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磷酸腺苷活化蛋白激酶对能量代谢平衡作用
能量是生物体生存的物质基础,因此,保持能量平衡对于生存具有关键作用.磷酸腺苷活化蛋白激酶(AMP-activated protein kinase ,AMPK)在调节细胞能量代谢平衡的蛋白激酶级联反应中起重要作用,特别是在能量供应不规律时维持机体代谢平衡,在胰岛素抵抗和代谢综合征的发生过程中均扮演重要角色.近年来,发现2种治疗糖尿病的一线药物-二甲双胍和罗格列酮均可以在肌肉组织中激活AMPK.本文对AMPK作用机制及其在2型糖尿病等代谢性疾病治疗中的作用作一综述.
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以表皮生长因子受体为靶点的抗癌新药--C225
酪氨酸蛋白激酶(tyrosine protein kinase,TPK)在细胞增殖及分化过程中具有重要的调控作用,TPK介导的细胞信号传递系统异常与肿瘤的发生和发展关系密切,大多数TPK能增强肿瘤细胞的能力和特征.表皮生长因子受体(epidermal growth factor receptor,EGFR)是TPK受体超家族中的重要一员,以EGFR为靶点的抗肿瘤治疗是当前分子靶向治疗的热点.
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氧化应激激活的信号转导通路与糖尿病合并症
糖尿病(DM)发病率及糖耐量异常人群在发达国家一直呈上升趋势,DM对人类健康的主要威胁来自于其合并症.近来的研究表明应激激活信号转导通路--核转录因子(NF-κB)、促细胞分裂剂激活性蛋白激酶(mitogen-actioted protein kinase,P38MAPK)和N端Jun激酶/应激激活的蛋白激酶(NH2-terminal Jun Kinases/stess-activated-protein kinnsse,JNK/SAPK)与DM合并症密切相关,而高血糖又是诱导NF-κB、p38MAPK及JNK/SAPK应激激活通路的始动环节之一[1,2,33~35].
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粘着斑激酶在甲状腺乳头状癌中的免疫组织化学研究
粘着斑激酶(focal adhesion kinase,FAK)是整合蛋白介导的信号转导过程中的中心分子.FAK参与形成粘着斑、Ras和丝裂原激活蛋白激酶(mitogen activated protein kinase,MARP)组成的信号转导通路、细胞周期和某些其它细胞生物学行为的调控[1].有文献报道FAK在浸润性及转移性直肠癌、乳腺癌、胃癌[2,3]中分布的量显著增多,但对甲状腺癌FAK研究的报道甚少[4].本研究采用免疫组织化学方法,对70例甲状腺乳头状癌的FAK分布情况进行研究,并探讨其意义.
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系膜细胞丝裂原活化蛋白激酶在糖尿病肾病发病中的作用
蛋白激酶C(PKC)在糖尿病肾病发病中的作用已受到广泛重视和研究[1].本研究采用免疫组化和激光共聚焦显微镜技术,观察丝裂原活化蛋白激酶(MAPK)在糖尿病大鼠肾脏中的表达和作用,并探讨其激活机制.
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JNK在沙土鼠脑缺血预处理中的作用及机制
Kitagawa等[1]在沙土鼠脑缺血的实验研究中,首次观察到机体对短暂亚致死性缺血的适应性反应能增加神经元对致死性缺血的耐受性,由此提出了脑缺血预处理(ischemic preconditioning, IP)的概念.此后各国学者对IP的机制进行了广泛的研究,提出了许多假说.近年来,以受体激活为起点,以细胞内信号转导为主线,构成预处理保护机制研究的重点,其中丝裂原激活的蛋白激酶(mitogen activated protein kinase, MAPK)途径在IP中的作用引起了人们的关注.
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死亡相关蛋白激酶与肿瘤关系的研究进展
死亡相关蛋白激酶(death-associated protein kinase,DAPK)是以色列Kimchi及其同事于1995年在基因组中扫描启动细胞凋亡的基因和抑癌基因时发现的一种钙调蛋白(CaM)调节的丝氨酸/苏氨酸蛋白激酶,是凋亡的正性调节因子之一,广泛参与多种途径介导的细胞凋亡,被认为是肿瘤的抑制剂,因其启动子区CpG岛高甲基化使基因转录沉默而失去功能,与肿瘤细胞的形成转移有关等原因备受人们的关注.本文将对DAPK的结构、功能、介导凋亡的途径及与肿瘤的关系作一综述.
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胃癌组织中DNA依赖性蛋白激酶KIP2表达及意义
DNA依赖性蛋白激酶(DNA-dependent protein kinase catalytic subunit,DNA-PKcs)是唯一由DNA末端激活的真核细胞激酶,它在双链DNA损伤修复中起重要作用.生化分析指出DNA-PKcs激酶只有DNA末端连接蛋白存在时才能激活,Seki等从人胎脑cDNA文库中分离出该蛋白的全长cDNA,命名为激酶相互作用蛋白2(kinase interacting protein2,KIP2),它与钙连接蛋白KIP/CIB、神经钙蛋白B(calcineurin B)和钙调节蛋白(calmodulin)分别具有46%、39%和30%的同源性.
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转录因子NF-κB与胰岛素抵抗关系
胰岛B细胞分泌的胰岛素与靶细胞表面胰岛素受体(In-sulin receptor,IR)结合后,激活IR内在的酪氨酸蛋白激酶活性,IR进而联结并激活含有酪氨酸残基(Tyr)的下游信号分子-Shc蛋白和胰岛素受体底物(Insulin receptor substrate,IRS-1、2),Shc与IRS蛋白通过自身的酪氨酸蛋白激酶活性激活下游分子来启动胞内有丝分裂原激活的蛋白激酶(Mito-gen-activated protein kinase,MAPK)及磷脂酰肌醇-3激酶(Phosphatidylinositol 3-kinase,P13-K)两条信号通路.
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海马5-羟色胺系统与抑郁症
抑郁症是危害全球人类心理健康的主要疾病之一.伴随着神经递质假说和受体假说的提出,5-羟色胺(5-hydroxytryptamine,5-HT)系统功能紊乱受到人们的关注.海马5-HT系统,特别是5-HT受体的功能改变在抑郁症脑机制和抗抑郁治疗中具有重要作用.其中5-HTiA受体功能失调是目前研究热点之一.5-HTiA受体通过"受体-G蛋白-环磷酸腺苷(cyclase adenosine monophosphate,cAMP)"信号传导系统,或者丝裂原蛋白激酶(mitogen-activated protein kinase,MAPK)通路发生改变,影响海马突触可塑性和长时程增强(l0ng-term potentiation,LTP)的产生,成为抗抑郁治疗的主要靶点.而且5-HT系统功能紊乱可能使应激初期即出现的皮质激素维持在高水平.在抑郁症患者中海马区体积选择性缩小,这种缩小与抑郁症的复发次数、持续时间及用药史有关[1],并且海马区的功能活动与抑郁症的症状有关.故本文选择海马5-HT系统作为切入点,综述海马5-HT系统与抑郁症的关系.
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MAPK信号转导在糖尿病肾病免疫机制中作用的研究进展
越来越多的研究结果表明2型糖尿病(Type 2 Diabetes Mellitus,T2DM)的发生与自身免疫机制有关,糖尿病肾病(Diabetic Nephropathy , DN)发病的免疫机制研究已成为T2DM研究的重点课题之一.丝裂原活化蛋白激酶(Mitogen Activated Protein Kinase,MAPK)家族作为免疫家族中的一员,是DN不同信号通路的交汇点,在其信号转导中扮演重要角色.本文就其目前研究进展综述如下.
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原发性肝癌患者血清死亡相关蛋白激酶基因启动子甲基化的检测
原发性肝癌(Hepatocellular carcinoma,HCC)是常见恶性肿瘤之一,如何早期发现是人们一直在探寻的课题.
关键词: 原发性肝癌 患者血清 死亡相关蛋白激酶基因 启动子甲基化 检测 protein kinase 早期发现 恶性肿瘤 课题 -
ERK5激酶及其与神经系统发生发展及疾病的关系
丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是丝氨酸/苏氨酸蛋白激酶的一个家族,可将细胞外刺激传递至细胞内,对生长因子和不同形式的压力作出应答,是真核细胞中主要的激酶传导通路[1].MAPKs调节细胞许多功能,包括细胞增殖、分化、新陈代谢和凋亡.在MAPK通路中信号通过三层连续的激酶传递,MAPKKK,MAPKK和MAPK,后两种激酶激活需双重磷酸化[2].在哺乳类动物中MAPK分为四个亚型,细胞外信号调节激酶1/2 (extracellular signal-regula-ted kinase,ERK1/2)、c-Jun 氨基末端激酶(c-Jun N-terminal kinase,JNK)、p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38MAPK)和细胞外信号调节激酶5(extracellular-regulated kinase 5,ERK5).近年ERK5已成为研究热点,是多种疾病尤其癌症新的治疗靶点,它在细胞增殖、存活及血管生成中起关键的作用,在神经系统发生发展及疾病的研究也逐步深入.
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p38 MAPK 信号转导通路研究进展
丝裂原活化蛋白激酶( mitogen activated protein kinase, MAPK)是细胞内的一类丝氨酸/苏氨酸蛋白激酶,它存在于大多数细胞内,是真核细胞转导细胞外信号到细胞内引起细胞反应的一类重要信号系统.它通过影响基因的转录和调控,进而影响细胞的生物学行为,如细胞增殖、分化、转化及凋亡等 [1].研究发现,其中的 p38 MAPK信号通路参与了细胞的生长发育及细胞间功能同步等多种生理过程,并与炎症、应激反应的调控密切相关,被认为是细胞信息传递的交汇点和共同通路.
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p38 MAPK在细胞内的定位及其对LPS刺激的反应
丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)转导通路调节着生长、分化、凋亡、细胞周期、应激反应等多种细胞过程.p38通路是新近鉴定的一条MAPK信号转导通路,参与了炎症、应激、细胞周期和凋亡等病理生理过程.蛋白激酶特定的细胞内定位及其在特定刺激作用下的移位是细胞信号维持特异性转导的重要机制之一.为了探讨p3 8信号转导的过程及其特异性机制,本研究应用激光共聚焦显微镜对p38 MAPK 4种不同的亚型在单核细胞、平滑肌细胞、心肌细胞和内皮细胞在静息和受到不同刺激的条件下的细胞内定位进行了观察,发现未受刺激的静止单核细胞,p38(α)蛋白激酶处于未激活状态,弥漫性地分布于细胞中;单核细胞、平滑肌细胞、心肌细胞和内皮细胞在受到LPS刺激后,p38( α)由胞浆移位到胞核;LPS 刺激单核细胞15 min后,p38开始出现明显的细胞核移位,于L PS刺激后45 min入核量(核区荧光强度)达到峰值,之后维持于平台期.LPS诱导RAW细胞p 38激酶活性呈一过性增强,在LPS刺激后2 h其活性逐渐恢复到接近基础水平.LPS刺激RAW细胞 p38移位入核明显滞后p38激活过程,提示p38移位后入细胞核依赖于p38磷酸化活化,p38磷酸化活化及由细胞浆移位到细胞核是一系列相继发生的连续事件.用p38-红色荧光蛋白融合表达载体在哺乳动物细胞的转染实验也证实了上述结果.
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It is well known that the main brain lesion in Alzheimer's disease (AD) brain is neurofibrillary tangles (NFT) and senile plaques (SP). The amount of NFT is positively correlated with clinical degree of dementia in AD. It is also well studied that the major component of NFT is abnormally hyperphosphorylated microtubule associated protein tau that is caused by an imbalance of protein kinase and protein phosphatase (PP). To reconstitute a specific AD model based on the above hypothesis, we have injected separately calcium calmodulin dependent protein kinase (CaMKKII) activator, bradykinin and PP-2B inhibitor, cyclosporin A into rat hippocampus in the present study. The results showed that the injection of bradykinin caused learning and memory deficient in rats as well as Alzheimer-like tau phosphorylation, including Ser-262/356, Thr-231/235 and Ser-396/404. On the other hand, the injection of cyclosporin A induced the same phosphorylation sites as above except Ser-262/356, however, it did not mimic rat behavior abnormality as bradykinin injection did. The data suggested that activating of CaMKII and the phosphorylation of Ser-262/356 at tau might responsible for the lesion of learning and memory in our model rats. We also incubated PP-2A and PP-1 inhibitor, okadaic acid with human neuroblastoma cell line (SH-SY5Y), and found that (1) inhibition of above PPs induced Alzheimer-like phosphorylation and accumulation of neurofilaments, and Alzheimer-like microtubule disruption, (2) melatonin showed certain protection of the cell from okadaic acid toxicity. The data obtained from this study is significant in AD specific model study.
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Bradykinin (BK) is a calcium/calmodulin dependent protein kinase Ⅱ (CaMKⅡ) specific activator, and Cyclosporin A (CSA) is reported to suppress protein phosphotase (PP)-2B activity. In vitro studies have shown that CaMKⅡ and PP-2B play an important role in Alzheimer-like phosphorylation of microtube-associated protein tau. To reconstitute an animal model based on the imbalance of protein kinase (s) and protein phosphatase (s) seen in Alzheimer brain, we injected BK and/or CSA into rat hippocampus. The results from behavioral study showed that an obvious disturbance in learning and memory was seen with BK or BK plus CSA injected rats. Moreover, the behavior abnormality appeared earlier in aged rats than young adults of the same kind after the injection. On the other hand, no obvious dysfunction in living and behavior was observed with CSA alone injected rats. The results obtained by immunohistochemical assay indicated that the staining for M4\, 12E8\, PHF-1 and CaMKⅡ was stronger, and for Tau-1 was weaker in BK injected rats compared with Control group. It was also found that the binding of M4 and PHF-1 but not 12E8 to tau was significantly increased in CSA injected rats. As the same as BK injection, binding of Tau-1 to tau was decreased after CSA injection. The immunostaining for 12E8\,PHF-1 and CaMKⅡ was increased, whereas for Tau-1\, M4\, and GSK-3 was decreased after combination injection of BK and CSA. In addition, the staining of PP-2B decreased in all the three models. To our knowledge, this is the first data shown in vivo that the activation of CaMKⅡ induces both Alzheimer-like tau phosphorylation and behavioral disturbance.
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The primary action of corticotropin releasing hormone (CRH) is stimulation of the synthesis and release of adrenocorticotropic hormone and β-endorphin from the pituitary in response to stress. In addition, a number of studies indicate that CRH exerts other physiological actions within the central nervous system which are independent of the pituitary. These include increased body temperature and thermogenesis. However, the intracellular mechanism responsible for pyrogenic action of CRH is still unclear. The purpose of these studies was to determine whether or not cAMP was involved in the pyrogenic action of CRH in the rat. Intracerebroventricular (icv) microinjection of CRH (2.5 μg, 5.0 μg, 10 μg) caused increases in colonic temperature and hypothalamus cAMP level in conscious rats. The pyrogenic effects of CRH were abolished or markedly inhibited by prior injection (icv) of an adenylate cyclase inhibitor, 2,,3,-dideoxyadenosine (DDA, 30 μg) or an inhibitor of cAMP-dependent protein kinase, adenosine-3,,5,-(cyclic) monophosphorothionate (Rp-cAMPs, 15 μg). This is the first report demonstrating the pyrogenic effcet of centrally administration of CRH on the rat via the cAMP-mediated protein kinase signal transduction pathway.
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AIM:Cytochrome P450 epoxygenase 2J2 and epoxyeicosatrienoic acids ( EETs) are known to protect against cardiac hypertrophy and heart failure, which involve activation of 5′-AMP-activated protein kinase ( AMPK) and Akt.Although the functional roles of AMPK and Akt are well established , the significance of crosstalk between them in the development of cardiac hypertrophy and anti -hy-pertrophy of CYP2J2 and EETs remains unclear .Here, we investigated whether CYP 2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1.Moreover, we tested whether EETs enhanced crosstalk between AMPKα2 and phosphorylated Akt1 ( p-Akt1), and stimulated the nuclear translocation of p-Akt1, to exert their anti-hypertrophic effects. METHODS:The recombinant rAAV9 vector was coupled to CYP2J2 and the rAAV9-CYP2J2 construct was injected into the caudal vein of AMPKα2-/-and littermate control mice .AMPKα2 -/-and littermate control mice that overexpressed CYP 2J2 in heart were treated with angiotensin II (Ang II) for 2 weeks.Hemodynamic and cardiac functions were also evaluated after 14 days of infusion with Ang II or saline.RESULTS:Interestingly, the overexpression of CYP2J2 suppressed cardiac hypertrophy , including decreased heart size, cross sectional area of cardiomyocytes , markers of cardiac hypertrophy [ brain natriuretic peptide ( BNP) ,β-myosin heavy chain (β-MHC) and skeletal muscle α-actin (ACTA1)] and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild-type mice but not AMPKα2 -/-mice.Measurement of left ventricular ejection fraction and fractional shortening showed that CYP2J2 overexpression prevented Ang II-induced ventricular systolic dysfunction in mice .Moreover, an Ang II-induced reduction in cardiac function, demonstrated by decreased dp/dtmax and dp/dtmin, was prevented by overexpression of CYP2J2.Mechanistically, the CYP2J2 metabolites 11,12-EET activated AMPKα2 to induce the nuclear translocation of p-Akt1, which increased production of ANP and thereby inhibited the development of cardiac hypertrophy .Furthermore , by co-immunoprecipitation analysis , we found that full-length Akt1 and an Akt1 fragment containing amino acids 150-408, which constitute the protein kinase domain , but not other frag-ments of Akt1, bind to the AMPKγ1 subunit.AMPKα2β2γ1 and p-Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain.This interaction was enhanced by 11,12-EET.CONCLUSION:Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hy-pertrophy and suggest that overexpression of CYP 2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure .
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AIM:Programmed necrosis ( necroptosis ) and apoptosis are crucially involved in multiple severe cardiac pathological conditions , including myocardial infarction, ischemia/reperfusion (I/R) injury, and heart failure.Whereas apoptotic signaling is well defined, the mechanisms underlying cardiomyocyte necroptosis remain elusive .METHODS AND RESULTS:Here we show that both mRNA and protein levels of receptor-interacting protein 3 (RIP3) in the hearts are increased by I/R injury and doxorubicin (Dox) treatment. In mice, RIP3 deficiency ameliorates myocardial necroptosis and heart failure induced by I /R (30-min ischemia/4-h or 8-week reper-fusion) or Dox treatment (20 mg/kg or 5 mg/kg ×4, i.p.).RIP3 overexpression induces cardiomyocyte necroptosis evidenced by de-creased intracellular ATP level and increased lactate dehydrogenase concentration in cell culture medium .RIP3 triggers myocardial ne-croptosis via activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), rather than the well-established RIP3 partners, RIP1 and MLKL (mixed lineage kinase domain-like protein).Specifically, our data indicate that I/R and Dox markedly activate myo-cardial CaMKII in wild-type but not RIP3-deficient mice , and that CaMKII inhibition or RIP 3 deficiency protect the heart from I/R-and Dox-induced cardiomyocyte necroptosis , cardiac remodeling and heart failure .Mechanistically , RIP3 activates CaMKII via both di-rect phosphorylation and indirect reactive oxidative species-dependent oxidation , and subsequently triggers opening of the mitochondrial permeability transition pore ( mPTP) and myocardial necroptosis .CONCLUSION: These findings identify CaMKII as a novel RIP 3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway , a promising target for the treatment of cardiac ischemic and oxidative damage , and heart failure .