The Effect of Glutathione on Regulatory and Protective Signaling Pathways during Endotoxemia in the Rat Uterus
V.R. Strutynskyi, L.A. Mys, R.I. Yanchiy
- Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz72.01.053

Abstract
Lipopolysaccharide triggers an inflammatory response,
oxidative stress, alterations in protein and receptor expression,
and disruptions to metabolic pathways, all of which affect
physiological processes in the uterus and impair the
reproductive ability of animals. Endotoxin significantly
increases oxytocin-induced uterine contractile activity, which
can disrupt the course of pregnancy and cause premature birth.
Our work aimed to determine the mRNA expression of genes
encoding oxytocin receptors, antioxidant and H
2
S-synthesizing
enzymes, as well as the Kir6.x subunit of ATP-sensitive
potassium channels (K
ATP
channels) in uterine tissues of female
rats after intraperitoneal administration of lipopolysaccharide
and glutathione. mRNA expression was determined by reverse
transcription and real-time PCR. Lipopolysaccharide was
administered intraperitoneally at a dose of 3 mg/kg one day
before removing the animals from the experiment. Glutathione
was injected intraperitoneally at a dose of 52 mg/kg
twice: one hour before lipopolysaccharide administration
and one day later. It was shown that lipopolysaccharide
led to a significant increase in the expression levels of
mRNA of genes encoding oxytocin receptors (by 4.6
times), the antioxidant enzyme catalase (by 3.3 times), the
H
2
S-synthesizing enzyme cystathionine-γ-lyase (by 5.8
times), and the Kir6.1 subunit of K
ATP
channels (by 2.4
times) in rat uterine tissue, and at the same time reduced
the expression levels of the antioxidant enzyme superoxide
dismutase (by 38%). Glutathione normalized the expression
of oxytocin receptors, superoxide dismutase, and catalase
to control values, partially prevented the increase in the
expression of cystathionine-γ-lyase, had practically no effect
on the expression of Kir6.1, and, conversely, suppressed the
expression of Kir6.2 (by 3.6 times). Thus, the early stages of
Вплив глутатіону на регуляторні та захисні сигнальні шляхи при ендотоксемії у матці щурів
59
lipopolysaccharide-induced endotoxemia are characterized, on
the one hand, by the development of inflammation, oxidative
stress, and increased expression of oxytocin receptors, and
on the other hand, by the activation of protective processes in
the body as a mechanism of adaptation to the inflammation.
Glutathione prevented lipopolysaccharide-induced changes,
suggesting its possible use in endotoxemia to prevent
reproductive disorders in animals.
Keywords:
glutathione, lipopolysaccharide, uterus, gene expression, oxytocin receptor, antioxidant enzymes, ATP-sensitive potassium channels, H2S, endotoxemia
References
- Skrzypczak-Wiercioch A, Sałat K. Lipopolysaccharide-induced model of neuroinflammation: mechanisms of action, research application and future directions for its use. Molecules. 2022 Aug 26;27(17):5481. doi: 10.3390/ molecules27175481
CrossRef
PubMed PubMedCentral
- Lu D, Hu W, Tian T, Wang M, Zhou M, Wu C. The mechanism of lipopolysaccharide's effect on secretion of endometrial mucins in female mice during pregnancy. Int J Mol Sci. 2022 Sep 1;23(17):9972.
CrossRef
PubMed PubMedCentral
- Bariani MV , Correa F, Leishman E, Domínguez Rubio AP, Arias A, Stern A, Bradshaw HB, Franchi AM. Resveratrol protects from lipopolysaccharide-induced inflammation in the uterus and prevents experimental preterm birth. Mol Hum Reprod. 2017 Aug 1;23(8):571-81.
CrossRef
PubMed PubMedCentral
- Hadi T, Bardou M, Mace G, Sicard P, Wendremaire M, Barrichon M, et al. Glutathione prevents preterm parturition and fetal death by targeting macrophageinduced reactive oxygen species production in the myometrium. FASEB J. 2015 Jun;29(6):2653-66. doi: 10.1096/fj.14-266783.
CrossRef
PubMed
- Yurttancikmaz ET, Ozcan P, Tanoglu FB, Tok OE, Timur HT, Cetin C. protective effect of glutathione administration on ovarian function in female rats with cyclophosphamide-induced ovarian damage. Gynecol Obstet Invest. 2024;89(2):120-30. doi: 10.1159/000536055.
CrossRef
PubMed PubMedCentral
- Strutynskyi VR, Diachuk OI, Yanchiy RI. The effect of glutathione on oxytocin-induced contractile activity and basal tone of the rat uterine myometrium under conditions of endotoxemia. Fiziol Zh. 2025;71(2):77-83. [Ukrainian]. doi:CrossRef
CrossRef
- Homma T, Fujii J. Application of glutathione as anti-oxidative and anti-aging drugs. Curr Drug Metab. 2015;16(7):560-71.
CrossRef
PubMed
- Guoyao Wu, Yun-Zhong Fang, Sheng Yang, Joanne R Lupton, Nancy D Turner. Glutathione metabolism and its implications for health. J Nutr. 2004 Mar;134(3):489-92.
CrossRef
PubMed
- Strutynska N, Goshovska Y, Mys L, Strutynskyi R, Luchkova A, Fedichkina R, Okhai I, Korkach Y , Sagach V . Glutathione restores the mitochondrial redox status and improves the function of the cardiovascular system in old rats. Front Physiol. 2023 Jan 9;13:1093388. doi: 10.3389/fphys.2022.1093388.
CrossRef
PubMed PubMedCentral
- Kim JY, Wu WH, Jun JH, Sohn J, Seo YS. Effects of corticotropin-releasing hormone on the expression of adenosine triphosphate-sensitive potassium channels (Kir6.1/SUR2B) in human term pregnant myometrium. Obstet Gynecol Sci. 2018 Jan;61(1):14-22. doi: 10.5468/ ogs.2018.61.1.14.
CrossRef
PubMed PubMedCentral
- Xu C, You X, Gao L, Zhang L, Hu R, Hui N, Olson DM, Ni X. Expression of ATP-sensitive potassium channels in human pregnant myometrium. Reprod Biol Endocrinol. 2011 Mar 21;9:35. doi: 10.1186/1477-7827-9-35.
CrossRef
PubMed PubMedCentral
- Xingji You, Zixi Chen, Huina Zhao , Chen Xu, Weina Liu, Qianqian Sun, Ping He, Hang Gu, Xin Ni. Endogenous hydrogen sulfide contributes to uterine quiescence during pregnancy. Reproduction. 2017 May;153(5):535-43. doi: 10.1530/REP-16-0549.
CrossRef
PubMed
- Ross RG, Sathishkumar K, Naik AK, Bawankule DU, Sarkar SN, Mishra SK, Prakash VR. Mechanisms of lipopolysaccharide-induced changes in effects of contractile agonists on pregnant rat myometrium. Am J Obstet Gynecol. 2004 Feb;190(2):532-40.
CrossRef.1016/S0002-9378(03)00949-9
PubMed
- Yulia A, Johnson MR. Myometrial oxytocin receptor expression and intracellular pathways. Minerva Ginecol. 2014 Jun;66(3):267-80.
- Strutynskyi R, Strutynska N, Mys L, Goshovska Y, Korkach Y, Fedichkina R, Okhai I, Strutynskyi V, Sagach V. Glutathione upregulates the expression of K ATP channels and vasorelaxation responses and inhibits mPTP opening and oxidative stress in the heart mitochondria of old rats. Biomed Res Int. 2023 May 24;2023:3562847. doi: 10.1155/2023/3562847.
CrossRef
PubMed PubMedCentral
- Strutynskyi VR, Diachuk OI, Yanchiy RI. Activation of ATP-sensitive potassium channels suppresses excessive oxytocin-induced contractile activity in rat uterine myometrium under conditions of endotoxemia. Fiziol Zh. 2025;71(5):31-7. [Ukrainian]. doi: https://doi. org/10.15407/fz71.05.031
CrossRef
- Strutynskyi VR, Yanchiy RI. Effect of lipopolysaccharide on the contractility of the uterine myometrium of rats ex vivo. Fiziol Zh. 2025;71(4):38-45. [Ukrainian]. doi: https://doi. org/10.15407/fz71.04.038
CrossRef
- Strutynska NA, Goshovska YV , Korkach YP, Mys LA, Strutynskyi RB, Sagach VF. Effects of glutathione on the expression of ATP-sensitive potassium channels, mitochondrial pores, and on oxidative stress in the heart of old rats. Fiziol Zh. 2020; 66(6): 66-73. [Ukrainian]. CrossRef
CrossRef
- Shepel E, Grushka N, Makogon N, Sribna V , Pavlovych S, Yanchii R. Changes in DNA integrity and gene expression in ovarian follicular cells of lipopolysaccharide-treated female mice. Pharmacol Rep. 2018 Dec;70(6):1146-9. doi: 10.1016/j.pharep.2018.06.005. Epub 2018 Jun 20. PMID: 30317130.
CrossRef
PubMed
- Method for modeling systemic endotoxemia in Albino mice. Patent of Ukraine No. 139296 from December 26, 2019. [Ukrainian].
- Chang EY, Zhang J, Sullivan S, Newman R, Singh I. N-acetylcysteine prevents preterm birth by attenuВ.Р. Струтинський, Л.А. Мись, Р.І. Янчій 60 ating the LPS-induced expression of contractile associated proteins in an animal model. J Matern Fetal Neonatal Med. 2012 Nov;25(11):2395-400. doi: 10.3109/14767058.2012.697942.
CrossRef
PubMed
- Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs. Physiol Rev. 2023 Jan 1;103(1):31-276. doi: 10.1152/physrev.00028.2021.
CrossRef
PubMed
- You X, Chen Z, Zhao H, Xu C, Liu W, Sun Q, He P, Gu H, Ni X. Endogenous hydrogen sulfide contributes to uterine quiescence during pregnancy. Reproduction. 2017 May;153(5):535-43. doi: 10.1530/REP-16-0549.
CrossRef
PubMed
- Strutynskyi R, Strutynska N, Piven O, Mys L, Goshovska Y, Fedichkina R, Okhai I, Strutynskyi V, Dosenko V, Dobrzyn P, Sagach V. Upregulation of ATP-sensitive potassium channels as a potential mechanism of cardioprotection and vasorelaxation under the action of pyridoxal-5-phosphate in old rats. J Cardiovascul Pharmacol Ther. 2023 Jan-Dec; 28: 10742484231213175. doi: 10.1177/10742484231213175
CrossRef
PubMed
- Mys L, Goshovska Y , Strutynska N, Fedichkina R, Kor-kach Y , Strutynskyi R, Sagach V . Pyridoxal-5-phosphate induced cardioprotection in aging associated with upexpression of cystathionine-γ-lyase, 3-mercaptopyruvate sulfurtransferase, and ATP-sensitive potassium channels. Eur J Clin Invest. 2022 Feb;52(2):e13683. doi: 10.1111/ eci.13683.
CrossRef
PubMed
- Corsello T, Komaravelli N, Casola A. Role of hydrogen sulfide in NRF 2 - and sirtuin-dependent maintenance of cellular redox balance. Antioxidants (Basel). 2018; 7(10):129.
CrossRef
PubMed PubMedCentral
- Strutyns'kyĭ RB, Kotsiuruba A V , Neshcheret OP, Rove-nets' RA, Moĭbenko OO. The changes of metabolism in myocardium at ischemia-reperfusion and activating of the ATP-sensitive potassium channels. Fiziol Zh. 2012;58(1):13-26. [Ukrainian]. doi: https://doi. org/10.15407/fz58.01.013
- Strutyns'kyĭ RB, Kotsiuruba AV, Rovenets' RA, Stru-tyns'ka NA, Iagupols'kyĭ IuL, Sagach VF, Moĭbenko OO. Biochemical mechanisms of the cardioprotective effect of the K(ATP) channels opener flocalin (medicinal form) in ischemia-reperfusion of myocardium. Fiziol Zh. 2013;59(4):16-27. [Ukrainian]. doi: https://doi. org/10.15407/fz59.04.016
CrossRef
PubMed
- Strutyns'kyĭ RB, Kotsiuruba A V , Neshcheret OP, Shysh AM, Rovenets' RA, Moĭbenko OO. Cardioprotective effects of activation of ATP-sensitive potassium channels in experiments in vivo: influence on blood biochemical parameters following ischemia-reperfusion of the myocardium. Fiziol Zh . 2009;55(6):12-9. [Ukrainian].
- Curley M, Cairns MT, Friel AM, McMeel OM, Morrison JJ, Smith TJ. Expression of mRNA transcripts for ATPsensitive potassium channels in human myometrium. Mol Hum Reprod. 2002 Oct;8(10):941-5. doi: 10.1093/ molehr/8.10.941.
CrossRef
PubMed
- Hong SH, Kyeong KS, Kim CH, Kim YC, Choi W, Yoo RY , Kim HS, Park YJ, Ji IW, Jeong EH, Kim HS, Xu WX, Lee SJ. Regulation of myometrial contraction by ATP-sensitive potassium (KATP) channel via activation of SUR2B and Kir 6.2 in mouse. J Vet Med Sci. 2016 Aug 1;78(7):1153-9. doi: 10.1292/jvms.15-0700.
CrossRef
PubMed PubMedCentral
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