NLRP3炎症小体/IL-1β信号通路在子宫内膜异位症中的研究进展

子宫内膜异位症（endometriosis,EMs）常发生于育龄期妇女,组织学上表现为子宫内膜组织的腺体和间质存在于子宫以外的部位,临床上主要表现为疼痛（痛经、性交痛、慢性盆腔疼痛和尿痛等）和不孕。目前EMs的发病机制尚不十分清楚,但炎症反应被认为是EMs发病机制中的主要病理生理过程。NLR家族Pyrin域蛋白3（NOD-like receptor family,pyrin domain containing protein 3,NLRP3）参与炎症小体的组装,而后者是机体固有免疫系统的重要组成部分。近年有研究显示,EMs的发生发展过程中涉及NLRP3炎症小体的激活,从而增加白细胞介素1β（interleukin 1β,IL-1β）的产生,增强异位子宫内膜细胞的黏附、增殖、分化和侵袭。针对NLRP3炎症小体/IL-1β信号通路在EMs中的研究进展进行了综述,以期为EMs的诊断和治疗提供新的思路。     

自噬反应在慢性子宫内膜炎发病中的潜在作用

慢性子宫内膜炎（chronic endometritis,CE）可引起不孕症、复发性流产和反复植入失败等不良生殖预后,其发病机制尚未阐明。CE患者的子宫内膜组织中存在异常的自噬反应,提示自噬在CE发病中发挥重要作用。研究发现,CE的发生与巨噬细胞分布、极化异常以及NOD样受体蛋白3（NOD-like receptor protein 3,NLRP3）炎症小体的异常激活密切相关。而且,巨噬细胞极化以及NLRP3炎症小体的组装和激活均受自噬反应调控。因此,自噬反应可能通过调节巨噬细胞极化影响NLRP3炎症小体激活,从而参与CE的发生。上述观点为CE发病机制提供了新的认识,也为其治疗提供了潜在的新靶点。     

炎症相关指标与妊娠期糖尿病关系的研究进展

妊娠期糖尿病(gestational diabetes mellitus, GDM)严重危害母儿健康, 其病因及发病机制尚不清楚, 这是临床干预的瓶颈所在。近年来, 炎症与GDM的关系成为研究热点, 但相关研究报道并无一致结论。因此本文对炎症相关指标与GDM关系的研究进展进行综述, 以期为GDM的诊治或预防提供理论基础。     

葡萄糖调节蛋白78在围生医学中的研究进展

作为热休克蛋白70家族成员之一的葡萄糖调节蛋白78（glucose regulation protein 78,GRP78）,不仅是细胞内重要的分子伴侣,也是内质网应激的特异性标志分子,在蛋白质的折叠、转运过程中发挥重要作用,通过多种途径调节细胞内环境的稳定,维持细胞存活。近年研究发现,GRP78在妊娠特发疾病如子痫前期、妊娠期糖尿病等产妇的血清及胎盘滋养细胞中高度表达,同时参与到高血压、糖尿病等的慢性并发症中,与多种疾病的发生发展密切相关。现就GRP78的生物学功能及与各种妊娠相关疾病的关系进行分析与总结,探讨该蛋白是否具有预测作用,为围生期相关疾病的预防及治疗提供新思路。     

胎盘线粒体功能在妊娠并发症发生机制中作用的研究

胎盘作为维持正常妊娠的基础,是母胎交流的重要媒介。胎盘组织处于纤维化、缺氧、慢性炎症和血液供应不足等状态可导致流产、子痫前期、妊娠期糖尿病和早产等妊娠并发症的发生,严重影响女性健康及胎儿结局。线粒体作为能量代谢的枢纽,其动力学、生物合成、氧化磷酸化等过程异常会引起胎盘组织炎症因子水平增加,氧化和抗氧化失衡,造成胎盘功能损伤,从而促进各种妊娠并发症的发生发展。综述目前关于胎盘线粒体功能障碍对多种妊娠并发症的影响,探讨其中的潜在机制。     

输卵管功能损伤因素和分子机制研究进展

健康完整的输卵管环境对于精子迁移、卵子拾取和(或)运输、受精、着床前胚胎发育和胚胎运输到子宫至关重要。目前认为,输卵管结构和功能损伤是导致输卵管妊娠和输卵管性不孕的重要原因。因而,明确输卵管的损伤因素和分子机制是防治输卵管相关疾病,尤其是输卵管妊娠和输卵管性不孕的前提。研究发现,输卵管结构和功能可受到年龄、感染、盆腔疾病、医疗、环境、行为和遗传等多种因素的影响,并导致输卵管炎症、积水、堵塞、通而不畅、粘连等一系列病理改变。本文对导致输卵管功能损伤的各种因素和分子机制进行综述,总结体内外因素如何通过激活氧化应激、炎症、纤维化、免疫反应和能量代谢等信号通路,诱导输卵管内上皮细胞结构紊乱、纤毛细胞数量和质量下降、肌层收缩活性和频率减弱,最终导致输卵管功能损害的研究进展,旨在为输卵管功能保护和女性生育力提升提供防护策略和研究思路。     

C反应蛋白与妊娠

早期诊断绒毛膜炎有利于及时治疗及维持妊娠,从而使胎儿进一步发育成熟并能减少感染所致的并发症。目前采用的实验检查项目如血沉、白细胞计数和分类、中性白细胞计数及形态学、血小板计数、阴道和羊水的细菌培养均不能对早期炎症进行诊断。临床症状如发热、胎心加快不可靠而且多在炎症晚期出现。C反应蛋白(CRP)是一种急性期反应物,在炎症时常升高,感染后48小时达到高峰,半衰期长达8～9小时,不受妊娠影响。CRP     

妊娠相关血浆蛋白-A在卵泡发育中的作用

妊娠相关血浆蛋白 A(PAPP A) ,是一种最早在孕妇血清中发现的高分子量的黏多糖蛋白 ,曾主要用于高危妊娠的产前筛查。随着分子生物学技术的发展和对子宫、卵巢分子水平的深入研究 ,人们发现 ,PAPP A不但存在于孕妇血清中 ,也存在于子宫内膜基质细胞、蜕膜细胞及卵巢颗粒细胞、卵泡液中。PAPP A属于胰岛素样生长因子结合蛋白 4(IGFBP 4 )蛋白酶 ,能水解IGFBP 4 ,参与构成胰岛素样生长因子 (IGF)系统。由于IGF系统在卵泡的发育过程中起重要作用 ,人们推测 ,PAPP A可能与卵泡的生长发育、闭锁以及优势卵泡的选择密切相关。本文…     

血小板激活因子与妊娠

<正> 血小板激活因子(Platelet activating fact-or,PAF)属磷脂(1-alkyl-2(R)-acetyl-glyce-ro-3-phospho-choline),至少由116种含饱和或非饱和烷基和酰基链的分子组成。人体内多种组织和细胞在免疫或非免疫刺激下活化,合成PAF,参与多种生理和病理机制。最     

组蛋白甲基转移酶Zeste同源蛋白2增强子在卵巢癌中的研究进展

卵巢癌是女性生殖系统常见的恶性肿瘤,由于其发病隐匿,大部分患者在确诊时已处于晚期,已成为致死率最高的妇科肿瘤。因此,寻找特异的分子标志物及有效的分子靶点对卵巢癌的诊断、疗效评估、预后判断及治疗等具有重要的意义。研究表明,表观遗传修饰在卵巢癌的发生、发展中起着关键作用。组蛋白甲基转移酶Zeste同源蛋白2增强子(enhancer of zeste homolog 2,EZH2)是多梳抑制复合体2(PRC2)的酶催化亚基,可通过对核小体组蛋白H3的27位赖氨酸(H3K27)进行甲基化修饰,进而导致下游靶基因的沉默,在细胞凋亡、细胞周期及细胞分化等重要生物学过程中发挥重要作用。现有研究表明EZH2在卵巢恶性肿瘤中高表达,其表达水平与卵巢癌患者的化疗疗效及预后密切相关。此外,EZH2作为表观遗传修饰因子,影响卵巢癌细胞的增殖、转移及耐药等生物学行为,在肿瘤进展中发挥重要的调控作用。因此,EZH2可能成为卵巢恶性肿瘤有效的治疗新靶点。     

miR-223-3p靶向NLRP3调控子痫前期胎盘中炎性反应的机制研究

目的:探讨miR-223-3p能否通过靶向NLRP3参与调节子痫前期(PE)胎盘中的炎性反应。方法:选取2018年12月至2020年01月在江苏省苏北人民医院住院行剖宫产分娩的60例孕妇,其中PE组30例,正常对照组30例。采用实时定量聚合酶链式反应(RT-qPCR)、蛋白免疫印迹、免疫组化法对胎盘组织中NLRP3和miR-223-3p的表达模式进行评估。通过生物信息学软件和双荧光素酶报告基因实验探究miR-223-3p与NLRP3的靶向关系。利用脂多糖(LPS)诱导HTR8/SVneo细胞构建PE胎盘滋养细胞炎症模型。在炎症模型中转染miR-223-3p过表达或miR-223-3p阴性对照质粒,评估miR-223-3p过表达对NLRP3炎性小体相关基因及下游因子的调控作用。结果:与正常对照组相比,PE胎盘中NLRP3在mRNA和蛋白水平上表达均显著上调(P<0.05),而miR-223-3p表达明显下调(P<0.05)。NLRP3是miR-223-3p的一个靶基因。在LPS诱导的HTR8/SVneo细胞炎症模型中,过表达miR-223-3p可有效抑制NLRP3炎性小体的激活(P<0.05)、下游炎性因子的分泌(P<0.05)和细胞焦亡(P<0.05)。结论:miR-223-3p可能通过靶向NLRP3抑制PE胎盘中的炎症反应和细胞焦亡,为PE的治疗提供了一个新的潜在治疗策略。     

Recurrent complete hydatidiform mole: where we are,is there a safe gestational horizon? Opinion and mini-review

Benign hydatidiform mole, complete or partial, is the most common type of gestational trophoblastic disease (GTD) characterised by excessive trophoblastic proliferation and abnormal embryonic development. Although most complete hydatidiform moles (CHMs) are diploid androgenetic, a few cases of CHMs are biparental, characterised by recurrence and familial clustering. In these rare cases, mutations in NLRP7 or KHDC3L genes, associated with maternal imprinting defects, have been implicated. Current data regarding future pregnancy options in hydatidiform moles are discussed and our opinion is presented based on an incidence that took place in our hospital with a woman with consecutive molar pregnancies. In recurrent hydatidiform moles, DNA testing should be performed and when NLRP7 or KHDC3L mutation are detected, oocyte donation should be proposed as an option to maximise woman’s chances of having a normal pregnancy.     

Innate immune defences in the human uterus during pregnancy

The prevention of uterine infection is critical to appropriate fetal development and term delivery. The innate immune system is one component of the uterine environment and has a role in prevention of uterine infection. Natural antimicrobials are innate immune molecules with anti-bacterial, anti-viral and anti-fungal activity. We discuss two groups of natural antimicrobials in relation to pregnancy: (i) the defensins; and (ii) the whey acidic protein motif containing proteins, secretory leukocyte protease inhibitor (SLPI) and elafin. Human beta-defensins (HBD) 1-3 are expressed by placental and chorion trophoblast, amnion epithelium and decidua in term and preterm pregnancy. Elafin shows a similar pattern of localisation while SLPI is produced only by amnion epithelium and decidua. Evidence suggests that there is aberrant production of some natural antimicrobials in pathologic conditions of pregnancy. In preterm premature rupture of membranes (PPROM) levels of SLPI and elafin are reduced in amniotic fluid and fetal membranes, respectively. Elafin and HBD3 increase in chorioamnionitis and levels of the alpha-defensins, HNP1-3, increase in maternal plasma and amniotic fluid in women affected by microbial invasion of the uterus. In vitro culture studies have suggested a mechanism for increased production of natural antimicrobials in chorioamnionitis. Elafin, SLPI, HBD2 and 3 are all upregulated by inflammatory molecules in cells derived from gestational tissues. In summary, production of natural antimicrobials at key sites within the pregnant uterus suggests an important role in prevention of uterine infection during pregnancy and labour. Aberrant production of these molecules in PPROM and chorioamnionitis suggests that they also have a role in pathologic conditions. In particular, upregulation of these molecules by inflammatory molecules present in chorioamnionitis will ensure a robust response to infection.     

Elevated serum levels of interleukin-15 and interleukin-16 in preeclampsia

A generalized inflammatory response has been considered to be the main pathology and has an important role in the pathogenesis of preeclampsia. The immune aberrations per se and immunomodulatory milieu present in serum need to be elucidated. The purpose of the current investigation was to characterize changes in serum levels of interleukin (IL)-15 and IL-16 in preeclampsia. Thirty-seven women with preeclampsia were recruited and 36 age- and gestational age-matched women with normal pregnancy served as control. Levels of IL-15 and IL-16 were detected with immune assays in all serum samples. We found that serum levels of IL-15 and IL-16 were significantly higher in preeclampsia than in normal pregnancy (p<0.001 for both). There were significant differences in serum IL-15 and IL-16 between mild and severe preeclampsia (p<0.01 for both). Our data corroborate the hypothesis of an increased inflammatory response in preeclampsia, as illustrated by the elevated serum levels of IL-15 and IL-16, suggesting their possible role in the pathogenesis of preeclampsia. These associations may offer insight into the pathophysiology of preeclampsia.     

Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth

The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.     

The placenta cytokine network and inflammatory signals

Throughout its entire lifespan, the placenta is able to produce as well as respond to a variety of inflammatory stimuli. Many signaling molecules and concurrent pathways responsible for the propagation of an inflammatory response have been identified in placental cells. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines and inflammatory molecules. Two aspects of the progression of an immune response have been particularly investigated: the highly regulated process of invasion and implantation and, the induction of preterm labor associated with infections. With the progression of pregnancy, the physiological role of most placental cytokines is more uncertain. Many placental cytokines are similar to adipose tissue derived cytokines. One possibility is that they contribute to the low grade systemic inflammation developing during the third trimester of pregnancy. The prevalent hypothesis is that activation of some inflammatory pathways is necessary to induce maternal insulin resistance which is required for the progression of normal gestation. As an integrative organ, the placenta may relay or enhance the contribution made by the cells of the adipose tissue and immune system in non-pregnant individuals. In pregnancy complicated with obesity or diabetes mellitus, continuous adverse stimulus is associated with dysregulation of metabolic, vascular and inflammatory pathways supported by increased circulating concentration of inflammatory molecules. It is believed that maternal adipose tissue and placental cells both contribute to the inflammatory situation by releasing common molecules. For example, the accumulation of leptin and TNF-alpha is associated with an increased production for markers of inflammation, fibrotic response, vascular remodeling and proteins facilitating lipid storage within the placenta.     

Immune pathogenesis of asymptomatic chlamydia trachomatis infections in the female genital tract

Chlamydia trachomatis (CT) infections of the female genital tract, although frequently asymptomatic, are a major cause of fallopian-tube occlusion and infertility. Early stage pregnancy loss may also be due to an unsuspected and undetected CT infection. In vitro and in vivo studies have demonstrated that this organism can persist in the female genital tract in a form undetectable by culture. The mechanism of tubal damage as well as the rejection of an embryo may involve an initial immune sensitization to the CT 60 kD heat shock protein (HSP), followed by a reactivation of HSP-sensitized lymphocytes in response to the human HSP and the subsequent release of inflammatory cytokines. The periodic induction of human HSP expression by various microorganisms or by noninfectious mechanisms in the fallopian tubes of women sensitized to the CT HSP may eventually result in tubal scarring and occlusion. Similarly, an immune response to human HSP expression during the early stages of pregnancy may interfere with the immune regulatory mechanisms required for the maintenance of a semiallogeneic embryo.