氧化应激对胎盘生命的影响

氧化应激不仅是氧化剂的产生与抗氧化剂防御系统之间的不平衡状态,也是众多细胞功能障碍和组织损伤的原因。氧化应激相关因子在多种疾病中发挥重要作用,通过多种途径调节细胞内环境稳定,维持细胞存活。近年研究发现,氧化应激与相关的氧化损伤是导致多种疾病的主要因素,氧化应激相关指标在妊娠特有疾病(如子痫前期、胎儿生长受限)孕妇的血清及胎盘滋养细胞中高度表达。氧化应激同时与肿瘤、高血压等多种慢性疾病有关,与多种疾病的发生、发展密切相关。氧化应激作为妊娠期特有疾病的"共同通路"被深入研究,其中氧化应激对胎盘功能的影响备受关注。分析与总结胎盘在不同缺氧状态下与妊娠相关疾病的关系,探索氧化应激相关因子是否具有预测作用,为围生期相关疾病的预防及诊疗提供新方向、新思路。     

缺氧诱导因子与妊娠期肝内胆汁淤积症

缺氧诱导因子（HIF）是广泛存在于人类细胞并调节细胞内氧代谢的关键因子,受缺氧信号调控,参与缺氧诱导多种基因的转录,目前研究较多的是HIF-1和-2。HIF类与正常妊娠胎盘胚胎的发育相关,其缺失或表达异常导致异常妊娠。妊娠期肝内胆汁淤积症（ICP）胎儿多有急慢性缺氧,近年对HIF类在ICP患者胎盘中作用开始有研究。其在胎盘中表达调节对维持胎盘功能起一定代偿作用,与该疾病发生发展有关。     

缺氧诱导因子与妊娠期肝内胆汁淤积症

缺氧诱导因子(HIF)是广泛存在于人类细胞并调节细胞内氧代谢的关键因子,受缺氧信号调控,参与缺氧诱导多种基因的转录,目前研究较多的是HIF-1和-2.HIF类与正常妊娠胎盘胚胎的发育相关,其缺失或表达异常导致异常妊娠.妊娠期肝内胆汁淤积症(ICP)胎儿多有急慢性缺氧,近年对HIF类在ICP患者胎盘中作用开始有研究,其在胎盘中表达调节对维持胎盘功能起一定代偿作用,与该疾病发生发展有关.     

胎盘生长因子、转化生长因子-β与妊娠期高血压疾病

胎盘生长因子促进妊娠早期时滋养细胞的增殖和分化,在正常妊娠胎盘形成和发育中起重要作用。转化生长因子-β可促进子宫内膜的蜕膜化过程,抑制滋养细胞的增生、迁移、浸润,参与胎盘结构的形成及功能调节,在胎盘和胚胎的生长发育中起重要作用。这两种因子表达异常可能与妊娠期高血压疾病滋养细胞功能低下、血管内皮损伤有关,可能参与妊娠期高血压疾病的发生和发展过程。     

胎盘生长因子、转化生长因子-β与妊娠期高血压疾病

胎盘生长因子促进妊娠早期时滋养细胞的增殖和分化,在正常妊娠胎盘形成和发育中起重要作用.转化生长因子-β可促进子宫内膜的蜕膜化过程,抑制滋养细胞的增生、迁移、浸润,参与胎盘结构的形成及功能调节,在胎盘和胚胎的生长发育中起重要作用.这两种因子表达异常可能与妊娠期高血压疾病滋养细胞功能低下、血管内皮损伤有关,可能参与妊娠期高血压疾病的发生和发展过程.     

芳香烃受体(AHR)在胎盘生成中的作用

胎盘是连接母体与胎儿的重要器官,在维持正常的妊娠过程中发挥着重要的作用。胎盘的结构和功能异常不仅易引发妊娠期高血压和糖尿病等妊娠并发症,还易导致早产、胎儿宫内生长受限(intrauterine growth retardation,IUGR)、流产等不良妊娠结局。芳香烃受体(aryl hydrocarbon receptor,AHR)作为一种配体激活性转录蛋白,参与了生殖调控、免疫功能调节、血管重塑等一系列重要的生理活动。AHR与滋养细胞的增殖和凋亡密切相关,并且具有调节滋养细胞细胞周期的作用。AHR在胎盘血管的生成及血流量的调节中也发挥着重要的作用,它通过调节促血管生成因子与血管生成抑制因子的平衡,参与胎盘血管的正常发育生长;同时AHR还很可能在胎盘的生长发育中介导了胎盘血管的生成以及滋养细胞的侵袭能力;AHR表达异常直接导致了相关妊娠期疾病的发生。     

肿瘤坏死因子α在子痫前期发生发展中的作用

子痫前期是妊娠期特有疾病,现今研究认为,肿瘤坏死因子仅是子痫前期发生发展机制中起重要作用的因子之一。肿瘤坏死因子α作为炎性分子,激活血管内皮细胞、间接影响血管舒缩功能,通过各种机制诱导胎盘滋养细胞凋亡增加,增加血管收缩因子（如内皮素）并减少血管舒张因子（如一氧化氮）的生成和释放,影响与脂类代谢相关的细胞因子。肿瘤坏死因子α从组织水平和分子细胞水平,广泛参与妊娠期子痫前期和子痫损伤和代偿的病理生理调节。     

MMP-2和MMP-9参与多种因素对胎盘滋养细胞侵袭力的调控

成功妊娠有赖于滋养细胞对子宫内膜的适度侵袭。侵袭功能出现异常,可导致滋养细胞对子宫内膜侵入过深或过浅、子宫螺旋动脉重塑障碍、胎盘缺氧缺血及母体全身血管内皮细胞损伤,导致多种不良妊娠结局以及妊娠相关疾病的发生。明胶酶基质金属蛋白酶2(matrix metallopeptidase 2,MMP-2)和MMP-9因可降解Ⅳ型胶原参与对滋养细胞侵入子宫内膜能力的调控。研究表明,激素、细胞因子、转录因子、环境污染物以及其他多种物理刺激等均可以影响滋养细胞的侵袭力,并且在探讨其影响机制时都最终以MMP-2和MMP-9表达水平的变化来解释。对影响滋养细胞侵袭力的多种因素进行综述,有助于以MMP-2和MMP-9为靶点的不良妊娠以及妊娠相关疾病的预防或治疗。     

子痫前期患者胎盘组织妊娠相关血浆蛋白-A基因的表达

子痢前期(preeclampsia,PE)为妊娠期特有的疾病,发病机制至今尚未阐明.PE的临床特点为胎盘娩出后,临床症状和体征自然消失,其特点及相关基础研究提示,胎盘在该疾病的发生发展中有重要作用~([1]).妊娠相关血浆蛋白-A(pregnancy-associated plasma protein-A,PAPP-A)是一种与妊娠密切相关的大分子糖蛋白,主要由胎盘合体滋养层细胞、蜕膜细胞合成并分泌进入血循环.近年来,PAPP-A在妊娠相关疾病的辅助诊断、预测等方面的研究取得了进展,也成为该领域的研究热点~([2-4]).本研究利用荧光定量聚合酶链反应(quantitative fluorescent-PCR,QF-PCR)技术测定PE患者胎盘组织中PAPP-A mRNA的表达水平,旨在探讨其在子痢前期发病过程中的作用.     

细胞因子信号传导抑制因子3与妊娠的研究进展

细胞因子信号转导抑制因子3（SOCS3）通过调节细胞因子信号传导通路对多种细胞及细胞因子具有调节作用,是炎症和细胞凋亡的关键调节物。妊娠时母-胎单位局部微环境存在大量细胞因子,细胞因子参与妊娠期胚胎植入、胎盘形成、胎儿生长和分娩等过程,细胞因子受多方面因素精密调控,使之处于稳定状态有助于正常妊娠。SOCS3作为细胞因子信号传导调节因子参与妊娠及分娩过程,研究表明SOCS3表达异常与流产、早产、妊娠期高血压疾病和妊娠期糖尿病等妊娠疾病的发生发展有关,深入研究SOCS3在妊娠疾病中的作用,可以为妊娠相关疾病的诊断和治疗等方面提供理论依据。     

Role of reactive oxygen species in gynecologic diseases

Free radicals derived from molecular oxygen and nitrogen are highly reactive metabolites called reactive oxygen species (ROS). Cells continuously produce free radicals and ROS as part of the metabolic process. They are involved in the various functions of the reproductive system. Antioxidants are enzymes or compounds that scavenge and reduce the presence of free radicals. Normally, a balance exists between concentrations of reactive oxygen species and antioxidant scavenging systems. The disruption of the delicate balance between pro- and antioxidants results in oxidative stress. Oxidative stress has been implicated in embryo fragmentation, DNA damage, apoptosis and poor pregnancy outcome. It has also been implicated in a large number of gynecologic diseases, such as endometriosis, pre-eclampsia and maternal diabetes. The use of antioxidants may be beneficial in combating the harmful effects of oxidative stress in many of these diseases. The present review outlines the importance of these species in the pathology of various gynecologic diseases. (Reprod Med Biol 2004; 3 : 177 – 199)     

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。     

Proteomics,oxidative stress and male infertility

Oxidative stress has been established as one of the main causes of male infertility and has been implicated in many diseases associated with infertile men. It results from high concentrations of free radicals and suppressed antioxidant potential, which may alter protein expression in seminal plasma and/or spermatozoa. In recent years, proteomic analyses have been performed to characterize the protein profiles of seminal ejaculate from men with different clinical conditions, such as high oxidative stress. The aim of the present review is to summarize current findings on proteomic studies performed in men with high oxidative stress compared with those with physiological concentrations of free radicals, to better understand the aetiology of oxidative stress-induced male infertility. Each of these studies has suggested candidate biomarkers of oxidative stress, among them are DJ-1, PIP, lactotransferrin and peroxiredoxin. Changes in protein concentrations in seminal plasma samples with oxidative stress conditions were related to stress responses and to regulatory pathways, while alterations in sperm proteins were mostly associated to metabolic responses (carbohydrate metabolism) and stress responses. Future studies should include assessment of post-translational modifications in the spermatozoa as well as in seminal plasma proteomes of men diagnosed with idiopathic infertility.Oxidative stress, which occurs due to a state of imbalance between free radicals and antioxidants, has been implicated in most cases of male infertility. Cells that are in a state of oxidative stress are more likely to have altered protein expression. The aim of this review is to better understand the causes of oxidative stress-induced male infertility. To achieve this, we assessed proteomic studies performed on the seminal plasma and spermatozoa of men with high levels of oxidative stress due to various clinical conditions and compared them with men who had physiological concentrations of free radicals. A variety of sperm and seminal plasma proteins were found to be expressed either in abundance (over-expressed) or in a lesser amount (underexpressed), while other proteins were found to be unique either to men with oxidative stress or to men with a balanced ratio of antioxidants/free radicals. Each study included in this review suggested several proteins that could possibly act as biomarkers of oxidative stress-induced male infertility, such as protein DJ-1, PIP, lactotransferrin and peroxiredoxin. Pathway analysis performed in these studies revealed that the changes in seminal plasma proteins in men with oxidative stress could be attributed to stress responses and regulatory pathways, while changes in sperm proteins were linked to stress responses and metabolic responses. Subsequent studies could look into post-translational modifications in the protein profile of men with idiopathic infertility. We hope that the information in this review will contribute to a better understanding of the main causes of idiopathic male infertility.     

Penfigoide gestacional recidivante en el puerperio

Like other organs and systems, the skin undergoes changes during pregnancy, including physiological alterations such as chloasma or the development of stretch marks. However, the skin is also affected by other pathological changes present in the context of pregnancy-related diseases, such as intrahepatic cholestasis, or dermatoses, whether pregnancy-specific or not.     

Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development

Developmental toxicity caused by exposure to a mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviours, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase susceptibility of offspring to diseases. There is evidence to suggest that the developmental toxicological mechanisms of chemicals and lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased ROS generation overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Data on the involvement of oxidative stress in the mechanism of developmental toxicity following exposure to environmental pollutants are reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on post-natal development and health outcomes.Developmental toxicity caused by exposure to mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviors, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase the susceptibility of offspring to development complications and diseases. There is evidence to suggest that the developmental toxicological mechanisms of human-made chemicals and unhealthy lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased generation of ROS overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Exposure to various environmental pollutants induces synergic and cumulative dose-additive adverse effects on prenatal development, pregnancy outcomes and neonate health. Data from the literature on the involvement of oxidative stress in the mechanism of developmental toxicity following in vivo exposure to environmental pollutants will be reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on postnatal development and health outcomes.     

Endogenous anti-oxidants in pregnancy and preeclampsia

Oxidative stress has been implicated in a wide variety of diseases and degenerative states including cancer, rheumatoid arthritis, cardiovascular disease and ageing. There is now considerable evidence to suggest that pregnancy leads to the generation of an increased oxidative burden, but whether this overwhelms the anti-oxidant capacity within the placenta and/or the peripheral circulation remains a point of conjecture. There is little doubt that oxidative stress is a significant contributor in the pathogenesis of preeclampsia. The use of exogenous anti-oxidants such as vitamins C and E in the prevention of preeclampsia is the subject of several large clinical trials currently being conducted in many countries around the world. The results of these studies are eagerly awaited, but what of the endogenous anti-oxidant systems that have evolved to combat the oxidative burden associated with living in an aerobic environment? This review will focus on several important anti-oxidant enzyme systems, their role in pregnancy and the evidence to suggest that endogenous anti-oxidants are important in the development of complications of pregnancy such as preeclampsia.     

The role of the oxidative-stress in the endometriosis-related infertility

Endometriosis is a common gynecological disorder of the reproductive age characterised by pelvic pain, dysmenorrhea and infertility. Classic theories have failed to propose a precise pathogenetic mechanism. Recent studies have investigated the role of the immune system and oxidative stress in the development of endometriosis as well as the identification of biomarkers for a non-invasive diagnosis of the disease. At endometriotic sites, inflammatory cells including eosinophils, neutrophils and macrophages generate reactive oxygen species that contribute to the development of oxidative stress in the peritoneal cavity. Oxidative stress further augments immune response in affected sites. The oxidants exacerbate the development of endometriosis by inducing chemoattractants and endometrial cell growth-promoting activity. The oxidative proinflammatory state of the peritoneal fluid is an important mediator of endometriosis. Many studies investigate the correlation of endometriosis and oxidative stress but the results are discrepant. Furthermore, oxidative stress has been implicated in unexplained infertility and has been associated with some of its causative factors. Oxidative stress influences womens reproductive capacity. The association between endometriosis and infertility is described in several studies and still remains debated.     

A review and psychometric evaluation of pregnancy-specific stress measures

Considerable evidence has accumulated on the association between pregnancy-specific stress and adverse birth outcomes with an increasing number of measures of pregnancy-specific stress being developed internationally. However, the introduction of these measures has not always been theoretically or psychometrically grounded, resulting in questions about the quality and direction of such research. This review summarizes evidence on the reliability and validity of pregnancy-specific stress measures identified between 1980 and October 2010. Fifteen pregnancy-specific stress measures were identified. Cronbach's alpha coefficient ranged from 0.51-0.96 and predictive validity data on preterm birth were reported for five measures. Convergent validity data suggest that pregnancy-specific stress is related to, but distinct from, global stress. Findings from this review consolidate current knowledge on pregnancy-specific stress as a consistent predictor of premature birth. This review also advances awareness of the range of measures of pregnancy-specific stress and documents their strengths and limitations based on published reliability and validity data. Careful consideration needs to be given as to which measures to use in future research to maximize the development of stress theory in pregnancy and appropriate interventions for women who experience stress in pregnancy. An international, strategic collaboration is recommended to advance knowledge in this area of study.     

The role of free radicals and antioxidants in reproduction

PURPOSE OF REVIEW: This review summarizes the role of free radicals and oxidative stress in the pathophysiology of human reproduction. RECENT FINDINGS: An extensive review of the literature on the role of oxidative stress in influencing assisted reproduction and its outcome is described in this article. Free radicals or reactive oxygen species mediate their action through many of the proinflammatory cytokines and this mechanism has been proposed as a common underlying factor for endometriosis, ovarian cancer, polycystic ovary disease, and various other pathologies affecting the female reproductive process, as highlighted in this review. Oxidative stress, sperm DNA damage, and apoptosis have been implicated in male infertility. Elevated reactive oxygen species levels correlate with the poor fertility outcomes seen in the assisted reproductive technology setting. SUMMARY: Oxidative stress has been implicated in male and female infertility, including fetal dysmorphogenesis, abortions, and intrauterine growth restriction. Accurate evaluation of seminal oxidative stress by standardized assays may help in the diagnosis and management of male infertility. There is evidence in the literature on the beneficial effects of oral antioxidant supplementation in male infertility. Current ongoing trials will provide answers on the safety and effectiveness of antioxidants in improving maternal and fetal outcomes. Further studies need to be conducted to determine if antioxidant supplementation will prevent fetal developmental defects in high-risk pregnancy with diabetes.     

Angiogenin and apoptosis in hypertension in pregnancy

Hypertension is a common medical condition that complicates pregnancy, and has significant adverse effects on pregnancy outcomes, including maternal and perinatal morbidity and mortality. In seeking the aetiology of pregnancy-related hypertension there has been a shift in focus from the foeto-placental axis to the maternal vasculature, and two possibly related pathophysiological mechanisms have been introduced – angiogenesis and apoptosis. Both processes have been extensively studied as possible pathophysiological mechanisms underlying a variety of diseases, including cardiovascular diseases such as hypertension, myocardial infarction, as well as conditions such as malignancy states, and there is a slowly developing body of knowledge justifying hypothesis of roles in pregnancy. This review presents the data regarding this position and explores the role of angiogenesis and apoptosis in the pathogenesis of hypertension in pregnancy and their effects on pregnancy outcomes.