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The neuro-incretin concept 神经促肠素的概念
Pub Date : 2014-11-01 DOI: 10.1016/j.regpep.2014.09.003
Bo Ahrén
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引用次数: 4
Insulin-like growth factor-1 inhibits colonic smooth muscle cell apoptosis in diabetic rats with colonic dysmotility 胰岛素样生长因子-1抑制糖尿病大鼠结肠平滑肌细胞凋亡
Pub Date : 2014-11-01 DOI: 10.1016/j.regpep.2014.11.005
Manyi Sun , Feng Wang , Ping Feng

Cellular apoptosis and colonic dysmotility are involved in diabetes mellitus (DM) complications. Insulin-like growth factor-1 (IGF-1) is known to affect apoptosis and proliferation. Here, we demonstrated that the treatment of 1500 ng/kg IGF-1 partly recovers the decrease of the muscle thickness, body weight and gastrointestinal transit rate in DM rats. The gastrointestinal transit rate is positively correlated with the IGF-I level, but negatively correlated with the level of colonic cellular apoptosis. The DM-induced colonic apoptosis is also attenuated by the IGF-1 stimulation. Moreover, IGF-1 inhibits the apoptosis of the isolated colonic SMCs in vitro via the activation of PI3K/Akt and ERK1/2 signaling pathways. Taken together, our data indicated that IGF-1 inhibits the DM-induced colonic SMC apoptosis and might be involved in the alleviation of colonic dysmotility in diabetic rats.

细胞凋亡和结肠运动障碍与糖尿病(DM)并发症有关。已知胰岛素样生长因子-1 (IGF-1)影响细胞凋亡和增殖。本研究表明,1500 ng/kg IGF-1处理可部分恢复DM大鼠肌肉厚度、体重和胃肠道转运率的下降。胃肠道转运率与IGF-I水平呈正相关,而与结肠细胞凋亡水平负相关。dm诱导的结肠细胞凋亡也可因IGF-1刺激而减弱。此外,IGF-1通过激活PI3K/Akt和ERK1/2信号通路抑制离体结肠SMCs的凋亡。综上所述,我们的数据表明IGF-1抑制dm诱导的结肠SMC凋亡,并可能参与缓解糖尿病大鼠结肠运动障碍。
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引用次数: 4
Expression and release of progalanin in fibroblasts 原丙氨酸在成纤维细胞中的表达和释放
Pub Date : 2014-11-01 DOI: 10.1016/j.regpep.2014.09.004
Hiroyuki Yamamoto , Kazuaki Iguchi , Keiko Unno , Kazuhiko Kaji , Minoru Hoshino

Galanin is a neuropeptide expressed in the central and peripheral nervous systems. Galanin is known to be biosynthesized in neural and endocrine cells, but little evidence exists for its synthesis in other cells. In this study, we explored galanin-releasing nonneural cells using radioimmunoassay, finding that some fibroblasts produced and released the galanin-like immunoreactive component (galanin-LI). The molecular weight of the galanin-LI obtained from the fibroblasts, as measured by gel filtration chromatography and Western blotting, was 14 kDa and suggested that the compound was progalanin. Peptide mass fingerprinting analysis identified the large form of galanin-LI as progalanin without its signal sequence. In addition, galanin-LI was located in the Golgi bodies and vesicle-like structures of the fibroblasts. Furthermore, the addition of brefeldin A, an inhibitor of transport from the ER, decreased the release of galanin-LI. In this study, we showed that the fibroblast, a nonneural and nonendocrine cell type, produced and released a galanin precursor, progalanin, without processing via Golgi bodies or secretory vesicles.

甘丙肽是一种在中枢和周围神经系统中表达的神经肽。已知甘丙肽在神经细胞和内分泌细胞中生物合成,但在其他细胞中合成的证据很少。在这项研究中,我们使用放射免疫分析法探索了释放甘丙肽的非神经细胞,发现一些成纤维细胞产生并释放甘丙肽样免疫反应成分(galanin-LI)。通过凝胶过滤层析和Western blotting测定,从成纤维细胞中获得的丙氨酸- li的分子量为14 kDa,表明该化合物为原丙氨酸。肽质量指纹图谱分析鉴定大形态的丙氨酸- li为原丙氨酸,没有其信号序列。此外,甘丙肽li位于成纤维细胞的高尔基体和囊泡样结构中。此外,brefeldin A(一种内质网转运抑制剂)的加入减少了丙氨酸- li的释放。在这项研究中,我们发现成纤维细胞,一种非神经和非内分泌的细胞类型,产生并释放一种丙氨酸前体,原丙氨酸,而不经过高尔基体或分泌囊泡加工。
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引用次数: 7
Mediators involved in the hyperthermic action of neuromedin U in rats 参与大鼠神经质素U热作用的介质
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.07.004
G. Telegdy , A. Adamik

Neuromedin U (NmU), first was isolated from the porcine spinal cord, has subsequently been demonstrated in a number of species, in which it is present in the periphery and also the brain. Two receptors have been identified: NmU1R is mainly present in peripheral tissues, and Nmu2R in the central nervous system. NmU, a potent endogenous anorectic, serves as a catabolic signaling molecule in the brain; it inhibits food uptake, increases locomotion, activates stress mechanism, having cardiovasscular effects and, causes hyperthermia. The mechanism of this hyperthermia is unknown. In the present experiments, the effects of NmU on the colon temperature following i.c.v administration were studied in rats. For an investigation of the possible role of receptors in mediating hyperthermia, the animals were treated simultaneously with CRF 9–41 and antalarmin, a CRH1 receptor inhibitors, astressin 2B, a CRH2 receptor antagonist, haloperidol a dopamine receptor antagonist, atropine a muscarinic cholinergic receptor antagonist, noraminophenazone a cyclooxygenase inhibitor or isatin, a prostaglandin receptor antagonist.

NmU increased the colon temperature, maximal action being observed at 2–3 h. CRF 9–41, antalarmin, astressin 2B haloperidol, atropine, noraminophenazone and isatin prevented the NmU-induced increase in colon temperature.

The results demonstrated that, when injected into the lateral brain ventricle NmU increased the body temperature, mediated by CRHR1 and CRHR2, dopamine and muscarinic cholinergic receptors. The final pathway involves prostaglandin.

神经质蛋白U (NmU)首先从猪脊髓中分离出来,随后在许多物种中被证明存在于外周和大脑中。目前已鉴定出两种受体:NmU1R主要存在于外周组织,而Nmu2R主要存在于中枢神经系统。NmU是一种有效的内源性厌食药,在大脑中作为分解代谢信号分子;它抑制食物摄取,增加运动,激活应激机制,对心血管有影响,并引起体温过高。这种热疗的机制尚不清楚。本实验研究了NmU对大鼠体外灌胃后结肠温度的影响。为了研究受体在介导高温中的可能作用,动物同时接受CRF 9-41和antalarmin(一种CRH1受体抑制剂)、astrressin 2B(一种CRH2受体拮抗剂)、haloperidol(一种多巴胺受体拮抗剂)、atropine(一种毒碱胆碱能受体拮抗剂)、noraminophenazone(一种环氧化酶抑制剂)或isatin(一种前列腺素受体拮抗剂)治疗。NmU使结肠温度升高,在2-3 h时达到最大作用。CRF 9-41、安talarmin、应激素2B氟哌啶醇、阿托品、去甲氨基那酮和isatin阻止了NmU引起的结肠温度升高。结果表明,注入侧脑室后,NmU通过CRHR1和CRHR2、多巴胺和毒蕈碱胆碱能受体介导升高体温。最后一条途径涉及前列腺素。
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引用次数: 4
The ghrelin–GHSR-1a system in the ocular neuro-humoral regulation. Pearls and controversies ghrelin-GHSR-1a系统在眼神经-体液调节中的作用。珍珠与争议
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.06.001
Amândio Rocha-Sousa
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引用次数: 0
Ghrelin and its receptor: The role of the ghrelin signaling system in regulating cardiac function 胃饥饿素及其受体:胃饥饿素信号系统在调节心功能中的作用
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.08.004
Takeshi Soeki
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引用次数: 2
Natriuretic peptides and cerebral hemodynamics 利钠肽与脑血流动力学
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.07.003
Song Guo , Filippa Barringer , Nora E. Zois , Jens P. Goetze , Messoud Ashina

Natriuretic peptides have emerged as important diagnostic and prognostic tools for cardiovascular disease. Plasma measurement of the bioactive peptides as well as precursor-derived fragments is a sensitive tool in assessing heart failure. In heart failure, the peptides are used as treatment in decompensated disease. In contrast, their biological effects on the cerebral hemodynamics are poorly understood. In this mini-review, we summarize the hemodynamic effects of the natriuretic peptides with a focus on the cerebral hemodynamics. In addition, we will discuss its potential implications in diseases where alteration of the cerebral hemodynamics plays a role such as migraine and acute brain injury including stroke. We conclude that a possible role of the peptides is feasible as evaluated from animal and in vitro studies, but more research is needed in humans to determine the precise response on cerebral vessels.

利钠肽已成为心血管疾病的重要诊断和预后工具。血浆测量生物活性肽以及前体衍生片段是评估心力衰竭的敏感工具。在心力衰竭中,肽被用作代偿性疾病的治疗。相反,它们对脑血流动力学的生物学作用却知之甚少。在这篇综述中,我们总结了利钠肽的血流动力学作用,重点是脑血流动力学。此外,我们将讨论其在脑血流动力学改变起作用的疾病中的潜在意义,如偏头痛和急性脑损伤包括中风。我们的结论是,从动物和体外研究中评估,肽的可能作用是可行的,但需要更多的研究来确定人类对脑血管的确切反应。
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引用次数: 11
Islet neogenesis-associated protein (INGAP): The role of its endogenous production as a positive modulator of insulin secretion 胰岛新生相关蛋白(INGAP):其内源性生产作为胰岛素分泌的积极调节剂的作用
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.08.003
Luis E. Flores , Héctor Del Zotto , Florencia Fragapane , Bárbara Maiztegui , Carolina L. Román , Antonio C. Boschero , Juan J. Gagliardino

Islet neogenesis-associated protein (INGAP) is a peptide found in pancreatic exocrine-, duct- and islet- non-β-cells from normal hamsters. Its increase induced by either its exogenous administration or by the overexpression of its gene enhances β-cell secretory function and increases β-cell mass by a combination of stimulation of cell replication and islet neogenesis and reduction of β-cell apoptosis. We studied the potential modulatory role of endogenous INGAP in insulin secretion using two different experimental approaches. Hamster islets transfected with INGAP-small interfering RNA (INGAP-siRNA) were used to study glucose-stimulated insulin secretion (GSIS). In parallel, freshly isolated islets were incubated with high glucose and the same concentration of either a specific anti-INGAP rabbit serum or normal rabbit serum. INGAP-siRNA transfected islets reduced their INGAP mRNA and protein content by 35.1% and 47.2%, respectively whereas GSIS decreased by 25.8%. GSIS by transfected islets attained levels comparable to those recorded in control islets when INGAP pentadecapeptide (INGAP-PP) was added to the culture medium. INGAP antibody in the medium decreased significantly GSIS in a dose-dependent manner. These results indicate that endogenous INGAP plays a “physiological” positive modulatory role in insulin secretion, supporting its possible use in the treatment of prediabetes and Type 2 diabetes.

胰岛新生相关蛋白(INGAP)是一种存在于正常仓鼠胰腺外分泌、胰岛导管和胰岛非β细胞中的肽。通过外源性给药或其基因的过度表达诱导其增加,通过刺激细胞复制和胰岛新生以及减少β细胞凋亡,增强β细胞分泌功能并增加β细胞质量。我们使用两种不同的实验方法研究了内源性INGAP在胰岛素分泌中的潜在调节作用。用转染ingap -小干扰RNA (INGAP-siRNA)的仓鼠胰岛研究葡萄糖刺激胰岛素分泌(GSIS)。同时,新鲜分离的胰岛用高葡萄糖和相同浓度的抗ingap兔血清或正常兔血清孵育。转染INGAP- sirna的胰岛INGAP mRNA和蛋白含量分别降低了35.1%和47.2%,而GSIS则降低了25.8%。当向培养基中添加INGAP五肽(INGAP- pp)时,转染胰岛的GSIS达到与对照胰岛相当的水平。培养基中的INGAP抗体呈剂量依赖性显著降低GSIS。这些结果表明,内源性INGAP对胰岛素分泌具有“生理性”正向调节作用,支持其在治疗前驱糖尿病和2型糖尿病中的可能应用。
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引用次数: 5
Dual effects of carnosine on energy metabolism of cultured cortical astrocytes under normal and ischemic conditions 肌肽对培养皮层星形胶质细胞正常和缺血状态下能量代谢的双重影响
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.08.005
Yao Shen, Yueyang Tian, Jianbo Yang, Xiaojie Shi, Li Ouyang, Jieqiong Gao, Jianxin Lu

Objective

The aim of this study was to investigate the effects of carnosine on the bioenergetic profile of cultured cortical astrocytes under normal and ischemic conditions.

Methods

The Seahorse Bioscience XF96 Extracellular Flux Analyzer was used to measure the oxygen consumption rates (OCRs) and extracellular acidification rates (ECARs) of cultured cortical astrocytes treated with and without carnosine under normal and ischemic conditions.

Results

Under the normal growth condition, the basal OCRs and ECARs of astrocytes were 21.72 ± 1.59 pmol/min/μg protein and 3.95 ± 0.28 mpH/min/μg protein respectively. Mitochondrial respiration accounted for ~ 80% of the total cellular respiration and 85% of this coupled to ATP synthesis. Carnosine significantly reduced basal OCRs and ECARs and ATP-linked respiration, but it strikingly increased the spare respiratory capacity of astrocytes. The cellular ATP level in carnosine-treated astrocytes was reduced to ~ 42% of the control. However, under the ischemic condition, carnosine upregulated the mitochondrial respiratory and cellular ATP content of astrocytes exposed to 8 h of oxygen–glucose deprivation (OGD) followed by 24 h of recovery under the normal growth condition.

Conclusions

Carnosine may be an endogenous regulator of astrocyte energy metabolism and a clinically safe therapeutic agent for promoting brain energy metabolism recovery after ischemia/reperfusion injury.

目的探讨肌肽对正常和缺血条件下培养的皮质星形胶质细胞生物能量谱的影响。方法采用海马Bioscience XF96细胞外通量分析仪测定经肌肽处理和不经肌肽处理的皮质星形胶质细胞在正常和缺血状态下的耗氧量(OCRs)和细胞外酸化率(ECARs)。结果在正常生长条件下,星形胶质细胞的基础ocr和ecar分别为21.72±1.59 pmol/min/μg蛋白和3.95±0.28 mpH/min/μg蛋白。线粒体呼吸约占细胞呼吸总量的80%,其中85%与ATP合成有关。肌肽显著降低基础ocr和ecar以及atp相关呼吸,但显著增加星形胶质细胞的备用呼吸能力。肌肽处理的星形胶质细胞的细胞ATP水平降低到对照组的42%。然而,在缺血条件下,肌肽上调了8 h氧葡萄糖剥夺(OGD)和24 h正常生长条件下恢复的星形胶质细胞的线粒体呼吸和细胞ATP含量。结论肌肽可能是星形胶质细胞能量代谢的内源性调节剂,是促进缺血再灌注损伤后脑组织能量代谢恢复的临床安全的治疗药物。
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引用次数: 18
Gene expression profiling of gastric mucosa in mice lacking CCK and gastrin receptors 缺乏CCK和胃泌素受体小鼠胃粘膜的基因表达谱
Pub Date : 2014-06-01 DOI: 10.1016/j.regpep.2014.08.002
Chun-Mei Zhao , Yosuke Kodama , Arnar Flatberg , Vidar Beisvag , Bård Kulseng , Arne K. Sandvik , Jens F. Rehfeld , Duan Chen

The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signaling pathways in the gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK1 and/or CCK2 receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK2 receptor KO mice but not in CCK1 receptor KO mice. However, in CCK1 + 2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation and the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). The basal part of the gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptide2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism.

胃产生酸,它可能在调节骨稳态中起重要作用。本研究的目的是揭示CCK1和/或CCK2受体敲除(KO)小鼠胃粘膜中涉及酸分泌和可能的骨代谢的信号通路。CCK2受体KO小鼠胃酸分泌受损,ECL细胞信号通路受到抑制,但CCK1受体KO小鼠没有受到抑制。然而,在CCK1 + 2受体双KO小鼠中,幽门结锁诱导的迷走神经刺激和ECL细胞通路的酸分泌部分正常化,这与垂体腺苷酸环化酶激活多肽(PACAP) 1型受体(PAC1)的上调有关。胃粘膜基底部在可能的ECL细胞亚群(也可能是其他细胞)中表达甲状旁腺激素样激素(PTHLH),在三叶肽2免疫反应细胞中表达维生素D3 1α羟化酶。综上所述,缺乏CCK受体的小鼠在控制ECL细胞和最终的酸分泌方面表现出从胃泌素-CCK途径到神经元途径的功能转变。将目前的数据与先前的发现结合起来,我们认为胃PTHLH与维生素D和骨代谢之间可能存在联系。
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引用次数: 6
期刊
Regulatory Peptides
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