Redox phospholipidomics of enzymatically generated oxygenated phospholipids as specific signals of programmed cell death

High fidelity and effective adaptive changes of the cell and tissue metabolism to changing environments require strict coordination of numerous biological processes. Multicellular organisms developed sophisticated signaling systems of monitoring and responding to these different contexts. Among these systems, oxygenated lipids play a significant role realized via a variety of re-programming mechanisms. Some of them are enacted as a part of pro-survival pathways that eliminate harmful or unnecessary molecules or organelles by a variety of degradation/hydrolytic reactions or specialized autophageal processes. When these “partial” intracellular measures are insufficient, the programs of cells death are triggered with the aim to remove irreparably damaged members of the multicellular community. These regulated cell death mechanisms are believed to heavily rely on signaling by a highly diversified group of molecules, oxygenated phospholipids (PLox). Out of thousands of detectable individual PLox species, redox phospholipidomics deciphered several specific molecules that seem to be diagnostic of specialized death programs. Oxygenated cardiolipins (CLs) and phosphatidylethanolamines (PEs) have been identified as predictive biomarkers of apoptosis and ferroptosis, respectively. This has led to decoding of the enzymatic mechanisms of their formation involving mitochondrial oxidation of CLs by cytochrome c and endoplasmic reticulum-associated oxidation of PE by lipoxygenases. Understanding of the specific biochemical radical-mediated mechanisms of these oxidative reactions opens new avenues for the design and search of highly specific regulators of cell death programs. This review emphasizes the usefulness of such selective lipid peroxidation mechanisms in contrast to the concept of random poorly controlled free radical reactions as instruments of non-specific damage of cells and their membranes. Detailed analysis of two specific examples of phospholipid oxidative signaling in apoptosis and ferroptosis along with their molecular mechanisms and roles in reprogramming has been presented

Влияние биогенных элементов на фитоэкстракцию кадмия из загрязненной почвы

The influence of substances containing biogenic elements (potassium chloride, sodium phosphate, ammonium nitrate, potassium and urea nitrate) on phytoextraction degree of cadmium from soil by cultivated oat (Avena sativa L.), cutting lettuce (Lactuca sativa L.) and charlock (Sinapis arvensis L.) has been investigated. As the results of experiment the factors used for estimation of relationship between the environment and a physiological role of a chemical element, and also for revealing of its share in biotic turnover and of a role of organisms-indicators and organisms-concentrators have been calculated: phytotoxic effect and factor of biological absorbing of cadmium by plants. It is shown that potassium nitrate promote the extraction of cadmium from soil in a greater degree in comparison with other substances containing biogenic elements.Исследовано влияние веществ , содержащих биогенные элементы ( хлорида калия , фосфата натрия , нитрата аммония , нитрата калия и мочевины ) на степень фитоэкстракции кадмия из почвы овсом посевным (Avena sativa L.), салатом листовым (Lactuca sativa L.) и горчицей полевой (Sinapis arvensis L.). По результатам эксперимента рассчитаны показатели, использующиеся для оценки связи среды и физиологической роли химического элемента, а также для выявления его участия в биотическом круговороте, роли организмов-индикаторов и организмов-концентраторов: фитотоксический эффект и коэффициент биологического поглощения кадмия растениями. Показано, что нитрат калия в большей степени, по сравнению с другими веществами, содержащими биогенные элементы, способствует извлечению кадмия из почвы

Применение янтарной кислоты в процессе фитоэкстракции свинца и кадмия из загрязненных почв

Succinic acid influence on migration properties of lead and cadmium in soil-plant system has been investigated. It has been shown that the addition the activator (succinic acid) into soil increases the efficiency of phytoextraction of lead and cadmium. The optimum conditions of succinic acid usage as the process activator have been established.В работе изучено влияние янтарной кислоты на миграционные свойства свинца и кадмия в системе «почва-рстения». Установлено, что внесение в почву активатора - янтарной кислоты повышает эффективность процесса фитоэкстракции свинца и кадмия. Установлены оптимальные условия применения янтарной кислоты в качестве активатора процесса

Уровень антропогенного воздействия на экосистемы как функция свойств растительных сообществ.

The approach of estimation of a level of anthropogenic impact on ecosystems as a function of properties of plant associations has been proposed. In the course of investigation it was established that it is possible to estimate the growth degree of anthropogenic impact on ecosystem by: the increase part of a ruderal vegetation in common composition of plant associations; the increase amount of a ruderal vegetation growing on one square meter of soil surface (thickness of sowing); the increase of lead and cadmium content in above ground part of the plants. The sufficiently high ability of lead extraction from soil by such plants-accumulators as great nettle and meadow fescue has been establishedПреложен подход к оценке уровня антропогенного воздействия на экосистемы в качестве функции свойств растительных сообществ. В ходе исследования установлено, что об увеличении степени антропогенного воздействия на экосистему можно судить по: увеличению доли рудеральных видов растений в общем составе растительного сообщества; увеличению количества рудеральных растений, произрастаю-щих на одном квадратном метре поверхности (густота стояния); увеличению содержания свинца и кадмия в наземной части растений. Установлена достаточно высокая способность извлечения свинца из почвы такими растениями-аккумуляторами, как крапива двудомная и овсяница луговая

The influence of salinity on the effects of Multi-walled carbon nanotubes on polychaetes

Salinity shifts in estuarine and coastal areas are becoming a topic of concern and are one of the main factors influencing nanoparticles behaviour in the environment. For this reason, the impacts of multiwalled carbon nanotubes (MWCNTs) under different seawater salinity conditions were evaluated on the common ragworm Hediste diversicolor, a polychaete species widely used as bioindicator of estuarine environmental quality. An innovative method to assess the presence of MWCNT aggregates in the sediments was used for the first time. Biomarkers approach was used to evaluate the metabolic capacity, oxidative status and neurotoxicity of polychaetes after long-term exposure. The results revealed an alteration of energy-related responses in contaminated polychaetes under both salinity conditions, resulting in an increase of metabolism and expenditure of their energy reserves (lower glycogen and protein contents). Moreover, a concentration-dependent toxicity (higher lipid peroxidation, lower ratio between reduced and oxidized glutathione and activation of antioxidant defences and biotransformation mechanisms) was observed in H. diversicolor, especially when exposed to low salinity. Additionally, neurotoxicity was observed by inhibition of Cholinesterases activity in organisms exposed to MWCNTs at both salinities.publishe

Стратегия DOTS – путь к ускоренному излечению впервые выявленных больных легочным туберкулезом в России

DOTS strategy includes several important points, primarily, detection of tuberculosis patients and a strong monitoring of treatment efficacy.Specialists on lung tuberculosis from Tomsk have 5-year experience in work with DOTS programme. They observed 675 patients asked medical care in tuberculosis settings of Tomsk region from the March 1995 to November 1996. The patients ere divided into the group A and B. The group A received anti-tuberculosis therapy adopted in Russia. The group В was given directly observed treatment short course (DOTS) according to WHO standard. It included the intensive phase (2 months for new diagnosed cases and 3 months for repeated therapy course) and the continued phase of 2–4 (new diagnosed cases) to 5 months (repeated course) length. Typical WHO modes were used the first line drugs, such as isoniasid, rifampicin, pyrasinamid, etambutol, streptomycin. The therapy delayed results were assessed with criteria accepted by WHO and in Russia as well. Seventy one per cent of the patients recovered: 69% from the group A and 74% from the group B. The treatment failures were registered in 15 (4.2%) patients of the group A and 18 (5.6%) of the group B. Residual lesions of respiratory system were less severe in the group A patients just at the early period; there was no significant difference between the groups by the 30-th month of the observation. Meantime the cost-effectiveness of WHO standard treatment is 1.9 times less than that of Russian traditional schemes. Generally, a positive tendency in lung tuberculosis patients’ treatment and observation effectiveness has been noted in the Tomsk region for the last 5 years due to the DOTS strategy, so that it takes a positive role for tuberculosis patients’ cure.Стратегия DOTS включает ряд важных элементов, в первую очередь выявление больных туберкулезом – бацилловыделителей и строгий мониторинг эффективности лечения больного.Томские фтизиатры имеют 5-летний опыт работы по программе DOTS. Наблюдалось 675 больных, обратившихся в противотуберкулезные учреждения Томской области в период с марта 1995 г. по ноябрь 1996 г. Пациенты были разделены на группы А и Б: группа А получала лечение по принципам традиционной российской фтизиатрии, группе Б назначали краткосрочный курс лечения под непосредственным наблюдением (ККХ) по стандартам ВОЗ, состоящий из интенсивной фазы (2 мес для новых случаев и 3 мес для повторного лечения) и продолжающей фазы длительностью от 2–4 мес (новые случаи) до 5 мес (повторное лечение). Использовались классические режимы ВОЗ с назначением препаратов первой линии: изониазид, рифампицин, пиразинамид, этамбутол, стрептомицин. Отдаленные результаты лечения оценивались по критериям, принятым как ВОЗ, так и в российской фтизиатрии. Излечено 71% пациентов: в группе А – 69%, в группе Б – 74%. Неудовлетворительные итоги лечения констатированы в группе А у 15 (4,2%) человек, в группе Б – у 18 (5,6%) больных. Характер остаточных изменений со стороны органов дыхания был более благоприятным в группе А только на раннем этапе, а к 30 мес наблюдения статистически значимой разницы между группами А и Б не отмечено. Вместе с тем затраты на лечение по протоколам ВОЗ в 1,9 раза меньше, чем по принятым в России методикам. В целом благодаря стратегии DOTS в Томской области за последние 5 лет достигнута положительная динамика показателей эффективности лечения и диспансерного наблюдения больных туберкулезом, что подтверждает позитивную роль стратегии в излечении больных

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Barriers to Non-Viral Vector-Mediated Gene Delivery in the Nervous System

Efficient methods for cell line transfection are well described, but, for primary neurons, a high-yield method different from those relying on viral vectors is lacking. Viral transfection has several drawbacks, such as the complexity of vector preparation, safety concerns, and the generation of immune and inflammatory responses when used in vivo. However, one of the main problems for the use of non-viral gene vectors for neuronal transfection is their low efficiency when compared with viral vectors. Transgene expression, or siRNA delivery mediated by non-viral vectors, is the result of multiple processes related to cellular membrane crossing, intracellular traffic, and/or nuclear delivery of the genetic material cargo. This review will deal with the barriers that different nanoparticles (cationic lipids, polyethyleneimine, dendrimers and carbon nanotubes) must overcome to efficiently deliver their cargo to central nervous system cells, including internalization into the neurons, interaction with intracellular organelles such as lysosomes, and transport across the nuclear membrane of the neuron in the case of DNA transfection. Furthermore, when used in vivo, the nanoparticles should efficiently cross the blood-brain barrier to reach the target cells in the brain