxidative stress may increase the risk of hepatocyte death and thus result in a series of liver diseases. Oxidative stress is mainly associated with the signaling pathways including nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B. Therefore, it is of great importance to understand the mechanism of oxidative stress in the development and progression of liver injury and related pathways. This article introduces oxidative system and antioxidative system, oxidative stress and damage factors, and oxidative stress and pathways associated with liver injury, so as to provide a reference for the selection of therapeutic targets for ALI and related clinical research.-
Key words:
- Acute Liver Injury /
- Oxidative Stress /
- NF-E2-Related Factor 2 /
- NF-kappa B
-
-
[1] SHRESTHA DB, BUDHATHOKI P, SEDHAI YR, et al., N-acetyl cysteine versus standard of care for non-acetaminophen induced acute liver injury: a systematic review and meta-analysis[J]. Ann Hepatol, 2021, 24: 100340. DOI: 10.1016/j.aohep.2021.100340. [2] XU FL, XU JX, XIONG X, et al. Salidroside inhibits MAPK, NF-kappaB, and STAT3 pathways in psoriasis-associated oxidative stress via SIRT1 activation[J]. Redox Rep, 2019, 24(1): 70-74. DOI: 10.1080/13510002.2019.1658377. [3] SEEN S. Chronic liver disease and oxidative stress-a narrative review[J]. Expert Rev Gastroenterol Hepatol, 2021, 15(9): 1021-1035. DOI: 10.1080/17474124.2021.1949289. [4] ZHONG X, ZHANG Z, SHEN H, et al. Hepatic NF-κB-inducing kinase and inhibitor of NF-κB kinase subunit α promote liver oxidative stress, ferroptosis, and liver injury[J]. Hepatol Commun, 2021, 5(10): 1704-1720. DOI: 10.1002/hep4.1757. [5] SINGH A, KUKRETI R, SASO L, et al. Oxidative stress: a key modulator in neurodegenerative diseases[J]. Molecules, 2019, 24(8): 1583. DOI: 10.3390/molecules24081583. [6] FOO BJ, EU JQ, HIRPARA JL, et al. Interplay between mitochondrial metabolism and cellular redox state dictates cancer cell survival[J]. Oxid Med Cell Longev, 2021, 2021: 1341604. DOI: 10.1155/2021/1341604. [7] HAJAM YA, RANI R, GANIE SY, et al. Oxidative stress in human pathology and aging: molecular mechanisms and perspectives[J]. Cells, 2022, 11(3): 552. DOI: 10.3390/cells11030552. [8] JUAN CA, PÉREZ DE LA LASTRA JM, PLOU FJ, et al. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies[J]. Int J Mol Sci, 2021, 22(9): 4642. DOI: 10.3390/ijms22094642. [9] NOLFI-DONEGAN D, BRAGANZA A, SHIVA S. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement[J]. Redox Biol, 2020, 37: 101674. DOI: 10.1016/j.redox.2020.101674. [10] VALLEJO FA, VANNI S, GRAHAM RM. UCP2 as a potential biomarker for adjunctive metabolic therapies in tumor management[J]. Front Oncol, 2021, 11: 640720. DOI: 10.3389/fonc.2021.640720. [11] YING JF, LU ZB, FU LQ, et al. The role of iron homeostasis and iron-mediated ROS in cancer[J]. Am J Cancer Res, 2021, 11(5): 1895-1912. [12] ZHANG Z, RONG L, LI YP. Flaviviridae viruses and oxidative stress: implications for viral pathogenesis[J]. Oxid Med Cell Longev, 2019, 2019: 1409582. DOI: 10.1155/2019/1409582. [13] TANIMIZU N, ICHINOHE N, SUZUKI H, et al. Prolonged oxidative stress and delayed tissue repair exacerbate acetaminophen-induced liver injury in aged mice[J]. Aging (Albany NY), 2020, 12(19): 18907-18927. DOI: 10.18632/aging.103973. [14] TODOROVI C ' VUKOTI C ' N, -DOR-DEVI C ' J, PEJI C ' S, et al. Antidepressants-and antipsychotics-induced hepatotoxicity[J]. Arch Toxicol, 2021, 95(3): 767-789. DOI: 10.1007/s00204-020-02963-4. [15] HAN H, DESERT R, DAS S, et al. Danger signals in liver injury and restoration of homeostasis[J]. J Hepatol, 2020, 73(4): 933-951. DOI: 10.1016/j.jhep.2020.04.033. [16] FAN X, LIN L, CUI B, et al. Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe[J]. Pharmacol Res, 2020, 159: 104945. DOI: 10.1016/j.phrs.2020.104945. [17] DUYGU F, KARSEN H, AKSOY N, et al. Relationship of oxidative stress in hepatitis B infection activity with HBV DNA and fibrosis[J]. Ann Lab Med, 2012, 32(2): 113-118. DOI: 10.3343/alm.2012.32.2.113. [18] XIANYU J, FENG J, YANG Y, et al. Correlation of oxidative stress in patients with HBV-induced liver disease with HBV genotypes and drug resistance mutations[J]. Clin Biochem, 2018, 55: 21-27. DOI: 10.1016/j.clinbiochem.2018.03.014. [19] HERRSCHER C, ROINGEARD P, BLANCHARD E. Hepatitis B virus entry into cells[J]. Cells, 2020, 9(6): 1486. DOI: 10.3390/cells9061486. [20] ALMAEEN AH, ALDURAYWISH AA, MOBASHER MA, et al. Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients[J]. Arch Med Sci, 2021, 17(2): 368-375. DOI: 10.5114/aoms.2019.91451. [21] SOBHANIMONFARED F, BAMDAD T, ROOHVAND F. Cross talk between alcohol-induced oxidative stress and HCV replication[J]. Arch Microbiol, 2020, 202(7): 1889-1898. DOI: 10.1007/s00203-020-01909-9. [22] GRAVIER-HERNÁNDEZ R, GIL-DEL VALLE L, VALDES-ALONSO L, et al. Oxidative stress in hepatitis C virus-human immunodeficiency virus co-infected patients[J]. Ann Hepatol, 2020, 19(1): 92-98. DOI: 10.1016/j.aohep.2019.05.009. [23] RAMÍREZ A, VÁZQUEZ-SÁNCHEZ AY, CARRIÓN-ROBALINO N, et al. Ion channels and oxidative stress as a potential link for the diagnosis or treatment of liver diseases[J]. Oxid Med Cell Longev, 2016, 2016: 3928714. DOI: 10.1155/2016/3928714. [24] GOU SH, HE M, LI BB, et al. Hepatoprotective effect of total flavonoids from Glycyrrhiza uralensis Fisch in liver injury mice[J]. Nat Prod Res, 2021, 35(24): 6083-6087. DOI: 10.1080/14786419.2020.1824223. [25] TAN HK, YATES E, LILLY K, et al. Oxidative stress in alcohol-related liver disease[J]. World J Hepatol, 2020, 12(7): 332-349. DOI: 10.4254/wjh.v12.i7.332. [26] WAN YM, WU HM, LI YH, et al. Corrigendum: TSG-6 inhibits oxidative stress and induces M2 polarization of hepatic macrophages in mice with alcoholic hepatitis via suppression of STAT3 activation[J]. Front Pharmacol, 2020, 11: 569. DOI: 10.3389/fphar.2020.00569. [27] HSU MF, KOIKE S, MELLO A, et al. Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice[J]. Redox Biol, 2020, 36: 101658. DOI: 10.1016/j.redox.2020.101658. [28] DONATO M, TOLOSA L. High-content screening for the detection of drug-induced oxidative stress in liver cells[J]. Antioxidants (Basel), 2021, 10(1): 106. DOI: 10.3390/antiox10010106. [29] GHANIM BY, AHMAD MI, ABDALLAH QM, et al. Modulation of NRF2/ARE pathway-and cell death-related genes during drug-induced liver injury[J]. Hum Exp Toxicol, 2021, 40(12): 2223-2236. DOI: 10.1177/09603271211027947. [30] VILLANUEVA-PAZ M, MORÁN L, LÓPEZ-ALCÁNTARA N, et al. Oxidative stress in drug-induced liver injury (DILI): From mechanisms to biomarkers for use in clinical practice[J]. Antioxidants (Basel), 2021, 10(3): 390. DOI: 10.3390/antiox10030390. [31] UNSAL V, CICEK M, SABANCILAR I ·. Toxicity of carbon tetrachloride, free radicals and role of antioxidants[J]. Rev Environ Health, 2021, 36(2): 279-295. DOI: 10.1515/reveh-2020-0048. [32] EZHILARASAN D, RAGHUNANDHAKUMAR S. Boldine treatment protects acetaminophen-induced liver inflammation and acute hepatic necrosis in mice[J]. J Biochem Mol Toxicol, 2021, 35(4): e22697. DOI: 10.1002/jbt.22697. [33] XU D, XU M, JEONG S, et al. The role of Nrf2 in liver disease: novel molecular mechanisms and therapeutic approaches[J]. Front Pharmacol, 2018, 9: 1428. DOI: 10.3389/fphar.2018.01428. [34] YI G, DIN JU, ZHAO F, et al. Effect of soybean peptides against hydrogen peroxide induced oxidative stress in HepG2 cells via Nrf2 signaling[J]. Food Funct, 2020, 11(3): 2725-2737. DOI: 10.1039/c9fo01466g. [35] SENTHIL KUMAR KJ, LIAO JW, XIAO JH, et al. Hepatoprotective effect of lucidone against alcohol-induced oxidative stress in human hepatic HepG2 cells through the up-regulation of HO-1/Nrf-2 antioxidant genes[J]. Toxicol In Vitro, 2012, 26(5): 700-708. DOI: 10.1016/j.tiv.2012.03.012. [36] GONG P, CEDERBAUM AI. Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1[J]. Hepatology, 2006, 43(1): 144-153. DOI: 10.1002/hep.21004. [37] YU Z, YANG L, DENG S, et al. Daidzein ameliorates LPS-induced hepatocyte injury by inhibiting inflammation and oxidative stress[J]. Eur J Pharmacol, 2020, 885: 173399. DOI: 10.1016/j.ejphar.2020.173399. [38] LV H, ZHU C, WEI W, et al. Enhanced Keap1-Nrf2/Trx-1 axis by daphnetin protects against oxidative stress-driven hepatotoxicity via inhibiting ASK1/JNK and Txnip/NLRP3 inflammasome activation[J]. Phytomedicine, 2020, 71: 153241. DOI: 10.1016/j.phymed.2020.153241. [39] HU J, ZHU Z, YING H, et al. Oleoylethanolamide protects against acute liver injury by regulating Nrf-2/HO-1 and NLRP3 pathways in mice[J]. Front Pharmacol, 2020, 11: 605065. DOI: 10.3389/fphar.2020.605065. [40] MITCHELL S, VARGAS J, HOFFMANN A. Signaling via the NF-κB system[J]. Wiley Interdiscip Rev Syst Biol Med, 2016, 8(3): 227-241. DOI: 10.1002/wsbm.1331. [41] LONG X, SONG J, ZHAO X, et al. Silkworm pupa oil attenuates acetaminophen-induced acute liver injury by inhibiting oxidative stress-mediated NF-κB signaling[J]. Food Sci Nutr, 2020, 8(1): 237-245. DOI: 10.1002/fsn3.1296. [42] WANG M, NIU J, OU L, et al. Zerumbone protects against carbon tetrachloride (CCl4)-induced acute liver injury in mice via inhibiting oxidative stress and the inflammatory response: involving the TLR4/NF-κB/COX-2 pathway[J]. Molecules, 2019, 24(10): 1964. DOI: 10.3390/molecules24101964. [43] LI R, YANG W, YIN Y, et al. Protective Role of 4-Octyl itaconate in murine LPS/D-GalN-induced acute liver failure via inhibiting inflammation, oxidative stress, and apoptosis[J]. Oxid Med Cell Longev, 2021, 2021: 9932099. DOI: 10.1155/2021/9932099. [44] ZHANG L, MENG B, LI L, et al. Boletus aereus protects against acute alcohol-induced liver damage in the C57BL/6 mouse via regulating the oxidative stress-mediated NF-κB pathway[J]. Pharm Biol, 2020, 58(1): 905-914. DOI: 10.1080/13880209.2020.1812672. [45] LIU Z, WANG X, LI L, et al. Hydrogen sulfide protects against paraquat-induced acute liver injury in rats by regulating oxidative stress, mitochondrial function, and inflammation[J]. Oxid Med Cell Longev, 2020, 2020: 6325378. DOI: 10.1155/2020/6325378.