前列腺素E2及其受体在卵泡发育中的作用

颗粒细胞受黄体生成激素（LH）刺激后分泌的前列腺素E2(PGE2),通过旁分泌和自分泌,结合卵丘细胞上的前列腺素受体2,进而激活腺苷酸环化酶,增加胞内cAMP含量并促进透明质酸合酶2和肿瘤坏死因子α介导蛋白6的合成,引起卵丘细胞扩展。PGE2还通过调控颗粒细胞类固醇代谢通路影响孕酮分泌,从而调节黄体的功能。本文就PGE2在卵泡发育的作用进行综述。     

卵泡发育过程中的Wnt信号通路

Wnt蛋白与细胞膜上相应受体结合,引起胞质中β-catenin集聚并向核内转移,激活下游相关靶基因的转录。该信号通路是调节卵泡生长发育的一个关键途径。Wnt2影响β-catenin的细胞定位来调节颗粒细胞的增殖;Wnt4是一个多功能因子,在卵泡发育的许多阶段都有表达并通过多种途径来调节卵泡的生长、发育和成熟。受体Fzd1调节卵丘扩展相关因子的表达。β-catenin还参与合成卵巢甾体激素和黄体的生成。该通路受损时,会引起卵巢早衰、诱发颗粒细胞肿瘤、排卵障碍和黄体功能不足等。阐述经典的Wnt信号通路及其在调节卵泡发育过程中的作用及其分子机制。     

前列腺素E2在环境内分泌干扰物对雄性生殖健康影响中的作用

环境内分泌干扰物(EEDs)污染是一种新型地球环境污染问题,近年来许多学者发现EEDs可能对雄性的生殖健康产生严重危害。前列腺素E_2(PGE_2)由下丘脑星形胶质细胞产生并释放到相邻的促性腺激素释放激素(GnRH)神经元间接调控生殖。本文拟就EEDs对雄性健康的影响及PGE_2在其中的作用加以综述。     

前列腺素E1治疗冠心病心力衰竭24例疗效观察

前列腺素是一组生物活性物质,品种多,生理作用各自不同。其中前列腺素E_1(PGE_1)目前广泛应用于临床心肺疾病。我们对1999年1年中收治的冠心病心力衰竭病人抽取24例,联合应用PGE_1,对其疗效进行观察分析。     

颗粒细胞与卵母细胞关系研究进展

颗粒细胞与卵母细胞共处于同一个微环境中,颗粒细胞通过复杂的缝隙连接与卵母细胞进行细胞之间的“对话”,并调控卵母细胞的生长与成熟。卵母细胞成熟后发生排卵,卵丘细胞通过自身及分泌作用影响着精卵结合及雄原核的形成。在哺乳动物的研究中发现,卵丘细胞与胚胎共培养能够克服发育阻滞,并对胚胎的发育起很好的支持作用。随着人类辅助生殖技术的发展,学者们越来越重视在基因及转录水平上对卵丘细胞的检测,从而对卵子及胚胎质量进行预测。综述颗粒细胞在卵子生长与成熟、受精及胚胎发育等方面的作用。     

人卵丘细胞与壁颗粒细胞的差异性研究进展

颗粒细胞（granulosa cell）是卵泡内的体细胞,在卵泡的生长发育过程中发挥着至关重要的作用。随着卵泡发育至窦卵泡期,颗粒细胞分化为在空间和功能上不同的2个种群,即围绕在卵母细胞周围的卵丘细胞（cumulus cell）和排列在卵泡壁上的壁颗粒细胞（mural granulosa cell）。卵丘细胞主要为卵母细胞的生长发育提供营养和能量,而壁颗粒细胞主要承担内分泌功能。卵丘细胞与壁颗粒细胞不仅是位置不同,还存在功能、基因等方面的差异。迄今为止,人卵丘细胞和壁颗粒细胞在代谢组学的差异尚少见报道。综述卵丘细胞和壁颗粒细胞差异学的相关研究进展,并提出卵丘细胞和壁颗粒细胞在代谢谱表达上存在差异的新猜想,探究两者之间的差异可能为开发评估卵母细胞和胚胎质量新的标志物提供新思路,这对预测妊娠结局具有重要的临床价值。     

MicroRNA调控卵巢颗粒细胞功能的研究进展

正卵巢颗粒细胞在卵泡形成窦腔时,分化为卵丘细胞(cumulus cells, CC)和壁层颗粒细胞(mural granulosa cells,MGC)。CC突起的尖端穿过透明带,终止于卵母细胞膜,从而形成卵丘-卵母细胞复合体。CC通过缝隙连接与卵母细胞进行双向信息传递,进而有助于卵母细胞的成熟、受精与早期胚胎发育[1]。MGC表面存在多种受体,并且能够分泌多种激素和细胞因子,     

煤尘对大鼠肺泡巨噬细胞分泌前列腺素E2的影响

AM分泌的PGE_2.是一种调节成纤维细胞生长代谢的细胞因子。PGE_2的主要作用是扩张血管,致炎症和抑制免疫反应。基于PGE_2的作用,本文利用细胞培养的方法,将三种不同品位的煤尘按不同的作用浓度和时间,对大鼠肺泡巨噬细胞(AM)进行培养后,测定培养液中PGE_2的含量,了解不同煤尘对AM毒作用的差异;为探讨不同煤质致病作用谱提供依据。     

合成洗衣粉损害作用机理研究

实验采用90只Wistar大鼠,以《荷花牌》合成洗衣粉(10 mg/m~3)作吸入染毒,每天6小时,共4个月。主要研究细胞及细胞膜功能状态,脂质代谢改变和机体适应性重建等。测定指标包括:环核苷酸类(cAMP——环腺苷酸、cGMP——环鸟苷酸)、前列腺素E_1(PGE_1),前列腺素F_2α(PGF_(2α))含量,Ca、Mg、Cu、Zn水平及~3H-胆固醇分布和蓄积等。研究发现,动物染毒后脏器(心、肺、肝、肾、脾)、血浆中PGE_1和cAMP含量变化最     

GnRH及其促效剂对试管内人黄体甾体生成作用的研究

通过培养人黄体细胞检查了促性腺激素释放激素(GnRH)及其强有力的促效剂[(imBzl)-D-His~6-Pro~9-NEt]-GnRH 对基础的和人绒毛膜促性腺激素(HCG)兴奋的孕酮(P),雄烯二酮(Δ~(?)A),雌二醇(E_2)产生的可能直接效应。作者从10名无妇科内分泌疾患行子宫全切除术的妇女中获得黄体组织。选择早期或中期黄体期的黄体,(晚期黄体在试管内对 HCG 或其他兴奋剂如PGE_2不发生孕酮分泌反应)。将黄体打碎成单细胞悬液,浓度为2.5～5.0×10~6活细胞/ml。在细胞悬液中分别不加任何物质(对照),或加 HCG,     

镉对免疫系统的影响及与前列腺素的关系

应用心得安和前列腺素动物模型观察了镉对免疫系统的影响及与前列腺素Ｅ２（ＰＧＥ２）的关系。结果表明：整体动物实验时，ＰＧＥ２和淋巴细胞ｃＡＭＰ在镉单独作用各组均有升高趋势。淋巴细胞ｃＡＭＰ在心得安单独作用时，５ｍｇ／ｋｇ组低于对照组（Ｐ＜０．０５）；１５ｍｇ／ｋｇ组高于对照组（Ｐ＜０．０５）。还见心得安高剂量组的ＰＧＥ２显著低于镉中剂量组和消炎痛＋镉组（Ｐ均＜０．０５）。体外培养人外周血淋巴细胞时见镉组及消炎痛＋镉组的ＡＣ酶活性和ｃＡＭＰ含量均显著升高；心得安＋镉组的ＡＣ酶活性与对照组比较无显著性差异，ｃＡＭＰ含量在两作用组中有一组无显著变化。此外，消炎痛可阻断巨噬细胞分泌ＰＣＥ２，且能缓解镉对巨噬细胞的抑制。结果提示：心得安的作用较消炎痛明显，即在镉的免疫毒性作用机制中，β肾上素能受体机制存在的可能性大于ＰＧＥｃＡＭＰ机制。     

Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet,Predict Prostaglandin E2 in Normal Human Colon Tissue

Prostaglandin E₂ (PGE₂) in the colon is a pro-inflammatory mediator that is associated with increased risk of colon cancer. In this study, expression of genes in the PGE₂ pathway were quantified in colon biopsies from a trial of a Mediterranean versus a Healthy Eating diet in 113 individuals at high risk for colon cancer. Colon biopsies were obtained before and after 6 months of intervention. Quantitative, real-time PCR was used to measure mRNA expression of prostaglandin H synthases (PTGS1 and 2), prostaglandin E synthases (PTGES1 and 3), prostaglandin dehydrogenase (HPGD), and PGE₂ receptors (PTGER2, PTGER4). The most highly expressed genes were HPGD and PTGS1. In multivariate linear regression models of baseline data, both colon saturated fatty acid concentrations and PTGS1 expression were significant, positive predictors of colon PGE₂ concentrations after controlling for nonsteroidal anti-inflammatory drug use, gender, age, and smoking status. The effects of dietary intervention on gene expression were minimal with small increases in expression noted for PTGES3 in both arms and in PTGER4 in the Mediterranean arm. These results indicate that short-term dietary change had little effect on enzymes in the prostaglandin pathway in the colon and other factors, such as differences in fatty acid metabolism, might be more influential.     

Index of Authors by Abstract Numbers

The role of beta-carotene and vitamin E in modifying the effect of cell differentiating agent has not been studied. This study has investigated the effects of beta-carotene and d-alpha-tocopheryl succinate (alpha-TS) on adenosine 3′,5′-cyclic monophosphate (cAMP) induced differentiated functions in murine neuroblastoma cells (NBP2) in culture.

Prostaglandin E1 (PGE1), a stimulator of adenylate cyclase, and 4-(3-butoxy-4-methoxy-benzyl)-2-imidazolidinone (R020-1724), an inhibitor of cyclic nucleotide phosphodiesterase, were used to induce differentiation in NB cells.

Both beta-carotene and alpha-TS markedly enhanced the level of morphologic differentiation (neurite formation) induced by both PGE1 and R020-1724. However, beta-carotene and alpha-TS by themselves were ineffective. These vitamins increased tyrosine hydroxylase (TH) activity. However, beta-carotene did not significantly affect PGE1- and R020-1724-stimulated rise in TH activity. alpha-TS at a higher concentration inhibited PGE1- and R020-1724-stimulated increase in TH activity. None of the above treatments affected basal choline acetyltransferase (ChAT) activity. beta-carotene and alpha-TS caused a transient increase in cAMP level, and they also enhanced the effect of PGE1 and R020-1724 on cAMP level in a transient manner.

These results suggest that beta-carotene and alpha-TS modify the effects of cAMP stimulating agents on differentiation of NB cells in culture.     

前列腺素E2和肿瘤坏死因子-α对肺成纤维细胞第二信使的影响

目的探讨前列腺素E2(PGE2)和肿瘤坏死因子-α(TNF-α)对鼠肺成纤维细胞第二信使的影响,为细胞因子治疗尘肺提供新靶点.方法在原代培养的小鼠肺成纤维细胞中,加10 ng/mlTNF-α或10 ng/ml TNF-α联合不同剂量的PGE2细胞因子,在不同的观察时点,用放射免疫分析法检测肺成纤维细胞内环磷酸腺苷(cAMP)、环磷酸鸟苷(cGMP)和1,4,5-三磷酸肌醇(IP3)等第二信使的量变模式对肺成纤维细胞增殖效应的影响.结果在120 s时点,10 ng/ml TNF-α与1 000 pg/ml PGE2联合时,成纤维细胞内IP3的计数值最高[(76.33±7.10)CPM];而cAMP/cGMP比值较低时(作用时点24 h,4.29),对成纤维细胞的增殖效应最强;当10 ng/ml TNF-α与500 pg/ml PGE2和2 000 pg/ml PGE2联合时,成纤维细胞内IP3的CPM值明显降低作用120 s时,CPM值分别为27.00±3.00、61.00±2.65;cAMP/cGMP比值在作用24 h时(分别为3.50、9.83),成纤维细胞的增殖效应明显下降.结论一定剂量的PGE2能提高肺成纤维细胞内cAMP/cGMP比值,拮抗TNF-α对成纤维细胞的增殖效应.     

JP-8 jet fuel exposure rapidly induces high levels of IL-10 and PGE2 secretion and is correlated with loss of immune function

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has demonstrated that JP-8 exposure is immunosuppressive. In the present study, the potential mechanisms for the effects of JP-8 exposure on the immune system were investigated. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents; namely, interleukin-10 (IL-10) and prostaglandin E2 (PGE2). JP-8 exposure rapidly induced a persistently high level of serum IL-10 and PGE2 at an exposure concentration of 1000 mg/m3. IL-10 levels peaked at 2 h post-JP-8 exposure and then stabilized at significantly elevated serum levels, while PGE2 levels peaked after 2-3 days of exposure and then stabilized. Elevated IL-10 and PGE2 levels may at least partially explain the effects of JP-8 exposure on immune function. Elevated IL-10 and PGE2 levels, however, cannot explain all of the effects due to JP-8 exposure (e.g., decreased organ weights and decreased viable immune cells), as treatment with a PGE2 inhibitor did not completely reverse the immunosuppressive effects of jet fuel exposure. Thus, low concentration JP-8 jet fuel exposures have significant effects on the immune system, which can be partially explained by the secretion of immunosuppressive modulators, which are cumulative over time.     

Development of a prostaglandin D2 receptor antagonist: discovery of a new chemical lead

A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.     

Prostaglandin E2 is involved in the increase of cytochrome P-450 2B1 expression by alpha-tocopheryl succinate in primary rat hepatocytes in the presence of phenobarbital

The modulation of cytochrome P-450 2B1 expression by alpha-tocopheryl succinate and whether prostaglandin E2 is involved in this modulation in primary rat hepatocytes in the presence of phenobarbital were investigated. A primary rat hepatocyte culture model that faithfully reproduces the phenobarbital response observed in vivo was used. Intracellular alpha-tocopherol content was dose dependently increased by alpha-tocopheryl succinate incubation. Hepatocytes were demonstrated to have prostaglandin E2-synthesizing capability. alpha-Tocopheryl succinate inhibited prostaglandin E2 synthesis by hepatocytes and increased cytochrome P-450 2B1 expression in the presence of phenobarbital; however, it had little effect on intracellular cAMP level. To mimic the exogenous source of prostaglandin E2 from nonparenchymal cells, various concentrations of prostaglandin E2 were added to the cell culture. High doses of exogenous prostaglandin E2 (100 and 1,000 nM) inhibited the cytochrome P-450 2B1 expression in the presence of phenobarbital compared with low doses (1 and 10 nM); however, the presence of high doses of prostaglandin E2 had no effect on intracellular cAMP level. Forskolin significantly increased intracellular cAMP level and inhibited cytochrome P-450 2B1 expression in the presence of phenobarbital. The results of this study indicate that alpha-tocopheryl succinate increases cytochrome P-450 2B1 expression via its inhibition of prostaglandin E2 synthesis in the presence of phenobarbital; however, changes in intracellular cAMP level are not related to cytochrome P-450 2B1 expression.     

The antitumor ether lipid edelfosine (ET-18-O-CH3) induces apoptosis in H-ras transformed human breast epithelial cells: by blocking ERK1/2 and p38 mitogen-activated protein kinases as potential targets

We previously reported that a novel alkylphospholipid type antitumor agent edelfosine (ET-18-O-CH3 ; 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine) induced apoptosis in human breast epithelial cells transfected with the H-ras oncogene (MCF10A-ras) which was causally linked to cyclooxygenase-2 (COX-2) up-regulation and production of 15-deoxy-Delta 12,14-prostaglandins J2 (15d-PGJ2). ET-18-O-CH3 treatment also enhanced the production of prostaglandin E2 (PGE2), a major COX-2 product. In this study, we found that ET-18-O-CH3 treatment resulted in elevated mRNA expression of the PGE2 receptor subunit, EP2 receptor. Exogenously added PGE2 inhibited the growth of MCF10A-ras cells and induced proteolytic cleavage of caspase 3. ET-18-O-CH3 also inhibited constitutive activation of ERK1/2, p38 MAPK, and Akt/protein kinase B, which was blunted by a selective COX-2 inhibitor SC58635. In addition, ET-18-O-CH3 inhibited DNA binding activity of NF-kappa B in MCF10A-ras cells, and this was again attenuated by SC58635. Based on these findings, it is likely that ET-18-O-CH3 inactivates ERK1/2, Akt, and NF-kappaB signaling via COX-2 induction in MCF10A-ras cells, thereby inducing apoptosis of these cells.     

Steroidogenesis,proliferation and apoptosis in bovine granulosa cells: role of tumour necrosis factor-alpha and its possible signalling mechanisms

This study was designed to investigate the presence of bioactive tumour necrosis factor-alpha (TNF-alpha) in bovine fluid collected from small (<5 mm) and large (>8 mm) follicles, as well as the production of the cytokine by the granulosa cells collected from the same type of follicles. Moreover, the effectiveness of 10, 1 and 0.1 ng mL(-1) of human TNF-alpha (hTNF-alpha) in affecting the main parameters of granulosa cell function, progesterone (P4) and oestradiol-17beta (E2) production, cell proliferation and apoptosis, was tested. In addition, the study aimed to determine whether the signalling mechanisms of TNF-alpha in these cells involve cAMP, nitric oxide or prostaglandin E2 (PGE2) and F2alpha (PGF2alpha). It emerged that bioactive TNF-alpha is present in follicular fluid from both types of follicles and can be measured in media conditioned by granulosa cells from large follicles. As for the effects of hTNF-alpha, it inhibits P4 production in cells from both types of follicles and stimulates E2 output in those from small follicles; it does not affect proliferation, but it stimulates granulosa cell apoptosis. Finally, the effects of hTNF-alpha on bovine granulosa cells are not mediated by nitric oxide or cAMP, as neither of these substances were affected by treatment with the cytokine; however, in some way, they could be mediated through PGE2 and PGF2alpha, the production of which was inhibited by TNF-alpha in cells from small follicles.