RU2669348C1 - Method for inhibiting nuclear kappa b factor with using 2-ethyl-6-methyl-3-hydroxipiridinium l-2,6-diaminohexanoate in culture of cells - Google Patents
Method for inhibiting nuclear kappa b factor with using 2-ethyl-6-methyl-3-hydroxipiridinium l-2,6-diaminohexanoate in culture of cells Download PDFInfo
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Abstract
Description
Способ ингибирования нуклеарного фактора каппа В с использованием 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата в культуре клетокMethod for inhibiting kappa B nuclear factor using 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate in cell culture
Изобретение относится к медицине, в частности к экспериментальной фармакологии.The invention relates to medicine, in particular to experimental pharmacology.
По известным литературным источникам – нуклеарный фактор каппа В (NF-κB) на сегодняшний день является одной из перспективных мишеней для разработки инновационных лекарственных средств в рамках развития современной фармакологии и формирования концепции таргетной терапии [Test system for evaluation of the influence of the biological activity of substances on the signal system of NF-κB: focus on the derivatives of 3 hydroxypyridine / Skachilova S.Y., Ragulina V.A., Kostina D.A., Burda Y.E. // Research result: pharmacology and clinical pharmacology. – 2017. – Vol. 3, №2. – Р. 50-56. doi: 10.18413/2313-8971-2017-3-2-50-56]. According to well-known literature, the nuclear factor kappa B (NF-κB) is today one of the promising targets for the development of innovative drugs in the development of modern pharmacology and the formation of the concept of targeted therapy [Test system for evaluation of the influence of the biological activity of substances on the signal system of NF-κB: focus on the derivatives of 3 hydroxypyridine / Skachilova SY, Ragulina VA, Kostina DA, Burda YE // Research result: pharmacology and clinical pharmacology. - 2017 .-- Vol. 3, No. 2. - R. 50-56. doi: 10.18413 / 2313-8971-2017-3-2-50-56].
NF-κB является одним из факторов транскрипции. Повышенный интерес к изучению биологической роли данной сигнальной системы и вкладе её в развитие сердечно-сосудистых, онкологических и аутоиммунных заболеваний очевиден [Role of nuclear factor-κB activation in acute ischaemia-reperfusion injury in myocardium / A. Kis, D.M. Yellon, G.F. Baxter // British Journal of Pharmacology. – 2003. – 138(5). – P. 894-900, doi:10.1038/sj.bjp.0705108; Nuclear factor kappa B: important transcription factor and therapeutic target. Lee JI, Burckart GJ. J Clin Pharmacol. 1998 Nov;38(11):981-93]. Целый ряд стимулов (провоспалительные цитокины: фактор некроза опухоли α, интерлейкин 1β; лиганд CD40 и др.), запускают канонический и неканонический пути активации сигнального пути NF-κB, что повышает экспрессию генов, регулирующих синтез цитокинов и хемокинов, пролиферацию и дифференцировку клеток, ангиогенез, иммунные реакции и апоптоз [Nuclear factor kappa B as a potential target for pharmacological correction endothelium-associated pathology / V.A. Ragulina, D.A. Kostina, A.P. Dovgan, Y.E. Burda, S.V. Nadezhdin // Research result: pharmacology and clinical pharmacology. – 2017. – Vol. 3, №1 – P. 114-124. DOI: 10.18413/2500-235X-2017-3-1-114-124].NF-κB is one of the transcription factors. An increased interest in studying the biological role of this signaling system and its contribution to the development of cardiovascular, oncological and autoimmune diseases is evident [Role of nuclear factor-κB activation in acute ischaemia-reperfusion injury in myocardium / A. Kis, D.M. Yellon, G.F. Baxter // British Journal of Pharmacology. - 2003 .-- 138 (5). - P. 894-900, doi: 10.1038 / sj.bjp.0705108; Nuclear factor kappa B: important transcription factor and therapeutic target. Lee JI, Burckart GJ. J Clin Pharmacol. 1998 Nov; 38 (11): 981-93]. A number of stimuli (pro-inflammatory cytokines: tumor necrosis factor α, interleukin 1β; CD40 ligand, etc.) trigger the canonical and noncanonical activation pathways of the NF-κB signaling pathway, which increases the expression of genes that regulate the synthesis of cytokines and chemokines, cell proliferation and differentiation, angiogenesis, immune responses, and apoptosis [Nuclear factor kappa B as a potential target for pharmacological correction endothelium-associated pathology / VA Ragulina, D.A. Kostina, A.P. Dovgan, Y.E. Burda, S.V. Nadezhdin // Research result: pharmacology and clinical pharmacology. - 2017 .-- Vol. 3, No. 1 - P. 114-124. DOI: 10.18413 / 2500-235X-2017-3-1-114-124].
Потенциальными кандидатами, снижающими активность данного транскрипционного фактора являются производные 3-оксипиридина. В связи с вышесказанным следует отметить актуальность изучения 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата в качестве ингибитора NF-κB in vitro с оценкой активности p65 субъединицы в мононуклеарных клетках (МНК) крови крыс линии Wistar, стимулированных бактериальным липополисахаридом.Potential candidates that reduce the activity of this transcription factor are 3-hydroxypyridine derivatives. In connection with the foregoing, the relevance of the study of 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate as an inhibitor of NF-κB in vitro with the assessment of the activity of p65 subunit in mononuclear cells (MNCs) of blood of Wistar rats should be noted. stimulated by bacterial lipopolysaccharide.
Известен способ ингибирования NF-κB композициями тритерпенов (патент на изобретение RU 2288706, публ. 10.12.2006). Сущность его заключается в ингибировании воспаления путем обеспечения клетки монотерпеновыми композициями, которые ингибируют фактор NF-κB. Композиция может включать дополнительные химические функциональные агенты. Технический результат - повышение эффективности лечения воспалительных состояний, в частности предраковых. A known method of inhibiting NF-κB compositions of triterpenes (patent for invention RU 2288706, publ. 10.12.2006). Its essence is to inhibit inflammation by providing cells with monoterpene compositions that inhibit NF-κB factor. The composition may include additional chemical functional agents. The technical result is an increase in the effectiveness of the treatment of inflammatory conditions, in particular precancerous.
Основным недостатком способа является то, что применяемые терапевтические дозы монотерпеновых/тритерпеновых соединений могут привести к значительным побочным эффектам или к другим неблагоприятным реакциям. У субъектов с далеко зашедшим заболеванием может наблюдаться определенная степень побочных эффектов при применении терапевтических доз монотерпеновых/тритерпеновых соединений.The main disadvantage of this method is that the therapeutic doses of monoterpene / triterpene compounds used can lead to significant side effects or other adverse reactions. In subjects with advanced disease, a certain degree of side effects may be observed with therapeutic doses of monoterpene / triterpene compounds.
Известно зависящее от концентрации влияние (R)- и (S)-флурбипрофена на активацию фактора транскрипции NF-κВ в RAW-клетках (патент на изобретение RU 2250103, публ. 20.04.2005). Анализ гельудерживания показывает, что липополисахарид (ЛПС) (1 мкг/мл) приводит к активации NF-κВ (комплекс р50/р65 NF-κВ). Микромолярные концентрации (R)-флурбипрофена были в состоянии ингибировать эту индуцированную ЛПС активацию NF-κВ.The concentration-dependent effect of (R) - and (S) -flurbiprofen on the activation of the transcription factor NF-κB in RAW cells is known (Patent RU 2250103, publ. 04/20/2005). Gel retention analysis shows that lipopolysaccharide (LPS) (1 μg / ml) leads to activation of NF-κB (p50 / p65 complex NF-κB). Micromolar concentrations of (R) -flurbiprofen were able to inhibit this LPS-induced activation of NF-κB.
Изобретение относится к области фармации, а именно к применению (R)-энантиомеров арилпропионовых кислот. Сущность изобретения - применение названных кислот для получения лекарственных средств, которые ингибируют каскад активации NF-κB. На основе их создана композиция. Технический результат - использование для лечения заболеваний, на которые может терапевтически положительно воздействовать ингибирование образования NF-κB. The invention relates to the field of pharmacy, and in particular to the use of (R) -enantiomers of arylpropionic acids. The essence of the invention is the use of these acids to obtain drugs that inhibit the activation cascade of NF-κB. Based on them, a composition was created. The technical result is the use for the treatment of diseases that can be therapeutically positively affected by the inhibition of the formation of NF-κB.
Недостатком данного изобретения является то, что арилпропионовые кислоты и их производные обладают рядом побочных эффектов при их применении, а именно тошнота, анорексия, метеоризм, запор, изжога, диарея, НПВС-гастропатия, вплоть до эрозивно-язвенных поражений ЖКТ.The disadvantage of this invention is that arylpropionic acids and their derivatives have a number of side effects when used, namely nausea, anorexia, flatulence, constipation, heartburn, diarrhea, NSAID gastropathy, up to erosive and ulcerative lesions of the gastrointestinal tract.
Наиболее близким к заявленному решению является способ ингибирования NF-κB с использованием производных 3-оксипиридина (Test system for evaluation of the influence of the biological activity of substances on the signal system of NF-κB: focus on the derivatives of 3hydroxypyridine / Skachilova S.Y., Ragulina V.A., Kostina D.A., Burda Y.E. // Research result: pharmacology and clinical pharmacology. – 2017. – Vol. 3, №2. – Р. 50-56), включающий добавление бактериального липополисахарида в концентрации 1 мкг/мл к свежевыделенным по стандартной методике на градиенте плотности фиколла МНК крови крыс Wistar, затем добавление к данной смеси исследуемого фармакологического агента, растворенного в фосфатно-солевом буфере, в соответствующей конечной концентрации, отличающийся тем, что в качестве фармакологического агента используют мексидол, этоксидол, 3-гидрокси-2-этил-6-метилпиридиния глутаминат, 3-гидрокси-2-этил-6-метилпиридиния аспарагинат, 3-гидрокси-2-этил-6-метилпиридиния 4-аминобензоат, 3-гидрокси-2-этил-6-метилпиридиния никотинат, 3-гидрокси-2-этил-6-метилпиридиния N-ацетиламиногексаноат, 3-гидрокси-2-этил-6-метилпиридиния N-ацетиламиноацетат, 3-гидрокси-2-этил-6-метилпиридиния N-ацетиламиноглутаминат, 3-гидрокси-2-этил-6-метилпиридиния ацетилсалицилат, бета-гидроксиникотиноилгидразон 2-метил-3-гидрокси-4-формил-5-оксиметилпиридина дигидрохлорид. Наибольшей ингибирующей способностью на ЛПС-индуцированную экспрессию p65 NF-κB в МНК обладали мексидол, этоксидол и бета-гидроксиникотиноилгидразон 2-метил-3-гидрокси-4-формил-5-оксиметилпиридина дигидрохлорид.Closest to the claimed solution is a method of inhibiting NF-κB using 3-hydroxypyridine derivatives (Test system for evaluation of the influence of the biological activity of substances on the signal system of NF-κB: focus on the derivatives of 3hydroxypyridine / Skachilova SY, Ragulina VA, Kostina DA, Burda YE // Research result: pharmacology and clinical pharmacology. - 2017. - Vol. 3, No. 2. - P. 50-56), including the addition of bacterial lipopolysaccharide at a concentration of 1 μg / ml to freshly isolated the standard method on a density gradient of ficoll MNCs of blood of Wistar rats, then adding the studied pharmacological agent to this mixture, p dissolved in phosphate-buffered saline, in the corresponding final concentration, characterized in that mexidol, ethoxidol, 3-hydroxy-2-ethyl-6-methylpyridinium glutamate, 3-hydroxy-2-ethyl-6-methylpyridinium asparaginate are used as a pharmacological agent 3-hydroxy-2-ethyl-6-methylpyridinium 4-aminobenzoate, 3-hydroxy-2-ethyl-6-methylpyridinium nicotinate, 3-hydroxy-2-ethyl-6-methylpyridinium N-acetylaminohexanoate, 3-hydroxy-2- ethyl 6-methylpyridinium N-acetylaminoacetate, 3-hydroxy-2-ethyl-6-methylpyridinium N-acetylaminoglutaminate, 3-hydroxy-2-ethyl-6 -methylpyridinium acetylsalicylate, beta-hydroxynicotinoylhydrazone 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine dihydrochloride. Mexidol, ethoxidol and beta-hydroxynicotinoylhydrazone 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine dihydrochloride had the highest inhibitory ability on LPS-induced expression of p65 NF-κB in MNCs.
Недостатком данного решения является то, что наблюдаемая ингибирующая активность in vitro в отношении сигнального пути NF-κB мексидола, этоксидола и бета-гидроксиникотиноилгидразон 2-метил-3-гидрокси-4-формил-5-оксиметилпиридина дигидрохлорида не достигает целевых значений и более чем в 3,5 раза отличается от значений интактных крыс.The disadvantage of this solution is that the observed in vitro inhibitory activity with respect to the NF-κB signal pathway of mexidol, ethoxidol and beta-hydroxynicotinoylhydrazone 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine dihydrochloride does not reach the target values and more than in 3.5 times different from intact rats.
Техническим результатом предлагаемого изобретения является эффективный способ ингибирования NF-κB с использованием 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата, подтверждаемый результатами оценки активности p65 субъединицы в МНК крови крыс Wistar, стимулированных бактериальным липополисахаридом, обладающий более благоприятным профилем безопасности по сравнению с рассмотренными аналогами и более высокой ингибирующей активностью NF-κB по сравнению с прототипом.The technical result of the present invention is an effective method of inhibiting NF-κB using 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate, confirmed by the results of evaluating the activity of the p65 subunit in WNCR blood rats stimulated with bacterial lipopolysaccharide, having more a favorable safety profile compared with the considered analogues and a higher inhibitory activity of NF-κB compared to the prototype.
Задачей предлагаемого изобретения является создание эффективного способа ингибирования нуклеарного фактора каппа В с использованием 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата в культуре мононуклеарных клеток крови крыс Wistar.The objective of the invention is the creation of an effective method of inhibiting the nuclear factor of kappa B using 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate in a culture of mononuclear blood cells of rats Wistar.
Поставленная задача достигается тем, что предложен способ ингибирования нуклеарного фактора каппа В с использованием 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата в культуре клеток, включающий добавление бактериального липополисахарида в концентрации 1 мкг/мл к свежевыделенным по стандартной методике на градиенте плотности фиколла МНК крови крыс Wistar, затем добавление к данной смеси исследуемого фармакологического агента, растворенного в фосфатно-солевом буфере, в соответствующей конечной концентрации, отличающийся тем, что в качестве фармакологического агента используют 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноат. This object is achieved by the fact that the proposed method of inhibiting the nuclear factor of kappa B using 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate in cell culture, comprising adding bacterial lipopolysaccharide at a concentration of 1 μg / ml to freshly isolated the standard method on the density gradient of Ficoll MNCs of blood of Wistar rats, then adding to this mixture the studied pharmacological agent dissolved in phosphate-saline buffer, in the corresponding final concentration, characterized in that 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate is used as a pharmacological agent.
Основным преимуществом предлагаемого способа является то, что введение нового производного 3-оксипиридина, 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата, в исследуемой in vitro концентрации, 35 мкг/мл, приводит к выраженному ингибированию NF-κB в культуре клеток, что подтверждается результатами оценки активности p65 субъединицы в МНК крови крыс Wistar, стимулированных бактериальным липополисахаридом. Помимо этого, предлагаемый способ обладает более благоприятным профилем безопасности по сравнению с рассмотренными аналогами и более высокой ингибирующей активностью NF-κB по сравнению с прототипом.The main advantage of the proposed method is that the introduction of a new derivative of 3-hydroxypyridine, 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate, in an in vitro test concentration of 35 μg / ml, leads to pronounced inhibition of NF -κB in a cell culture, as evidenced by the results of evaluating the activity of the p65 subunit in WNar rat MNCs stimulated with bacterial lipopolysaccharide. In addition, the proposed method has a more favorable safety profile compared with the considered analogues and a higher inhibitory activity of NF-κB compared to the prototype.
СПОСОБ ПОЛУЧЕНИЯ 2-ЭТИЛ-6-МЕТИЛ-3-ГИДРОКСИПИРИДИНИЯ L-2,6-ДИАМИНОГЕКСАНОАТАMETHOD FOR PRODUCING 2-Ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate
В трехгорлую колбу, снабженную мешалкой, термометром и обратным холодильником, загружают 30 мл этилового спирта. При перемешивании добавляют 2,74 г (0,02 м) 2-этил-6-метил-3-гидроксипиридина. После растворения добавляют постепенно 3,92 г (0,02 м) L-2,6-диаминогексановой кислоты. Массу нагревают до 75 °C, выдерживают при этой температуре в течение 1 часа, полученный раствор фильтруют. От фильтрата отгоняют растворитель, приливают к остатку 15 мл ацетонитрила, кристаллизуют при +5 °C в течение 8-10 часов. Кристаллы отделяют фильтрацией, сушат в вакууме при 35-40 °C, получают 5,4 г гигроскопичного мелкокристаллического вещества, растворимого в воде. C14H25N3O3 In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 30 ml of ethanol are charged. 2.74 g (0.02 m) of 2-ethyl-6-methyl-3-hydroxypyridine are added with stirring. After dissolution, 3.92 g (0.02 m) of L-2,6-diaminohexanoic acid is added gradually. The mass is heated to 75 ° C, maintained at this temperature for 1 hour, the resulting solution is filtered. The solvent is distilled off from the filtrate, 15 ml of acetonitrile are added to the residue, and crystallized at +5 ° C for 8-10 hours. The crystals are separated by filtration, dried in vacuo at 35-40 ° C, and 5.4 g of a hygroscopic finely crystalline substance soluble in water are obtained. C 14 H 25 N 3 O 3
Найдено, % : C 59,21; H 8,94; N 14,79Found,%: C 59.21; H 8.94; N 14.79
Вычислено, % : C 59,34; H 8,89; N 14,83; O 16,94Calculated,%: C 59.34; H 8.89; N, 14.83; O 16.94
ИК-спектр, ν см-1: 3495 (OH); 3370, 3285 (NH2); 2560 (N+); 1645, 1610 (C=C); 1287 (CH2)IR spectrum, ν cm -1 : 3495 (OH); 3370, 3285 (NH 2 ); 2560 (N +); 1645, 1610 (C = C); 1287 (CH 2 )
УФ-спектр, нм: 231, 296 (0,001% раствор в воде)UV spectrum, nm: 231, 296 (0.001% solution in water)
ТСХ: система бензол-ацетон (2-3), пластины Merck, Rf – 0,43TLC: benzene-acetone system (2-3), Merck, Rf plates - 0.43
ФАРМАКОЛОГИЧЕСКИЕ СВОЙСТВА PHARMACOLOGICAL PROPERTIES
2-ЭТИЛ-6-МЕТИЛ-3-ГИДРОКСИПИРИДИНИЯ L-2,6-ДИАМИНОГЕКСАНОАТА2-Ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate
При изучении ингибирующей активности в отношении NF-κB были исследованы 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноат и мексидол (препарат сравнения), которые добавляли к свежевыделенным по стандартной методике на градиенте плотности фиколла (ρ = 1,077, «Панэко», Россия) МНК крови крыс линии Wistar. Исследуемая in vitro концентрация каждого препарата составляет 35 мкг/мл.When studying the inhibitory activity against NF-κB, 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate and mexidol (reference preparation) were studied, which were added to the freshly isolated by the standard method on a density gradient of ficoll (ρ = 1,077, "Paneko", Russia) MNCs of blood of the Wistar rats The in vitro concentration studied for each preparation is 35 μg / ml.
В каждой экспериментальной группе 6 крыс, 3 самца и 3 самки. Для исследования взяты крысы без внешних признаков заболевания, прошедшие карантинный режим, массой 225-275 г.In each experimental group, 6 rats, 3 males and 3 females. For the study, rats were taken without external signs of the disease, which passed the quarantine regime, weighing 225-275 g.
Исследование активности NF-κB проводили в 2 мл пробирках типа Eppendorf (Gen Follower, Китай), куда вносили 1 мл суспензии МНК крови крыс, 1×106 клеток в 1 мл среды RPMI-1640 («Панэко», Россия) с 5% сыворотки эмбрионов коров (HiClone, США), затем добавляли бактериальный липополисахарид («Пирогенал», ГУ НИИЭМ им. Н.Ф. Гамалеи, Россия) в концентрации 1 мкг/мл, затем добавляли исследуемый препарат, растворенный в фосфатно-солевом буфере, в соответствующей конечной концентрации. Клетки инкубировали в течение 30 мин при 37°С на шейкере, после чего центрифугировали 5 мин при 200g, надосадочную жидкость удаляли, осадок МНК исследовали на активность p65 субъединицы NF-κB в строгом соответствии с инструкцией к набору NFkB p65 TotalMultispecies InstantOne™ ELISA Kit (Invitrogen / Thermo Fisher Scientific, cat. 85-86081-11).The study of the activity of NF-κB was carried out in 2 ml Eppendorf tubes (Gen Follower, China), where 1 ml of a suspension of rat blood MNC, 1 × 106 cells in 1 ml of RPMI-1640 medium (Paneko, Russia) with 5% serum was added cow embryos (HiClone, USA), then added bacterial lipopolysaccharide (Pyrogenal, NII Gamalei State Research Institute of Nuclear Medicine, Russia) at a concentration of 1 μg / ml, then the test drug dissolved in phosphate-buffered saline was added in the appropriate final concentration. Cells were incubated for 30 min at 37 ° C on a shaker, then centrifuged for 5 min at 200 g, the supernatant was removed, the MNC sediment was examined for p65 subunit activity of NF-κB in strict accordance with the instructions for the NFkB p65 TotalMultispecies InstantOne ™ ELISA Kit ( Invitrogen / Thermo Fisher Scientific, cat. 85-86081-11).
МНК крови крыс в количестве 1×106 лизировали в 1 мл лизирующего буфера, входящего в состав набора, супернатант вносили в лунки 96-луночного планшета из указанного ИФА набора. После нескольких этапов продукты сэндвич-реакции определяли на микропланшетном ридере Multiskan FC (Thermo Fisher, Германия) при 450 нм. Rat blood MNCs in the amount of 1 × 106 were lysed in 1 ml of the lysis buffer included in the kit; the supernatant was added to the wells of a 96-well plate from the indicated ELISA kit. After several steps, the products of the sandwich reaction were determined on a Multiskan FC microplate reader (Thermo Fisher, Germany) at 450 nm.
Для упрощения расчетов относительного влияния исследуемых веществ были выбраны единицы оптической плотности, непосредственно получаемые с микропланшетного ридера, округленные до 2-го знака после запятой. Статистическую обработку результатов проводили в программе MS Excel 2013 с модулем Attestatv.13 с применением метода непараметрической статистики – критерия Крускала-Уоллиса, т.к. распределение активности p65 субъединицы NF-κB в клетках не являлось нормальным.To simplify the calculations of the relative influence of the studied substances, we selected units of optical density directly obtained from the microplate reader, rounded to the 2nd decimal place. Statistical processing of the results was carried out in MS Excel 2013 with the Attestatv.13 module using the nonparametric statistics method - the Kruskal-Wallis test, because the distribution of p65 activity of the NF-κB subunit in cells was not normal.
ПРИМЕР КОНКРЕТНОГО ВЫПОЛНЕНИЯEXAMPLE OF SPECIFIC PERFORMANCE
Результаты оценки ингибирующей NF-κB активности исследуемых препаратов представлены в табл. 1 (Медианы – Ме и 1, 3 квартили – Q1; Q3).The results of the evaluation of the inhibitory NF-κB activity of the studied drugs are presented in table. 1 (Medians - Me and 1, 3 quartiles - Q1; Q3).
Как видно из табл. 1, наибольшей ингибирующей способностью на ЛПС-индуцированную экспрессию p65 NF-κB в МНК крови крыс Wistar в исследуемых концентрациях обладает 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноат. Ингибирующая активность NF-κB 2-этил-6-метил-3-гидроксипиридиния L-2,6-диаминогексаноата выше на 34,6%, чем у препарата сравнения мексидола, в конечной концентрации 35 мкг/мл при индуцированной ЛПС активации NF-κВ.As can be seen from the table. 1, 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate possesses the highest inhibitory ability for LPS-induced expression of p65 NF-κB in the blood MNCs of Wistar rats. The inhibitory activity of NF-κB 2-ethyl-6-methyl-3-hydroxypyridinium L-2,6-diaminohexanoate is higher by 34.6% than that of the mexidol comparison drug at a final concentration of 35 μg / ml with LPS-induced NF-κB activation .
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