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Quercetin Protects Hepatocytes against CCl4-Induced Apoptosis via SIRT1 Regulation

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Abstract

Quercetin (Que) is a flavonoid compound found ubiquitously in nature with a variety of biological activities, including anti-apoptosis, anti-oxidant, free-radical scavenging, anti-inflammatory and anti-tumor effects. Carbon tetrachloride (CCl4), a commonly used toxic laboratory reagent which causes liver lesion and liver fibrosis, has been extensively applied in liver-related studies. The complex mechanisms of CCl4-induced hepatotoxicity involve apoptosis, oxidative stress, and inflammation. This study aimed to clarify the possible protective effects of Que against CCl4-induced hepatotoxicity using a murine hepatocyte cell culture model. Our results indicate that Que significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Additionally, Que increased cell viability, glutathione (GSH), and superoxide dismutase (SOD) levels. Overall, Que significantly abrogated CCl4-induced cell apoptosis by upregulating the expression of Bcl-2 and decreasing the levels of Bax and cleaved caspase-3. Furthermore, Que obviously reversed the inhibition of Sirtuin 1 (SIRT1) expression. Our results provide the first evidence that Que protected against CCl4-induced apoptosis in hepatocytes by regulating the SIRT1 pathway.

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REFERENCES

  1. Ahadpour, M., Eskandari, M.R., Mashayekhi, V., Tehrani, K.H.M.E., Jafarian, I., Naserzadeh, P., and Hos-seini, M.J., Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria, Drug. Chem. Toxicol., 2016, vol. 39, pp. 224–232.

    Article  CAS  Google Scholar 

  2. Bhadauria, S., Mishra, R., Kanchan, R., Tripathi, C., Srivastava, A., Tiwari, A., and Sharma, S., Isoniazid-induced apoptosis in HepG2 cells: generation of oxidative stress and Bcl-2 down-regulation, Toxicol. Mech. Methods, 2010, vol. 20, pp. 242–251.

    Article  CAS  Google Scholar 

  3. Ebeid, H.M., Gibriel, A.A., Al-Sayed, H.M., Elbehairy, S.A., and Motawe, E.H., Hepatoprotective and antioxidant effects of wheat, carrot, and mango as nutraceutical agents against CCl4-induced hepatocellular toxicity, J. Am. Coll. Nutr., 2015, vol. 34, pp. 228–231.

    Article  CAS  Google Scholar 

  4. Gao, B. and Bataller, R., Alcoholic liver disease: pathogenesis and new therapeutic targets, Gastroenterology, 2011, vol. 141, pp. 1572–1585.

    Article  CAS  Google Scholar 

  5. Guha Mazumder, D.N., Effect of chronic intake of arsenic-contaminated water on liver, Toxicol. Appl. Pharmacol., 2005, vol. 206, pp. 169–175.

    Article  CAS  Google Scholar 

  6. Guo, G., Gong, L., Sun, L., and Xu, H., Quercetin supports cell viability and inhibits apoptosis in cardiomyocytes by downregulation miR-199a, Artif. Cells. Nanomed. Biotechnol., 2019, vol. 47, pp. 2909–2916.

    Article  CAS  Google Scholar 

  7. Huang, Y.J., Lee, C.Y., Cao, J., Lee, H.S., Chang, C.H., Chen, P.D., and Wu, Y.M., Therapeutic potential of plasma proteins derived from umbilical cord blood for acute liver failure, Mol. Pharm., 2019, vol. 16, pp. 1092–1104.

    Article  CAS  Google Scholar 

  8. Ichi, I., Kamikawa, C., Nakagawa, T., Kobayashi, K., Kataoka, R., Nagata, E., Kitamura, Y., Nakazaki, C., Matsura, T., and Kojo, S., Neutral sphingomyelinase-induced ceramide accumulation by oxidative stress during carbon tetrachloride intoxication, Toxicology, 2009, vol. 261, pp. 33–40.

    Article  CAS  Google Scholar 

  9. Iskender, H., Dokumacioglu, E., Sen, T.M., Ince, I., Kanbay, Y., and Saral, S., The effect of hesperidin and quercetin on oxidative stress, NF-κB and SIRT1 levels in a STZ-induced experimental diabetes model, Biomed. Pharmacother., 2017, vol. 90, pp. 500–508.

    Article  CAS  Google Scholar 

  10. Kanter, M., Coskun, O., and Budancamanak, M., Hepatoprotective effects of Nigella sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme systems and liver enzymes in carbon tetrachloride-treated rats, World J. Gastroenterol., 2005, vol. 11, pp. 6684–6688.

    Article  Google Scholar 

  11. Kemelo, M.K., Pierzynova, A., Kutinova Canova, N., Kucera, T., and Farghali, H., The involvement of sirtuin 1 and heme oxygenase 1 in the hepatoprotective effects of quercetin against carbon tetrachloride-induced sub-chronic liver toxicity in rats, Chem. Biol. Interact., 2017, vol. 269, pp. 1–8.

    Article  CAS  Google Scholar 

  12. Kim, J.E., Woo, Y.J., Sohn, K.M., Jeong, K.H., and Kang, H., Wnt/β-catenin and ERK pathway activation: a possible mechanism of photobiomodulation therapy with light-emitting diodes that regulate the proliferation of human outer root sheath cells, Lasers. Surg. Med., 2017, vol. 49, pp. 940–947.

    Article  Google Scholar 

  13. Lei, Y.C., Li, W., and Luo, P., Liuweiwuling tablets attenuate acetaminophen-induced acute liver injury and promote liver regeneration in mice, World J. Gastroenterol., 2015, vol. 21, pp. 8089–8095.

    Article  Google Scholar 

  14. Lin, Y., Sheng, M., Weng, Y., Xu, R., Lu, N., Du, H., and Yu, W., Berberine protects against ischemia/reperfusion injury after orthotopic liver transplantation via activating Sirt1/FoxO3α induced autophagy, Biochem. Biophys. Res. Commun., 2017, vol. 483, p. 885.

    Article  CAS  Google Scholar 

  15. Massey, V.L., Stocke, K.S., Schmidt, R.H., Tan, M., Ajami, N., Neal, R., Petrosino, J.F., Barve, S., and Arteel, G.E., Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction, Toxicol. Appl. Pharmacol., 2015, vol. 284, pp. 304–314.

    Article  CAS  Google Scholar 

  16. Nakamura, K., Zhang, M., Kageyama, S., Ke, B., Fujii, T., Sosa, R.A., Reed, E.F., Datta, N., Zarrinpar, A., Busuttil, R.W., Araujo, J.A., and Kupiec-Weglinski, J.W., Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury, J. Hepatol., 2017, vol. 67, pp. 1232–1242.

    Article  CAS  Google Scholar 

  17. Peng, J., Li, Q., Li, K., Zhu, L., Lin, X., Shen, Q., Li, G., and Xie, X., Quercetin improves glucose and lipid metabolism of diabetic rats: involvement of Akt signaling and SIRT1, J. Diabetes Res., 2017, vol. 2017, p. 3417306.

    Article  Google Scholar 

  18. Preethi, K.C., and Kuttan, R., Hepato and reno protective action of Calendula officinalis L. flower extract, Indian J. Exp. Biol., 2009, vol. 47, pp. 163–168.

    CAS  PubMed  Google Scholar 

  19. Que, X., Zhang, Y., Zhang, S., Zhai, J., Gao, H., Tao, L., and Song, Y., Dysregulation of BSEP and MRP2 may play an important role in isoniazid-induced liver injury via the SIRT1/FXR pathway in rats and HepG2 cells, Biol. Pharm. Bull., 2018, vol. 41, pp. 1211–1218.

    Article  Google Scholar 

  20. Roh, Y.S., Zhang, B., Loomba, R., and Seki, E., TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration, Am. J. Physiol. Gastrointest. Liver Physiol., 2015, vol. 309, pp. G30–G41.

    Article  CAS  Google Scholar 

  21. Sahreen, S., Khan, M.R., Khan, R.A., and Alkreathy, H.M., Cardioprotective role of leaves extracts of Carissa opaca against CCl4 induced toxicity in rats, BMC Res. Notes, 2014, vol. 7, p. 224.

    Article  Google Scholar 

  22. Santra, A., Das, G.J., De, B.K., Roy, B., and Guha Mazumder, D.N., Hepatic manifestations in chronic arsenic toxicity, Indian J. Gastroenterol., 1999, vol. 18, pp. 152–155.

    CAS  PubMed  Google Scholar 

  23. Szymonik-Lesiuk, S., Czechowska, G., Stryjecka-Zimmer, M., Slomka, M., Madro, A., Celinski, K., and Wi-elosz, M., Catalase, superoxide dismutase, and glutathione peroxidase activities in various rat tissues after carbon tetrachloride intoxication, J. Hepatobiliary. Pancreat. Surg., 2003, vol. 10, pp. 309–315.

    Article  Google Scholar 

  24. Tian, R., Yao, C., Yang, C., Zhu, Z., Li, C., Zhi, E., Wang, J., Li, P., Chen, H., Yuan, Q., He, Z., and Li, Z., Fibroblast growth factor-5 promotes spermatogonial stem cell proliferation via ERK and AKT activation, Stem Cell. Res. Ther., 2019, vol. 10, p. 40.

    Article  CAS  Google Scholar 

  25. Tang, Y., Ma, N., Luo, H., Chen, S., and Yu, F., Downregulated long non-coding RNA LINC01093 in liver fibrosis promotes hepatocyte apoptosis via increasing ubiquitination of SIRT1, J. Biochem., 2020, vol. 167, pp. 525–534.

    Article  CAS  Google Scholar 

  26. Tian, X.F., Ji, F.J., Zang, H.L., and Cao, H., Activation of the miR-34a/SIRT1/p53 signaling pathway contributes to the progress of liver fibrosis via inducing apoptosis in hepatocytes but not in HSCs, PLoS One, 2016, vol. 11, e0158657.

    Article  Google Scholar 

  27. Wan, H.F., Li, J.X., Liao H.T., Liao, M.H., Luo, L., Xu, L., Yuan, K.F., and Zeng, Y., Nicotinamide induces liver regeneration and improves liver function by activating SIRT1, Mol. Med. Rep., 2019, vol. 19, pp. 555–562.

    CAS  PubMed  Google Scholar 

  28. Wu, H., Qiu, Y., Shu, Z., Zhang, X., Li, R., Liu, S., Chen, L., Liu, H., and Chen, N., Protective effect of Trillium tschonoskii saponin on CCl4-induced acute liver injury of rats through apoptosis inhibition, Can. J. Physiol. Pharmacol., 2016, vol. 94, pp. 1291–1297.

    Article  CAS  Google Scholar 

  29. Wu, Y., Liu, X., Zhou, Q., Huang, C., Meng, X., Xu, F., and Li, J., Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion, Toxicol. Appl. Pharmacol., 2015, vol. 289, pp. 163−176.

    Article  CAS  Google Scholar 

  30. Zhang, T., Ikejima, T., Li, L., Wu, R., Yuan, X., Zhao, J., Wang, Y., and Peng, S., Impairment of mitochondrial biogenesis and dynamics involved in isoniazid-induced apoptosis of HepG2 cells was alleviated by p38 MAPK pathway, Front. Pharmacol., 2017, vol. 8, p. 753.

    Article  Google Scholar 

  31. Zhang, W., Chen, L., Feng, H., Wang, W., Cai, Y., Qi, F., Tao, X., Liu, J., Shen, Y., Ren, X., Chen, X., Xu, J., and Shen, Y., Rifampicin-induced injury in HepG2 cells is alleviated by TUDCA via increasing bile acid transporters expression and enhancing the Nrf2-mediated adaptive response, Free Radic. Biol. Med., 2017, vol. 112, pp. 24–35.

    Article  CAS  Google Scholar 

  32. Zhang, Y., Zhang, W., Tao, L., Zhai, J., Gao, H., Song, Y., and Qu, X., Quercetin protected against isoniazide-induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway, J. Biochem. Mol. Toxicol., 2019, vol. 33, e22369.

    PubMed  Google Scholar 

  33. Zhao, Q., Liu, F., Cheng, Y., Xiao, X.R., Hu, D.D., Tang, Y.M., Bao, W.M., Yang, J.H., Jiang, T.J., Hu, P., Gonzalez, F.J., and Li, F., Celastrol protects from cholestatic liver injury through modulation of SIRT1-FXR signaling, Mol. Cell. Proteomics, 2019, vol. 18, pp. 520–533.

    Article  CAS  Google Scholar 

  34. Zhu, W., Chen, S., Li, Z., Zhao, X., Li, W., Sun, Y., Zhang, Z., Ling, W., and Feng, X., Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice, Nutr. Metab. (Lond)., 2014, vol. 11, p. 35.

    Article  Google Scholar 

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Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03028112), and Advancement of Science and Creativity (KOFAC) Grant funded by the Korea government (MEST).

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Contributions

S. H. Kim (So Hyun Kim): working with cell experiments, receiving hepatocytes, sample preparation, statistical processing, writing text, analysis of cytometry results, statistical data processing; J. C. Lee (Jae Chul Lee): the concept and design of the study, writing, editing and approval of the final version of the article, responsibility for the integrity of all parts of the article.

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Correspondence to J. C. Lee.

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The authors declare that they have no conflict of interest.

This article does not contain any results of studies involving animal or human material as an object of investigation performed by any author within this work.

Additional information

Abbreviations: ALT—alanine aminotransferase, AST—aspartate aminotransferase, CCl4—carbon tetrachloride, GSH—glutathione, Que—quercetin, SOD—superoxide dismutase.

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Kim, S.H., Lee, J.C. Quercetin Protects Hepatocytes against CCl4-Induced Apoptosis via SIRT1 Regulation. Cell Tiss. Biol. 15, 381–387 (2021). https://doi.org/10.1134/S1990519X21040039

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