The role of peroxidases in the pathogenesis of atherosclerosis

Reactive oxygen species (ROS), which include superoxide anions and peroxides, induce oxidative stress, contributing to the initiation and progression of cardiovascular diseases involving atherosclerosis. The endogenous and exogenous factors hypercholesterolemia, hyperglycemia, hypertension, and shear stress induce various enzyme systems such as nicotinamide adenine dinucleotide (phosphate) oxidase, xanthine oxidase, and lipoxygenase in vascular and immune cells, which generate ROS. Besides inducing oxidative stress, ROS mediate signaling pathways involved in monocyte adhesion and infiltration, platelet activation, and smooth muscle cell migration. A number of antioxidant enzymes (e.g., superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins) regulate ROS in vascular and immune cells. Atherosclerosis results from a local imbalance between ROS production and these antioxidant enzymes. In this review, we will discuss 1) oxidative stress and atherosclerosis, 2) ROS-dependent atherogenic signaling in endothelial cells, macrophages, and vascular smooth muscle cells, 3) roles of peroxidases in atherosclerosis, and 4) antioxidant drugs and therapeutic perspectives.     

雌激素受体信号通路在乳腺癌发生和治疗中的作用

雌激素受体信号通路在调控乳腺细胞增殖和凋亡等生理机能中发挥重要功能,该通路出现调控异常时可导致乳腺癌发生。雌激素受体在乳腺癌发生中的作用机制包括核受体介导的基因组信号通路和膜受体介导的非基因组信号通路以及二者的相互作用。基于雌激素受体信号通路及其关键信号分子的靶向治疗是开展乳腺癌治疗的重要策略与有效途径。对雌激素受体结构以及雌激素受体信号通路在乳腺癌发生和治疗中的作用作一综述。     

Anoikis molecular pathways and its role in cancer progression

Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix, behaving as a critical mechanism in preventing adherent-independent cell growth and attachment to an inappropriate matrix, thus avoiding colonizing of distant organs. As anchorage-independent growth and epithelial–mesenchymal transition, two features associated with anoikis resistance, are vital steps during cancer progression and metastatic colonization, the ability of cancer cells to resist anoikis has now attracted main attention from the scientific community. Cancer cells develop anoikis resistance due to several mechanisms, including change in integrins' repertoire allowing them to grow in different niches, activation of a plethora of inside-out pro-survival signals as over-activation of receptors due to sustained autocrine loops, oncogene activation, growth factor receptor overexpression, or mutation/upregulation of key enzymes involved in integrin or growth factor receptor signaling. In addition, tumor microenvironment has also been acknowledged to contribute to anoikis resistance of bystander cancer cells, by modulating matrix stiffness, enhancing oxidative stress, producing pro-survival soluble factors, triggering epithelial–mesenchymal transition and self-renewal ability, as well as leading to metabolic deregulations of cancer cells. All these events help cancer cells to inhibit the apoptosis machinery and sustain pro-survival signals after detachment, counteracting anoikis and constituting promising targets for anti-metastatic pharmacological therapy. This article is part of a Special Section entitled: Cell Death Pathways. Guest Editors: Frank Madeo and Slaven Stekovic.     

The role of computational methods in the identification of bioactive compounds

Computational methods play an ever increasing role in lead finding. A vast repertoire of molecular design and virtual screening methods emerged in the past two decades and are today routinely used. There is increasing awareness that there is no single best computational protocol and correspondingly there is a shift recommending the combination of complementary methods. A promising trend for the application of computational methods in lead finding is to take advantage of the vast amounts of HTS (High Throughput Screening) data to allow lead assessment by detailed systems-based data analysis, especially for phenotypic screens where the identification of compound-target pairs is the primary goal. Herein, we review trends and provide examples of successful applications of computational methods in lead finding.     

Glycosphingolipids promote pro-atherogenic pathways in the pathogenesis of hyperglycemia-induced accelerated atherosclerosis

Introduction

Three out of four people with diabetes will die of cardiovascular disease. However, the molecular mechanisms by which hyperglycemia promotes atherosclerosis, the major underlying cause of cardiovascular disease, are not clear.

Objectives

Three distinct models of hyperglycemia-associated accelerated atherosclerosis were used to identify commonly altered metabolites and pathways associated with the disease.

Methods

Normoglycemic apolipoprotein-E-deficient mice served as atherosclerotic control. Hyperglycemia was induced by multiple low-dose streptozotocin injections, or by introducing a point-mutation in one copy of insulin-2 gene. Glucosamine-supplemented mice, which experience accelerated atherosclerosis to a similar extent as hyperglycemia-induced models without alterations in glucose or insulin levels, were also included in the analysis. Untargeted plasma metabolomics were used to investigate hyperglycemia-associated accelerated atherosclerosis in three disease models. The effect of specific significantly altered metabolites on pro-atherogenic processes was investigated in cultured human vascular cells.

Results

Hyperglycemic and glucosamine-supplemented mice showed distinct metabolomic profiles compared to controls. Meta-analysis of three disease models revealed 62 similarly altered metabolite features (FDR-adjusted p?<?0.05). Identification of shared metabolites revealed alterations in glycerophospholipid and sphingolipid metabolism, and pro-atherogenic processes including inflammation and oxidative stress. Post-multivariate and pathway analyses indicated that the glycosphingolipid pathway is strongly associated with hyperglycemia-induced accelerated atherosclerosis in these atherogenic mouse models. Glycosphingolipids induced oxidative stress and inflammation in cultured human vascular cells.

Conclusion

Glycosphingolipids are strongly associated with hyperglycemia-induced accelerated atherosclerosis in three distinct models. They also promote pro-atherogenic processes in cultured human cells. These results suggest glycosphingolipid pathway may be a potential therapeutic target to block or slow atherogenesis in diabetic patients.

     

自然杀伤细胞和自然杀伤T细胞在动脉粥样硬化形成中的作用

动脉粥样硬化发生发展与免疫细胞参与的免疫反应密切相关,其中自然杀伤细胞主要是通过释放IFN-γ、穿孔素和颗粒酶等方式发挥生物学作用,自然杀伤T细胞通过释放多种细胞因子影响动脉粥样硬化形成,但其具体机制未明。本文就自然杀伤细胞和自然杀伤T细胞对动脉粥样硬化的影响做一综述,为动脉粥样硬化及其相关疾病的防治研究提供新的思路。     

The role of endotoxin of gram negative bacteria in the pathogenesis of atherosclerosis

Literature data and the results of own research on the role played by lipopolysaccharide (endotoxin) of Gram negative bacteria in the initiation and progressing of atherosclerosis are summarized. Endotoxin promotes activation of all cells taking part in the formation of atherosclerotic plaques, induces the transformation of macrophages of arterial intima into foam cells as well as endothelial lesions and hyperlipidemia, reduces the ratio of cholesterol in lipoproteins of high specific density to total blood cholesterol. With chlamydiae and enterobacteria used as examples, the role of Gram negative bacteria and their endotoxin in the etiology and pathogenesis of atherosclerosis is discussed.     

1,000 Ways to die: natural compounds modulate non-canonical cell death pathways in cancer cells

Over the past decades, apoptosis emerged as a leading strategy to eliminate cancer cells. Nowadays, it becomes progressively clear that apoptosis is not the only programmed cell death mechanism implicated in the elimination of malignant cells. This review will discuss non-apoptotic cell death modalities and will focus on natural compounds acting as inducers of these recently described processes. We will describe the major molecular characteristics of each individual death mechanism and we will detail the effects of natural and naturally-derived compounds on these cellular mechanisms.     

Macrophages in the pathogenesis of atherosclerosis

In atherosclerosis, the accumulation of apolipoprotein B-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages and dendritic cells. Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolving inflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, and matrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis.     

Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways

Bioactive compounds can be valuable research tools and drug leads, but it is often difficult to identify their mechanism of action or cellular target. Here we investigate the potential for integration of chemical-genetic and genetic interaction data to reveal information about the pathways and targets of inhibitory compounds. Taking advantage of the existing complete set of yeast haploid deletion mutants, we generated drug-hypersensitivity (chemical-genetic) profiles for 12 compounds. In addition to a set of compound-specific interactions, the chemical-genetic profiles identified a large group of genes required for multidrug resistance. In particular, yeast mutants lacking a functional vacuolar H(+)-ATPase show multidrug sensitivity, a phenomenon that may be conserved in mammalian cells. By filtering chemical-genetic profiles for the multidrug-resistant genes and then clustering the compound-specific profiles with a compendium of large-scale genetic interaction profiles, we were able to identify target pathways or proteins. This method thus provides a powerful means for inferring mechanism of action.     

The dichotomous role of nitric oxide in the pathogenesis of accelerated atherosclerosis associated with systemic lupus erythematosus

Atherosclerosis is an inflammatory disorder, and the inflammation associated with systemic lupus erythematosus (SLE) accelerates the development of atherosclerosis. Nitric oxide (NO) is an important mediator of inflammation including the inflammation associated with atherosclerosis and SLE. Endothelial nitric oxide synthase (NOS3)-mediated constitutive expression of NO promotes endothelial integrity and normal vascular function. In contrast, inducible nitric oxide synthase- (NOS2) mediated expression of NO promotes endothelial dysfunction and atherogenesis. Statins appear to have anti-inflammatory properties and reverse many of the deleterious effects associated with NO metabolism in atherosclerosis. Statins augment NOS3 expression and inhibit the induction of NOS2. Therefore, the balance between normal vascular function and atherogenesis may be mediated by differences in the quantity, location, and timing of NO production within vessel walls.     

Discovery and molecular engineering of sugar-containing natural product biosynthetic pathways in actinomycetes

Significant progress has recently been made concerning the engineering of deoxysugar biosynthesis. The biosynthetic gene clusters of several deoxysugars from various polyketides and aminoglycosides-producing microorganisms have been cloned and studied. This review introduces the biosynthetic pathways of several deoxysugars and the generation of novel hybrid macrolide antibiotics via the coexpression of deoxysugar biosynthetic gene cassettes and the substrateflexible glycosyltransferases in a host organism as well as the production of TDP-deoxysugar derivatives via one-pot enzymatic reactions with the identified enzymes. These recent developments in the engineering of deoxysugars biosynthesis may pave the way to create novel secondary metabolites with potential biological activities.     

The role of microbiota and probiotics in stress-induced gastro-intestinal damage

Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host", and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFkappaB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stress-related intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting.     

The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer

Glutathione S-transferase P is abundantly expressed in some mammalian tissues, particularly those associated with malignancies. While the enzyme can catalyze thioether bond formation between some electrophilic chemicals and GSH, novel nondetoxification functions are now ascribed to it. This review summarizes recent material that implicates GSTP in mediating S-glutathionylation of specific clusters of target proteins and in reactions that define a negative regulatory role in some kinase pathways through ligand or protein:protein interactions. It is becoming apparent that GSTP participates in the maintenance of cellular redox homeostasis through a number of convergent and divergent mechanisms. Moreover, drug platforms that have GSTP as a target have produced some interesting preclinical and clinical candidates.     

The role of suppressor cells in the pathogenesis of common variable hypogammaglobulinemia and the immunodeficiency associated with myeloma.

The role of suppressor cells in the pathogenesis of immunodeficiency was analyzed using a technique that permits study of the differentiation of B lymphocytes into immunoglobulin-synthesizing plasma cells. Lymphocytes from normals synthesized 4,910 ng of IgM, 1,270 ng of IgA, and 1,625 ng of IgG per 2 X 10(6) cells when cultured for 7 days in the presence of pokeweed mitogen. In contrast the lymphocytes from patients with common variable hypogammaglobulinemia did not synthesize significant quantities of immunoglobulin. When lymphocytes from 9 of 13 patients with common variable hypogammaglobulinemia studied were cocultured with normal lymphocytes, the synthesis of immunoglobulin by the normal lymphocytes was depressed by 75-100%. A comparable suppression of immunoglobulin synthesis by normal lymphocytes was observed when they were cocultured with T cells from hypogammaglobulinemic patients. These studies suggest that in some patients the disease common variable hypogammaglobulinemia may not be due to an intrinsic defect of B cells alone but may be cuased or perpetuated by an abnormality of regulatory T cells that act to suppress B-cell maturation and antibody production. Peripheral blood lymphocytes from myeloma patients also had a drastically reduced capacity to produce polyclonal immunoglobulins. Three of 6 myeloma patients tested had circulating mononuclear cells that suppressed immunoglobulin production by cocultured normal lymphocytes. Purified T cells from myeloma patients did not mediate this suppressor effect. These observations suggest that one mechanism for the humoral immune deficiency observed in myeloma patients is a block of polyclonal B-cell maturation by suppressor cells.     

The role of complement in atherosclerosis

PURPOSE OF REVIEW: Although it has long been recognized that atherosclerotic lesions show evidence of complement activation, the functional roles of the complement system in atherogenesis are not yet fully resolved. This article highlights recent publications on the complement system in the atherosclerosis field. RECENT FINDINGS: There have been a number of recent papers reporting on the association of complement proteins and complement regulators with high density lipoproteins, complement activation by enzymatically-modified LDL, signalling pathways downstream of C3a and C5a receptors and membrane C5b-9 assembly, and the prevention of C5b-9 assembly on endothelial cells via upregulation of CD59 expression in response to arterial laminar flow. C1q has been found to play a protective role in early lesion formation in LDL receptor deficient mice, and Crry-Ig and soluble C1 inhibitor have both been shown to have therapeutic effects in models of vascular injury in ApoE deficient mice. The possibility that the Y402H Factor H polymophism influences atherosclerosis has been supported in a recent paper showing increased risk in white hypertensive individuals. SUMMARY: The articles that have emerged over the last year highlight the relevance of the complement system to the atherosclerosis field.     

The dual role of bacteriocins as anti- and probiotics

Bacteria employed in probiotic applications help to maintain or restore a host’s natural microbial floral. The ability of probiotic bacteria to successfully outcompete undesired species is often due to, or enhanced by, the production of potent antimicrobial toxins. The most commonly encountered of these are bacteriocins, a large and functionally diverse family of antimicrobials found in all major lineages of Bacteria. Recent studies reveal that these proteinaceous toxins play a critical role in mediating competitive dynamics between bacterial strains and closely related species. The potential use of bacteriocin-producing strains as probiotic and bioprotective agents has recently received increased attention. This review will report on recent efforts involving the use of such strains, with a particular focus on emerging probiotic therapies for humans, livestock, and aquaculture.     

The role of leukemia inhibitory factor in pathogenesis of pre-eclampsia: molecular and cell signaling approach

Journal of Molecular Histology - Endothelial dysfunction is considered as the main hallmark of Preeclampsia (PE). Despite the unknown pathogenesis of PE, different possible causes have been...     

The role of peptidoglycan in pathogenesis

Bacterial pathogens rely on a variety of virulence factors to establish the colonization of a new niche. Although peptidoglycan and its muropeptide derivatives have been known to possess potent biological properties, until recently the molecular bases were poorly understood. With the identification of the cytosolic surveillance mechanism mediated by the nucleotide-binding oligomerization domain (Nod)1 and Nod2 proteins, which detect unique peptidoglycan-derived muropeptides, these muropeptides should be considered as potential virulence factors. Recent research highlights the role of peptidoglycan in the pathogenesis of different human pathogens such as Streptococcus pneumoniae, Listeria monocytogenes or Helicobacter pylori.