Thymoquinone attenuates doxorubicin-induced lung damage via heat shock proteins, inflammation and endoplasmic reticulum stress


Publiée : Jul 4, 2023
Versions :
2023-07-04 (1)
E Öztürk
https://orcid.org/0000-0003-0756-0329
E Kaymak
AT Akin
D Karabulut
B Yakan
Résumé

The aim of this study is to determine possible therapeutic effects of THQ on doxorubicin induced lung damage in rats. Rats were divided into five groups (n = 8): control, THQ, olive oil, DOX (a single dose of 15 mg/kg intraperitoneally (i.p.) on seventh day of the experiment), and DOX+THQ (10 mg/kg THQ per day and 15 mg/kg DOX i.p. on seventh day). Animals were euthanized, and lung tissues were evaluated histopathologically. Caspase3, GRP78, GADD153, HSP90, HSP70, PCNA, COX2 and TNFα immunostaining were performed to determine the expression levels of these proteins among groups. TUNEL method was used for evaluation of apoptotic index. Moreover, total antioxidant status (TAS), total oxidant status (TOS) and IL6 in lung tissue were measured by ELISA assay. The DOX group had histopathological deterioration compared to the control group. There was an increase in apoptotic index, caspase 3, GRP78, GADD153, HSP90, HSP70, PCNA, COX2 and TNFα expressions in the DOX group. While TAS level of the DOX group decreased, IL6 and TOS level increased when compared with the other groups. However, there was improvement in lung tissue in DOX + THQ group compared to the DOX group. There was a decrease in apoptotic index, caspase 3, GRP78, GADD153, HSP90, HSP70, PCNA, COX2, TNFα expressions and TOS, IL6 in DOX+THQ group compared to the DOX group. We suggest that THQ can be used as a protective agent to reduce the toxic effects of DOX.

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Références
Ahmed, F.; Urooj, A. & Karim, A.A. Protective effects of Ficus racemosa
stem bark against doxorubucin-induced renal and testicular toxicity.
Pharmacogn Mag., 9(34):130-134, 2013.
Al-Gabri, N.A.; Qaid, M.M.; El-Shaer, N.H.; Ali, M.H. & Abudabos, AM.
Thymoquinone ameliorates pulmonary vascular damage induced
byEscherichia coli-derived lipopolysaccharide via cytokine downregulation in rats. Environ Sci Pollut Res Int., 26(18):18465-18469,
Alzohairy MA, Khan AA, Alsahli MA, Almatroodi SA, Rahmani AH.
Protective Effects of Thymoquinone, an Active Compound of Nigella sativa, on Rats with Benzo(a)pyrene-induced Lung Injury through
Regulation of Oxidative Stress and Inflammation. Molecules.,
(11):3218, 2021.
Bhandary, B.; Marahatta, A.; Kim, H.R. & Chae, H.J. An involvement
of oxidative stress in endoplasmic reticulum stress and its associated
diseases. Int J Mol Sci., 14(1):434-456, 2012.
Boskabady M, Khazdair MR, Bargi R, Saadat S, Memarzia A, Mohammadian Roshan N, Hosseini M, Askari VR, Boskabady MH. Thymoquinone Ameliorates Lung Inflammation and Pathological Changes
Observed in Lipopolysaccharide-Induced Lung Injury. Evid Based
Complement Alternat Med., 2021: 6681729, 2021.
Chen, Y.; Tang, Y.; Xiang, Y.; Xie, Y.Q.; Huang, X.H. & Zhang, Y.C.
Shengmai injection improved doxorubicin-induced cardiomyopathy by alleviating myocardial endoplasmic reticulum stress and
caspase-12 dependent apoptosis. Biomed Res Int., 2015:952671,
Ciocca, D.R. & Calderwood, S.K. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress
Chaperones., 10(2):86-103, 2005.
Darakhshan, S.; Pour, A.B.; Colagar, A.H. & Sisakhtnezhad, S. Thymoquinone and its therapeutic potentials. Pharmacol Res., 95-96:138-
, 2015.
Gao, G.; Jiang, S.; Ge, L.; Zhang, S.; Zhai, C.; Chen, W. & Sui, S. Atorvastatin Improves Doxorubicin-Induced Cardiac Dysfunction by
Modulating Hsp70, Akt, and MAPK Signaling Pathways. J Cardiovasc Pharmacol., 73(4):223-231, 2019.
Hinz, B. & Brune, K. Cyclooxygenase-2--10 years later. J Pharmacol Exp
Ther., 300(2):367-375, 2002.
Iurlaro, R. & Muñoz-Pinedo, C. Cell death induced by endoplasmic reticulum stress. Febs J., 283(14):2640-2652, 2016.
Jo, C.H.; Kim, S.; Park, J.S. & Kim, G.H. Anti-Inflammatory Action of
Sitagliptin and Linagliptin in Doxorubicin Nephropathy. Kidney
Blood Press Res., 43(3):987-999, 2018.
Karabulut D, Ozturk E, Kuloglu N, Akin AT, Kaymak E & Yakan B. Effects of vitamin B12 on methotrexate hepatotoxicity: evaluation of receptor-interacting protein (RIP) kinase. Naunyn Schmiedebergs Arch
Pharmacol., 393(12):2473-2480, 2020.
Kelleni, M.T.; Amin, E.F. & Abdelrahman, A.M. Effect of Metformin
and Sitagliptin on Doxorubicin-Induced Cardiotoxicity in Rats: Impact of Oxidative Stress, Inflammation, and Apoptosis. J Toxicol.,
:424813, 2015.
Molehin, O.R.; Adeyanju, A.A.; Adefegha, S.A.; Oyeyemi, A.O.; Idawu
KA Protective mechanisms of protocatechuic acid against doxorubicin-induced nephrotoxicity in rat model. J Basic Clin Physiol Pharmacol., 30(4), 2019.
Norbury, C.J. & Hickson, I.D. Cellular responses to DNA damage. Annu
Rev Pharmacol Toxicol., 41:367-401, 2001.
Öztürk, E.; Kaymak, E.; Akin, A.T.; Karabulut, D.; Unsal, H.M. & Yakan, B. Thymoquinone is a protective agent that reduces the negative
effects of doxorubicin in rat testis. Hum Exp Toxicol., 39(10):1364-
, 2020.
Pecoraro, M.; Sorrentino, R.; Franceschelli, S.; Pizzo, M.D.; Pinto, A. &
Popolo, A. Doxorubicin-Mediated Cardiotoxicity: Role of Mitochondrial Connexin 43. Cardiovasc Toxicol., 15(4):366-76, 2015.
Radli, M. & Rüdiger, S.G.D. Dancing with the Diva: Hsp90-Client Interactions. J Mol Biol., 430:3029-3040, 2018.
Roy, P.S. & Saikia, B.J. Cancer and cure: A critical analysis. Indian J
Cancer., 53(3):441-442, 2016.
Schopf, F.H.; Biebl, M.M. & Buchner, J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol., 18(6):345-360, 2017.
So, J.S. Roles of Endoplasmic Reticulum Stress in Immune Responses.
Mol Cells., 41(8):705-716, 2018.
Srdjenovic B, Milic-Torres V, Grujic N, Stankov K, Djordjevic A, Vasovic V. Antioxidant properties of fullerenol C60(OH)24 in rat kidneys,
testes, and lungs treated with doxorubicin. Toxicol Mech Methods,
(6):298-305, 2010.
Suddek, G.M.; Ashry, N.A. & Gameil, N.M. Thymoquinone attenuates
cyclophosphamide-induced pulmonary injury in rats. Inflammopharmacology., 21(6):427-35, 2013.
Take G, Yamaç D, Ozoğul C, Erdogan D. Ultrastructural damage
in lung tissues in rats treated with doxorubicin and paclitaxel. Adv
Ther. 25(2):115-22, 2008.
Wang, Y.; Sun, Y.; Guo, X.; Fu, Y.; Long, J.; Wei, C.X. & Zhao, M. Creatine phosphate disodium salt protects against Dox-induced cardiotoxicity by increasing calumenin. Med Mol Morphol., 51(2):96-101,
Yetkin NA, Büyükoğlan H, Sönmez MF, Tutar N, Gülmez I, Yilmaz I.
The protective effects of thymoquinone on lung damage caused by
cigarette smoke. Biotech Histochem., 95(4):268-275, 2020.
Zhang, X.J.; Cao, X.Q.; Zhang, C.S. & Zhao, Z. 17β-estradiol protects
against doxorubicin-induced cardiotoxicity in male Sprague-Dawley
rats by regulating NADPH oxidase and apoptosis genes. Mol Med
Rep, 15(5):2695-2702, 2017