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Thymoquinone Attenuates Acetaminophen Overdose-Induced Acute Liver Injury and Inflammation Via Regulation of JNK and AMPK Signaling Pathway

    https://doi.org/10.1142/S0192415X19500307Cited by:11
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    Abstract

    Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1β release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.

    References

    • Arulkumaran, N., R.J. Unwin and F.W. Tam . A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin. Investig. Drugs 20: 897–915, 2011. Crossref, Medline, Google Scholar
    • Ates, B., L. Abraham and N. Ercal . Antioxidant and free radical scavenging properties of N-acetylcysteine amide (NACA) and comparison with N-acetylcysteine (NAC). Free Radic. Res. 42: 372–377, 2008. Crossref, Medline, Google Scholar
    • Aycan, I.O., A. Tufek, O. Tokgoz, O. Evliyaoglu, U. Firat, G.O. Kavak, H. Turgut and M.U. Yuksel . Thymoquinone treatment against acetaminophen-induced hepatotoxicity in rats. Int. J. Surg. 12: 213–218, 2014. Crossref, Medline, Google Scholar
    • Bai, T., Y. Yang, Y.L. Wu, S. Jiang, J.J. Lee, L.H. Lian and J.X. Nan . Thymoquinone alleviates thioacetamide-induced hepatic fibrosis and inflammation by activating LKB1-AMPK signaling pathway in mice. Int. Immunopharmacol. 19: 351–357, 2014. Crossref, Medline, Google Scholar
    • Blackford, M.G., T. Felter, M.D. Gothard and M.D. Reed . Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: A retrospective review. Clin. Ther. 33: 1322–1330, 2011. Crossref, Medline, Google Scholar
    • Chen, M.C., N.H. Lee, H.H. Hsu, T.J. Ho, C.C. Tu, D.J. Hsieh, Y.M. Lin, L.M. Chen, W.W. Kuo and C.Y. Huang . Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38. J. Agric. Food Chem. 63: 1540–1546, 2015. Crossref, Medline, Google Scholar
    • Darakhshan, S., A. Bidmeshki Pour, A. Hosseinzadeh Colagar and S. Sisakhtnezhad . Thymoquinone and its therapeutic potentials. Pharmacol. Res. 95–96: 138–158, 2015. Crossref, Medline, Google Scholar
    • Das, J., J. Ghosh, P. Manna and P.C. Sil . Acetaminophen induced acute liver failure via oxidative stress and JNK activation: Protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic. Res. 44: 340–355, 2010. Crossref, Medline, Google Scholar
    • Du, K., A. Ramachandran and H. Jaeschke . Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biol. 10: 148–156, 2016. Crossref, Medline, Google Scholar
    • Du, K., Y. Xie, M.R. McGill and H. Jaeschke . Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity. Expert. Opin. Drug. Metab. Toxicol. 11: 1769–1779, 2015. Crossref, Medline, Google Scholar
    • Elshazly, S.M., M.A. El-Moselhy and W. Barakat . Insights in the mechanism underlying the protective effect of alpha-lipoic acid against acetaminophen-hepatotoxicity. Eur. J. Pharmacol. 726: 116–123, 2014. Crossref, Medline, Google Scholar
    • Feng, L., Y. Chen, R. Ding, Z. Fu, S. Yang, X. Deng and J. Zeng . P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: Involvement of peroxynitrite. J. Neuroinflammation 12: 190, 2015. Crossref, Medline, Google Scholar
    • Fujiyoshi, M. and M. Ozaki . Molecular mechanisms of liver regeneration and protection for treatment of liver dysfunction and diseases. J. Hepatobiliary Pancreat. Sci. 18: 13–22, 2011. Crossref, Medline, Google Scholar
    • Gholamnezhad, Z., S. Havakhah and M.H. Boskabady . Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: A review. J. Ethnopharmacol. 190: 372–386, 2016. Crossref, Medline, Google Scholar
    • Green, D.R., L. Galluzzi and G. Kroemer . Cell biology. Metabolic control of cell death. Science 345: 1250256, 2014. Crossref, Medline, ISI, Google Scholar
    • Guldiken, N., Q. Zhou, O. Kucukoglu, M. Rehm, K. Levada, A. Gross, R. Kwan, L.P. James, C. Trautwein, M.B. Omary and P. Strnad . Human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with c-jun amino-terminal kinase activation and protein adduct formation. Hepatology 62: 876–886, 2015. Crossref, Medline, Google Scholar
    • Gunawan, B.K., Z.X. Liu, D. Han, N. Hanawa, W.A. Gaarde and N. Kaplowitz . c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 131: 165–178, 2006. Crossref, Medline, ISI, Google Scholar
    • Hamilton, L.A., A. Collins-Yoder and R.E. Collins . Drug-induced liver injury. AACN Adv. Crit. Care 27: 430–440, 2016. Crossref, Medline, Google Scholar
    • Han, D., L. Dara, S. Win, T.A. Than, L. Yuan, S.Q. Abbasi, Z.X. Liu and N. Kaplowitz . Regulation of drug-induced liver injury by signal transduction pathways: Critical role of mitochondria. Trends Pharmacol. Sci. 34: 243–253, 2013. Crossref, Medline, Google Scholar
    • Hoque, R., M.A. Sohail, S. Salhanick, A.F. Malik, A. Ghani, S.C. Robson and W.Z. Mehal . P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 302: G1171–G1179, 2012. Crossref, Medline, Google Scholar
    • Jaeschke, H., Y. Xie and M.R. McGill . Acetaminophen-induced liver injury: From animal models to humans. J. Clin. Transl. Hepatol. 2: 153–161, 2014. Medline, Google Scholar
    • Jiang, S., Y. Zhang, J.H. Zheng, X. Li, Y.L. Yao, Y.L. Wu, S.Z. Song, P. Sun, J.X. Nan and L.H. Lian . Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation. Pharmacol. Res. 117: 82–93, 2017. Crossref, Medline, Google Scholar
    • Johnson-Ajinwo, O.R. and W.W. Li . Stable isotope dilution gas chromatography-mass spectrometry for quantification of thymoquinone in black cumin seed oil. J. Agric. Food Chem. 62: 5466–5471, 2014. Crossref, Medline, Google Scholar
    • Lee, S.S., J.T. Buters, T. Pineau, P. Fernandez-Salguero and F.J. Gonzalez . Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem. 271: 12063–12067, 1996. Crossref, Medline, Google Scholar
    • Leem, K.H., M.G. Kim, Y.T. Hahm and H.K. Kim . Hypoglycemic effect of Opuntia ficus-indica var. saboten is due to enhanced peripheral glucose uptake through activation of AMPK/p38 MAPK pathway. Nutrients 8: 1–15, 2016. Crossref, Google Scholar
    • Lin, F., M.C. de Gooijer, D. Hanekamp, G. Chandrasekaran, L.C. Buil, N. Thota, R.W. Sparidans, J.H. Beijnen, T. Wurdinger and O. van Tellingen . PI3K-mTOR pathway inhibition exhibits efficacy against high-grade glioma in clinically relevant mouse models. Clin. Cancer Res. 23: 1286–1298, 2017. Crossref, Medline, Google Scholar
    • Liu, X., J. Lian, C.H. Hu and C. Deng . Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKalpha-SREBP-1 and PPARalpha-dependent pathways. Pharmacol. Res. 100: 36–46, 2015. Crossref, Medline, Google Scholar
    • Mao, H., T. Tao, D. Song, M. Liu, X. Wang, X. Liu and D. Shi . Zedoarondiol inhibits platelet-derived growth factor-induced vascular smooth muscle cells proliferation via regulating amp-activated protein kinase signaling pathway. Cell Physiol. Biochem. 40: 1506–1520, 2016. Crossref, Medline, Google Scholar
    • Martin-Murphy, B.V., M.P. Holt and C. Ju . The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol. Lett. 192: 387–394, 2010. Crossref, Medline, ISI, Google Scholar
    • Muhl, H. STAT3, a key parameter of cytokine-driven tissue protection during sterile inflammation — The case of experimental acetaminophen (paracetamol)-induced liver damage. Front. Immunol. 7: 163, 2016. Crossref, Medline, Google Scholar
    • Nagi, M.N., H.A. Almakki, M.M. Sayed-Ahmed and A.M. Al-Bekairi . Thymoquinone supplementation reverses acetaminophen-induced oxidative stress, nitric oxide production and energy decline in mice liver. Food Chem. Toxicol. 48: 2361–2365, 2010. Crossref, Medline, Google Scholar
    • Nakada, D., T.L. Saunders and S.J. Morrison . Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468: 653–658, 2010. Crossref, Medline, Google Scholar
    • National Research Council, Guide for the Care and Use of Laboratory Animals, Washington (DC), 2011. Google Scholar
    • Ni, H.M., A. Bockus, N. Boggess, H. Jaeschke and W.X. Ding . Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55: 222–232, 2012. Crossref, Medline, Google Scholar
    • Nishina, T., S. Komazawa-Sakon, S. Yanaka, X. Piao, D.M. Zheng, J.H. Piao, Y. Kojima, S. Yamashina, E. Sano, T. Putoczki, T. Doi, T. Ueno, J. Ezaki, H. Ushio, M. Ernst, K. Tsumoto, K. Okumura and H. Nakano . Interleukin-11 links oxidative stress and compensatory proliferation. Sci. Signal. 5: ra5, 2012. Crossref, Medline, Google Scholar
    • Park, I.J., W.K. Yang, S.H. Nam, J. Hong, K.R. Yang, J. Kim, S.S. Kim, W. Choe, I. Kang and J. Ha . Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma. Apoptosis 19: 615–628, 2014. Crossref, Medline, Google Scholar
    • Remien, C.H., F.R. Adler, L. Waddoups, T.D. Box and N.L. Sussman . Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: Early discrimination between survival and death. Hepatology 56: 727–734, 2012. Crossref, Medline, Google Scholar
    • Saberi, B., M.D. Ybanez, H.S. Johnson, W.A. Gaarde, D. Han and N. Kaplowitz . Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways. Hepatology 59: 1543–1554, 2014. Crossref, Medline, Google Scholar
    • Saito, C., J.J. Lemasters and H. Jaeschke . c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol. Appl. Pharmacol. 246: 8–17, 2010a. Crossref, Medline, Google Scholar
    • Saito, C., C. Zwingmann and H. Jaeschke . Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51: 246–254, 2010b. Crossref, Medline, ISI, Google Scholar
    • Shin, D., Y. Lee, Y.H. Huang, H.W. Lim, K. Jang, D.D. Kim and C.J. Lim . Probiotic fermentation augments the skin anti-photoaging properties of Agastache rugosa through up-regulating antioxidant components in UV-B-irradiated HaCaT keratinocytes. BMC Complement. Altern. Med. 18: 196, 2018. Crossref, Medline, Google Scholar
    • Tavakkoli, A., V. Mahdian, B.M. Razavi and H. Hosseinzadeh . Review on clinical trials of black seed (Nigella sativa) and its active constituent, thymoquinone. J. Pharmacopuncture 20: 179–193, 2017. Crossref, Medline, Google Scholar
    • Wang, Z., J.N. Hu, M.H. Yan, J.J. Xing, W.C. Liu and W. Li . Caspase-mediated anti-apoptotic effect of ginsenoside rg5, a main rare ginsenoside, on acetaminophen-induced hepatotoxicity in mice. J. Agric. Food Chem. 65: 9226–9236, 2017. Crossref, Medline, Google Scholar
    • Waring, W.S. Novel acetylcysteine regimens for treatment of paracetamol overdose. Ther. Adv. Drug Saf. 3: 305–315, 2012. Crossref, Medline, Google Scholar
    • Williams, C.D., D.J. Antoine, P.J. Shaw, C. Benson, A. Farhood, D.P. Williams, T.D. Kanneganti, B.K. Park and H. Jaeschke . Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury. Toxicol. Appl. Pharmacol. 252: 289–297, 2011. Crossref, Medline, Google Scholar
    • Williams, C.D., A. Farhood and H. Jaeschke . Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. Toxicol. Appl. Pharmacol. 247: 169–178, 2010. Crossref, Medline, Google Scholar
    • Woolbright, B.L. and H. Jaeschke . Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J. Hepatol. 66: 836–848, 2017. Crossref, Medline, Google Scholar
    • Worthen, D.R., O.A. Ghosheh and P.A. Crooks . The in vitro anti-tumor activity of some crude and purified components of blackseed, Nigella sativa L. Anticancer Res. 18: 1527–1532, 1998. Medline, ISI, Google Scholar
    • Xie, Y., C.D. Williams, M.R. McGill, M. Lebofsky, A. Ramachandran and H. Jaeschke . Purinergic receptor antagonist A438079 protects against acetaminophen-induced liver injury by inhibiting p450 isoenzymes, not by inflammasome activation. Toxicol. Sci. 131: 325–335, 2013. Crossref, Medline, Google Scholar
    • Xu, J.J., B.S. Hendriks, J. Zhao and D. de Graaf . Multiple effects of acetaminophen and p38 inhibitors: Towards pathway toxicology. FEBS Lett. 582: 1276–1282, 2008. Crossref, Medline, Google Scholar
    • Yang, Y., T. Bai, P. Sun, L.-H. Lian, Y.-L. Yao, H.-X. Zheng, X. Li, J.-B. Li, Y.-L. Wu and J.-X. Nan . Thymoquinone, a bioactive component of Nigella sativa Linn seeds or traditional spice, attenuates acute hepatic failure and blocks apoptosis via the MAPK signaling pathway in mice. RSC Adv. 5: 7285–7290, 2015. Crossref, Google Scholar
    • Yang, Y., T. Bai, Y.L. Yao, D.Q. Zhang, Y.L. Wu, L.H. Lian and J.X. Nan . Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicol. Lett. 262: 80–91, 2016. Crossref, Medline, Google Scholar
    • Yue, J.L. and X.F. Pan . Chemical constituents of essential oil of Agastache rugosa of northeast China. J. Northeast Forestry Univ. 26: 3, 1998. Google Scholar
    • Zheng, T., X. Yang, D. Wu, S. Xing, F. Bian, W. Li, J. Chi, X. Bai, G. Wu, X. Chen, Y. Zhang and S. Jin . Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3beta pathway. Br. J. Pharmacol. 172: 3284–3301, 2015. Crossref, Medline, Google Scholar
    Published: 12 April 2019
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