核因子 -kB 在动脉粥样硬化中的研究进展

动脉粥样硬化(atherosclerosis,AS)与心脑血管疾病及周围血管疾病等多种疾病的发病关系密切,而AS的慢性炎症性特征已被广泛认可,从早期内皮功能紊乱到最终的斑块破裂,炎性进程伴随于AS形成的各个阶段。核因子-κB(NF-κB)作为调控炎症信号的重要转录因子,通过调节细胞因子、趋化因子、粘附分子、免疫受体、氧化应激相关酶等一系列特异基因的表达而参与AS的病理过程,并在细胞凋亡和细胞增殖等方面发挥着重要的作用,是AS形成及防治相关研究中的重要靶点。本文通过概述近年来关于NF-κB通路的信号传导在AS形成中的作用,回顾本通路相关药物的研究进展,旨在探讨NF-κB在动脉粥样硬化研究中所面临的问题,为以NF-κB为靶点的抗AS药物研究提供理论参考。     

核因子-κB在动脉粥样硬化中的研究进展

动脉粥样硬化(atherosclerosis,AS)与心脑血管疾病及周围血管疾病等多种疾病的发病关系密切,而AS的慢性炎症性特征已被广泛认可,从早期内皮功能紊乱到最终的斑块破裂,炎性进程伴随于AS形成的各个阶段。核因子-κB(NF-κB)作为调控炎症信号的重要转录因子,通过调节细胞因子、趋化因子、粘附分子、免疫受体、氧化应激相关酶等一系列特异基因的表达而参与AS的病理过程,并在细胞凋亡和细胞增殖等方面发挥着重要的作用,是AS形成及防治相关研究中的重要靶点。本文通过概述近年来关于NF-κB通路的信号传导在AS形成中的作用,回顾本通路相关药物的研究进展,旨在探讨NF-κB在动脉粥样硬化研究中所面临的问题,为以NF-κB为靶点的抗AS药物研究提供理论参考。     

p38MAPK与心肌缺血再灌注损伤

丝裂原活化蛋白激酶(Mitogen-activated protein kinases,MAPKs)是广泛表达的丝氨酸/酪氨酸激酶,在哺乳动物细胞多种信号转导通路中起重要作用,MAPKs有3个主要家族:ERKs,JNKs和p38MAPKs.p38信号通路是MAPK通路的一重要分支,在心肌缺血再灌注的损伤中起很重要的作用,p38MAPK信号通路与心肌缺血再灌注机制都有或多或少的联系,本文就以p38MAPK在这一病理过程的研究进展做一综述.     

甘草抗动脉粥样硬化机制的网络药理学研究

利用网络药理学方法探讨甘草在抗动脉粥样硬化中的分子机制。本研究利用中医药系统药理学数据库和分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)分析甘草中的有效活性成分,并获得有效成分的作用靶点。通过Cytoscape软件构建可视化靶点互相作用网络,对网络中的关键靶点进行基因本体(GO)富集分析和KEGG通路富集分析。结果显示甘草中40种有效活性成分的预测靶点共97个,47个靶点与动脉粥样硬化(AS)相关,其中18个是血管保护药物和脂质修饰药物的作用靶点,表明甘草可作为调控AS发展的药物。基于97个预测靶点的GO富集分析,发现甘草可参与多种生物学过程,尤其是应对外源性刺激,以及参与细胞凋亡等过程。通过构建甘草靶点与AS疾病靶点相互作用网络(PPI),确定了AKT1、MAPK3、MAPK1、JUN和CASP3等关键靶点,并对关键靶点进行KEGG富集分析,结果表明甘草主要影响调控细胞增殖、生存以及凋亡的细胞信号转导相关通路,并激活先天免疫相关信号通路,调节炎性细胞因子释放,从而发挥抗动脉粥样硬化作用。甘草具有多成分、多靶点、多途径的作用特点,主要通过PI3K-AKT信号途径、MAPK信号途径、NOD样受体信号通路调控细胞增殖和凋亡,同时发挥免疫调控作用,从而影响动脉粥样硬化的发展,由此可见,甘草可作为动脉粥样硬化疾病治疗的候选中草药。     

P38 MAPK 信号传导通路与卵巢癌关系的研究进展

丝裂原活化蛋白激酶(mitogen-activated proteinkinases,MAPKs)级联反应是细胞内重要的信号传导系统之一,参与细胞生长、发育、分化和凋亡等一系列生理、病理过程.P38 MAPK信号传导通路是MAPK通路的分支之一,介导了应激、炎性细胞因子、细菌产物等多种刺激引起的细胞反应,对细胞周期调控具有重要作用.但对不同的卵巢癌细胞系,或者不同的刺激,P38通路的作用不完全相同,甚至可能相反,提示对P38通路的功能仍需进一步的研究,他可能是肿瘤治疗的新靶点.本文就P38 MAPK信号传导通路与卵巢癌关系作一综述。     

MKP-1在结核分枝杆菌感染中的作用和研究进展

有丝分裂原激活的蛋白激酶(Mitogen-Activated Protein Kinase,MAPK)信号通路是细胞感知外源性刺激并作出有效免疫应答的最重要的细胞内信号通路之一。近年来的研究表明:MAPK的表达异常与结核病的发生、发展密切相关。MAPK磷酸酶(MAPK phosphatases,MKPs)是一类在细胞内水解MAPKs家族的磷酸酶,通过负向调控MAPKs的活性,从而在调节细胞的应激、分化、增殖、凋亡等过程中发挥重要的作用,其中MKP-1是MKPs家族中被报道最多的成员,具有最强的去磷酸化能力。本文综述了MKP-1在结核分枝杆菌感染中的作用和研究进展。     

P38MAPK信号传导通路与卵巢癌关系的研究进展

丝裂原活化蛋白激酶（mitogen-activatedproteinkinases,MAPKs）级联反应是细胞内重要的信号传导系统之一,参与细胞生长、发育、分化和凋亡等一系列生理、病理过程．P38MAPK信号传导通路是MAPK通路的分支之一,介导了应激、炎性细胞因子、细菌产物等多种刺激引起的细胞反应,对细胞周期调控具有重要作用．但对不同的卵巢癌细胞系,或者不同的刺激,P38通路的作用不完全相同,甚至可能相反,提示对P38通路的功能仍需进一步的研究,他可能是肿瘤治疗的新靶点．本文就P38MAPK信号传导通路与卵巢癌关系作一综述。     

SUMO对NF-κB信号通路的调控作用

核转录因子NF-κB是一种广泛存在于真核细胞内的,具有多向性、多功能的重要调节蛋白,与机体免疫应答、炎症反应,以及肿瘤的发生发展等多种生理病理过程相关.蛋白质翻译后修饰对NF-κB信号通路能起调控作用,而小泛素相关修饰物(small ubiquitin-related modifier,SUMO)是近年报道的参与调控NF-κB信号通路的一种非常重要的小分子蛋白,本文就SUMO对NF-κB信号通路的调节作用做一介绍.     

Wnt信号通路与高血压疾病的研究进展

Wnt信号分子是一类在无脊椎与脊椎动物的多种组织中广泛表达且进化上高度保守的信号刺激分子,他们在生长、发育、代谢和干细胞调节等多种生物学过程中发挥重要作用。在健康成人的器官中Wnt信号是沉默的,但是在病理情况下Wnt信号激活。近年发现Wnt信号通路在心血管疾病的发生发展过程中扮演重要角色。本文将详细介绍Wnt信号通路,及其与高血压疾病的研究进展,试图将对Wnt信号通路的调控作为治疗高血压疾病的新的方向。     

microRNA155在动脉粥样硬化发生过程中的网络调控机制

动脉粥样硬化(atherosclerosis,AS)是一种慢性进行性的血管炎症性疾病,其发病机制主要包括内皮细胞损伤,脂质浸润及炎症介质分泌等。microRNA155(miR-155)是参与AS炎性调控、免疫和自噬信号等通路的微小非编码RNA。系统性研究miR-155及其靶基因的网络调控机制,能全面理解miR-155在AS中的作用,促进其在临床诊断中的应用开发。利用miRNA靶基因预测数据库miRDB、miRmap和Starbase获取miR-155的靶基因集。R语言分析基因表达综合数据库(gene expression omnibus,GEO)共享平台动脉粥样硬化斑块差异表达基因(GSE24702),筛选出18 076个差异表达基因。利用基因集富集分析(gene set enrichment analysis,GSEA)分析,观察这些差异表达基因共同富集在IL6-JAK-STAT3信号通路、炎症反应和TNFα等炎症信号通路。与miR-155靶基因交叉匹配得到371个交集mRNA,其中159个在动脉粥样硬化斑块中上调,212个在动脉粥样硬化斑块中下调。基因本体(gene ontology,GO)及基因组数据库(kyoto encyclopedia of genes and genomes,KEGG)分析研究基因功能,GO富集分析371个差异基因主要富集炎症和凋亡信号通路的负调控等功能,KEGG分析371个差异基因主要富集TGFβ等炎症信号通路。蛋白相互作用网络(protein-protein interaction networks,PPI)分析获得关键节点基因是ARRB2、FBXO11、SOCS1、FBXO22、FBXO30、KRAS、RNF19A、TRIM32、HERC4、PJA1、RCHY1和DET1。本研究表明,miR-155主要通过调控炎症反应等相关信号通路影响斑块细胞炎症、自噬及凋亡等功能,进而影响动脉粥样硬化的各个进程。     

Rice MAPKs

Mitogen-activated protein kinase (MAPK) cascades are evolutionary conserved from unicellular to complex eukaryotic organisms, and constitute one of the major signalling pathways involved in regulating a wide range of cellular activities from growth and development to cell death. MAPKs of rice (Oryza sativa L.), the most important of all food crops and an established monocot plant research model, have seen considerable progress mainly on their identification and characterization during the past one year alone. These studies have provided new information on the response and regulation of rice MAPKs, in particular on their possible role/function in the rice self-defense pathways. It is believed that further work on MAPK cascades in rice will widen our understanding of the MAPK signalling pathways, and may lead to the establishment of a biological model on this critical early signalling event in monocots. In this review, we bring together all the recent developments in rice MAPKs and discuss their significance and future direction in light of the present data and the progress made in dicot model plants.     

Brassinosteroid-regulated GSK3/Shaggy-like Kinases Phosphorylate Mitogen-activated Protein (MAP) Kinase Kinases,Which Control Stomata Development in Arabidopsis thaliana

Brassinosteroids (BRs) are steroid hormones that coordinate fundamental developmental programs in plants. In this study we show that in addition to the well established roles of BRs in regulating cell elongation and cell division events, BRs also govern cell fate decisions during stomata development in Arabidopsis thaliana. In wild-type A. thaliana, stomatal distribution follows the one-cell spacing rule; that is, adjacent stomata are spaced by at least one intervening pavement cell. This rule is interrupted in BR-deficient and BR signaling-deficient A. thaliana mutants, resulting in clustered stomata. We demonstrate that BIN2 and its homologues, GSK3/Shaggy-like kinases involved in BR signaling, can phosphorylate the MAPK kinases MKK4 and MKK5, which are members of the MAPK module YODA-MKK4/5-MPK3/6 that controls stomata development and patterning. BIN2 phosphorylates a GSK3/Shaggy-like kinase recognition motif in MKK4, which reduces MKK4 activity against its substrate MPK6 in vitro. In vivo we show that MKK4 and MKK5 act downstream of BR signaling because their overexpression rescued stomata patterning defects in BR-deficient plants. A model is proposed in which GSK3-mediated phosphorylation of MKK4 and MKK5 enables for a dynamic integration of endogenous or environmental cues signaled by BRs into cell fate decisions governed by the YODA-MKK4/5-MPK3/6 module.     

APOE2 promotes the development and progression of subretinal neovascularization in age-related macular degeneration via MAPKs signaling pathway

BackgroundNeovascular age-related macular degeneration (nvAMD) is one of the main pathological features of wet AMD. Apolipoprotein E2 is involved in the formation of nvAMD but the molecular mechanism has not been reported.MethodsThe APOE alleles in AMD patients were detected by genotyping. Mouse models were divided into 4 groups according to transfection different gene segments and laser-induced treatment. APOE2, VEGF, PDGF-BB, b-FGF and inflammatory cytokines (including p-NF-κB, TNF-α, IL-1β and IL-6) were tested by ELISA in mice retinal lysate. The formation of nvAMD in the indicated treatment groups at 3rd, 7th and 14th day after laser-induced damage were detected by FFA. Besides, qRT-PCR was used to determine the mRNA levels of p38, JNK and ERK in ARPE-19 cells. Finally, the inflammatory cytokines and MAPK proteins (including P38, p-P38, JNK, p-JNK, ERK and p-ERK) were detected by western blot.ResultsThe statistics of APOE alleles showed that APOE2 allele carriers were more likely to nvAMD. VEGF, PDGF-BB, b-FGF and related inflammatory cytokines were up-regulated significantly after treatment with APOE2, which were reduced after silencing the MAPK family genes, however. Further, the expression levels of neovascular growth factors and inflammatory cytokines were highly consistent between mouse models and ARPE-19 cells. Besides, the phosphorylation levels of p38, JNK and ERK were affected by APOE2.ConclusionnvAMD was affected directly by the overexpression of VEGF, PDGF-BB and b-FGF, which were regulated by APOE2 through activating MAPKs pathway.     

MAPK对高等植物细胞分裂和生长的调节

综述了MAPKs参与植物细胞周期调控的最新进展 ,植物激素与MAPK ,MAPK与植物细胞有丝分裂 ,以及MAPK与植物细胞分裂和生长的调控等三方面 ,阐述MAPK参与调控高等植物细胞分化和有丝分裂的机制。     

ABA信号转导途径中的MAPKs

脱落酸（ABA）是植物体内一种重要的激素分子,在调节植物生长发育和对环境适应的过程中发挥重要的信号作用。促分裂原活化蛋白激酶（MAPK）是一种广泛存在于真核生物中的信号转导途径,由环境胁迫、细胞因子、植物激素、生长因子等诱导,是植物细胞信号转导过程中的主要级联途径之一。已知许多蛋白激酶和蛋白磷酸酶参与了ABA信号途径,MAPKs作为ABA信号转导的下游组分发挥着重要的调节作用。本文就MAPK级联参与ABA信号转导途径的相关研究进展进行叙述,以便对MAPKs和ABA信号之间的交互作用（cross-talk）机制有更深入了解。     

Cleavage of Host Cytokeratin-6 by Lysine-Specific Gingipain Induces Gingival Inflammation in Periodontitis Patients

Background/PurposeLysine-specific gingipain (Kgp) is a virulence factor secreted from Porphyromonas gingivalis (P. gingivalis), a major etiological bacterium of periodontal disease. Keratin intermediate filaments maintain the structural integrity of gingival epithelial cells, but are targeted by Kgp to produce a novel cytokeratin 6 fragment (K6F). We investigated the release of K6F and its induction of cytokine secretion.MethodsK6F present in the gingival crevicular fluid of periodontal disease patients and in gingipain-treated rat gingival epithelial cell culture supernatants was measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometer-based rapid quantitative peptide analysis using BLOTCHIP. K6F in gingival tissues was immunostained, and cytokeratin 6 protein was analyzed by immunofluorescence staining and flow cytometry. Activation of MAPK in gingival epithelial cells was evaluated by immunoblotting. ELISA was used to measure K6F and the cytokines release induced by K6F. Human gingival fibroblast migration was assessed using a Matrigel invasion chamber assay.ResultsWe identified K6F, corresponding to the C-terminus region of human cytokeratin 6 (amino acids 359–378), in the gingival crevicular fluid of periodontal disease patients and in the supernatant from gingival epithelial cells cultured with Kgp. K6F antigen was distributed from the basal to the spinous epithelial layers in gingivae from periodontal disease patients. Cytokeratin 6 on gingival epithelial cells was degraded by Kgp, but not by Arg-gingipain, P. gingivalis lipopolysaccharide or Actinobacillus actinomycetemcomitans lipopolysaccharide. K6F, but not a scrambled K6F peptide, induced human gingival fibroblast migration and secretion of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1. These effects of K6F were mediated by activation of p38 MAPK and Jun N-terminal kinase, but not p42/44 MAPK or p-Akt.ConclusionKgp degrades gingival epithelial cell cytokeratin 6 to K6F that, on release, induces invasion and cytokine secretion by human gingival fibroblasts. Thus, Kgp may contribute to the development of periodontal disease.     

Functional analysis of the type 3 effector nodulation outer protein L (NopL) from Rhizobium sp. NGR234: symbiotic effects, phosphorylation, and interference with mitogen-activated protein kinase signaling

Pathogenic bacteria use type 3 secretion systems to deliver virulence factors (type 3 effector proteins) directly into eukaryotic host cells. Similarly, type 3 effectors of certain nitrogen-fixing rhizobial strains affect nodule formation in the symbiosis with host legumes. Nodulation outer protein L (NopL) of Rhizobium sp. strain NGR234 is a Rhizobium-specific type 3 effector. Nodulation tests and microscopic analysis showed that distinct necrotic areas were rapidly formed in ineffective nodules of Phaseolus vulgaris (cv. Tendergreen) induced by strain NGRΩnopL (NGR234 mutated in nopL), indicating that NopL antagonized nodule senescence. Further experiments revealed that NopL interfered with mitogen-activated protein kinase (MAPK) signaling in yeast and plant cells (Nicotiana tabacum). Expression of nopL in yeast disrupted the mating pheromone (α-factor) response pathway, whereas nopL expression in N. tabacum suppressed cell death induced either by overexpression of the MAPK gene SIPK (salicylic acid-induced protein kinase) or by SIPK(DD) (mutation in the TXY motif resulting in constitutive MAPK activity). These data indicate that NopL impaired function of MAPK proteins or MAPK substrates. Furthermore, we demonstrate that NopL was multiply phosphorylated either in yeast or N. tabacum cells that expressed nopL. Four phosphorylated serines were confirmed by mass spectrometry. All four phosphorylation sites exhibit a Ser-Pro pattern, a typical motif in MAPK substrates. Taken together, data suggest that NopL mimics a MAPK substrate and that NopL suppresses premature nodule senescence by impairing MAPK signaling in host cells.     

How does the G protein,Gi2, transduce mitogenic signals?

Serpentine receptors coupled to the heterotrimeric G protein, G_i2, are capable of stimulating DNA synthesis in a variety of cell types. A common feature of the G_i2-coupled stimulation of DNA synthesis is the activation of the mitogen-activated protein kinases (MAPKs). The regulation of MAPK activation by the G_i2-coupled thrombin and acetylcholine muscarinic M₂ receptors occurs by a sequential activation of a network of protein kinases. The MAPK kinase (MEK) which phosphorylates and activates MAPK is also activated by phosphorylation. MEK is phosphorylated and activated by either Raf or MEK kinase (MEKK). Thus, Raf and MEKK converge at MEK to regulate MAPK. G_i2-coupled receptors are capable of activating MEK and MAPK by Raf-dependent and Raf-independent mechanisms. Pertussis toxin catalyzed ADP-ribosylation of α_i2 inhibits both the Raf-dependent and-independent pathways activated by G_i2-coupled receptors. The Raf-dependent pathway involves Ras activation, while the Raf-independent activation of MEK and MAPK does not involve Ras. The Raf-independent activation of MEK and MAPK most likely involves the activation of MEKK. The vertebrate MEKK is homologous to the Ste11 and Byr2 protein kinases in the yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The yeast Ste11 and Byr2 protein kinases are involved in signal transduction cascades initiated by pheromone receptors having a 7 membrane spanning serpentine structure coupled to G proteins. MEKK appears to be conserved in the regulation of G protein-coupled signal pathways in yeast and vertebrates. Raf represents a divergence in vertebrates from the yeast pheromone-responsive protein kinase system. Defining MEKK and Raf as a divergence in the MAPK regulatory network provides a mechanism for differential regulation of this system by G_i2-coupled receptors as well as other receptor systems, including the tyrosine kinases.     

Novel and Expanded Roles for MAPK Signaling in Arabidopsis Stomatal Cell Fate Revealed by Cell Type–Specific Manipulations

Mitogen-activated protein kinase (MAPK) signaling networks regulate numerous eukaryotic biological processes. In Arabidopsis thaliana, signaling networks that contain MAPK kinases MKK4/5 and MAPKs MPK3/6 function in abiotic and biotic stress responses and regulate embryonic and stomatal development. However, how single MAPK modules direct specific output signals without cross-activating additional downstream processes is largely unknown. Studying relationships between MAPK components and downstream signaling outcomes is difficult because broad experimental manipulation of these networks is often lethal or associated with multiple phenotypes. Stomatal development in Arabidopsis follows a series of discrete, stereotyped divisions and cell state transitions. By expressing a panel of constitutively active MAPK kinase (MAPKK) variants in discrete stomatal lineage cell types, we identified a new inhibitory function of MKK4 and MKK5 in meristemoid self-renewal divisions. Furthermore, we established roles for MKK7 and MKK9 as both negative and (unexpectedly) positive regulators during the major stages of stomatal development. This has expanded the number of known MAPKKs that regulate stomatal development and allowed us to build plausible and testable subnetworks of signals. This in vivo cell type–specific assay can be adapted to study other protein families and thus may reveal insights into other complex signal transduction pathways in plants.