Ghrelin与生殖

ghrelin是1999年发现的一个含有28个氨基酸残基的多肽,为生长激素促分泌素受体(GHS-R)的内源性配体。具有调节能量平衡等多种生物学功能。近年来许多研究表明ghrelin对生殖激素、性腺、胎儿的发育、妊娠和泌乳均有一定的影响,并且,ghrelin及其受体广泛存在于生殖轴中。提示ghrelin对生殖系统具有重要的调节作用。     

雌性生殖系统中血管生成的分子调控

血管生成是新血管在原有血管的基础上向无血管区扩展的过程。成年生理性血管生成仅限于雌性生殖道中卵巢、子宫、胎盘的周期性发育。因此,血管生成对这些组织的生长和功能起重要作用。血管生成异常会导致多种妇科疾病。近来的研究证实,多种因素包括血管内皮生长因子(VEGF)和血管生成素(Ang)及其受体参与了血管生成的调节。本文主要介绍近年来雌性生殖系统中有关血管生成调控的研究进展。     

Ghrelin与内分泌代谢异常

Ghrelin是近年来新发现的一种小分子活性肽, 主要由胃底的X/A 样细胞分泌,是生长激素促分泌物受体(GHS-R)的内源性配体.Ghrelin及其受体也可表达于肠道、胰腺、肾脏、性腺、胎盘、甲状腺、肾上腺、下丘脑、垂体等多种内分泌组织或器官.研究表明,ghrelin与糖代谢、甲状腺疾病、肥胖、多囊卵巢综合征等多种内分泌代谢疾患有关.本文将就ghrelin与内分泌代谢异常的关系的研究进展作简要介绍.     

胚胎着床的过程与机制研究进展

哺乳动物的胚胎着床是胚胎与子宫内膜建立紧密联系的过程,是妊娠的起始和关键步骤,胚胎着床的失败直接导致妊娠失败和不孕。近年来,随着技术的进步,胚胎着床的研究工作取得了长足的进展。本文旨在对近10年取得的和胚胎着床有关的研究成果进行综述,重点关注包括腔上皮和腺上皮的子宫内膜上皮在着床过程中的变化、作用及分子机制,以及上皮细胞与胚胎滋养层细胞和子宫基质细胞之间的相互作用。     

Ghrelin与疼痛研究进展

Ghrelin为1999年从大鼠胃粘膜及下丘脑中发现的一种生长激素促分泌素受体(growth hor-mone secretagogue receptor,GHS-Rs)的天然配体,由28个氨基酸残基组成。Ghrelin广泛分布于机体的多个组织器官,如下丘脑、垂体、胃肠道、胰腺、心脏、性腺等。Ghrelin与其受体结合后,具有促进生长激素的释放、增加摄食、刺激胃蠕动和胃酸分泌,改善心血管等多种生物学作用。近年来有研究表明,Ghrelin在中枢神经系统具有广泛分布,并且具有镇痛作用,其主要通过调节与疼痛有关的系统和抑制促炎细胞因子的分泌进而缓解疼痛。现将Ghrelin在疼痛方面的研究做一综述。     

Hippo信号通路在雌性生殖系统中的研究进展

Hippo信号通路是一条存在于果蝇属和哺乳动物体内的保守且新兴的信号通路,具有复杂多变的特点。该通路由多种抑癌基因和一种原癌基因组成,与其他信号通路存在诸多交联对话。Hippo信号通路具有调控器官大小、参与调节细胞周期和凋亡及维持内环境稳定等生物学效应。近年来已有研究表明,Hippo信号通路参与雌性生殖系统发育的调控,因此,其在生殖系统发育及疾病治疗中的作用逐渐引起人们的广泛关注。该文综合论述了Hippo信号通路的生理特性及功能,着重阐述其在雌性生殖系统主要生殖器官(如卵巢、乳腺及卵泡等)中的调控机制。     

酪氨酸对大鼠子宫卵巢和睾丸组织核酸合成的影响

据报道,酪氨酸可能影响生殖机能。本实验证明,酪氨酸对大鼠子宫、卵巢、睾丸和肝脏的 RNA 合成有显著抑制作用,同对照组比较,各组P<0.001;对DNA合成也有抑制性影响,各组P<0.05—0.01。而酪氨酸不影响~3H-UR或~3H-TdR 对心脏、脾脏和肾脏核酸的参入。提示酪氨酸对核酸代谢的影响有器官特异性。实验还比较了酪氨酸、孕酮和放线菌素D 对大鼠子宫和卵巢核酸合成的作用,结果表明,三者对DNA和RNA合成均有抑制效应。提示酪氨酸可能是影响大鼠某些性器官核酸生物合成的因子之一。     

斯钙素与哺乳动物生殖的研究进展

斯钙素(stanniocalcin,STC)是一类首先在硬骨鱼类发现的糖蛋白激素,其生理作用在于调节钙磷稳态。近年来在入和哺乳动物组织中也发现存在有STC,并且以旁分泌方式参与机体的多种生理功能。本文综述了近年来哺乳动物胚胎发育、妊娠及哺乳期间STC基因在卵巢内的表达,早期胚胎植入过程中STC基因在子宫内膜的表达,以及人绒毛膜促性腺激素(hCG)对STC分泌的调节作用及其作用机制。研究表明,新生个体的STC基因表达首先出现在卵巢的膜细胞内,随后出现于卵巢基质的间质细胞和内膜细胞;但STC基因的表达产物STC却聚积于卵母细胞和黄体细胞内,提示STC参与卵母细胞的成熟过程。胚胎植入、妊娠、分娩与哺乳期间卵巢内STC基因表达量的动态变化行为,提示STC在哺乳动物生殖过程的各个环节均发挥一定的作用。     

细胞周期蛋白D3在兔妊娠早期子宫和胚胎中的表达与调节

利用免疫组织化学及RT—PCR的方法,研究了细胞周期蛋白D3(Cyclin D3)在兔早期妊娠子宫和着床前胚胎中的表达情况,以揭示CyclinD3在兔胚胎着床过程中的可能作用。结果显示：(1)在兔妊娠第3～8天的子宫近肌层的腺上皮中有CyclinD3免疫染色,并且其表达强度在第7天以后呈现下降的趋势,着床的胚胎中未见CyclinD3免疫染色;(2)在第2～5天的假孕兔子宫的腺上皮中有较强的CyclinD3免疫染色;(3)在发情周期的兔子宫中未见其有表达;(4)在切除卵巢的兔中,注射雌激素后子宫中未见CyclinD3免疫染色,注射孕酮后在子宫腺上皮中有CyclinD3免疫染色,在孕酮和雌激素共同处理后的子宫腺上皮中有较强的CyclinD3免疫染色;(5)利用RT—PCR的方法在早期胚胎中均能检测到CyclinD3,但从胚泡期开始表达上升,到扩展胚泡时其表达最强。上述结果表明,CyclinD3的表达可能对兔胚泡的着床具有一定的调节作用。     

细胞凋亡与哺乳动物生殖

许多与细胞凋亡有关的基因产物与哺乳动物的生殖过程紧密相关,细胞凋亡在雄性缪勒氏管的正常退化,精子发生过程中正常精子的产生,卵泡闭锁,黄体退化,着床前胚胎发育,着床过程中滋养层侵入子宫内膜上皮,子宫内膜蜕膜退化及母体-胎儿免疫耐受等过程中起着至关重要的作用。     

鱼类ghrelin研究进展

1999年日本学者Kojima,et al．^[1]在大鼠胃组织中首次发现了一种多肽,当这种多肽与生长激素促分泌素受体（Growth hormone secretagogue receptor,GHS—R）结合后,能刺激生长激素（Growth hormone,GH）的分泌,因此将其命名为ghrelin（ghre即grow之意）。此后,人们相继发现ghrelin在摄食、能量平衡、体重、心血管等方面显示出多种调节作用。目前有关人类和哺乳动物ghrelin的研究主要集中在药学研究和畜牧饲料开发两大方面,并取得了一定成效。国内外有关鱼类ghrelin的研究资料较少,相关报道仅见于少数的几种鱼类。本文从鱼类ghrelin的结构、组织分布及生理功能三个方面综述了鱼类ghrelin研究的进展情况;     

Beyond the metabolic role of ghrelin: a new player in the regulation of reproductive function

Ghrelin is a gastric peptide, discovered by Kojima et al. (1999) [55] as a result of the search for an endogenous ligand interacting with the “orphan receptor” GHS-R1a (growth hormone secretagogue receptor type 1a). Ghrelin is composed of 28 aminoacids and is produced mostly by specific cells of the stomach, by the hypothalamus and hypophysis, even if its presence, as well as that of its receptors, has been demonstrated in many other tissues, not least in gonads. Ghrelin potently stimulates GH release and participates in the regulation of energy homeostasis, increasing food intake, decreasing energy output and exerting a lipogenetic effect. Furthermore, ghrelin influences the secretion and motility of the gastrointestinal tract, especially of the stomach, and, above all, profoundly affects pancreatic functions. Despite of these previously envisaged activities, it has recently been hypothesized that ghrelin regulates several aspects of reproductive physiology and pathology. In conclusion, ghrelin not only cooperates with other neuroendocrine factors, such as leptin, in the modulation of energy homeostasis, but also has a crucial role in the regulation of the hypothalamic–pituitary gonadal axis. In the current review we summarize the main targets of this gastric peptide, especially focusing on the reproductive system.     

Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neuroprotection. Furthermore, ghrelin could promote overall health and longevity by acting directly in the immune system and promoting an extended antigen repertoire. The development of mice lacking either ghrelin (ghrelin−/−) or its receptor (ghsr−/−) have provided a valuable tool for determining the relevance of ghrelin and its receptor in these multiple and diverse roles. In this review, we summarize the most important findings and lessons learned from the ghrelin−/− and ghsr−/− mice.     

Role of ghrelin system in neuroprotection and cognitive functions: implications in Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by loss of memory and cognitive deficits, strongly influenced by the metabolic status, in which the impairment of neuropeptides/neurotransmitters systems has been previously observed. Ghrelin is a multifunctional hormone produced in a wide variety of tissues, which has been associated with the progression of obesity and metabolic syndrome, but has been also linked to neuromodulation, neuroprotection and memory and learning processes. In addition, ghrelin system also acts in an autocrine/paracrine fashion where the majority of its components [ghrelin variants (native ghrelin, In1-ghrelin), acylation enzyme (GOAT) and receptors (GHS-Rs)] are expressed in the different regions of central nervous system. In spite of all these pieces of information strongly suggesting a close association between ghrelin system and AD, which could be of pathophysiological relevance, few studies have been addressed to clarify this relationship. In this work, the role of ghrelin system in neuroprotection, memory consolidation and learning is reviewed, and its influence in AD, as well as the regulation of its expression in the brain of AD patients, is discussed.     

Regulation of ghrelin structure and membrane binding by phosphorylation

The peptide hormone ghrelin requires Ser-3 acylation for receptor binding, orexigenic and anti-inflammatory effects. Functions of desacylghrelin are less well understood. In vitro kinase assays reveal that the evolutionarily conserved Ser-18 in the basic C-terminus is an excellent substrate for protein kinase C. Circular dichroism reveals that desacylghrelin is 12% helical in aqueous solution and 50% helical in trifluoroethanol. Ser-18-phosphorylation, Ser-18-Ala substitution, or Ser-3-acylation reduces the helical character in trifluoroethanol to 24%. Both ghrelin and desacylghrelin bind to phosphatidylcholine:phosphatidylserine sucrose-loaded vesicles in a phosphatidylserine-dependent manner. Phosphoghrelin and phosphodesacylghrelin show greatly diminished phosphatidylserine-dependent binding. These results are consistent with binding of ghrelin and desacylghrelin to acidic lipids via the basic face of an amphipathic helix with Ser-18 phosphorylation disrupting both helical character and membrane binding.     

Recent advances in the phylogenetic study of ghrelin

To understand fully the biology of ghrelin, it is important to know the evolutionary history of ghrelin and its receptor. Phylogenetic and comparative genomic studies of mammalian and non-mammalian vertebrates are a useful approach to that end. Ghrelin is a hormone that has apparently evaded natural selection during a long evolutionary history. Surely ghrelin plays crucial physiological roles in living animals. Phylogenetic studies reveal the nature and evolutionary history of this important signaling system.     

High plasma ghrelin protects from coronary heart disease and Leu72Leu polymorphism of ghrelin gene from cancer in healthy adults during the 19 years follow-up study

The aim of our investigation was to find out if ghrelin concentrations or polymorphisms predict the future risk for cardiovascular diseases and cancer in a population-based cohort initiated in 1991 (491 hypertensive and 513 control subjects). Total mortality and hospital events were followed up for 19 years. Fasting total ghrelin concentrations were determined and Arg51Gln, Leu72Met and −501A > C polymorphisms identified. Cox regression analysis was performed. The mean value in the control cohort was 674 pg/ml whereas in the hypertensive cohort it was 661 pg/ml. The associations found suggest that in the controls the highest ghrelin quartile protected from CHD (coronary heart disease). The results were significant without or with adjustments for age, sex, smoking, systolic blood pressure and LDL cholesterol, BMI, type 2 diabetes or QUICK index. C/C variant of the promoter associated with the prevention of IHD (ischemic heart disease) in the hypertensive group (p < 0.05). The controls with the Leu72Leu genotype had less cancer (p < 0.05). In conclusion, high plasma ghrelin concentration was related to protection from CHD and Leu72Leu genotype to prevention of cancer in healthy adults during the 19 years follow-up. C/C promoter protects from IHD in the hypertensive subjects.     

Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats

Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 μg/kg) significantly increased food intake within the first 30 min post-injection. Desacyl ghrelin at 64 and 127 μg/kg injected simultaneously with ghrelin abolished the stimulatory effect of ghrelin on food intake. Desacyl ghrelin alone at both doses did not alter food intake. Both doses of desacyl ghrelin injected separately in the light phase had no effects on food intake when rats were fasted for 12 h. Ghrelin and desacyl ghrelin (64 μg/kg) injected alone increased the number of Fos positive neurons in the arcuate nucleus compared to vehicle. The effect on neuronal activity induced by ghrelin was significantly reduced when injected simultaneously with desacyl ghrelin. Double labeling revealed that nesfatin-1 immunoreactive neurons in the arcuate nucleus are activated by simultaneous injection of ghrelin and desacyl ghrelin. These results suggest that desacyl ghrelin suppresses ghrelin-induced food intake by curbing ghrelin-induced increased neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons.     

Central mechanisms involved in the orexigenic actions of ghrelin

Ghrelin is a stomach hormone, secreted into the bloodstream, that initiates food intake by activating NPY/AgRP neurons in the hypothalamic acruate nucleus. This review focuses on recent evidence that details the mechanisms through which ghrelin activate receptors on NPY neurons and downstream signaling within NPY neurons. The downstream signaling involves a novel CaMKK-AMPK-CPT1-UCP2 pathway that enhances mitochondrial efficiency and buffers reactive oxygen species in order to maintain an appropriate firing response in NPY. Recent evidence that shows metabolic status affects ghrelin signaling in NPY is also described. In particular, ghrelin does not activate NPY neurons in diet-induced obese mice and ghrelin does not increase food intake. The potential mechanisms and implications of ghrelin resistance are discussed.