Notch信号通路研究进展

1917年,Morgan及其同事在果蝇体内发现一种基因,因其功能部分缺失可导致果蝇翅缘出现缺口,故命名该基因为Notch.随后的研究发现,Notch从无脊椎动物到脊椎动物的多个物种中表达,其家族成员的结构具有高度保守性,在细胞分化、发育中起着关键作用.迄今研究已阐明Notch信号通路的主要成员及核心转导过程,然而随着研究的深入,人们逐渐认识到该通路实际上处于十分复杂的调控网络之中,而这与其在发育过程中功能的多样性相符合.本文结合新进展,系统阐述Notch信号通路的组成,功能,作用机制及调控,并揭示该通路异常与疾病的联系.

Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti-vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.

Wnt信号通路在口腔医学中的研究进展

Wnt信号通路是参与胚胎及器官发育的主要四大类信号传导途径之一,是公认的在胚胎及器官发育过程中对模式形成和分化起指导作用的一种重要信号系统.

Wnt信号通路及其拮抗剂与胃癌关系的研究进展

胃癌发病率在世界范围内居恶性肿瘤的第2位,它也是上海男性发病第2位、女性发病第3位的恶性肿瘤[1].胃癌的发生机制一直是研究热点.近期有学者[2]发现,Wnt信号通路(Wnt signaling pathway)的异常激活与肿瘤的发生、发展有着密切的关系.目前已知,包括胃癌在内的多种高发性恶性肿瘤与Wnt信号通路的失调密切相关.现对Wnt信号通路及其拮抗剂与胃癌发生机制的研究进展作一综述.

WISP1基因多态性与肺癌易感性及铂类药物化疗敏感性的关系

Wnt诱导信号通路蛋白1（Wnt inducible signaling pathway protein 1, WISP1）是生长因子CCN家族的成员。前期研究发现WISP1基因多态性与多种肺疾病的发生发展相关，包括哮喘、急性肺损伤等。本研究旨在探索WISP1基因多态性是否与肺癌易感性及肺癌铂类药物化疗敏感性相关。我们在中南大学湘雅医院收集了325例肺癌患者及254例健康对照血样。根据实体瘤化疗敏感性评价指南(RECIST)筛选出118例化疗敏感和174例化疗耐药的患者。所有血液样本均用Promega公司生产的基因组DNA纯化试剂盒提取基因组DNA。我们根据以下原则挑选了47个候选单核苷酸多态性位点（single nucleotide p olymorphism, SNP）：(1)在中国人群中小等位基因频率（Minor Allele Frequency, MAF）不小于5％；(2)基因区域的标签SNP；(3)位于启动子、3’非翻译区（UTR）和外显子区的SNPs。基因区域的标签SNPs（r2≥0.8）运用Haploview 4.2软件来挑选，所有SNPs都通过飞行质谱（sequenom）方法进行分型。所有SNP位点都进行Hardy-Weinberg平衡检验，并通过非条件Logistic回归计算OR值来评价多态与肺癌易感性及化疗敏感性的关系。OR值的计算校正了以下因素：年龄、性别、吸烟状况、肿瘤病理类型、肿瘤分级和化疗方案，并且运用Bonferroni校正法进行多重检验校正。所有统计分析采用SPSS 13.0和PLINK 1.07软件完成。经统计学分析，我们发现rs2977549与非小细胞肺癌患者化疗敏感性显著相关（P≤0.001），并且与小细胞肺癌患者化疗敏感性（P=0.017）及肺癌易感性（P=0.026）也具有相关性，但后两者经校正后差异无统计学意义。因此，我们认为WISP1 rs2977549有可能是非小细胞肺癌铂类药物化疗敏感性的一个诊断标志物。

BACKGROUND:Cytochrome P450 ( CYP) epoxygenases metabolize arachidonic acids ( AA) to form epoxyeicosatrienoic acids
(EETs), which exert beneficial roles in the treatment of cardiovascular diseases , but little is known about its role on adventitial remo-deling.METHODS:We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts ( AFs) in vitro treated with angiotensin II (Ang II) to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling .RESULTS:CYP/sEH system was found to exist in human adventitia , and involved in adventitial remodeling process .Exogenous EETs administra-tion significantly inhibited Ang II-induced AFs activation , characterized by differentiation , proliferation, migration, and collagen syn-thesis.These protective effects were partially reversed by PPARγantagonist GW9662 pretreatment or SOCS3 siRNA transfection.EETs suppressed Ang II-induced IκBαphosphorylation , subsequent NF-κB nuclear translocation via PPARγdependent signaling pathway in AFs.Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor-STAT3 nuclear transloca-tion, which were mediated by SOCS3 induction but independent of PPARγactivation.Furthermore, rAAV-CYP2J2 gene delivery re-duced vessel wall thickening , AFs differentiation , proliferation and collagen deposition in aortic adventitia induced by Ang II infusion , which were mediated by NF-κB and SOCS3/JAK/STAT signaling pathways in blood pressure-dependent and -independent manners , re-spectively.CONCLUSION:We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARγ-dependent NF-κB and PPARγ-independent SOCS 3/JAK/STAT inflammatory signaling pathways .

AIM:Atherosclerosis primarily involved systemic arteries .Luminal surface , a monolayer of endothelial cells , of artery directly exposes to blood and is susceptible to active substances in the blood .Exosomes contain significantly amount of proteins and RNAs .Ex-osomes can be good and bad for cells , depending on their component .Thus, exosomes may contribute to atherosclerosis by affecting endothelial cells .This study analyzed the relationship of exosome proteins and atherosclerosis .METHODS: Fifty-six patients and healthy subjects were recruited and divided into two comparisons:healthy subjects vs atherosclerosis ( HS vs AS) , and hypertension vs hypertension plus atherosclerosis ( HT vs HT+AS) .Serum exosomes were decoded by protein mass spectrometry .The protein profile and function were analyzed by gene ontology ( GO) .RESULTS:It was found that five child terms repeatedly appeared in “response to stimulus” and “immune system process” of BP of the two categories ( HS vs AS and AS vs HT+AS):“positive regulation of innate immune response”,“immune response-activating signal transduction”,”activation of innate immune response”,“innate immune re-sponse-activating signal transduction” and “innate immune response activating cell surface receptor signaling pathway ”.Two child terms repeatedly showed in “binding” of MF of the two categories:“antigen binding” and “enzyme binding”.Two proteins, PSMA6 and PSMA7, were repeatedly shown in the two categories .CONCLUSION:GO analysis was utilized for structure hierarchy “tree” to illustrate these proteins involved in various terms in BP , CC and MF.The PPI analysis supplied proteins which may play potentially im-portant roles in AS process .Innate immune system and blood coagulation pathway contribute to AS formation .The proteins, PSMA6, PSMA7 and Annexin A2, may can be the new target proteins for prevention and treatment of AS .

AIM:Early calcification of atherosclerotic plaques are colocalized with macrophage and high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions .Our study aims to evaluate whether HMGB1 induces ectopic mineralization via promoting the secretion of matrix vesicles ( MVs) from macrophages .METHODS:HMGB1 was added to the medium of macrophages , the secretion of MVs in the supernatant was tested by flow cytometry analysis .The mineral deposition in calcifying medium was detected by Alizarin Red staining and von Kossa staining .Transmission electron microscopy showed the formation of hydroxyapatite crystals in MVs .Then we subcutaneous injection into mice with MVs to induce regional minera-lization.RESULTS:HMGB1 significantly promoted secretion of MVs from macrophages as raveled by flow cytometry analysis .TNAP activity, considered as a marker of MVs maturation , was higher in HMGB1-induced MVs compared to the control-MVs.HMGB1-MVs also led to mineral deposition in an in vitro MVs-collagen mineralization model .Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization .Mechanistic experiments revealed that HMGB 1 activated neutral sphingomyelinase 2 ( nSMase2 ) that involved the receptor for advanced glycation end products ( RAGE ) and p38 MAPK (upstream of nSMase2).Inhibition of nSMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and min-eral deposition .CONCLUSIONS: HMGB1 induces MVs secretion from macrophages at least in part , via the RAGE/p38 MAPK/nSMase2 signaling pathway .Our findings thus reveal a novel mechanism by which HMGB 1 may participated in the early calcification of atherosclerotic plaques .

高糖状态下JAK2-STAT3通路的活化对系膜细胞转化生长因子β1、纤连蛋白表达的影响

JAK-STAT通路是近年发现的一组信号转导通路,能介导多种细胞因子和生长因子的细胞内信号转导过程.有研究提示JAK2-STAT3通路可能与系膜细胞的增殖、肥大及细胞外基质分泌有关[1].本研究旨在探讨高糖培养下大鼠肾小球系膜细胞JAK2-STAT3信号转导通路的活性变化及用AG-490(tyrphostin B42,JAK-STAT通路特异性阻断剂)抑制此通路活化对大鼠肾小球系膜细胞转化生长因子β1(TGF-β1)、纤连蛋白(FN)表达的影响,为进一步探讨JAK-STAT信号转导通路与糖尿病肾病发病机制的关系提供新的思路.

Wnt信号通路在肾病发病中的作用

Wnt信号通路早先发现时被认为其主要与细胞增殖旺盛的胚胎发育和肿瘤发生相关[1].目前研究发现,在肾脏发育及急性肾小管损伤中.Wnt信号通路发挥了积极的促进其发育和修复损伤的作用[2,3];但却又是多囊肾病及肾癌的关键发病机制之一[4,5].南此表明,肾脏的发育、形态以及功能的维持均有赖于Wnt信号通路正常"开启"和及时"关闭".本文就近年来Wnt信号通路在肾脏疾病发生、发展中的作用作一综述.

Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), a multifunctional endocytic and cell signaling receptor, is widely expressed on the surface of multiple cell types such as hepatocytes, ifbroblasts, neu-rons, astrocytes, macrophages, smooth muscle cells, and malignant cells. Emerging invitro and invivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression. For example, LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase (MMP)-2 and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor, the serine/threonine protein kinase signaling pathway, and the expression of Caspase-3. LRP1-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion. In addition, LRP1 has been shown to be down-regulated by microRNA-205 and methylation ofLRP1 CpG islands. Furthermore, a novel fusion gene,LRP1-SNRNP25, promotes osteosarcoma cell invasion and migration. Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

JAK-STAT3信号通路与非小细胞肺癌生物学行为相关性的研究进展

在世界上许多国家肺癌都是肿瘤致死的首要因素.于是针对肺癌生物学行为的研究也迅速开展起来,其中JAK-STAT3信号通路与非小细胞肺癌(non-small cell lungcancer,NSCLC)生物学行为相关性的研究逐渐受到重视.越来越多的证据表明,肿瘤的发生是基因改变累积的结果.

Mitogenic and Anti-apoptotic Effects of Insulin in En-dometrial Cancer Cells Are Phosphatidylinositol 3-ki-nase/Akt Dependent

Background and objective Endometrial carcinoma is the most common gynecologic malignancy in the world. Although the insulin-resistant state or hyperinsulinemia was recently suggested as a potent risk factor for endometrial carcinogenesis and progression, there is only limited supporting evidence and the mechanism is unclear. In this study, we explored the roles of phosphatidylinositol 3-k/nase (PI3K)/Akt signaling pathway in the response of a human endometrial cancer cell line, Ishikawa3-H-12 cells, to insulin.Methods The Ishikawa 3-H-12 cells were serum-starved and then stimulated by insulin at various concentrations and for different time periods. To identify the insnlin-mediated signal pathway in the cells, LY294002, a selective inhibitor of PI3K, was used. The proliferation and the apoptotic rates were determined with methyl thiazolyl tetrazolium (MTT) and flow cytometric assays, respectively.Results The insulin receptor positive Ishikawa 3-H-12 cells had enhanced proliferation upon insulin stimulation in a rinse-and time-dependent manner. The growth promoting effect of insulin was blocked when the cells were pre-incubated with LY294002 for 60 rains.Insulin was able to protect the cells from serum-starvation-induced apoptosis in a concentration-dependent manner, while the anti-apoptotic effects of insulin was reversed by adding LY294002. Treatment with insulin at 1 μM for 15 rain resulted in an increased level of activated Akt The insulin-induced Akt activation was inhibited by LY294002 in a dose-dependent manner.Conclusion Insulin activates PI3K/Akt signaling pathway and is a mitogenic and anti-apoptotic agent for Ishikewa 3-H-12 endometrial cancer cells.

Wnt信号通路与神经管缺陷关系的研究进展

神经管缺陷(neural tube,defects,NTD)是神经管闭合不全引起的一类先天性畸形,主要包括无脑、脑膨出、脑膜膨出和脊柱裂等.研究神经管发育机制及NTD致畸机制对预防畸形发生有一定的意义.Wnt信号通路在神经管发育过程中发挥重要的作用,不但参与了胚胎背腹轴的形成,而且与细胞极性建立、细胞命运决定等多个发育事件有关.阻断Wnt信号途径,动物胚胎会产生明显的突变表型,如果蝇的异常表皮、小鼠腹侧化肢体、线虫EMS细胞丧失不对称分裂等.近来研究发现,Wnt信号通路异常与神经管畸形发生密切相关,Wnt信号通路某一环节发生异常或中断都可能导致畸形的发生.

Objective:To study the effect of preoperative compound rhizomacurcumaepowder treatment on serum markers and related signaling pathways function in endometrial tissue of patients with endometriosis.Methods:Endometriosis patients in our hospital were chosen for study and randomly divided into the treatment group (n=35) and the control group (n=35). The treatment group received preoperative compound rhizomacurcumaepowder treatment; the control group received preoperative conventional treatment. Then serum markers and function of related signaling pathways in endometrial tissues were compared.Results:After drug treatment, serum SCF, SDC-1, HLA-G, VEGF and Ang-2 contents of treatment group showed a significantly decreasing trend; mRNA contents and protein contents of Wnt, Frizzled, Dsh,β-catenin, cyclinD1, integrinα6β1, ERK1, ERK2, MMP9 and MMP27 in ectopic endometrial tissue of the treatment group all showed a significantly decreasing trend.Conclusion:Preoperative compound rhizomacurcumaepowder treatment is helpful to control the condition of endometriosis and inhibit the activation of cell cycle related signaling pathways and invasion related signaling pathways in ectopic endometrial tissue.