An experimental and theoretical study of intramolecular cyclization of phosphorylated thioureas

New 1,3,2-thiazaphospholines were prepared, and their steric and electronic structures were examined. The steric and electronic structure of N-[(O-methyl)chloromethylthiophosphoryl]thiourea and the pathways of their intramolecular cyclization and rearrangement were studied by ab initio and semiempirical methods. The influence exerted by the conformational factors in thiourea and in the anion formed from it under the conditions of base catalysis on the direction of the reactions involving these species was revealed, and the structure of intermediate complexes and the final products was determined. ©2005 Pleiades Publishing, Inc

Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes

2, 4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in “diet pills”, despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular mechanism of its action in the mitochondria is far from being understood. The sensitivity of DNP’s uncoupling action in mitochondria to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), suggests the involvement of ANT and probably other mitochondrial proton-transporting proteins in the DNP’s protonophoric activity. To test this hypothesis, we investigated the contribution of recombinant ANT1 and the uncoupling proteins UCP1-UCP3 to DNP-mediated proton leakage using the well-defined model of planar bilayer lipid membranes. All four proteins significantly enhanced the protonophoric effect of DNP. Notably, only long-chain free fatty acids were previously shown to be co-factors of UCPs and ANT1. Using site-directed mutagenesis and molecular dynamics simulations, we showed that arginine 79 of ANT1 is crucial for the DNP-mediated increase of membrane conductance, implying that this amino acid participates in DNP binding to ANT1

Hairy cell leukemia. Clinical recommendations

Hairy cell leukemia. Clinical recommendation

Branched Chain Fatty Acids Reduce the Incidence of Necrotizing Enterocolitis and Alter Gastrointestinal Microbial Ecology in a Neonatal Rat Model

Branched chain fatty acids (BCFA) are found in the normal term human newborn's gut, deposited as major components of vernix caseosa ingested during late fetal life. We tested the hypothesis that premature infants' lack of exposure to gastrointestinal (GI) BCFA is associated with their microbiota and risk for necrotizing enterocolitis (NEC) using a neonatal rat model.Pups were collected one day before scheduled birth. The pups were exposed to asphyxia and cold stress to induce NEC. Pups were assigned to one of three experimental treatments. DF (dam-fed); Control, hand-fed rat milk substitute; BCFA, hand-fed rat milk substitute with 20%w/w BCFA. Total fat was equivalent (11%wt) for both the Control and BCFA groups. Cecal microbiota were characterized by 16S rRNA gene pyrosequencing, and intestinal injury, ileal cytokine and mucin gene expression, interleukin-10 (IL-10) peptide immunohistochemistry, and BCFA uptake in ileum phospholipids, serum and liver were assessed.NEC incidence was reduced by over 50% in the BCFA group compared to the Control group as assessed in ileal tissue; microbiota differed among all groups. BCFA-fed pups harbored greater levels of BCFA-associated Bacillus subtilis and Pseudomonas aeruginosa compared to Controls. Bacillus subtilis levels were five-fold greater in healthy pups compared to pups with NEC. BCFA were selectively incorporated into ileal phospholipids, serum and liver tissue. IL-10 expression increased three-fold in the BCFA group versus Controls and no other inflammatory or mucosal mRNA markers changed.At constant dietary fat level, BCFA reduce NEC incidence and alter microbiota composition. BCFA are also incorporated into pup ileum where they are associated with enhanced IL-10 and may exert other specific effects

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation

Анализ потерянных лет жизни в результате преждевременной смертности от злокачественных новообразований в Российской Федерации

Background. Burden of disease estimation allows analyses to be carried out integrally, including cause and effect assessment. the rate of life years lost due to premature mortality is part of the burden of disease analysis. given that the burden of cancer is steadily increasing, analysis of the number of years lost makes it possible to identify new strategic directions, as well as to adjust decisions already made, in the health care of cancer patients.Purpose: to estimate the loss of life expectancy as a result of premature mortality from cancer in the population of the Russian Federation.Material and Methods. the analysis was carried out using international statistical databases for disease burden estimation, databases of the Federal state statistics service (Rosstat). to determine the target groups of priority reduction of mortality from neoplasms in the Russian Federation, an estimation of the lost years of life expectancy as a result of premature mortality in the form of the e† (e-dagger) indicator was carried out. the analyzed period of the study was 2010–2019.Results. the Russian Federation is characterized by the smallest share of losses from cancer in the structure of losses from all causes of death compared to the analyzed countries (Japan, France, germany, latvia, lithuania, estonia). However, the share of losses has been intensively increasing for 10 years (in 2010 – 14.79 %, in 2019 – 17.54 %). in comparison with the analyzed countries, Russia is more characterised by losses from cancer at a younger age, with the highest value of life years lost in the age group 60–64 years. the age-standardized number of years lost in men in Russia is 67.1 % higher than in women. in the age group from 25 to 49 years of age, the loss of life expectancy due to cancer in women is higher and accounts for 0.4 years (or 19 %) of all losses, which is not typical of other age groups in which losses in men prevail. A significant regional differentiation of mortality in the constituent entities of the Russian Federation has been revealed, which is also reflected in the number of years lost.Conclusion. the potential of preventive strategies in the Russian Federation has not been fully realized – the loss of life years in young and middle age requires the correction of measures to improve preventive services and oncological care. the revealed regional differentiation allows us to identify regions with high losses for priority solutions.Актуальность. Оценка бремени болезни позволяет проводить анализ интегрально, включая оценку причин и последствий. Показатель потерянных лет жизни в результате преждевременной смертности является частью анализа бремени болезни. Учитывая, что бремя злокачественных новообразований (ЗНО) неуклонно растет, анализ числа потерянных лет позволяет определить новые стратегические направления, а также скорректировать уже принятые решения в области здравоохранения онкологических пациентов.Цель исследования – оценить потери продолжительности жизни в результате преждевременной смертности от ЗНО населения Российской Федерации (РФ).Материал и методы. Анализ проведен с использованием международных статистических баз данных для оценки бремени заболеваний, баз данных Федеральной службы государственной статистики (Росстат). Для определения целевых групп приоритетного снижения смертности от новообразований в РФ проведена оценка потерянных лет продолжительности жизни в результате преждевременной смертности в виде показателя e† (e-dagger). Анализируемый период исследования – 2010–2019 гг.Результаты. Для Российской Федерации характерна наименьшая доля потерь от ЗНО в структуре потерь от всех причин смерти по сравнению с анализируемыми странами (Япония, Франция, Германия, Латвия, Литва, Эстония). Однако доля потерь интенсивно растет на протяжении 10 лет (в 2010 г. – 14,79 %, в 2019 г. – 17,54 %). В сравнении с анализируемыми странами для России в большей степени характерны потери от ЗНО в более молодом возрасте с наибольшим значением потерянных лет жизни в возрастной группе 60–64 года. Стандартизованное по возрасту число потерянных лет у мужчин в РФ на 67,1 % выше, чем у женщин. В возрастной группе от 25 до 49 лет потери ожидаемой продолжительности жизни от ЗНО у женщин выше и составляют 0,4 года (или 19 %) от всех потерь, что не характерно для других возрастных групп, в которых у мужчин потери превалируют. Выявлена значительная региональная дифференциация смертности в субъектах РФ, что также отражается в количестве потерянных лет.Заключение. Потенциал профилактических стратегий в РФ не реализован в полной мере – потери лет жизни в молодом и среднем возрасте требуют коррекции мероприятий по улучшению профилактической службы и онкологической помощи. Выявленная региональная дифференциация позволяет определить регионы с высокими потерями для первоочередных решений

Lactobacillus rhamnosus GG improves outcome in experimental pseudomonas aeruginosa pneumonia: potential role of regulatory T cells

Introduction—Recent clinical trials show Lactobacillus rhamnosus GG (LGG) administration in critical illness has the potential to reduce nosocomial infections and improve clinical outcome. However, the mechanism(s) of LGG-mediated benefit following illness and injury remain elusive. Objective—The aim of this study was to determine the effect of LGG treatment on survival and lung injury in a mouse model of Pseudomonas aeruginosa–induced pneumonia. As increased T regulatory (Treg) cell numbers have been shown to improve outcome in experimental pneumonia, we examined the potential role of Treg cells in probiotic-mediated benefit. Methods—FVB/N mice were subjected to intratracheal injection of either P. aeruginosa or saline and received LGG or vehicle immediately before procedure. T regulatory cell responses in the lung were evaluated by polymerase chain reaction, Western blotting, and flow cytometry. Results—Mice treated with LGG had significantly improved 7-day survival (P < 0.01) compared with saline-treated control pneumonia mice (55% LGG vs. 14% control). The survival advantage was associated with reduced bacterial counts in bronchoalveolar lavage and with decreased markers of the systemic inflammatory response and improved lung pathology in the probiotic group. Probiotic treatment influenced immune response in the lungs of mice with pneumonia as demonstrated by increased levels of Treg cell marker Foxp3. Conclusions—These data demonstrate that early administration of LGG improves outcome following P. aeruginosa–induced pneumonia. An effect of LGG on Treg cells may play a role in this protection