Effect of CFP-10/ESAT-6 secretory proteins on long-term non-specific immunological memory in mouse macrophages

Innate immune cells (monocytes/macrophages, NK) can also develop immune memory, which means that these cells are trained after their first encounter with pathogens so that they exhibit a nonspecific immunological response to the same or another pathogen. Bacilli Calmette–Gu rin (BCG) induces nonspecific innate memory (trained immunity) in innate immune cells. We examined nonspecific innate memory in macrophages of BALB/c mice in response to mycobacteria with or without the RD1 region in the genome. Mice were immunized with BCG vaccine, and peritoneal macrophages were isolated on day 7, and then stimulated with bacterial lipopolysaccharide, CFP-10, or ESAT-6. In addition, mice were immunized with Mycobacterium tuberculosis uro-BCG vaccine (RD1-) and Mycobacterium tuberculosis strain H37Rv (RD1+) subcutaneously or intravenously; peritoneal macrophages were isolated and stimulated with lipopolysaccharide on day 4. Alveolar macrophages were obtained from lung explants of mice infected with Mycobacterium tuberculosis strain H37Rv mice, were expanded to confluence 70-80% and further stimulated with lipopolysaccharide. Lactate, cytokines, and glucose levels were examined in conditioned macrophage medium. Peritoneal macrophages from mice primed with BCG vaccine were shown to increase IL-1b, TNFa, and lactate production in response to CFP-6 and ESAT-10 (p < 0.05). Of note is the fact that lipopolysaccharide also increased production of IL-1b, TNFa, and also increased glucose uptake by peritoneal macrophages primed with BCG vaccine (p < 0.05). Peritoneal macrophages primed with Uro-BCG were shown to increase spontaneous production of IL-1b and decrease spontaneous production of TNFa (p < 0.05). When macrophages were primed by subcutaneous or intravenous administration of Mycobacterium tuberculosis strain H37Rv differentially affected cytokine production, by decreasing IL-1b production and increasing TNFa and IL-10, was observed. In response to lipopolysaccharide, peritoneal macrophages increased IL-1b, TNFa, IL-10 production and glucose consumption (p < 0.05). The mode of priming of macrophages with Mycobacterium tuberculosis strain H37Rv also led to multidirectional levels of cytokine production. Alveolar macrophages were shown to retain trained immunity, as they produced elevated levels of IL-1b, TNFa, and IL-10 (p < 0.05). Thus, mouse macrophages formed a trained immunity phenotype in response to different types of mycobacteria, which persists for a long time after primary contact with the pathogen, particularly in alveolar macrophages

To the 50th anniversary of hematology service of the Republic of Tatarstan

The article presents an overview of the development of hematology service in the Republic of Tatarstan. The well-known scientist Nikolay Konstantinovich Goryaev (1875-1943), who worked in Kazan for a long time, began to develop this direction and after passing an internship in Germany proposed an improved device for calculating the blood elements known throughout the world. Adherents of Professor Goryaev continued research in the field of hematology, a blood transfusion station was organized. Professor S.I. Sherman proposed new methods of diagnosis and treatment of B12 deficiency anemia. Professor Sh.I. Ratner studied the changes in the blood picture in diseases of the abdominal cavity. The first 15 specialized hematological beds were opened in 1968 in the hospital named “Old Clinic”. The physician who treated such patients was Rakhil Sholomovna Dashevskaya, PhD. At present, hematology service is provided by three hospitals in Kazan, hematological and therapeutical beds in Naberezhnye Chelny and Nizhnekamsk, outpatient hematology service in Zelenodolsk. In recent years, the introduction of stem cell therapy has begun, and modern combined methods of chemotherapy have been introduced

Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination

Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAF

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

Разработка системы взаимосвязанных классификаций: сопоставление Государственного рубрикатора научно-технической информации и Универсальной десятичной классификации

The authors discuss the findings of the study to compare relevant master versions of the State Rubricator of Sci-tech Information and Universal Decimal Classification (UDC) in Russian. The classifications are compared through the method of intellectual analysis of intrinsic and semantic characteristics of SRSTI subject headings and UDC main schedules and its general and special subdivision tables. The UDC compound numbers are assigned to over the half of all rubrication vertexes. Over one third of SRSTI headings are assigned the compound UDC numbers made of two+ simple or compound numbers. The semantic matches between SRSTI headings and assigned UDC numbers are established as logical match, inclusion or extension overlapping with provision for terminological, structural and semantic features of the classifications being compared, as well as of the substance of the subject areas and their indexing principles. The interreflection of SRSTI and UDC numbers is executed in three types of relations: equivalence, hierarchy, association. Based on the analysis of coefficients of distribution by types of relations between semantic SRSTI headings and UDC numbers, the conclusion is made on the relatively high matching of terminology and structure of the given classification systems in almost every thematic class of subject areas. The value of the study is that the “converter” between SRSTI and UDC is to expand functionality of the interrelated classifications.Russian National Public Library for Science and Technology, within the framework of the Government Order No. 075-01235-23-01, R&D theme No. 1021070112681-2-1.2.1;5.8.3, has been pursuing research for building the single network of links between classifications, development of “converters” between them for the purpose of computer-aided thematic systematization, and integration of dispersed information resources. The State Rubricator of Scientific and Technical Information (SRSTI) is the core classification of the unified networked classification links.В статье приводятся результаты исследований по сопоставлению актуальных эталонных версий ГРНТИ и таблиц Универсальной десятичной классификации (УДК) на русском языке. Сопоставление классификаций выполнено с использованием метода интеллектуального анализа сущностных и содержательных характеристик понятий рубрик ГРНТИ и понятий, систематизированных в основных таблицах и таблицах общих и специальных определителей УДК. Более чем половине всех рубрикационных вершин ГРНТИ присвоены сложные индексы УДК. Свыше одной трети рубрик государственного рубрикатора присвоены комбинированные индексы, образованные из двух и более простых или сложных индексов. Смысловые соответствия между рубриками ГРНТИ и присвоенными им индексами УДК установлены как отношения логического совпадения, включения и пересечения объёмов понятий с учётом терминологических, структурных и семантических особенностей сопоставляемых классификаций, а также сущности предметных областей и принципов их индексирования. Взаимные отражения рубрик ГРНТИ и индексов УДК представлены тремя видами связей: эквивалентность, иерархическая подчинённость, ассоциация. Анализ значений коэффициентов долевого распределения по видам смысловых связей рубрик тематических классов ГРНТИ и индексов УДК-позволяет сделать вывод о достаточно высокой степени соответствия терминологии и структурной организации сопоставляемых классификационных систем практически по всем направлениям тематической систематизации предметных областей. Выполненные исследования по созданию «переходника» между ГРНТИ и УДК расширяют функциональные возможности системы взаимосвязанных классификаций.В ГПНТБ России в рамках выполнения темы НИР № 1021070112681-21.2.1;5.8.3 Государственного задания № 075-01235-23-01 ведутся исследования по созданию единой сети связей классификаций и разработке конвертеров, так называемых «переходников», между классификациями для автоматической тематической систематизации и интеграции разобщённых информационных ресурсов. Базовой классификацией единой сети связей классификаций является Государственный рубрикатор научно-технической информации (ГРНТИ)

Direct observation of topoisomerase IA gate dynamics

Type IA topoisomerases cleave single-stranded DNA and relieve negative supercoils in discrete steps corresponding to the passage of the intact DNA strand through the cleaved strand. Although type IA topoisomerases are assumed to accomplish this strand passage via a protein-mediated DNA gate, opening of this gate has never been observed. We developed a single-molecule assay to directly measure gate opening of the Escherichia coli type IA topoisomerases I and III. We found that after cleavage of single-stranded DNA, the protein gate opens by as much as 6.6 nm and can close against forces in excess of 16 pN. Key differences in the cleavage, ligation, and gate dynamics of these two enzymes provide insights into their different cellular functions. The single-molecule results are broadly consistent with conformational changes obtained from molecular dynamics simulations. These results allowed us to develop a mechanistic model of interactions between type IA topoisomerases and single-stranded DNA

Физико-химические свойства лактоферрина в условиях окислительного/галогенирующего стресса

Lactoferrin (Lf) was discovered in the thirties of the twentieth century. Since that time a number of useful properties of Lf (antibacterial, antiviral, pro- and anti-inflammatory, etc.) have been found. That’s why Lf became a promising candidate for pharmaceuticals use. The concentration of Lf strikingly increases in inflammatory focuses due to neutrophil degranulation. At the same time, activated neutrophils starts to generate reactive oxygen and halogen species (ROS and RHS), which leads to the development of oxidative/halogenative stress. In this work, using the fluorescence analysis we found the change of the Lf structure and properties in the inflammation conditions (under oxidatives/halogenative stress). We use two forms of Lf – human Lf, excreted from human milk, and recombinant Lf, excreted from milk of transgenic goats. It was established that the amino acids of Lf (decreasing the number of tryptophanils and primary amines) and protein restructuring undergo modification under the HOCl action, while H2O2 has no influence. These changes in the molecule under the HOCl treatment result in decreasing the iron-binding capacity of Lf.Лактоферрин (Лф) является перспективным объектом для использования в качестве лекарственного средства благодаря ряду полезных свойств (антибактериальное, противовирусное, про- и антивоспалительное и др.). Он содержится в секрете экзокринных желез, во вторичных гранулах нейтрофилов, в молоке человека и некоторых животных. Концентрация Лф быстро увеличивается в очагах воспаления за счет дегрануляции нейтрофилов. Там же за счет активации нейтрофилов идет наработка высокореакционных активных форм кислорода и галогенов, что приводит к развитию окислительного/галогенирующего стресса. В данной работе с помощью флуоресцентных методов впервые показано изменение структуры и свойств Лф (выделенного из женского грудного молока и рекомбинантного Лф человека, выделенного из молока трансгенных коз), находящегося в условиях воспаления (окислительный/галогенирующий стресс). Установлено, что HOCl вызывает модификацию аминокислотного состава Лф (из менение числа триптофанилов и первичных аминов), а также перестройку глобулы. В то же время при действии H2O2 вышеперечисленные изменения не наблюдаются. Произошедшие с молекулой изменения при действии HOCl проявляются в уменьшении способности Лф связывать ионы железа

ЖЕЛЕЗОСВЯЗЫВАЮЩАЯ СПОСОБНОСТЬ ЛАКТОФЕРРИНА ПРИ ВОСПАЛЕНИИ

Lactoferrin (Lf) is a biologically important molecule, that accomplishes a number of useful functions in an organism. Lf can be situated in conditions associated with enrichment of reactive halogen species (asthma, infectious disease, heart-disease etс.). It was shown using spectrophotometric and fluorescence methods that HOCl and particularly HOBr lead to significant destruction of Trp residues and iron-binding capacity of Lf.Лактоферрин (Лф), выполняющий ряд полезных функций в организме, может находиться в условиях, ассоциированных с накоплением активных форм галогенов (астма, инфекционные заболевания, болезни сердца и т. д.). В работе с применением спектрофотометрического и флуоресцентного методов показано, что HOCl и особенно HOBr вызывают значительные разрушения остатков Trp и нарушение железосвязывающей способности Лф

Bioactive Secondary Metabolites from a New Terrestrial Streptomyces sp. TN262

During our search for Streptomyces spp. as new producers of bioactive secondary metabolites, the ethyl acetate extract of the new terrestrial Streptomyces isolate TN262 delivered eight antimicrobially active compounds. They were identified as 1-acetyl-β-carboline (1), tryptophol (2), cineromycin B (3), 2,3-dihydrocineromycin B (4), cyclo-(tyrosylprolyl) (5), 3-(hydroxyacetyl)-indole (6), brevianamide F (7), and cis-cyclo-(l-prolyl-l-leucyl) (8). Three further metabolites were detected in the unpolar fractions using GC–MS and tentatively assigned as benzophenone (9), N-butyl-benzenesulfonamide (10), and hexanedioic acid-bis-(2-ethylhexyl) ester (11). This last compound is known as plasticizer derivatives, but it has never been described from natural sources. In this article, we describe the identification of the new Streptomyces sp. isolate TN262 using its cultural characteristics, the nucleotide sequence of the corresponding 16S rRNA gene and the phylogenetic analysis, followed by optimization, large-scale fermentation, isolation of the bioactive constituents, and determination of their structures. The biological activity of compounds (2), (3), (4), and those of the unpolar fractions was addressed as well

Аколат — антагонист лейкотриенов, новый препарат для базисной терапии бронхиальной астмы

The open investigation of 60 mild to moderate bronchial asthma patients was caried out to test the efficacy and safety of "Akolat". Non-smoking adult males and females who received short-acting inhaled beta-agonists as monotherapy or combinated with inhaled corticosteroids in dose up to 1000 meg daily were involved in this investigation. The efficacy was evaluated according to the asthmatic symptoms score, dynamics of pulmonary function parameters and to changes in frequency of taking beta-agonists.The significant improvement in daytime asthma symptoms evaluation (score number decreased by 56%), reduction of freqiency of nighttime awakenings because of asthma (by 53%) and reduction of mean number of mornings with asthma in a week (from 4.5 to 2.5) were registered after 6-week treatment with “Akolat” in 20 mg 2 times daily. Also the improvement of lung function (FEV1 and REF values increased accordingly by 16.8% and 22.6%) and reduction of beta-agonists necessity were noted. All the changes were statistically reliable. Side effects were basically mild to moderate and as a rule they did not require to abolish the drug. Two patients only had given up taking the drug because of unfavourable phenomens which were solved for two days.Conclusion: “Akolat" is effective and well-tolerable drug for basic therapy of mild to moderate asthma.Для изучения эффективности и безопасности “Аколат а” было проведено открытое исследование на 60 пациентах, страдающих бронхиальной астмой легкой/средней степени тяжести.В исследование включались некурящие взрослые мужчины и женщины, получающие по поводу астмы терапию только короткодействующими ингаляционными (β2-агонистами или в сочетании с ингаляционными кортикостероидами в суточной дозе не более 1000 мкг.Эффективность оценивали по шкале симптомов астмы, динамике показателей функции внешнего дыхания и изменениям в частоте приема (32-агонистов.После 6 недель терапии “Аколатом” в дозе 20 мг 2 раза в сутки отмечалось значительное улучшение в оценке дневных симптомов астмы (снижение по баллам на 56% ), уменьшение частоты ночных пробуждений из-за астмы (на 53%), уменьшение среднего числа дней в неделю с наличием утренних проявлений астмы (с 4,5 до 2,5). Также отмечалось улучшение функции дыхания (показатели FEV1 и PEF возросли на 16,8% и 22,6% соответственно) и снижение потребности в приеме р2-агонистов. Все изменения были статистически достоверными.Побочные явления были в основном легкие и умеренные и, как правило, не требовали отмены препарата. Только два пациента прекратили прием препарата из-за неблагоприятных явлений, которые разрешились в течение двух дней.Заключение: “Аколат” является эффективным и хорошо переносимым препаратом для базисной терапии астмы легкой и средней тяжести течения