Dimitry A. Chistiakov

Genetic determinants of aggression and impulsivity in humans

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.

Macrophage‐mediated cholesterol handling in atherosclerosis

Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro‐inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low‐density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR‐A1 and lectin‐like oxLDL receptor‐1 (LOX‐1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase‐1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out‐flowed from macrophages by cholesterol ATP‐binding cassette (ABC) transporters ABCA1 and ABCG1 and SR‐BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.

Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes

Macrophages are essential players in induction and progression of atherosclerotic inflammation. The complexity of macrophage phenotypes was observed in human plaques and atherosclerotic lesions in mouse models of atherosclerosis. Plaque macrophages were shown to exhibit a phenotypic range that is intermediate between two extremes, M1 (pro-inflammatory) and M2 (anti-inflammatory). Indeed, in atherosclerosis, macrophages demonstrate phenotypic plasticity to rapidly adjust to changing microenvironmental conditions. In the plaque, serum lipids, serum lipoproteins and various pro- or anti-inflammatory stimuli such as cytokines, chemokines and small bioactive molecules could greatly influence the macrophage phenotype inducing switch towards more proinflammatory or anti-inflammatory properties. Dynamic plasticity of macrophages is achieved by up-regulation and down-regulation of an overlapping set of transcription factors that drive macrophage polarization. Understanding of mechanisms of macrophage plasticity and resolving functional characteristics of distinct macrophage phenotypes should help in the development of new strategies for treatment of chronic inflammation in atherosclerosis and other cardiovascular diseases.

Contribution of microRNAs to radio- and chemoresistance of brain tumors and their therapeutic potential.

Glioblastomas, particularly high grade brain tumors such as glioblastoma multiforme, are characterized by increased anaplasy, malignancy, proliferation, and invasion. These tumors exhibit high resistance to radiation therapy and treatment with anti-cancer drugs. The radio- and chemoresistance of gliomas is attributed to cancer stem cells (CSCs) that are considered as major contributors for maintenance and propagation of tumor cell mass, cancer malignancy and invasiveness, and tumor cell survival after courses of radiotherapy and medical interventions. MicroRNAs (miRNAs), key post-transcriptional gene regulators, have altered expression profiles in gliomas. Some of miRNAs whose expression is markedly up-regulated in brain tumors are likely to have a pro-oncogenic role through supporting growth, proliferation, migration, and survival of cancer stem and non-stem cells. In contrast, a population of miRNA possessing anti-tumor effects is suppressed in gliomas. In this review, we will consider miRNAs and their influence on radio- and chemoresistance of gliomas. These miRNAs harbor a great therapeutic significance as potent agents in future targeted anti-cancer therapy to sensitize glioma tumor cells and CSCs to cytotoxic effects of radiation exposure and treatment with anti-cancer drugs.

Endothelial Barrier and Its Abnormalities in Cardiovascular Disease.

Endothelial cells (ECs) form a unique barrier between the vascular lumen and the vascular wall. In addition, the endothelium is highly metabolically active. In cardiovascular disease such as atherosclerosis and hypertension, normal endothelial function could be severely disturbed leading to endothelial dysfunction that then could progress to complete and irreversible loss of EC functionality and contribute to entire vascular dysfunction. Proatherogenic stimuli such as diabetes, dyslipidemia, and oxidative stress could initiate endothelial dysfunction and in turn vascular dysfunction and lead to the development of atherosclerotic arterial disease, a background for multiple cardiovascular disorders including coronary artery disease, acute coronary syndrome, stroke, and thrombosis. Intercellular junctions between ECs mediate the barrier function. Proinflammatory stimuli destabilize the junctions causing the disruption of the endothelial barrier and increased junctional permeability. This facilitates transendothelial migration of immune cells to the arterial intima and induction of vascular inflammation. Proatherogenic stimuli attack endothelial microtubule function that is regulated by acetylation of tubulin, an essential microtubular constituent. Chemical modification of tubulin caused by cardiometabolic risk factors and oxidative stress leads to reorganization of endothelial microtubules. These changes destabilize vascular integrity and increase permeability, which finally results in increasing cardiovascular risk.

Vascular extracellular matrix in atherosclerosis.

The extracellular matrix (ECM) is an essential component of the human body that is responsible for the proper function of various organs. Changes in the ECM have been implicated in the pathogenesis of several cardiovascular conditions including atherosclerosis, restenosis, and heart failure. Matrix components, such as collagens and noncollagenous proteins, influence the function and activity of vascular cells, particularly vascular smooth muscle cells and macrophages. Matrix proteins have been shown to be implicated in the development of atherosclerotic complications, such as plaque rupture, aneurysm formation, and calcification. ECM proteins control ECM remodeling through feedback signaling to matrix metalloproteinases (MMPs), which are the key players of ECM remodeling in both normal and pathological conditions. The production of MMPs is closely related to the development of an inflammatory response and is subjected to significant changes at different stages of atherosclerosis. Indeed, blood levels of circulating MMPs may be useful for the assessment of the inflammatory activity in atherosclerosis and the prediction of cardiovascular risk. The availability of a wide variety of low-molecular MMP inhibitors that can be conjugated with various labels provides a good perspective for specific targeting of MMPs and implementation of imaging techniques to visualize MMP activity in atherosclerotic plaques and, most interestingly, to monitor responses to antiatheroslerosis therapies. Finally, because of the crucial role of ECM in cardiovascular repair, the regenerative potential of ECM could be successfully used in constructing engineered scaffolds and vessels that mimic properties of the natural ECM and consist of the native ECM components or composite biomaterials. These scaffolds possess a great promise in vascular tissue engineering.

The role of miR-126 in embryonic angiogenesis, adult vascular homeostasis, and vascular repair and its alterations in atherosclerotic disease

Expression of microRNA (miR)-126 is enriched in endothelial cells (ECs) and endothelial progenitor cells (EPCs). MiR-126 is considered a master regulator of physiological angiogenesis. In embryonic vasculogenesis, this miRNA is involved in induction of angiogenic signaling, supports differentiation of embryonic stem cells to EPCs and ECs, and promotes EC maturation. However, in mature ECs and adult EPCs, miR-126 contributes to vascular homeostasis by inhibiting angiogenesis and maintaining the quiescent endothelial phenotype associated with increased vascular integrity and inhibited proliferation and motility. In a case of vessel injury and/or hypoxia, miR-126 up-regulation activates EPCs and ECs and contributes to vascular healing and neovessel formation. Indeed, miR-126 exhibits vasculoprotective and atheroprotective properties. The promising regenerative and proangiogenic potential of this miRNA will be helpful for development of cardioprotective strategies and cardiovascular repair therapies of myocardial infarction, heart failure, and other cardiovascular pathology.

Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability

Atherosclerosis is a continuous pathological process that starts early in life and progresses frequently to unstable plaques. Plaque rupture leads to deleterious consequences such as acute coronary syndrome, stroke and atherothrombosis. The vulnerable lesion has several structural and functional hallmarks that distinguish it from the stable plaque. The unstable plaque has large necrotic core (over 40% plaque volume) composed of cholesterol crystals, cholesterol esters, oxidized lipids, fibrin, erythrocytes and their remnants (haeme, iron, haemoglobin), and dying macrophages. The fibrous cap is thin, depleted of smooth muscle cells and collagen, and is infiltrated with proinflammatory cells. In unstable lesion, formation of neomicrovessels is increased. These neovessels have weak integrity and leak thereby leading to recurrent haemorrhages. Haemorrhages deliver erythrocytes to the necrotic core where they degrade promoting inflammation and oxidative stress. Inflammatory cells mostly presented by monocytes/macrophages, neutrophils and mast cells extravagate from bleeding neovessels and infiltrate adventitia where they support chronic inflammation. Plaque destabilization is an evolutionary process that could start at early atherosclerotic stages and whose progression is influenced by many factors including neovascularization, intraplaque haemorrhages, formation of cholesterol crystals, inflammation, oxidative stress and intraplaque protease activity.

Cardiac-specific miRNA in cardiogenesis, heart function, and cardiac pathology (with focus on myocardial infarction).

Cardiac miRNAs (miR-1, miR133a, miR-208a/b, and miR-499) are abundantly expressed in the myocardium. They play a central role in cardiogenesis, heart function and pathology. While miR-1 and miR-133a predominantly control early stages of cardiogenesis supporting commitment of cardiac-specific muscle lineage from embryonic stem cells and mesodermal precursors, miR-208 and miR-499 are involved in the late cardiogenic stages mediating differentiation of cardioblasts to cardiomyocytes and fast/slow muscle fiber specification. In the heart, miR-1/133a control cardiac conductance and automaticity by regulating all phases of the cardiac action potential. miR-208/499 located in introns of the heavy chain myosin genes regulate expression of sarcomeric contractile proteins. In cardiac pathology including myocardial infarction (MI), expression of cardiac miRNAs is markedly altered that leads to deleterious effects associated with heart wounding, arrhythmia, increased apoptosis, fibrosis, hypertrophy, and tissue remodeling. In acute MI, circulating levels of cardiac miRNAs are significantly elevated making them to be a promising diagnostic marker for early diagnosis of acute MI. Great cardiospecific capacity of these miRNAs is very helpful for enhancing regenerative properties and survival of stem cell and cardiac progenitor transplants and for reprogramming of mature non-cardiac cells to cardiomyocytes.

Extracellular vesicles shed by glioma cells: pathogenic role and clinical value

Extracellular vesicles (EVs) are commonly used by normal and tumor cells for communication at long distances to exchange by complex molecular messages and deliver a variety of essential biomolecules. EVs (exosomes and microvesicles) released in large numbers by glioma cells represent a key mechanism of intercellular signaling. Tumor-derived EVs are produced to regulate all vital functions of tumor cells including growth, proliferation, migration, survival, malignancy, invasion, and resistance to host anti-tumor immunity and anti-cancer drugs. Glioma EVs were shown to carry a variety of biomolecules such as oncogenic growth factors, receptors, enzymes, transcription factors, signaling and immunomodulatory molecules, DNA of mutated and nonmutated oncogenes, RNA transcripts, and noncoding RNA including retrotransposons, vault RNA, and microRNAs. Glioma-derived EVs can be useful as a source of potential tumor-associated biomarkers essential for development and validation of new diagnostic and prognostic tools for glioma and glioblastoma. Tumor EVs are enriched with glioma antigens that could be helpful, for example, for development of new advanced anti-tumor immune vaccines based on autologous dendritic cells stimulated by tumor-specific antigens.