核因子E2相关因子2在女性生殖系统中的作用

doi:10.12280/gjszjk.20210580

摘要/Abstract

摘要：

核因子E2相关因子2（nuclear factor-erythroid 2-related factor 2,Nrf2）是抗氧化防御系统的重要因子,参与氧化、炎症和代谢应激的及时保护反应。当细胞受到氧化压力或某些化学物质刺激时,Nrf2与伴侣蛋白Kelch 样ECH相关蛋白1（Kelch-like ECH-associated protein 1,Keap1）解离,与下游靶基因启动子的抗氧化反应元件（antioxidant response element,ARE）结合,促进大量抗氧化靶基因转录活化,促进机体发挥抗氧化功能,以维持氧化还原稳态。研究发现多囊卵巢综合征、子宫内膜异位症等生殖系统疾病的发生均与氧化应激有关,而Nrf2通路可通过参与调节卵巢、子宫和胎盘等器官抗氧化、抗炎的功能,保护女性生殖系统相关细胞、组织和器官免受氧化应激损伤。Nrf2通路关键靶点有望用于预防和治疗多囊卵巢综合征、子宫内膜异位症及子宫腺肌病等女性生殖系统相关疾病。

关键词: 氧化性应激, 抗氧化反应元件, 女（雌）性泌尿生殖系统疾病, 多囊卵巢综合征, 子宫内膜异位症, 核因子E2相关因子2

Abstract:

Nuclear factor-erythroid 2-related factor (Nrf2) is a key transcription factor which contributes to various cellular defence mechanisms and involves in timely protection against oxidative, inflammation and metabolic stress reactions. Under oxidative stress or certain chemical stimulations, Nrf2 dissociates from the chaperone protein Kelch-like ECH-associated protein 1 (Keap1), and translocates into the nucleus. Nrf2 binds to an antioxidant response element (ARE), contributes to activate a large number of downstream antioxidant target genes and then maintains the physical redox homeostasis. Importantly, the increased evidences indicate that female reproductive endocrine diseases, including polycystic ovary syndrome and endometriosis, are associated with oxidative stress. The Nrf2 pathway can protect the cells, tissues and organs related to the female reproductive system from oxidative stress by participating in regulating the antioxidant and anti-inflammatory functions in ovary, uterus, placenta and other organs. The key target of the Nrf2 pathway is expected to be used to prevent and treat female reproductive system diseases, such as polycystic ovary syndrome, endometriosis, adenomyosis and so on.

Key words: Oxidative stress, Antioxidant response elements, Female urogenital diseases, Polycystic ovary syndrome, Endometriosis, Nuclear factor-erythroid 2-related factor 2

卢铃菁, 李娟, 马红霞, 胡敏. 核因子E2相关因子2在女性生殖系统中的作用[J]. 国际生殖健康/计划生育, 2022, 41(2): 134-138.

LU Ling-jing, LI Juan, MA Hong-xia, HU Min. The Role of Nrf2 in Female Reproductive System[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(2): 134-138.

参考文献 30

[1]	Robledinos-Antón N, Fernández-Ginés R, Manda G, et al. Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development[J]. Oxid Med Cell Longev, 2019, 2019:9372182. doi: 10.1155/2019/9372182. doi: 10.1155/2019/9372182 pmid: 31396308
[2]	Jamali N, Mostafavi-Pour Z, Zal F, et al. Antioxidant ameliorative effect of caffeic acid on the ectopic endometrial cells separated from patients with endometriosis[J]. Taiwan J Obstet Gynecol, 2021, 60(2):216-220. doi: 10.1016/j.tjog.2020.12.003. doi: 10.1016/j.tjog.2020.12.003 pmid: 33678318
[3]	Jamali N, Zal F, Mostafavi-Pour Z, et al. Ameliorative Effects of Quercetin and Metformin and Their Combination Against Experimental Endometriosis in Rats[J]. Reprod Sci, 2021, 28(3):683-692. doi: 10.1007/s43032-020-00377-2. doi: 10.1007/s43032-020-00377-2 pmid: 33141412
[4]	Zhang Y, Zhao W, Xu H, et al. Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome[J]. J Physiol, 2019, 597(15):3927-3950. doi: 10.1113/JP277879. doi: 10.1113/JP277879 URL
[5]	Akino N, Wada-Hiraike O, Isono W, et al. Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary[J]. Reprod Biol Endocrinol, 2019, 17(1):23. doi: 10.1186/s12958-019-0466-y. doi: 10.1186/s12958-019-0466-y URL
[6]	Baird L, Yamamoto M. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway[J]. Mol Cell Biol, 2020, 40(13):e00099-20. doi: 10.1128/MCB.00099-20. doi: 10.1128/MCB.00099-20
[7]	Huang KF, Ma KH, Jhap TY, et al. Ultraviolet B irradiation induced Nrf2 degradation occurs via activation of TRPV1 channels in human dermal fibroblasts[J]. Free Radic Biol Med, 2019, 141:220-232. doi: 10.1016/j.freeradbiomed.2019.06.020. doi: 10.1016/j.freeradbiomed.2019.06.020 URL
[8]	Samir SM, Elalfy M, Nashar E, et al. Cardamonin exerts a protective effect against autophagy and apoptosis in the testicles of diabetic male rats through the expression of Nrf2 via p62-mediated Keap-1 degradation[J]. Korean J Physiol Pharmacol, 2021, 25(4):341-354. doi: 10.4196/kjpp.2021.25.4.341. doi: 10.4196/kjpp.2021.25.4.341 URL
[9]	王甜甜, 陈淳媛, 杨雷, 等. Nrf2/HO-1信号轴在氧化应激性疾病中的机制[J]. 中南大学学报(医学版), 2019, 44(1):74-80. doi: 10.11817/j.issn.1672-7347.2019.01.012. doi: 10.11817/j.issn.1672-7347.2019.01.012
[10]	He F, Ru X, Wen T. NRF2, a Transcription Factor for Stress Response and Beyond[J]. Int J Mol Sci, 2020, 21(13):4777. doi: 10.3390/ijms21134777. doi: 10.3390/ijms21134777 URL
[11]	Lu J, Zhao Y, Liu M, et al. Toward improved human health: Nrf2 plays a critical role in regulating ferroptosis[J]. Food Funct, 2021, 12(20):9583-9606. doi: 10.1039/d1fo01036k. doi: 10.1039/d1fo01036k URL
[12]	Li S, Eguchi N, Lau H, et al. The Role of the Nrf2 Signaling in Obesity and Insulin Resistance[J]. Int J Mol Sci, 2020, 21(18):6973. doi: 10.3390/ijms21186973. doi: 10.3390/ijms21186973 URL
[13]	Kim EH, Ridlo MR, Lee BC, et al. Melatonin-Nrf2 Signaling Activates Peroxisomal Activities in Porcine Cumulus Cell-Oocyte Complexes[J]. Antioxidants (Basel), 2020, 9(11):1080. doi: 10.3390/antiox9111080. doi: 10.3390/antiox9111080
[14]	梁程程, 杨红, 齐聪, 等. 氧化应激对卵巢储备功能下降的影响及中西医抗氧化治疗研究进展[J]. 中国中西医结合杂志, 2021, 41(7):885-889. doi: 10.7661/j.cjim.20201120.370. doi: 10.7661/j.cjim.20201120.370
[15]	Khadrawy O, Gebremedhn S, Salilew-Wondim D, et al. Endogenous and Exogenous Modulation of Nrf2 Mediated Oxidative Stress Response in Bovine Granulosa Cells: Potential Implication for Ovarian Function[J]. Int J Mol Sci, 2019, 20(7):1635. doi: 10.3390/ijms20071635. doi: 10.3390/ijms20071635 URL
[16]	Akino N, Wada-Hiraike O, Isono W, et al. Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary[J]. Reprod Biol Endocrinol, 2019, 17(1):23. doi: 10.1186/s12958-019-0466-y. doi: 10.1186/s12958-019-0466-y URL
[17]	Kadam L, Gomez-Lopez N, Mial TN, et al. Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth[J]. Reprod Sci, 2017, 24(12):1590-1599. doi: 10.1177/1933719117697128 doi: 10.1177/1933719117697128 URL
[18]	陈茜, 钟晓珠, 李晓伟, 等. 子宫内膜浆液性癌发病起源的研究进展[J]. 中华妇产科杂志, 2020, 55(2):142-144. doi: 10.3760/cma.j.issn.0529-567X.2020.02.017. doi: 10.3760/cma.j.issn.0529-567X.2020.02.017
[19]	Ullah A, Jahan S, Razak S, et al. Protective effects of GABA against metabolic and reproductive disturbances in letrozole induced polycystic ovarian syndrome in rats[J]. J Ovarian Res, 2017, 10(1):62. doi: 10.1186/s13048-017-0359-7. doi: 10.1186/s13048-017-0359-7 pmid: 28915843
[20]	Zhang Y, Hu M, Meng F, et al. Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome[J]. EBioMedicine, 2017, 18:157-170. doi: 10.1016/j.ebiom.2017.03.023. doi: 10.1016/j.ebiom.2017.03.023 URL
[21]	Hu M, Zhang Y, Guo X, et al. Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant reactive oxygen species production[J]. Am J Physiol Endocrinol Metab, 2019, 316(5):E794-E809. doi: 10.1152/ajpendo.00359.2018. doi: 10.1152/ajpendo.00359.2018 URL
[22]	Song X, Long D. Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases[J]. Front Neurosci, 2020, 14:267. doi: 10.3389/fnins.2020.00267. doi: 10.3389/fnins.2020.00267 URL
[23]	Wang Y, Li N, Zeng Z, et al. Humanin regulates oxidative stress in the ovaries of polycystic ovary syndrome patients via the Keap1/Nrf2 pathway[J]. Mol Hum Reprod, 2021, 27(2):gaaa081. doi: 10.1093/molehr/gaaa081. doi: 10.1093/molehr/gaaa081
[24]	Huang Y, Zhang X. Luteolin alleviates polycystic ovary syndrome in rats by resolving insulin resistance and oxidative stress[J]. Am J Physiol Endocrinol Metab, 2021, 320(6):E1085-E1092. doi: 10.1152/ajpendo.00034.2021. doi: 10.1152/ajpendo.00034.2021 URL
[25]	Kyei G, Sobhani A, Nekonam S, et al. Assessing the effect of MitoQ(10) and Vitamin D3 on ovarian oxidative stress, steroidogenesis and histomorphology in DHEA induced PCOS mouse model[J]. Heliyon, 2020, 6(7):e04279. doi: 10.1016/j.heliyon.2020.e04279. doi: 10.1016/j.heliyon.2020.e04279 URL
[26]	Kapoor R, Sirohi VK, Gupta K, et al. Naringenin ameliorates progression of endometriosis by modulating Nrf2/Keap1/HO1 axis and inducing apoptosis in rats[J]. J Nutr Biochem, 2019, 70:215-226. doi: 10.1016/j.jnutbio.2019.05.003. doi: 10.1016/j.jnutbio.2019.05.003 URL
[27]	Liu Y, Zhang Z, Lu X, et al. Anti-nociceptive and anti-inflammatory effects of sulforaphane on sciatic endometriosis in a rat model[J]. Neurosci Lett, 2020, 723:134858. doi: 10.1016/j.neulet.2020.134858. doi: 10.1016/j.neulet.2020.134858 URL
[28]	Siracusa R, D′Amico R, Cordaro M, et al. The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways[J]. Int J Mol Sci, 2021, 22(8):3991. doi: 10.3390/ijms22083991. doi: 10.3390/ijms22083991 URL
[29]	沈豪飞, 贾天玉, 王奕翔, 等. 子宫腺肌病的诊治进展[J]. 国际生殖健康/计划生育杂志, 2019, 38(6):519-522. doi: 10.3969/j.issn.1674-1889.2019.06.018. doi: 10.3969/j.issn.1674-1889.2019.06.018
[30]	Chen N, Du B, Zhou H, et al. Abnormal expression of Nrf2 may play an important role in the pathogenesis and development of adenomyosis[J]. PLoS One, 2017, 12(8):e0182773. doi: 10.1371/journal.pone.0182773. doi: 10.1371/journal.pone.0182773 URL