Receptors, Ghrelin

受体,Ghrelin
  • 文章类型: Journal Article
    背景:焦虑症是最常见的精神障碍之一。Ghrelin是调节食物摄取和代谢的关键的促食性脑肠肽。最近,ghrelin系统因其在精神疾病中的关键作用而受到更多关注,包括抑郁和焦虑.然而,所涉及的潜在神经机制尚未得到充分研究.
    方法:在本研究中,研究了正常和急性应激大鼠伏隔核ghrelin信号传导对焦虑样行为的影响和潜在机制,通过使用免疫荧光,qRT-PCR,神经药理学,分子操纵和行为测试。
    结果:我们报道,在NAc核心注射生长素释放肽可引起显著的抗焦虑作用。Ghrelin受体生长激素促分泌素受体(GHSR)在NAc核心神经元中高度定位和表达。GHSR的拮抗作用阻断了生长素释放肽诱导的抗焦虑作用。此外,GHSR诱导的抗焦虑作用的分子敲低。此外,在NAc核心中注射ghrelin或过度表达GHSR可降低急性束缚应激诱导的焦虑作用。
    结论:这项研究表明,NAc核心中的ghrelin及其受体GHSR积极参与调节急性应激引起的焦虑,并通过靶向ghrelin信号系统提供治疗焦虑症的机会。
    BACKGROUND: Anxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated.
    METHODS: In the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests.
    RESULTS: We reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects.
    CONCLUSIONS: This study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system.
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  • 文章类型: Journal Article
    Ghrelin是一种胃源性激素,可增加摄食,并因慢性社会心理压力而升高。ghrelin对摄食的影响是通过ghrelin与生长激素促分泌素受体(GHSR)的结合来介导的,位于下丘脑和下丘脑外区域的受体,对调节食物摄入和代谢率很重要。ghrelin进入大脑的能力,然而,似乎仅限于室外器官,如正中隆起和脑干后区域(AP),而ghrelin不容易进入其他GHSR表达区域,例如腹侧被盖区(VTA)。有趣的是,社会压力导致血脑屏障通透性增加,因此,这可以促进ghrelin进入大脑。为了调查这一点,我们将老鼠暴露在社会失败压力下21天,然后外周注射Cy5标记的生物活性生长素释放肽类似物。结果表明,除ARC外,慢性应激小鼠在几个下丘脑区域表现出更高的Cy5-ghrelin荧光,包括海马和中脑.此外,Cy5-ghrelin注射导致慢性应激小鼠中与奖励系统相关的区域中FOS表达增加。进一步的组织学分析发现,ARC正中隆起接合处下丘脑星形胶质细胞的分支减少,提示血脑屏障通透性增加。这些数据支持这样的假设,即在慢性应激等代谢挑战性疾病中,ghrelin可能更能够穿过血脑屏障并在整个大脑中扩散到远离室外器官的表达GHSR的大脑区域。意义声明Ghrelin是响应于包括压力在内的负能量平衡状态而分泌的,并且与食物摄入和能量平衡的变化有关。ghrelin的受体遍布大脑,但ghrelin似乎仅到达血脑屏障更多孔的室周区域。在本文中,我们证明了慢性社会失败压力会增加对ghrelin的脑通透性,以允许进入和激活在非压力条件下ghrelin无法进入的中脑边缘多巴胺能系统中的目标部位。总的来说,这些结果为ghrelin如何以状态依赖的方式进入中脑边缘多巴胺能系统提供了解释。
    Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extrahypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brainstem area postrema, whereas ghrelin does not readily enter other GHSR-expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood-brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 d and then peripherally injected a Cy5-labelled biologically active ghrelin analog. The results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in chronically stressed mice. Further histologic analyses identified a reduction in the branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood-brain barrier and diffuse throughout the brain to target GHSR-expressing brain regions away from circumventricular organs.
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  • 文章类型: Journal Article
    生长素释放肽受体的潜在作用,也被称为生长激素促分泌素受体(GHSR),在伏隔核(NAcc)中调节药物成瘾和喂养已有文献记载;然而,它在这个网站上的表达模式仍然难以捉摸。在这项研究中,我们表征了GHSR1a和1b的表达模式,GHSR的两种亚型,通过免疫组织化学在大鼠脑的NAcc内。我们在视觉上检测到GHSR信号,第一次,在NAcc中的蛋白质水平上,它们主要在神经元中表达,包括中型多刺神经元(MSN)和非MSN。此外,发现GHSR1a表达为位于细胞膜附近或部分位于细胞质中,而GHSR1b仅在整个大的细胞质区域表达。在这项研究中确定的NAcc中GHSR的存在和亚细胞表达模式将有助于提高我们对GHSR介导的神经信号在摄食和药物成瘾中的作用的理解。
    The potential role of the ghrelin receptor, also known as the growth hormone secretagogue receptor (GHSR), within the nucleus accumbens (NAcc) in regulating drug addiction and feeding has been documented; however, the pattern of its expression in this site remains elusive. In this study, we characterized the expression patterns of GHSR1a and 1b, two subtypes of GHSRs, within the NAcc of the rat brain by immunohistochemistry. We visually detected GHSR signals, for the first time, at the protein level in the NAcc in which they were mostly expressed in neurons including both medium spiny neurons (MSNs) and non-MSNs. Furthermore, GHSR1a was found expressed as localized near the cellular membrane or some in the cytoplasm, whereas GHSR1b expressed solely throughout the large cytoplasmic area. The existence and subcellular expression pattern of GHSRs in the NAcc identified in this study will contribute to improving our understanding about the role of GHSR-mediated neurosignaling in feeding and drug addiction.
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  • 文章类型: Journal Article
    胃源激素ghrelin调节基本生理功能。生长素释放肽受体(GHSR)具有不依赖配体的作用;因此,GHSR基因缺失可能是研究该系统在喂养行为和饮食诱导的肥胖(DIO)中的作用的合理方法。这里,我们研究了长期(12个月)高脂肪(HFD)与常规饮食对全球GHSR-KO和野生型(WT)Wistar雄性和雌性大鼠肥胖相关指标的影响.我们的主要发现是,GHSR基因缺失可以保护雄性大鼠在HFD期间抵抗DIO并减少食物摄入,而不是雌性大鼠。GHSR基因缺失可增加雄性大鼠的产热和脑葡萄糖摄取,并以性别特异性方式改变HFD对脑葡萄糖代谢的影响。如用小动物正电子发射断层扫描评估。我们使用RNA测序显示GHSR-KO大鼠在棕色脂肪组织中上调了负责脂肪氧化的基因表达。新型GHSR反向激动剂的中央管理,PF-5190457,减弱生长素释放肽诱导的食物摄入,但只有男性,不是在雌性老鼠身上。HFD诱导的暴饮暴食可通过两性的反向激动来减少。我们的结果支持GHSR作为肥胖新药物疗法的有希望的靶标。
    The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.
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  • 文章类型: Journal Article
    胰岛β细胞分泌胰岛素是葡萄糖稳态的重要支柱,在肥胖和衰老的情况下受损。生长激素促分泌素受体(GHSR)是营养敏感激素ghrelin的受体。以前,我们表明β细胞GHSR调节年轻小鼠的葡萄糖刺激的胰岛素分泌(GSIS)。在目前的研究中,我们进一步研究了GHSR对饮食诱导的肥胖(DIO)和链脲佐菌素(STZ)诱导的衰老β细胞损伤的雄性小鼠胰岛素分泌的影响。β细胞特异性Ghsr缺陷型(Ghsr-βKO)小鼠在DIO下没有表现出血糖表型,但在衰老中显示出离体GSIS显着改善。我们还检测到体内和离体衰老过程中胰岛素敏感性降低和胰岛素分泌受损。因此,葡萄糖转运蛋白的表达有年龄相关的改变,胰岛素信号通路,和炎症基因。为了进一步确定GHSR缺乏是否影响β细胞对急性损伤的易感性,年轻,中年,和老年Ghsr-βKO小鼠接受STZ。我们发现中年和老年Ghsr-βKO小鼠受到STZ诱导的高血糖和胰岛素分泌受损的保护,与胰岛中胰岛素信号调节因子表达增加相关,但促炎细胞因子降低。总的来说,我们的发现表明,β细胞GHSR对衰老而不是肥胖的胰岛素分泌有重要影响,和GHSR缺乏保护STZ诱导的衰老中的β细胞损伤。
    Insulin secretion from pancreatic β cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that β-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced β-cell injury in aging. β-cell-specific-Ghsr-deficient (Ghsr-βKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected β-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-βKO mice were subjected to STZ. We found that middle-aged and old Ghsr-βKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that β-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced β-cell injury in aging.
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  • 文章类型: Journal Article
    脂肪肝是肝脏对过量饮酒的最早反应。以前我们发现长期饮酒会增加胃源性激素水平,ghrelin,通过降低循环胰岛素水平,最终有助于酒精相关性肝病(ALD)的发展。此外,ghrelin通过增强从头脂肪生成直接促进肝细胞中的脂肪积累。除了推广ALD,众所周知,ghrelin会增加对酒精的渴望和摄入量。在这项研究中,我们使用ghrelin受体(GHSR)敲除(KO)大鼠模型来表征ghrelin在ALD发展中的具体贡献,重点是能量稳态。雄性Wistar野生型(WT)和GHSR-KO大鼠配对喂食Lieber-DeCarli对照或乙醇饮食6周。在喂养期结束时,进行了葡萄糖耐量试验,并收集组织样本。与先前的研究相比,我们观察到GHSR-KO减少了酒精摄入量,其中WT大鼠随意喂食乙醇饮食。Further,当WT成对馈送给GHSR-KO时,KO大鼠通过改善胰岛素分泌/敏感性以减少脂肪分解和肝脏脂肪酸摄取/合成并增加脂肪酸氧化而表现出对发展ALD的抵抗力。此外,蛋白质组学数据显示,与WT大鼠相比,乙醇喂养的KO表现出较少的酒精诱导的线粒体功能障碍和氧化应激。蛋白质组数据还证实,与WT大鼠相比,乙醇喂养的KO是胰岛素敏感的并且对肝性脂肪变性发展具有抗性。一起,这些数据证实,抑制生长素释放肽的作用可预防酒精诱导的肝脏和脂肪功能障碍,而与减少酒精摄入量无关.
    Fatty liver is the earliest response of the liver to excessive alcohol consumption. Previously we identified that chronic alcohol administration increases levels of stomach-derived hormone, ghrelin, which by reducing circulating insulin levels, ultimately contributes to the development of alcohol-associated liver disease (ALD). In addition, ghrelin directly promotes fat accumulation in hepatocytes by enhancing de novo lipogenesis. Other than promoting ALD, ghrelin is known to increase alcohol craving and intake. In this study, we used a ghrelin receptor (GHSR) knockout (KO) rat model to characterize the specific contribution of ghrelin in the development of ALD with emphasis on energy homeostasis. Male Wistar wild type (WT) and GHSR-KO rats were pair-fed the Lieber-DeCarli control or ethanol diet for 6 weeks. At the end of the feeding period, glucose tolerance test was conducted, and tissue samples were collected. We observed reduced alcohol intake by GHSR-KOs compared to a previous study where WT rats were fed ethanol diet ad libitum. Further, when the WTs were pair-fed to GHSR-KOs, the KO rats exhibited resistance to develop ALD through improving insulin secretion/sensitivity to reduce adipose lipolysis and hepatic fatty acid uptake/synthesis and increase fatty acid oxidation. Furthermore, proteomic data revealed that ethanol-fed KO exhibit less alcohol-induced mitochondrial dysfunction and oxidative stress than WT rats. Proteomic data also confirmed that the ethanol-fed KOs are insulin sensitive and are resistant to hepatic steatosis development compared to WT rats. Together, these data confirm that inhibiting ghrelin action prevent alcohol-induced liver and adipose dysfunction independent of reducing alcohol intake.
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  • 文章类型: Journal Article
    颗粒细胞(GCs)的增殖和凋亡影响卵泡发育和生殖障碍,microRNAs发挥着至关重要的调节作用。先前的研究表明miR-128-3p在山羊卵泡发育的不同阶段的差异表达,这表明其在卵泡发育中的潜在调节作用。在这项研究中,通过细胞计数试剂盒-8测定,EDU检测,流式细胞术,定量实时聚合酶链反应,蛋白质印迹,和双荧光素酶报告分析,我们以永生的人卵巢颗粒细胞(KGN)细胞为材料,研究miR-128-3p及其预测的靶基因生长激素促分泌素受体(GHSR)对GC增殖和凋亡的影响。结果表明miR-128-3p过表达抑制KGN细胞增殖,促进细胞凋亡,并抑制增殖细胞核抗原(PCNA)和B细胞淋巴瘤2(BCL2)的表达,同时促进Bcl-2相关X蛋白(BAX)的表达。双荧光素酶报告基因分析显示miR-128-3p与GHSR的3'非翻译区序列结合,导致GHSR蛋白的表达受到抑制。研究GHSR对GC增殖和凋亡的影响,发现GHSR过表达促进PCNA和BCL2的表达,增强GC增殖,抑制细胞凋亡,而当GHSR表达被抑制时,观察到相反的效果。此外,miR-128-3p和GHSR可影响细胞外信号调节激酶1/2蛋白的表达。总之,miR-128-3p通过下调GHSR基因的表达抑制KGN细胞增殖并促进细胞凋亡。
    The proliferation and apoptosis of granulosa cells (GCs) affect follicle development and reproductive disorders, with microRNAs playing a crucial regulatory role. Previous studies have shown the differential expression of miR-128-3p at different stages of goat follicle development, which suggests its potential regulatory role in follicle development. In this study, through the Cell Counting Kit-8 assay, the EDU assay, flow cytometry, quantitative real-time polymerase chain reaction, Western blot, and the dual-luciferase reporter assay, we used immortal human ovarian granulosa tumor cell line (KGN) cells as materials to investigate the effects of miR-128-3p and its predicted target gene growth hormone secretagogue receptor (GHSR) on GC proliferation and apoptosis. The results show that overexpression of miR-128-3p inhibited the proliferation of KGN cells, promoted cell apoptosis, and suppressed the expression of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2 (BCL2) while promoting that of Bcl-2 associated X protein (BAX). The dual-luciferase reporter assay revealed that miR-128-3p bound to the 3\' untranslated region sequence of GHSR, which resulted in the inhibited expression of GHSR protein. Investigation of the effects of GHSR on GC proliferation and apoptosis revealed that GHSR overexpression promoted the expression of PCNA and BCL2, enhanced GC proliferation, and inhibited cell apoptosis, whereas the opposite effects were observed when GHSR expression was inhibited. In addition, miR-128-3p and GHSR can influence the expression of extracellular signal-regulated kinase 1/2 protein. In conclusion, miR-128-3p inhibits KGN cell proliferation and promotes cell apoptosis by downregulating the expression of the GHSR gene.
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  • 文章类型: Journal Article
    肥胖与中枢神经系统(CNS)的慢性炎症有关,神经炎症已被证明对情绪和认知有不利影响。生长激素促分泌素受体(GHSR),促食欲激素ghrelin的生物学相关受体,主要在大脑中表达。我们先前的研究表明,神经元GHSR缺失可预防高脂饮食诱导的肥胖(DIO)。这里,我们研究了神经元GHSR缺失对DIO情绪和认知功能的影响。与DIO下的同窝对照相比,神经元特异性GHSR缺陷型小鼠表现出降低的抑郁和改善的空间记忆。我们进一步检查了大脑皮层和海马,调节认知和情绪行为的主要区域,发现GHSR的神经元缺失通过抑制促炎趋化因子/细胞因子和减少小胶质细胞活化来减少DIO诱导的神经炎症。此外,我们的数据显示,神经元GHSR缺失通过下调神经元中的AMPK-自噬信号传导来抑制神经炎症.总之,我们的数据显示,神经元GHSR抑制保护免受DIO诱导的抑郁样行为和空间认知功能障碍,至少在某种程度上,通过AMPK-自噬信号介导的神经炎症。
    Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.
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  • 文章类型: Journal Article
    用于生物医学研究的非人灵长类动物可能由于各种原因而经历临床上显著的体重减轻。厌食症(完全食欲不振)或缺氧(食欲不振)的发作可导致明显的体重减轻。可能会改变动物福利和科学研究。美国食品和药物管理局已经批准了几种食欲兴奋剂用于国内物种,但目前没有批准用于NHP。NHP中食欲不振和体重减轻的治疗通常依赖于这些化合物的标签外使用。卡莫瑞林是生长素释放肽受体激动剂。作为生长激素促分泌素,卡莫瑞林增加食欲,导致体重增加。在几个物种中的研究表明,卡莫瑞林的给药与体重增加之间存在正相关;2017年,卡莫瑞林的口服溶液获得FDA批准用于狗。我们在健康的成年恒河猴(n=3雄性和3雌性)中测试了该溶液对体重和胰岛素样生长因子-1(IGF-1)的影响。对照组(n=2名男性和2名女性)用于比较。治疗后的猕猴每天口服3mg/kg,持续7d。每天观察临床体征。重量是以前收集的,治疗期间和结束时。之前抽血,在治疗期间和治疗后测量IGF-1水平以及标准血液学和生物化学参数。在开始治疗7d后,与对照组猴子相比,基线调整后的平均体重和IGF-1水平显着升高(体重为10.5±0.1kg(平均值±SEM)和10.1±0.1kg,IGF-1分别为758±43ng/mL和639±22ng/mL,分别)。卡莫瑞林的给药与接受治疗的猕猴的血液学和生化值的明显变化无关。这些发现表明,卡莫瑞林可能对治疗NHP的食欲不振和体重减轻有用,根据血液分析,7天疗程似乎不会引起急性毒性。
    Nonhuman primates used in biomedical research may experience clinically significant weight loss for a variety of reasons. Episodes of anorexia (complete loss of appetite) or hyporexia (decreased appetite) can result in significant weight loss, potentially altering animal welfare and scientific studies. The FDA has approved several appetite stimulants for use in domestic species, but currently none are approved for use in NHP. Treatment of inappetence and weight loss in NHP often relies on the extralabel use of these compounds. Capromorelin is a ghrelin receptor agonist. As a growth hormone secretagogue, capromorelin increases appetite, leading to weight gain. Studies in several species have shown a positive correlation between capromorelin administration and weight gain; in 2017, an oral solution of capromorelin received FDA approval for use in dogs. We tested this solution in healthy adult rhesus macaques (n = 3 males and 3 females) for its effects on body weight and insulin like growth factor-1 (IGF-1). A control group (n = 2 males and 2 females) was used for comparison. Treated macaques received a 3mg/kg oral dose daily for 7 d. Clinical signs were observed daily. Weights were collected before, during and at the end of treatment. Blood was drawn before, during and after treatment for measurement of IGF-1 levels and standard hematology and biochemistry parameters. Baseline-adjusted mean body weights and IGF-1 levels were significantly higher in treated as compared with control monkeys after 7 d of beginning treatment (body weight of 10.5±0.1kg (mean ± SEM) and 10.1±0.1kg, respectively; IGF-1 of 758±43ng/mL and 639±22ng/mL, respectively). Capromorelin administration was not associated with appreciable changes in hematologic and biochemical values in treated macaques. These findings suggest that capromorelin may be useful for treating inappetence and weight loss in NHP, and based on blood analysis, a 7-d course of treatment does not appear to cause acute toxicity.
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  • 文章类型: Journal Article
    脓毒症是由感染引起的炎症反应紊乱状态。免疫系统的激活和调节在脓毒症的发展中起着至关重要的作用。我们先前的研究表明ghrelin可以改善脓毒症的肠功能障碍。关于ghrelin及其受体(GHSR)对肠屏障和巨噬细胞免疫功能的调控机制知之甚少。我们的研究目的是探讨ghrelin/GHSR轴对脓毒症大鼠肠功能障碍和巨噬细胞极化的调控作用及其分子机制。采用盲肠结扎穿刺术(CLP)建立脓毒症大鼠模型。然后,用生长素释放肽受体激动剂(TZP-101)或生长素释放肽抑制剂(obestatin)治疗脓毒症大鼠.结果表明,TZP-101进一步增强了脓毒症大鼠结肠和脾脏中ghrelin和GHSR的表达,结果相反。Ghrelin/GHSR轴改善脓毒症大鼠结肠结构破坏和肠上皮紧密连接损伤。此外,ghrelin/GHSR轴促进巨噬细胞M2型极化,其特征是IL-1β的减少,IL-6和TNF-α,以及IL-10的增加。机械上,ghrelin/GHSR轴促进脓毒症大鼠E2F2表达,抑制NF-κB信号通路的激活。总的来说,脓毒症期间靶向ghrelin/GHSR可能是治疗肠屏障损伤的一种新的治疗方法。
    Sepsis is an inflammatory reaction disorder state that is induced by infection. The activation and regulation of the immune system play an essential role in the development of sepsis. Our previous studies have shown that ghrelin ameliorates intestinal dysfunction in sepsis. Very little is known about the mechanism of ghrelin and its receptor (GHSR) on the intestinal barrier and the immune function of macrophage regulation. Our research is to investigate the regulatory effect and molecular mechanism of the ghrelin/GHSR axis on intestinal dysfunction and macrophage polarization in septic rats. A rat model of sepsis was established by cecal ligation and puncture (CLP) operation. Then, the sepsis rats were treated with a ghrelin receptor agonist (TZP-101) or ghrelin inhibitor (obestatin). The results suggested that TZP-101 further enhanced ghrelin and GHSR expressions in the colon and spleen of septic rats and obestatin showed the opposite results. Ghrelin/GHSR axis ameliorated colonic structural destruction and intestinal epithelial tight junction injury in septic rats. In addition, the ghrelin/GHSR axis promoted M2-type polarization of macrophages, which was characterized by the decreases of IL-1β, IL-6, and TNF-α, as well as the increase of IL-10. Mechanistically, the ghrelin/GHSR axis promoted E2F2 expression and suppressed the activation of the NF-κB signaling pathway in septic rats. Collectively, targeting ghrelin/GHSR during sepsis may represent a novel therapeutic approach for the treatment of intestinal barrier injury.
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