Ghrelin及其受体在肿瘤发生中的作用

Ghrelin是1999年发现的首个生长激素促泌物受体的内源性配体,具有广泛的生物学效应。包括促进生长激素分泌,增进食欲,维持能量代谢正平衡,调节心血管和免疫系统功能等。目前Ghrelin和肿瘤疾病之间相互关系受到了广泛重视,已经积累了许多的研究成果,表明Ghrelin及其受体参与了多种肿瘤的发病机理和相关病理生理改变。     

谷氨酰胺和生长激素联合应用在疾病治疗中的作用

谷氨酰胺和生长激素是人体两种主要的免疫营养要素,谷氨酰胺是一种重要的营养底物,而生长激素是一种促合成激素。近年来许多研究发现,谷氨酰胺和生长激素具有促进蛋白质合成、保护肠黏膜屏障及增强机体免疫功能等作用,两者联合应用于短肠综合征、肝硬化、烧伤、肿瘤等患者的营养支持时具有协同作用。本文对谷氨酰胺和生长激素联合应用在临床疾病治疗中的作用作一综述。     

Ghrelin与慢性心力衰竭

Ghrelin是近年来发现的一种肽类激素,是生长激素促泌物受体(GHS-R)的内源性配体。Ghrelin除了刺激生长激素分泌外,还具有许多其他的生理作用。研究发现:在心血管疾病特别是慢性心力衰竭的治疗方面具有潜在的功效。     

Ghrelin与胃肠疾病关系的研究进展

Ghrelin是生长激素促分泌素受体的内源性配体,与受体结合后产生广泛的生物学效应,可刺激生长激素分泌、调节能量代谢等作用.而在消化系统中,Ghrelin具有保护胃肠黏膜、调节胃肠动力、促进胃酸分泌及控制肿瘤细胞增殖的作用,现将其与胃肠病疾病的研究进展综述如下.     

生长激素与肾脏

生长激素与肾脏天津市儿童医院内科（３０００７４）张碧丽综述近年来研究发现，生长激素（ＧＨ）和／或其局部效应物胰岛素样生长因子－１（ＩＧＦ－１）参与肾脏功能与肾脏生长，简述如下。１生长激素的生理ＧＨ的分泌接受丘脑下部生长激素释放激素（ＧＨＲＨ）和生长激...     

Ghrelin与心力衰竭

Ghrelin是一种由28个氨基酸组成的多肽,是生长激素促分泌素受体的内源性配体.近年来研究显示心力衰竭时ghrelin及其受体的表达及功能发生变化;Ghrelin除具有促进生长激素分泌的作用外,还具有抑制心肌细胞凋亡、抑制心室重构、增强心肌收缩力、直接保护心肌、改善心肌能量代谢、改善心功能、延缓心源性恶病质的生物学效应.这就提示ghrelin可能从上述多方面发挥抗心力衰竭的作用,具有治疗心力衰竭的潜在功效.     

基因重组生长激素对大鼠肝细胞生长激素受体表达及血清蛋白的影响

研究发现,肾病综合征(NS)患者体内胰岛素样生长因子-1(IGF-1)浓度降低,但其生长激素(GH)浓度正常[1],可能是生长激素受体(growth hormone receptor,GHR)表达下降导致GH生物效应受到抑制,机体IGF-1合成及分泌减少,使GH/IGF-1轴强大的合成功能受限,加重了NS患者的低蛋白血症.     

Glrelin的分子结构及体内分布

Ghrelin是1999年由Kojima等应用反向药理学的方法从胃中发现的一个脑肠肽,由28个氨基酸组成,下丘脑,弓状核、胎盘、肾脏等处也有少量分泌。它是体内促生长激素分泌素受体（GHS—receptor,GHS—R）的天然配体,具有强烈的刺激生长激素（growthhormone,GH）分泌的作用。GH从垂体释放不仅被下丘脑的生长激素释放激素（GH—releasinghormone,GHRH）调节,     

肝硬化生长激素-胰岛素样生长因子轴的基础与临床研究

生长激素(GH)是由脑腺垂体前叶嗜酸性粒细胞分泌的一种含191个氨基酸的蛋白质多肽。肝脏是生长激素最主要的靶器官。生长激素可直接与靶组织特异性受体结合发挥其生物学作用；另一方面，生长激素又可通过生长激素-肝-胰岛素样生长因子轴(GH—IGF轴)，刺激肝、肾及其他部位产生胰岛素样生长因子(insulin—like growth factors，IGFs)而间接发挥其生物学效应。     

脂肪因子apelin与肥胖和胰岛素抵抗

apelin是孤独G蛋白耦联受体APJ的内源性配体,在组织中分布广泛,具有多种生物学效应。最新研究表明apelin是由脂肪细胞分泌的一种新的脂肪因子,胰岛素、肿瘤坏死因子及生长激素等因素可诱导其表达,它与肥胖、胰岛素抵抗密切相关。     

Ghrelin in obesity

Ghrelin was discovered for its ability to bind the growth hormone secretagogue receptor (GHSR1a) and stimulate growth hormone release. However, much research conducted with this novel stomach hormone is focused on proposed roles for it to participate in regulating energy balance. Exogenous administration of ghrelin stimulates food consumption in experimental animals and humans, presenting the hormone as the first to stimulate appetite after peripheral administration and implicates it for an etiology of obesity. The hormone also presents other exceptional characteristics that solicit need for future study. The peptide is modified by acylation with a mediumchain fatty acid on its third residue, and it is that ghrelin peptide that binds GHS-R1a. Enzymes or transfer proteins responsible for such acylation and de-acylation remain unknown. Specific assays for both acyl- and des-acyl ghrelin are not available nor are methods to prevent de-acylation in blood samples. Such knowledge is important because des-acyl ghrelin is reported to bestow biology distinct from that of ghrelin and that signal may actually oppose those prescribed for its acylated parent. This review of ghrelin data relating to obesity recognizes the complexity of ghrelin endocrinology and attempts to be cautious when discussing studies that measured ghrelin during different physiological states. Although much more exploration is needed, we placed more emphasis on reviewing studies during different physiological states when conclusions are less dependent on measurement of ghrelin. Despite these shortcomings, we conclude that there is ample evidence indicating ghrelin participates in regulating energy balance.     

Endocrinological activities of ghrelin: new insights

Ghrelin is a potent endogenous growth hormone secretagogue in supraphysiological doses. It also exhibits several other endocrinological (e.g. lactotrophic and corticotrophic) activities when given intravenously. However, the significance of these effects in a normal physiological situation is still unknown, and subcutaneous administration of ghrelin seems to only increase growth hormone secretion. Interest in ghrelin research is currently focused on energy metabolism; the link between ghrelin and the regulation of both growth and energy metabolism is missing. In this paper we present an up-to-date review of the endocrinological activities of ghrelin.     

Stimulatory effect of ghrelin on isolated porcine somatotropes

Research on the mechanism for growth hormone secretagogue (GHS) induction of growth hormone secretion led to the discovery of the GHS receptor (GHS-R) and later to ghrelin, an endogenous ligand for GHS-R. The ability of ghrelin to induce an increase in the intracellular Ca(2+) concentration - [Ca(2+)](i) - in somatotropes was examined in dispersed porcine pituitary cells using a calcium imaging system. Somatotropes were functionally identified by application of human growth hormone releasing hormone. Ghrelin increased the [Ca(2+)](i) in a dose-dependent manner in 98% of the cells that responded to human growth hormone releasing hormone. In the presence of (D-Lys(3))-GHRP-6, a specific receptor antagonist of GHS-R, the increase in [Ca(2+)](i) evoked by ghrelin was decreased. Pretreatment of cultures with somatostatin or neuropeptide Y reduced the ghrelin-induced increase of [Ca(2+)](i). The stimulatory effect of ghrelin on somatotropes was greatly attenuated in low-calcium saline and blocked by nifedipine, an L-type calcium channel blocker, suggesting involvement of calcium channels. In a zero Na(+) solution, the stimulatory effect of ghrelin on somatotropes was decreased, suggesting that besides calcium channels, sodium channels are also involved in ghrelin-induced calcium transients. Either SQ-22536, an adenylyl cyclase inhibitor, or U73122, a phospholipase C inhibitor, decreased the stimulatory effects of ghrelin on [Ca(2+)](i) transiently, indicating the involvement of adenylyl cyclase-cyclic adenosine monophosphate and phospholipase C inositol 1,4,5-trisphosphate pathways. The nonpeptidyl GHS, L-692,585 (L-585), induced changes in [Ca(2+)](i) similar to those observed with ghrelin. Application of L-585 after ghrelin did not have additive effects on [Ca(2+)](i). Preapplication of L-585 blocked the stimulatory effect of ghrelin on somatotropes. Simultaneous application of ghrelin and L-585 did not cause an additive increase in [Ca(2+)](i). Our results suggest that the actions of ghrelin and synthetic GHS closely parallel each other, in a manner that is consistent with an increase of hormone secretion.     

Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines

This study has examined the expression of two new facets of the growth hormone axis, the growth hormone secretagogue receptor (GHS-R) and its recently identified putative natural ligand ghrelin, in prostate cancer cells. GHS-R 1a and 1b isoforms and ghrelin mRNA expression were detected by RT-PCR in the ALVA-41, LNCaP, DU145 and PC3 prostate cancer cell lines. A normal prostate cDNA library expressed GHS-R1a, but not the 1b isoform or ghrelin. Immunohistochemical staining for the GHS-R 1a isoform and ghrelin was positive in the four cell lines studied. PC3 cells showed increased cell proliferation in vitro in response to ghrelin to levels 33% above untreated controls, implying a potential tumour-promoting role for ghrelin in this tissue. This study is the first to demonstrate the co-expression of the GHS-R and ghrelin in prostate cancer cells. It is also the first study to provide evidence that a previously unrecognised autocrine/paracrine pathway involving ghrelin, that is capable of stimulating growth, exists in prostate cancer.     

Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.     

The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.     

Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer

Employing in vitro selection techniques, we have generated biostable RNA-based compounds, so-called Spiegelmers, that specifically bind n-octanoyl ghrelin, the recently discovered endogenous ligand for the type 1a growth hormone secretagogue (GHS) receptor. Ghrelin is a potent stimulant of growth hormone release, food intake, and adiposity. We demonstrate that our lead compound, L-NOX-B11, binds ghrelin with low-nanomolar affinity and inhibits ghrelin-mediated GHS-receptor activation in cell culture with an IC(50) of 5 nM. l-NOX-B11 is highly specific for the bioactive, n-octanoylated form of ghrelin. Like the GHS receptor, it does not recognize the inactive unmodified peptide and requires only the N-terminal five amino acids for the interaction. The i.v. administration of polyethylene glycol modified l-NOX-B11 efficiently suppresses ghrelin-induced growth hormone release in rats. These results demonstrate that the neutralization of circulating bioactive ghrelin leads to inhibition of ghrelin's secretory effects in the CNS.     

Central and peripheral roles of ghrelin on glucose homeostasis

Ghrelin, an acylated 28-amino-acid peptide, is an endogenous ligand of the growth hormone secretagogue type 1a (GHS-R1a). Ghrelin is best known for its hypothalamic actions on growth hormone-releasing hormone neurons and neuropeptide Y/agouti-related peptide neurons; however, ghrelin affects multiple organ systems and the complexity of its functions is only now being realized. Although ghrelin is mainly produced in the stomach, it is also produced in low levels by the hypothalamus and by most peripheral tissues. GHS-R1a is expressed predominantly in the anterior pituitary gland, at lower levels in the brain including hypothalamic neurons that regulate feeding behavior and glucose sensing, and at even lower levels in the pancreas. A reciprocal relationship exists between ghrelin and insulin, suggesting that ghrelin regulates glucose homeostasis. Ablation of ghrelin in mice increases glucose-induced insulin secretion, and improves peripheral insulin sensitivity. This review focuses on the newly emerging role of ghrelin in glucose homeostasis and exploration of whether ghrelin is a potential therapeutic target for diabetes.