Сравнительный анализ экспериментальной фармакокинетики новых нейротропных пептидных лекарственных средств

Experimental pharmacokinetics of new pharmacologically active peptides, modified analogues of endogenous neuropeptides, has been investigated in rats and rabbits. The study icluded 3 new drugs: (i) the nootropic drug noopept (phenylacetyl-prolyl-glycine ethyl ester); (ii) dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) – the antipsychotic with positive mnemotropic action; (iii) compound GB-115 – selective anxiolytic (phenylhexanoyl-prolyl-tryptophan amide). Differences in pharmacokinetics and biotransformation of the studied drugs depended on their structural features. The ether derivatives noopept and dilept underwent intensive metabolism by rat gastrointestinal esterases and peptidases with the formation of active metabolites. Being an amide, the compound GB-115 was more resistant to the enzymatic effects of peptidases and was detected for a longer period in the blood of experimental animals. In rabbits the studied compounds were less exposed to the enzymatic action by gastrointestinal peptidases, and were detected plasma of rabbits for a longer period. The higher stability of the compounds studied in rabbits may be attributed not only to the structural features of the studied dipeptides, but also to differences in the activity of the enzymatic systems of the gastrointestinal tract participating in their metabolism, as well as differences in the rate of hepatic and renal blood flow in rats and rabbits.Приведены результаты изучения сравнительной экспериментальной фармакокинетики и метаболизма новых фармакологически активных лекарственных средств (ЛС) пептидной природы у животных 2 видов (крысы, кролики). Объектами исследований были 3 новых ЛС: (i) ноотропный препарат ноопепт – этиловый эфир фенилацетил-пролил-глицина; (ii) антипсихотик с положительным мнемотропным действием дилепт – метиловый эфир N-капроил-L-пролил-L-тирозина; (iii) селективный анксиолитик – соединение ГБ-115 – амид фенилгексаноил-пролил-триптофана. Установлены различия фармакокинетики и биотрансформации изучаемых ЛС в зависимости от структурных особенностей субстанций этих соединений. Установлено, что эфирные производные ноопепт и дилепт подвергаются интенсивному метаболизму в организме крыс под влиянием эстераз и пептидаз ЖКТ с образованием активных метаболитов. Соединение ГБ-115, являющееся амидом, более устойчиво к энзиматическому воздействию пептидаз и более продолжительное время определяется в крови экспериментальных животных в неизмененном виде. В организме кроликов изучаемые соединения в меньшей степени подвергаются энзиматическому воздействию со стороны пептидаз ЖКТ и более продолжительное время определяются в плазме крови этих животных в неизмененном виде, что связано не только со структурными особенностями изучаемых дипептидов, но и различиями активности энзиматических систем ЖКТ, принимающих участие в их метаболизме, а также с различиями в скорости печеночного и почечного кровотока у крыс и кроликов

Characterization of new cell line stably expressing CHI3L1 oncogene

Aim. To characterize the immortalized 293 cell line afterstable transfection with human oncogene (CHI3L1). Methods. 293 cells, stably transfected with pcDNA3.1_CHI3L1, and 293 cells, stably transfected with pcDNA3.1 as a negative control, were used throughout all experiments. The clones of CHI3L1-expressing 293 cells and 293 cells, transfected with pcDNA3.1, were analyzed by immunofluorescence and confocal microscopy. Cell proliferation was measured using MTT assay; analyses of ERK1/2 and AKT activation and their cellular localization were performed with anti-phospho-ERK and anti-phospho-AKT antibodies. Specific activation of MAP and PI3 kinases was measured by densitometric analysis of Western-blot signals. Results. The obtained results show quite modest ability of CHI3L1 to stimulate cell growth and reflect rather an improved cellular plating efficiency of the 293 cells stably transfected with pcDNA3.1_CHI3L1 as compared to the 293 cells transfected with an «empty» vector. ERK1/2 and AKT are activated in the 293_CHI3L1 cells. In these cells phosphorylated ERK1/2 were localized in both cell cytoplasm and nuclei while AKT only in cytoplasm. The 293_CHI3L1 cells differed from the 293 cells, transfected with an «empty» vector, in their size and ability to adhere to the culture plates. Conclusions. The overexpression of CHI3L1 is likely to have an important role in tumorigenesis via a mechanism which involves activation of PI3K and ERK1/2 pathways. The tumors which can be induced by orthotopic implantation of the transformed human cells with overexpressed human oncogene CHI3L1 into the rat brain can be used as a target for anticancer drug development. Key words: chitinase 3-like 1 protein (CHI3L1), brain tumor, MAP kinase, PI3 kinase.Мета. Охарактеризувати імморталізовану клітинну лінію 293 після стабільної трансфекції онкогена CHI3L1. Методи. Клітини 293, стабільно трансфековані pcDNA3.1_CHI3L1, та клітини 293, стабільно трансфековані pcDNA3.1 як негативний контроль, використано в усіх експериментах. Клони 293 експресуючих CHI3L1 клітин та клітини 293, трансфековані «порожнім» вектором, проаналізовано методами імунофлуоресценції та конфокальної мікроскопії. Клітинну проліферацію визначено за допомогою MTT, активацію ERK1/2 i AKT та їxню локалізацію в клітинax – із застосуванням анти-фосфо-ERK- та анти-фосфо-AKT-антитіл. Специфічну активацію кіназ MAP і PI3 визначено денситометричним аналізом Вестерн-блот сигналів. Результати. Отримані результати демонструють помірну здатність CHI3L1 стимулювати клітинний ріст, алe відображають скоріше підвищену здатність до прикріплення 293 клітин, стабільно трансфекованих pcDNA3.1_CHI3L1 порівняно з клітинами 293, трансфекованими «порожнім» вектором. У 293_ CHI3L1 клітинах ERK1/2 та AKT перебувають в активованому стані. У цих клітинах фосфорильованi ERK1/2 локалізованi як у цитоплазмі, так і в ядрі, тоді як AKT – лише в цитоплазмі. 293_CHI3L1-клітини відрізняються від клітин 293_pcDNA3.1 за морфологією та їхньою здатністю до прикріплення до культуральних чашок. Висновки. Нaдeкспресія CHI3L1, очевидно, має важливе значення в пухлиноутворунні і опоседковується активацією PI3K- і MAPK- сигнальних шляхів. Пухлини, спричинені ортотопічною імплантацією трансформованих клітин людини з нaдекспресованимCHI3L1 у мозок щурів, стають вірогідною мішенню для антиракової терапії. Ключові слова: хітиназа 3-подібний білок 1 (CHI3L1), пухлини гoлoвного мозку, MAP-кіназа, PI3-кіназа.Цель. Охарактеризовать иммортализованную клеточную линию 293 после стабильной трансфекции онкогена CHI3L1. Методы. Клетки 293, стабильно трансфецированные pcDNA3.1_CHI3L1, и клетки 293, стабильно трансфецированные pcDNA3.1 в качестве отрицательного контроля, использованы во всех экспериментах. Клоны 293_CHI3L1 и клетки 293_ pcDNA3.1 анализировали методами иммунофлюоресценции и конфокальной микроскопии. Клеточную пролиферацию определяли с помощью MTT, активацию и локализацию ERK1/2 и AKT анализировали с применением анти-фосфо-ERK- и анти-фосфо-AKT-антител. Специфическую активацию MAP- и PI3-киназ определяли денситометрическим анализом Вестерн-блот сигналов. Результаты. Полученные ре - зультаты демонстрируют умеренную способность CHI3L1 стимулировать клеточный рост и отражают скорее повышенную способность к прикреплению клеток, стабильно трансфецированных pcDNA3.1_CHI3L1 по сравнению с 293-клетками, транс - фецированными «пустым» вектором. ERK1/2 и AKT в клетках 293_CHI3L1 находятся в активированном состоянии. В этих клетках фосфорилированныe ERK1/2 локализованы как в цитоплазме, так и в ядре, в то время как AKT – только в цитоплазме. Клетки 293_CHI3L1 отличаются от клеток 293_pcDNA3.1 по морфологии и способности прикрепления к культуральным чашкам. Выводы. Сверхэкспрессия CHI3L1, очевидно, имеет важное значение в опухолеобразовании и опосредуется активацией PI3Kи MAPK-сигнальных путей. Опухоли, которые индуцируются ортотопической имплантацией трансформированных человеческих клеток со сверхэкспрессированным CHI3L1 в мозг крыс, мо - гут служить мишенью для антираковой терапии. Ключевые слова: хитиназа 3-подобный белок 1 (CHI3L1), опухоли гoлoвного мозга, MAP-киназа, PI3-киназ

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

Search for TeV-scale gravity signatures in high-mass final states with leptons and jets with the ATLAS detector at sqrt [ s ] = 13TeV

A search for physics beyond the Standard Model, in final states with at least one high transverse momentum charged lepton (electron or muon) and two additional high transverse momentum leptons or jets, is performed using 3.2 fb−1 of proton–proton collision data recorded by the ATLAS detector at the Large Hadron Collider in 2015 at √s = 13 TeV. The upper end of the distribution of the scalar sum of the transverse momenta of leptons and jets is sensitive to the production of high-mass objects. No excess of events beyond Standard Model predictions is observed. Exclusion limits are set for models of microscopic black holes with two to six extra dimensions

Search for strong gravity in multijet final states produced in pp collisions at √s=13 TeV using the ATLAS detector at the LHC

A search is conducted for new physics in multijet final states using 3.6 inverse femtobarns of data from proton-proton collisions at √s = 13TeV taken at the CERN Large Hadron Collider with the ATLAS detector. Events are selected containing at least three jets with scalar sum of jet transverse momenta (HT) greater than 1TeV. No excess is seen at large HT and limits are presented on new physics: models which produce final states containing at least three jets and having cross sections larger than 1.6 fb with HT > 5.8 TeV are excluded. Limits are also given in terms of new physics models of strong gravity that hypothesize additional space-time dimensions

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction