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AIM:Atherosclerotic calcification is highly linked with plaque instability and cardiovascular events .Adenosine monophosphate-activated protein kinase ( AMPK) has been involved in the pathogenesis of various cardiovascular disease .The contributions of AMPKαsubunits to the development of atherosclerotic calcification in vivo remained unknown .We hypothesized that AMPKαsubunits may play a role in the development of atherosclerotic calcification .METHODS: Atherosclerotic calcification was generated by 24-week fed of western diet in ApoE-/-background mice .Calcification was evaluated in aortic roots and innominate arteries of ApoE-/-mice or in mice with dual deficiencies of ApoE and AMPKαsubunits globally ( AMPKα1 and AMPKα2 ) , or vascular smooth muscle cell ( VSMC)-specific or macrophage-specific knockout of AMPKα1 with atherosclerotic calcification pone diet . The mechanism of AMPKα1 in regulating Runx2 was further explored in human aortic VSMC .RESULTS: Ablation of AMPKα1 but not AMPKα2 in ApoE-/-background promoted atherosclerotic calcification with increased Runt -related transcription factor ( Runx2 ) expression in VSMC compared with ApoE-/-mice.Conversely, chronic administration of metformin, which activated AMPK, markedly reduced ath-erosclerotic calcification and Runx2 expression in ApoE-/-mice but had less effects in ApoE-/-/AMPKα1 -/-mice.Furthermore, VSMC-but not macrophage-specific deficiency of AMPKα1 in ApoE-/-background promoted atherosclerotic calcification in vivo com-pared with the controls .AMPKα1 silencing in human aortic VSMC prevented Runx 2 from proteasome degradation to trigger osteoblastic differentiation of VSMC .Conversely , activation of AMPK led to Runx 2 instability by inducing its small ubiquitin-like modifier modifi-cation (SUMOylation).Protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, was directly phosphorylated by
AMPKα1 at serine 510, to enhance its SUMO E3-ligase activity.Ablation of PIAS1 serine 510 phosphorylation inhibited metformin-in-duced Runx2 SUMOylation, and subsequently prevented the effect of metformin on reducing oxLDL-triggered Runx2 expression in hu-man aortic VSMC.CONCLUSION:Deficiency of AMPKα1 in VSMC increases Runx2 expression and promotes atherosclerotic calcifi-cation in vivo.AMPKα1 phosphorylates PIAS1 to enhance Runx2 SUMOyalation and subsequent degradation . -
血管紧张素Ⅱ通过p38丝裂原蛋白激酶通路上调人足细胞血管内皮生长因子表达
血管内皮细胞生长因子(VEGF)在.肾脏主要由足细胞产生[1].
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2013年ASCO黑色素瘤治疗新进展
2013年的ASCO年会上,黑色素瘤仍是与会专家学者关注的热点。
在近几年的ASCO大会上,黑色素瘤的治疗一直在创造一个又一个神话。3年前,细胞毒性T淋巴细胞相关抗原(CTLA)单抗ipilimumab(Ipi,商标名称为Yervoy)第一次被证实能够延长晚期黑色素瘤患者的总生存。2年前, BRAF抑制剂威罗菲尼(vemurafenib, PLX4032)将晚期黑色素瘤的疗效由过去的7%~8%,提高到53%,并大大延长无进展生存期(Progress Free Survival,PFS)和总生存期(Overall Survival,OS)。1年前,BRAF抑制剂联合MEK(有丝分裂原激活蛋白激酶,mintogen activated protein kinase,MAPK)或细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)抑制剂将晚期黑色素瘤治疗有效率提高到75%左右,并进一步延长了PFS,这种联合治疗的不良反应比单药明显降低。而今年,抗PD1/PD-L1单抗横空出世,对无特异基因突变的晚期患者治疗有效率达到35%~47%,并大大延长了PFS和OS,这彻底颠覆了专家学者既往对免疫靶向治疗有效率低的认识。 -
Rho激酶在心肌细胞凋亡和存活中的作用
Rho激酶又称Rho 相关卷曲螺旋形成蛋白激酶(Rho associated coiled-coil forming protein kinase, ROCK),作为小GTP结合蛋白Rho的下游效应分子,参与调节许多基本的细胞功能,如收缩、迁移、增殖和凋亡.自从1996年被发现以来,ROCK就备受关注,目前越来越多的研究表明Rho/ROCK信号转导通路在心血管疾病的发生和发展中起重要作用[1-2].既往研究认为ROCK信号在心肌细胞中起着促凋亡作用,但随着研究的深入发现ROCK还可能介导心肌细胞存活信号,使得我们对ROCK有了新的认识.本文就近年来ROCK在心肌细胞凋亡和存活中作用的研究进展作一综述.
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Rho相关卷曲螺旋蛋白激酶与细胞凋亡
细胞凋亡是生命的基本现象之一,可以发生在生理或病理条件下.形态学表现为胞膜对称性丧失、染色质凝集、细胞皱缩、DNA破碎、线粒体肿胀和凋亡小体形成.它与一系列复杂的生化反应及不同基因的表达及调控、信号转导系统的正负调节密切相关.近的研究表明,Rho相关卷曲螺旋蛋白激酶(Rho-associated coiled-coil containing protein kinase,ROCK)在调节多种细胞表型和动物疾病模型的凋亡方面起重要作用.本文就ROCK在细胞凋亡中所起的功能及作用作一综述.
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乙酰肝素酶与相关信号通路的研究进展
细胞的增殖、凋亡、调控失衡和恶性转化过程涉及多条信号转导通路的异常.许多癌基因由于信号转导通路的活化而表达,参与细胞重要的生理和病理过程.肿瘤的转移和侵袭与信号转导通路息息相关.这一过程中信号转导通路担当了重要的角色,本文将从蛋白激酶(mitogen-activated protein kinase,MAPK)、磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(Akt)、Wnt/β-catenin信号转导通路与乙酰肝素酶(heparanase,HPSE)之间的调控机制作一综述.
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以MAPK通路为靶向的肿瘤生物治疗
丝裂原激活蛋白激酶(mitogen-activated protein kinase, MAPK)是一组被不同的细胞外刺激(如生长因子、细胞因子、激素、药物及细胞应激等)激活的丝氨酸-苏氨酸蛋白激酶[1].MAPK通路的基本组成是一种从酵母到人类都保守的MAPK激酶激酶(MAPKKK)、MAPK激酶(MAPKK)及MAPK三级激酶模式.
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BRAF基因突变与甲状腺癌关系的研究进展
丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK),也叫细胞外信号调节激酶(extracellular signal-regulated kinase, ERK),是MAPK信号传导通路RAS→RAF→MEK→ERK的下游蛋白激酶,在肿瘤形成和生长、转移过程中起重要作用.70℅甲状腺癌与MAPK通路串联激酶的激活有关[1].甲状腺腺瘤、滤泡状腺癌(follicular thyroid cancer, FTC)主要与RAS基因突变有关;甲状腺乳头状癌(papillary thyroid cancer, PTC)与染色体重组致癌基因融合(RET/PTC1,RET/PTC3),BRAF基因突变等有关.目前,基因分型诊断已成为甲状腺癌的重要研究内容.散发性成年人PTC的BRAF基因突变率高,且有BRAF T1799A(V600E)突变热点,本文就BRAF T1799A突变基因型甲状腺癌的临床病理特性、预后以及临床应用前景综述如下.
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MKK7分子生物学特性及其与肿瘤关系的研究进展
丝裂原活化蛋白激酶( mitogen -activated protein ki-nase,MAPK)信号通路在介导细胞对生长因子、激素、细胞因子及环境压力等细胞外信号所引起的细胞生物反应中发挥重要作用。丝裂原活化蛋白激酶激酶7(mitogen -activated protein kinase kinase 7, MKK7,又称 JNKK2、 MEK7或SAPKK4),是丝裂原活化蛋白激酶激酶(mitogen -activated protein kinase kinase,MAPKK,MKK)家族成员,参与促炎细胞因子和环境压力应激下信号转导介导的细胞应答,在细胞增殖、分化、凋亡和肿瘤发生等生物学效应中扮演着重要的角色。然而,MKK7在肿瘤发生发展过程中的作用极其复杂,因此本文对 MKK7的生物学特性及其与肿瘤的关系作一综述。
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MAPK 信号通路与非酒精性脂肪肝关系的研究进展
丝裂原活化蛋白激酶(mitogen -activated protein kinase, MAPK)信号通路是哺乳动物体内广泛存在的信号通路,主要调节细胞的增殖、分化、迁移、凋亡、坏死等多种生理病理过程,包括 ERK1/2、P38MAPK、JNK 与 ERK54条信号通路,有研究发现 MAPK 信号通路参与了非酒精性脂肪肝(non -alco-holic fatty liver disease,NAFLD)的发生发展过程,本文就近年来 MAPK 信号通路与 NAFLD 形成关系的研究作一综述。
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小檗碱治疗多囊卵巢综合征患者胰岛素抵抗的机制
多囊卵巢综合征(polycystic ovary syndrome,PCOS)是育龄期女性常见的内分泌紊乱性疾病之一,以持续性无排卵、雄激素过多和胰岛素抵抗(insulin resistance,IR)为主要的临床特征[1],流行病学调查报道发病率高达6%~10%[2].IR是PCOS的重要病理生理变化,指外周组织对胰岛素敏感性降低,使胰岛素的生物效能低于正常[1].研究显示50%~60%PCOS患者存在IR[3].目前PCOS患者治疗IR主要采用胰岛素增敏剂二甲双胍,但因胃肠道反应常见,部分患者无法耐受[4].小檗碱(berberine),俗称黄连素,是从黄连等植物中提取的一种异喹啉类生物碱,具有广泛的药理作用.近年来有学者用小檗碱治疗糖尿病取得良好疗效,具有改善IR、降低血糖、纠正脂质紊乱的作用[5-8].目前小檗碱治疗糖尿病的机制尚不清楚,有研究提示可能是通过磷酸腺苷活化的蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)途径改善IR[9].下面就小檗碱经AMPK途径改善PCOS患者IR的相关机制进行综述.
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黄酮类化合物改善记忆的机制研究进展
黄酮类化合物是一类具有显著抗氧化和螯合性能的次生植物酚类物质。黄酮类化合物能够诱导提高记忆的获取、巩固、存储和重现。它们通过作用于记忆相关脑区的细胞和分子结构来有效地逆转与年龄相关的记忆力减退。它们可能涉及激活细胞外信号调节激酶(extracellular signal-regulated kinase 1/2, ERK1/2)和cAMP应答元件结合蛋白(cAMP-response element binding protein, CREB)信号通路,磷脂酰肌醇-3-羟激酶/丝氨酸/苏氨酸蛋白激酶(phosphatidyl inositol 3-kinase/serine/threonine protein kinase, PI3K/Akt)信号通路,诱导产生海马区血管效应,抑制神经炎症反应等。本文就黄酮类化合物改善记忆力的机制进行综述。
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钙调素及钙调素依赖性蛋白激酶Ⅱ与新生儿脑损伤
新生儿脑损伤(Brain damage.BD)是围产期各种原因所引起的,其中常见的原因是中、重度窒息所致的缺氧缺血性脑病(HIE),其次是颅内出血引起的脑局部缺血损伤,再有是高胆红素血症所致的胆红素中毒性脑病.HIE被认为是多因素共同作用所致,其早、基本的是能量代谢障碍,随后发生一系列"瀑布"反应如氧自由基生成增加,细胞内钙超载以及兴奋性氨基酸毒性作用等,促使受损神经细胞趋向死亡,其死亡形成以凋亡为主,严重时可出现坏死,同时存在大量细胞凋亡(1).胆红素中毒性脑病是由于未结合胆红素(UCB)在脑细胞的沉积所致,其发病与某些危险因素相关,如新生儿临床状态与血清胆红素水平,血脑屏障功能状态与脑内胆红素水平,胆红素联结状态与游离胆经素水平等,导致脑细胞功能状态与能量代谢水平变化均为危险因素(2).近年来,通过使用神经分子化学技术对BD的机理研究发现BD与钙(Ca2+)及钙调素(Calmodulin.CaM)以及靶酶钙调素依赖性蛋白激酶Ⅱ(Ca2+/CaM-dependent Protein KinaseⅡ,Ca2+/CaM PK Ⅱ)的变化有密切关系.现就有关此方面的新研究综述如下.
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p38MAPK与血管再狭窄
p38 mitogen-activated protein kinase(p38MAPK)是丝裂素激活蛋白激酶超家族的新成员,参与多种细胞的胞内信号传递.p38MAPK调节着细胞的许多应激反应[1,2].近年的研究表明,p38MAPK参与多种生物反应,特别是在肌细胞分化中起着至关重要的作用[3-4].本文就其在血管再狭窄中对血管平滑肌和内皮细胞增殖的影响作一综述.
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LKB1-AMPK-mTOR信号传导通路在肿瘤中的研究进展
肿瘤可以认为是一种基因疾病,其中癌基因的激活和抑癌基因的失活是肿瘤发生、发展过程中为关键的环节之一[1].近年来,一个新的抑癌基因LKB1,又名STK11(serine threonine protein kinase 11),在肿瘤中的作用引起了越来越多的关注.哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路是目前肿瘤信号传导通路研究的热点之一.
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P38MAPK与糖尿病肾病
糖尿病(DM)时,蛋白质非酶糖化、多元醇通路激活、蛋白激酶C(PKC)激活、氧化应激、肾脏血流动力学改变、遗传等相关病因病机对糖尿病肾病(DN)细胞内信号转导通路产生影响.目前有丝分裂原蛋白激酶(mitogen-activated protein kinase,MAPK)、一种与PKC相关在细胞信号通路中起重要作用的蛋白激酶在糖尿病肾病发病中受到重视,其亚族P38MAPK成为细胞信号传导和糖尿病肾病研究热点.
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P38MAPK信号传导通路与炎症性肠病
丝裂原活化蛋白激酶(mitogen-actived protein kinase,MAPK)介导了细胞的生长、发育、分裂、死亡、以及细胞间的功能同步等多种细胞生理过程.目前在哺乳动物中已发现和成功克隆了ERK、JNK/SAPK、P38MAPK、BRK5四个MAFK亚族,这些MAPK介导了炎性细胞子、细菌产物、物理、化学应激等多种刺激引起的细胞反应.在生物进化过程中,MAPK信导传导的三级激酶级联反应高度保守,即MAPKKK(MAP kinase kinase kinase)→MAPKK(MAP kinase kinase)→MAPK.细胞受到刺激后,MAPKKK首先被磷酸化而激活,然后转而磷酸化激活MAPKK,激活后的MAPKK通过对苏氨酸和酪氨酸双位点的磷酸化激活MAPK.不同的MAPK被不同的细胞外刺激所调节,并具有不同的底物作用特异性.细胞对特定的刺激起反应,引起特定的细胞生理反应,说明细胞内每条MAPK信号传导通路具有相对独立的功能.其中,P38MAPK在介导炎症、应激等细胞反应中为引人注,是目前信号传导领域研究的热点.本文结合国内外文献综述了P38MAPK的结构特征、组成成员、激活与生物学效应,及其在炎症性肠病发病机制中的作用与治疗前景,旨在为炎症性肠病的诊治研究提供一条新的途径[2].
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酪氨酸蛋白激酶及其抑制剂在肝星状细胞激活中的研究进展
肝纤维化(liver fibrosis)是继发于肝脏炎症或损伤后组织修复过程的代偿反应,表现为细胞外基质(extracellular matrix,ECM)在肝内过量沉积.[1] .肝星状细胞(又称贮脂细胞,Ito细胞或窦周细胞,hepatic stellate cells,HSC)激活并转化为肌成纤维样细胞(myofibroblastic-like cell,MFLC)和成纤维细胞(fibroblast cell,FC)是肝纤维化发生、发展的核心环节.[2] .酪氨酸蛋白激酶(tyrosine protein kinase,TPK)在HSC激活过程中细胞内信号传递方面起了重要的作用.酪氨酸蛋白激酶抑制剂(tyrosine kinase inhibitor,TKI)可能通过抑制细胞内信号传导而影响HSC激活.本文就酪氨酸蛋白激酶、酪氨酸蛋白激酶抑制剂与肝星状细胞的激活作一综述.
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于福興實驗室研究計劃
1 Molecular regulation of corneal wound healing Rapid healing of the corneal epithelium in response to injury is essential for maintenance of its barrier function. The long-term goal of this project is to obtain basic information about the molecular and cell biology of corneal wound healing. The project will test the hypotheses that amyloid β/A4 precursor-like protein controls serine proteinase activity, mediates cell adhesion, and promotes cell migration during corneal reepithelialization. This study should provide the basis to begin constructing a detailed nap of the molecular pathways and interconnecting networks of proteins functioning in wound repair and to develop therapeutics for treatment of corneal diseases like recurrent erosions and persistent defects of the epithelium.2 Developing an ex vivo model for ocular irritation testThe objective of this project is to develop an ex vivo assay system to predict ocular irritation potential of test chemicals and consumer products. Our hypothesis has been that activation of these transcription factors and disruption of corneal integrity can be used as endpoints/ markers for evaluating ocular toxicity in organ culture. Our goal is to develop a sensitive, efficient, economical and reliable ex vivo model for predicting irritation potential of a chemical or consumer product with mechanistic basis.3 Modulation of epithelial barrier function during corneal infectionThe long-term goal of this project is to understand the mechanisms underlying the induction of the inflammatory reaction and breakdown of the epithelial barrier in the cornea upon infection. We will test the hypothesis that in the cornea TLRs confer responsiveness of HCE cells to pathogens, and PA challenge-induced TLR signaling, through activation of NF-?B and/ or mitogen-activated protein kinase (MAPK), contributes to infection-induced epithelial barrier breakdown. The following studies will be carried out. An understanding of how TLRs transmit signals that lead to epithelial response, including modulation of barrier function,may allow the development of therapeutic agents that prevent breakdown or enhance recovery of barrier function during infection and, as an adjuvant therapy, eliminate the corneal scarring and vision loss associated with bacterial keratitis.4 Developing an adjuvant therapy to reduce inflammatory response induced by bacterial infection of the cornea (bacterial keratitis).
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肝纤维化发生中的MAPK信号传导通路
慢性肝病的重要病理基础是肝纤维化,慢性肝病通过纤维化的发展走向肝硬化.近年来丝裂原激活蛋白激酶(Mitogen activated protein kinase,MAPK)通路是激活后向核内转移,作用于核内转录因子的一个蛋白激酶家族.MAPKKK对MAPKK的丝氨酸、苏氨酸双位点磷酸化而将其活化;进而MAPKK对MAPK进行苏氨酸、丝氨酸双位点磷酸化活化,活化后的蛋白激酶转移至核内激活相应的基因受体,进而促进相应基因的表达.