p38丝裂原活化蛋白激酶信号级联在炎症反应中的作用

在急、慢性疾病中，细胞释放的炎症介质可以活化多种信号转导级联反应，丝裂原活化蛋白激酶(MAPK)信号转导通道在招募白细胞于炎症部位聚集起着重要的作用。同时，p38MAPK异构体的活化可以激活致炎细胞因子，而后刺激白细胞活化。然而，p38MAPK引起的白细胞招募这一系列的功能过程包括：粘附、游走和效应器的功能如氧化爆发以及p38MAPK介导的复杂细胞因子网络在炎症中的作用仍有待研究。针对减少炎症介质产生和以p38MAPK为治疗靶点的研究正在进行中，不远的将来可能会成为治疗炎症疾病的新策略。     

骨骼肌丝裂原活化蛋白激酶信号级联与运动

运动是一个非常重要的刺激因素,可对骨骼肌中的多种代谢和转录过程起调节作用.MAPK信号级联中有多种独立的信号途径参与了骨骼肌运动性适应的细胞调控过程,对骨骼肌中葡萄糖转运,胰岛素信号转导,钾离子转运,工作肌的可塑性等产生影响.     

P38MAPK抑制剂对缺血/再灌注大鼠肾脏功能损伤的保护作用

目的：观察P38MAPK抑制剂对缺血／再灌注大鼠肾脏功能损伤的保护作用。方法：夹闭肾动脉制遣大鼠肾脏缺血／再灌注损伤动物模型，静脉注射P38MAPK抑制剂阻断P38MAPK信号转导通路，测量其对肾功能及细胞因子含量的影响。结果：肾脏和血浆中TNF—α和IL-β含量随缺血／再灌注时间的延长而升高，肾功能损伤也随缺血／再灌注时间的延长而加重。应用P38MAPK抑制剂可显著降低TNF-α和IL-β含量，对缺血／再灌注所致的肾功能损伤具有明显改善作用。结论：P38MAPK抑制剂可通过抑制致炎因子的产生而减轻缺血/再灌注所致的大鼠肾脏功能损伤。     

Costello syndrome: Clinical phenotype,genotype, and management guidelines

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence‐based guidelines due to the lack of data for this rare condition.     

Differential regulation of cytokine genes in gingival epithelial cells challenged by Fusobacterium nucleatum and Porphyromonas gingivalis

IL-8 mRNA in human gingival epithelial cells (HGECs) is up-regulated by Fusobacterium nucleatum, and up-/down-regulated by Porphyromonas gingivalis in a complex interaction in the early stages (< or = 4 h) after infection. The mechanisms involved in this regulation in response to F. nucleatum and/or P. gingivalis infection, and identification of co-regulated cytokine genes, are the focus of this investigation. Heat, formalin or protease treatment of F. nucleatum cells attenuated the IL-8 mRNA up-regulation. NF-kappaB, mitogen-activated protein kinase (MAPK) p38 and MAPK kinase/extracellular signal-regulated kinase (MEK/ERK) pathways were involved in IL-8 mRNA induction by F. nucleatum. Pretreatment of P. gingivalis with heat, formalin or protease enhanced IL-8 mRNA induction. NF-kappaB, MARK p38, and MEK/ERK pathways were also involved in this induction. In contrast, down-regulation of IL-8 mRNA by P. gingivalis involved MEK/ERK, but not NF-kappaB or MAPK p38 pathways. cDNA arrays analysis revealed that mRNA down-regulation by P. gingivalis is a specific reaction that only a number of genes, e.g. IL-1beta, IL-8, macrophage inflammatory protein-2alpha, and migration inhibitory factor-related protein-14, are affected based on examination of 278 cytokine/receptor genes. These data indicate that F. nucleatum and P. gingivalis trigger specific and differential gene regulation pathways in HGECs.     

Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis

Increased expression of the hepatocyte growth factor (HGF) receptor (c-met) and urokinase type plasminogen (uPA) correlated with the development and metastasis of cancers. To investigate the role of HGF/c-met signaling on metastasis in cancer cells stimulated with HGF, we examined the effects of a specific MEK1 inhibitor (PD98059) and a p38 MAP kinase inhibitor (SB203580) on HGF-induced uPA expression in pancreatic cancer cell lines, L3.6PL and IMIM-PC2. Pretreatment of PD98059 decreased HGF-mediated phosphorylation of extracellular receptor kinase (ERK), uPA secretion and expression of matrix metalloproteinases (MMP-2 and MMP-9) in a dose-dependent manner. In contrast, SB203580 pretreatment increased HGF-stimulated ERK phosphorylation, uPA secretion and expression of MMPs. SB203580 also reversed the inhibition of HGF-mediated ERK activation and uPA secretion in the PD98059-pretreated cells. These results suggest that ERK activation by HGF might play important roles in the metastasis of pancreatic cancer and the p38 MAPK pathway also involved in the HGF-mediated uPA secretion and metastasis by regulation of ERK pathway. This revised version was published online in July 2006 with corrections to the Cover Date.     

p38γMAPK蛋白在结肠癌组织中的表达及临床意义

目的探讨人结肠癌中p38γMAPK蛋白的表达及其临床意义。方法应用免疫组织化学法检测54例结肠癌组织、近癌旁组织、癌周正常组织和15例腺瘤息肉组织中p38γ蛋白的表达情况。结果p38γ蛋白的表达主要定位于胞质中,仅少量在胞核中表达。p38γ蛋白在结肠癌组织、癌旁组织、癌周正常组织中的高表达率分别为75.93%、51.85%、37.04%,在结肠腺瘤息肉组织中高表达率为33.33%。p38γ蛋白在结肠癌中的表达明显高于癌旁组织、癌周正常组织和腺瘤息肉组织,有统计学意义（P〈0.01）。p38γ的表达与Duke分期,组织分化程度及有无淋巴结转移有显著差异（P〈0.01）,p38γ的表达与年龄、性别、肿瘤大小、肿瘤位置无明显相关（P〉0.05）。结论结肠癌组织中p38γ蛋白处于过度表达状态,与结肠癌的发生、发展和转移密切相关。     

Role of caspases in dexamethasone-induced apoptosis and activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase in human eosinophils

Eosinophils are the principal effector cells for the pathogenesis of allergic inflammation. Glucocorticoids such as dexamethasone have long been used therapeutically for eosinophilia in allergic inflammation by inducing eosinophil apoptosis, but little is known about the intracellular mechanisms mediating dexamethasone-induced apoptosis. In the present study, we investigated the effect of dexamethasone on three mitogen-activated protein kinases (MAPK) involved in the intracellular signalling pathway: c-Jun NH2-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK). We found that dexamethasone could activate JNK and p38 MAPK in a time-dependent manner but not ERK. Further, SB 203580, a specific p38 MAPK inhibitor, was additive with dexamethasone in inducing eosinophil apoptosis, while JNK1/2 antisense phosphorothioate oligodeoxynucleotides did not show any significant effect. These suggest that dexamethasone-induced JNK1/2 and p38 MAPK activation are not crucial to the induction of apoptosis. Pretreatment of eosinophils with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.FMK), a broad-spectrum caspase inhibitor, could inhibit dexamethasone-induced apoptosis in eosinophils dose-dependently. Moreover, Z-VAD.FMK partially inhibited dexamethasone-activated JNK and p38 MAPK activities. However, dexamethasone treatment did not activate specific caspase-3, -8 activity in eosinophils compared with spontaneous apoptosis. We therefore conclude that dexamethasone-induced apoptosis and activation of JNK and p38 MAPK activity in eosinophils are regulated by caspases but not through the common apoptosis-related caspase-3, -8 as in other cell types. Elucidation of the important role of caspases in eosinophil apoptosis may facilitate the development of more specific and effective treatment for allergic inflammation.     

Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells

Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, PI-3 kinase inhibitors, Wortmannin and LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor and the PI3-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activation of dual signaling pathways, MEK1-MAPK and PI3K-Akt, is required for the FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic target for cancer. This revised version was published online in July 2006 with corrections to the Cover Date.     

Cooperation between IL-7 and the pre-B cell receptor: a key to B cell selection

Hematopoiesis is regulated by a variety of signals that either originate within a developing cell or are supplied by the surrounding environment in secreted- or contact-dependent forms. This review discusses the effects of one secreted factor, interleukin-7, on the development of B lymphocytes. We describe a molecular mechanism for a crucial checkpoint during B lineage maturation, based on the integration of signals mediated by the pre-B cell receptor, the interleukin-7 receptor, and the environment in which these signals are received.