Water-soluble phenol TS-13 combats acute but not chronic inflammation

Menshchikova, E. B.; Tkachev, Victor; Lemza, A. E.; Sharkova, T. V.; Кандалинцева, Н. В.; Вавилин, В. А.; Safronova, O. G.; Зенков, Н. К.

doi:10.1007/s00011-014-0746-0

Cited by 13 publications

(8 citation statements)

References 33 publications

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“…tBHQ inhibits IL-2 and CD25 expression, which correlates with decreased NFκB transcriptional activity in the cell [56]. As for treatment with TS-13, also has an anti-inflammation activity [33], we shown downregulation of p50 and p65 subunits of NFkB [34]. …”

Section: Discussionmentioning

confidence: 95%

“…In particular, some phenolic antioxidants, namely, classic phase II inducers, have an anti-inflammatory effect [9, 27, 28], which is thought to be mediated by activation of Nrf2 [29, 30], inhibition of nuclear factor κB (NFkB; a key regulator of immune and inflammatory responses) [27, 30, 31], and by influence on MAPKs engaged in complex crosstalk between Nrf2 and NFkB pathways [32]. The anti-inflammatory effect of TS-13 was shown on in vivo models of acute inflammation [33]. We have recently shown that the mechanism of this effect may be related to downregulation of p65 and p50 subunits of NFkB and reduced phosphorilation of activating transcription factor 2 (ATF-2) [34].…”

Section: Introductionmentioning

confidence: 99%

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The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate of sodium

et al. 2017

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Tert-butylhydroquinone (tBHQ) is a highly effective phenolic antioxidant used in edible oils and fats in foods as well as in medicines and cosmetics. TBHQ has been shown to have both chemoprotective and carcinogenic effects. Furthermore, it has potential anti-inflammatory, antiatherogenic, and neuroprotective activities. TBHQ induces phase II detoxification enzymes via the Keap1/Nrf2/ARE mechanism, which contributes to its chemopreventive functions. Nonetheless, there is growing evidence that biological effects of tBHQ may be mediated by Nrf2-independent mechanisms related to various signaling cascades. Here, we studied changes in gene expression of phase I, II, and III drug metabolizing enzymes/transporters as well as protein levels and activities of cytochromes P450 (CYPs) elicited by tBHQ and its structural homolog TS-13 in the mouse liver. Next, we carried out gene expression analysis to identify signal transduction pathways modulated by the antioxidants. Mice received 100 mg/kg tBHQ or TS-13 per day or only vehicle. The liver was collected at 12 hours and after 7 days of the treatment. Protein and total RNA were extracted. Gene expression was analyzed using Mouse Drug Metabolism and Signal Transduction PathwayFinder RT2Profiler™PCR Arrays. A western blot analysis was used to measure protein levels and a fluorometric assay was employed to study activities of CYPs. Genes that were affected more than 1.5-fold by tBHQ or TS-13 treatment compared with vehicle were identified. Analysis of the gene expression data revealed changes in various genes that are important for drug metabolism, cellular defense mechanisms, inflammation, apoptosis, and cell cycle regulation. Novel target genes were identified, including xenobiotic metabolism genes encoding CYPs, phase II/III drug metabolizing enzymes/transporters. For Cyp1a2 and Cyp2b, we observed an increase in protein levels and activities during tBHQ or TS-13 treatment. Changes were found in the gene expression regulated by NFκB, androgen, retinoic acid, PI3K/AKT, Wnt, Hedgehog and other pathways.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate of sodium

et al. 2017

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“…рис. 5) на клетках линии J774 и ранее на клетках аденокарциномы молочной железы человека MCF-7 [20]), in vivo увеличивать экспрессию мРНК, содержание белка и активность GSTP1, а также образование комплексов ядерных белков с олигонуклеотидной последовательностью, соответствующей ARE (гель-ретардационный анализ) [21]).…”

Section: результаты и их обсуждениеunclassified

Effect of new water-soluble phenolic antioxidants on the activity of Nrf2-driven enzymes, glutathione system, and Nrf2 translocation into the nucleus

Menshchikova¹,

Зенков²,

Кожин³

et al. 2020

SSMJ

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Understanding the role of reactive oxygen and nitrogen species in eustress (redox balance) and distress (oxidative stress) development poses new challenges for biomedical scientists and pharmacologists in the search for compounds that can not only have a direct antioxidant (antiradical) effect, but also affect redox-sensitive signaling pathways, primarily Keap1/Nrf2/ARE system. Aim of the study was to investigate the influence of novel water-soluble structurally related monophenols on key elements of Keap1/Nrf2/ARE system induction (activity of Nrf2-driven enzymes, the state of the glutathione system, and intracellular redistribution of transcription factor Nrf2). Material and methods. Five original hydrophilic structurally related monophenols, differing in the number of tert-butyl ortho-substituents, the length of the para-alkyl substituent, and the presence of a divalent sulfur or selenium atom in it were investigated (phenoxane, the potassium salt of phenosan acid, was used as a reference compound). Cell lines U937 and J774 were cultured for 24 h in the presence of tested compounds, and comparative analysis was performed of its ability to induce the synthesis of Nrf2-driven enzymes of phase II xenobiotic detoxification pathway and antioxidant enzymes (NAD(P)H: quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST), glutathione peroxidases, glutathione reductase (biochemical spectrophotometric methods were used to study their activity), as well as to influence the state of glutathione system (spectrophotometry) and translocation of transcription factor Nrf2 into the nucleus (immunofluorescent staining, confocal microscopy) (key events of Keap1/Nrf2/ARE signaling system activation). Results and discussion. Monophenol TS-13 have found to be the most effective inducer of tested enzymes in U937 cells among the structural analogs, while the structure of the para-alkyl substituent and the degree of OH group hindrance are important for the implementation of this effect; TS-13 also effectively enhanced Nrf2 import into J774 cell nucleus. The NQO1-and GST-inducing abilities of structurally related monophenols are closely interrelated, which indicates the possibility of coordinated induction of these enzymes and the presence of a common regulatory system that ensures their activation in response to cell treatment with phenolic antioxidants.

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“…Существует общее мнение, что Nrf2 оказывает протективный эффект в отношении системных инфекций за счет влияния на NF-κB и модулирования экспрессии провоспалительных генов в макрофагах [16]. Ранее показано, что оригинальный синтетический монофенол ТС-13, индуцирующий Nrf2зависимый сигнальный путь в экспериментах in vitro [3] и in vivo [8] и ингибирующий NF-κBопосредованный сигналинг in vivo [14], обладает выраженным защитным эффектом in vivo в отношении острых воспалительных процессов, увеличивая выживаемость животных при септическом шоке [8].…”

Section: рис 1 динамика выживаемости мышей после инфицирования M Tunclassified

“…На 30 сутки после инфицирования в печени животных, получавших с питьевой водой антиоксидант ТС-13, наблюдалось достоверное снижение численной плотности гранулем (в 2,5 раза) и их диаметра (на 30 %). В экспериментах на мышах и крысах показано, что ТС-13 обладает выраженным защитным эффектом in vivo в отношении острых воспалительных процессов, способствуя уменьшению продукции АКМ и выраженности окислительного стресса, увеличивая выживаемость животных (септический шок) [8].…”

unclassified

Monophenol Ts-13 Improves Survival in Mice Infected With Virulent Mycobacterium Tuberculosis

2018

SSMJ

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Water-soluble phenol TS-13 combats acute but not chronic inflammation

Abstract: The data suggest that the anti-inflammatory effects of Keap1/Nrf2/ARE system are more prominent against acute innate-mediated inflammation than chronic immune inflammation. This narrows the potential therapeutic efficacy of ARE inducers in inflammation treatment.

Cited by 13 publications

References 33 publications

The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate of sodium

The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate of sodium

Effect of new water-soluble phenolic antioxidants on the activity of Nrf2-driven enzymes, glutathione system, and Nrf2 translocation into the nucleus

Monophenol Ts-13 Improves Survival in Mice Infected With Virulent Mycobacterium Tuberculosis

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