To study the interrelations between the rs4073 polymorphism of the IL-8 gene, IL-8 serum levels and severity of alcoholic hepatitis (AH).

Some brain-derived neurotrophic factor (BDNF)-targeted miRNAs such as miR-30a-5p may be associated with alcohol addiction; however, their relationship with alcohol withdrawal syndrome (AWS) is not described. We aimed to measure serum BDNF concentration and relative content of miR-30a-5p over the course of alcohol abstinence and compare results with the clinics of AWS. Apart from that, we studied the serum relative content of miR-122, a miRNA that does not target BDNF but is associated with alcohol use disorder. Serum BDNF concentration increases over the course of alcohol abstinence. In contrast, the relative content of miR-122, but not miR-30a-5p, decreased. Moreover, miR-122 (but not miR-30a-5p) negatively correlated with serum BDNF concentrations in the course of AWS. The relative content of miR-122 negatively correlated with depression and anxiety levels on day 8 of abstinence. According to multiple regression analysis, the severity of craving for alcohol and cognitive disturbances may be predictors of serum BDNF concentration on day 21 of abstinence, and vice versa. Thus, serum BDNF concentration and relative content of miR-122 are associated with some aspects of AWS clinical manifestations and may dynamically reflect AWS severity.

Формирование сердечно-сосудистой патологии при чрезмерном употреблении алкоголя сопряжено с повышением концентрации в крови таких медиаторов воспаления, как интерлейкины 6 (IL6) и 8 (IL8) и хемоаттрактанта моноцитов CCL2 (C-C motif ligand 2), а также молекул, участвующих в функционировании эндотелия, в частности фактора роста сосудистого эндотелия (VEGFA, vascular endothelial growth factor А), молекулы клеточной адгезии (ICAM1, intercellular adhesion molecule 1) и эндотелина (EDN1). Предполагается, что данный процесс генетически детерминирован, однако до настоящего момента исследований в этом направлении не проводилось. Целью работы явилось изучение ассоциации носительства аллелей полиморфных локусов, расположенных в генах IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 и rs2010963), ICAM1 (rs281437) и EDN1 (rs1800541) с содержанием соответствующих полипептидов в циркуляторном русле и развитием сердечно-сосудистых заболеваний на фоне хронического злоупотребления алкоголем. В исследование были включены лица, злоупотребляющие алкоголем, без выраженной соматической патологии, а также пациенты, у которых на фоне злоупотребления развились заболевания сердечно-сосудистой системы. Уровень IL6, IL8, CCL2, VEGFA, ICAM1 и EDN1 в сыворотке крови оценивали посредством ИФА. Аллели полиморфных локусов были определены посредством ПЦР в режиме реального времени. Установлено, что среди лиц, злоупотребляющих алкоголем, с клинически выраженной патологией сердечно-сосудистой системы значительно чаще встречаются только носители гомозиготного генотипа GG или аллеля G полиморфного локуса в гене IL6 (rs1800795). Кроме того, носительство генотипа GG повышает вероятность развития сердечно-сосудистых заболеваний при хроническом злоупотреблении алкоголем. Однако, дополнительное влияние оказывают демографические факторы и клинические характеристики пациентов. В частности, введение поправки на возраст и пол, а также учет наличия цирроза печени, гипертензии и сахарного диабета, сопровождающих злоупотребление алкоголем, нивелируют повышение риска патологии сердечно-сосудистой системы. Ассоциации полиморфных вариантов в генах IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 и rs2010963), ICAM1 (rs281437) и EDN1 (rs1800541) с содержанием белковых продуктов соответствующих генов в циркуляторном русле выявлено не было. Cardiovascular diseases in alcohol abusers are associated with elevation of plasma levels of proinflammatory cytokines such as IL6, IL8 and CCL2 as well as molecules involved in endothelial functioning including VEGFA, ICAM1 and EDN1. This phenomenon is supposed to be genetically determined. However to date the issue has not been investigated. Thus, we aimed to study the relationship between carriage of SNPs of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) genes with the serum levels of their products and the development of cardiovascular diseases in alcohol abusers. The study included alcohol abusers without apparent somatic pathology and alcohol abusers with clinical manifestations of cardiovascular disease. Serum levels of IL6, IL8, CCL2, VEGFA, ICAM1 and EDN1 were estimated by EIA. SNPs were determined by means of real-time PCR. We found that among the SNPs studied only carriers of homozygous GG genotype and G allele of IL6 (rs1800795) were more frequent in alcohol abusers with cardiovascular diseases. Moreover, carriage of homozygous GG genotype of IL6 (rs1800795) increases the probability of development of cardiovascular pathology in alcohol abusers. However, adjustment for age, gender and the presence of liver cirrhosis, hypertension and diabetes mellitus as co-variates eliminates the enhanced risk of cardiovascular pathology. Polymorphisms of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) did not determine serum levels of the related polypeptides.

Background: Isolated brain of experimental animals is a useful model to study transport of substances, including drugs, across the blood-brain barrier, mechanisms of convulsive activity, ischemic and reperfusion brain injury. Normal functioning of neurons, especially cortical, in the central nervous system requires adequate supply of oxygen. Therefore oxygen carriers or fluorocarbon substances with high oxygen capacity are often used in animal brain perfusion experiments. New method: In the present study of the in situ rat brain perfusion oxygen carriers were not used. The optimum oxygen capacity of the perfusion media (adequate to the arterio-venous difference) was achieved by a high oxygen tension (2400 -2600 mm Hg) in the solution under normal barometric pressure. Perfusate was depressurized and delivered at normal rat systemic hydrostatic pressure to the brain via a cannula inserted transcardially into the ascending aorta, with both subclavian arteries ligated. Perfusate was delivered using normal hydrostatic pressure. Results: In these experimental conditions of the brain perfusion the pattern of electrocorticogram has been stable in the course of 5h and more. The release of lactic acid in the perfusion solution was 3 times less than in perfusion under partial oxygen tension of 900 mm Hg; excessive activation of the lipid peroxidation process in the brain tissue was not observed. Conclusion: The presented new model of the isolated brain perfusion may be used in experiments with other isolated organs and in studies of toxic effects of oxygen.

Цель: оценить интенсивность перекисного окисления липидов и содержание антиоксидантных факторов в ткани изолированного головного мозга в условиях перфузии in situ раствором, не содержащим переносчиков О. Методика. Предложена оригинальная модель перфузии головного мозга крыс in situ раствором с повышенным напряжением кислорода без его переносчиков и без помещения препарата в барокамеру, т.е. при внешнем нормальном барометрическом давлении. Результаты. Выживаемость перфузируемого мозга (по критериям: - амплитуда электрокортикограммы не менее 35 мкВ и быстрый рост перфузионного давления более 60 мм рт. ст.) при давлении в оксигенационной камере 900 мм рт. ст. и 2400-2600 мм рт. ст. составляли более 3 ч и 4 ч соответственно. Установлено, что при напряжении кислорода в перфузионном растворе, равном 2400-2600 мм рт. ст., содержание перекисей липидов и диеновых конъюгатов в ткани мозга не превышает нормальных значений или даже ниже, чем при перфузии мозга раствором с напряжением кислорода 970 мм рт. ст. В этих условиях содержание в мозге, витамина Е и SH-групп белков не изменяется. Таким образом, при напряжении кислорода в 2400-2600 мм рт. ст. в перфузионном растворе признаки оксидативного стресса в мозге отсутствуют. Заключение. Предлагаемая методика перфузии головного мозга крыс in situ обеспечивает его функционирование без переносчиков кислорода в условиях нормального внешнего барометрического давления, такое же, как и при использовании перфузии с переносчиками кислорода. Данный метод представляет собой удобную и экономичную модель для исследования функций изолированного мозга. The aim. To evaluate intensity of lipid peroxidation and content of antioxidative factors in the isolated brain perfused with a solution without oxygen carriers. Methods. We used an original model of in situ rat brain perfusion using a solution with a high oxygen tension. Neither O carriers nor a barometric chamber were used, i.e., the brain was perfused under normal external barometric pressure. Results. Survival time of the perfused brain (criteria: electrocorticogram amplitude >35 mV and rapid elevation of the perfusion pressure to >60 mm Hg) at the oxygenation chamber pressure of 900 mm Hg and 2400-2600 mm Hg was 3 h and 4 h, respectively. At the O tension of 2400-2600 mm Hg in the perfusion solution, contents of lipid peroxides and conjugated dienes in the brain were not higher or even lower than at the perfusion solution O tension of 970 mm Hg, while the content of ascorbic acid was slightly increased and contents of vitamin E and protein SH-groups were not significantly changed. Therefore, at the O tension of 2400-2600 mm Hg in the perfusion solution, there were no signs of oxidative stress in the brain tissue. Conclusion. The proposed model of in situ brain perfusion provides the brain functioning under normal external barometric pressure without oxygen carriers similar to perfusion with oxygen carriers. This method represents a suitable and simple model to study functions of the isolated brain.

Инфламмасома - важный компонент нативного иммунитета. Она представляет собой макромолекулярный комплекс, включающий сенсорные элементы, адапторные белки и зимоген каспазы-1. Под действием продуктов распада тканей и патогенных микроорганизмов инфламмасома активируется и превращает про-IL-1b и про-IL-18 в активные интерлейкины. Активация инфламмасом отмечена при многих воспалительных заболеваниях и служит мишенью для терапевтических воздействий. В настоящем обзоре обсуждается вклад инфламмасом в патогенез социально-значимых заболеваний человека, таких, как атеросклероз, ишемическая болезнь сердца, сахарный диабет, артриты, болезни легких, печени и почек. Результаты клинических исследований и модельных экспериментов на линиях мышей с нокаутированными генами компонентов инфламмасомы говорят о существенной роли этих структур в прогрессировании патологии, связанной с воспалительным повреждением тканей.An inflammasome becomes activated under the action of tissue decay products or pathogenic microorganisms and converts pro-IL-1 and pro-IL-18 to their active forms. Activation of inflammasomes has been reported in many inflammatory diseases and serves as a target for therapeutic interventions. The present review discusses the contribution of inflammasomes to pathogenesis of diseases with a high impact on public health, such as atherosclerosis, ischemic heart disease, diabetes mellitus, arthritis, diseases of lungs and kidneys. Results of clinical studies and animal experiments on knockout mouse strains with a deficit of inflammasome components suggest a significant role of these structures in progression of pathology associated with inflammatory damage to tissues.

Inflammasomes are macromolecular complexes that contain many copies of receptors recognizing molecular patterns of pathogenic agents (PAMP) and damage-associated structures (DAMP), and also include molecules of adapter protein ASC and procaspase-1. Activation of inflammasomes leads to the formation of active caspase-1 that, in turn, provides the maturation of pro-IL-1β and pro-IL-18 to IL-1β and IL-18. The latter cytokines play an important role in control of neuroinlfammation in the central nervous system contributing to the pathogenesis of a series of neurological, neurodegenerative and mental disorders. The review discusses the involvement of NLRP3 inflammasome and other their types in the development of the traumatic brain injury, ischemic and hemorrhagic stroke, brain tumors, CNS infections, Alzheimer's and Parkinson's diseases, epilepsy, amyotrophic lateral sclerosis, depressiver, and consequences of alcohol abuse. The elucidation of molecular mechanisms and signaling pathways controlled by inflammasomes will allow the development of new therapeutic measures for diseases, in which neuroinflammation plays a leading pathogenetic role.

We conducted a comparative study of content proinflammatory cytokines, biomarkers of inflammatory process, biochemical indicators of congestive heart failure (CHF) and hemodynamic parameters in patients with alcoholic cardiomyopathy (ACMP) and ischemic heart disease (IHD) with various NYHA classes. We examined 62 men with ACMP (n = 45) and IHD (n = 17) and NYHA class III-IV CHF. Patients of both groups had lowered ejection fraction (EF), dilated cardiac chambers, and increased left ventricular (LV) myocardial mass index (MMI). Relative LV wall thickness was within normal limits but in the ACMP group it was significantly lower than in IHD group what corresponded to the eccentric type of myocardial hypertrophy. Higher NYHA class was associated with lower EF and larger end diastolic and end systolic LV dimensions. In ACMP it was also associated with larger dimension of the right ventricle while in IHD--with substantially larger (by 30%) dimension of atria. Substantial amount of endotoxin found in blood plasma of patients with IHD corresponded to the conception of increased intestinal permeability of in CHF. Alcohol abuse was an aggravating factor of endotoxin transmission and its concentration in patients with ACMP was 3 times higher than in patients with IHD. Patients with ACMP had substantially elevated blood concentrations of interleukins (IL) 6, 8, 12, tumor necrosis factor α (TNF-α), and its soluble receptor s-TNF-R; they also had twofold elevation of C-reactive protein concentration. ACMP was associated with manifold rise of blood content of brain natriuretic peptide (BNP). Patients with IHD also had elevated blood concentrations of IL 6, 8 and 12 but their values were 1.5-2 times lower than ACMP group. Blood content of TNF-α and s-TNF-R in IHD group was within normal limits. Higher NYHA class in ACMP patients was associated with higher concentrations of IL 6 and 8, TNF-a, and BNP. In both groups of patients contents of IL-12, s-TNF-R, TGF-1β and factors of acute phase of inflammation did not reflect severity of CHF. Functional insufficiency of myocardium in IHD patients was best characterized by blood content of IL-6 while in ACMP patients--of BNP.

We present in this review contemporary views on pathogenesis of alcoholic cardiomyopathy. Alcoholic cardiomyopathy has features of dilated cardiomyopathy and is manifested by increased volume and hypertrophy of the left ventricle, diminished contractile capacity, and when decompensated - by lowering of cardiac output. Pathogenic action of alcohol on cardiomyocytes leads to activation of apoptosis, dysfunction of intracellular organelles, alterations of the system of myofilaments, disorder of intracellular homeostasis of calcium. Ethanol metabolite acetaldehyde, products of minor pathway of catecholamine metabolism, changes in the endocannabinoid system, and activation of processes of lipid peroxidation all contribute to the myocardial damage. The basis of pathogenesis of alcoholic cardiomyopathy constitute proliferation of microperoxisomes and disbalance between acyloxidase and catalase leading to accumulation of hydrogen peroxide inside myocytes.

Current knowledge of immunocellular and lipoprotein mechanisms of the liver-induced anti-endotoxin tolerance has been summarized. The role of T regulatory cells, different macrophage phenotypes, high density lipoproteins, oxidized low density lipoproteins and their receptors as the key players in mechanism of tolerance to endotoxin has been discussed.

Цель. Выяснить связь между проявлениями ОС у больных с СД 2 и следующими факторами: 1) уровнем глюкозы в плазме крови; 2) наличием поздних осложнений СД 2; 3) длительностью заболевания. Материалы и методы. В исследование включено 65 пациентов с СД 2. Все пациенты получали сахароснижающую терапию (препараты сульфонилмочевины, метформин, инсулинотерапия), на фоне которой в момент начала обследования у 19 пациентов (группа Б) отмечалась компенсация углеводного обмена и у 46 (группа В) - декомпенсация его (уровни глюкозы натощак соответственно < или > 7,8 ммоль/л). Состояние антиоксидантной системы организма оценивалось по показателю антиперекисной активности (АПА) плазмы крови, представляющему собой отношение показателя хемилюминесценции, индуцированной перекисью водорода, к ее спонтанной хемилюминесценции. Активность перекисного окисления липидов в плазме крови при ОС определяли по уровню малонового диальдегида (МДА). Результаты. При сопоставлении данных групп Б и В выявлено, что у больных с хорошей и удовлетворительной компенсацией СД 2 имеются статистически достоверные более низкие значения ПИХЛбаз и ПИХЛстим. Выводы. Для выраженности ОС при СД 2 степень гипергликемии имеет существенно большее значение, чем длительность заболевания или наличие специфических для диабета поздних осложнений. Это требует обязательного проведения у пациентов с СД 2 наряду со специфической и антиоксиданот-ной терапии

The immunocytograms of 166 patients with opiomania, primarily of the heroin variation, aged 15 to 19, were examined. 18 healthy teenagers of the same age were in the control group. The sampling comprised both patients without any signs of infectious diseases (86 persons) and patients with viral hepatitis B and C. The deviations of the immune-cellular status comprised, in drug addicts, a deficit of T-helpers and NK-cells as well as an increased quantity of "zero" lymphocytes. An essential reduction in the level of T-suppressors (killers) was additional found in the group of drug-addicts with viral hepatices. The signs of cytolysis of hepatocytes were detected in young heroin addicts. The contents of lipid peroxides was significantly higher in the blood plasma of teenagers abusing the opium drugs; while the concentration of antioxidant factor was as follows: Vitamin E, sulfhydric proteins and urate were found to be decreased. A reliable correlation was found between the changes of the quantity of T-helpers, T-suppresses (killers) and 0-lymphocytes, on the one hand, and the activity of hepatic transaminases, on the other hand, (for AST = 0.65-0.70; p < 0.01). The disorders in the immune-cellular status persist for as long as three to four weeks after the refusal from drug consumption; it is noteworthy, that their severity can essentially go up. The activity of 5'-nucleotidase, involved in the transformation of receptor signals in T- and B-lymphocytes, was histochemically studied in immunocytes. The activity of the enzyme essentially went down in both populations of lymphocytes by the 7th day of abstinence; it remained at the mentioned level up to the 14th day (in patients with hepatitis) or up to 21st day (in patients without hepatitis). Therefore, the quantitative deficit of immunocytes in drug addicts was accompanied, during the abstinence period, by an inhibition of their functional activity.

Chronic opiate intoxication has been shown to cause various pathologic changes in the liver almost in 100% of cases. Earlier it has been demonstrated that acute or chronic morphine intoxication evokes activation of lipid peroxidation in the liver, heart, and brain cells. The aim of the present work was to assess parameters reflecting cytolysis in the liver and heart, and the plasma content of factors contributing to the peroxyl radical-scavenging system of the blood of teenagers using heroin. Blood samples were obtained from 20 male patients from 14 to 16 years old, with a mean duration of regular heroin use of 1.7 years. The control group included 13 healthy teenagers which denied the previous drug use. Mean plasma ALT and myocardial isoform of LDH activities were significantly higher (1.7- and 1.4-times respectively) in the heroin users than in the control group. The mean plasma level of lipid peroxides in the heroin users is increased by 20% compared to the control individuals. In teenagers using heroin a high level of correlation was observed between the plasma content of lipid peroxides and myocardial LDH activity (r = 0.76; P < 0.01). The effect of heroin use on the content of the plasma peroxyl radical-scavenging factors--vitamin E, ascorbic acid, and protein SH-groups--was not found. It has been concluded that heart injury during heroin use in teenagers may be associated with activation of lipid peroxidation reactions in the myocardium.

Diverse behavioral disorders and the intensity of lipid peroxidation (LPO) of biological membranes were estimated in different rat tissues after the 7-day administration and subsequent withdrawal of morphine or promedol. 24 hours after the withdrawal of the analgetics the demonstrated a high initial level of motor activity in the open field. Naloxone, an antagonist of opiate receptors, potentiated motor activity and the intensity of withdrawal syndrome (by 160%) in rats with morphine rather than promedol dependence. The behavioral disorders in dependent animals were accompanied by LPO activation in liver and brain membranes.