Platelets and their chemokines in atherosclerosis-clinical applications

The concept of platelets as important players in the process of atherogenesis has become increasingly accepted due to accumulating experimental and clinical evidence. Despite the progress in understanding the molecular details of atherosclerosis, particularly by using animal models, the inflammatory and thrombotic roles of activated platelet s especially in the human system remain difficult to dissect, as often only the complications of atherosclerosis, i.e., stroke and myocardial infarction are definable but not the plague burden. Platelet indices including platelet count and mean platelet volume (MPV) and soluble mediators released by activated platelets are associated with atherosclerosis. The chemokine CXCL4 has multiple atherogenic activities, e.g., altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5. CCL5 is released and deposited on endothelium by activated platelets thereby triggering atherogenic monocyte recruitment, which can be attenuated by blocking the corresponding chemokine receptor CCR5. Atheroprotective and plague stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells. Its release from luminal attached platelets accelerates endothelial healing after injury. Platelet surface molecules GPIIb/IIIa, GP1b alpha, P-selectin, JAM-A and the CD40/CD40L dyade are crucially involved in the interaction with endothelial cells, leukocytes and matrix molecules affecting atherogenesis. Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages. Current medical therapies for the prevention of atherosclerotic therapies enable the elucidation of mechanisms linking platelets to inflammation and atherosclerosis

Решение задачи квадратичного программирования на основе операторов-проекторов

Изучение и реализация алгоритма нахождения экстремума целевой функции для смешанных систем линейных ограничений с использованием оператора-проектора.Research and realization of the algorithm for finding the extremum of the function with the linear constraints system using the projection operato

Novel mechanisms and therapeutic targets in atherosclerosis: inflammation and beyond

This review based on the ESC William Harvey Lecture in Basic Science 2022 highlights recent experimental and translational progress on the therapeutic targeting of the inflammatory components in atherosclerosis, introducing novel strategies to limit side effects and to increase efficacy. Since the validation of the inflammatory paradigm in CANTOS and COLCOT, efforts to control the residual risk conferred by inflammation have centred on the NLRP3 inflammasome-driven IL-1 beta-IL6 axis. Interference with the co-stimulatory dyad CD40L-CD40 and selective targeting of tumour necrosis factor-receptor associated factors (TRAFs), namely the TRAF6-CD40 interaction in macrophages by small molecule inhibitors, harbour intriguing options to reduce established atherosclerosis and plaque instability without immune side effects. The chemokine system crucial for shaping immune cell recruitment and homoeostasis can be fine-tuned and modulated by its heterodimer interactome. Structure-function analysis enabled the design of cyclic, helical, or linked peptides specifically targeting or mimicking these interactions to limit atherosclerosis or thrombosis by blunting myeloid recruitment, boosting regulatory T cells, inhibiting platelet activity, or specifically blocking the atypical chemokine MIF without notable side effects. Finally, adventitial neuroimmune cardiovascular interfaces in advanced atherosclerosis show robust restructuring of innervation from perivascular ganglia and employ sensory neurons of dorsal root ganglia to enter the central nervous system and to establish an atherosclerosis-brain circuit sensor, while sympathetic and vagal efferents project to the celiac ganglion to create an atherosclerosis-brain circuit effector. Disrupting this circuitry by surgical or chemical sympathectomy limited disease progression and enhanced plaque stability, opening exciting perspectives for selective and tailored intervention beyond anti-inflammatory strategies

The marriage of chemokines and galectins as functional heterodimers

Trafficking of leukocytes and their local activity profile are of pivotal importance for many (patho)physiological processes. Fittingly, microenvironments are complex by nature, with multiple mediators originating from diverse cell types and playing roles in an intimately regulated manner. To dissect aspects of this complexity, effectors are initially identified and structurally characterized, thus prompting familial classification and establishing foci of research activity. In this regard, chemokines present themselves as role models to illustrate the diversification and fine-tuning of inflammatory processes. This in turn discloses the interplay among chemokines, their cell receptors and cognate glycosaminoglycans, as well as their capacity to engage in new molecular interactions that form hetero-oligomers between themselves and other classes of effector molecules. The growing realization of versatility of adhesion/growth-regulatory galectins that bind to glycans and proteins and their presence at sites of inflammation led to testing the hypothesis that chemokines and galectins can interact with each other by protein-protein interactions. In this review, we present some background on chemokines and galectins, as well as experimental validation of this chemokine-galectin heterodimer concept exemplified with CXCL12 and galectin-3 as proof-of-principle, as well as sketch out some emerging perspectives in this arena

Touch of chemokines

Chemoattractant cytokines or chemokines constitute a family of structurally related proteins found in vertebrates, bacteria, or viruses. So far, 48 chemokine genes have been identified in humans, which bind to around 20 chemokine receptors These receptors belong to the seven transmembrane G-protein-coupled receptor family. Chemokines and their receptors were originally studied for their role in cellular trafficking of leukocytes during inflammation and immune surveillance. It is now known that they exert different functions under physiological conditions such as homeostasis, development, tissue repair, and angiogenesis but also under pathological disorders including tumorigenesis, cancer metastasis, inflammatory, and autoimmune diseases. Physicochemical properties of chemokines and chernokine receptors confer the ability to homo- and hetero-oligornerize. Many efforts are currently performed in establishing new therapeutically compounds able to target the chemokine/chemokine receptor system. In this review, we are interested in the role of chemokines in inflammatory disease and leukocyte trafficking with a focus on vascular inflammatory diseases, the operating synergism, and the emerging therapeutic approaches of chemokines

Технология ликвидации аварийного разлива нефти в болотистой местности

Объектом исследования является месторождение, болота Томской области, почвы и растительность загрязненных территорий, а так же технологии по рекультивации нефтезагрязненных болотных почв, вследствие аварии на межпромысловом нефтепроводе. Цель работы – Анализ технологии и ликвидации аварийного разлива нефти на межпромысловом нефтепроводе. В процессе исследования проводились расчеты по определению ущерба окружающей природной среде при аварии на промысловом нефтепроводе.The object of the study is a deposit, marshes of the Tomsk region, soils and vegetation of contaminated areas, as well as technologies for reclamation of oil-contaminated bog soils, as a result of an accident at an inter-oil pipeline. The purpose of the work is to analyze the technology and eliminate the oil spill on the inter-pipeline oil pipeline. In the course of the study, calculations were carried out to determine the damage to the natural environment in the event of an oil pipeline accident

Роботизированные пожарные системы для защиты объектов с массовым пребыванием людей

В статье показано значение автоматизированных систем пожаротушения на базе пожарных роботов для защиты объектов с массовым пребыванием людей, рассмотрена их функциональная схема, проанализированы их достоинства, представлена нормативно-правовая база применения пожарных роботов

Геология и особенности извлечения урана методом подземного скважинного выщелачивания на месторождение Буденовское (Южный Казахстан)

Эпигенетические месторождения урана региональных зон пластового окисления представлены большой группой месторождений в пределах Шу-Сарысуйской и Сырдарьинской ураново-рудных провинций. Общие ресурсы, заключенные в месторождениях пластово-инфильтрационного типа, весьма значительны и составляют более 75% всех ресурсов урана Республики Казахстан.The Chu-Sarysu Basin is located in south-central Kazakhstan. It is as much as 250 km wide and extends for more than 600 km from the foothills of the Tien Shan mountains to the south and southeast, and merges into the flats of the Aral Sea depression to the northwest. The northern and western boundary coincides roughly with the course of the Sarysu River while the Chu river flows across the southern part of the basin. The basin is bounded to the SW by the NW-SE-trending Karatau mountain range, which separates the Chu-Sarysu Basin from the southwesterly located Syr-Darya Basin. These two basins originally formed a single basin before they were separated by periodical uplift s of the Karatau Range. The separation took place after the formation of the U deposits