胰高血糖素样肽-1对胰岛β细胞的影响

胰高血糖素样肽-1,作为一种"肠促胰素",对胰岛β细胞具有多方面积极的影响.它可刺激胰岛β细胞分泌胰岛素,促进它的增殖分化再生并抑制其凋亡,在糖尿病的治疗中有很好的应用前景.     

胰高血糖素样肽-1及其类似物对心血管系统的影响

心血管病变是糖尿病常见的并发症,胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)作为一种肠促胰素,不仅具有葡萄糖浓度依赖性降糖作用、促进胰腺β细胞增生和修复、改善胰岛素抵抗,而且还可减轻体质量、调节脂质代谢、改善心血管危险因素。研究表明GLP-1可直接作用于血管内皮细胞和心肌细胞,对心血管系统可能具有保护效应。     

胰高血糖素样肽-2

胰高血糖素样肽GLP 1和GLP 2由小肠和大肠的内分泌细胞产生并分泌。GLP 2通过对胃的动力作用和营养吸收作用保持小肠粘膜上皮的完整 ,对小肠损伤修复等均有重要的调节作用 ,GLP 2在循环中二肽肽酶Ⅳ (DPIV)的作用下氨基末段迅速裂解失去活性 ,并通过肾脏清除。利用这些肽对营养吸收和能量平衡及在糖尿病动物模型和小肠疾病的作用 ,可供临床应用并治疗人类的疾病     

基于胰高血糖素样肽1受体及其下游信号探讨有氧运动对小鼠心梗模型心功能康复的影响

目的:探讨有氧运动训练(AET)对心肌梗死(MI)小鼠的心脏保护作用,并阐明其作用机制是否与胰高血糖素样肽1受体(GLP-1R)激活有关.方法:在实验1(研究AET对MI小鼠的心脏保护作用及对心脏组织中GLP-1R表达的影响)中,67只小鼠分为3组:假手术(sham)组(n=14)、MI组(n=28)和MI+AET组(...     

胎盘胰高血糖素样肽-1水平与胎儿出生体重关系的研究

目的探讨胎盘胰高血糖素样肽-1(GLP-1)水平与胎儿出生体重的关系。方法采用免疫组织化学SABC法检测30例分娩正常出生体重儿组(AGA组)、28例高出生体重儿组(LGA组)及28例低出生体重儿组(SGA组)胎盘组织中GLP-1的表达水平。结果①LGA组胎盘组织中GLP-1的表达水平低于AGA组,差异有统计学意义(P<0.05)。SGA组胎盘组织中GLP-1的表达水平高于AGA组,差异有统计学意义(P<0.05)。②胎盘组织中GLP-1的表达水平与胎儿出生体重呈负相关(r=-0.454,P<0.05)。结论胎盘组织中GLP-1表达水平的变化可能在胎儿出生体重的调节中起重要作用。     

胰高血糖素样肽-1对胰岛β细胞的影响

 胰高血糖素样肽-1,作为一种“肠促胰素”,对胰岛β细胞具有多方面积极的影响。它可刺 激胰岛β细胞分泌胰岛素,促进它的增殖分化再生并抑制其凋亡,在糖尿病的治疗中有很好的应用前景 。     

胰高血糖素样肽-1对胰岛素分泌传导通路中胰十二指肠同源盒-1基因的调控作用

胰高血糖素样肽-1(GLP-1)是一种肠促胰岛素,它通过多种复杂的机制使血糖降低的同时,促进胰岛β细胞增殖与再生;胰十二指肠同源盒-1( PDX-1)是β细胞内重要的转录因子,参与β细胞胰岛素基因的转录调控,GLP-1通过上调PDX-1基因蛋白的表达而影响胰岛β细胞增殖与再生.     

胰高血糖素样多肽-1受体在饲饵性高脂大鼠卵巢的表达

目的:探讨大鼠卵巢是否存在胰高血糖素样多肽-1受体(GLP-1R),并对大鼠卵巢GLP-1R mRNA的表达水平进行测定.方法:建立饲饵性高脂大鼠模型,口服葡萄糖耐量试验确定其高胰岛素状态,采用免疫组织化学SABC法观察卵巢GLP-1R免疫反应阳性细胞,采用实时定量PCR方法检测大鼠卵巢GLP-1R mRNA表达水平.结果:卵巢组织呈GLP-1R阳性表达.高脂大鼠胰岛素曲线下面积和胰岛素抵抗指数(HOMA-IR)高于对照大鼠,高脂大鼠卵巢GLP-1R mRNA相对表达量低于对照大鼠,为对照大鼠的63%.结论:大鼠卵巢存在GLP-1R.高脂状态下卵巢GLP-1R mRNA表达下调,可能与高脂血症或高胰岛素血症有关.     

胰高血糖素样肽1-受体/沉默信息调节因子1通路参与高糖诱导大鼠嗜铬细胞瘤细胞系PC12细胞衰老

目的:探讨胰高血糖素样肽1-受体(GLP-1R)/沉默信息调节因子1(SIRT1)信号通路参与高糖诱导大鼠嗜铬细胞瘤细胞系(PC12)细胞衰老的机制。方法:培养PC12细胞用作神经细胞模型,采用β-半乳糖苷酶染色评价PC12细胞衰老情况;免疫印迹检测SIRT1、GLP-1R表达。结果:葡萄糖能剂量依赖性诱导PC12细胞衰老,并抑制SIRT1和GLP-1的表达,且均在葡萄糖(30 mmol/L,48 h)时效果最明显。SIRT1激动剂白藜芦醇(10μmol/L)能抑制高糖促进PC12细胞衰老的作用,而SIRT1的特异性抑制剂splitomicin(10μmol/L)能阻断白藜芦醇的作用。GLP-1R的激动剂GLP-1(10 nmol/L)能逆转高糖对SIRT1表达的抑制作用并缓解PC12细胞的衰老,而GLP-1R特异性拮抗剂exendin(9-39)则阻断了GLP-1的作用。结论:GLP-1R/SIRT1信号通路参与了高糖诱导的神经细胞衰老的作用。     

胰高血糖素样肽-1及类似物对心血管系统作用的研究进展

胰高血糖素样肽-1(GLP-1)因其有效的降糖作用,为临床治疗2型糖尿病带来了新的契机.心血管病变是糖尿病的常见并发症,研究发现GLP-1及类似物可以通过改善内皮功能,抑制炎性反应,减少心梗面积及缺血/再灌注损伤,抑制心肌细胞凋亡和改善心肌能量代谢等作用来降低心血管疾病风险,这将为临床治疗心血管疾病提供新的途径和方法.     

Sigma-1 Receptor Expression in DRG Neurons During a Carrageenan-Provoked Inflammation

Sigma 1 receptor (σ1R) is a non-opioid receptor that modulates pain perception and is strongly expressed in dorsal root ganglion (DRG) neurons. We studied the changes in the expression of σ1R in different sub-populations of DRG neurons during the first 48 hr in a carrageenan-induced inflammation rat model, with σ1R being a possible base for the development of neuropathic pain after inflammation. Twenty Sprague Dawley rats were divided into five groups (N = 4 in each group): the control (C) group was sacrificed immediately; all other animals received an intraplantar injection of 0.1 mL 2% carrageenan and were sacrificed in 6, 12, 24 or 48 hr after the injection and DRGs were collected and processed for immunohistochemistry. σ1R fluorescence intensity decreased slightly but significantly in up to 24 hr post-carrageenan injection in all sub-populations of DRG neurons (ib4+; ib4− medium, ib4− large and ib4− in total; P < 0.05 – P < 0.001), with the exception of the ib4− small neurons (<25 μm; P > 0.05). This decrement was followed by a subsequent increase in σ1R fluorescence intensity 48 hr after the plantar carrageenan injection (P < 0.05 – P < 0.0001). The same trend was also observed in the CGRP+ population of the DRG neurons, in the total population as well as in the CGRP+ small (<25 μm) and larger CGRP (>25 μm) sub-populations (P < 0.05 – P < 0.001). The presented results may contribute to further understanding of role of σ1R in the development of peripheral sensitization during inflammation. They may also be valuable for the therapeutic application of σ1R antagonists, particularly in the adjustment of the antagonist's dosage in a particular time window. Anat Rec, 302:1620–1627, 2019. © 2019 American Association for Anatomy     

Impaired Secretion of Total Glucagon-like Peptide-1 in People with Impaired Fasting Glucose Combined Impaired Glucose Tolerance

Objective: We assessed the serum glucagon-like peptide-1 (GLP-1) levels for Chinese adults with pre-diabetes (PD) and newly-diagnosed diabetes mellitus (NDDM) during oral glucose tolerance test (OGTT). The relationships between total GLP-1 level and islet β cell function, insulin resistance (IR) and insulin sensitivity (IS) were also investigated.Methods: A 75g glucose OGTT was given to 531 subjects. Based on the results, they were divided into groups of normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined IGT (IFG+IGT) and NDDM. Total GLP-1 levels were measured at 0- and 2-hour during OGTT. Homeostasis model assessment of β cell function (HOMA-β), HOMA of insulin resistance (HOMA-IR), Gutt and Matsuda indexes were calculated. The relationships between GLP-1 level and β cell function, IR and IS were analyzed.Results: The levels of total fasting GLP-1 (FGLP-1), 2h GLP-1 (2hGLP-1) and 2hGLP-1 increments (∆GLP-1) following OGTT reduced significantly in IFG+IGT and NDDM groups (P<0.005). HOMA-β , HOMA-IR, Gutt and Matsuda indexes demonstrated various patterns among NGT, isolated IFG, isolated IGT, IFG+IGT and NDDM groups (P<0.05). Spearman rank correlation analysis and multivariable linear regression model suggested that some levels of correlation between GLP-1 levels, ∆GLP-1 and β cell function, IR (P<0.05).Conclusions: The total GLP-1 levels and its response to glucose load decreased significantly in IFG+IGT group, compared to isolated IFG or IGT group. They were even similar to that of NDDM group. Moreover, there were observable correlations between impaired GLP-1 secretion and β cell function, IR and IS.     

Transplacental Transfer of Interleukin‐1 Receptor Agonist and Antagonist Following Maternal Immune Activation

To describe and analyze the benefit of immunomodulatory drugs for recurrent miscarriages and implantation failures. The literature research was conducted in Medline, Embase and Cochrane Library concerning recurrent miscarriages and implantation failures and steroids, progesterone, intralipids, TNF‐α antagonists, G‐CSF, hydroxychloroquine, intravenous immunoglobulins, endometrial scratching. Using meta‐analysis, modest benefit was found for progesterone to obtain a live birth, with odds ratio at 1.38 (95% CI: 1.07–1.77) and significant heterogeneity (P = 0.01, I² = 78%). In early ≥3 miscarriages, patients treated by TNF‐α antagonists (adalimumab or etanercept; n = 17) combined with low‐dose aspirin, heparin and intravenous immunoglobulins have a live births of 71% (12/17), vs 19% with aspirin+heparin (4/21) (P = 0.0026). Sixty‐eight patients with unexplained recurrent miscarriage were randomized to receive either G‐CSF (filgastrim, Neupogen, 1 μ/kg/day SC, n = 35) after the ovulation until the 9th weeks of gestation or placebo (n = 33). Among patients treated with G‐CSF, 29/35 (82.8%) have live birth and 16/33 (48.5%) of controls (P = 0.006). Among 200 women with recurrent miscarriages and implantation failure treated with intralipids, the pregnancy rate was 52%, with pregnancy ongoing/live birth rate at 91%. The physiopathological rational for immunotolerance failure in this topic raise the need to demonstrate the efficacy of immunomodulatory drugs, define the patients subsets and develop treatment strategies.     

Involvement of capsaicin-sensitive afferents and the Transient Receptor Potential Vanilloid 1 Receptor in xylene-induced nocifensive behaviour and inflammation in the mouse

The inflammatory actions of xylene, an aromatic irritant and sensitizing agent, were described to be predominantly neurogenic in the rat, but the mechanism and the role of the Transient Receptor Potential Vanilloid 1 (TRPV1) capsaicin receptor localized on a subpopulation of sensory nerves has not been elucidated. This paper characterizes the involvement of capsaicin-sensitive afferents and the TRPV1 receptor in nociceptive and acute inflammatory effects of xylene in the mouse. Topical application of xylene on the paw induced a short, intensive nocifensive behaviour characterized by paw liftings and shakings, which was more intensive in Balb/c than in C57Bl/6 mice. Genetic deletion of the TRPV1 receptor as well as destroying capsaicin-sensitive nerve terminals with resiniferatoxin (RTX) pretreatment markedly reduced, but did not abolish nocifensive behaviours. In respect to the xylene-induced plasma protein extravasation detected by Evans blue leakage, significant difference was neither observed between the Balb/c and C57Bl/6 strains, nor the ear and the dorsal paw skin. These inflammatory responses were diminished in the RTX pretreated group, but not in the TRPV1 gene-deleted one. Injection of the antioxidant N-acetylcysteine 15 min prior to xylene smearing significantly reduced plasma protein extravasation at both sites. These results demonstrate that xylene-induced acute nocifensive behaviour is mediated by capsaicin-sensitive afferents via TRPV1 receptor activation in mice. Neurogenic inflammatory components play an important role in xylene-induced plasma protein extravasation, but independently of the TRPV1 ion channel. Reactive oxygen or carbonyl species participate in this process presumably via stimulation of the TRPA1 channel.     

Cytokeratin 1 and gC1qR Mediate High Molecular Weight Kininogen Binding to Endothelial Cells

High molecular weight kininogen (HK) attaches to endothelial cells by separate sites on the heavy and light chains and requires 15-50 microM zinc. Previously identified binding proteins include gC1qR, cytokeratin 1, and the urokinase plasminogen activator receptor; however, their relative contributions to binding are not yet clarified. We have prepared affinity columns to which were coupled either cleaved HK or peptide LDCNAEVYVVPWEKKIYPTVNCQPLGM derived from heavy-chain domain 3. Endothelial cell membranes were solubilized and chromatographed in the presence or absence of zinc ion, the bound proteins were eluted, and active fractions were identified by dot blot using biotinylated HK, SDS/PAGE, and Western blot analysis. The peptide containing column eluate revealed but one band at 68 kDa if zinc ion was present which was identified as cytokeratin 1 by amino acid sequencing of an internal peptide. The HK affinity column revealed bands at 68 kDa (cytokeratin 1), 33 kDa (gC1qR), and 66 kDa (unidentified). HK or domain 3-derived peptide bound to the 68 kDa band; prekallikrein and Factor XII did not. HK or Factor XII bound to the 33-kDa band if zinc was present while no binding to the 66 kDa band was observed. Antibody to cytokeratin 1 inhibited HK binding to endothelial cells by 30%, antibody to gC1qR inhibited HK binding to endothelial cells by 72%, and a mixture of both inhibited binding by 86%. Our data suggest HK binding by interaction of the heavy-chain domain 3 with cytokeratin 1 and the light chain with gC1qR.     

Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells

Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll-like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC.