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通讯作者:

张婷,E-mail:zhangting@njmu.edu.cn

中图分类号:R71

文献标识码:A

文章编号:1007-4368(2024)02-263-08

DOI:10.7655/NYDXBNSN230989

参考文献 1
FOREMAN R E,GEORGE A L,REIMANN F,et al.Pep⁃ tidomics:a review of clinical applications and methodolo⁃ gies[J].J Proteome Res,2021,20(8):3782-3797
参考文献 2
KARAS J A,WADE J D,HOSSAIN M A.The chemical synthesis of insulin:an enduring challenge[J].Chem Rev,2021,121(8):4531-4560
参考文献 3
HOOK V,LIETZ C B,PODVIN S,et al.Diversity of neu⁃ ropeptide cell ⁃cell signaling molecules generated by pro⁃ teolytic processing revealed by neuropeptidomics mass spectrometry[J].J Am Soc Mass Spectrom,2018,29(5):807-816
参考文献 4
YAN Y,LI Y,ZHANG Z,et al.Advances of peptides for antibacterial applications[J].Colloids Surf B Biointerfac⁃ es,2021,202:111682
参考文献 5
HELLINGER R,SIGURDSSON A,WU W,et al.Peptido⁃ mics[J].Nat Rev Methods Primers,2023,3:25
参考文献 6
SUN J,WANG Z,YANG C.Ion mobility mass spectrome⁃ try development and applications[J].Crit Rev Anal Chem,2022:1-8
参考文献 7
郑琬琳,万磊磊,李水明,等.多肽组学技术在体液生物标志物中的研究进展[J].质谱学报,2021,42(5):926-941
参考文献 8
LYAPINA I,IVANOV V,FESENKO I.Peptidome:chaos or inevitability[J].Int J Mol Sci,2021,22(23):13128
参考文献 9
SIROLLI V,PIERONI L,DI LIBERATO L,et al.Urinary peptidomic biomarkers in kidney diseases[J].Int J Mol Sci,2019,21(1):96
参考文献 10
MUQAKU B,OECKL P.Peptidomic approaches and ob⁃ servations in neurodegenerative diseases[J].Int J Mol Sci,2022,23(13):7332
参考文献 11
LHEUREUX S,BRAUNSTEIN M,OZA A M.Epithelial ovarian cancer:evolution of management in the era of pre⁃ cision medicine[J].CA Cancer J Clin,2019,69(4):280-304
参考文献 12
STEWART C,RALYEA C,LOCKWOOD S.Ovarian can⁃ cer:an integrated review[J].Semin Oncol Nurs,2019,35(2):151-156
参考文献 13
XU J,WANG X,XU P,et al.Mass spectrometry ⁃ based peptidome profiling of human serous ovarian cancer tis⁃ sues[J].Int J Biochem Cell Biol,2019,107:53-61
参考文献 14
WANG X,LIU G,SHENG N,et al.Peptidome character⁃ ization of ovarian cancer serum and the identification of tumor suppressive peptide zyx36⁃58[J].Ann Transl Med,2020,8(15):925
参考文献 15
HUANG X,ZHOU J,TANG R,et al.Potential signifi⁃ cance of peptidome in human ovarian cancer for patients with ascites[J].Int J Gynecol Cancer,2018,28(2):355-362
参考文献 16
ZHAI X,BROWNELL J E.Biochemical perspectives on targeting kmt2 methyltransferases in cancer[J].Trends Pharmacol Sci,2021,42(8):688-699
参考文献 17
ESTEBAN⁃VILLARRUBIA J,SOTO⁃CASTILLO J J,PO⁃ ZAS J,et al.Tyrosine kinase receptors in oncology[J].Int J Mol Sci,2020,21(22):8529
参考文献 18
BURMEISTER C A,KHAN S F,SCHÄFER G,et al.Cer⁃ vical cancer therapies:current challenges and future per⁃ spectives[J].Tumour Virus Res,2022,13:200238
参考文献 19
VAN OSTADE X,DOM M,TJALMA W,et al.Candidate biomarkers in the cervical vaginal fluid for the(self⁃)diag⁃ nosis of cervical precancer[J].Arch Gynecol Obstet,2018,297(2):295-311
参考文献 20
MAHENDRU S,ROY K,KUKRETI S.Peptide biomark⁃ers:exploring the diagnostic aspect[J].Curr Protein Pept Sci,2017,18(9):914-919
参考文献 21
SHI F,LI X,MA Z,et al.Label⁃free quantitative compari⁃ son of cervical mucus peptides in subjects with endocervi⁃ cal adenocarcinoma and adenocarcinoma in situ[J].Tech⁃ nol Cancer Res Treat,2021,20:1533033821997825
参考文献 22
GUO C,LIU S,SUN M Z.Potential role of anxa1 in cancer [J].Future Oncol,2013,9(11):1773-1793
参考文献 23
CHAPRON C,MARCELLIN L,BORGHESE B,et al.Re⁃ thinking mechanisms,diagnosis and management of endo⁃ metriosis[J].Nat Rev Endocrinol,2019,15(11):666-682
参考文献 24
BULUN S E,YILMAZ B D,SISON C,et al.Endometriosis [J].Endocr Rev,2019,40(4):1048-1079
参考文献 25
XUE Y,XU P,XU S,et al.Peptidomic analysis of endo⁃ metrial tissue from patients with ovarian endometriosis [J].Cell Physiol Biochem,2018,47(1):107-118
参考文献 26
KONG D⁃H,KIM Y K,KIM M R,et al.Emerging roles of vascular cell adhesion molecule⁃1(vcam⁃1)in immunolog⁃ ical disorders and cancer[J].Int J Mol Sci,2018,19(4):1057
参考文献 27
CHOPYAK V V,KOVAL H D,HAVRYLYUK A M,et al.Immunopathogenesis of endometriosis ⁃ a novel look at an old problem[J].Cent Eur J Immunol,2022,47(1):109-116
参考文献 28
XU Y,QIAO J.Association of insulin resistance and ele⁃ vated androgen levels with polycystic ovarian syndrome(pcos):a review of literature[J].J Healthc Eng,2022,2022:9240569
参考文献 29
CENA H,CHIOVATO L,NAPPI R E.Obesity,polycystic ovary syndrome,and infertility:a new avenue for glp⁃1 re⁃ ceptor agonists[J].J Clin Endocrinol Metab,2020,105(8):e2695-e2709
参考文献 30
JIA G,TAO H,XUE Y,et al.Analysis of secreted pepti⁃ dome from omental adipose tissue in polycystic ovarian syndrome patients[J].J Cell Physiol,2018,233(8):5885-5894
参考文献 31
DUFAU J,SHEN J X,COUCHET M,et al.In vitro and ex vivo models of adipocytes[J].Am J Physiol Cell Physiol,2021,320(5):C822-C841
参考文献 32
LEUNG R K K,LIN Y,LIU Y.Recent advances in under⁃ standings towards pathogenesis and treatment for intra⁃ uterine adhesion and disruptive insights from single ⁃ cell analysis[J].Reprod Sci,2021,28(7):1812-1826
参考文献 33
DREISLER E,KJER J J.Asherman’s syndrome:current perspectives on diagnosis and management[J].Int J Wo⁃ mens Health,2019,11:191-198
参考文献 34
ZHANG L,WANG X,FENG M,et al.Peptidomics analy⁃ sis reveals peptide pdcryab1 inhibits doxorubicin ⁃ in⁃ duced cardiotoxicity[J].Oxid Med Cell Longev,2020,2020:7182428
参考文献 35
KANASAKI K,NAGAI T,NITTA K,et al.N⁃acetyl⁃seryl⁃ aspartyl⁃lysyl⁃proline:a valuable endogenous anti⁃fibrotic peptide for combating kidney fibrosis in diabetes[J].Front Pharmacol,2014,5:70
参考文献 36
HUA X,ZHANG Y,XU J,et al.Peptidome analysis of hu⁃ man intrauterine adhesion tissues and the identification of antifibrotic peptide[J].J Biomed Res,2022,36(4):280-296
参考文献 37
NGALAME A N,MUBIANA ⁃MBEWE M,DIONNE J A.Genital tract infections in women,pregnancy and neonates [J].Obstet Gynecol Clin North Am,2022,49(4):751-769
参考文献 38
YAN L,LUAN T,HUA Q,et al.Peptidomic analysis of fe⁃ male reproductive tract secretion to identify putative anti⁃ infection peptides in the female genital system via nano⁃ technologies[J].J Biomed Nanotechnol,2018,14(1):215-226
参考文献 39
MONIN L,WHETTLOCK E M,MALE V.Immune re⁃ sponses in the human female reproductive tract[J].Immu⁃ nology,2020,160(2):106-115
参考文献 40
IVES C W,SINKEY R,RAJAPREYAR I,et al.Pre⁃ eclampsia ⁃ pathophysiology and clinical presentations:jacc state⁃of⁃the⁃art review[J].J Am Coll Cardiol,2020,76(14):1690-1702
参考文献 41
RANA S,LEMOINE E,GRANGER J P,et al.Preeclamp⁃ sia:pathophysiology,challenges,and perspectives[J].Circ Res,2019,124(7):1094-1112
参考文献 42
FILIPEK A,JUREWICZ E.Preeclampsia ⁃ a disease of pregnant women[J].Postepy Biochem,2018,64(4):232-229
参考文献 43
DAI X,SONG X,RUI C,et al.Peptidome analysis of hu⁃ man serum from normal and preeclamptic pregnancies [J].J Cell Biochem,2017,118(12):4341-4348
参考文献 44
WONG M K,SHAWKY S A,ARYASOMAYAJULA A,et al.Extracellular matrix surface regulates self⁃assembly of three ⁃ dimensional placental trophoblast spheroids[J].PloS One,2018,13(6):e0199632
参考文献 45
PARAMESHWAR P K,SAGRILLO ⁃ FAGUNDES L,FOURNIER C,et al.Disease⁃specific extracellular matrix composition regulates placental trophoblast fusion effi⁃ ciency[J].Biomater Sci,2021,9(21):7247-7256
参考文献 46
STARODUBTSEVA N,NIZYAEVA N,BAEV O,et al.SERPINA1 peptides in urine as a potential marker of pre⁃ eclampsia severity[J].Int J Mol Sci,2020,21(3):914
参考文献 47
邵慧静,王天俊,张嘉嘉,等.子痫前期胎盘样本的多肽组学分析及差异多肽功能的初步探究[J].南京医科大学学报(自然科学版),2021,41(8):1151-1159
参考文献 48
YOSHIDA K,KUSAMA K,FUKUSHIMA Y,et al.Alpha⁃ 1 antitrypsin ⁃ induced endoplasmic reticulum stress pro⁃motes invasion by extravillous trophoblasts[J].Int J Mol Sci,2021,22(7):3683
参考文献 49
CHEN T,ZHANG Z,LU Q,et al.Screening and function⁃ al analysis of the differential peptides from the placenta of patients with healthy pregnancy and preeclampsia using placental peptidome[J].Front Genet,2022,13:1014836
参考文献 50
BRKIĆ J,DUNK C,SHAN Y,et al.Differential role of smad2 and smad3 in the acquisition of an endovascular trophoblast ⁃ like phenotype and preeclampsia[J].Front Endocrinol,2020,11:436
参考文献 51
PLOWS J F,STANLEY J L,BAKER P N,et al.The patho⁃ physiology of gestational diabetes mellitus[J].Int J Mol Sci,2018,19(11):3342
参考文献 52
YIN L,HUAI Y,ZHAO C,et al.Early second ⁃trimester peptidomic identification of serum peptides for potential prediction of gestational diabetes mellitus[J].Cell Physi⁃ ol Biochem,2018,51(3):1264-1275
参考文献 53
SHIRAKAWA J,TERAUCHI Y.Newer perspective on the coupling between glucose ⁃mediated signaling and β⁃ cell functionality[J].Endocr J,2020,67(1):1-8
参考文献 54
KC K,SHAKYA S,ZHANG H.Gestational diabetes mel⁃ litus and macrosomia:a literature review[J].Ann Nutr Metab,2015,66(Suppl 2):14-20
参考文献 55
LIU F,ZHAO C,LIU L,et al.Peptidome profiling of um⁃ bilical cord plasma associated with gestational diabetes ⁃ induced fetal macrosomia[J].J Proteomics,2016,139:38-44
参考文献 56
MUNSHAW S,REDPATH A N,PIKE B T,et al.Thymo⁃ sin β4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein re⁃ lated protein 1(lrp1)[J].Int Immunopharmacol,2023,115:109702
参考文献 57
LI X,LUO J,MOU K,et al.SDPR inhibits tgf⁃β induced cancer metastasis through fatty acid oxidation regulation in gastric cancer[J].Int J Biol Sci,2023,19(10):2999-3014
参考文献 58
WALANI S R.Global burden of preterm birth[J].Int J Gynaecol Obstet,2020,150(1):31-33
参考文献 59
ACKERMAN W E,BUHIMSCHI I A,BRUBAKER D,et al.Integrated microrna and mrna network analysis of the human myometrial transcriptome in the transition from quiescence to labor[J].Biol Reprod,2018,98(6):834-845
参考文献 60
TATTERSALL M,CORDEAUX Y,CHARNOCK ⁃JONES D S,et al.Expression of gastrin ⁃ releasing peptide is in⁃ creased by prolonged stretch of human myometrium,and antagonists of its receptor inhibit contractility[J].J Physi⁃ ol,2012,590(9):2081-2093
参考文献 61
FAN Y,HOU W,XING Y,et al.Peptidomics analysis of myometrium tissues in term labor compared with term nonlabor[J].J Cell Biochem,2020,121(2):1890-1900
参考文献 62
RICHTER R,SCHULZ ⁃ KNAPPE P,SCHRADER M,et al.Composition of the peptide fraction in human blood plasma:database of circulating human peptides[J].J Chromatogr B Biomed Sci Appl,1999,726(1⁃2):25-35
参考文献 63
SCHRADER M.Origins,technological development,and applications of peptidomics[J].Methods Mol Biol,2018,1719:3-39
目录contents

    摘要

    多肽是涉及人体内多种细胞功能的生物活性物质,主要来源于氨基酸脱水缩合和蛋白质降解这两种途径。所有细胞都能合成多肽物质,细胞功能活动也受多肽的调节。基于质谱的多肽组学研究已应用于疾病诊断和治疗中,多项相关研究也已开始深入探究卵巢癌、子痫前期、妊娠期糖尿病、宫颈癌、子宫内膜异位症等妇产科疾病的发病机制。因此,通过对多肽组学的研究去寻找这些妇产科疾病可能的发病机制以及潜在的生物标志物具有重要的临床意义。

    Abstract

    Peptides are bioactive substances involved in various cellular functions in the human body,mainly derived from two pathways:amino acid dehydration condensation and protein degradation. All cells can synthesize peptide substances,and cell function activities are also regulated by peptides. Peptidomics based on mass spectrometry has been applied in disease diagnosis and treatment. A few related studies have also begun to explore the pathogenesis of gynecological and obstetric diseases,such as ovarian cancer, preeclampsia,gestational diabetes mellitus,cervical cancer,endometriosis,etc. Therefore,it is of great clinical significance to study peptidomics to explore the potential pathogenesis and biomarkers of these obstetrics and gynecology diseases.

  • 多肽作为蛋白质降解产物之一,是重要的生物活性分子,在体内扮演着激素、神经递质和抗菌剂的角色。研究表明,疾病的发生可能与某些信号肽的失调密切相关,而靶向肽途径已成为开发新型疗法的成功策略之一。越来越多的人意识到多肽在生物学中的重要性,研究多肽分子的功能及其在疾病中的调节作用成为当今研究的热点。本文讨论了多肽组学在妇产科疾病诊断中的近期研究成果,并对新发现多肽的机制及其诊断价值提供了一些见解。

  • 1 多肽组学

  • 多肽是由3个或3个以上氨基酸分子脱水缩合形成的肽,属于相对分子质量小于10 kDa的小分子物质。多肽大多由 DNA 或 RNA 编码,或蛋白质降解产生。多肽分子形态各异,介于简单的线性分子和高度功能化、大量修饰的分子之间,这一现象赋予了它们丰富的生物学特征[1]。多肽在许多生理病理过程中起着关键作用,可以作为信号分子,如神经肽和肽激素,用于细胞间的交流;也可以作为防御分子参与机体免疫及应激反应。在临床上,多肽作为生物标志物和治疗药物受到广泛关注。例如,胰岛素和胰高血糖素是临床广泛应用的胰肽类激素,它们参与葡萄糖代谢的激素调节,成为糖尿病诊断和疗效检测的重要指标[2];P物质和脑啡肽等神经肽在中枢神经系统内发出信号并参与疼痛的调节[3];20多种已知的抗菌肽在先天免疫系统中发挥重要作用[4]。迄今为止,已有60余种多肽类药物获批上市,150余种处于临床研发阶段[5]

  • 多肽组学是蛋白质组学的一个新型分支,其目的是识别样品中存在的多肽,分析它们的潜在活性。与蛋白质组学相同,多肽组学利用量化技术测量不同环境下多肽相对表达水平,以识别样本中存在的未知肽。目前,多肽组学已逐渐成为快速发展的多学科领域,通过应用液相色谱和现代质谱等新型组学平台,在微量临床样品中发现低丰度肽成为可能。最新的质谱分析两步法将离子淌度分离与飞行时间质谱(time of flight,TOF)或Orbitrap分析仪集成在一起,实现了前所未有的高灵敏度和高通量[6]

  • 多肽组学工作流程包括遗传信息分析、多肽表征和数据计算处理,具体细分为:样本采集、提取、分离、质谱分析、鉴定和数据挖掘[7]。近年来,随着多肽组学“自上而下”提取技术的开创、现代质谱分析技术的快速发展以及遗传生物信息数据库的爆炸式增长,多肽组学在生物标志物识别方面愈发重要。研究人员可以从患者组织或体液中鉴定出数万种在来源、功能和特性方面存在显著差异的多肽,作为疾病潜在生物标志物或治疗靶点[8]。例如,有学者研究尿液多肽组学与肾脏疾病的关联[9],脑脊液多肽组学与神经退行性疾病的关系[10]。在妇产科学领域,同样有许多研究致力于构建差异多肽谱系,以实现妇产科疾病临床诊断和治疗领域的新突破。

  • 2 多肽组学与妇科疾病的研究

  • 2.1 妇科肿瘤

  • 多肽组学在妇科肿瘤的研究主要聚焦于卵巢癌(ovarian cancer,OC)和宫颈癌。OC是世界妇科肿瘤死亡的第2大病因,由于卵巢肿瘤细胞的无症状生长以及有效筛查指征的缺乏[11],导致大多数 OC 患者诊断时已处于晚期,无法实现早期发现和治疗。OC全球5年生存率偏低,在47.4%左右[12],因此 OC 早期诊断生物标志物的发现极其重要。Sirolli等[9] 的多肽组学研究表明,差异多肽主要参与局部黏附、蛋白质消化吸收以及细胞外基质(extracellu⁃ lar matrix,ECM)受体相互作用途径,与OC易发生腹膜转移的特征高度一致。体外实验证实,来源于 S38AA 蛋白的多肽(peptide1 derived from S38AA, P1DS)[13] 可能通过竞争性结合肿瘤迁移相关蛋白,显著抑制OC细胞的迁移;而来源于斑联蛋白(zyxin, ZYX)的多肽ZYX36-58可能通过结合和提高凝血酶敏感蛋白⁃1(thrombin sensitive protein 1,TSP1)水平抑制 OC 细胞的转移,促进 OC 细胞凋亡[14]。晚期 OC 常转移至腹水,其内含有肿瘤细胞与周围环境相互作用而释放的多种可溶性因子。有研究人员通过筛选腹水差异多肽以探究 OC 发生、侵袭及转移的具体机制,多肽序列 VLTALLNSR 和 VAARNV⁃ LLTNGHVA 的前体蛋白赖氨酸甲基转移酶 2A (lysine methyltransferase2A,KMT2A)和集落刺激因子 ⁃ 1 受体(colony ⁃ stimulating factor 1receptor, CSF1R)与肿瘤转移密切相关[15]。KMT2A参与转录起始复合物的组装和激活,一定程度影响抑癌基因的活性[16]。CSF1R具有活化蛋白激酶C家族成员的功能,促进癌症细胞的侵袭。活性状态的CSF1R还通过生长因子受体结合蛋白2(growth factor receptor⁃ bound protein 2,GRB2)等蛋白质传递信号介导丝裂原活化蛋白激酶(mitogen⁃activated protein kinases, MAPK)的活化,以多种途径参与细胞生长、分化和死亡,并与包括黑色素瘤、胶质瘤和前列腺癌等几种类型恶性肿瘤的发生和发展有关[17]。以上研究提示,腹水 VLTALLNSR 和 VAARNVLLTNGHVA 等多肽序列可能作为 OC 患者晚期转移的生物标志物。但OC的早期多肽类生物标志物仍需要进一步的研究和关注。

  • 宫颈癌是全球女性第4大常见癌症,也是世界第 4 大癌症死亡原因,每年约有 60 万新发病例和 34 万死亡病例。宫颈癌大致分为3大类:鳞状细胞癌(squamous cell carcinoma,SCC)、宫颈管腺癌 (endocervical adenocarcinoma,EAC)和其他上皮肿瘤。SCC可以使用宫颈细胞学检查和高危型人乳头瘤病毒(high risk human papilloma virus,HR⁃HPV)检测进行早期筛查,该方法显著改善了 SCC 预后[18]。 EAC由于临床上筛查方法的局限性,经常导致EAC 及其癌前病变原位腺癌(adenocarcinoma in situ, AIS)的漏诊。因此与 SCC 相比,腺癌预后更差、生存率更低、病死率更高。宫颈黏液(cervical mucus, CM)主要来源于宫颈内膜,少量由子宫内膜蜕膜和羊膜分泌。CM性质和成分的变化可以反映生殖道的生理和病理生理状态。蛋白质组学表明CM差异蛋白α⁃肌动蛋白⁃4、玻连蛋白、膜联蛋白A1(annexin A1,ANXA1)、环化酶相关蛋白1、膜联蛋白A2和黏蛋白⁃5B皆与早期宫颈癌密切相关[19]。在SCC癌前病变中CM有十几种蛋白质(14⁃3⁃3蛋白ε、肌动蛋白相关蛋白3、α⁃肌动蛋白⁃4、膜联蛋白A2)的表达同样具有显著差异[19]。与蛋白质相比,免疫原性弱、可以被血液快速吸收扩散以及反映蛋白酶变化的多肽成为临床诊断、预后、监测和治疗的新型生物标志物[20]。Shi 等[21] 应用液相色谱电离串联质谱 (liquid chromatography electrospray ionisation tandem mass spectrometry,LC⁃ESI⁃MS/MS)技术从 CM 样本中发现差异性多肽序列FIENEEQEYVQTVK表达减少,且其前体蛋白ANXA1在EAC和AIS中均显著下调。ANXA1 是肿瘤组织的非特异性调节蛋白,不仅在宫颈癌中存在显著差异,在其他恶性肿瘤中也被广泛研究。例如,ANXA1上调与肝细胞癌、胰腺癌、黑色素瘤、皮肤癌症和子宫内膜癌的发生、侵袭、转移和耐药显著正相关。而 B 细胞淋巴瘤、喉癌、鼻咽癌和肝门胆管癌中 ANXA1 低表达,肿瘤分化较差,进展较快[22]。因此,宫颈癌多肽序列 FIENEEQEYVQTVK 差异表达提示,其前体蛋白 ANXA1 可能参与宫颈腺上皮病变的发生发展,在接下来的研究中,可以此为研究靶点,通过体外功能实验和动物实验明确其参与宫颈癌的具体机制。

  • 2.2 子宫内膜异位症

  • 子宫内膜异位症是子宫外存在子宫内膜样组织,主要临床表现为下腹痛、痛经和不孕[23]。子宫内膜异位症根据发生部位不同,分为腹膜型、卵巢型、深部浸润型、瘢痕内异症及远处内异症这几种不同的组织学亚型。卵巢子宫内膜异位症(ovarian endometriosis,OvE)发病率最高,且逐年增加,但发病机制仍不清楚。目前,OvE主要有两种治疗方法:药物和手术治疗。对于有生育要求的育龄期女性,腹腔镜切除病变是首选方法,但复发率较高,而且会降低自然受孕概率[24]。因此,以全新角度探究 OvE 发生的早期敏感分子事件,对 Ove 早期诊断和治疗是必要的。Xue等[25] 在OvE子宫内膜样组织中鉴定出42个差异多肽,其分子功能主要包括肌动蛋白结合、ATP供能和ECM合成3大生物过程,调节细胞基质黏附和细胞迁移。细胞黏附和迁移是子宫内膜异位症的重要生物学行为,消耗大量ATP,因此本文推测42个差异多肽在子宫内膜异位症的发生发展中发挥重要作用。Xue等[25] 还通过实验验证来源于血管细胞黏附分子1(vascular cell adhesion mol⁃ ecule⁃1,VCAM⁃1)的差异多肽序列AGRSRKEVELI⁃ IQVT降低E⁃钙黏蛋白的表达水平,促进胚胎干细胞 (embryonic stem cell,ESC)的迁移。VCAM⁃1属于细胞黏附分子家族,参与细胞间相互作用并介导各种免疫炎症过程[26]。有研究表明VCAM⁃1参与子宫内膜异位症的病理过程[27],而Xue等[25] 的研究进一步验证了该机制假说,为OvE的诊断和治疗提供了潜在靶点。

  • 2.3 多囊卵巢综合征(polycystic ovarian syndrome, PCOS)

  • PCOS是常见的妇科内分泌疾病之一。PCOS可通过不孕症、痤疮、闭经或月经稀发、多毛症、胰岛素抵抗、肥胖、高雄激素血症和超声检查多囊卵巢等临床表征来诊断。流行病学研究显示38%~88% 的 PCOS 女性表现为超重或肥胖,并且随着体重增加,PCOS 患者胰岛素抵抗增强,导致高雄激素血症和生殖功能障碍,增加了阻塞性睡眠呼吸暂停、血脂异常和非酒精性脂肪性肝病等并发症的患病率[28]。由肠道细胞分泌的胰高血糖素样肽1(glucagon⁃like peptide⁃1,GLP⁃1)属于常见的激素肽,能刺激胰岛β 细胞分泌胰岛素并抑制胰高血糖素的分泌。GLP⁃1 动力学改变与PCOS发病机制存在潜在的病理生理学关联。有文献报道GLP⁃1在PCOS治疗中起重要作用,GLP ⁃1 受体激动剂利拉鲁肽可以显著降低 PCOS 患者的体重指数(body mass index,BMI)和血清睾酮水平,提示GLP⁃1受体激动剂在未来可能成为PCOS治疗的药物[29]

  • 高雄激素血症导致腹部脂肪堆积,加重胰岛素抵抗和高胰岛素血症[28],与 PCOS 的发生密切相关。Jia等[30] 使用液相色谱质谱法(liquid chromatog⁃ raphy mass spectrometry,LC⁃MS/MS)法构建PCOS患者腹部脂肪组织中的差异多肽表达谱系,发现差异多肽与胶原蛋白合成异常密切相关,参与卵泡发育过程ECM的调节,影响颗粒细胞骨架形成、卵巢囊肿发育和细胞形状变化等。脂肪组织中含有多种免疫细胞[31],而脂肪组织中来源于细胞黏附分子1 (cell adhesion molecule1,CADM1)的多肽序列 1MASVVLPS8、补体 C3 的多肽序列 231SFEVIVEPT240 和血清可溶性CD163的多肽序列770GSAHFGEGTG⁃ PI781,与免疫应答过程密切相关[30]。以此带来了新的思考,未来可以从免疫功能调节方面深入探讨 PCOS的发病机制。

  • 2.4 宫腔粘连(intrauterine adhesions,IUA)

  • IUA又称Asherman综合征,常起因于产后刮除术、感染、子宫肌瘤切除术和宫腔镜手术后,造成功能性子宫内膜的丧失、子宫腔被瘢痕组织闭塞、导致反复流产及继发不孕,严重影响女性的生育能力和生活质量。IUA的病理学表现以子宫内膜异常纤维化为主要特征,而任何情况引起的子宫内膜基底层损伤都可能导致纤维化因子的产生,刺激成纤维细胞的增殖和ECM的过度沉积,导致纤维结缔组织的增殖和瘢痕的形成[32]。因此,防止子宫内膜纤维化是促进子宫内膜再生的前提,预防、抑制甚至逆转子宫内膜纤维化对防治IUA具有重要意义[33]。一些内源性多肽已经被认为是纤维化的重要调节剂,来自Cryab蛋白的多肽序列SPFYLRPPSF可以抑制心肌细胞凋亡,减少活性氧的产生,改善体外和体内心肌纤维化[34]。N⁃乙酰丝氨酸⁃天冬氨酸⁃赖氨酸 ⁃脯氨酸(N⁃acetyl⁃seryl⁃aspartyl⁃lysyl⁃proline,AcSD⁃ KP)内源性肽可以诱导成纤维细胞生长因子信号通路,抑制上皮⁃间叶细胞转化(epithelial ⁃mesenchy⁃ mal transition,EMT)过程,对于抗纤维化具有公认的临床价值[35]。上述结果提示多肽可能参与调节子宫内膜纤维化,在未来可以作为防治IUA的重要靶点。

  • 同时,IUA 组织多肽组学研究发现 6 种差异表达的内源性多肽,多肽序列 YLDHNALESVPLN、 YLDNNKISNIPDE、HVVPDQLMAFGGSSEP 和 WG⁃ KVNVDEVGGEAL 在 IUA 中显著下调,多肽序列 VDETNMYEGVGRMF 和TFGGAPGFPLGSPLSSPVF⁃ PR 则表达上调。其中多肽序列 TFGGAPGFPLG⁃ SPLSSPVFPR 在组间差异显著,研究学者将其与转化生长因子⁃β(transforming growth factor⁃β,TGF⁃β1) 和人胚胎干细胞(human embryonic stem cell, hESC)、孤雌胚胎干细胞(parthenogenetic haploid em⁃ bryonic stem cell,phESC)共培养,发现α⁃肌动蛋白 2、Ⅰ型胶原蛋白α1、波形蛋白、N⁃钙黏蛋白和纤连蛋白等纤维化基因的mRNA表达水平均显著降低,提示多肽序列 TFGGAPGFPLGSPLSSPVFPR 可以剂量依赖性抑制 TGF ⁃β1 信号通路诱导的 hESC 和 phESC纤维化,提示该肽段很可能是未来IUA有效治疗的新靶点[36]。然而,此多肽抑制IUA纤维化的具体作用途径仍需通过大量的临床队列进行验证。

  • 2.5 生殖道病原体感染疾病

  • 全球女性生殖道病原体感染的疾病包括细菌性阴道病(bacteria vaginosis,BV)、外阴阴道念珠菌病(vulvovaginal candidiasis,VVC)、人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染和人乳头瘤病毒(human papilloma virus,HPV)感染,具有较高发病率。生殖道病原体感染的诊断主要基于血清学检测和微生物培养等,并不复杂。然而近一半的患者在接受治疗12个月内复发,且发病原因不明[37],反复感染、潜伏感染和无效治疗对女性患者的生活质量产生严重影响。Yan等[38] 对女性生殖道感染分泌物使用纳流液相色谱⁃串联质谱仪进行多肽组学研究,发现黏蛋白家族是感染分泌物中差异多肽的主要前体蛋白家族,6 种差异多肽与 BV、HIV、HPV 和 VVC 感染密切相关,其前体黏蛋白 Mucin4、Mu⁃ cin5A、Mucin5B、Mucin6、Mucin17和Mucin19均在感染分泌物中过度表达。黏蛋白是高度糖基化的大分子蛋白,是覆盖在阴道的黏液屏障[39]。上述研究提示女性生殖道感染病原体后,机体黏膜免疫反应可代偿性升高,以抵抗病原体入侵。目前多肽与女性生殖道感染的研究并不多,接下来可以更为深入细致地划分生殖道感染的病因,将多肽作为新的研究靶点,探究生殖道感染的具体作用机制,为该病的治疗提供科学依据。

  • 3 多肽组学与产科疾病的研究

  • 3.1 子痫前期(pre⁃eclampsia,PE)

  • PE 是指妊娠 20 周后出现收缩压≥140 mmHg 和/或舒张压≥90 mmHg,并伴有蛋白尿或其他器官功能障碍的一种严重危害母婴健康的妊娠并发症,发病率为 2%~8%[40]。PE 的主要临床特征是水肿、高血压和蛋白尿,可能伴有母体肝肾功能衰竭、弥散性血管内凝血、子宫胎盘功能障碍和胎儿生长迟缓等不良妊娠结局,增加了孕产妇死亡的风险[41]。妊娠早期胎盘血管系统发育异常可导致胎盘血流灌注不足,引起缺血缺氧,血管内皮功能失调,导致妊娠期高血压的发生发展[42]。近年来多肽组学与 PE的研究日益增多,Dai等[43] 使用LC⁃ESI⁃MS/MS构建了PE血清差异多肽表达谱,与健康孕妇相比,PE 患者中显著上调的21种多肽与成纤维胶原、成网状结构胶原等ECM过程相关。越来越多的证据表明, ECM在滋养层细胞增殖和分化中起着重要作用[44-45]。因此,考虑ECM异常导致人胎盘滋养细胞发生异常迁移/侵袭,介导PE的发生发展。同时,有学者通过多肽组学筛选出源于 Serpina1 基因的多肽片段在 PE患者尿液、血液及胎盘中同时表达上调,提示其对PE的诊断具有重要作用[46-47]。在机制方面,邵慧静等[47] 发现经Serpina1处理后的人胎盘滋养细胞基质金属蛋白酶 2(matrix metalloproteinase⁃2,MMP2) 表达量增加,基质金属蛋白酶抑制因子1(tissue in⁃ hibitor of metalloproteinases,TIMP1)表达量降低,提示Serpina1参与调节滋养层侵袭和螺旋动脉转化的生理机制,防止滋养层绒毛过度侵入子宫壁,减缓 PE的病程。然而PE时,特别是细胞滋养细胞、合胞滋养细胞以及蜕膜板中,Serpina1水平代偿性升高,纤维蛋白堆积,绒毛间隙减少,滋养层结构阻塞,限制滋养层侵入子宫螺旋动脉,进一步加剧胎盘血流的紊乱,导致恶性循环[48]。上述研究提示,Serpina1 与PE的发生密切相关,可以作为重要的研究靶点,进一步探究Serpina1与PE的具体发病机制,研究其作为 PE 早期诊断和治疗的可能性。另一方面, Chen等[49] 认为靶向TGF⁃β/Smad信号通路是治疗PE 的有效策略。来源于前体蛋白起始因子 4B(initia⁃ tion factor,IF4B)的多肽序列AASAKKKNKKGKTISL 能与 TGF ⁃β1 结合,进而导致 TGF ⁃β磷酸化,结合 Smad4以调节滋养层细胞的侵袭和增殖[50]。多肽序列 AASAKKKNKKGKTISL 是通过多肽组学筛选出的内源性多肽,具有分子量低、稳定性高、亲脂性好、易进入细胞等优点,对PE同样具有潜在的研究价值。

  • 3.2 妊娠期糖尿病(gestational diabetes mellitus, GDM)

  • GDM是一种常见的妊娠期并发症,表现为妊娠前糖代谢正常而妊娠期糖代谢异常,影响了全球约 16.5%的孕妇,明显增加了妊娠期高血压、巨大儿、胎儿先天性畸形和新生儿呼吸窘迫综合征等不良结局的发生风险[51]。GDM是一种常见的内分泌代谢疾病,其特征是糖脂代谢紊乱,尽管GDM的病理生理学尚未完全阐明,但胰岛素抵抗和胰腺β细胞功能障碍被认为是GDM发病机制的关键因素。Yin 等[52] 收集孕中期(妊娠16~18周)血清,通过不良妊娠结局是否发生,对GDM进行分组。该研究对比鉴定出表达差异的 297 种多肽,其中有 228 种多肽的前体蛋白质涉及脂质代谢、分子转运和小分子生物化学网络。值得注意的是,GDM 组的多肽序列 RTYSLTT 表达显著高于对照组。RTYSLTT 是胰岛素受体底物 2(insulin receptor substrate⁃2,IRS⁃2)的多肽片段,IRS⁃2的表达对调节胰岛β细胞的代谢和存活都至关重要。胰岛β细胞IRS⁃2表达增加导致胰岛β细胞活性升高,可有效预防糖尿病的发生[53]。多肽序列RTYSLTT在GDM血清中的丰度差异直接反映了IRS⁃2表达和功能的变化,有望成为GDM早期预测的潜在标志物。

  • GDM 会导致巨大儿的发生[54]。巨大儿是指出生体重显著高于平均水平(≥4 000 g)的新生儿,是 GDM主要的不良结局。一方面产妇因产程延长易发生产道损伤和产后出血,另一方面则增加胎儿肩难产、代谢紊乱、窘迫的概率。到目前为止,GDM诱发巨大儿的详细分子机制并未明确。GDM巨大儿多肽组学研究重点选取了分子量为2 471.7 Da和1 446.5 Da的差异多肽,2 471.7 Da的多肽来源于胸腺肽β⁃4(thymosin beta4 X,TMSB4X),该蛋白在血管内膜和血管中层显著上调,会随溶血磷脂、甘油三酯、饱和脂肪酸和鞘磷脂水平升高而升高[55-56]。 GDM脐带血浆中TMSB4X的增加,可能通过脐带循环增加胎儿血液中TMSB4X的浓度,在脂质积累中发挥关键作用,从而导致巨大儿的发生。1 446.5 Da 的多肽在GDM组中显著减少,主要来源于人血清剥夺反应蛋白(human serum deprivation response,SD⁃ PR),SDPR是Cavin家族蛋白的重要成分,构成细胞质膜,在脂质调节中也起着一定作用[57]。TMSB4X 和SDPR均促进脂质代谢,可能与GDM巨大儿的发生有关。由此,可以继续深入研究GDM糖脂代谢紊乱对于胎儿的不良影响,为探索GDM诱导巨大儿的机制以及日后可能导致的并发症提供新的线索,有助于降低产科并发症和2型糖尿病的发生率。

  • 3.3 早产(preterm birth,PTB)

  • PTB是指妊娠达到28周但不足37周而发生的分娩,其发生率约为11%,占新生儿(<28 d)死亡总数的28%[58]。因此,PTB被认为是最重要的产科问题之一。在过去10年中,PTB的全球发病率仍在上升。然而,PTB缺乏有效的预防方法。在过去50年中,由于学者们对肌层静止和收缩力等机制理解的局限性,用于治疗和预防早产的方式几乎没有变化。成功的分娩需要子宫能够产生协调有力的阶段性收缩以推动胎儿娩出的过程。保持子宫平滑肌细胞(smooth muscle cell,SMC)处于增殖状态并抑制子宫肌收缩可能是预防 PTB 的有效策略[59]。先前的研究发现肽在分娩中起着重要作用:胎盘分泌的胃泌素释放肽(gastrin⁃releasing peptide,GRP)被证明可以调节SMC的收缩,抑制GRP的分泌可以防止早产[60]。因此,多肽组学能为分娩中子宫肌层的收缩提供一个新的视角。有研究人员基于LC⁃ MS/MS 技术对足月非分娩(term non labor,TNL)患者和足月分娩(term labor,TL)患者的子宫肌层进行多肽组学研究。结果表明,ECM重塑在子宫肌层收缩中起着至关重要的作用[61]。富含脯氨酸⁃谷氨酸⁃ 缬氨酸⁃赖氨酸(proline⁃glutamine⁃valine⁃lysine,PE⁃ VK)的元件可以通过与F肌动蛋白相互作用来调节肌肉收缩,对于肌层收缩具有重要作用[62]。位于 PEVK功能结构域的Titin同样可以调节肌丝长度和肌动蛋白间的相互作用,而差异表达性多肽序列 KTSGK位于Titin的PEVK⁃21结构域中。上述研究提示,虽然缺乏Titin和其多肽序列KTSGK在子宫肌层收缩方面的研究,但它们可能是分娩过程的关键因素,或可为PTB发现和治疗提供新的策略。

  • 4 小结

  • 20 年前,从人类外周血中的各种蛋白质分子中鉴定出了超过20 000个天然循环肽片段,对其切割位点的分析揭示了体内许多血浆蛋白质的加工途径[62]。基于这些实验数据,提出了“多肽组学”的概念,定义为体液和组织中的一整套多肽片段。越来越多的证据表明,人体中的多肽与人类健康有关[63]。因此,多肽片段可能作为新的疾病标志物。

  • 质谱分析的最新进展对多肽领域的前景产生了重大影响。多肽组学工作流程和分析工具的进步改进了生物活性肽的识别和其功能表征的研究方法,还有助于研究调节性多肽的肽酶和分子途径,扩展了对细胞内外多肽的认识,尤其是近几年妇产科学领域中涌现了关于多肽组学的研究,为寻找更具特异性的生物靶点提供了新思路。然而,质谱分析对于完整的多肽组学表征的分析仍存在一些不足,如低丰度肽的检测问题、某些理化性质肽的偏向性检测、难以正确识别修饰的天然肽等[32]。需要进一步改进检测方法并排除样品制备过程中的干扰,开发用于识别和分析未表征多肽的方法。

  • 参考文献

    • [1] FOREMAN R E,GEORGE A L,REIMANN F,et al.Pep⁃ tidomics:a review of clinical applications and methodolo⁃ gies[J].J Proteome Res,2021,20(8):3782-3797

    • [2] KARAS J A,WADE J D,HOSSAIN M A.The chemical synthesis of insulin:an enduring challenge[J].Chem Rev,2021,121(8):4531-4560

    • [3] HOOK V,LIETZ C B,PODVIN S,et al.Diversity of neu⁃ ropeptide cell ⁃cell signaling molecules generated by pro⁃ teolytic processing revealed by neuropeptidomics mass spectrometry[J].J Am Soc Mass Spectrom,2018,29(5):807-816

    • [4] YAN Y,LI Y,ZHANG Z,et al.Advances of peptides for antibacterial applications[J].Colloids Surf B Biointerfac⁃ es,2021,202:111682

    • [5] HELLINGER R,SIGURDSSON A,WU W,et al.Peptido⁃ mics[J].Nat Rev Methods Primers,2023,3:25

    • [6] SUN J,WANG Z,YANG C.Ion mobility mass spectrome⁃ try development and applications[J].Crit Rev Anal Chem,2022:1-8

    • [7] 郑琬琳,万磊磊,李水明,等.多肽组学技术在体液生物标志物中的研究进展[J].质谱学报,2021,42(5):926-941

    • [8] LYAPINA I,IVANOV V,FESENKO I.Peptidome:chaos or inevitability[J].Int J Mol Sci,2021,22(23):13128

    • [9] SIROLLI V,PIERONI L,DI LIBERATO L,et al.Urinary peptidomic biomarkers in kidney diseases[J].Int J Mol Sci,2019,21(1):96

    • [10] MUQAKU B,OECKL P.Peptidomic approaches and ob⁃ servations in neurodegenerative diseases[J].Int J Mol Sci,2022,23(13):7332

    • [11] LHEUREUX S,BRAUNSTEIN M,OZA A M.Epithelial ovarian cancer:evolution of management in the era of pre⁃ cision medicine[J].CA Cancer J Clin,2019,69(4):280-304

    • [12] STEWART C,RALYEA C,LOCKWOOD S.Ovarian can⁃ cer:an integrated review[J].Semin Oncol Nurs,2019,35(2):151-156

    • [13] XU J,WANG X,XU P,et al.Mass spectrometry ⁃ based peptidome profiling of human serous ovarian cancer tis⁃ sues[J].Int J Biochem Cell Biol,2019,107:53-61

    • [14] WANG X,LIU G,SHENG N,et al.Peptidome character⁃ ization of ovarian cancer serum and the identification of tumor suppressive peptide zyx36⁃58[J].Ann Transl Med,2020,8(15):925

    • [15] HUANG X,ZHOU J,TANG R,et al.Potential signifi⁃ cance of peptidome in human ovarian cancer for patients with ascites[J].Int J Gynecol Cancer,2018,28(2):355-362

    • [16] ZHAI X,BROWNELL J E.Biochemical perspectives on targeting kmt2 methyltransferases in cancer[J].Trends Pharmacol Sci,2021,42(8):688-699

    • [17] ESTEBAN⁃VILLARRUBIA J,SOTO⁃CASTILLO J J,PO⁃ ZAS J,et al.Tyrosine kinase receptors in oncology[J].Int J Mol Sci,2020,21(22):8529

    • [18] BURMEISTER C A,KHAN S F,SCHÄFER G,et al.Cer⁃ vical cancer therapies:current challenges and future per⁃ spectives[J].Tumour Virus Res,2022,13:200238

    • [19] VAN OSTADE X,DOM M,TJALMA W,et al.Candidate biomarkers in the cervical vaginal fluid for the(self⁃)diag⁃ nosis of cervical precancer[J].Arch Gynecol Obstet,2018,297(2):295-311

    • [20] MAHENDRU S,ROY K,KUKRETI S.Peptide biomark⁃ers:exploring the diagnostic aspect[J].Curr Protein Pept Sci,2017,18(9):914-919

    • [21] SHI F,LI X,MA Z,et al.Label⁃free quantitative compari⁃ son of cervical mucus peptides in subjects with endocervi⁃ cal adenocarcinoma and adenocarcinoma in situ[J].Tech⁃ nol Cancer Res Treat,2021,20:1533033821997825

    • [22] GUO C,LIU S,SUN M Z.Potential role of anxa1 in cancer [J].Future Oncol,2013,9(11):1773-1793

    • [23] CHAPRON C,MARCELLIN L,BORGHESE B,et al.Re⁃ thinking mechanisms,diagnosis and management of endo⁃ metriosis[J].Nat Rev Endocrinol,2019,15(11):666-682

    • [24] BULUN S E,YILMAZ B D,SISON C,et al.Endometriosis [J].Endocr Rev,2019,40(4):1048-1079

    • [25] XUE Y,XU P,XU S,et al.Peptidomic analysis of endo⁃ metrial tissue from patients with ovarian endometriosis [J].Cell Physiol Biochem,2018,47(1):107-118

    • [26] KONG D⁃H,KIM Y K,KIM M R,et al.Emerging roles of vascular cell adhesion molecule⁃1(vcam⁃1)in immunolog⁃ ical disorders and cancer[J].Int J Mol Sci,2018,19(4):1057

    • [27] CHOPYAK V V,KOVAL H D,HAVRYLYUK A M,et al.Immunopathogenesis of endometriosis ⁃ a novel look at an old problem[J].Cent Eur J Immunol,2022,47(1):109-116

    • [28] XU Y,QIAO J.Association of insulin resistance and ele⁃ vated androgen levels with polycystic ovarian syndrome(pcos):a review of literature[J].J Healthc Eng,2022,2022:9240569

    • [29] CENA H,CHIOVATO L,NAPPI R E.Obesity,polycystic ovary syndrome,and infertility:a new avenue for glp⁃1 re⁃ ceptor agonists[J].J Clin Endocrinol Metab,2020,105(8):e2695-e2709

    • [30] JIA G,TAO H,XUE Y,et al.Analysis of secreted pepti⁃ dome from omental adipose tissue in polycystic ovarian syndrome patients[J].J Cell Physiol,2018,233(8):5885-5894

    • [31] DUFAU J,SHEN J X,COUCHET M,et al.In vitro and ex vivo models of adipocytes[J].Am J Physiol Cell Physiol,2021,320(5):C822-C841

    • [32] LEUNG R K K,LIN Y,LIU Y.Recent advances in under⁃ standings towards pathogenesis and treatment for intra⁃ uterine adhesion and disruptive insights from single ⁃ cell analysis[J].Reprod Sci,2021,28(7):1812-1826

    • [33] DREISLER E,KJER J J.Asherman’s syndrome:current perspectives on diagnosis and management[J].Int J Wo⁃ mens Health,2019,11:191-198

    • [34] ZHANG L,WANG X,FENG M,et al.Peptidomics analy⁃ sis reveals peptide pdcryab1 inhibits doxorubicin ⁃ in⁃ duced cardiotoxicity[J].Oxid Med Cell Longev,2020,2020:7182428

    • [35] KANASAKI K,NAGAI T,NITTA K,et al.N⁃acetyl⁃seryl⁃ aspartyl⁃lysyl⁃proline:a valuable endogenous anti⁃fibrotic peptide for combating kidney fibrosis in diabetes[J].Front Pharmacol,2014,5:70

    • [36] HUA X,ZHANG Y,XU J,et al.Peptidome analysis of hu⁃ man intrauterine adhesion tissues and the identification of antifibrotic peptide[J].J Biomed Res,2022,36(4):280-296

    • [37] NGALAME A N,MUBIANA ⁃MBEWE M,DIONNE J A.Genital tract infections in women,pregnancy and neonates [J].Obstet Gynecol Clin North Am,2022,49(4):751-769

    • [38] YAN L,LUAN T,HUA Q,et al.Peptidomic analysis of fe⁃ male reproductive tract secretion to identify putative anti⁃ infection peptides in the female genital system via nano⁃ technologies[J].J Biomed Nanotechnol,2018,14(1):215-226

    • [39] MONIN L,WHETTLOCK E M,MALE V.Immune re⁃ sponses in the human female reproductive tract[J].Immu⁃ nology,2020,160(2):106-115

    • [40] IVES C W,SINKEY R,RAJAPREYAR I,et al.Pre⁃ eclampsia ⁃ pathophysiology and clinical presentations:jacc state⁃of⁃the⁃art review[J].J Am Coll Cardiol,2020,76(14):1690-1702

    • [41] RANA S,LEMOINE E,GRANGER J P,et al.Preeclamp⁃ sia:pathophysiology,challenges,and perspectives[J].Circ Res,2019,124(7):1094-1112

    • [42] FILIPEK A,JUREWICZ E.Preeclampsia ⁃ a disease of pregnant women[J].Postepy Biochem,2018,64(4):232-229

    • [43] DAI X,SONG X,RUI C,et al.Peptidome analysis of hu⁃ man serum from normal and preeclamptic pregnancies [J].J Cell Biochem,2017,118(12):4341-4348

    • [44] WONG M K,SHAWKY S A,ARYASOMAYAJULA A,et al.Extracellular matrix surface regulates self⁃assembly of three ⁃ dimensional placental trophoblast spheroids[J].PloS One,2018,13(6):e0199632

    • [45] PARAMESHWAR P K,SAGRILLO ⁃ FAGUNDES L,FOURNIER C,et al.Disease⁃specific extracellular matrix composition regulates placental trophoblast fusion effi⁃ ciency[J].Biomater Sci,2021,9(21):7247-7256

    • [46] STARODUBTSEVA N,NIZYAEVA N,BAEV O,et al.SERPINA1 peptides in urine as a potential marker of pre⁃ eclampsia severity[J].Int J Mol Sci,2020,21(3):914

    • [47] 邵慧静,王天俊,张嘉嘉,等.子痫前期胎盘样本的多肽组学分析及差异多肽功能的初步探究[J].南京医科大学学报(自然科学版),2021,41(8):1151-1159

    • [48] YOSHIDA K,KUSAMA K,FUKUSHIMA Y,et al.Alpha⁃ 1 antitrypsin ⁃ induced endoplasmic reticulum stress pro⁃motes invasion by extravillous trophoblasts[J].Int J Mol Sci,2021,22(7):3683

    • [49] CHEN T,ZHANG Z,LU Q,et al.Screening and function⁃ al analysis of the differential peptides from the placenta of patients with healthy pregnancy and preeclampsia using placental peptidome[J].Front Genet,2022,13:1014836

    • [50] BRKIĆ J,DUNK C,SHAN Y,et al.Differential role of smad2 and smad3 in the acquisition of an endovascular trophoblast ⁃ like phenotype and preeclampsia[J].Front Endocrinol,2020,11:436

    • [51] PLOWS J F,STANLEY J L,BAKER P N,et al.The patho⁃ physiology of gestational diabetes mellitus[J].Int J Mol Sci,2018,19(11):3342

    • [52] YIN L,HUAI Y,ZHAO C,et al.Early second ⁃trimester peptidomic identification of serum peptides for potential prediction of gestational diabetes mellitus[J].Cell Physi⁃ ol Biochem,2018,51(3):1264-1275

    • [53] SHIRAKAWA J,TERAUCHI Y.Newer perspective on the coupling between glucose ⁃mediated signaling and β⁃ cell functionality[J].Endocr J,2020,67(1):1-8

    • [54] KC K,SHAKYA S,ZHANG H.Gestational diabetes mel⁃ litus and macrosomia:a literature review[J].Ann Nutr Metab,2015,66(Suppl 2):14-20

    • [55] LIU F,ZHAO C,LIU L,et al.Peptidome profiling of um⁃ bilical cord plasma associated with gestational diabetes ⁃ induced fetal macrosomia[J].J Proteomics,2016,139:38-44

    • [56] MUNSHAW S,REDPATH A N,PIKE B T,et al.Thymo⁃ sin β4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein re⁃ lated protein 1(lrp1)[J].Int Immunopharmacol,2023,115:109702

    • [57] LI X,LUO J,MOU K,et al.SDPR inhibits tgf⁃β induced cancer metastasis through fatty acid oxidation regulation in gastric cancer[J].Int J Biol Sci,2023,19(10):2999-3014

    • [58] WALANI S R.Global burden of preterm birth[J].Int J Gynaecol Obstet,2020,150(1):31-33

    • [59] ACKERMAN W E,BUHIMSCHI I A,BRUBAKER D,et al.Integrated microrna and mrna network analysis of the human myometrial transcriptome in the transition from quiescence to labor[J].Biol Reprod,2018,98(6):834-845

    • [60] TATTERSALL M,CORDEAUX Y,CHARNOCK ⁃JONES D S,et al.Expression of gastrin ⁃ releasing peptide is in⁃ creased by prolonged stretch of human myometrium,and antagonists of its receptor inhibit contractility[J].J Physi⁃ ol,2012,590(9):2081-2093

    • [61] FAN Y,HOU W,XING Y,et al.Peptidomics analysis of myometrium tissues in term labor compared with term nonlabor[J].J Cell Biochem,2020,121(2):1890-1900

    • [62] RICHTER R,SCHULZ ⁃ KNAPPE P,SCHRADER M,et al.Composition of the peptide fraction in human blood plasma:database of circulating human peptides[J].J Chromatogr B Biomed Sci Appl,1999,726(1⁃2):25-35

    • [63] SCHRADER M.Origins,technological development,and applications of peptidomics[J].Methods Mol Biol,2018,1719:3-39

  • 参考文献

    • [1] FOREMAN R E,GEORGE A L,REIMANN F,et al.Pep⁃ tidomics:a review of clinical applications and methodolo⁃ gies[J].J Proteome Res,2021,20(8):3782-3797

    • [2] KARAS J A,WADE J D,HOSSAIN M A.The chemical synthesis of insulin:an enduring challenge[J].Chem Rev,2021,121(8):4531-4560

    • [3] HOOK V,LIETZ C B,PODVIN S,et al.Diversity of neu⁃ ropeptide cell ⁃cell signaling molecules generated by pro⁃ teolytic processing revealed by neuropeptidomics mass spectrometry[J].J Am Soc Mass Spectrom,2018,29(5):807-816

    • [4] YAN Y,LI Y,ZHANG Z,et al.Advances of peptides for antibacterial applications[J].Colloids Surf B Biointerfac⁃ es,2021,202:111682

    • [5] HELLINGER R,SIGURDSSON A,WU W,et al.Peptido⁃ mics[J].Nat Rev Methods Primers,2023,3:25

    • [6] SUN J,WANG Z,YANG C.Ion mobility mass spectrome⁃ try development and applications[J].Crit Rev Anal Chem,2022:1-8

    • [7] 郑琬琳,万磊磊,李水明,等.多肽组学技术在体液生物标志物中的研究进展[J].质谱学报,2021,42(5):926-941

    • [8] LYAPINA I,IVANOV V,FESENKO I.Peptidome:chaos or inevitability[J].Int J Mol Sci,2021,22(23):13128

    • [9] SIROLLI V,PIERONI L,DI LIBERATO L,et al.Urinary peptidomic biomarkers in kidney diseases[J].Int J Mol Sci,2019,21(1):96

    • [10] MUQAKU B,OECKL P.Peptidomic approaches and ob⁃ servations in neurodegenerative diseases[J].Int J Mol Sci,2022,23(13):7332

    • [11] LHEUREUX S,BRAUNSTEIN M,OZA A M.Epithelial ovarian cancer:evolution of management in the era of pre⁃ cision medicine[J].CA Cancer J Clin,2019,69(4):280-304

    • [12] STEWART C,RALYEA C,LOCKWOOD S.Ovarian can⁃ cer:an integrated review[J].Semin Oncol Nurs,2019,35(2):151-156

    • [13] XU J,WANG X,XU P,et al.Mass spectrometry ⁃ based peptidome profiling of human serous ovarian cancer tis⁃ sues[J].Int J Biochem Cell Biol,2019,107:53-61

    • [14] WANG X,LIU G,SHENG N,et al.Peptidome character⁃ ization of ovarian cancer serum and the identification of tumor suppressive peptide zyx36⁃58[J].Ann Transl Med,2020,8(15):925

    • [15] HUANG X,ZHOU J,TANG R,et al.Potential signifi⁃ cance of peptidome in human ovarian cancer for patients with ascites[J].Int J Gynecol Cancer,2018,28(2):355-362

    • [16] ZHAI X,BROWNELL J E.Biochemical perspectives on targeting kmt2 methyltransferases in cancer[J].Trends Pharmacol Sci,2021,42(8):688-699

    • [17] ESTEBAN⁃VILLARRUBIA J,SOTO⁃CASTILLO J J,PO⁃ ZAS J,et al.Tyrosine kinase receptors in oncology[J].Int J Mol Sci,2020,21(22):8529

    • [18] BURMEISTER C A,KHAN S F,SCHÄFER G,et al.Cer⁃ vical cancer therapies:current challenges and future per⁃ spectives[J].Tumour Virus Res,2022,13:200238

    • [19] VAN OSTADE X,DOM M,TJALMA W,et al.Candidate biomarkers in the cervical vaginal fluid for the(self⁃)diag⁃ nosis of cervical precancer[J].Arch Gynecol Obstet,2018,297(2):295-311

    • [20] MAHENDRU S,ROY K,KUKRETI S.Peptide biomark⁃ers:exploring the diagnostic aspect[J].Curr Protein Pept Sci,2017,18(9):914-919

    • [21] SHI F,LI X,MA Z,et al.Label⁃free quantitative compari⁃ son of cervical mucus peptides in subjects with endocervi⁃ cal adenocarcinoma and adenocarcinoma in situ[J].Tech⁃ nol Cancer Res Treat,2021,20:1533033821997825

    • [22] GUO C,LIU S,SUN M Z.Potential role of anxa1 in cancer [J].Future Oncol,2013,9(11):1773-1793

    • [23] CHAPRON C,MARCELLIN L,BORGHESE B,et al.Re⁃ thinking mechanisms,diagnosis and management of endo⁃ metriosis[J].Nat Rev Endocrinol,2019,15(11):666-682

    • [24] BULUN S E,YILMAZ B D,SISON C,et al.Endometriosis [J].Endocr Rev,2019,40(4):1048-1079

    • [25] XUE Y,XU P,XU S,et al.Peptidomic analysis of endo⁃ metrial tissue from patients with ovarian endometriosis [J].Cell Physiol Biochem,2018,47(1):107-118

    • [26] KONG D⁃H,KIM Y K,KIM M R,et al.Emerging roles of vascular cell adhesion molecule⁃1(vcam⁃1)in immunolog⁃ ical disorders and cancer[J].Int J Mol Sci,2018,19(4):1057

    • [27] CHOPYAK V V,KOVAL H D,HAVRYLYUK A M,et al.Immunopathogenesis of endometriosis ⁃ a novel look at an old problem[J].Cent Eur J Immunol,2022,47(1):109-116

    • [28] XU Y,QIAO J.Association of insulin resistance and ele⁃ vated androgen levels with polycystic ovarian syndrome(pcos):a review of literature[J].J Healthc Eng,2022,2022:9240569

    • [29] CENA H,CHIOVATO L,NAPPI R E.Obesity,polycystic ovary syndrome,and infertility:a new avenue for glp⁃1 re⁃ ceptor agonists[J].J Clin Endocrinol Metab,2020,105(8):e2695-e2709

    • [30] JIA G,TAO H,XUE Y,et al.Analysis of secreted pepti⁃ dome from omental adipose tissue in polycystic ovarian syndrome patients[J].J Cell Physiol,2018,233(8):5885-5894

    • [31] DUFAU J,SHEN J X,COUCHET M,et al.In vitro and ex vivo models of adipocytes[J].Am J Physiol Cell Physiol,2021,320(5):C822-C841

    • [32] LEUNG R K K,LIN Y,LIU Y.Recent advances in under⁃ standings towards pathogenesis and treatment for intra⁃ uterine adhesion and disruptive insights from single ⁃ cell analysis[J].Reprod Sci,2021,28(7):1812-1826

    • [33] DREISLER E,KJER J J.Asherman’s syndrome:current perspectives on diagnosis and management[J].Int J Wo⁃ mens Health,2019,11:191-198

    • [34] ZHANG L,WANG X,FENG M,et al.Peptidomics analy⁃ sis reveals peptide pdcryab1 inhibits doxorubicin ⁃ in⁃ duced cardiotoxicity[J].Oxid Med Cell Longev,2020,2020:7182428

    • [35] KANASAKI K,NAGAI T,NITTA K,et al.N⁃acetyl⁃seryl⁃ aspartyl⁃lysyl⁃proline:a valuable endogenous anti⁃fibrotic peptide for combating kidney fibrosis in diabetes[J].Front Pharmacol,2014,5:70

    • [36] HUA X,ZHANG Y,XU J,et al.Peptidome analysis of hu⁃ man intrauterine adhesion tissues and the identification of antifibrotic peptide[J].J Biomed Res,2022,36(4):280-296

    • [37] NGALAME A N,MUBIANA ⁃MBEWE M,DIONNE J A.Genital tract infections in women,pregnancy and neonates [J].Obstet Gynecol Clin North Am,2022,49(4):751-769

    • [38] YAN L,LUAN T,HUA Q,et al.Peptidomic analysis of fe⁃ male reproductive tract secretion to identify putative anti⁃ infection peptides in the female genital system via nano⁃ technologies[J].J Biomed Nanotechnol,2018,14(1):215-226

    • [39] MONIN L,WHETTLOCK E M,MALE V.Immune re⁃ sponses in the human female reproductive tract[J].Immu⁃ nology,2020,160(2):106-115

    • [40] IVES C W,SINKEY R,RAJAPREYAR I,et al.Pre⁃ eclampsia ⁃ pathophysiology and clinical presentations:jacc state⁃of⁃the⁃art review[J].J Am Coll Cardiol,2020,76(14):1690-1702

    • [41] RANA S,LEMOINE E,GRANGER J P,et al.Preeclamp⁃ sia:pathophysiology,challenges,and perspectives[J].Circ Res,2019,124(7):1094-1112

    • [42] FILIPEK A,JUREWICZ E.Preeclampsia ⁃ a disease of pregnant women[J].Postepy Biochem,2018,64(4):232-229

    • [43] DAI X,SONG X,RUI C,et al.Peptidome analysis of hu⁃ man serum from normal and preeclamptic pregnancies [J].J Cell Biochem,2017,118(12):4341-4348

    • [44] WONG M K,SHAWKY S A,ARYASOMAYAJULA A,et al.Extracellular matrix surface regulates self⁃assembly of three ⁃ dimensional placental trophoblast spheroids[J].PloS One,2018,13(6):e0199632

    • [45] PARAMESHWAR P K,SAGRILLO ⁃ FAGUNDES L,FOURNIER C,et al.Disease⁃specific extracellular matrix composition regulates placental trophoblast fusion effi⁃ ciency[J].Biomater Sci,2021,9(21):7247-7256

    • [46] STARODUBTSEVA N,NIZYAEVA N,BAEV O,et al.SERPINA1 peptides in urine as a potential marker of pre⁃ eclampsia severity[J].Int J Mol Sci,2020,21(3):914

    • [47] 邵慧静,王天俊,张嘉嘉,等.子痫前期胎盘样本的多肽组学分析及差异多肽功能的初步探究[J].南京医科大学学报(自然科学版),2021,41(8):1151-1159

    • [48] YOSHIDA K,KUSAMA K,FUKUSHIMA Y,et al.Alpha⁃ 1 antitrypsin ⁃ induced endoplasmic reticulum stress pro⁃motes invasion by extravillous trophoblasts[J].Int J Mol Sci,2021,22(7):3683

    • [49] CHEN T,ZHANG Z,LU Q,et al.Screening and function⁃ al analysis of the differential peptides from the placenta of patients with healthy pregnancy and preeclampsia using placental peptidome[J].Front Genet,2022,13:1014836

    • [50] BRKIĆ J,DUNK C,SHAN Y,et al.Differential role of smad2 and smad3 in the acquisition of an endovascular trophoblast ⁃ like phenotype and preeclampsia[J].Front Endocrinol,2020,11:436

    • [51] PLOWS J F,STANLEY J L,BAKER P N,et al.The patho⁃ physiology of gestational diabetes mellitus[J].Int J Mol Sci,2018,19(11):3342

    • [52] YIN L,HUAI Y,ZHAO C,et al.Early second ⁃trimester peptidomic identification of serum peptides for potential prediction of gestational diabetes mellitus[J].Cell Physi⁃ ol Biochem,2018,51(3):1264-1275

    • [53] SHIRAKAWA J,TERAUCHI Y.Newer perspective on the coupling between glucose ⁃mediated signaling and β⁃ cell functionality[J].Endocr J,2020,67(1):1-8

    • [54] KC K,SHAKYA S,ZHANG H.Gestational diabetes mel⁃ litus and macrosomia:a literature review[J].Ann Nutr Metab,2015,66(Suppl 2):14-20

    • [55] LIU F,ZHAO C,LIU L,et al.Peptidome profiling of um⁃ bilical cord plasma associated with gestational diabetes ⁃ induced fetal macrosomia[J].J Proteomics,2016,139:38-44

    • [56] MUNSHAW S,REDPATH A N,PIKE B T,et al.Thymo⁃ sin β4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein re⁃ lated protein 1(lrp1)[J].Int Immunopharmacol,2023,115:109702

    • [57] LI X,LUO J,MOU K,et al.SDPR inhibits tgf⁃β induced cancer metastasis through fatty acid oxidation regulation in gastric cancer[J].Int J Biol Sci,2023,19(10):2999-3014

    • [58] WALANI S R.Global burden of preterm birth[J].Int J Gynaecol Obstet,2020,150(1):31-33

    • [59] ACKERMAN W E,BUHIMSCHI I A,BRUBAKER D,et al.Integrated microrna and mrna network analysis of the human myometrial transcriptome in the transition from quiescence to labor[J].Biol Reprod,2018,98(6):834-845

    • [60] TATTERSALL M,CORDEAUX Y,CHARNOCK ⁃JONES D S,et al.Expression of gastrin ⁃ releasing peptide is in⁃ creased by prolonged stretch of human myometrium,and antagonists of its receptor inhibit contractility[J].J Physi⁃ ol,2012,590(9):2081-2093

    • [61] FAN Y,HOU W,XING Y,et al.Peptidomics analysis of myometrium tissues in term labor compared with term nonlabor[J].J Cell Biochem,2020,121(2):1890-1900

    • [62] RICHTER R,SCHULZ ⁃ KNAPPE P,SCHRADER M,et al.Composition of the peptide fraction in human blood plasma:database of circulating human peptides[J].J Chromatogr B Biomed Sci Appl,1999,726(1⁃2):25-35

    • [63] SCHRADER M.Origins,technological development,and applications of peptidomics[J].Methods Mol Biol,2018,1719:3-39

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