环氧合酶、前列腺素与子宫内膜异位症发病关系的研究进展

环氧合酶、前列腺素和生殖系统的多种疾病相关,包括恶性肿瘤、子宫内膜异位症等,虽然调节这些病理过程的具体机制仍不很明确,但许多证据都支持环氧合酶前列腺素前列腺素受体这一细胞内信号传导系统在血管形成、凋亡、增生、组织的侵袭性及转移能力、免疫抑制等方面起着相当重要的作用。现对这方面的研究进展作一综述,重点是环氧合酶、前列腺素E2、前列腺素F2α在非孕妇女子宫内膜异位症形成和发展中的作用。     

环氧合酶-2和前列腺素类物质在子宫内膜异位症的表达研究

目的:研究环氧合酶-2(Cox-2)、6-酮-前列腺素F1α(6-k-PGF1α)和血栓素B2(TXB2)与子宫内膜异位症(EMs)的发生及临床病理因素的关系。方法:采用免疫组织化学SABC法检测45例EMs和30例正常子宫内膜Cox-2蛋白的表达;采用放射免疫法检测组织液6-k-PGF1α和TXB2的含量。结果:Cox-2在腺上皮的胞浆中表达,EMs组Cox-2表达明显高于对照组(P<0.001);EMs的AFS分期、疼痛分级以及瘤体大小之间Cox-2表达差异无统计学意义(P>0.05)。EMs组TXB2和6-k-PGF1α的含量明显高于对照组(P<0.001);有症状组6-k-PGF1α的含量高于无症状组,差异有统计学意义(P<0.05);TXB2含量两组无差别。Cox-2蛋白的表达与6-k-PGF1α和TXB2的含量相关。结论:Cox-2、6-k-PGF1α及TXB2的高表达可能与EMs的发生相关。6-k-PGF1α可能与痛经相关。     

环氧合酶-2与子宫内膜异位症疼痛的相关性研究

目的检测环氧合酶-2(cyclooxygenase-2,COX-2)在子宫内膜异位症(endometrosis,EMs)患者在位和异位内膜的表达以及血清中的水平,探讨COX-2与EMs疼痛的关系。方法通过免疫组化方法检测60例EMs和29例正常子宫内膜C0X-2蛋白的表达,ELISA方法测定血清COX-2水平,视觉模拟评分法对月经期疼痛进行评分。结果 EMs异位内膜COX-2的表达明显高于在位内膜(P<0.05),在位内膜高于正常子宫内膜(P<0.05);EMs在位子宫内膜COX-2的表达和血清COX-2的水平变化相一致,并与EMs的疼痛程度成正相关性。结论 EMs患者子宫内膜和血清中C0X-2异常高表达,可能参与EMs的发生及疼痛的产生。     

细胞凋亡与子宫内膜异位症

子宫内膜异位症（EMs）发病原因尚未明了。EMs是妇科常见良性疾病,但却有增生、浸润、转移及复发等恶性行为,对其预防和治疗仍是目前难点。凋亡是基因控制的程序性细胞自我消亡过程,对机体维持自身稳态和组织器官正常生理功能至关重要。近年有资料表明,凋亡异常可促进EMs的发生发展。综述细胞凋亡途径,凋亡相关基因及凋亡在正常子宫内膜与EMs的在位、异位内膜中的不同表达,期望能操控细胞程序性死亡并应用于EMs的预防和治疗中。     

环氧合酶-2与子宫内膜异位症相关性的研究进展

子宫内膜异位症是一种妇科常见病,至今其发病机制仍不清楚。近年研究发现,环氧合酶2(COX-2)在子宫内膜异位症的在位和异位内膜表达增高,与该病密切相关。COX-2可通过抑制细胞凋亡途径促进子宫内膜异位病灶的生长,主要是通过调节抗凋亡蛋白和促凋亡酶的表达来起作用;COX-2还可通过血管生成途径促进异位子宫内膜细胞增殖生长,这种作用是基于提高促血管生成因子的表达来实现的。就近年来COX-2与子宫内膜异位症相关性的研究进展作一综述。     

细胞凋亡与子宫内膜异位症

子宫内膜异位症（EMs）发病原因尚未明了。EMs是妇科常见良性疾病,但却有增生、浸润、转移及复发等恶性行为,对其预防和治疗仍是目前难点。凋亡是基因控制的程序性细胞自我消亡过程,对机体维持自身稳态和组织器官正常生理功能至关重要。近年有资料表明,凋亡异常可促进EMs的发生发展。综述细胞凋亡途径,凋亡相关基因及凋亡在正常子宫内膜与EMs的在位、异位内膜中的不同表达,期望能操控细胞程序性死亡并应用于EMs的预防和治疗中。     

消炎痛对人子宫内膜细胞摄取前列腺素E_2的影响

<正> 放置宫内节育器(IUD)后的一个最常见的副反应是子宫异常出血。近十多年来,这种副反应与放置IUD后子宫前列腺素(PGs)的生物合成异常以及子宫对PGs的敏感性增强的关系愈来愈明确。临床使用消炎痛PGs合成酶抑制,能有效地防治IUD子宫异常出血,但具体的作用途径尚不明确。PGs对子宫内膜细胞产生效应,首先必须由子宫内膜细胞将PGs摄入细胞内。本文用细胞摄取功能测定法,观察人子宫内膜细胞摄取[~3H]PGE_2的功能状态及其在消炎痛作用后的变化,从中探索消炎痛影响子宫内膜细胞与     

子宫内膜异位症患者内膜细胞中孕激素受体与凋亡因子Bcl-2、Bax表达的研究

目的:通过检测孕激素受体(PR)、凋亡抑制基因Bcl-2、促凋亡基因Bax(bcl-associated x protein)在子宫内膜异位症(EMT)中的表达,研究PR与Bcl-2、Bax的关系,探讨EMT的发病机制及选择更有效的药物治疗方案.方法:用免疫组织化学方法及图像分析技术检测PR、Bcl-2、Bax在EMT患者异位及在位内膜细胞中的表达情况.结果:两种检测方法检测结果一致,异位内膜PR、Bcl-2表达低于在位内膜(P<0.05),异位内膜Bax表达高于在位内膜(P<0.05),在位内膜与异位内膜PR、Bcl-2、Bax增殖期与分泌期表达差异无统计学意义(P>0.05).结论:无论是增殖期还是分泌期,EMT中在位内膜PR表达均高于异位内膜及正常内膜,使在位子宫内膜细胞持续低水平增殖,更易于迁徙和种植.在位内膜及异位内膜中Bcl-2和Bax的表达均与子宫内膜周期性改变无关,不受卵巢激素调节,EMT细胞凋亡持续性减弱,增殖性能持续性增强.     

米非司酮对子宫内膜异位症细胞PTEN基因表达与凋亡的影响

目的:探讨米非司酮对子宫内膜异位症细胞PTEN基因表达及凋亡的影响。方法:体外原代培养人异位子宫内膜细胞,应用四甲基偶氮噻唑兰(MTT)法测定子宫内膜异位症细胞体外增殖活性;应用流式细胞仪(FCM)检测在不同浓度米非司酮作用24h后,子宫内膜异位症细胞PTEN蛋白表达率、增殖率和凋亡率;应用吖啶橙荧光染色法和透射电镜技术研究子宫内膜异位症细胞的形态学变化。结果:米非司酮能够抑制子宫内膜异位症细胞的增殖且呈明显的剂量依赖性;AO荧光染色及透射电镜观察表明,经米非司酮培养的子宫内膜异位症细胞出现了典型的细胞凋亡的特征性变化;米非司酮能够使子宫内膜异位症细胞出现细胞周期阻滞,使其停滞于G1 期,降低S期细胞比例;PTEN蛋白的表达率明显增加,与对照组相比差异显著。结论:米非司酮能够明显抑制人异位子宫内膜细胞的体外增殖并促进其凋亡,其促凋亡作用与上调PTEN基因的表达有关。     

二甲双胍诱导子宫内膜异位症在位内膜细胞凋亡的研究

目的:研究二甲双胍对大鼠子宫内膜异位症模型在位内膜细胞凋亡的影响。方法:采用手术自体移植法建立大鼠子宫内膜异位症模型,随机将成模鼠分为A组(二甲双胍50mg/kg·d),B组(二甲双胍100mg/kg·d)和C组(二甲双胍200mg/kg·d)各10只,D组(0.9%氯化钠溶液对照)8只。用药4周后采用TUNEL法检测细胞凋亡指数,逆转录PCR(RT-PCR)技术分别检测在位子宫内膜组织中Bcl-2、Bax和P53基因转录水平;Westernblotting检测磷酸化AMPK和磷酸化mTOR蛋白的表达;流式细胞仪分析细胞周期的分布情况。结果:A、B、C组凋亡率均高于D组(P<0.05),其中B组效果更显著;A、B、C组Bcl-2mRNA、BaxmRNA、P53mR-NA、Bcl-2mRNA/BaxmRNA比值、P-AMPK、P-mTOR与D组比较,差异均有统计学意义(P<0.05)。A、B、C组在位内膜细胞G0/G1期比例明显高于D组(P<0.05),且B组高于A组(P<0.05)、A组高于C组(P<0.05)。结论:二甲双胍调节Bcl-2、Bax和P53基因表达,从而诱导在位内膜细胞凋亡,以100mg/kg·d效果最明显。     

美洛昔康对子宫内膜异位症内膜间质细胞生长和VEGF表达的影响

目的:观察选择性环氧化酶-2(COX-2)抑制剂美洛昔康(Meloxicam)对体外培养的子宫内膜异位症在位内膜间质细胞的生长和血管内皮生长因子(VEGF)表达的影响。方法:(1)分离、培养10例子宫内膜异位症患者的子宫内膜间质细胞,测细胞生长曲线,用免疫组化鉴定细胞。(2)观察不同浓度美洛昔康作用下细胞的生长情况,用流式细胞仪检测细胞的凋亡,用实时荧光定量PCR和Western-blot分析细胞内VEGF的表达。结果:美洛昔康对体外培养的子宫内膜间质细胞的生长有一定的抑制作用,美洛昔康高浓度(1×10-3mol/L)时呈现明显的细胞凋亡,不同浓度美洛昔康均可明显抑制子宫内膜间质细胞中VEGF的表达。结论:COX-2抑制剂美洛昔康对子宫内膜间质细胞的生长有一定的抑制作用,高浓度时可诱导子宫内膜间质细胞凋亡,明显抑制间质细胞内VEGF的表达。     

Co-localization of microsomal prostaglandin E synthase-1 with cyclooxygenase-1 in layer II of murine placental syncytiotrophoblasts

The placenta is an organ that secretes prostaglandin (PG) E₂ into the fetal-placental circulation to regulate both vascular tone and remodeling of the fetal ductus arteriosus. Placental PGE₂ synthesis might be mediated by microsomal PGE synthase-1 (mPGES-1), in addition to cyclooxygenase (COX) isoforms. Thus, the purpose of this study is to clarify the temporal and spatial expression patterns of mPGES-1, together with COX-1 and COX-2, in murine placenta. We found that mPGES-1 and COX-1 protein levels continuously increased in the placental labyrinth from gestational day (GD) 13.5 to GD19.5, becoming higher than in the decidua or the junctional zone by GD17.5. The PGE₂ level at GD17.5 was also highest in the labyrinth. Immunofluorescence stainings for mPGES-1 and COX-1 in the labyrinth at GD17.5 overlapped and were located on the fetal side of the signals for connexin 26, which forms gap junctions between maternal-facing (SynT-I) and fetal-facing (SynT-II) syncytiotrophoblast layers, and on the maternal side of the signals for glucose transporter 1 on the basal plasma membrane of SynT-II. On the other hand, the signals for COX-2 did not overlap with those for mPGES-1. These results indicate that COX-1 and mPGES-1 are co-localized in murine placental SynT-II, facing the fetal-placental circulation. Therefore, SynT-II could contribute to placental synthesis of PGE₂ for release into the fetal-placental circulation.     

Suppression of IL-1beta-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells

OBJECTIVE: Over-production of cyclooxygenase-2 (COX-2) plays an important role in the positive feedback loop that leads to proliferation and inflammation in endometriosis. Following our observation that histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and valproic acid (VPA) can suppress proliferation of endometrial stromal cells, we sought to determine whether TSA suppresses IL-1beta-induced COX-2 expression in endometrial stromal cells. STUDY DESIGN: In vitro study using a recently established immortalized endometrial stromal cell line. The stromal cells were pretreated with TSA before stimulation with IL-1beta, and COX-2 gene and protein expression was measured by real-time quantitative RT-PCR and Western blot analysis, respectively. RESULTS: IL-1beta stimulated COX-2 expression in a concentration-dependent manner in endometrial stromal cells. The induced COX-2 gene and protein expression were suppressed by TSA pretreatment. CONCLUSIONS: TSA suppresses IL-1beta-induced COX-2 gene and protein expression in endometrial stromal cells. This finding, coupled with the findings that TSA and another HDACI, valproic acid, suppress proliferation and induce cell cycle arrest, suggests that HDACIs are a promising class of compound that has therapeutic potential for endometriosis.     

Effects of letrozole on proliferation and apoptosis in cultured leiomyoma cells treated with prostaglandin E(2)

OBJECTIVE: The objective was to determine the direct effect of letrozole on the proliferation and apoptosis of cultured leiomyoma cells co-treated with prostaglandin E(2) (PGE(2)). STUDY DESIGN: Leiomyoma cells were obtained from three groups of patients who had undergone hysterectomy due to leiomyoma. Percentages of antiproliferative cells were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis was assessed with sub-G1 cell counts by flow cytometry and Western blot analysis. RESULTS: Combined treatment with 100 microM letrozole and 10 microM PGE(2) for 48 h resulted in a significantly lower viability rate (25.9+/-4.5%) and an increased cell death rate (31.6+/-4.4%) than groups treated with letrozole or PGE(2) alone. However, after adding 10nM estradiol to the combined treatment group, the cell viability rate was restored (75.1+/-7.7%) and the cell death rate was decreased (10.5+/-3.1%). Increased caspase-3 expression was found in the letrozole and PGE(2) combined treatment group, but not in the group in which estradiol was added. CONCLUSION: The present results demonstrate that letrozole inhibits growth and induces apoptosis of leiomyoma cells by blocking the aromatase up-regulated by PGE(2) treatment. These findings support the need for further investigation of aromatase inhibitors as a medical treatment option in leiomyoma.     

Correlation of cyclooxygenase-2 (COX-2) and aromatase expression in human endometrial cancer: tissue microarray analysis

OBJECTIVE: The objective of this study was to compare the prevalence of cyclooxygenase-2 (COX-2), aromatase, and hormone receptor immunohistochemical (IHC) expression to well defined clinical-pathologic prognostic factors in a large group of surgically staged endometrial cancer patients. STUDY DESIGN: A tissue microarray (TMA) was constructed from 336 separate specimens of endometrial cancer. IHC was performed for estrogen (ER) and progesterone (PR) receptor, COX-2, COX-1, and aromatase. RESULTS: The majority of tumors expressed COX-2 (59%) and aromatase (65%). COX-2 staining significantly correlated with aromatase expression ( P < .014) but did not correlate with ER and PR. COX-2 expression was correlated with worsening histologic grade ( P < .026) and approached statistical significance for deep myometrial invasion ( P < .055). After applying multivariate analysis, no single IHC or combination of IHCs correlated with intrauterine poor prognostic factors or advanced stage. Only myometrial invasion >50% (OR 6.98, P < .001) and nonendometrioid histology (OR 4.933, P < .001) were predictive of advanced stage after multivariate analysis. CONCLUSION: COX-2 and aromatase are expressed in the majority of endometrial cancer patients. COX-2 expression was not associated with the great majority of surgical-pathologic prognostic factors. COX-2 expression did significantly correlate with aromatase expression, suggesting that intratumoral production of estrogen in endometrial cancer may be an important mechanism in tumorigenesis.     

Interferon gamma antagonizes interleukin-1beta-induced cyclooxygenase-2 expression and prostaglandin E(2) production in human myometrial cells

OBJECTIVE: To evaluate the effect of interferon gamma (IFNgamma) on interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNFalpha)-promoted prostaglandin E(2) (PGE(2)) production and to investigate the interaction of IFNgamma and IL-1 on cyclooxygenase-2 (COX-2) expression, as well as nuclear factor-kappaB (NF-kappaB) activation in human myometrial cells.METHODS: An immortalized human myometrial cell line was cultured in Dulbecco modified Eagle medium (DMEM) fortified with 10% (v/v) fetal calf serum (FCS) in multiwell plates until near confluency. Twenty-four hours before the start of the experiments, the medium was replaced with FCS-free medium containing 0.5% bovine serum albumin. Prostaglandin E(2) was determined in the medium with a specific radioimmunoassay having a sensitivity of 10 pg. The COX-2 and NF-kappaB inhibitory protein (IkappaB) protein levels were measured in cell extracts by Western blot.RESULTS: Cell cultures primed with IFNgamma produced significantly less (P <.05-.01) PGE(2) in response to cytokines than cells exposed to IL-1, TNF-alpha, or the combination of the two. This result corresponded to a similar inhibition of IkappaB degradation (a prerequisite of NF-kappaB activation) as well as COX-2 protein steady state levels.CONCLUSION: Interferon gamma acts as a partial antagonist of IL-1 signaling in this cell model at a site upstream from the activation of the NF-kappaB pathway, causing a partial inhibition of COX-2 expression and PGE(2) production.     

Effects of a selective COX-2 inhibitor in patients with uterine endometrial cancers

Purpose  

COX-2 is highly expressed in endometrial cancers, suggesting that a selective COX-2 inhibitor could be valuable for treating endometrial cancers that overexpress COX-2. In this study, we investigated the anti-tumor effects of the selective COX-2 inhibitor etodolac on endometrial cancer patients.     

孕三烯酮对体外培养异位子宫内膜细胞生长及凋亡的影响

目的　探讨孕三烯酮对体外培养的子宫内膜异位症(内异症)患者的异位子宫内膜细胞(异位内膜细胞)生长及凋亡的影响,及第10号染色体缺失的磷酸酶和张力蛋白同源物(phosphataseandtensionhomologuedeletedonchromosome10,PTEN)基因在异位内膜细胞表达的变化。方法　以0、10. 6和10 .4 mol/L浓度的孕三烯酮,对体外培养的异位内膜细胞分别进行处理;采用四甲基偶氮唑蓝比色法,检测孕三烯酮对异位内膜细胞作用0 ~48h的细胞抑制情况并绘制细胞生长曲线;应用透射电镜观察孕三烯酮对异位内膜细胞作用24h时的细胞超微结构变化;采用流式细胞仪检测异位内膜细胞凋亡率及细胞周期变化;应用PTEN单克隆抗体,经流式细胞仪分析异位内膜细胞PTEN基因的表达。结果　孕三烯酮作用于异位内膜细胞8、16、24、32、40和48h的细胞生长率,在孕三烯酮浓度为10 .6 mol/L时,分别为99 .6%、87 .3%、79 .8%、62 .3%、51. 7%和44. 2%;在10 .4 mol/L时,分别为99 .2%、77 .1%、69. 6%、51 .1%、33 .7%和23 .6%。同一浓度各作用时间比较,差异均有统计学意义(P<0 .05)。孕三烯酮作用24h后,异位内膜细胞发生典型的细胞凋亡形态学改变。浓度为10 6、10 4 mol/L的孕三烯酮作用于异位内膜细胞后,凋亡率分别为1 3%、15 .0%;浓度为0mol/L的孕三烯酮