核转录因子(NF-κB)信号通路与子宫内膜异位症发病关系的研究及针对性治疗
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摘要
子宫内膜异位症是常见的妇科疾病,可以导致妇女痛经、不孕等,具有类似肿瘤的浸润、转移及复发的恶性行为,发病机制尚不完全明确。近年来研究表明异位的子宫内膜浸润与转移调节涉及多条信号转导通路,其中核转录因子NF-κB信号通路与子宫内膜异位症的发生与发展有密切关系,其参与子宫内膜异位症的发生、发展、作用机制等可能与调节炎症反应和黏附、侵袭、血管生成一系列生物学行为相关因子的表达有关。基于此机制,目前学者们也针对子宫内膜异位症开始研究针对作用于NF-κB信号通路的新的治疗方法及治疗药物。
Endometriosis is a common gynecological disease. It can cause dysmenorrhea and infertility in women. It has malignant behavior similar to tumor invasion,metastasis,and recurrence. The pathogenesis is still not completely clear. Recent studies have shown that ectopic endometrium infiltration and metastasis involve multiple signal transduction pathways,and the nuclear factor kappa signal pathway is closely related to the occurrence and development of endometriosis. The occurrence,development,and mechanism of action of its involvement in EMS may be related to the regulation of inflammatory responses and the expression of related factors of adhesion,invasion,and angiogenesis. Based on this mechanism,scholars have also begun to study new therapeutic methods and therapeutic drugs targeting NF-κB signaling pathways for EMS.
Endometriosis is a common gynecological disease. It can cause dysmenorrhea and infertility in women. It has malignant behavior similar to tumor invasion,metastasis,and recurrence. The pathogenesis is still not completely clear. Recent studies have shown that ectopic endometrium infiltration and metastasis involve multiple signal transduction pathways,and the nuclear factor kappa signal pathway is closely related to the occurrence and development of endometriosis. The occurrence,development,and mechanism of action of its involvement in EMS may be related to the regulation of inflammatory responses and the expression of related factors of adhesion,invasion,and angiogenesis. Based on this mechanism,scholars have also begun to study new therapeutic methods and therapeutic drugs targeting NF-κB signaling pathways for EMS.
引文
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[2]Akoum A,Kats R,Metz CN.Macrophage migration inhibitory factor is markedly expressed in active and early-stage endometriotic lesions[J].Clin Endocrinol Metab,2002,87:883-889.
[3]Morin M,Bellehumeur C,Therriault MJ,et al.Elevated levels of macrophage migration inhibitory factor in the peripheral blood of women with endometriosis[J].Fertil Steril,2005,83(4):865-872.
[4]Veillat V,Lavoie CH,Metz CN,et al.Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin-1 beta in ectopic endometrial cells[J].Fertil Steril,2009,91(5Suppl):2148-2156.
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[6]张喜,吴瑞瑾.核转录因子κB与子宫内膜异位症发病机制[J].国际妇产科学杂志,2008,35(4):265-268.Zhang X,Wu RJ.Nuclear factorκB and the pathogenesis of endometriosis[J].Int J Gynecol,2008,35(4):265-268.
[7]Khan KN,kitajima M,Inoue T,et al.17β-Estradiol and lipopolysaccharide additively promote pelvic inflammation and growth of endometriosis[J].Reprod Sci,2015,22(5):585-594.
[8]Yamauchi N,Harada T,Taniguchi F,et al.Tumor necrosis factoralpha induced the release of interleukin-6 from endometriotic stromal cells by the nuclear factor-KappaB and mitogen-activated protein kinase pathways[J].Fertil Steril,2004,82:1023-1028.
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[11]谭毅,黄荷凤,朱依敏.子宫内膜异位症性不孕症与MMP-2及性激素的关系[J].中国现代医学杂志,2002,12(14):50-53.Tan Y,Huang HF,Zhu YM.The relationship between endometriosis infertility and MMP-2 and sex hormones[J].Chin J Modern Med,2002,12(14):50-53.
[12]Sharpe-Timms KL,Keisler LW,Mclntush EW.Tissue inhibitor of metalloproteinase-1 concentration are attenuated in peritoneal fluid and sera of women with endometriosis and restored ii sera by gonadotropin.Releasing hormone agonist therapy[J].Fertil Steril,1998,69(6):1128-1134.
[13]Chang HW,Wen Y,Chun SH.Mateix metauoprotinases-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis a vationle for endometriotic invasiveness[J].Fertil Steril,2001,75(1):152-159.
[14]Donnez J,Donnez O.Endometriosis and infertility[J].Panminerva Med,2016,58(2):143-150.
[15]王芳,何援利,罗敏,等.子宫内膜异位症核转录因子和血管内皮生长因子表达与预后的关系[J].西北国防医学杂志,2007,28(2):116-119.Wang F,He YL,Luo M,et al.Relationship between expression of nuclear transcription factor and vascular endothelial growth factor and prognosis in endometriosis[J].Northwest Defense Med J,2007,28(2):116-119.
[16]Li B,Chen M,Liu X,et al.Constitutive and tumor necrosis factora-induced activation of nuclear factor-kB inadenomyosis and its inhibition by and rographolide[J].Fertil Steril,2013,100(2):568-577.
[17]Roghaei MA,Tehrany HG,Taherian A,et al.Effects of letrozole compared with Danazol on patients with confirmed endometriosis:A Randomized Clin T[J].IJFS,2010,4(2):67-72.
[18]Alborzi S,Hamedi B,Omidvar A,et al.A comparison of the effect of shortterm aromatase inhibitor(letrozole)and GnRH agonist(triptorelin)versus case control on pregnancy rate and symptom and sign recurrence after laparoscopic treatment of endometriosis[J].Arch Gynecol Obstet,2011,284(1):105-110.
[19]王康,陈素琴.来曲唑对子宫内膜异位症大鼠TNF-α,IL-6,NF-κB表达的影响[J].现代妇产科进展,2012,21(11):882-887.Wang K,Chen SQ.Effects of letrozole on the expression of TNF-α,IL-6,NF-κB in rats with endometriosis[J].Modern Adv Gynecol,2012,21(11):882-887.
[20]宋淑芳,尹利荣,齐之迎,等.来曲唑治疗大鼠子宫内膜异位症模型作用及机制的研究[J].现代妇产科进展,2011,20(1):35-38.Song SF,Yin LR,Qi ZY,et al.Study on the effect and mechanism of letrozolide on endometriosis model in rats[J].Modern Adv Gynecol,2011,20(1):35-38.
[21]李建超,吕秀萍.来曲唑对大鼠子宫内膜异位症病灶survivin表达的影响[J].现代妇产科进展,2009,18(5):351-353.Li JC,LüXP.Effects of letrozole on the expression of survivin in rat endometriosis lesions[J].Modern Adv Gynecol,2009,18(5):351-353.
[22]高霞,邢军,聂改红,等.来曲唑对离体异位子宫内膜基质细胞凋亡的影响[J].实用医学杂志,2009,25(21):3560-3562.Gao X,Xing J,Nie GH,et al.Effects of letrozole on apoptosis of ectopic endometrial stromal cells in vitro[J].Practical J Med,2009,25(21):3560-3562.
[23]Trentini A,Maritati M,Cervellati C,et al.Vaginal lactoferrin modulates PGE2,MMP-9,MMP-2,and TIMP-1 amniotic fluid concentrations[J].Medictors Inflamm,2016,2016:3648719.
[24]谢伟.米非司酮对子宫内膜异位症患者异位内膜组织中侵袭基因、凋亡基因表达的影响[J].海南医学院学报,2017,23(18):2528-2534.Xie W.Effect of mifepristone on invasion gene and apoptosis gene expression in ectopic endometrial tissue of patients with endometriosis[J].J Hainan Med College,2017,23(18):2528-2534.
[25]Mancini F,Milardi D,Carfaqna P,et al.Low-dose SKA progesterone and interleukin-10 modulate the inflammatory pathway in endometriotic cell lines[J].Int Immunopharmacol,2018,55:223-230.
[26]Horie S,Harada T,Mitsunari M,et al.Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells[J].Fertil Steril,2008,89(2):311-317.
[27]陈洪琴,郭铭川,曾莉,等.NF-κB抑制剂PDTC治疗大鼠子宫内膜异位症的实验研究[J].实用妇产科杂志,2010,26(11):853-855.Chen HQ,Guo MC,Zeng L,et al.Experimental study on treatment of endometriosis in rats with NF-κB inhibitor PDTC[J].Pract J Gynecol,2010,26(11):853-855.
[28]Celik O,Ersahin A,Acet M,et al.Disulfiram,as a candidate NF-κB and proteasome inhibitor,prevents endometriotic implant growing in a rat model of emdometriosis[J].Europ Rev Mid Pharmacological Sci,2016,20(20):4380-4389.
[29]彭容,詹宏,林俊.PRL-3抑制剂对子宫内膜异位症大鼠异位病灶的作用[J].现代妇产科进展,2017,26(9),678-681.Peng R,Zhan H,Lin J.Effect of PRL-3 Inhibitors on Ectopic Lesion in Rats with Endometriosis[J].Modern Adv Gynecol,2017,26(9):678-681.
[30]Jana S,Paul S,Swarnakar S,et al.Curcumin as anti-endometriotic agent:Implication of MMP-3 and intrinscic apoptotic pathway[J].Biochem Pharmacol,2012,83(6):797-804.
[31]Kim KH,Park JK,Choi YW,et al.Hexane extract of aged black garlic reduces cell proliferation and attenuates the expression of ICAM-I and VCAM-I in TNF-αactivated human endometrial stromal cells[J].Int J Mol Med,2013,31(1):67-68.
[32]Ji-Hyun Kim,Seung-Hyun Jung,Yeong-In Yang,et al.Artemisia leaf extract induces apoptosis in huamn endometriotic cells through regulations of the p38 and NF-κB pathways[J].J Ethnopharmacol,2013,145(3):767-775.
[33]Zheng Y,Liu XS.Therapeutic potential of andrographolide for treating endometriosis[J].Hum Reprod,2012,27(5):1300-1313.
[2]Akoum A,Kats R,Metz CN.Macrophage migration inhibitory factor is markedly expressed in active and early-stage endometriotic lesions[J].Clin Endocrinol Metab,2002,87:883-889.
[3]Morin M,Bellehumeur C,Therriault MJ,et al.Elevated levels of macrophage migration inhibitory factor in the peripheral blood of women with endometriosis[J].Fertil Steril,2005,83(4):865-872.
[4]Veillat V,Lavoie CH,Metz CN,et al.Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin-1 beta in ectopic endometrial cells[J].Fertil Steril,2009,91(5Suppl):2148-2156.
[5]Cao WG,Morin M,Metz C,et al.Stimulation of macrophage migration inhibitory factor expression in endometrial stromal cells by interleukin 1,beta involving the nuclear transcription factor NFkappaB[J].Biol Reprod,2005,73(3):565-570.
[6]张喜,吴瑞瑾.核转录因子κB与子宫内膜异位症发病机制[J].国际妇产科学杂志,2008,35(4):265-268.Zhang X,Wu RJ.Nuclear factorκB and the pathogenesis of endometriosis[J].Int J Gynecol,2008,35(4):265-268.
[7]Khan KN,kitajima M,Inoue T,et al.17β-Estradiol and lipopolysaccharide additively promote pelvic inflammation and growth of endometriosis[J].Reprod Sci,2015,22(5):585-594.
[8]Yamauchi N,Harada T,Taniguchi F,et al.Tumor necrosis factoralpha induced the release of interleukin-6 from endometriotic stromal cells by the nuclear factor-KappaB and mitogen-activated protein kinase pathways[J].Fertil Steril,2004,82:1023-1028.
[9]Wickiewicz D,Chrobak A,Gmyrek GB,et al.Diagnostic accuracy of interleukin-6 levels inperitoneal fluid for detection of endometriosis[J].Arch Gynecol Obstet,2013,288(4):805-814.
[10]Sakamoto Y,Harada T,Horie S,et al.Tumor necrosis factor-alpha-induced interleukin-8(IL-8)expression in endometriotic stromal cells,probably through nuclear factor-kappa B activation:gonadotropin-releasing hormone agonist treatment reduced IL-8expression[J].Clin Endocrinol Metab,2003,88(2):730-735.
[11]谭毅,黄荷凤,朱依敏.子宫内膜异位症性不孕症与MMP-2及性激素的关系[J].中国现代医学杂志,2002,12(14):50-53.Tan Y,Huang HF,Zhu YM.The relationship between endometriosis infertility and MMP-2 and sex hormones[J].Chin J Modern Med,2002,12(14):50-53.
[12]Sharpe-Timms KL,Keisler LW,Mclntush EW.Tissue inhibitor of metalloproteinase-1 concentration are attenuated in peritoneal fluid and sera of women with endometriosis and restored ii sera by gonadotropin.Releasing hormone agonist therapy[J].Fertil Steril,1998,69(6):1128-1134.
[13]Chang HW,Wen Y,Chun SH.Mateix metauoprotinases-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis a vationle for endometriotic invasiveness[J].Fertil Steril,2001,75(1):152-159.
[14]Donnez J,Donnez O.Endometriosis and infertility[J].Panminerva Med,2016,58(2):143-150.
[15]王芳,何援利,罗敏,等.子宫内膜异位症核转录因子和血管内皮生长因子表达与预后的关系[J].西北国防医学杂志,2007,28(2):116-119.Wang F,He YL,Luo M,et al.Relationship between expression of nuclear transcription factor and vascular endothelial growth factor and prognosis in endometriosis[J].Northwest Defense Med J,2007,28(2):116-119.
[16]Li B,Chen M,Liu X,et al.Constitutive and tumor necrosis factora-induced activation of nuclear factor-kB inadenomyosis and its inhibition by and rographolide[J].Fertil Steril,2013,100(2):568-577.
[17]Roghaei MA,Tehrany HG,Taherian A,et al.Effects of letrozole compared with Danazol on patients with confirmed endometriosis:A Randomized Clin T[J].IJFS,2010,4(2):67-72.
[18]Alborzi S,Hamedi B,Omidvar A,et al.A comparison of the effect of shortterm aromatase inhibitor(letrozole)and GnRH agonist(triptorelin)versus case control on pregnancy rate and symptom and sign recurrence after laparoscopic treatment of endometriosis[J].Arch Gynecol Obstet,2011,284(1):105-110.
[19]王康,陈素琴.来曲唑对子宫内膜异位症大鼠TNF-α,IL-6,NF-κB表达的影响[J].现代妇产科进展,2012,21(11):882-887.Wang K,Chen SQ.Effects of letrozole on the expression of TNF-α,IL-6,NF-κB in rats with endometriosis[J].Modern Adv Gynecol,2012,21(11):882-887.
[20]宋淑芳,尹利荣,齐之迎,等.来曲唑治疗大鼠子宫内膜异位症模型作用及机制的研究[J].现代妇产科进展,2011,20(1):35-38.Song SF,Yin LR,Qi ZY,et al.Study on the effect and mechanism of letrozolide on endometriosis model in rats[J].Modern Adv Gynecol,2011,20(1):35-38.
[21]李建超,吕秀萍.来曲唑对大鼠子宫内膜异位症病灶survivin表达的影响[J].现代妇产科进展,2009,18(5):351-353.Li JC,LüXP.Effects of letrozole on the expression of survivin in rat endometriosis lesions[J].Modern Adv Gynecol,2009,18(5):351-353.
[22]高霞,邢军,聂改红,等.来曲唑对离体异位子宫内膜基质细胞凋亡的影响[J].实用医学杂志,2009,25(21):3560-3562.Gao X,Xing J,Nie GH,et al.Effects of letrozole on apoptosis of ectopic endometrial stromal cells in vitro[J].Practical J Med,2009,25(21):3560-3562.
[23]Trentini A,Maritati M,Cervellati C,et al.Vaginal lactoferrin modulates PGE2,MMP-9,MMP-2,and TIMP-1 amniotic fluid concentrations[J].Medictors Inflamm,2016,2016:3648719.
[24]谢伟.米非司酮对子宫内膜异位症患者异位内膜组织中侵袭基因、凋亡基因表达的影响[J].海南医学院学报,2017,23(18):2528-2534.Xie W.Effect of mifepristone on invasion gene and apoptosis gene expression in ectopic endometrial tissue of patients with endometriosis[J].J Hainan Med College,2017,23(18):2528-2534.
[25]Mancini F,Milardi D,Carfaqna P,et al.Low-dose SKA progesterone and interleukin-10 modulate the inflammatory pathway in endometriotic cell lines[J].Int Immunopharmacol,2018,55:223-230.
[26]Horie S,Harada T,Mitsunari M,et al.Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells[J].Fertil Steril,2008,89(2):311-317.
[27]陈洪琴,郭铭川,曾莉,等.NF-κB抑制剂PDTC治疗大鼠子宫内膜异位症的实验研究[J].实用妇产科杂志,2010,26(11):853-855.Chen HQ,Guo MC,Zeng L,et al.Experimental study on treatment of endometriosis in rats with NF-κB inhibitor PDTC[J].Pract J Gynecol,2010,26(11):853-855.
[28]Celik O,Ersahin A,Acet M,et al.Disulfiram,as a candidate NF-κB and proteasome inhibitor,prevents endometriotic implant growing in a rat model of emdometriosis[J].Europ Rev Mid Pharmacological Sci,2016,20(20):4380-4389.
[29]彭容,詹宏,林俊.PRL-3抑制剂对子宫内膜异位症大鼠异位病灶的作用[J].现代妇产科进展,2017,26(9),678-681.Peng R,Zhan H,Lin J.Effect of PRL-3 Inhibitors on Ectopic Lesion in Rats with Endometriosis[J].Modern Adv Gynecol,2017,26(9):678-681.
[30]Jana S,Paul S,Swarnakar S,et al.Curcumin as anti-endometriotic agent:Implication of MMP-3 and intrinscic apoptotic pathway[J].Biochem Pharmacol,2012,83(6):797-804.
[31]Kim KH,Park JK,Choi YW,et al.Hexane extract of aged black garlic reduces cell proliferation and attenuates the expression of ICAM-I and VCAM-I in TNF-αactivated human endometrial stromal cells[J].Int J Mol Med,2013,31(1):67-68.
[32]Ji-Hyun Kim,Seung-Hyun Jung,Yeong-In Yang,et al.Artemisia leaf extract induces apoptosis in huamn endometriotic cells through regulations of the p38 and NF-κB pathways[J].J Ethnopharmacol,2013,145(3):767-775.
[33]Zheng Y,Liu XS.Therapeutic potential of andrographolide for treating endometriosis[J].Hum Reprod,2012,27(5):1300-1313.