Exposure to the Epstein-Barr viral antigen latent membrane protein 1 induces myelin-reactive antibodies in vivo

© 2017 Lomakin, Arapidi, Chernov, Ziganshin, Tcyganov, Lyadova, Butenko, Osetrova, Ponomarenko, Telegin, Govorun, Gabibov and Belogurov. Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system (CNS). Cross-reactivity of neuronal proteins with exogenous antigens is considered one of the possible mechanisms of MS triggering. Previously, we showed that monoclonal myelin basic protein (MBP)-specific antibodies from MS patients cross-react with Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1). In this study, we report that exposure of mice to LMP1 results in induction of myelin-reactive autoantibodies in vivo. We posit that chronic exposure or multiple acute exposures to viral antigen may redirect B cells from production of antiviral antibodies to antibodies, specific to myelin antigen. However, even in inbred animals, which are almost identical in terms of their genomes, such an effect is only observed in 20-50% of animals, indicating that this change occurs by chance, rather than systematically. Cross-immunoprecipitation analysis showed that only part of anti-MBP antibodies from LMP1-immunized mice might simultaneously bind LMP1. In contrast, the majority of anti-LMP1 antibodies from MBP-immunized mice bind MBP. De novo sequencing of anti-LMP1 and anti-MBP antibodies by mass spectrometry demonstrated enhanced clonal diversity in LMP1-immunized mice in comparison with MBP-immunized mice. We suggest that induction of MBP-reactive antibodies in LMP1-immunized mice may be caused by either Follicular dendritic cells (FDCs) or by T cells that are primed by myelin antigens directly in CNS. Our findings help to elucidate the still enigmatic link between EBV infection and MS development, suggesting that myelin-reactive antibodies raised as a response toward EBV protein LMP1 are not truly cross-reactive but are primarily caused by epitope spreading

Оценка эффективности применения комбинации силимарина и берберина в составе самоэмульгирующейся системы при экспериментальном поражении печени парацетамолом

The hepatoprotective properties of the silymarin and the plant alkaloid berberine combinationin experimental paracetamol-inducedliver damage were studied. Silymarin was obtained from milk thistle seeds. The conditions for extraction of flavonolignans (silymarin) were optimized. 70 % ethyl alcohol, ethyl acetate and water were used as extractants. It was shown that the optimal conditions for the extraction of flavonolignans in order to obtain the maximum yield of flavonolignans were alcohol extraction in a Soxhlet apparatus. The experiment showed that the combined of silymarin and berberine was greater than their individual actions, which most effectively permitted stabilization of hepatocyte membranes and prevented altering their integrity in paracetamol-induced toxic liver damage. The self-emulsifying system with silymarin and berberine to a greater extent a significant extent prevented dystrophic changes in hepatocytes and necrosis in liver tissue, reduced hyperfermentemia in rat blood serum, prevented disturbance in the activity of thioredoxin reductase and enzymes of the glutathione antioxidant system and there by more effectively prevented hepatocyte functional impairment.. Изучены гепатозащитные свойства комбинации силимарина и растительного алкалоида берберина при экспериментальном поражении печени парацетамолом. Силимарин получали из семян расторопши пятнистой. Проведена оптимизация условий экстракционного извлечения флаволигнанов (силимарина). В качестве экстрагентов использовали 70 %-ный этиловый спирт, этилацетат и воду. Показано, что оптимальными условиями экстракции флаволигнанов для получения их максимального выхода является спиртовая экстракция в аппарате Сокслета. Установлено, что сочетанное применение силимарина с берберином в большей степени по сравнению с их действием в отдельности стабилизирует мембраны гепатоцитов и предотвращает нарушение их целостности при токсическом поражении печени парацетамолом. Выявлено, что силимарин и берберин в составе разработанной самоэмульгирующейся системы в большей мере предотвращают дистрофические изменения гепатоцитов и некрозы в ткани печени, снижают степень выраженности гиперферментемии в сыворотке крови крыс, предотвращают нарушение активности тиоредоксинредуктазы и ферментов глутатионовой антиоксидантной системы и тем самым эффективнее предотвращают нарушение функциональных способностей гепатоцитов

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome

Introduction: The acute respiratory distress syndrome (ARDS), secondary to viral pneumonitis, is one of the main causes of high mortality in patients with COVID-19 (novel coronavirus disease 2019)—ongoing SARS-CoV-2 infection— reached more than 0.7 billion registered cases.Methods: Recently, we elaborated a non-surgical and reproducible method of the unilateral total diffuse alveolar damage (DAD) of the left lung in ICR mice–a publicly available imitation of the ARDS caused by SARS-CoV-2. Our data read that two C–C chemokine receptor 5 (CCR5) ligands, macrophage inflammatory proteins (MIPs) MIP-1α/CCL3 and MIP-1β/CCL4, are upregulated in this DAD model up to three orders of magnitude compared to the background level.Results: Here, we showed that a nonpeptide compound TAK-779, an antagonist of CCR5/CXCR3, readily prevents DAD in the lung with a single injection of 2.5 mg/kg. Histological analysis revealed reduced peribronchial and perivascular mononuclear infiltration in the lung and mononuclear infiltration of the wall and lumen of the alveoli in the TAK-779-treated animals. Administration of TAK-779 decreased the 3–5-fold level of serum cytokines and chemokines in animals with DAD, including CCR5 ligands MIP-1α/β, MCP-1, and CCL5. Computed tomography revealed rapid recovery of the density and volume of the affected lung in TAK-779-treated animals.Discussion: Our pre-clinical data suggest that TAK-779 is more effective than the administration of dexamethasone or the anti-IL6R therapeutic antibody tocilizumab, which brings novel therapeutic modality to TAK-779 and other CCR5 inhibitors for the treatment of virus-induced hyperinflammation syndromes, including COVID-19

Results of tests and studies of American materials in the channel of the MHD facility U-02 (Phase III). [LaCrO/sub 3/]

In accordance with the US--USSR Cooperative Program in MHD joint US--USSR tests were conducted in May 1978 at the U-02 facility of an MHD generator section consisting of U.S.-built electrode blocks and USSR-built insulating walls. The main purpose of the experiment was to conduct continuous 100-hour duration tests of materials and structures of electrode blocks; in particular, to study the behavior of ceramic electrodes and insulators in operating conditions of an MHD generator, the electro-physical and thermal characteristics of the working section as a whole and electrodes in particular, and to analyze the change in the phase composition and structure of materials during the test. The main thrust of the experiment was a study of electrode material behavior. Six varieties of electrodes based on doped lanthanum chromite were tested and investigated. The electrodes were made of fine grained, hot-pressed mass (the porosity of the ceramic was 2 to 3%). The interelectrode insulators were made of magnesial and magnesial-spinel ceramic also manufactured by the hot pressing method. Results are presented and discussed