Role of endothelial cell cytoskeleton in control of endothelial permeability

Increased permeability of the pulmonary microvasculature is felt to cause acute noncardiogenic lung edema, and histological studies of edematous lungs show gaps between apparently healthy endothelial cells. To determine whether alterations in endothelial cell cytoskeletons would alter endothelial permeability, we exposed monolayers of pulmonary artery endothelial cells grown on micropore filters to cytochalasin B or D. Cytochalasin exposed monolayers demonstrated a 2- to 3-fold increase in endothelial permeability that was readily reversible by washing the monolayers free of cytochalasins. Parallel phase contrast and fluorescence microscopy demonstrated retraction of cell cytoplasm and disruption of bundles of microfilaments in cytochalasin exposed cells. These changes also were readily reversed after washing the cells free from cytochalasins. To test the relevance of these findings to an in situ microvasculature, we added cytochalasin B to the perfusate of isolated rabbit lungs and observed that cytochalasin B caused a high permeability lung edema. These studies suggest that endothelial cell cytoskeletons may be important determinants of endothelial permeability.     

Role of endothelial nitric oxide synthase in endothelial cell migration.

Endothelium-derived nitric oxide (NO) and its precursor L-arginine have been implied to promote angiogenesis, but little is known about the precise mechanism. The inhibition of endogenous NO formation by Nomega-nitro-L-arginine methyl ester (L-NAME) (1 mmol/L) but not its inactive enantiomer D-NAME (1 mmol/L) inhibited endothelial cell sprouting from the scratched edge of the cultured bovine aortic endothelial cell monolayer. Inhibition of endogenous NO release by L-NAME was confirmed by amperometric measurement using an NO-specific electrode. In the modified Boyden chamber, L-NAME (1 mmol/L) significantly inhibited endothelial cell migration, whereas L-NAME did not affect endothelial DNA synthesis as assessed by analysis of [3H]thymidine incorporation. We then examined alteration of endothelial cell adhesion molecule expression after the inhibition of NO by L-NAME in cultured human umbilical vein endothelial cells. In both normoxic and hypoxic conditions, L-NAME (1 mmol/L) inhibited surface expression of integrin alphavbeta3, which is an important integrin facilitating endothelial cell survival and angiogenesis. However, L-NAME did not affect the expression of platelet endothelial cell adhesion molecule-1, intercellular adhesion molecule-1, vascular endothelial adhesion molecule-1, gap junction protein connexin 43, and VE-cadherin, which have been reported to potentially affect angiogenesis. In summary, inhibition of endothelial NO synthase by L-NAME attenuated endothelial cell migration but not proliferation in vitro. Furthermore, endogenous endothelium-derived NO maintains the functional expression of integrin alphavbeta3, a mediator for endothelial migration, survival, and angiogenesis. Endothelium-derived NO, thus, may play an important role in mediating angiogenesis by supporting endothelial cell migration, at least partly, via an integrin-dependent mechanism.     

MicroRNA在胃癌中的研究进展

MicroRNA(miRNA)是一类进化过程中高度保守的内源性非编码小RNA.他们具有高度保守性、时序性和组织特异性,通过参与基因表达调控,在肿瘤的发生发展过程中扮演着重要的角色.本文就miRNA在胃癌方面的研究进展作一综述.     

MicroRNAs在血管钙化中的作用

血管的钙化在冠心病患者是非常常见的,许多研究证实microRNAs(miRs)是血管钙化过程中一类重要的调节因子。人们对miRs的研究已取得一定进展,发现它可以通过调控平滑肌细胞的转分化、调节钙磷稳态、下调平滑肌细胞收缩表型等来引起血管钙化的发生。本文对miRs在血管钙化中所起的作用做一综述。     

microRNAs在心肌肥厚中的作用

生理或病理性刺激会导致心肌肥厚性生长,表现为心肌细胞增大,蛋白合成增加及胎儿基因的再表达。在心脏中有很多信号分子影响着基因表达、细胞凋亡、细胞因子释放等病理生理过程。利用心肌细胞肥厚模型已经发现病理性心肌肥厚可以被抑制或逆转,这些发现为寻找调控心肌肥厚的因子及信号通路提供了基础。该文着重讨论近年来发现的microRNAs(miRNAs)在调节心肌肥厚中的作用。     

Role of microRNAs in gastric cancer

Although gastric cancer(GC)is one of the leading causes of cancer-related death,major therapeutic advances have not been made,and patients with GC still face poor outcomes.The prognosis of GC also remains poor because the molecular mechanisms of GC progression are incompletely understood.MicroRNAs(miRNAs)are noncoding RNAs that are associated with gastric carcinogenesis.Studies investigating the regulation of gene expression by miRNAs have made considerable progress in recent years,and abnormalities in miRNA expression have been shown to be associated with the occurrence and progression of GC.miRNAs contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors,affecting cell proliferation,apoptosis,motility,and invasion.Moreover,a number of miRNAs have been shown to be associated with tumor type,tumor stage,and patient survival and therefore may be developed as novel diagnostic or prognostic markers.In this review,we discuss the involvement of miRNAs in GC and the mechanisms through which they regulate gene expression and biological functions.Then,we review recent research on the involvement of miRNAs in GC prognosis,their potential use in chemotherapy,and their effects on Helicobacter pylori infections in GC.A greater understanding of the roles of miRNAs in gastric carcinogenesis could provide insights into the mechanisms of tumor development and could help to identify novel therapeutic targets.     

Role of leukotrienes in asthma pathophysiology

Inflammation is an essential component of asthma pathophysiology. While beta(2)-agonists are often used for short-term relief of acute bronchospasm, anti-inflammatory agents are required for the long-term management of chronic inflammation in this disease. Corticosteroids have emerged as the first-line anti-inflammatory therapy for asthma management. However, in some patients, especially children, the high doses of corticosteroids that may be required to control features of hyperresponsiveness, including exercise-induced asthma, raise safety concerns. Thus, there is a need for complementary anti-inflammatory, steroid-sparing agents in asthma therapy. Several inflammatory mediators have been targeted in an attempt to thwart this inflammatory process, but so far with little success. The cysteinyl leukotrienes (CysLT), LTC(4), LTD(4), and LTE(4), have been shown to be essential mediators in asthma, making them obvious targets for therapy. These cysteinyl leukotrienes, previously known as the slow-reacting substance of anaphylaxis (SRS-A), mediate many of the features of asthma, including bronchial constriction, bronchial hyperreactivity, edema, and eosinophilia. Data show that selective cysteinyl leukotriene receptor antagonists (CysLTRAs) effectively reverse these pathologic changes. Corticosteroids do not inhibit the production of CysLTs in vivo, suggesting that CysLTRAs and corticosteroids affect different targets. The bronchodilator properties of CysLTRAs seem to be additive to those of beta(2)-agonists and corticosteroids. These data suggest that CysLTs are important therapeutic targets in the management of inflammation in asthma.     

Role of circulating microRNAs in liver diseases

MicroRNAs(miRNAs) are small RNAs regulate gene expression by inhibiting the turnover of their target mRNAs. In the last years, it became apparent that miRNAs are released into the circulation and circulating miRNAs emerged as a new class of biomarkers for various diseases. In this review we summarize available data on the role of circulating miRNAs in the context of acute and chronic liver diseases including hepatocellular and cholangiocellular carcinoma. Data from animal models are compared to human data and current challenges in the field of miRNAs research are discussed.     

MicroRNAs与心肌缺血再灌注损伤

MicroRNAs（miRNAs）是一类高度保守的非编码小分子RNA,经转录后调节细胞的增殖、迁移、分化、凋亡和免疫应答等。miRNAs与心血管疾病发生发展密切相关。心肌缺血后多种miRNA。异常表达,它们在介导心肌缺血再灌注损伤和调控心肌缺血保护环节中起重要作用,可作为诊断缺血再灌注损伤的标志物和潜在治疗靶点。     

Role of endothelial cell survival and death signals in angiogenesis

Angiogenesis, the process of new microvessel development, is encountered in a select number of physiological processes and is central to the pathogenesis of a wide variety of diseases. There is now convincing evidence that regulated patterns of endothelial cell survival and death, a process known as apoptosis, play a central role in the periodic remodeling of the vasculature, and in the timely evolution and regression of angiogenic responses. In this review we discuss the current evidence suggesting a role for inducers and inhibitors of angiogenesis as well as other mediators that modify endothelial cells functions in the survival and death of endothelial cells. We also discuss how dysregulation of apoptosis can lead to aberrant angiogenesis as demonstrated in the pathogenesis of retinopathy of prematurity and cancer. This revised version was published online in June 2006 with corrections to the Cover Date.     

姜黄素在内脂素诱导内皮细胞炎症损伤中的作用机制

目的观察姜黄素(Cur)对内脂素(visfatin)诱导的人脐静脉内皮细胞(HUVECs)炎症损伤过程的影响,探讨Cur改善内皮功能的信号传导机制。方法将HUVECs随机分组,根据前期实验结果,给予1×10~(-5)mol/L的visfatin进行诱导,加入Cur后MTT法检测内皮细胞活力变化。通过酶联免疫吸附法(ELISA)检测单核细胞趋化蛋白-1(MCP-1)、E选择素(E-selectin)的含量变化,蛋白质印迹法(Western blotting)检测细胞黏附分子-1(ICAM-1)、需肌醇激酶/核酸内切酶1(IRE1)、葡萄糖调节蛋白78(GRP78)的表达。结果 MTT检测结果表明,正常HUVECs加入Cur后,不影响内皮细胞活力;而与正常对照组相比,给予1×10~(-5)mol/L visfatin处理后,MCP-1和E-selectin含量明显增加,ICAM-1、IRE1及GRP78的表达增加,差异有统计学意义(P0.05)。与visfatin组相比,给予不同浓度Cur处理后,可显著降低MCP-1和E-selectin的含量,同时ICAM-1、IRE1及GRP78的表达也显著降低,差异有统计学意义(P0.05)。结论Cur可能通过抑制内质网应激(ESR)来拮抗visfatin诱导HUVECs炎症损伤。     

Role of bowel pathophysiology in voiding dysfunction

A great deal of neural overlap and “cross-talk” exists among the pelvic viscera, a prerequisite for normal pelvic physiologic function. However, after an acute or chronic irritative or infectious pelvic insult, pelvic “cross-sensitization” may occur, leading to the development of chronic pelvic pain and its associated and/or overlapping disorders. As such, comorbid pathophysiologic alterations of the bowel and bladder are common, as exemplified by the overlap of irritable bowel syndrome and interstitial cystitis/painful bladder syndrome, the two most common chronic pelvic pain disorders. Although less common, voiding dysfunction may likewise be seen in inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and diverticulitis. In support of these clinical associations and shedding further light on the role of bowel pathophysiologic mechanisms in voiding dysfunction, in bowel → bladder cross-sensitization studies conducted by the authors, colonic irritation induced irritative micturition patterns (both acutely and chronically) and sensitized the mechanoreceptive and chemoreceptive properties of urinary bladder C-fibers. Furthermore, convergence of bowel and bladder afferents was seen at the peripheral level and may also play a role. Thus, physiologic functions of the bowel and bladder are intimately related by neural pathways and are at risk for comorbid disease associations.     

Role and therapeutic potential of microRNAs in diabetes

The discovery in mammalian cells of hundreds of small RNA molecules, called microRNAs, with the potential to modulate the expression of the majority of the protein-coding genes has revolutionized many areas of biomedical research, including the diabetes field. MicroRNAs function as translational repressors and are emerging as key regulators of most, if not all, physiological processes. Moreover, alterations in the level or function of microRNAs are associated with an increasing number of diseases. Here, we describe the mechanisms governing the biogenesis and activities of microRNAs. We present evidence for the involvement of microRNAs in diabetes mellitus, by outlining the contribution of these small RNA molecules in the control of pancreatic β-cell functions and by reviewing recent studies reporting changes in microRNA expression in tissues isolated from diabetes animal models. MicroRNAs hold great potential as therapeutic targets. We describe the strategies developed for the delivery of molecules mimicking or blocking the function of these tiny regulators of gene expression in living animals. In addition, because changes in serum microRNA profiles have been shown to occur in association with different human diseases, we also discuss the potential use of microRNAs as blood biomarkers for prevention and management of diabetes.     

Exercise training in hypertension: Role of microRNAs

Hypertension is a complex disease that constitutes an important public health problem and demands many studies in order to understand the molecular mechanisms involving his pathophysiology. Therefore, an increasing number of studies have been conducted and new therapies are continually being discovered. In this context, exercise training has emerged as an important non-pharmacological therapy to treat hypertensive patients, minimizing the side effects of pharmacological therapies and frequently contributing to allow pharmacotherapy to be suspended. Several mechanisms have been associated with the pathogenesis of hypertension, such as hyperactivity of the sympathetic nervous system and renin-angiotensin aldosterone system,impaired endothelial nitric oxide production, increased oxygen-reactive species, vascular thickening and stiffening, cardiac hypertrophy, impaired angiogenesis, and sometimes genetic predisposition. With the advent of microRNAs(miRNAs), new insights have been added to the perspectives for the treatment of this disease, and exercise training has been shown to be able to modulate the miRNAs associated with it. Elucidation of the relationship between exercise training and miRNAs in the pathogenesis of hypertension is fundamental in order to understand how exercise modulates the cardiovascular system at genetic level. This can be promising even for the development of new drugs. This article is a review of how exercise training acts on hypertension by means of specific miRNAs in the heart, vascular system, and skeletal muscle.     

Role of microRNAs in Arbovirus/Vector Interactions

The role of microRNAs (miRNAs) as small non-coding RNAs in regulation of gene expression has been recognized. They appear to be involved in regulation of a wide range of cellular pathways that affect several biological processes such as development, the immune system, survival, metabolism and host-pathogen interactions. Arthropod-borne viruses impose great economic and health risks around the world. Recent advances in miRNA biology have shed some light on the role of these small RNAs in vector-virus interactions. In this review, I will reflect on our current knowledge on the role of miRNAs in arbovirus-vector interactions and the potential avenues for their utilization in limiting virus replication and/or transmission.