Oligosaccharides as Potential Therapeutics against Atherosclerosis.

Atherosclerosis is the major cause of cardiovascular-disease-related death worldwide, resulting from the subendothelial accumulation of lipoprotein-derived cholesterol, ultimately leading to chronic inflammation and the formation of clinically significant atherosclerotic plaques. Oligosaccharides have been widely used in biomedical research and therapy, including tissue engineering, wound healing, and drug delivery. Moreover, oligosaccharides have been consumed by humans for centuries, and are cheap, and available in large amounts. Given the constantly increasing number of obesity, diabetes, and hyperlipidaemia cases, there is an urgent need for novel therapeutics that can economically and effectively slow the progression of atherosclerosis. In this review, we address the current state of knowledge in oligosaccharides research, and provide an update of the recent in vitro and in vivo experiments that precede clinical studies. The application of oligosaccharides could help to eliminate the residual risk after the application of other cholesterol-lowering medicines, and provide new therapeutic opportunities to reduce the associated burden of premature deaths because of atherosclerosis.

Potential Application of the Plant-Derived Essential Oils for Atherosclerosis Treatment: Molecular Mechanisms and Therapeutic Potential.

Essential oils (EOs) are complex secondary metabolites identified in many plant species. Plant-derived EOs have been widely used in traditional medicine for centuries for their health-beneficial effects. Some EOs and their active ingredients have been reported to improve the cardiovascular system, in particular to provide an anti-atherosclerotic effect. The objective of this review is to highlight the recent research investigating the anti-inflammatory, anti-oxidative and lipid-lowering properties of plant-derived EOs and discuss their mechanisms of action. Also, recent clinical trials exploring anti-inflammatory and anti-oxidative activities of EOs are discussed. Future research on EOs has the potential to identify new bioactive compounds and invent new effective agents for treatment of atherosclerosis and related diseases such as diabetes, metabolic syndrome and obesity.

Local Accumulation of Lymphocytes in the Intima of Human Aorta Is Associated with Giant Multinucleated Endothelial Cells: Possible Explanation for Mosaicism of Atherosclerosis.

Distribution of different types of atherosclerotic lesions in the arterial wall is not diffuse, but is characterized by mosaicism. The causes of such distribution remain to be established. At the early stages of atherogenesis, low-density lipoprotein (LDL) particles and immune cells penetrate into the intimal layer of the arterial wall through the endothelium. In adult humans, the luminal surface of the arterial wall is a heterogeneous monolayer of cells with varying morphology including typical endothelial cells (ECs) and multinucleated variant endothelial cells (MVECs). We hypothesized that distribution of MVECs in the endothelial monolayer can be related to the distribution pattern of early atherosclerotic lesions. We obtained en face preparations of intact adult (22-59 years old) aortic wall sections that allowed us to study the endothelial monolayer and the subendothelial layer. We compared the distribution of MVECs in the endothelial monolayer with the localization of early atherosclerotic lesions in the subendothelial layer, which were characterized by lipid accumulation and immune cell recruitment. In primary culture, MVECs demonstrated increased phagocytic activity compared to mononuclear ECs. Moreover, we have shown that unaffected aortic intima contained associates formed as a result of aggregation and/or fusion of LDL particles that are non-randomly distributed. This indicated that MVECs may be involved in the accumulation of LDL in the subendothelial layer through increased transcytosis. Interaction of LDL with subendothelial cells of human aorta in primary culture increased their adhesive properties toward circulating immune cells. Study of unaffected aortic intima revealed non-random distribution of leukocytes in the subendothelial layer and increased localization of CD45+ leukocytes in the subendothelial layer adjacent to MVECs. Together, our observations indicate that MVECs may be responsible for the distribution of atherosclerotic lesions in the arterial wall by participating in LDL internalization and immune cell recruitment.

Significance of Mitochondrial Dysfunction in the Progression of Multiple Sclerosis.

The prevalence of multiple sclerosis and the complexity of its etiology and pathogenesis require further study of the factors underlying the progression of this disease. The prominent role of mitochondria in neurons makes this organelle a vulnerable target for CNS diseases. The purpose of this review is to consider the role of mitochondrial dysfunction in the pathogenesis of multiple sclerosis, as well as to propose new promising therapeutic strategies aimed at restoring mitochondrial function in multiple sclerosis.

Molecular Mechanisms Underlying Pathological and Therapeutic Roles of Pericytes in Atherosclerosis.

Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.

Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis.

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.

New biomarkers for diagnosis and prognosis of localized prostate cancer.

The diagnostics and management of localized prostate cancer is complicated because of cancer heterogeneity and differentiated progression in various subgroups of patients. As a prostate cancer biomarker, FDA-approved detection assay for serum prostate specific antigen (PSA) and its derivatives are not potent enough to diagnose prostate cancer, especially high-grade disease (Gleason ≥7). To date, a collection of new biomarkers was developed. Some of these markers are superior for primary screening while others are particularly helpful for cancer risk stratification, detection of high-grade cancer, and prediction of adverse events. Two of those markers such as proPSA (a part of the Prostate Health Index (PHI)) and prostate specific antigen 3 (PCA3) (a part of the PCA3 Progensa test) were recently approved by FDA for clinical use. Other markers are not PDA-approved yet but are available from Clinical Laboratory Improvement Amendment (CLIA)-certified clinical laboratories. In this review, we characterize diagnostic performance of these markers and their diagnostic and prognostic utility for prostate cancer.

The role of monocytosis and neutrophilia in atherosclerosis.

Monocytosis and neutrophilia are frequent events in atherosclerosis. These phenomena arise from the increased proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) and HSPC mobilization from the bone marrow to other immune organs and circulation. High cholesterol and inflammatory signals promote HSPC proliferation and preferential differentiation to the myeloid precursors (i.e., myelopoiesis) that than give rise to pro-inflammatory immune cells. These cells accumulate in the plaques thereby enhancing vascular inflammation and contributing to further lesion progression. Studies in animal models of atherosclerosis showed that manipulation with HSPC proliferation and differentiation through the activation of LXR-dependent mechanisms and restoration of cholesterol efflux may have a significant therapeutic potential.

Potential of anti-inflammatory agents for treatment of atherosclerosis.

Chronic inflammation is a central pathogenic mechanism of atherosclerosis induction and progression. Vascular inflammation is associated with accelerated onset of late atherosclerosis complications. Atherosclerosis-related inflammation is mediated by a complex cocktail of pro-inflammatory cytokines, chemokines, bioactive lipids, and adhesion molecules, and blocking the key pro-atherogenic inflammatory mechanisms can be beneficial for treatment of atherosclerosis. Therapeutic agents that specifically target some of the atherosclerosis-related inflammatory mechanisms have been evaluated in preclinical and clinical studies. The most promising anti-inflammatory compounds for treatment of atherosclerosis include non-specific anti-inflammatory drugs, phospholipase inhibitors, blockers of major inflammatory cytokines, leukotrienes, adhesion molecules, and pro-inflammatory signaling pathways, such as CCL2-CCR2 axis or p38 MAPK pathway. Ongoing studies attempt evaluating therapeutic utility of these anti-inflammatory drugs for treatment of atherosclerosis. The obtained results are important for our understanding of atherosclerosis-related inflammatory mechanisms and for designing randomized controlled studies assessing the effect of specific anti-inflammatory strategies on cardiovascular outcomes.

Thrombospondins: A Role in Cardiovascular Disease.

Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-ß, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-ß signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial.

Anti-Atherosclerotic Effects of a Phytoestrogen-Rich Herbal Preparation in Postmenopausal Women.

The risk of cardiovascular disease and atherosclerosis progression is significantly increased after menopause, probably due to the decrease of estrogen levels. The use of hormone replacement therapy (HRT) for prevention of cardiovascular disease in older postmenopausal failed to meet expectations. Phytoestrogens may induce some improvements in climacteric symptoms, but their effect on the progression of atherosclerosis remains unclear. The reduction of cholesterol accumulation at the cellular level should lead to inhibition of the atherosclerotic process in the arterial wall. The inhibition of intracellular lipid deposition with isoflavonoids was suggested as the effective way for the prevention of plaque formation in the arterial wall. The aim of this double-blind, placebo-controlled clinical study was to investigate the effect of an isoflavonoid-rich herbal preparation on atherosclerosis progression in postmenopausal women free of overt cardiovascular disease. One hundred fifty-seven healthy postmenopausal women (age 65 ± 6) were randomized to a 500 mg isoflavonoid-rich herbal preparation containing tannins from grape seeds, green tea leaves, hop cone powder, and garlic powder, or placebo. Conventional cardiovascular risk factors and intima-media thickness of common carotid arteries (cIMT) were evaluated at the baseline and after 12 months of treatment. After 12-months follow-up, total cholesterol decreased by 6.3% in isoflavonoid-rich herbal preparation recipients (p = 0.011) and by 5.2% in placebo recipients (p = 0.020); low density lipoprotein (LDL) cholesterol decreased by 7.6% in isoflavonoid-rich herbal preparation recipients (p = 0.040) and by 5.2% in placebo recipients (non-significant, NS); high density lipoprotein (HDL) cholesterol decreased by 3.4% in isoflavonoid-rich herbal preparation recipients (NS) and by 4.5% in placebo recipients (p = 0.038); triglycerides decreased by 6.0% in isoflavonoid-rich herbal preparation recipients (NS) and by 7.1% in placebo recipients (NS). The differences between lipid changes in the isoflavonoid-rich herbal preparation and placebo recipients did not reach statistical significance (p > 0.05). Nevertheless, the mean cIMT progression was significantly lower in isoflavonoid-rich herbal preparation recipients as compared to the placebo group (6 µm, or <1%, versus 100 µm, or 13%; p < 0.001 for the difference). The growth of existing atherosclerotic plaques in isoflavonoid-rich herbal preparation recipients was inhibited by 1.5-fold (27% versus 41% in the placebo group). The obtained results demonstrate that the use of isoflavonoid-rich herbal preparation in postmenopausal women may suppress the formation of new atherosclerotic lesions and reduce the progression of existing ones, thus promising new drug for anti-atherosclerotic therapy. Nevertheless, further studies are required to confirm these findings.

Modified low density lipoprotein and lipoprotein-containing circulating immune complexes as diagnostic and prognostic biomarkers of atherosclerosis and type 1 diabetes macrovascular disease.

In atherosclerosis; blood low-density lipoproteins (LDL) are subjected to multiple enzymatic and non-enzymatic modifications that increase their atherogenicity and induce immunogenicity. Modified LDL are capable of inducing vascular inflammation through activation of innate immunity; thus, contributing to the progression of atherogenesis. The immunogenicity of modified LDL results in induction of self-antibodies specific to a certain type of modified LDL. The antibodies react with modified LDL forming circulating immune complexes. Circulating immune complexes exhibit prominent immunomodulatory properties that influence atherosclerotic inflammation. Compared to freely circulating modified LDL; modified LDL associated with the immune complexes have a more robust atherogenic and proinflammatory potential. Various lipid components of the immune complexes may serve not only as diagnostic but also as essential predictive markers of cardiovascular events in atherosclerosis. Accumulating evidence indicates that LDL-containing immune complexes can also serve as biomarker for macrovascular disease in type 1 diabetes.

Potential Use of Antioxidant Compounds for the Treatment of Inflammatory Bowel Disease.

Since inflammatory bowel diseases (IBDs) are chronic, the development of new effective therapeutics to combat them does not lose relevance. Oxidative stress is one of the main pathological processes that determines the progression of IBD. In this regard, antioxidant therapy seems to be a promising approach. The role of oxidative stress in the development and progression of IBD is considered in detail in this review. The main cause of oxidative stress in IBD is an inadequate response of leukocytes to dysbiosis and food components in the intestine. Passage of immune cells through the intestinal barrier leads to increased ROS concentration and the pathological consequences of exposure to oxidative stress based on the development of inflammation and impaired intestinal permeability. To combat oxidative stress in IBD, several promising natural (curcumin, resveratrol, quercetin, and melatonin) and artificial antioxidants (N-acetylcysteine (NAC) and artificial superoxide dismutase (aSOD)) that had been shown to be effective in a number of clinical trials have been proposed. Their mechanisms of action on pathological events in IBD and clinical manifestations from their impact have been determined. The prospects for the use of other antioxidants that have not yet been tested in the treatment of IBD, but have the properties of potential therapeutic candidates, have been also considered.

The Role of Selenium in Atherosclerosis Development, Progression, Prevention and Treatment.

Selenium is an essential trace element that is essential for various metabolic processes, protection from oxidative stress and proper functioning of the cardiovascular system. Se deficiency has long been associated with multiple cardiovascular diseases, including endemic Keshan's disease, common heart failure, coronary heart disease, myocardial infarction and atherosclerosis. Through selenoenzymes and selenoproteins, Se is involved in numerous crucial processes, such as redox homeostasis regulation, oxidative stress, calcium flux and thyroid hormone metabolism; an unbalanced Se supply may disrupt these processes. In this review, we focus on the importance of Se in cardiovascular health and provide updated information on the role of Se in specific processes involved in the development and pathogenesis of atherosclerosis (oxidative stress, inflammation, endothelial dysfunction, vascular calcification and vascular cell apoptosis). We also discuss recent randomised trials investigating Se supplementation as a potential therapeutic and preventive agent for atherosclerosis treatment.

The Role of Pericytes in Regulation of Innate and Adaptive Immunity.

Pericytes are perivascular multipotent cells wrapping microvascular capillaries, where they support vasculature functioning, participate in tissue regeneration, and regulate blood flow. However, recent evidence suggests that in addition to traditionally credited structural function, pericytes also manifest immune properties. In this review, we summarise recent data regarding pericytes' response to different pro-inflammatory stimuli and their involvement in innate immune responses through expression of pattern-recognition receptors. Moreover, pericytes express various adhesion molecules, thus regulating trafficking of immune cells across vessel walls. Additionally, the role of pericytes in modulation of adaptive immunity is discussed. Finally, recent reports have suggested that the interaction with cancer cells evokes immunosuppression function in pericytes, thus facilitating immune evasion and facilitating cancer proliferation and metastasis. However, such complex and multi-faceted cross-talks of pericytes with immune cells also suggest a number of potential pericyte-based therapeutic methods and techniques for cancer immunotherapy and treatment of autoimmune and auto-inflammatory disorders.

Involvement of Bacterial Extracellular Membrane Nanovesicles in Infectious Diseases and Their Application in Medicine.

Bacterial extracellular membrane nanovesicles (EMNs) are attracting the attention of scientists more and more every year. These formations are involved in the pathogenesis of numerous diseases, among which, of course, the leading role is occupied by infectious diseases, the causative agents of which are a range of Gram-positive and Gram-negative bacteria. A separate field for the study of the role of EMN is cancer. Extracellular membrane nanovesicles nowadays have a practical application as vaccine carriers for immunization against many infectious diseases. At present, the most essential point is their role in stimulating immune response to bacterial infections and tumor cells. The possibility of nanovesicles' practical use in several disease treatments is being evaluated. In our review, we listed diseases, focusing on their multitude and diversity, for which EMNs are essential, and also considered in detail the possibilities of using EMNs in the therapy and prevention of various pathologies.

Familial Hypercholesterolaemia as a Predisposing Factor for Atherosclerosis.

Lipid metabolism alterations are an important component of the pathogenesis of atherosclerosis. However, it is now clear that the atherogenesis process involves more than one mechanism, and more than one condition can predispose this condition. Multiple risk factors contribute to the atherosclerosis initiation and define its course. Familial hypercholesterolaemia is a disorder of lipid metabolism that often leads to atherosclerosis development. As is clear from the disease name, the hallmark is the increased levels of low-density lipoprotein cholesterol (LDL-C) in blood. This creates favourable conditions for atherogenesis. In this review, we briefly described the familial hypercholesterolaemia and summarized data on the relationship between familial hypercholesterolaemia and atherosclerosis.

Functional Phenotypes of Intraplaque Macrophages and Their Distinct Roles in Atherosclerosis Development and Atheroinflammation.

Macrophages are the key inflammatory cell type involved in all stages of atherosclerosis development and progression, as demonstrated by numerous studies. Correspondingly, macrophages are currently regarded as a promising therapeutic target for the development of new treatment approaches. The macrophage population is heterogeneous and dynamic, as these cells can switch between a number of distinct functional states with pro- and anti-atherogenic activity in response to various stimuli. An atherosclerotic plaque microenvironment defined by cytokine levels, cell-to-cell interactions, lipid accumulation, hypoxia, neoangiogenesis, and intraplaque haemorrhage may guide local macrophage polarization processes within the lesion. In this review, we discuss known functional phenotypes of intraplaque macrophages and their distinct contribution to ahteroinflammation.

Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson's Disease.

Impaired mitophagy is one of the hallmarks of the pathogenesis of Parkinson's disease, which highlights the importance of the proper functioning of mitochondria, as well as the processes of mitochondrial dynamics for the functioning of dopaminergic neurons. At the same time, the main factors leading to disruption of mitophagy in Parkinson's disease are mutations in the Pink1 and Parkin enzymes. Based on the characterized mutant forms, the marked cellular localization, and the level of expression in neurons, these proteins can be considered promising targets for the development of drugs for Parkinson's therapy. This review will consider such class of drug compounds as mitophagy activators and these drugs in the treatment of Parkinson's disease.

Emerging role of pericytes in therapy of cardiovascular diseases.

Pericytes are mural vascular cells covering microvascular capillaries, where they contribute to the formation, maturation, maintenance, stabilisation and remodelling of vasculature. They actively interact and communicate with other cells to maintain the capillary structural integrity, vascular permeability and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. In this review, we summarise recent data regarding pericyte metabolism, trans-differentiation, angiogenesis and immunomodulation in connection with different cardiovascular pathologies. Further, we discuss an application of pericytes as a new cell therapy approach to treat coronary artery disease, congenital heart disease, atherosclerotic plaques calcification and calcific valvular heart disease in different in vivo animal models and in vitro studies. Also, we discuss different methods and pharmacological therapies for CVDs treatment with pericyte-mediated effects. Finally, we present a comprehensive overview of the role of pericytes in CVDs and as a pharmacological target for different novel drugs and techniques and highlight the potential application of pericytes to treat CVDs.