Anti-inflammatory drugs and atherosclerosis

PURPOSE OF REVIEW: Inflammation contributes to the formation and progression of atherosclerosis and the therapeutic potential of some anti-inflammatory drugs has been evaluated for possible antiatherosclerotic effects. This review will briefly describe the mechanisms underlying the inflammation-atherosclerosis connection, the effect of various anti-inflammatory therapies on atherosclerotic disease and a sampling of the potential targets and agents under evaluation. RECENT FINDINGS: Some agents with anti-inflammatory properties appear to have beneficial effects on atherosclerosis or subsequent risk for cardiovascular events, while others have been disappointing. The anti-inflammatory actions of statins have been linked retrospectively with their favorable effects on atherosclerosis progression and clinical outcomes. The cardiovascular safety of COX-2 inhibitors is being assessed prospectively in patients with atherosclerosis. Potential new therapeutic agents targeting other inflammatory mechanisms and oxidative stress are being evaluated in animal models and clinical trials. SUMMARY: Due to the contributory inflammatory pathways in atherosclerosis, the properties of existing and novel anti-inflammatory agents are being carefully and actively evaluated in cardiovascular disease. Advances in our understanding of both atherosclerosis and the inflammatory contributors may play an important role in future strategies to decrease the incidence of atherosclerotic cardiovascular disease.     

Exosomes: New players in cell-cell communication

Exosomes are small membrane vesicles of endosomal origin, which are secreted from a variety of cell types. During the 1980s exosomes were first described as organelles to remove cell debris and unwanted molecules. The discovery that exosomes contain proteins, messenger and microRNAs suggests a role as mediators in cell-to-cell communication. Exosomes can be transported between different cells and influence physiological pathways in the recipient cells. In the present review, we will summarize the biological function of exosomes and their involvement in physiological and pathological processes. Moreover, the potential clinical application of exosomes as biomarkers and therapeutic tools will be discussed.     

Recent progress in the emerging role of exosome in hepatocellular carcinoma

Exosomes are small membrane vesicles 50‐150 nm in diameter released by a variety of cells, which contain miRNAs, mRNAs and proteins with the potential to regulate signalling pathways in recipient cells. Exosomes deliver nucleic acids and proteins to participate in orchestrating cell‐cell communication and microenvironment modulation. In this review, we summarize recent progress in our understanding of the role of exosomes in hepatocellular carcinoma (HCC). This review focuses on recent studies on HCC exosomes, considering biogenesis, cargo and their effects on the development and progression of HCC, including chemoresistance, epithelial‐mesenchymal transition, angiogenesis, metastasis and immune response. Finally, we discuss the clinical application of exosomes as a therapeutic agent for HCC.     

Pathophysiology and treatment of atherosclerosis

Recent years have brought a significant amount of new results in the field of atherosclerosis. A better understanding of the role of different lipoprotein particles in the formation of atherosclerotic plaques is now possible. Recent cardiovascular clinical trials have also shed more light upon the efficacy and safety of novel compounds targeting the main pathways of atherosclerosis and its cardiovascular complications.In this review, we first provide a background consisting of the current understanding of the pathophysiology and treatment of atherosclerotic disease, followed by our future perspectives on several novel classes of drugs that target atherosclerosis. The focus of this update is on the pathophysiology and medical interventions of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)).     

Exosomes as a novel cell-free therapeutic approach in gastrointestinal diseases

Cell communication through extracellular vesicles (EVs) has been defined for many years and it is not limited only to neighboring cells, but also distant ones in organisms receive these signals. These vesicles are secreted from the variety of cells and are composed of a distinctive component such as proteins, lipids, and nucleic acids. EVs have different classified subgroups regarding their cell origin, in this context, exosomes are the most appealing particles in cell biology, especially clinical in recent years and are represented as novel therapeutic agents with numerous advantages alongside and/or over cell therapy. However, cell therapy had a hopeful outcome in gastrointestinal diseases which have minimal alternatives in their treatments. Inflammatory bowel disease (IBD), liver fibrosis, gastrointestinal cancers are the examples that cell therapy and immunotherapy were applied in their treatment, therefore, the cell products like exosomes are the beneficial option in their treatment even cancers with promising results in animal models. In this review, we consider the main defined biogenesis, function, and component of secreted exosomes in different cells with a specific focus on the potential application of these exosomes as a cell-free therapeutic approach in gastrointestinal diseases like IBD, gastric cancer, and colon cancer. Additionally, exosomes role as therapeutic reagents mainly mesenchymal stem cells and dendritic cell-derived exosomes in different studies have been under intense investigation and even they are being studied in different clinical trials. Therefore, all these striking functions described for secretome implies the importance of these biocarriers.     

The potential role of exosomes derived from ovarian cancer cells for diagnostic and therapeutic approaches

Most patients with ovarian cancer (OC) are diagnosed at the advanced stages due to the absence of appropriate early diagnostic markers. Thus, OC is a gynecological disease with a low-survival rate. Exosomes are extracellular vesicles that are widely being considered as mediators for the noninvasive diagnosis of OC. Exosomes are expected to aid in the effective diagnosis of OC because they carry components, such as RNAs, proteins, and lipids, the compositions of which vary depending on the pathological characteristics of the patient. In this review, we document the methods that have been developed to detect exosomes and their components in OC. We also assess the potential biomarkers contained in exosomes that could be clinically useful, such as proteins, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and phospholipids. Moreover, we described the role played by exosomes in the tumor microenvironment and in OC angiogenesis, migration, and tumor growth. Various types of cells in the tumor microenvironment, including macrophages, fibroblasts, and mesenchymal stem cells (MSCs), interact directly with exosomes and promote or inhibit the progression of OC. Therefore, we summarize the studies that have suggested a therapeutic approach to OC using exosomes. Collectively, understanding the mechanism of exosome-based OC progression would broaden our knowledge regarding the diagnosis and therapy of OC.     

Thematic review series: The immune system and atherogenesis. Cytokine regulation of macrophage functions in atherogenesis

This review will focus on the role of cytokines in the behavior of macrophages, a prominent cell type of atherosclerotic lesions. Once these macrophages have immigrated into the vessel wall, they propagate the development of atherosclerosis by modifying lipoproteins, accumulating intracellular lipids, remodeling the extracellular environment, and promoting local coagulation. The numerous cytokines that have been detected in atherosclerosis, combined with the expression of large numbers of cytokine receptors on macrophages, are consistent with this axis being an important contributor to lesion development. Given the vast literature on cytokine-macrophage interactions, this review will be selective, with an emphasis on the major cytokines that have been detected in atherosclerotic lesions and their effects on properties that are relevant to lesion formation and maturation. There will be an emphasis on the role of cytokines in regulating lipid metabolism by macrophages. We will provide an overview of the major findings in cell culture and then put these in the context of in vivo studies.     

Exosomes: A New Weapon to Treat the Central Nervous System

The potential of exosomes to treat central nervous system (CNS) pathologies has been recently demonstrated. These studies make way for a complete new field that aims to exploit the natural characteristics of these vesicles, considered for a long time as side products of physiological cellular pathways. Recently, however, the biological significance of exosomes has been evaluated and exosomes can now be viewed upon as new relevant functional entities for development of novel therapeutic strategies. In this review, we aim to summarize the state-of-the-art role of exosomes in the CNS and to speculate about possible future therapeutic applications of exosomes. In particular, we will speculate about the use of these vesicles as a substitute of cell-based therapies for the treatment of brain damage and review the potential of exosomes as drug delivery vehicles for the CNS.     

Is it just paraoxonase 1 or are other members of the paraoxonase gene family implicated in atherosclerosis?

PURPOSE OF REVIEW: During the past decade, paraoxonase 1, a HDL-associated protein, has been demonstrated to be an important contributor to the antioxidant capacity of HDL. Studies using paraoxonase 1 null mice by gene targeting and transgenic mice corroborated the hypothesis that paraoxonase 1 protects against atherosclerosis. In contrast to paraoxonase 1, the other two members of the paraoxonase gene family, namely paraoxonase 2 and paraoxonase 3, are either undetectable (paraoxonase 2) or detected at very low levels (paraoxonase 3) on HDL, and are considered to participate in intracellular antioxidant mechanisms. In this review, we summarize studies reported in the past 2 years suggesting a protective role for paraoxonase 2 and paraoxonase 3 in the development of atherosclerosis in mice. RECENT FINDINGS: Adenovirus-mediated expression of human paraoxonase 2 or paraoxonase 3 proteins protects against the development of atherosclerosis in apolipoprotein E-deficient mice. Paraoxonase 2-deficient mice develop significantly larger atherosclerotic lesions than their wild-type and heterozygous counterparts on an atherogenic diet despite having lower levels of apolipoprotein B-containing lipoproteins. Atherosclerotic lesions were significantly lower in male hPON3Tg/LDLR null mice than in LDLR null mice on a western diet. SUMMARY: We conclude that, in addition to paraoxonase 1, both paraoxonase 2 and paraoxonase 3 proteins are protective against the development of atherosclerosis in mice. These findings underscore the utility of all members of the paraoxonase gene family as therapeutic targets for the treatment of atherosclerosis.     

The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

Exosomes are nanoscale membrane vesicles, which carry biologically active substances of their cell of origin and play an important role in signal transduction and intercellular communication. At present, exosomes have been identified as a promising non-invasive liquid biopsy biomarker in the tissues and circulating blood of nasopharyngeal carcinoma (NPC) and found to participate in regulating pathophysiological process of the tumor. We here review recent insights gained into the molecular mechanisms of exosome-induced cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance and chemotherapy resistance in the development and progression of NPC, as well as the clinical application of exosomes as diagnostic biomarkers and therapeutic agents. We also discuss the limitations and challenges in exosome application. We hope this review may provide some references for the use of exosomes in clinical intervention.     

In vivo molecular imaging of vascular stress

Noninvasive in vivo imaging is an emerging specialty in experimental radiology aiming at developing hardware and appropriate contrast agents to visualize the molecular basis and pathophysiological processes of many pathological conditions, including atherosclerosis. The list of potentially useful tracers and targets for in vivo molecular imaging in the cascade of early atherosclerotic events has been narrowed down to some very promising endothelial factors, i.e., cell adhesion molecules, macrophages, apoptosis, lipoproteins, heat shock proteins, and others. In this review, we will update on the progress of recent developments in the field of noninvasive molecular imaging in experimental atherosclerosis.     

Roles of exosomes in liver metastases: Novel diagnosis and treatment choices

Tumors tend to metastasize to the liver. Premetastatic niche formation is a vital step in liver metastasis. Tumor-derived exosomes can influence premetastatic niche formation from three aspects: vascular leakiness and angiogenesis, recruitment of nonresident cells, and changes in local resident cells. Exosomes from other tissues, such as mesenchymal stem cell-derived exosomes and engineered exosomes, also have therapeutic potential, but further research on these exosomes is required. Based on the mechanism of premetastatic niche formation, we summarize the therapeutic and diagnostic potential of exosomes in inhibiting liver metastases in this review in an attempt to provide new avenues for the prevention and treatment of liver metastases.     

Advances in retroviral transduction of hematopoietic stem cells for the gene therapy of atherosclerosis

PURPOSE OF REVIEW: Atherosclerosis is a chronic inflammatory disease that is the primary cause of morbidity and mortality in the developed world. Many studies have shown that macrophages and T-cells play critical roles in multiple aspects of the pathogenesis of the disease. Given that these cells are ultimately derived from bone marrow precursors, the concept of performing gene therapy for atherosclerosis through the retroviral transduction of hematopoietic stem cells has received much attention. This review will highlight recent advances that will help bring this goal closer. RECENT FINDINGS: The clinical application of retroviral gene transfer into hematopoietic stem cells has been hampered, in part, by the absence of vectors that can direct long-lasting, cell-type specific gene expression. In this review we will detail recent developments in the design of novel retroviral and lentiviral vectors that appear to overcome these problems, offering approaches to express therapeutic genes in specific cell-types within atherosclerotic lesions. We will also highlight advances in our understanding of the pathogenesis of atherosclerosis that may offer new gene therapeutic targets. SUMMARY: The use of retroviral transduction of hematopoietic stem cells for treatment of patients with atherosclerosis still remains a long-term goal. However, the recent development of retroviral vectors capable of directing expression to specific cell types within the lesion will allow more targeted therapeutic strategies to be devised. In addition, these vectors will provide powerful experimental tools to further our understanding of the pathogenesis of the disease.     

The critical role of exosomes in tumor biology

Exosomes are a type of extracellular vesicles (diameter, 30-160 nm), which contain multiple proteins, nucleic acids, lipid molecules, and other substances. Most types of cells can secrete exosomes, although the biogenesis, composition, and function is specific to different cell types. Recently, many studies have demonstrated that exosomes play a critical role in tumor development. In this review, we briefly summarize the biogenesis, composition, and function of exosomes. We also discuss the recent advances in the critical role of exosomes in tumor biology with a special focus on their application in tumor diagnosis and treatment.     

Strategies for the assessment of genetic coronary artery disease risk.

In atherosclerotic diseases, genetic factors have a substantial influence on the age of onset and the frequency and severity of clinical symptoms, as well as response to therapy. In myocardial infarctions occurring at young age, genetics may be the leading causative factor. Despite such a prominent role of genetics in the pathophysiology of atherosclerosis clinical risk assessment and therapeutic decision making are still based on classical risk factors. In this paper we analyse the reasons for the current lack of predictive power of genetics-based algorithms and we speculate why future developments might open the door to a role for genetics in the clinical management of atherosclerosis.     

Xenogenic macrophage immunization reduces atherosclerosis in apolipoprotein E knockout mice

Atherosclerosis is a complex chronic inflammatory disease in which macrophages play a critical role, and the intervention of the inflammatory process in atherogenesis could be a therapeutic strategy. In this study, we investigated the efficacy of xenogenic macrophage immunization on the atherosclerotic lesion formation in a model of murine atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were repeatedly immunized with formaldehyde-fixed cultured human macrophages (phorbol ester-stimulated THP-1 cells), using human serum albumin as a control protein or HepG2 cells as human control cells, once a week for four consecutive weeks. The vehicle phosphate-buffered saline was injected in the nonimmunized controls. THP-1 immunization induced antibodies that are immunoreactive with mouse macrophages. Although the plasma lipid levels were unchanged by the immunization, the atherosclerotic lesion area in the aortic root was significantly reduced by >50% in 16-wk-old THP-1-immunized apoE-KO mice compared with that in control mice. THP-1 immunization reduced in vivo macrophage infiltration, reduced in vitro macrophage adhesion, and changed cytokine production by macrophages to the antiatherogenic phenotype. Xenogenic macrophage immunization protects against the development of atherosclerosis in apoE-KO mice by modulating macrophage function in which antibodies induced by the immunization are likely to be involved. This method is a novel and potentially useful cell-mediated immune therapeutic technique against atherosclerosis. antibody; THP-1 cells     

Horizontal transfer of microRNAs: molecular mechanisms and clinical applications

A new class of RNA regulatory genes known as microRNAs (miRNAs) has been found to introduce a whole new layer of gene regulation in eukaryotes. The intensive studies of the past several years have demonstrated that miRNAs are not only found intracellularly, but are also detectable outside cells, including in various body fluids (e.g. serum, plasma, saliva, urine and milk). This phenomenon raises questions about the biological function of such extracellular miRNAs. Substantial amounts of extracellular miRNAs are enclosed in small membranous vesicles (e.g. exosomes, shedding vesicles and apoptotic bodies) or packaged with RNA-binding proteins (e.g. high-density lipoprotein, Argonaute 2 and nucleophosmin 1). These miRNAs may function as secreted signaling molecules to influence the recipient cell phenotypes. Furthermore, secreted extracellular miRNAs may reflect molecular changes in the cells from which they are derived and can therefore potentially serve as diagnostic indicators of disease. Several studies also point to the potential application of siRNA/miRNA delivery as a new therapeutic strategy for treating diseases. In this review, we summarize what is known about the mechanism of miRNA secretion. In addition, we describe the pathophysiological roles of secreted miRNAs and their clinical potential as diagnostic biomarkers and therapeutic drugs. We believe that miRNA transfer between cells will have a significant impact on biological research in the coming years.     

Caveolins and macrophage lipid metabolism

The identification of caveolin-1 more than a decade ago initiated active research into its role in the formation of caveolae, membrane trafficking, signal transduction pathways, and lipid homeostasis. Although caveolins are ubiquitously expressed, the majority of the available information comes from differentiated cells rich in caveolins, such as fibroblasts, adipocytes, and endothelial cells. During the development of atherosclerosis, macrophages play a pivotal role in the formation of the fatty streak lesions. They take up large amounts of lipids and accumulate in the subendothelial space, forming foam cells that fill up the lesion area. Since caveolins have been implicated in the regulation of cellular cholesterol metabolism in several cell types, it is of interest to examine their potential function in macrophages. In this review, we attempt to summarize current knowledge and views on the role of caveolins in cholesterol metabolism with emphasis on macrophages.     

Imagerie moléculaire de la plaque d’athérome vulnérable. Évaluation préclinique et clinique de traceurs radioactifs

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of mortality worldwide, accounting for greater than 19.10⁶ deaths annually. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. Indeed, an acute heart attack is the first symptom of atherosclerosis in as much as 50% of individuals with severe disease. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerosis in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could potentially allow the identification of vulnerable patients by non-invasive scintigraphic imaging following administration of a radiolabeled tracer. The development of radiolabeled probes that specifically bind to and allow the in vivo imaging of vulnerable atherosclerotic plaques is therefore the subject of intense ongoing experimental and clinical research. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET imaging. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable atherosclerotic plaques in the carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of the coronary arteries remains a challenging issue because of the small size of atherosclerotic lesions and of their vicinity with blood and the circulating tracer activity.