以PTP1B为靶点的胰岛素增敏剂的实验研究

蛋白酪氨酸磷酸酶1B（protein tyrosine phosphatase 1B，PTP1B）是蛋白酪氨酸磷酸酶家族中的主要成员之一，在胰岛素信号传导系统的平衡中，起着重要作用。胰岛素信号传导系统主要是通过信号分子的磷酸化程度来调节的。信号分子的酪氨酸磷酸化与去磷酸化的平衡，对胰岛素发挥生物效应极其重要。阿PTP1B是催化分子酪氨酸去磷酸化的蛋白酪氨酸磷酸酶家族中的主要成员之一，可以使胰岛素受体底物（IRSs）等许多信号分子的酪氨酸去磷酸化而失活，在胰岛素信号传导系统中起着重要作用。阿PTP1B抑制剂已成为胰岛素增敏剂的靶点之一。     

060 扫描新的药物分子

蛋白酪氨酸磷酸酶抑制剂 蛋白酪氨酸磷酸酶（PIP）和酪氨酸激酶调节蛋白酪氨酸磷酸化水平，成为控制细胞内信号转导通路的关键机制之一。有多种疾病与不能调节磷酸酶的活性有关，例如PIP一。和cdc25磷酸酶提示可能与癌变有关。故这些酶成为令人感兴趣的治疗靶标。合成PIP抑制剂的一种方法是针对一种特异PIP设计有选择性的抑制剂，     

脑缺血再灌注后NMDA受体亚基2B酪氨酸磷酸化的调节机制(英文)

目的:研究沙土鼠脑缺血再灌注后海马突触体N-甲基-D-天冬氨酸(NMDA)受体亚基2B(NR2B)酪氨酸磷酸化调节的机制。方法:沙土鼠双侧颈总动脉结扎形成前脑缺血模型;NR2B酪氨酸磷酸化通过免疫沉淀和免疫印渍分析。结果:脑缺血15分钟导致蛋白酪氨酸磷酸化水平明显下降;再灌注引起包括180kDa蛋白在内的多种蛋白酪氨酸磷酸化水平快速(再灌注15分钟)、持续(至少48小时)升高。免疫沉淀和免疫印渍证实,180 kDa条带为NR2B。缺血15分钟,再灌注6小时,NR2B酪氨酸磷酸化明显高于对照组,为对照组的1.8倍,而NR2B蛋白表达量则无变化。缺血前腹腔注射非竞争性NR拮抗剂氯胺酮或L-型电压门控钙通道(L-type VGCC)阻滞药硝苯地平,对NR2B酪氨酸磷酸化水平升高有明显的拮抗作用,而对NR2B蛋白表达量均无影响。在此条件下,非NMDA受体拮抗剂6,7-二硝基喹恶啉土卫四(DNQX)对NR2B酪氨酸磷酸化水平无影响。酪氨酸蛋白磷酸酶(PTP)抑制剂钒酸钠使脑缺血再灌注诱导的NR2B酪氨酸磷酸化进一步增加,而酪氨酸蛋白激酶(PTK)抑制剂金雀异黄素则使其减少。Src能与NR2B免疫共沉淀。结论:沙土鼠脑缺血再灌注NR2B的酪氨酸磷酸化的升高是通过NR和L-type VGCC介导的;PTK和PTP参与脑缺血再灌注NR2B酪氨酸磷酸化的调节,与NR2B以物理方式结合的Src可能在这种     

阿尔茨海默病与tau蛋白的磷酸化及去磷酸化

本简要介绍了阿尔茨海默病的研究现状以及发病机理和病理学特征，并介绍了作为阿尔茨海默病标志蛋白的tau蛋白的结构、功能，以及其过度磷酸化修饰与阿尔茨海默病发生的关系。同时，总结了近几年来针对细胞内各种蛋白激酶和蛋白磷酸酶在tau蛋白的磷酸化平衡系统中所起作用的最新研究进展，并说明了因蛋白磷酸酶活力缺陷导致的tau蛋白过磷酸化的可逆性。在此理论基础上，扼要介绍了蛋白磷酸酶激活剂在治疗阿尔茨海默病中的研究进展及展望。     

与2型糖尿病相关的蛋白酪氨酸磷酸酶及其新型降糖药的开发

蛋白酪氨酸磷酸酶作为负性调节胰岛素信号转导的关键酶，对糖尿病的发生、发展有着重要的意义。2型糖尿病和胰岛素抵抗患者体内特异的蛋白酪氨酸磷酸酶含量及活性均有所增加，当蛋白酪氨酸磷酸酶被剔除后，不仅胰岛素敏感性增高，而且糖尿病症状也有所改善。以蛋白酪氨酸磷酸酶作为靶点治疗2型糖尿病显示了其独特的潜力，因此开发蛋白酪氨酸磷酸酶抑制剂和其他以蛋白酪氨酸磷酸酶为靶点的药物具有良好的前景。     

扫描新的药物分子

蛋白酪氨酸磷酸酶抑制剂蛋白酪氨酸磷酸酶(PTP)和酪氨酸激酶调节蛋白酪氨酸磷酸化水平,成为控制细胞内信号转导通路的关键机制之一。有多种疾病与不能调节磷酸酶的活性有关,例如PTP-α和Cdc25磷酸酶提示可能与癌变有关。故这些酶成为令人感兴趣的治疗靶标。合成PTP抑制剂的一种方法是针对一种特异PTP设计有选择性的抑制剂,但所有PTP催化机制相同,高活性位点也相同,故较难达到。但与PTP1B结合的双配体化合物及3位点结合化合物有一定活性。基于基本结构(1),用液相法合成了104个化合物库。用未纯化的鼠疫耶尔森菌(Yersiniapestis)PTP…     

PTEN蛋白在喉鳞癌中表达的研究

<正>PTEN抑癌基因是迄今为止发现的第1个具有磷酸酶活性的抑癌基因,定位于人类染色体10q23,全长200kb。PTEN蛋白定位于细胞质,具有双特异性磷酸酶活性,在酪氨酸磷酸酶和丝氨酸/苏氨酸磷酸酶介导的信号传递过程中具有重要作用。PTEN基因异常表达与肿瘤的侵袭、转移和生长有关。本研究采用免疫组织化学技术对喉鳞状细胞癌中PTEN蛋白的表达情况进行研究,旨在探讨PTEN蛋白在喉鳞癌的发生、发展中的临床意义。     

蛋白酪氨酸磷酸酶在胰岛素信号转导通路中的作用

蛋白酪氨酸磷酸酶(protein tyrosine phos-phates,PTPs)是调节胰岛素信号转导的关键酶。PTPs通过对胰岛素受体和胰岛素受体底物蛋白磷酸化和去磷酸化调控胰岛素信号转导。PTPs抑制剂是潜在的治疗糖尿病和肥胖症的靶点药物,可以延长胰岛素信号的转导,加速葡萄糖的吸收,使血糖降低。本文主要概述PTPs在胰岛素信号转导通路中的作用及其作为新的治疗糖尿病药物靶点的研究进展。     

PTP1B在常见组织炎症中的研究进展

蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase 1B,PTP1B)属于蛋白磷酸酶超家族,能够将蛋白酪氨酸残基去磷酸化,在细胞生命活动过程中起着重要的作用。过度的炎症反应能够对正常组织产生损害,导致器官功能障碍及不可逆结构破坏。近年来,越来越多的科学研究发现,PTP1B在组织炎症中发挥着不可或缺的作用:一方面通过调控炎症信号通路调节巨噬细胞及小胶质细胞的功能,另一方面能够影响组织细胞的凋亡,两者共同作用促进组织炎症的发生发展。本文将综述PTP1B在不同组织炎症中的作用及机制,为后续研究及发现有效的药物作用靶点奠定理论基础。     

酪氨酸激酶受体的小分子抑制剂

酪氨酸激酶（TK）和酪氨酸磷酸酶是调节蛋白酪氨酸磷酸化、控制细胞生长和分化所必需的酶。TK分为两类：非跨膜和跨膜生长因子受体TK（RTK），非跨膜或非受体TK有其内在的激酶活性，存在于细胞质和细胞核内，参与各种信号途径。非受体TK可分为多个亚群，最大的亚群为src家族，包括src，lck，lyn，yes，fyn，fgr，hck，blk等。其它非受体TK家族包括abl，jak，fak，syk，zap和csk。这些酶均为新药开发的靶点，本文对此作一重点介绍。生长因子与细胞表面各受体的胞外域结合，促进受体胞浆域的二聚化和活化作用，同时进行自身磷酸化。受体…     

Impact of oncogenic protein tyrosine phosphatases in cancer

Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that can exert both positive and negative effects on signaling pathways. They play dominant roles in setting the levels of intracellular phosphorylation downstream of many receptors including receptor tyrosine kinases and G protein-coupled receptors. As observed with kinases, deregulation of PTP activity can also contribute to cancer. This review will examine a broad array of PTP family members that positively affect oncogenesis in human cancer tissues. We will describe the PTP family, their biological significance in oncology, and how recent progress is being made to more effectively target specific PTPs. Finally, we will discuss the therapeutic implications of targeting these oncogenic PTPs in cancer.     

High-throughput methods in identification of protein tyrosine phosphatase inhibitors and activators

Reversible protein tyrosine phosphorylation, catalysed by the counter-actors protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs), is a fundamentally important regulatory mechanism of proteins in living cells, controlling cell communication, proliferation, differentiation, motility, and molecular trafficking. The activities of PTPs and PTKs are derailed in several diseases such as cancer and type II diabetes, making them attractive drug targets. Developing drugs against PTKs has started a decade earlier than that on PTPs, and at present there are several molecules targeting PTKs on the market. PTPs in turn are of raising interest, with PTP1B on the lead for its effects on type II diabetes and obesity. In the search for modulators of PTP activity, high-throughput methods are important as the initial step to find suitable lead compounds for drug development. Also, high-throughput methods are very useful in elucidating the specific function of different PTPs. In this review, the different high-throughput studies performed to find inhibitors and activators of classical PTPs are discussed.     

Metastatic potential of human neoplasms

Primary human neoplasms are heterogeneous for a large number of properties that include invasion and metastasis. The process of metastasis consists of multiple selective steps. The outcome of metastasis is determined by the continuous interaction of metastatic cells with host homeostatic mechanisms. Since the outcome of metastasis is influenced by both the intrinsic properties of the tumor cell and host factors, the successful metastatic cell must be viewed as a cell able to manipulate its new microenvironment. For many years, our efforts to treat cancer have concentrated on the destruction of tumor cells. Strategies to treat tumor cells and to modulate the host organ microenvironment should provide an additional approach for cancer treatment. Recent advancements in our understanding of the biological basis of cancer metastasis present unprecedented possibilities for translating basic research to the clinical reality of cancer treatment.     

Protein tyrosine phosphatases, new targets for cancer therapy

Cellular growth and development are regulated by reversible phosphorylation of tyrosine residues in target proteins. Protein tyrosine phosphatases (PTPs) catalyse removal, and protein tyrosine kinases (PTKs) the addition of phosphate. Data from various sources support a role for PTKs in transformation and it has long been hypothesized that some PTPs will function as tumour suppressor genes. Specific PTPs are down-regulated in some tumours, sometimes in association with ectopic expression of PTKs. Alternatively, other PTPs dephosphorylate and activate PTKs, and are themselves oncogenic. Much current interest surrounds the clinical introduction of specific PTK inhibitors, whereas targeting of PTPs remains largely unexplored. Phosphatases represent 4% of the drugable human genome and PTPs appear an important new target for cancer therapy. Here we briefly, describe PTP structure and function. Secondly, we review experimental and clinical data, which support a role for PTPs in neoplastic development. Next, we review current strategies for generation of agents targeting PTPs; these include re-expression of tumour suppressor genes (mediated via adenoviral vectors), and generation of small molecules designed to inhibit oncogenic activity. Finally, we address the role of PTPs in melanoma, an increasingly common tumour that may represent an appropriate target for therapeutic manipulation of PTP activity.     

Targeting the PTPome in human disease

Protein tyrosine phosphatases (PTPs) play vital roles in numerous cellular processes and are implicated in a growing number of human diseases, ranging from cancer to cardiovascular, immunological, infectious, neurological and metabolic diseases. There are at least 107 genes in the human genome, collectively referred to as the human ‘PTPome’. Here the authors review the involvement of PTPs in human disease, discuss their potential as drug targets, and current efforts to develop PTP inhibitors for the treatment of human disease. Finally, the authors present their view of the future for PTPs as drug targets.     

长链非编码RNA调控胃癌转移的研究进展

胃癌是消化系统常见的癌症,致死率较高。肿瘤细胞发生远处转移是导致治疗失败和患者死亡的主要原因之一。寻找胃癌转移的治疗靶点,对于提高患者的生存率意义重大。最近大量研究表明长链非编码RNA(LncRNA)与胃癌的转移密切相关,它们参与了胃癌转移的多种生物学过程。该文对LncRNA调控胃癌转移的研究进展进行综述,旨在为理解胃癌转移的发生机制提供理论基础。     

Inflammatory fibroblasts in cancer

The association between inflammation and cancer has been studied widely. Indeed, the tumor microenvironment is influenced by inflammatory cells and affects tumor progression, tumor growth, and the survival of cancer cells. Also, the tumor microenvironment is essential to invasion and metastasis of cancer. Fibroblasts, immune cells, the extracellular matrix and other various components all constitute the tumor stroma, ordinarily referred to as the ‘reactive stroma’. Cancer-associated fibroblasts (CAFs), which are activated fibroblasts and one of the components of the tumor microenvironment, are associated with cancer progression, invasiveness and metastasis, and their functional contributions to these processes are beginning to emerge. CAFs mediate tumor-promoting inflammation through various signaling pathways. Epithelial–mesenchymal transition is a process for producing mesenchymal cells during invasion and metastasis of cancer cells. Fibroblasts have been identified as a key player in this mechanism. In the present review, we summarize the relationships between fibroblasts, inflammatory response, the tumor microenvironment and cancer progression. This review provides useful information for the development of cancer prevention and treatment therapies through controlling the inflammatory responses.     

Targeting the PTPome in human disease

Protein tyrosine phosphatases (PTPs) play vital roles in numerous cellular processes and are implicated in a growing number of human diseases, ranging from cancer to cardiovascular, immunological, infectious, neurological and metabolic diseases. There are at least 107 genes in the human genome, collectively referred to as the human 'PTPome'. Here the authors review the involvement of PTPs in human disease, discuss their potential as drug targets, and current efforts to develop PTP inhibitors for the treatment of human disease. Finally, the authors present their view of the future for PTPs as drug targets.     

早期胃癌的临床病理特征及发生淋巴结转移的危险因素研究

目的探讨早期胃癌(EGC)的临床病理特征以及发生淋巴结转移的危险因素。方法122例早期胃癌患者,根据是否发生淋巴结转移分为淋巴结未转移组(101例)和淋巴结转移组(21例)。对所有患者进行病理检查,比较两组患者的性别、年龄、镜分型、病理类型、浸润深度、分化程度、肿瘤直径、肿瘤位置,并进行Logistic回归分析,总结早期胃癌患者发生淋巴结转移的危险因素。结果两组患者的性别、年龄、病灶数、肿瘤部位、内镜分型、病理类型比较差异无统计学意义(P>0.05);淋巴结未转移组患者肿瘤直径、浸润深度、分化程度均优于淋巴结转移组,差异有统计学意义(χ2=10.499、5.333、6.228,P<0.05)。经Logistic回归分析显示,肿瘤直径≥2 cm、分化程度低以及浸润深度深是早期胃癌患者发生淋巴结转移的危险因素(P<0.05)。结论肿瘤直径≥2 cm、分化程度低以及浸润深度深是早期胃癌患者发生淋巴结转移的危险因素,通过对早期胃癌的临床病理特征进行研究,可以有效判断患者是否出现淋巴结转移的情况,对临床治疗及诊断早期胃癌有着重要意义。     

肾小球足突细胞黏蛋白，肿瘤内皮标记物-8，血管内皮生长因子D在结、直肠癌中的表达及意义

目的：分析肾小球足突细胞黏蛋白（Podoplanin），肿瘤内皮标记物-8（TEM-8），血管内皮生长因子D（VEGF-D）在结、直肠癌中的表达及其意义。方法：用实时定量PCR方法分析30结、肠癌标本中TEM-8，Podoplanin及VEGF-D的表达，并结合病理学分期，淋巴结转移等肿瘤特点进行分析。结果：Podoplanin在肿瘤组织中的表达较正常组织中高，并与淋巴结转移及肿瘤分期相关；VEGF-D在肿瘤组织中的表达较正常组织中高，并与淋巴结转移相关，而与肿瘤分期无明显相关性；TEM-8在正常组织中基本无阳性表达，而在结、直肠癌组织中阳性表达率为90％，与肿瘤分期，淋巴结转移相关。结论：TEM-8，Podoplanin，VEGF-D均可作为结、直肠癌的标记物，并可反映淋巴结转移状况，TEM-8更可作为肿瘤特异性标记物，在结、直肠癌的诊断、治疗、预后判断中可望发挥重要作用。