肿瘤坏死因子-α通过内皮型一氧化氮合酶和小凹蛋白-1介导内皮细胞功能失调的研究

血管内皮细胞功能失调是致动脉粥样硬化形成的重要机制之一。其中,内皮型一氧化氮合酶和小凹蛋白-1是调节脂质物质摄取和炎症细胞跨内皮迁移的重要蛋白。肿瘤坏死因子-α为多效性促炎症反应细胞因子,可通过核因子-κB信号通路下调内皮型一氧化氮合酶表达,上调小凹蛋白-1表达,诱导内皮细胞胞吞转运作用失衡和炎症细胞跨内皮迁移,促使局部血管斑块形成。现就肿瘤坏死因子-α通过核因子-κB信号通路诱导血管内皮功能失调的机制做一简要综述。     

Ghrelin和糖尿病

Ghrelin是近年来发现的一种内源性生长激素促分泌剂受体的配体.大量研究已证实,ghrelin不仅能促进生长激素的分泌,而且还具有增加体重及调节能量代谢的作用.新近研究发现,ghrelin与胰岛素及糖脂代谢密切相关,低ghrelin水平可以作为2型糖尿病和糖耐量减低的一个危险因子,并且ghrelin还参与炎症及免疫应答的调节.     

Ghrelin对脓毒症小鼠肺脏炎症及JAK/STAT通路的影响

目的 通过观察生长素释放肽(ghrelin)对脓毒症小鼠肺组织炎症反应、肺组织janus激酶/信号转导通路和转录激活因子mRNA、STAT3蛋白及肺组织炎细胞因子肿瘤细胞α(TNF-α)、IL-6的表达水平的影响,探讨ghrelin在脓毒症炎症反应中的调节作用及可能的分子机制.方法 选用腹腔注射脂多糖的方法制作小鼠脓毒性模型:选取雌性小鼠54只,随机分为对照组、模型组及ghrelin干预组,对照组经腹腔注射等量生理盐水;模型组经腹腔内注射脂多糖(6 mg/kg);干预组先经腹腔注射ghrelin(200 μg/kg),30 min后再经腹腔注射脂多糖(6 mg/kg);各组分别于3、9、18h随机处死小鼠各6只,光镜下观察肺组织炎症改变;反转录聚合酶链反应(RT-PCR)法检查肺组织STAT3mRNA的基因转录水平;酶联免疫吸附测定(ELISA)法测定肺组织STAT3、TNF-α、IL-6的表达量.结果 Ghrelin可抑制肺组织STAT3mRNA基因转录活性,从而降低STAT3蛋白表达、减少炎症因子TNF-α、IL-6的分泌(P值均＜0.05);改善脓毒症小鼠肺组织病理结构损伤(充血、水肿、炎症细胞浸润).结论 ghrelin可减轻脓毒症小鼠肺脏炎症反应,其作用机制可能与抑制了janus激酶/信号转导和转录激活因子(JAK/STAT通路)、下调TNF-α和IL-6的表达有关.     

核因子-κB抑制蛋白在动脉粥样硬化中的作用及其中医药研究进展

动脉粥样硬化(AS)的发病机制涉及多种学说,炎症学说是AS发病机制中的重要学说。核因子-κB(NF-κB)是炎症反应中的主要转录因子,参与炎症细胞凋亡和细胞增殖的基因调控。NF-κB抑制蛋白通过调节NF-κB信号通路的活动,调控炎症因子的表达,在AS的发生、发展过程中发挥重要的作用。现探究中医药通过调控NF-κB信号通路干预治疗AS的作用机制,以期为中医药治疗动脉粥样硬化提供更多的思路。     

转录因子T-bet与支气管哮喘

转录因子T bet可以调节T辅助细胞 1(TH1 )和T辅助细胞 2(TH2 )的平衡。TH1 /TH2水平降低,是哮喘发病的重要机制之一。本文就T bet调节TH1 /TH2平衡,以及调节TH1细胞释放的相关细胞因子,从而调节哮喘的炎症反应作一综述。     

NF-κB与炎症性肠病

NF-κB是一类重要的转录调节因子,调控免疫反应和炎症反应中多种蛋白的基因转录。NF-κB的活化及其对基因转录的调节与炎症性肠病的发病机制和治疗关系密切。     

NF—κB与炎症性肠病

NF-κB是一类重要的转录调节因子，调控免疫反应和炎症反应中多种蛋白的基因特录。NF—κB的活化及其对基因特录的调节与炎症性肠病的发病机制和治疗关系密切。     

MIF介导ox-LDL对内皮细胞功能的影响及作用机制

目的 探讨巨噬细胞迁移抑制因子（MIF）介导氧化型低密度脂蛋白（ox-LDL）对血管内皮细胞功能的影响及其作用机制。方法 人脐静脉内皮细胞（HUVECS），给予ox-LDL(100 nmol/L)处理，蛋白免疫电泳检测相关蛋白的表达及功能；实时定量PCR监测炎症相关因子的表达；药物阻断和基因干预关键分子观察对下游基因的表达的影响；Griess反应检测在干预措施下内皮细胞一氧化氮（NO）的产生情况；体外用乙酰胆碱诱导的血管舒张反应作为评估内皮依赖性血管舒张功能的指标检测内皮细胞功能。结果 ox-LDL能增加内皮细胞胆固醇调节元件结合蛋白（SREBP2）和MIF的表达，应用药物特异性阻断以及siRNA抑制MIF的表达均可显著降低SREBP2的表达和激活（P<0.05）；离体实验证实MIF通过SREBP2抑制血管内皮细胞功能（P<0.05）。结论 ox-LDL等氧化应激刺激能通过MIF增加SREBP2介导的炎症小体（inflammasome）的表达和炎症相关内皮细胞表面黏附分子的表达，从而破坏内皮细胞功能，这可能是动脉粥样硬化（AS）发生发展的重要机制之一。     

ghrelin调控神经生长因子信号途径介导心肌梗死后神经重构

目的ghrelin是最近在胃中分离出来的生长激素释放肽受体的内源性配体,在心血管系统显示出了保护效应。本实验探讨了ghrelin对心肌梗死（MI）后大鼠神经重构的影响及其作用机制。方法sD大鼠结扎冠状动脉制作MI模型作为对照组,干预组在手术后第1天开始给予ghrelin皮下注射,剂量为100μg／kg,每天两次。对照组开胸后在冠状动脉下穿线,但不结扎,给予盐水作皮下注射。经过4个星期治疗后,处死动物。检测梗死区及梗死边缘区神经生长因子,神经纤维标志物以及炎症介质的表达,同时用蛋白免疫印迹法检测了核因子KB（NF-KB）蛋白的表达。结果与对照组相比,ghrelin注射明显减少了梗死区及梗死周边区神经纤维标记物生长相关蛋白43（GAP43）及酪氨酸羟化酶（TH）的阳性表达,同时减少了神经生长因子（NGF）的mRNA及蛋白表达。ghrelin还抑制了炎症因子白细胞介素-1β（IL-1β）,肿瘤细胞生长因子-α[（TNF-α）以及内皮素-1（ET-1）的mRNA表达,而且非梗死区ET-1mRNA表达与NGF蛋白含量成正相关。ghrelin治疗组梗死边缘区NF-KB活性较对照组明显降低。结论Ghrelin干预能够抑制大鼠MI后神经增生,炎症因子及NGF信号途径可能参与其中。     

急性坏死性胰腺炎大鼠Ghrelin表达的变化及GHRP-2对其的影响

重症急性胰腺炎（server acute pancreatitis,SAP）患者早期病情变化迅速、病死率高,虽然近年SAP的治疗手段有很大进步,但寻找早期干预疾病进程、减少疾病重症化仍是本领域的研究热点之一.生长激素释放肽-2（growthhormone releasing peptides,GHRP-2）是ghrelin受体激动剂,它可以减轻肝脏炎症、急性肺损伤,而且外源性ghrelin对急性胰腺炎（acute pancreatitis,AP）的炎症反应有抑制作用,但内源性ghrelin与AP发病机制的关系未明确.本研究观察GHRP-2干预急性坏死性胰腺炎（acute necrotizing pancreatitis,ANP）大鼠后内源性ghrelin表达的变化.     

Ghrelin treatment suppresses neutrophil-dominant inflammation in airways of patients with chronic respiratory infection

BACKGROUND: Persistent neutrophil influx into the airways is a characteristic of chronic respiratory infection and contributes to the deterioration of pulmonary function. Ghrelin is a novel growth hormone (GH)-releasing peptide with potential anti-inflammatory activities. The present study investigated whether or not ghrelin can reduce neutrophil-dominant inflammation in airways of patients with chronic respiratory infection. POPULATIONS AND METHODS: Synthesized ghrelin was administered intravenously for 3 weeks to 7 cachectic patients with chronic respiratory infection to confirm ghrelin's effects on airway inflammation and nutrition state. Neutrophils, neutrophil products and inflammatory cytokines in sputum were used as markers of airway inflammation. Changes in serum protein levels were also evaluated along with plasma catecholamine levels. Exercise tolerance was assessed by measuring 6-min walking distance before and after 3 weeks of ghrelin treatment. RESULTS: Three-week ghrelin administration decreased neutrophil density and inflammatory cytokine levels in sputum, reduced plasma norepinephrine level, and increased body weight, serum protein level, and 6-min walking distance. CONCLUSIONS: Ghrelin administration suppressed airway inflammation by decreasing neutrophil accumulation in lungs and increased body weight. These findings may contribute to the development of supportive therapies for patients with refractory chronic respiratory infection.     

The effects of ghrelin on inflammation and the immune system

A number of hormones and metabolic mediators signal the brain of changes in the body's energy status and when an imbalance occurs; the brain coordinates the appropriate changes in energy intake and utilization via the control of appetite and food consumption. Under conditions of chronic inflammation and immune activation, there is often a significant loss of body mass and appetite suggesting the presence of shared ligands and signaling pathways mediating "crosstalk" between the immune and neuroendocrine systems. Ghrelin, the endogenous ligand for growth hormone secretagogue receptor (GHS-R), is produced primarily by cells in the stomach and serves as a potent circulating orexigenic hormone controlling food intake, energy expenditure, adiposity and GH secretion. The functional roles of ghrelin and other growth hormone secretagogues (GHS) within the immune system and under states of inflammatory stress and injury are only now coming to light. A number of reports over the past decade have described ghrelin to be a potent anti-inflammatory mediator both in vitro and in vivo and a promising therapeutic agent in the treatment of inflammatory diseases and injury. Moreover, ghrelin has also been shown to promote lymphocyte development in the primary lymphoid organs (bone marrow and thymus) and to ablate age-associated thymic involution. In the current report, we review the literature supporting a role for ghrelin as an anti-inflammatory agent and immunoregulatory hormone/cytokine and its potential use in the treatment of inflammatory diseases and injury.     

Hypothalamic ghrelin treatment modulates NPY-but not CRH-ergic activity in adrenalectomized rats subjected to food restriction: Evidence of a novel hypothalamic ghrelin effect

It has been proposed that ghrelin induces food intake by a mechanism due to the stimulation of hypothalamic NPY-ergic activity. It is recognized that bilateral adrenalectomy (ADX) enhances hypothalamic CRH-ergic function and reduces appetite. Thus, the aim of the present study was to test whether, icv-administered, ghrelin modulates NPY- and CRH-ergic functions after food restriction (FR) and glucocorticoid deprivation. For this purpose; 1 μg ghrelin was administered icv to ad libitum (AL) eating and to corticosterone (B)-depleted (ADX) and- replete (sham and ADX+B) male animals habituated, for 15 d, to FR. Food intake, hypothalamic function, and peripheral ghrelin, ACTH, and B concentrations were evaluated 2 h after ghrelin administration. Results indicate that while icv ghrelin treatment stimulated 2-h food intake in AL rats, it failed to do so in sham- and ADX+B-FR animals; moreover, 2-h food intake was inhibited by icv ghrelin treatment in ADX-FR rats. Regarding peripheral hormone levels: (a) basal circulating ghrelin levels, already enhanced (vs AL rats) by FR, significantly increased 2 h after icv ghrelin treatment in AL and sham-FR rats; (b) central ghrelin treatment stimulated ACTH secretion in circulation of AL and glucocorticoid-replete-FR rats; and (c) B circulating levels remained unchanged after ghrelin treatment, although they were in relation to the food intake condition of rats. Finally, hypothalamic NPY mRNA expression was enhanced by FR and, in response to icv ghrelin treatment, it decreased in ADX-FR rats only. ADX-enhanced hypothalamic CRH mRNA levels were reduced by ghrelin icv administration only when antimals received B replacement therapy. Our data indicate an inhibitory effect of hypothalamic ghrelin on NPY-ergic activity in FR rats lacking endogenous glucocorticoid.     

Expression,regulation and biological actions of growth hormone (GH) and ghrelin in the immune system

Immune and neuroendocrine systems have bidirectional communications. Growth hormone (GH) and an orexigenic hormone ghrelin are expressed in various immune cells such as T lymphocytes, B lymphocytes, monocytes and neutrophils. These immune cells also bear receptors for hormones: growth hormone receptor (GHR) for GH and growth hormone secretagogue receptor (GHS-R) for ghrelin. The expression of GH in immune cells is stimulated by ghrelin as in anterior pituitary cells, whereas the regulation of GH secretion in the immune system by other peptides seems to be different from that in the anterior pituitary gland. Cytokines and mitogens enhance GH secretion from immune cells. GH has several biological actions in the immune system: enhancing thymopoiesis and T cell development, modulating cytokine production, enhancing B cell development and antibody production, priming neutrophils and monocytes for superoxide anion secretion, enhancing neutrophil adhesion and monocyte migration and anti-apoptotic action. Biological actions of ghrelin include attenuation of septic shock and anti-inflammatory actions, modulating phagocytosis, and enhancing thymopoiesis. The effect of ghrelin may be direct or through GH production, and that of GH may be direct or through insulin like growth factor-I (IGF-I) production. Elucidation of the roles of GH and ghrelin in the immune system may shed light on the treatment and prevention of immunological disorders such as AIDS and organ damages due to obesity/ageing-related chronic inflammation.     

Therapeutic action of ghrelin in a mouse model of colitis

BACKGROUND & AIMS: Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. METHODS: We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. RESULTS: Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. CONCLUSIONS: Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.     

Endocrine impact of Helicobacter pylori: focus on ghrelin and ghrelin o-acyltransferase

Ghrelin is predominantly produced by the gastric enteroendocrine cell compartment and is octanoylated by the recently discovered ghrelin o-acyltransferase (GOAT) before secretion into the bloodstream. This octanoylation is essential for many of the biological properties of ghrelin including appetite stimulation and anti-inflammatory properties as only the acylated form of ghrelin binds to the ghrelin receptor, the growth hormone secretagogue receptor (GHS-R). Given the gastric location of ghrelin production...     

Malignant gastric ghrelinoma with hyperghrelinemia

A characteristic feature of neuroendocrine tumors is production and release of peptide hormone. Ghrelin is a 28-amino acid hormone that stimulates GH release. In this paper, we describe a patient with a metastasizing gastric neuroendocrine tumor displaying intense immunoreactivity for ghrelin and extremely high circulating levels of ghrelin.Tumor tissue biopsies from the primary tumor and one liver metastasis were examined by immunohistochemistry. Ghrelin and several other hormones and tumor markers were measured in blood. The clinical course of the patient was followed.Tumor tissue biopsies showed immunoreactivity for cytokeratin, chromogranin A, human synaptic vesicle protein 2, synaptophysin, and ghrelin. Grossly elevated circulating levels of total ghrelin, 2100 microg/liter (reference interval < 5 microg/liter) and active ghrelin, 28 microg/liter (reference interval < 0.1 microg/liter) were found at presentation. Chromogranin A, chromogranin B, and calcitonin levels were also increased. Both total and active ghrelin increased, despite treatment, during follow-up of the patient.We have identified and characterized a patient with a malignant gastric neuroendocrine tumor secreting ghrelin as the main hormone. This might be a new tumor entity of the stomach, and it is suggested that patients with malignant gastric neuroendocrine tumors should be investigated for ghrelin production.     

Hormonal protection in acute pancreatitis by ghrelin,leptin and melatonin

Acute pancreatitis is a nonbacterial disease of the pancreas.The severe form of this ailment is characterized by high mortality.Whether acute pancreatitis develops as the severe type or resolves depends on the intensity of the inflammatory process which is counteracted by the recruitment of innate defense mechanisms.It has been shown that the hormones ghrelin,leptin and melatonin are able to modulate the immune function of the organism and to protect the pancreas against inflammatory damage.Experimental studies have demonstrated that the application of these substances prior to the induction of acute pancreatitis significantly attenuated the intensity of the inflammation and reduced pancreatic tissue damage.The pancreatic protective mechanisms of the above hormones have been related to the mobilization of non-specific immune defense,to the inhibition of nuclear factor kappa B and modulation of cytokine production,to the stimulation of heat shock proteins and changes of apoptotic processes in the acinar cells,as well as to the activation of antioxidant system of the pancreatic tissue.The protective effect ofghrelin seems to be indirect and perhaps dependent on the release of growth hormone and insulin-like growth factor 1.Leptin and ghrelin,but not melatonin,employ sensory nerves in their beneficial action on acute pancreatitis.It is very likely that ghrelin,leptin and melatonin could be implicated in the natural protection of the pancreatic gland against inflammatory damage because the blood levels of these substances increase in the initial phase of pancreatic inflammation.The above hormones could be a part of the innate resistance system which might remove noxious factors and could suppress or attenuate the inflammatory process in the pancreas.     

From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion

Growth hormone (GH)-releasing hormone and somatostatin modulate GH secretion. A third mechanism has been discovered in the last decade, involving the action of GH secretagogues. Ghrelin is a new acylated peptide produced mainly by the stomach, but also synthesized in the hypothalamus. This compound increases both GH release and food intake. The relative roles of hypothalamic and circulating ghrelin on GH secretion are still unknown. Endogenous ghrelin might amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GH-releasing hormone. This peptide activates multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, as ghrelin induces a greater release of GH in vivo, its main site of action is the hypothalamus. In this paper we review the available data on the discovery of ghrelin, the mechanisms of action and possible physiological roles of GH secretagogues and ghrelin on GH secretion, and, finally, the regulation of GH release in man after intravenous administration of these peptides.     

Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and hypertension in a random sample of middle-aged subjects

AIMS/HYPOTHESIS: Experimental studies have suggested that ghrelin, a novel gastrointestinal peptide hormone, could play a role in glucose homeostasis. In addition, ghrelin has been associated with beneficial haemodynamic effects in experimental settings. Since the Arg51Gln mutation changes the carboxyterminal amino acid of the mature hormone and is associated with low ghrelin concentrations, we assessed the hypothesis that Arg51Gln mutation is a risk factor for Type 2 diabetes, impaired glucose tolerance, and hypertension. METHODS: Blood pressure recordings and oral glucose tolerance test were carried out in the hypertensive ( n=519) and control cohorts ( n=526) of our well-defined OPERA study. The genotypes and plasma IGF-I and IGFBP-1 concentrations of 1031 subjects were analysed. RESULTS: The ghrelin 51Gln allele was a risk factor for Type 2 diabetes, and the effect remained significant after adjustment for age, BMI, and study group (OR=2.53, CI: 1.11-5.75, p=0.027). In addition, the 51Gln allele was a risk factor for hypertension (OR=2.63, CI: 1.37-5.08, p=0.003). 51Gln carriers had lower concentrations of IGF-I and higher concentrations of IGFBP-1 compared to non-carriers. CONCLUSION/INTERPRETATION: The ghrelin 51Gln allele could increase the risk for Type 2 diabetes and hypertension. The low IGF-I concentrations in 51Gln carriers suggest that the mechanism might be associated with low GH concentrations.