Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer

The phenomenon of high sugar consumption by tumor cells is known as Warburg effect. It results from a high glycolysis rate, used by tumors as preferred metabolic pathway even in aerobic conditions. Targeting the Warburg effect to specifically deliver sugar conjugated cytotoxic compounds into tumor cells is a promising approach to create new selective drugs. We designed, synthesized, and analyzed a library of novel 6-S-(1,4-naphthoquinone-2-yl)-d-glucose chimera molecules (SABs)—novel sugar conjugates of 1,4-naphthoquinone analogs of the sea urchin pigments spinochromes, which have previously shown anticancer properties. A sulfur linker (thioether bond) was used to prevent potential hydrolysis by human glycoside-unspecific enzymes. The synthesized compounds exhibited a Warburg effect mediated selectivity to human prostate cancer cells (including highly drug-resistant cell lines). Mitochondria were identified as a primary cellular target of SABs. The mechanism of action included mitochondria membrane permeabilization, followed by ROS upregulation and release of cytotoxic mitochondrial proteins (AIF and cytochrome C) to the cytoplasm, which led to the consequent caspase-9 and -3 activation, PARP cleavage, and apoptosis-like cell death. These results enable us to further clinically develop these compounds for effective Warburg effect targeting

ПРОДУКЦИЯ ФАКТОРОВ РОСТА И ДЕСКВАМАЦИЯ ЭНДОТЕЛИОЦИТОВ В СЕРДЦЕ ПРИ ИШЕМИЧЕСКОЙ КАРДИОМИОПАТИИ

oai:oai.kpccz.elpub.ru:article/1324Highlights Dysregulation of angiogenesis may be the pathogenetic factor of ischemic cardiomyopathy (ICMP). Aim. To determine the content of growth factors and desquamated endothelial cells (DEC) in the blood from the coronary sinus and ulnar vein in association with the number of progenitor endothelial cells (PEC) in the blood from the ulnar vein in patients with coronary heart disease (CHD), suffering and not suffering from ICMP.Methods. The study included 30 patients with ICMР and 22 patients with CHD, and 18 healthy donors. The content of DEC (CD45–CD146+) was determined in blood from the cubital vein (peripheral) and coronary sinus, and the content of DEC (CD14+CD34+VEGFR2+) was determined in peripheral blood by flow cytometry (antibodies “BD Biosciences”, USA). The concentrations of VEGF-A, VEGF-B, PDGF, SDF-1, SCF, FGF-1, TGF-β1 in blood plasma from both locations were evaluated by multiplex analysis (set “Cloud-Clone Corp.”, USA).Results. The content of DEC in peripheral blood was elevated in patients with CHD of both groups, and in patients with ICMP in sinus blood was higher than in peripheral. At the same time, in patients with CHD without cardiomyopathy, an excess of PEC and SDF-1 in the blood from the ulnar vein was established in combination with an increase in the concentration of PDGF and a decrease in the content of VEGF-B in the blood from the coronary sinus relative to the parameters of systemic blood flow. In patients with ICMP, these changes were not detected, but there was an increase in the concentration of TGF-β1 in sinus blood compared with peripheral blood. Regardless of the presence of ICMP, the concentration of SCF, FGF-1, VEGF-A in the blood from the ulnar vein corresponded to the norm and that in sinus blood; the content of VEGF-A in the coronary bloodstream exceeded its systemic level.Conclusion. In patients with ICMP, desquamation of the coronary vascular endothelium is enhanced against the background of violations of its repair processes due to insufficient (relative to CHD without cardiomyopathy) mobilization of PEC from the bone marrow due to the absence of an excess of SDF-1 in the blood and their insufficient homing into the myocardium due to weak PDGF production in the heart.Основные положенияПатогенетическим фактором ишемической кардиомиопатии может быть нарушение регуляции ангиогенеза. Цель. Определить содержание факторов роста и десквамированных эндотелиальных клеток (ДЭК) в крови из коронарного синуса и локтевой вены в ассоциации с численностью прогениторных эндотелиальных клеток (ПЭК) в крови из локтевой вены у больных ишемической болезнью сердца (ИБС), страдающих и не страдающих ишемической кардиомиопатией (ИКМП).Материалы и методы. В исследование включили 30 пациентов с ИБС и ИКМП, 22 больных ИБС без ИКМП, 18 здоровых доноров. Содержание ДЭК (CD45–CD146+) определяли в крови из локтевой вены (периферическая) и коронарного синуса (синусовая), а содержание ПЭК (CD14+CD34+VEGFR2+) – в периферической крови методом проточной цитофлуориметрии (антитела BD Biosciences, США). В плазме обоих образцов крови оценивали концентрацию VEGF-A, VEGF-B, PDGF, SDF-1, SCF, FGF-1, TGF-β1 методом мультиплексного анализа (набор Cloud-Clone Corp., США).Результаты. Содержание ДЭК в периферической крови было повышенным у больных ИБС обеих групп, а в синусовой крови у пациентов с ИКМП было выше, чем в периферической. У больных ИБС без ИКМП установлен избыток ПЭК и SDF-1 в крови из локтевой вены в сочетании с увеличением концентрации PDGF и снижением содержания VEGF-В в крови из коронарного синуса относительно параметров системного кровотока. У пациентов с ИКМП данные изменения не выявлены, но отмечен рост концентрации TGF-β1 в синусовой крови по сравнению с периферической. Вне зависимости от ИКМП концентрация SCF, FGF-1, VEGF-А в крови из локтевой вены соответствовала норме и таковой в синусовой крови; содержание VEGF-А в коронарном кровотоке превышало системный уровень.Заключение. При ИКМП усилена десквамация эндотелия коронарных сосудов на фоне нарушений его репарации за счет недостаточной (относительно ИБС без ИКМП) мобилизации ПЭК из костного мозга ввиду отсутствия избытка SDF-1 в крови и недостаточного их хоминга в миокард вследствие слабой продукции PDGF в сердце

THE CONTENT AND THE STRUCTURE OF THE NUCLEAR AND CIRCUMNUCLEAR ZONES OF LEXICAL-SEMANTIC FIELD “INTERPERSONAL RELATIONS” ON THE MATERIAL OF F. DOSTOEVSKY’S NOVEL “THE IDIOT”

The article discusses the structure of lexical-semantic field “interpersonal relations” based on the novel “The Idiot”, by F. Dostoevsky. In the article we describe the set of lexical item representing the field, as well as the place of units of the field in the author's style. The subject of the research was chosen by the relevance of studying vocabulary as a layer of a literary language that discloses information about the material and spiritual culture of society. The relevance of this work can also be considered from the point of view of the need for the development of a comprehensive methodology for the linguistic analysis of semantic relations within the lexical-semantic field “interpersonal relations”. Our goal is to highlight all the variety of units of lexical-semantic field “interpersonal relations” used in F.M. Dostoevsky’s novel. Also we want to reveal the uniqueness of their contextual use, as well as to trace the dynamics of relations and at the same time the change in the lexical content as for relation descriptions between characters. We have developed criteria for selecting lexical markers. We used continuous sampling method, analysis of vocabulary definitions and componential analysis during the preparation of the article. It is established that the lexical-semantic field “interpersonal relations” is a clearly structured system, a well- structured system, which units are united by common semantic features. The pre-nuclear zone is made up of units united by the name of field “relation”, but with a small number of differential signs. In the field we are considering, these are 'negative attitude', 'positive attitude', 'intense', 'non-intensive', 'benevolence', 'hostility', 'sympathy', 'pity', 'indifference'. These features determine the structure and place of the field we are considering in the lexical-semantic system of the Russian language, helping to native speakers’ mind to expand the idea of the content and structure of the lexical-semantic field “interpersonal relations”. Most of the vocabulary of lexical-semantic field “interpersonal relations” are words with a high emotional code that characterizes the author’s style. The linguistic personality of Dostoevsky can be called an individually and creatively verbalized world view through the prism of the writer's consciousness