Background: Abnormal angiogenesis plays vital role in the pathogenesis of adenomyosis (AM). Emerging evidence suggests that exosomes derived from endometrial cells can accelerate the progression of AM. In this study, we aim to investigate the pro-angiogenic role and potential mechanisms of ectopic endometrial mesenchymal stem cells (eMSCs)-derived exosomes (Ec-exo). Methods: MicroRNA sequencing was conducted to identify differentially expressed miRNAs (DE-miRNAs) in exosomes derived from normal eMSCs (N-exo) and Ec-exo. Candidate miRNAs were selected using quantitative real-time polymerase chain reaction (qRT-PCR). The effects of miR-4466 on human umbilical vein endothelial cells (HUVECs) proliferation, invasion/migration, and tube formation were analysed in vitro. The target gene of miR-4466 was predicted via bioinformatics analysis and validated by qRT-PCR, western blotting, luciferase assays, and rescue experiments. Results: We identified 81 up-regulated and 92 down-regulated miRNAs between N-exo and Ec-exo. Among these DE-miRNAs, miR-4466 was the most significantly up-regulated. The internalisation assay demonstrated that exosomal miR-4466 can be internalised by HUVECs. Overexpression or inhibition of miR-4466 significantly promoted or inhibited HUVEC proliferation, invasion/migration, and tube formation. Bioinformatics predictions and luciferase assays revealed that runt-related transcription factor 1 (RUNX1) is a direct target of miR-4466. Moreover, rescue experiments confirmed that RUNX1 overexpression reversed the pro-angiogenic effect of miR-4466 by inhibiting vascular endothelial growth factor A (VEGFA) expression. Conclusions: Our study demonstrates that exosomal miR-4466 derived from ectopic eMSCs promotes angiogenesis by targeting the RUNX1/VEGFA axis in AM. These findings may offer new insights into therapeutic targets and treatment strategies for the anti-angiogenic treatment of AM.

Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial–mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM.

Endometriosis, a persistent inflammatory disease, is associated with pelvic or abdominal pain. The immune system and sensory nervous system show a synergistic effect on regulation of pain. In particular, Interleukin-33 (IL-33) is released as a danger signal and drives key hallmarks of severe endometriosis. To explore the mechanistic involvement of IL-33 in pain associated with endometriosis, both an in vivo murine endometriosis model and in vitro experiments with RAW 264.7 cells and dorsal root ganglion (DRG) neurons were utilized. In vivo, we demonstrated that IL-33 significantly exacerbated endometriosis and induced hyperalgesia in mice. By interacting with the ST2 receptor in macrophages, IL-33 enhanced the release of tumor necrosis factor α (TNF-α) and Interleukin 1β (IL-1β). This process set off an inflammatory cascade, which further facilitated macrophages recruitment and neurogenesis in ectopic lesions. As an ion channel expressed by nociceptors, transient receptor potential vanilloid 1 (TRPV1) expression was significantly increased in DRG in the presence of IL-33. In vitro, we confirmed that IL-33 elevated the release of TNF-α in macrophages. Ultimately, macrophage-derived TNF-α increased TRPV1 protein level in DRG neuronal cells through the TNFR1/p38 MAPK signaling pathway. Overall, these results revealed an inductive role of IL-33 in pain associated with endometriosis, and highlighted the interaction between macrophages and sensory neurons.

Ethnopharmacological relevance Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. Aims of the study The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. Materials and methods The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. Results WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. Conclusion WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.

目的 探讨止带汤加减联合宫颈敷料对宫颈LEEP术后创面愈合的临床疗效.方法 将180例宫颈上皮内瘤变患者随机分为对照组(62例)、宫颈敷料组(66例)和联合治疗组(52例).对照组采用常规方法进行换药,宫颈敷料组在对照组基础上加用宫颈敷料,联合治疗组在宫颈敷料组基础上加服止带汤加减4周.观察阴道流血、排液,创面愈合、感染、出血以及宫颈管粘连等情况.结果 3组均未见术后创面感染.与对照组相比,宫颈敷料组和联合治疗组的阴道流血、排液及创面愈合时间明显缩短(P＜0.05);联合治疗组阴道排液、创面愈合时间显著短于宫颈敷料组(P＜0.01).宫颈敷料组和联合治疗组的术后并发症发生率低于对照组(P＜0.05);其中,联合治疗组的术后并发症发生率较宫颈敷料组显著降低(P＜0.01).结论 止带汤加减联合宫颈敷料有助于宫颈上皮内瘤变患者LEEP术后创面愈合,避免术后并发症发生,有临床推广应用价值.

This study aimed to identify differentially expressed genes (DEGs) and molecular pathways in eutopic endometrial stromal cells (EuESCs) from adenomyosis (AM) patients and to provide a new insight into the disease mechanisms. The gene expression profiles in adenomyotic EuESCs (A-EuESCs) and normal ESCs (N-ESCs) were analyzed by RNA-sequencing (RNA-Seq) and validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were performed to obtain insights into the functions of DEGs. The protein-protein interaction (PPI) network was constructed using the STRING database and visualized by Cytoscape software, and their hub genes were identified. A total of 458 up-/363 down-regulated genes were identified in A-EuESCs versus N-ESCs. The GO enrichment analysis showed that these genes were significantly enriched in calcium-dependent cell-cell adhesion. The most significant term of the KEGG pathway analysis was cytokine-cytokine receptor interaction. There were 145 nodes in the PPI network of the 157 DEGs, which were identified in significant enrichment pathway by the KEGG pathway analysis in N-ESCs and A-EuESCs. The PPI network revealed that IL-6 was a central hub gene. Besides, IL-6 was found as a central hub gene in the pro-inflammatory/chemotactic subnetwork, and EGF was noted as a central hub gene in the angiogenesis subnetwork. Our study indicated the alterations of transcriptomic profiles in A-EuESCs and provided new insights into the pathogenesis of AM. The A-EuESCs in women with AM have fundamental abnormalities that may predispose to pro-invasion/migration and angiogenesis.

目的 研究宫颈高危型人乳头状瘤病毒(HR?HPV)感染中医证型、体质分布及相关危险因素,为中医药防治提供临床依据.方法 通过流行病学调查分析宫颈HR?HPV感染患者的中医证型、体质及两者相关性,多因素logistic回归分析宫颈HR?HPV感染相关危险因素.结果 本研究共调查782例,其中宫颈HR?HPV感染309例,总体感染率为39.51％;不同年龄段的感染率分布大致呈"U"形.感染人群多见脾虚湿热证(50.48％,156/309),体质分布以湿热质(25.89％,80/309)、阳虚质(17.48％,54/309)为主;部分体质与中医证型联系紧密.多因素回归结果显示,年龄20～39岁、多孕多产和湿热质体质为宫颈HR?HPV感染独立危险因素(Ρ<0.05),平和质体质是保护因素(Ρ<0.05).结论 宫颈HR?HPV感染受到多因素的影响,临床工作中应做到体、病、证三位一体,及早针对相关危险因素采取干预措施,以达到未病先防、既病防变、预后防复的效果.

子宫内膜异位症在育龄期女性中发病率高达10％,是育龄期女性的常见病.近年来,子宫内膜异位症的治疗理念发生了翻天覆地的改变,从过去的根治性手术逐步发展为更加个体化、人性化的"缓解疼痛,改善生育,综合治疗,长期管理"的治疗理念.对于有症状的子宫内膜异位症患者,手术是非常重要的治疗方法.随着腹腔镜手术的发展,子宫内膜异位症的手术治疗水平得到了极大的提高.微创手术逐渐取代了过去的开腹手术.笔者结合国内外报道就子宫内膜异位症的微创治疗进展做一综述.

子宫内膜异位症(endometriosis,EM)是一种常见的妇科良性疾病,病因机制复杂,缺乏统一认识,近年来,干/祖细胞学说逐渐受到学者认可.子宫内膜中存在干/祖细胞,研究人员对干/祖细胞特异性标志物的认识得到了进一步发展,这对分选干/祖细胞并进一步阐述其在EM发病机制中的作用有着重要意义.目前,研究较多的子宫内膜干细胞信号通路包括Wnt、Hedgehog、Notch、磷脂酰肌醇-3-激酶/蛋白激酶B、Smad/结缔组织生长因子、CXCL12/CXCR4等,这些信号通路可调节子宫内膜干/祖细胞的增殖和迁移从而参与EM的发生发展.探究信号通路如何调节干细胞参与EM的发病,有助于阐明EM的具体发病机制并为其治疗提供新方向.该文将对其展开综述.

杨桂云教授认为子宫腺肌病的病理基础是血瘀,或因外邪入侵,或因寒凝血滞,或因痰凝瘀阻,使经血瘀滞于体内形成血瘀内滞的症状,血瘀难以排泻而日以益大,形成癥瘕.杨师治疗以活血化瘀为主,且由于本病病程较长,久病及肾,在用药期间注重扶助正气,补肾助阳.与此同时,应用"分期疗法""方-体相应"治疗子宫腺肌病,疗效显著,其对此病病因病机的把握及遣方用药能够为临床诊断与治疗提供依据.

目的 探讨碘适量地区妊娠中期不同铁储备水平孕妇间甲状腺素水平的差异,并分析铁储备水平与妊娠期亚临床甲减(亚甲减)的关系.方法 选取2017年1月至2018年10月南京地区妊娠中期常规产检孕妇703例,记录人口学资料并分析其血清铁蛋白(Ferr),游离三碘甲状腺原氨酸(FT3),游离甲状腺素(FT4),血清促甲状腺激素(TSH),血红蛋白(Hb)等指标检测结果.根据Ferr及Hb检测结果,将其分为健康对照组(A组,n=388)、铁储备减少组(B组,n=259)、缺铁性贫血(IDA)组(C组,n=56),采用单因素方差分析方法,分析三组妊娠中期妇女Ferr、FT3、FT4、TSH等指标的差异;采用二元Logistic回归分析法,进一步分析妊娠期亚甲减的危险因素.结果 ①三组间Ferr、FT3、BMI、TSH水平比较,A组与B组、C组差异有统计学意义(P＜0.05),而B组与C组之间差异无统计学意义(P＞0.05);Hb水平比较,A、B、C三组之间差异均有统计学意义(P＜0.05);孕妇年龄及FT4水平比较,三组之间差异无统计学意义(P＞0.05).②二元Logistic回归分析显示:Ferr(＜ 20ng/mL)是妊娠期亚甲减的危险因素(OR:1.579,CI:1.018 ～2.449);年龄(24～29岁)是妊娠期亚甲减的保护因素(OR:0.440,CI:O.235～0.825).结论 Ferr水平降低影响FT3、TSH的水平.铁储备减少(Ferr＜ 20ng/mL)是并发妊娠期亚甲减的危险因素,而适合的孕龄(24～ 29岁)是并发妊娠期亚甲减的保护因素.Ferr水平可能是并发妊娠期亚甲减敏感的预测指标.

子宫内膜息肉(EP)是常见的妇科疾病之一,其发病机制目前尚不明确.近年来随着诊疗水平的提高、辅助检查技术的完善和广泛应用,EP患者越来越多见,且存在恶变的可能.目前EP的治疗多以手术治疗为主,但易复发,为降低EP的复发率,临床上常建议患者在经手术去除息肉后服用屈螺酮炔雌醇片或放置曼月乐环.但不论何种治疗方法都有其局限性,因此,对于EP发病机制的探究显得尤为重要,亟待找出更有效的方式治疗EP.本文就EP发病机制的研究进展进行综述.

每个孩子都是上天赐予父母最好的礼物,在感恩节这天,徐妈妈收到了上天赐予的一份"重"礼!二胎剖宫产生下5.5千克重的大胖儿子. 当助产士从主刀医生手上接过这个沉甸甸的宝宝时,心中便预感新生儿体重要破记录了.果然称重结果5655克, 打破了这个医院新生儿体重的最高记录!

目的 观察补肾活血汤对肾虚血瘀型子宫内膜异位症相关性不孕患者宫腔冲洗液中IL-6与LIF水平的影响.方法 选取肾虚血瘀型子宫内膜异位症相关性不孕患者50例病例作为研究对象,给予补肾活血汤治疗3个月经周期,采用经阴道彩色多普勒超声及酶联免疫吸附法(ELISA)测定治疗前后着床口期子宫内膜厚度、类型、子宫动脉血流参数及宫腔冲洗液中白细胞介素-6(IL-6)与白血病抑制因子(LIF)的水平.结果 补肾活血汤治疗后着床口期子宫内膜厚度、A型子宫内膜的比率、宫腔冲洗液中IL-6与LIF表达水平显著高于治疗前,子宫动脉血流参数RI值和PI值显著低于治疗前,差异有统计学意义(P<0.05).结论 补肾活血汤可提高肾虚血瘀型子宫内膜异位症相关性不孕患者宫腔冲洗液中IL-6与LIF水平,改善子宫内膜容受性.

Objective To explore the feasibility of using serum microRNAs as biomarkers for the molecular diagnosis of adenomyosis.Methods Seventy-eight patients with adenomyosis confirmed by the pathological diagnosis from March 2015 to March 2018 in Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine (here in after referred to as "our hospital") were selected as the study group.At the same time,78 healthy subjects in our hospital physical examination center whose age,gender basically matched with the adenomyosis group were collected as the control group.All miRNAs in the serum of both groups were screened and validated using high-throughput sequencing technology.Results The expression level of microRNAs in the serum of the study group was significantly different from that in the control group (P ＜ 0.05).There were 316 up-regulated miRNAs and 24 down-regulated miRNAs.After further screening and verification,3 miRNAs were found to include miR-22-3p,miR-103a-3p,and miR-182-5p,and AUC were 0.900 (95％ CI:0.839-0.961) and 0.828 (95％ CI:0.747-0.909),0.844 (95％ CI:0.766-0.921) respectively.Conclusion Serum microRNAs may be biomarkers for the diagnosis of adenomyosis.

子宫腺肌病多发于育龄女性,主要表现是经量显著增多、经期明显延长,并出现渐进性的痛经.其中,痛经是临床上困扰患者生活质量的主要症状之一,而痛经的有关发病机制尚不清楚.现代医学研究的主要重点是子宫内膜的基底层功能失调、神经源性因素、免疫炎症、激素水平反应异常、遗传基因等方面因素.本文就近年以来子宫腺肌病痛经的发病相关发病机制方面的研究进展做一综述.

目的 观察补肾活血汤对子宫内膜异位症相关性不孕患者子宫内膜容受性的影响.方法 选取2014年5月～2015年8月在南京中医药大学附属中西医结合医院就诊,因不孕行宫腹腔镜联合治疗,经腹腔镜术中所见及术后病理证实为子宫内膜异位症,同时宫腔镜检查子宫内膜无异常的患者54例作为研究对象,将其随机分为治疗组和对照组,各27例.治疗组术后连续服用补肾活血汤3个月经周期,对照组术后不予药物口服.比较两组子宫内膜厚度、类型、子宫动脉血流参数及子宫内膜中血管内皮生长因子(VEGF)表达情况,并随访半年妊娠率.结果 治疗后治疗组子宫内膜厚度明显高于对照组,而子宫动脉血流参数搏动指数、阻力指数低于对照组(P＜0.05);治疗组子宫内膜类型以A、B型为主,而对照组子宫内膜类型以B型为主,两组比较差异有统计学意义(P＜0.05).治疗组VEGF表达水平较对照组强(P＜0.05).随访半年,治疗组妊娠率明显高于对照组,差异有统计学意义(P＜0.05).结论 补肾活血汤可改善子宫内膜的类型及血流分布情况,增加子宫内膜厚度及VEGF的表达,提高子宫内膜容受性.

Ethnopharmacological relevance: Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine prescription, exerted a good therapeutic effect on endometriosis. However, the underlying mechanism is unclear. In the present study, we sought to evaluate the effect of WXT on the proliferation and migration of ectopic endometriotic stromal cells and explore the potential molecular mechanism.Materials and methods: Primary stromal cells derived from ectopic endometriotic lesions of patients with endometriosis were isolated and cultured. The inhibition effect of WXT on cell proliferation was determined by MIT. Apoptosis of ectopic endometriotic cells treated with WXT was analyzed with Annexin V-FITC/7-AAD staining. The activation of caspases was detected by western blot analysis. The influence of WXT on migration of ectopic endometriotic cells was measured by scratch wound healing assay and Transwell assay. The DNA binding activity of NF-kappa B and the expression of nuclear p65 protein were determined by electrophoretic mobility shift assay and western blot analysis, respectively. The impact of WXT on the expression of NF-kappa B regulated gene products involved in apoptosis and migration was determined by western blot analysis.Results: WXT inhibited the proliferation of ectopic endometriotic cells in a time- and dose-dependent manner. In addition, WXT treatment resulted in significant induction of apoptosis through the activation of caspases and inhibition of migration in ectopic endometriotic cells. WXT notably suppressed constitutive NF-kappa B-DNA-binding activity as well as TNF-alpha induced nuclear translocation of NF-kappa B p65 subunit in ectopic endometriotic cells. Moreover, WXT diminished the expression of NF-kappa B regulated gene products involved in apoptosis and migration, including c-IAP1, c-IAP2, XIAP, survivin, Mcl-1, COX-2 and MMP-9.Conclusions: our results indicate that WXT induces apoptosis and inhibits migration of ectopic endometriotic stromal cells. (C) 2016 Published by Elsevier Ireland Ltd.

目的:观察滋肾宁心汤治疗子宫内膜异位症术后患者应用Gn RH-a致类绝经期症状的临床疗效。方法:选取临床上手术病理确诊为子宫内膜异位症的患者90例,随机分为3组,每组30例。所有患者均于术后月经周期第1天给予Gn RH-a注射（戈舍瑞林3.6mg皮下注射）,每4周注射1次。对照组于第28天继续给予Gn RH-a注射,研究1组于第28天继续给予Gn RH-a注射的同时加用坤泰胶囊;研究2组于第28天继续给予Gn RH-a注射的同时加用中药方滋肾宁心汤,比较3组患者治疗前后中医临床症状体征、绝经症状评分及记录不良反应。结果:3组患者治疗后第12周相比,研究1组及研究2组中医临床症状体征积分均较同组治疗前明显下降,具有显著性差异（P＜0.05）;治疗后第12周,3组患者Kupermann评分均较同组治疗前显著升高（P＜0.05）,且按对照组、研究1组、研究2组的顺序依次呈下降趋势,具有显著性差异（P＜0.05）;对照组治疗期间出现了一系列的类绝经期症状,研究1组及研究2组治疗期间出现的类绝经期症状发生例数明显低于对照组。结论:滋肾宁心汤治疗子宫内膜异位症术后患者应用Gn RH-a致类绝经期症状的疗效确切,可有效缓解Gn RH-a所引起的低雌激素症状,且疗效优于坤泰胶囊。

目的:观察补肾活血散瘀汤治疗肾虚血瘀型卵巢子宫内膜异位症的临床疗效. 方法:选择50例患者,随机分为治疗组(口服补肾活血散瘀汤)30例和对照组(口服米非司酮片)20例,均治疗3个月.比较2组治疗前后痛经程度、中医证候评分、异位囊肿大小及血清CA125的变化. 结果:(1)治疗组与对照组对痛经的疗效类似(P>0.05),均较治疗前明显减轻痛经程度. (2)治疗组与对照组均能显著降低中医证候评分(P<0.01),且治疗组优于对照组(P<0.05). (3)治疗组总有效率83.33%与对照组(85.00%)临床疗效类似. 结论:补肾活血散瘀汤治疗肾虚血瘀型卵巢子宫内膜异位症临床疗效确切,且无明显副作用,值得临床推广应用.