Pathogenic mechanisms of pancreatitis

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pan-creatitis characterized by marked stroma formation with a high number of infiltrating granulocytes(such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells(PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in pro-moting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways(i.e., Transforming growth factor-β/SMAD, mitogen--activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin(IL)-1, IL-1β, IL-6, IL--8 IL-10, IL-18, IL--33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.     

Reactive oxygen species： A double-edged sword in oncogenesis

Reactive oxygen species （ROS） are molecules or ions formed by the incomplete one-electron reduction of oxygen. Of interest, it seems that ROS manifest dual roles, cancer promoting or cancer suppressing, in tumorigenesis. ROS participate simultaneously in two signaling pathways that have inverse functions in tumorigenesis, Ras-Raf-MEK1/2-ERK1/2 signaling and the p38 mitogen-activated protein kinases （MAPK） pathway. It is well known that Ras-Raf-MEK1/2-ERK1/2 signaling is related to oncogenesis, while the p38 MAPK pathway contributes to cancer suppression, which involves oncogene-induced senescence, inflammation- induced cellular senescence, replicative senescence, contact inhibition and DNA-damage responses. Thus, ROS may not be an absolute carcinogenic factor or cancer suppressor. The purpose of the present review is to discuss the dual roles of ROS in the pathogenesis of cancer, and the signaling pathway mediating their role in tumorigenesis.     

Glycosyltransferases and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases(GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized.     

髓系细胞表达的触发受体1与肺部疾病

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor protein mainly expressed on the surface of neutrophils and macrophages,and belongs to the member of immunoglobulin superfamily. When infectious diseases occur in the body, TREM-1 combines with its ligand and transmembrane protein DAP12 through the short-tail region, activates downstream signal transduction pathways to lead to the increase of proinflammatory mediators such as interleukin-8, tumor necrosis factor-α,and plays an important role in the amplification process of inflammatory response. In human infectious diseases,lung infection is more common. In the acute lung infection, macrophages are activated, TREM-1 sheds from the surface. It can provide the new value for the diagnosis and treatment of lung infection diseases by detecting sTREM-1 (TREM-1 in soluble form) in the bronchoalveolar lavage fluid. This article reviews the relationship between TREM-1 and lung diseases.     

Role of platelet-activating factor in pathogenesis of acute pancreatitis

Platelet-activating factor(PAF)is a potentproinflammatory phospholipid mediator that belongsto a family of biologically active,structurally relatedalkyl phosphoglycerides with diverse pathologicaland physiological effects.This bioactive phospholipidmediates processes as diverse as wound healing,physiological inflammation,angiogenesis,apoptosis,reproduction and long-term potentiation.PAF actsby binding to a specific G protein-coupled receptorto activate multiple intracellular signaling pathways.Since most cells both synthesize and release PAFand express PAF receptors,PAF has potent biologicalactions in a broad range of cell types and tissues.Inappropriate activation of this signaling pathway isassociated with many diseases in which inflammationis thought to be one of the underlying features.Acutepancreatitis(AP)is a common inflammatory disease.The onset of AP is pancreatic autodigestion mediatedby abnormal activation of pancreatic enzyme caused bymultiple agents,which subsequently induce pancreaticand systemic inflammatory reactions.A number ofexperimental pancreatitis and clinical trials indicatethat PAF does play a critical role in the pathogenesisof AP.Administration of PAF receptor antagonist cansignificantly reduce local and systemic events that occurin AP.This review focuses on the aspects that are morerelevant to the pathogenesis of AP.     

Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination

Invasion and metastasis are the deadly face of malignant tumors. Considering the high rate of incidence and mortality of colorectal cancer, it is critical to determine the mechanisms of its dissemination. In the parallel investigation of the invasive front and tumor center area of colorectal cancer （CRC）, observation of heterogeneous β-catenin distribution and epithelial-mesenchymal transition （EMT） at the invasive front suggested that there might be a crosstalk between tumor cells and the tumor microenvironment. Wnt signaling pathway is also involved in the cancer progression due to its key role in CRC tumorigenesis. Moreover, in recent years, there is increasing evidence that the regulators of microenvironment, including extracellular matrix, growth factors and inflammatory factors, are associated with the activation of Wnt pathway and the mobility of tumor cells. In this review, we will try to explain how these molecules trigger metastasis via the Wnt pathway.     

Effects of Bufei decoction on TLR2/NF-κB signal pathway in HMGB1-induced idiopathic pulmonary fibrosis cells

<正>Objective To investigate the effects of Bufei Decoction( BFD) on morphological damage,inflammatory response,and Toll like receptors 2/myeloid differential protein-88/nuclear factor kappa-B( TLR2/My D88/NF-κB) signaling pathways in human non-small cell lung cancer( A549) cells and human lung fibroblasts( HFL1)cells induced by high mobility family protein B1( HMGB1).Methods BFD lyophilized powder was prepared by freezing technique,     

呼吸机相关性肺损伤与炎症反应

呼吸机相关性肺损伤是由于机械牵张和高浓度氧吸入等因素触发多种肺组织细胞的感受器,激活阳离子通道、模式识别受体、丝裂原活化蛋白激酶等多种信号传导通路,引起细胞因子、趋化因子和黏附分子的合成与释放,诱发过度炎症反应,造成肺组织损伤。因此,对呼吸机相关性肺损伤中炎症反应的触发机制、作用通路及炎症因子做深入研究,可以为呼吸机相关性肺损伤的防治工作提供借鉴。     

Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension

Caveolae are cell plasma membrane microdomains implicated in organizing and concentrating many signaling molecules. In the lung, caveolae are in endothelium, smooth muscle, fibroblasts, and pneumocytes. Caveolin is the main structural protein of caveolae. Caveolin 1 is down-regulated in transformed cells and may be a tumor suppressor protein. Caveolin 2 is coexpressed and hetero-oligomerizes with caveolin 1. Because the cells of the plexiform lesions in severe pulmonary hypertension (PH) are phenotypically altered, we wondered whether these cells lack caveolin. We now demonstrate by immunolocalization that while caveolin is expressed in lung endothelial, smooth-muscle, and alveolar septal cells, its expression is absent or decreased in plexiform lesions and in some muscularized precapillary arterioles. In contrast, Western blot analysis of total lung extracts from patients with severe PH shows no significant reduction in caveolin. Similar to the human lung tissue, a rat model of severe PH demonstrates absent-to-decreased caveolin expression in the complex vascular lesions. Additionally, it appears that caveolin and heme oxygenase 1 (HO-1) [a heat shock protein] are co-expressed since HO-1 expression parallels caveolin expression in vascular lesions. We propose that loss of caveolin expression in the cells of the complex vascular lesions in severe PH reflects the proliferating and apoptosis-resistant nature of these cells.     

MEK抑制剂治疗非小细胞肺癌的研究进展

随着对肿瘤分子机制的深入研究,非小细胞肺癌的分子靶向治疗已获得重大进展。蛋白激酶抑制剂是新近研发的靶向药物之一,其通过阻碍细胞内分子传导,影响肿瘤细胞的生存与增殖而起作用。丝裂原细胞外激酶（mitogenextracellularkinase,MEK）在Ras／Raf／MEK／ERK信号通路中发挥重要作用,大量的基础及临床研究提示MEK广泛作用于多种信号通路并在各类实体肿瘤中过度表达,因此MEK抑制剂可能具备广谱的抗肿瘤的优势。本文以新型MEK抑制剂司美替尼（selumetinib,AZD6244,ARRXY-142886）为例,重点阐述Ras／Raf／MEK／ERK信号通路、MEK抑制剂的作用机制及研究进展。     

Regulation of G protein and mitogen-activated protein kinase signaling by ubiquitination: insights from model organisms

Guanine nucleotide binding proteins (G proteins) and mitogen-activated protein kinases are highly conserved signaling molecules engaged in a wide variety of cellular processes. The strength and duration of signaling mediated by G proteins and mitogen-activated protein kinases are well known to be regulated via phosphorylation of pathway components. Over the past few years, it has become evident that many of the same signaling proteins also undergo ubiquitination, a posttranslational modification that typically leads to protein degradation. Consequently the strength and duration of signaling can also be modulated by regulating the abundance of signaling proteins. This article describes G protein- and mitogen-activated protein kinase-mediated signaling pathways that are known to be regulated by ubiquitination. The focus is on studies performed in the budding yeast Saccharomyces cerevisiae, as many principles governing this new regulatory mechanism were initially discovered in this model organism. Similar mechanisms uncovered in other model systems are also briefly discussed to illustrate the importance and universality of signaling regulation by ubiquitination.     

小窝蛋白-1与肺纤维化关系的研究进展

小窝蛋白-1(Caveolin-1)是小窝标志性的蛋白,主要通过"脚手架"结构区域,参与负性调控多条信号通路,干预多种疾病进程.目前研究证实:特发性肺纤维化的肺组织中的Caveolin-1表达明显减低,而提高Caveolin-1水平抑制转化生长因子β_1/Smad、JNK、MEK/ERK、wnt/β-Catenin/Lef-1等信号转导通路因子的激活,可减少细胞外基质的合成和上皮细胞的异常修复,阻断肺纤维化进程.深入研究Caveolin-1参与肺纤维化的分子机制,有望为特发性肺纤维化提供新的分子治疗靶点.     

Downregulated RPL6 inhibits lung cancer cell proliferation and migration and promotes cell apoptosis by regulating the AKT signaling pathway

BackgroundLung cancer is still one of the most common causes of cancer-related mortality, and the overall survival is less than 5%. It is important and necessary to elucidate the mechanism of lung cancer progression. Recently, more and more research has demonstrated that many ribosomal proteins (RPs) are dysregulated in tumors. Among these RPs, ribosomal protein L6 (RPL6) is reported to promote cell growth and cell cycle progression in gastric cancer cells through upregulating cyclin E. However, its function in lung cancer is still unknown.MethodsWe first explored RPL6 expression in lung cancer samples. Next, we used gene knockdown to analyze the unknown regulatory role of RPL6 in lung cancer carcinoma and lung cancer cell lines. Furthermore, we explored the potential signaling pathway of RPL6 with Western blotting.ResultsIn this study, we demonstrated that RPL6 expression was highly expressed in lung cancer tissues and lung cancer cell lines. RPL6 downregulation inhibited H1299 and H2975 cell proliferation, migration and induced cell apoptosis. Also RPL6 downregulation increased the protein levels of cleaved caspase-3 and Bax, while decreasing the protein level of B-cell lymphoma 2 (Bcl-2). Western blotting results showed that proteins activating the AKT signaling pathway, such as p-AKT and p-S6, were downregulated in RPL6 knockdown lung cancer cells.ConclusionsThese findings show that RPL6 can be used as a potential therapeutic and preventive biomarker in lung cancer treatment and prognosis by regulating the AKT signaling pathway.     

Von Hippel-Lindau protein and respiratory diseases

Von Hippel-Lindau protein (pVHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although pVHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor (HIF)-α, pVHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that pVHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of pVHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and FoxM1, leading to pulmonary arterial hypertension. Loss of pVHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of pVHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fibrosis. In alveolar epithelial cells, pVHL mediates Na-K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that pVHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.     

Acyl homoserine-lactone quorum-sensing signal generation

Acyl homoserine lactones (acyl-HSLs) are important intercellular signaling molecules used by many bacteria to monitor their population density in quorum-sensing control of gene expression. These signals are synthesized by members of the LuxI family of proteins. To understand the mechanism of acyl-HSL synthesis we have purified the Pseudomonas aeruginosa RhlI protein and analyzed the kinetics of acyl-HSL synthesis by this enzyme. Purified RhlI catalyzes the synthesis of acyl-HSLs from acyl-acyl carrier proteins and S-adenosylmethionine. An analysis of the patterns of product inhibition indicated that RhlI catalyzes signal synthesis by a sequential, ordered reaction mechanism in which S-adenosylmethionine binds to RhlI as the initial step in the enzymatic mechanism. Because pathogenic bacteria such as P. aeruginosa use acyl-HSL signals to regulate virulence genes, an understanding of the mechanism of signal synthesis and identification of inhibitors of signal synthesis has implications for development of quorum sensing-targeted antivirulence molecules.     

Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment

Oncogenic signaling pathways have emerged as key targets for the development of small-molecule inhibitors, with several protein kinase inhibitors already in clinical use for cancer patients. In addition to their role in tumorigenesis, many of the molecules and signaling pathways targeted by these inhibitors are also important in the signaling and interaction of immune cells, such as T cells and dendritic cells. Not surprisingly, there is increasing evidence that many of these inhibitors can have a substantial impact on immune function, both stimulating and downregulating an immune response. In order to illustrate the important role of signaling molecule inhibition in the modulation of immune function, we will discuss the exemplary pathways MAPK, AKT-PI3K-mTOR and VEGF-VEGFR, as well as selected small-molecule inhibitors, whose impact on immune cells has been studied more extensively.