丝裂原活化蛋白激酶在急性肝损伤发病机制中的作用

<正>肝脏是体内最大的消化器官,在机体代谢和内环境稳态维持过程中起着重要作用。但由于肝脏是一个高度血管化的器官,因此也是创伤失血性休克及内毒素性休克后最易受损器官之一,急性肝损伤也成为重症监护室病死率较高的一种危重病。研究表明,丝裂原活化蛋白激酶(MAPKs)信号通路参与多种病理及生理过程的调节,是失血性休克及内毒素性休克致急     

丝裂原活化蛋白激酶及其抑制剂与哮喘

丝裂原活化蛋白激酶信号转导通路是一类在进化过程中非常保守的信号通路,其通过细胞因子、生长因子、神经递质以及各种环境应激在信号转导中起重要作用。在哮喘中,这些胞外刺激引发出复杂的炎症反应和结构改变,包括T细胞的活化、嗜酸粒细胞和肥大细胞浸润、气道高反应性以及气道重构等等,在哮喘的发病机制中起着至关重要的作用,而研制相应的抑制剂必将在哮喘的治疗中具有重要意义。     

缺血性脑血管病与丝裂原活化蛋白激酶

丝裂原活化蛋白激酶（MAPK）是信号从细胞表面转导到细胞内部的重要传递者，参与细胞生长、增殖、分化、凋亡和细胞间功能的同步等多种生理学过程。脑缺血早期MAPK可被激活，在缺血区胶质细胞和神经元表达增加，并呈现为时间相关性，提示MAPK信号通路在脑缺血神经元凋亡过程中起重要的调控作用，在信号通路水平阻断和凋控MAPK表达和活性有望成为治疗缺血性卒中的一条新的途径。     

丝裂原活化蛋白激酶激活的蛋白激酶2在心血管系统中的作用

心血管疾病的发生发展与慢性炎症有关。p38丝裂原活化蛋白激酶(MAPK)介导的信号通路在心血管细胞炎症、增殖、分化、迁移和代谢中起着重要作用。抑制p38MAPK可有效抑制炎症介质的表达,由于p38抑制剂在安全性方面不可接受,故研究其下游底物是很有必要的。丝裂原活化蛋白激酶激活的蛋白激酶2(MK2)是p38MAPK重要的下游底物且参与了心血管疾病的发生发展。因此抑制MK2的活性在心血管疾病的治疗及预防中具有重大的临床意义。文章主要对MK2的结构功能和在心血管疾病中的作用展开综述。     

p38丝裂原活化蛋白激酶在肿瘤治疗中的作用

p38丝裂原活化蛋白激酶(p38MAPK)最早因为与应激相关而引起注意,近来发现它在多种肿瘤包括宫颈癌,卵巢癌,肝癌,淋巴瘤中,与凋亡的启动、细胞周期的静止等密切相关,并且具有细胞特异性,在不同肿瘤细胞作用并不相同,甚至起了完全相反的作用.因此,具体研究p38MAPK信号途径在各种肿瘤及正常细胞中的作用可为进一步的肿瘤治疗提供理论指导.     

缺血性脑血管病与丝裂原活化蛋白激酶

丝裂原活化蛋白激酶(MAPK)是信号从细胞表面转导到细胞内部的重要传递者,参与细胞生长、增殖、分化、凋亡和细胞间功能的同步等多种生理学过程。脑缺血早期MAPK可被激活,在缺血区胶质细胞和神经元表达增加,并呈现为时间相关性,提示MAPK信号通路在脑缺血神经元凋亡过程中起重要的调控作用,在信号通路水平阻断和调控MAPK表达和活性有望成为治疗缺血性卒中的一条新的途径。     

丝裂原活化蛋白激酶信号转导通路与骨质疏松

丝裂原活化蛋白激酶(MAPK)是信号从细胞表面传导到细胞核内部的重要传递者，包括细胞外信号调节激酶(ERK)、p38、c-Jun氨基末端激酶(JNK)和ERK5。某些与骨质疏松相关的因子如核因子．xB受体活化因子配体(RANKL)、白介素(IL)-1、IL-6、转化生长因子．B、骨形态形成蛋白等通过与MAPK信号转导通路相互作用，参与了成骨细胞和破骨细胞的分化、增殖和凋亡的信号转导，在骨质疏松症的发生中发挥了重要作用。     

丝裂原活化蛋白激酶在幽门螺杆菌致胃癌发生中的作用机制研究

大量研究表明 ,幽门螺杆菌 (Hp)感染与人胃癌发生有关。丝裂原活化蛋白激酶 (MAPK)是细胞内信号的重要传递者 ,但MAPK是否参与了Hp感染致胃癌的过程尚不清楚。我们检测胃癌及癌前病变中MAPK的表达及其与Hp感染的关系 ,探讨MAPK在Hp感染致胃癌发生中的作用。一、材料和方法1.病例及分组 :12 0例标本随机选自我院行胃癌切除术及行胃镜检查的患者 ,4周内服用过抗Hp药物及抗生素者剔除。其中慢性萎缩性胃炎及肠上皮化生组 4 4例 ,不典型增生组 12例 ,胃癌组 37例 ,以大致正常胃黏膜或慢性浅表性胃炎 2 4例作为对照组。上述标本均经 10 …     

P38丝裂原活化蛋白激酶在肝纤维化中的作用

丝裂原活化蛋白激酶是生物体内重要的信号转导系统之一,在细胞的生长、发育、分化等方面发挥重要作用。P38丝裂原活化蛋白激酶是其中的重要一员。本文对近年来有关P38丝裂原活化蛋白激酶信号通路对肝星状细胞的调控作用及其在肝纤维化模型动物的表达进行了综述。     

丝裂原活化蛋白激酶系统与主动脉瘤发生的研究进展

<正>动脉硬化性主动脉瘤是老龄化社会的常见病,其发生机制未明。丝裂原活化蛋白激酶(Mitogen-activated protein ki-nase,MAPKs)是进化保守的酶系,在细胞表面受体与细胞内重要调节靶位之间起重要的信号传递作用。MAPKs对细胞外的理化信号做出反应,以控制细胞的生存与适应。哺乳动     

Evidence for a role of mitogen-activated protein kinases in the treatment of experimental acute pancreatitis

Acute pancreatitis(AP) is an inflammatory disease characterized by acute inflammation and necrosis of the pancreatic parenchyma. AP is often associated with organ failure, sepsis, and high mortality. The pathogenesis of AP is still not well understood. In recent years several papers have highlighted the cellular and molecular events of acute pancreatitis. Pancreatitis is initiated by activation of digestive enzymes within the acinar cells that are involved in autodigestion of the gland, followed by a massive infiltration of neutrophils and macrophages and release of inflammatory mediators, responsible for the local and systemic inflammatory response. The hallmark of AP is parenchymal cell necrosis that represents the cause of the high morbidity and mortality, so that new potential therapeutic approaches are indispensable for the treatment of patients at high risk of complications. However, not all factors that determine the onset and course of the disease have been explained. Aim of this article is to review the role of mitogen-activated protein kinases in pathogenesis of acute pancreatitis.     

黏附分子和动脉粥样硬化

近年来研究发现黏附分子与动脉粥样硬化密切相关,参与了动脉粥样硬化的发生、发展过程,特别是循环血液中可溶性黏附分子的水平与疾病的活动程度和斑块的稳定性有关。抑制黏附分子及其介导的黏附作用可望成为治疗动脉粥样硬化的有效手段之一。     

Alterations in cell adhesion molecules and other biomarkers of cardiovascular disease in patients with metabolic syndrome

Metabolic syndrome is considered a hyperinsulinemic and inflammatory state closely associated to endothelial dysfunction causing an increased incidence of ischemic cardiovascular events and high mortality. The main objective of the present study was to determine whether leukocitary and soluble cell adhesion molecules were altered in patients with metabolic syndrome in comparison with control subjects. Cell adhesion molecules, mainly of leukocitary location, have been not previously evaluated in specifically designed cross-sectional studies involving male patients with metabolic syndrome. Moreover, other circulating markers of different candidate atherogenic risk parameters were also studied and the potential existence of a progressive relation between the number of metabolic syndrome components and the above mentioned biomarkers was analyzed. Thirty one male patients with metabolic syndrome (ATPIII definition) and 56 male control subjects were studied. We evaluated different markers of insulin resistance, inflammation and atherosclerosis, as well as protective factors. Patients with metabolic syndrome showed (a) hypoadiponectinemia (4551 ± 2302 ng/ml vs. 5865 ± 2548 ng/ml, respectively; p < 0.05), (b) an atherogenic lipid and lipoprotein profile, (c) altered HDL chemical composition accompanied by higher cholesteryl ester-triglyceride interchange carried out by CETP, (d) diminished Lp-PLA₂ activity (6.5 ± 1.9 vs. 7.3 ± 2.2, p < 0.05, respectively), antioxidant enzyme related with LDL oxidation, which was positively associated with QUICKI and negatively with VCAM-1 and lymphocyte CD18, and (e) high soluble (VCAM-1: 17 ± 5 vs. 13 ± 4 ng/ml, respectively; p < 0.0005) and leukocyte adhesion molecule expression (monocyte CD54: 52 ± 15 vs. 45 ± 12 arbitrary units, respectively; p < 0.0005; and lymphocyte CD49d: 312 ± 56 vs. 284 ± 64 arbitrary units, respectively; p < 0.05). The increment in leukocyte and soluble cell adhesion molecules, crucial for leukocyte interaction with the endothelium and migration into the artery wall, in combination with the other disorders described above reinforce the presence of a clinical status with high propensity to type 2 diabetes and atherosclerotic cardiovascular disease.     

细胞外调节蛋白激酶在蛛网膜下腔出血中的研究进展

细胞外调节蛋白激酶(ERK)是丝裂原活化蛋白激酶(MAPK)家族中的一类,磷酸化激活的ERK由胞质转位于胞核,激活下游的信号分子,从而发挥相应的生物学效应。近期的研究表明,该蛋白在蛛网膜下腔出血(SAH)后的炎症、自噬、凋亡及脑血管痉挛中发挥着重要的作用。进一步阐述SAH后ERK参与炎症、自噬、凋亡及脑血管痉挛的相关分子机制,以ERK作为分子靶点,有效地利用该激酶在SAH病理条件下表达的变化,将为研究SAH提供新的方向。     

The role of inflammation in the association between overall and visceral adiposity and subclinical atherosclerosis

Background and aimsInflammation may underlie the association between obesity, atherosclerosis and cardiovascular disease. We investigated to what extent markers of inflammation mediate associations between overall and visceral body fat and subclinical atherosclerosis.Methods and resultsIn this cross-sectional analysis of the Netherlands Epidemiology of Obesity study we estimated total body fat (TBF) by bio-impedance analysis, carotid artery intima media thickness (cIMT) by ultrasound, C-reactive protein (hs-CRP) and glycoprotein acetyls (GlycA) concentrations in fasting blood samples (n = 5627), and visceral adipose tissue (VAT) by magnetic resonance imaging (n = 2247). We examined associations between TBF and VAT, and cIMT using linear regression, adjusted for potential confounding factors, and for mediators: cardiometabolic risk factors (blood pressure, glucose and low-density lipoprotein cholesterol), and inflammation using CRP and GlycA as proxies.Mean (SD) cIMT was 615 (90) μm. Per SD of TBF (8%), cIMT was 19 μm larger (95% confidence interval, CI: 10, 28). This association was 17 μm (95% CI: 8, 27) after adjustment for cardiometabolic risk factors, and did not change after adjustment for markers of inflammation. Per SD (56 cm²) VAT, cIMT was 9 μm larger (95% CI: 2, 16) which changed to 5 μm (95% CI: −3, 12) after adjustment for cardiometabolic risk factors, and did not change after adjustment for inflammatory markers.ConclusionOur results suggest that associations between measures of overall and visceral body fat and subclinical atherosclerosis are not mediated by inflammation as measured by CRP and GlycA. Obesity may exert cardiovascular risk via other markers of systemic inflammation.     

抗氧化剂对老年2型糖尿病糖负荷后粘附分子表达的影响

目的 探索不同剂量的大豆异黄酮(isoflavones，IFs)和维生素C(VC)、维生素E(VE)混合干预物对老年2型糖尿病(2—DM)病人糖负荷后血液中粘附分子(adhesion motecules AMs)表达的影响。方法 随机将115例已确诊的老年2—DM病人分为空白(B组)、低剂量(C组)、中间剂量(D组)和高剂量(E组)的大豆异黄酮和VC、VE混合干预物组，与正常人对照(A组)比较，观察各组糖负荷(OGTT)前、后AMs的表达。结果 OGTT中，A组、B组和C组血液中可溶性细胞粘附分子-1(sICAM—1)、E—选择素(E—selectin)都显著增高，而D组、E组无这种现象，两组间无显著差异。结论 高血糖可产生过氧化应激而引起血液中AMs的过度表达。由150 mg IFs和500 mg VC、400IU VE组成的混合干预物(每日顿服剂量)，可作为2—DM人群以防治动脉粥样硬化(atherosclerosis，AS)等并发症为目的的推荐摄入量。     

A high-fat meal is accompanied by increased plasma interleukin-6 concentrations

Background and aimEnhanced and prolonged postprandial lipaemia is associated with coronary heart disease (CHD). However, the mechanisms linking postprandial lipaemia to the increased risk of atherosclerosis and CHD remain to be determined. The aim of the present study was to examine the effects of a high-fat meal on plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and cellular adhesion molecules in CHD patients and control subjects.Methods and resultsForty-one middle-aged men with premature CHD and 26 healthy male controls were investigated. The plasma triglyceride response to the high-fat meal was significantly greater among cases than controls. The oral fat load induced a twofold increase in plasma concentrations of IL-6, an increase that was similar in CHD patients and control subjects. No changes could be detected in plasma concentrations of cellular adhesion molecules in response to postprandial lipaemia in either CHD patients or control subjects.ConclusionThe results of the present study suggest that a high-fat meal affects mechanisms that induce increased inflammatory activity, which is recognised as a key modulator in the development of atherosclerosis and CHD. However, the increased levels of plasma IL-6 appear not to be determined by the magnitude of the postprandial triglyceridaemia.     

The association of early atherosclerosis and retinopathy in adolescents with type 1 diabetes: preliminary report

Recent studies have shown a close correlation between advanced diabetic retinopathy and the late stages of atherosclerosis. The purpose of this study was to analyse the association between diabetic retinopathy and early atherosclerotic changes in adolescents with type 1 diabetes. We studied 28 adolescents with type 1 diabetes. Eight patients with nonproliferative retinopathy were compared with the remaining 20 patients, and with 11 healthy controls. The function of endothelium was assessed by measuring flow-mediated dilatation (FMD), the intima-media thickness (IMT) of the common carotid arteries and adhesion molecules (sICAM-1, sVCAM-1, sE-selectin). In the group with retinopathy FMD equalled 7.8±4.1% vs. 12.1±5.1% in the control group (p=0.04), and in the group without retinopathy, 7.6±5.5% (p=0.04 compared to controls). Higher IMT was found in all patients with diabetes in comparison with healthy controls: 0.49±0.06 mm vs. 0.42±0.03 mm (p=0.001). Patients with retinopathy had a significantly higher value of IMT in comparison not only with controls but also with patients without complications: 0.56±0.06 mm vs. 0.47±0.03 mm (p=0.0001). Adhesion molecule levels were not changed in patients with retinopathy. Higher IMT was found in adolescents with diabetic retinopathy in comparison with patients without complications, which may suggest that macrovascular changes are more advanced in these patients than in their diabetic peers without retinopathy.     

Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway

Inflammatory and immune responses are highly relevant processes in the pathogenesis of atherosclerosis, as illustrated by the central event of monocyte accumulation in atherosclerotic plaques. Integrin LFA-1-mediated adhesion of circulating monocytes to the endothelium is a prerequisite for recruitment of monocytes to these areas. Integrin-mediated adhesion is tightly regulated and integrins are only functional in response to particular monocyte activation stimuli. We investigated the role of oxidized low-density lipoprotein (LDL) in adhesion of resting monocytes prepared by elutriation from endothelium. Our results showed that: (1) oxidized LDL (and MCP-1) induced both LFA-1-mediated adhesion of monocytes to endothelial cells and transendothelial migration of monocytes; (2) oxidized LDL functionally transformed monocyte LFA-1 to an activated form; (3) oxidized LDL induced F-actin polymerization and cytoskeletal rearrangement within seconds; and (4) the LDL-associated antioxidant, -tocopherol, but not β-tocopherol, inhibited both F-actin polymerization and LFA-1-mediated adhesion of monocytes, which paralleled the effect of protein kinase C (PKC) inhibitors. Our results indicate that oxidized LDL plays a pivotal role in triggering LFA-1 activation and LFA-1-mediated adhesion and transmigration of monocytes to sites of atherosclerotic plaques, via the PKC pathway.