APPL1研究进展

APPL1（adaptor protein,phosphotyros ineinteraction,PH domain and leucine zipper containing 1）是近来发现的一种细胞内转接蛋白,是介导脂联素信号的调节蛋白,并可参与胰岛素等多种信号转导通路,与胰岛素抵抗、内皮细胞功能紊乱、肥胖及2型糖尿病等相关。有研究表明,低水平APPL1可预测2型糖尿病的发生危险,其可能参与胰岛素抵抗和2型糖尿病的病理生理过程。     

糖皮质激素与2型糖尿病

糖皮质激素与2型糖尿病的发生、发展密切相关,但其诱导2型糖尿病发生的具体机制尚不明确.研究认为,糖皮质激素可能通过对胰岛β细胞增殖和发育、分泌功能的作用,以及对胰岛素信号转导通路、糖、脂代谢、葡萄糖转运和吸收等方面的影响,参与2型糖尿病的发生.11β-羟类固醇脱氢酶、糖皮质激素受体、热休克蛋白等通过影响糖皮质激素的作用,成为治疗2型糖尿病的新靶点.     

脂肪细胞型脂肪酸结合蛋白与胰岛素抵抗和2型糖尿病的关系

脂肪细胞型脂肪酸结合蛋白（A—FABP）是近年来新发现的一种脂肪因子,具有广泛的生物学功能。A．FABP作为脂肪酸结合蛋白家族成员之一,不仅调控脂肪细胞的分化,而且还参与糖及脂肪的代谢。A—FABP与多种临床疾病,如2型糖尿病、动脉粥样硬化、血脂紊乱、肥胖、胰岛素抵抗和代谢综合征等密切相关。现仅就A—FABP与胰岛素抵抗、2型糖尿病的关系综述如下。     

SHIP 2基因与2型糖尿病

2型糖尿病主要特征是胰岛素分泌异常和胰岛素抵抗,环境因素和遗传因素交互作用共同促成了糖尿病的发生。研究发现多种基因参与糖尿病的发生,最近发现SHIP2基因与胰岛素抵抗及2型糖尿病相关,该基因可抑制胰岛素分泌、降低机体对胰岛素的敏感性,研究也表明当该基因不起作用时,胰岛素分泌就会失控,可导致严重的低血糖发生,因此,SHIP2基因可成为2型糖尿病的一个重要的治疗靶点。     

自身免疫与糖尿病大血管病变

糖尿病大血管病变是以动脉粥样硬化为主要病理特征的糖尿病慢性并发症之一.近年来,自身免疫因素在动脉粥样硬化发病中的作用越来越受到关注,多种自身抗体、自身抗原和免疫系统成分参与动脉粥样硬化的发生和发展.检测血液中几种自身抗原及其抗体,如氧化型低密度脂蛋白、p2糖蛋白Ⅰ、热休克蛋白的变化,可间接预测糖尿病患者动脉粥样硬化的发生、发展.对糖尿病大血管病变相关自身免疫更深入的研究,将为糖尿病大血管病变的早期诊断、监测和治疗开辟一条新的途径.     

颗粒蛋白前体与糖尿病及肥胖的关系

颗粒蛋白前体是一种分泌性蛋白,广泛表达于各种组织,尤其是快速增殖的细胞中,参与胚胎发育、损伤修复、细胞周期等病理生理过程.炎性反应与2型糖尿病及肥胖相关,并且是胰岛素抵抗形成的重要机制之一.最新研究发现,颗粒蛋白前体在2型糖尿病及肥胖患者的体内表达明显升高,并通过白细胞介素-6炎性反应信号通路参与慢性炎性反应状态及胰岛素抵抗的形成,提示颗粒蛋白前体可能与2型糖尿病及肥胖的发病密切相关.     

热休克蛋白70与2型糖尿病及大血管病变的关系

据世界卫生组织统计,目前全世界糖尿病患者约有1.8亿人,而2型糖尿病患者占90％.大量研究结果证实,氧化应激及炎症反应等是2型糖尿病及心血管疾病的潜在危险因素[1].热休克蛋白(Hsp) 70家族在生物细胞中含量最高,可诱导性最强,具有多种生物学功能.近年来研究发现Hsp70与2型糖尿病及大血管病有着密切关系.我们对Hsp70与2型糖尿病及大血管病变的关系作一综述.     

Ghrelin与糖尿病大血管病变

糖尿病大血管并发症是糖尿病尤其是2型糖尿病致死致残的主要原因,约占70％左右,众所周知,2型糖尿病的病理生理基础为胰岛素抵抗和胰岛13细胞分泌功能减退而有胰岛素相对缺乏。B细胞分泌胰岛素从代偿性增多到绝对减少,引起多种代谢异常,并有神经、内分泌、免疫系统的参与,从而导致动脉粥样硬化。动脉粥样硬化的病理改变为在动脉发生粥样硬化以前,常见有内皮细胞损伤或剥脱,     

诺和锐30治疗2型糖尿病35例疗效观察

胰岛素是目前治疗糖尿病的最后手段，大部分2型糖尿病最后均需胰岛素治疗，目前在临床上有多种胰岛素，从动物胰岛素到基因重组人胰岛素是一大进步，诺和锐30是30％的可溶性门冬胰岛（胰岛素类似物）和70％精蛋白门冬胰岛素（诺和灵N）混合而成。其临床疗效较以前人胰岛素有进一步改善，笔者应用诺和锐30治疗2型糖尿病35例，现报告如下。     

抑制基质金属蛋白酶2改善血管内皮功能,预防胰岛素抵抗大鼠高血压

众所周知,胰岛素抵抗与高血压相关。研究者认为胰岛素抵抗性高血压和血管内皮功能障碍是血管基质金属蛋白酶(matrix metalloproteinase,MMP)2活性增加的结果。由于MMP2能水解多种细胞外基质蛋白,研究者假设其通过降解内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)或其辅助因子:热休克蛋白90(heat shock protein,HSP90)而造成血管内皮功能受损。方法:该研究通过小牛冠状动     

HSP72 protects against obesity-induced insulin resistance

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.     

Characterization of distinct heat shock- and thapsigargin-induced cytoprotective proteins in FRTL-5 thyroid cells.

Heat shock induces the expression of proteins with molecular weights of 70-72 kd and 90 kd, whereas thapsigargin induces the expression of a glucose-regulated protein 78 kd (GRP-78) in certain cells. In this study we examined the induction and cytoprotective effects of heat shock- and thapsigargin-induced proteins in FRTL-5 rat thyroid cells. New protein synthesis was assessed in [35S]methionine-labeled cells and quantitated densitometrically. The expression of specific stress proteins was identified using Western blots, whereas cytoprotection provided by these proteins was evaluated by trypan blue exclusion. Exposure to heat shock (45 degrees C, 15 minutes) induced the expression of proteins with molecular weights at the range of low 70 kD and low 90 kD that peaked between 2-6 hours and returned to baseline within 24 hours. Treatment of cells with thapsigargin (200 nM, 15 minutes) induced the expression of different molecular weight proteins, most likely GRP-78 and -94, that peaked at 4-6 hours and lasted for 24 hours. Neither the removal of growth factors (thyroid-stimulating hormone and insulin) for 5 days nor the elimination of extracellular Ca2+ with EGTA or clamping of the intracellular Ca2+ with BAPTA for 15 minutes affected expression of the heat shock- and the thapsigargin-induced stress proteins. In contrast, protein kinase C inhibitors H7 and GF109203X abolished the expression of all three groups of stress proteins. Both heat shock- and thapsigargin-inuced proteins completely protected cells from subsequent thermal injury (47 degrees C, 35 minutes). The induction of cytoprotective proteins by heat shock and thapsigargin requires the presence of protein kinase C but is Ca(2+)- and growth factor-independent.     

Expression of HSP70 and JNK-related proteins in human liver cancer: Potential effects on clinical outcome

BACKGROUND: Activation of stress-activated protein kinase/c-Jun N-terminal kinase was inhibited in cells, in which heat shock protein70 was induced to a high level, indicating that heat shock protein70 might be anti-apoptosis protein. AIM: We examined the expression of heat shock protein70 and c-Jun N-terminal kinase signal transduction pathway in human liver carcinoma to explore their relationship and clinical parameters. PATIENTS AND METHODS: The expression of heat shock protein70, c-Jun N-terminal kinase1, c-Jun N-terminal kinase2 and c-Jun were detected immunohistochemically in 62 samples of liver cancer. Western blot was used to confirm immunostaining results. RESULTS: Heat shock protein70 expression showed a positive correlation with the malignant differentiation in liver carcinoma (r=0.449, P<0.0005). The expression of c-Jun N-terminal kinase1, c-Jun N-terminal kinase2, and c-Jun showed a negative correlation with the malignant differentiation in liver carcinoma (r=-0.351, P=0.005; r=-0.303, P=0.017; r=-0.302, P=0.017). Heat shock protein70 expression was correlated with c-Jun N-terminal kinase1 (r=-0.385, P=0.002), c-Jun N-terminal kinase2 (r=-0.309, P=0.015) and c-Jun (r=-0.302, P=0.017). Expression of heat shock protein70, as well as c-Jun N-terminal kinase1, was correlated with recurrence-free survival after the resection. Heat shock protein70 was associated with prognosis (P=0.004). CONCLUSION: Expression of heat shock protein70 and c-Jun N-terminal kinase-related proteins might be an indicator of malignant potential in liver carcinoma. The balance between heat shock protein70 and c-Jun N-terminal kinase-related protein may increase the stability of liver cancer cells in stress. Negative expression of heat shock protein70 might be a protective factor of recurrence of liver carcinoma.     

Heat shock proteins and skin diseases

Heat shock proteins are chaperones to construct protein molecules and are widely distributed in prokaryotic and eukaryotic cells. They are also induced by environmental stress to protect cells. Human heat shock proteins cross-react with bacterial heat shock proteins to modulate immune responses to induce autoimmunity. They are involved in the differentiation and growth of neoplastic cells as well as normal cells. They are also involved in various inflammatory skin diseases and in fibrotic process. Heat shock proteins play important roles in the pathogenesis of many skin diseases.     

寄生虫应激蛋白的研究进展

应激蛋白是细胞或生物体受到各种不同环境因素刺激后产生的一种非特异性蛋白,主要包括急性期反应蛋白、热激蛋白、某些酶或细胞因子等。其中,急性期反应蛋白是一种起动迅速的机体防御机制,属于分泌型蛋白;热激蛋白是细胞受到热应激后新合成的一类遗传上高度保守的蛋白,属于非分泌型蛋白,在应激蛋白中研究最为深入。该文主要阐述了热激蛋白家族的历史和分类,对热激蛋白在寄生虫学领域的研究进展进行了综述。     

Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis

Metabolic syndrome and type 2 diabetes are progressive, indolent, multi-organ diseases. Understanding the abnormalities of heat shock proteins (HSPs) in these diseases is paramount to understanding their pathogenesis. In insulin resistant states and diabetes, heat shock factor 1(HSF-1) is low in insulin sensitive tissues, resulting in low Hsp 60, 70, and 90 levels. We propose that low Hsps levels are the result of decreased insulin action leading to less phosphorylation of PI3K, PKB, and glycogen synthase kinase-3 (GSK-3). Importantly, less GSK-3 phosphorylation (and thus more GSK-3 activity) will lower HSF-1. Low Hsps make organs vulnerable to injury, impair the stress response, accelerate systemic inflammation, raise islet amyloid polypeptide, and increase insulin resistance. Feeding this cycle is excess saturated fat and calorie consumption, hypertension, inactivity, aging, and genetic predisposition- all of which are a associated with high GSK-3 activity and low Hsps. Support for the proposed "vicious" cycle is based on the observation that GSK-3 inhibition and Hsp stimulation result in increased insulin sensitivity, reduced accumulation of degenerative proteins with in the cell, improved wound healing, decreased organ damage and improved recovery from vascular ischemia. Recognizing GSK-3 and Hsps in the pathogenesis of insulin resistance, the central common feature of the metabolic syndrome, and type 2 diabetes will expand our understanding of the disease, offering new therapeutic options.     

Heat Shock Protein Studies in Type 1 and Type 2 Diabetes and Human Islet Cell Culture

Heat shock proteins (HSP) play an important role in auto-immunity and infection. Glutamic acid decarboxylase (GAD) the prime antigen in Type 1 diabetes has similar amino acid sequences to HSP65. An ELISA was developed using a plant-derived HSP65 antibody. HSP65 antibody was present in the serum of all normal subjects (median 1.64 AU, IQ range 1.49-1.74). Lower levels were found in established Type 1 diabetes (1.41 AU, 1.32-1.61, p<0.001) and Type 2 diabetes (1.45 AU, 1.35-1.59, p<0.006). In Type 1 HSP antibody levels fell with age (p = 0.007) and with duration (p = 0.008) and women with Type 1 had lower levels than men (p = 0.009). Human islet cell culture subjected to heat shock revealed an approximate four fold increase in heat shock protein antigen in the surrounding medium. The release of HSP antigen from stressed islet cells together with the finding of HSP antibody in the serum of all subjects suggest that HSP65 should not be completely discarded as having a possible role in the development of Type 1 diabetes. Low levels of HSP antibody in patients with established diabetes is probably a manifestation of imparied immunity induced by the diabetic state.     

Myocardial heat shock protein 60 expression in insulin-resistant and diabetic rats

Heat shock protein 60 (HSPD1) plays a critical role in myocardial protection. Its reduced expression may lower myocardial protection against ischemic injury in the diabetic state. This study was conducted to investigate the natural course of fructose-fed insulin-resistant rats, define changes in myocardial HSPD1 expression, and determine the effects of thiazolidinedione or anti-hypertensive treatment. Results showed that insulin resistance with hyperinsulinemia and hypertension developed after 6 weeks of fructose feeding. This time-course study also showed that myocardial HSPD1 expression was mildly increased in week 6 (P=0.05) and significantly increased in week 8. Rosiglitazone-treated rats had restored systolic blood pressure (BP) and normalized plasma insulin level during oral glucose tolerance tests, whereas amlodipine-treated rats restored only systolic BP. Both amlodipine and rosiglitazone treatments normalized the abundance of myocardial HSPD1 expression in fructose-fed rats. When these rats received streptozotocin injection and diabetes developed, myocardial HSPD1 expression decreased despite persistent hypertension. In conclusion, this is the first study to report that myocardial HSPD1 expression is increased in high-fructose-fed rats, which may be due to increased BP. Once the high-fructose-fed rats developed diabetes with insulin deficiency, the myocardial HSPD1 expression decreased in spite of persistent hypertension.     

热休克蛋白72重组腺病毒包装及其对细胞凋亡的影响

目的 包装热休克蛋白72重组腺病毒表达载体,探讨其对ECV304细胞凋亡的影响.方法采用细菌同源重组法构建了热休克蛋白72重组腺病毒表达载体;流式细胞仪检测重组腺病毒对细胞凋亡的影响;荧光报告系统和蛋白印迹分析重组腺病毒对p53转录的调节和蛋白表达的影响.结果 成功包装了热休克蛋白72重组腺病毒,热休克蛋白72能够促进细胞凋亡,从转录水平上调p53蛋白的表达.结论 热休克蛋白72可能通过上调p53蛋白的表达促进细胞凋亡.