卵巢衰老加剧缺血性脑卒中损伤的病理机制及姜黄素的干预作用*

doi:10.3870/j.issn.1672-0741.25.09.039

摘要/Abstract

摘要： 目的明确卵巢衰老(OVA)加剧缺血性脑卒中(IS)损伤的病理机制,及基于病理靶点筛选的姜黄素对该类脑卒中损伤的作用机制。方法挖掘GEO数据库中OVA(GSE81579)与IS(GSE16561)相关数据集,经差异表达分析、GSEA富集及Venn分析筛选核心交集基因,结合David数据库进行KEGG/GO富集分析;通过Coremine Medicine数据库筛选相关中药,并结合文献筛选活性成分;以雌性SD大鼠构建大脑中动脉阻塞/再灌注(MCAO/R)模型,分为假手术(Sham)组、MCAO/R组、卵巢切除+MCAO/R(M&OVA)组、卵巢切除+MCAO/R+姜黄素治疗(M&OVA&Cur)组和卵巢切除+MCAO/R+姜黄素治疗+烟酰胺(M&OVA&Cur&Nico)组,采用神经功能评分、TTC染色、HE染色、免疫荧光、透射电镜及蛋白质免疫印迹实验验证姜黄素的作用。结果 OVA与IS核心基因有80个交集,富集于炎症反应、C-X3-C趋化因子结合和NOD样受体信号通路等;筛选出中药姜黄及其活性成分姜黄素。动物实验显示,相较于MCAO/R组,M&OVA组大鼠脑损伤程度显著增加;200 mg/(kg·d)姜黄素可缓解M&OVA大鼠神经功能损伤,减小脑梗死体积并抑制NLRP3炎性小体活性。SIRT1抑制剂烟酰胺处理后,姜黄素保护作用减弱。结论卵巢衰老通过激活炎症反应进一步加剧缺血性脑卒中的损伤,姜黄素可通过调控SIRT1-NLRP3轴减轻这一损伤。

关键词: 卵巢衰老, 缺血性脑卒中, 姜黄素, NLRP3炎性小体, SIRT1

Abstract: Objective To explore the pathological mechanism underlying the exacerbation of ischemic stroke(IS)injury by ovarian aging(OVA),and to elucidate the therapeutic mechanism of curcumin screened based on pathological targets against OVA-aggravated IS injury.Methods Datasets of OVA(GSE81579)and IS(GSE16561)were retrieved from the Gene Expression Omnibus(GEO)database.Core intersecting genes were screened through differential expression analysis,Gene Set Enrichment Analysis(GSEA),and Venn analysis.The Database for Annotation,Visualization and Integrated Discovery(David)was used for Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analyses.Potential traditional Chinese medicines(TCMs)were screened via the Coremine Medicine database,and their active ingredients were further identified through literature review.A middle cerebral artery occlusion/reperfusion(MCAO/R)model was established in female Sprague-Dawley(SD)rats.The rats were randomly divided into five groups:the sham operation(Sham)group,MCAO/R model group,ovariectomy combined with MCAO/R(M&OVA)group,ovariectomy+MCAO/R+curcumin treatment(M&OVA&Cur)group,and ovariectomy+MCAO/R+curcumin+nicotinamide intervention(M&OVA&Cur&Nico)group.Multiple detection methods including neurological function scoring,2,3,5-triphenyltetrazolium chloride(TTC)staining,hematoxylin-eosin(H&E)staining,immunofluorescence assay,transmission electron microscopy(TEM),and Western blot were adopted to verify the protective effect and mechanism of curcumin.Results A total of 80 core intersecting genes were identified between OVA and IS,which were mainly enriched in the inflammatory response,C-X3-C chemokine binding,and NOD-like receptor signaling pathways.Curcuma longa and its active ingredient curcumin were finally screened as the targeted therapeutic agent.In vivo animal experiments demonstrated that rats in the M&OVA group exhibited significantly aggravated cerebral injury compared with those in the sole MCAO/R group.Treatment with curcumin at the dose of 200 mg/kg per day remarkably alleviated neurological deficits,reduced cerebral infarct volume,and inhibited the activation of NLRP3 inflammasome in M&OVA rats.Moreover,the neuroprotective effects of curcumin were markedly abrogated after intervention with nicotinamide,a specific SIRT1 inhibitor.Conclusion Ovarian aging aggravates ischemic stroke injury by activating inflammatory responses.Curcumin can attenuate OVA-aggravated cerebral ischemic injury via regulating the SIRT1-NLRP3 signaling axis,which provides a reliable theoretical basis for the clinical treatment of OVA-complicated ischemic stroke.

Key words: ovarian aging, ischemic stroke, curcumin, NLRP3 inflammasome, SIRT1

中图分类号:

R743.33

张希源, 陈亚军, 曾巧春, 王碧洁, 汪诗娆, 李姝雅, 曹晓璐. 卵巢衰老加剧缺血性脑卒中损伤的病理机制及姜黄素的干预作用^*[J]. 华中科技大学学报（医学版）, 2026, 55(4): 465-474.

Zhang Xiyuan, Chen Yajun, Zeng Qiaochun, et al. The Pathological Mechanism of Ovarian Aging Aggravating Ischemic Stroke Injury and the Pharmacological Effect of Curcumin Intervention[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(4): 465-474.

参考文献

[1] Taylor E B,Jocelyn A,Esteban L,et al.The aging ovary impairs acute stroke outcomes[J].J Neuroinflammation,2023,20(1):159-159.
[2] Courtney E S,Farida S.Gonadal hormones and stroke risk:PCOS as a case study[J].Front Neuroendocrinol,2020,58:100853.
[3] Rexrode K,Tracy E M,Amy Y X Y,et al.The impact of sex and gender on stroke[J].Circ Res,2022,130(4):512-528.
[4] Heather V,Chen A,Kathryn J G.The hypothalamic-pituitary-ovarian axis,ovarian disorders,and brain aging[J].Endocrinology,2025,166(10):bqaf137.
[5] Dean P E.Regulation of signal transduction pathways by estrogen and progesterone[J].Annu Rev Physiol,2005,67(1):335-376.
[6] Thomas T,Nolwenn A,Sakina M,et al.Reproductive function and behaviors:An update on the role of neural estrogen receptors alpha and beta[J].Front Endocrinol(Lausanne).2024,15:1408677.
[7] Traci A T,Kay M J.Menopause[J].Med Clin North Am,2015,99(3):521-534.
[8] Hao Q K,Malavika T,Martin O,et al.Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high-risk transient ischaemic attack:Systematic review and meta-analysis[J].BMJ,2018,363(1):k5108.
[9] Vida N,Mohammad K,Reza A,et al.Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury[J].Iran J Basic Med Sci,2015,18(2):138-144.
[10] Lu D,Qu Y,Shi F,et al.Activation of G protein-coupled estrogen receptor 1(GPER-1)ameliorates blood-brain barrier permeability after global cerebral ischemia in ovariectomized rats[J].Biochem Biophys Res Commun,2016,477(2):209-214.
[11] Yana V,Carol C,Julia H.Use of hormone replacement therapy and risk of breast cancer:Nested case-control studies using the QResearch and CPRD databases[J].BMJ,2020,371(1):m3873.
[12] Todd R S,Julie R P,Lynn A R,et al.Exogenous hormone use and endometrial cancer in U.S.black women[J].Cancer Epidemiol Biomarkers Prev,2018,27(5):558-565.
[13] Yang J A,Yang Q.Identification of core genes and screening of potential targets in glioblastoma multiforme by integrated bioinformatic analysis[J].Front Oncol,2021,10:615976.
[14] Ma L,Zheng J J,Chen H J,et al.A systematic screening of traditional Chinese medicine identifies two novel inhibitors against the cytotoxic aggregation of amyloid beta[J].Front Pharmacol,2021,12:637766.
[15] Zheng W X,Cao X L,Wang F,et al.Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-A-mediated transactivity[J].Eur J Pharmacol,2015,767:201-210.
[16] Yang Y R,Wang R Y and Wang P S.Early and late treadmill training after focal brain ischemia in rats[J].Neurosci Lett,2003,339(2):91-94.
[17] Somayyeh S T,Ehsan F Y,Azam A,et al.Biological and ph-ysiological characteristics of human cumulus cells in adherent culture condition[J].Int J Reprod Biomed,2020,18(1):1-10.
[18] Turathum B,Guo E M,Chian R C,et al.The function of cumulus cells in oocyte growth and maturation and in subsequent ovulation and fertilization[J].Cells,2021,10(9):2292.
[19] Charles E W,Maureen K.Influence of estradiol and fetal st-ress on luteinizing hormone,follicle-stimulating hormone,and prolactin in late-gestation fetal sheep[J].Neonatology,2011,100(2):155-161.
[20] Rachida G.Progesterone in the brain:Hormone,neurosteroid and neuroprotectant[J].Int J Mol Sci,2020,21(15):5271.
[21] Meng L B,Zhang Y M,Shan M J,et al.Pivotal micro factors associated with endothelial cells[J].Chin Med J(Engl),2019,132(16):1965-1973.
[22] Wu J C,Liu Y,Song Y H,et al.Aging conundrum:A perspective for ovarian aging[J].Front Endocrinol(Lausanne),2022,13:952471.
[23] 李锐,肖燕,和心依,等.中药姜黄化学成分、生物活性及体内代谢研究进展[J].西华大学学报,2013,32(3):98-104.
Li R,Xiao Y,He X Y,et al.Research progress on chemical constituents,biological activities and in vivo metabolism of Curcuma longa L[J].Journal of Xihua University,2013,32(3):98-104.
[24] Mohammad J D,Hamid G,Mehran N,et al.Antioxidant and anti-inflammatory effects of curcumin/turmeric supplementation in adults:A GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials[J].Cytokine,2023,164:156144.
[25] Mahvash S,Sajad D,Ali A,et al.Curcumin and chemokines:mechanism of action and therapeutic potential in inflammatory diseases[J].Inflammopharmacology,2023,31(3):1069-1093.
[26] Jürgen R.Antiviral and virucidal properties of essential oils and isolated compounds-A scientific approach[J].Planta Med,2022,88(8):587-603.
[27] Abdul R W,Kanchan Y,Aadil K,et al.An updated and comprehensive review of the antiviral potential of essential oils and their chemical constituents with special focus on their mechanism of action against various influenza and coronaviruses[J].Microb Pathog,2021,152:104620.
[28] Mohamed T E,Yang T,Sameh A K,et al.Impacts of turmeric and its principal bioactive curcumin on human health:Pharmaceutical,medicinal,and food applications:A comprehensive review[J].Front Nutr,2023,9:1040259.
[29] Patchaya P,Panisara S,Rattana P,et al.Utilization of UPLC-PDA and GC-MS/MS coupled with metabolomics analysis to identify bioactive metabolites in medicinal turmeric at different ages for the quality assurance[J].Phytomedicine,2022,102(1):154-157.
[30] Zhang Y N,Luo L,Xu X M,et al.Acetylation is required for full activation of the NLRP3 inflammasome[J].Nat Commun,2023,14(1):83-96.
[31] Xie L J,Li C Q,Wang C,et al.Aspirin-mediated acetylation of SIRT1 maintains intestinal immune homeostasis[J].Adv Sci(Weinh),2024,11(19):e2306378.
[32] Sun H Y,Li D,Wei C J,et al.The relationship between SIRT1 and inflammation:A systematic review and meta-analysis[J].Front Immunol,2024,15:1465849.
[33] 陈建,洪秀琴.雌激素对心血管系统的细胞作用机制的探讨[J].中华老年心脑血管病杂志,2019,21(3):314-316.
Chen J,Hong X Q.Discussion on cellular mechanism of estrogen acting on cardiovascular system[J].Chinese Journal of Geriatric Heart,Brain and Vessel Diseases,2019,21(3):314-316.
[34] Thomas T,Nolwenn A,Sakina M,et al.Reproductive functi-on and behaviors:An update on the role of neural estrogen receptors alpha and beta[J].Front Endocrinol(Lausanne).2024,15:1408677.
[35] Meena S S,Aurelie J,Paula C B,et al.CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases[J].Pharmacol Ther,2022,231:107989.
[36] Severina N H,Charles R W.Estradiol regulation of constitutive and keratinocyte growth factor-induced CCL20 and CXCL1 secretion by mouse uterine epithelial cells[J].Am J Reprod Immunol,2014,72(1):34-44.
[37] Gabrielle L,Llucia A S,Sabrina D,et al.Dissecting the mechanism of cytokine release induced by T-cell engagers highlights the contribution of neutrophils[J].Oncoimmunology,2022,11(1):2039432.
[38] Zou G L,Tang Y L,Yang J,et al.Signal-induced NLRP3 ph-ase separation initiates inflammasome activation[J].Cell Res,2025,35(6):437-452.
[39] Yi L,Liang Y,Zhao Q M,et al.CX3CL1 induces vertebral microvascular barrier dysfunction via the Src/P115-RhoGEF/ROCK signaling pathway[J].Front Cell Neurosci,2020,14:96.
[40] Fabienne B,Daniela B,Aline R,et al.NLRP3 inflammasome activation controls vascular smooth muscle cells phenotypic switch in atherosclerosis[J].Int J Mol Sci,2021,23(1):340.
[41] Aliabbas Z,Tahereh F,Ali Mohammad P,et al.The role of curcumin in aging and senescence:Molecular mechanisms[J].Biomed Pharmacother,2021,134:111119.
[42] 李晶晶,李瑞青,张建云,等.线粒体生物发生在脑缺血再灌注损伤中作用的研究进展[J].华中科技大学学报(医学版),2025,54(2):298-304.
Li J J,Li R Q,Zhang J Y,et al.Research progress on the mechanism of mitochondrial biogenesis in cerebral ischemia-reperfusion injury[J].Acta Med Univ Sci Technol Huazhong,2025,54(2):298-304.
[43] Jennifer A,Sun Q,Steven B S,et al.Age-dependent loss of hepatic SIRT1 enhances NLRP3 inflammasome signaling and impairs capacity for liver fibrosis resolution[J].Aging Cell,2023,22(5):e13811.
[44] Mohamed A S,Mostafa A R,Nesrine S E S,et al.Neuroprotective effect of curcumin against experimental autoimmune encephalomyelitis-induced cognitive and physical impairments in mice:An insight into the role of the AMPK/SIRT1 pathway[J].Inflammopharmacology,2024,32(2):1499-1518.

卵巢衰老加剧缺血性脑卒中损伤的病理机制及姜黄素的干预作用^*

The Pathological Mechanism of Ovarian Aging Aggravating Ischemic Stroke Injury and the Pharmacological Effect of Curcumin Intervention

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