Tannic acid attenuates hepatic oxidative stress, apoptosis and inflammation by activating the Keap1‑Nrf2/ARE signaling pathway in arsenic trioxide‑toxicated rats

Li,Mengying; Liu,Panpan; Xue,Yucong; Liang,Yingran; Shi,Jing; Han,Xue; Zhang,Jianping; Chu,Xi; Chu,Li

doi:10.3892/or.2020.7764

Tannic acid attenuates hepatic oxidative stress, apoptosis and inflammation by activating the Keap1‑Nrf2/ARE signaling pathway in arsenic trioxide‑toxicated rats

Authors:
- Mengying Li
- Panpan Liu
- Yucong Xue
- Yingran Liang
- Jing Shi
- Xue Han
- Jianping Zhang
- Xi Chu
- Li Chu
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Affiliations: School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China, Department of Pharmacy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
Published online on: September 11, 2020 https://doi.org/10.3892/or.2020.7764
Pages: 2306-2316

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Abstract

The present study was performed to investigate the protective effects of tannic acid (TA) on liver injury induced by arsenic trioxide (ATO) and to elucidate the mechanism involved as related to the Kelch‑like ECH‑associated protein 1 (Keap1)‑nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. Adult rats were intraperitoneally injected with TA, while ATO was administered 1 h later. On the 11th day, the rats were euthanized to determine any liver histological changes, liver function, and the activities of antioxidant, antiapoptosis and proinflammatory cytokines in the liver. Furthermore, the protein expression levels of nuclear Nrf2, total Nrf2, Keap1, Heme oxygenase‑1 (HO‑1), NADPH quinine oxidoreductase‑1 (NQO1), and γ‑glutamylcysteine synthetase (γ‑GCS) were determined using western blot analysis. The results showed that TA treatment ameliorated ATO‑induced liver histological changes and decreased the ATO‑induced increased alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Activities of the antioxidant enzymes significantly were increased, while the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were attenuated following TA treatment. In addition, TA treatment inhibited ATO‑induced liver apoptosis and inflammatory responses, increased Bcl‑2 protein expression level and reduced the levels of Bax, caspase‑3, interleukin (IL)‑1β, IL‑6 and tumor necrosis factor (TNF)‑α. Furthermore, TA treatment increased the protein expression levels of Nrf2 and Keap1, HO‑1, NQO1 and γ‑GCS. The results demonstrated that TA has a protective effect on ATO‑treated hepatic toxicity and that its underlying mechanism could be due to TA activation of the Keap1‑Nrf2/ARE signaling pathway, to reduce oxidative stress, apoptosis and inflammation in ATO‑intoxicated rats.

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1	Kim PG, Bridgham K, Chen EC, Vidula MK, Pozdnyakova O, Brunner AM and Fathi AT: Incident adverse events following therapy for acute promyelocytic leukemia. Leuk Res Rep. 9:79–83. 2018.PubMed/NCBI
2	Benramdane L, Accominotti M, Fanton L, Malicier D and Vallon JJ: Arsenic speciation in human organs following fatal arsenic trioxide poisoning-a case report. Clin Chem. 45:301–306. 1999. View Article : Google Scholar : PubMed/NCBI
3	You BR and Park WH: Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion. Oncol Rep. 28:749–757. 2012. View Article : Google Scholar : PubMed/NCBI
4	Abhilash S, Siviyasankar R, Binu P, Arathi P and Harikumaran Nair R: Different administration patterns of docosahexaenoic acid in combating cytotoxic manifestations due to arsenic trioxide (acute promyelocytic leukemia drug) induced redox imbalance in hepatocytes. Prostaglandins Other Lipid Mediat. 136:64–75. 2018. View Article : Google Scholar : PubMed/NCBI
5	Ahmed S, Mahabbat-e Khoda S, Rekha RS, Gardner RM, Ameer SS, Moore S, Ekstrom EC, Vahter M and Raqib R: Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood. Environ Health Perspect. 119:258–264. 2010. View Article : Google Scholar : PubMed/NCBI
6	Zheng Y, Yamaguchi H, Tian C, Lee MW, Tang H, Wang HG and Chen Q: Arsenic trioxide (As(2)O(3)) induces apoptosis through activation of Bax in hematopoietic cells. Oncogene. 24:3339–3347. 2005. View Article : Google Scholar : PubMed/NCBI
7	Bao J, Ding R, Zou L, Zhang C, Wang K, Liu F, Li P, Chen M, Wan JB, Su H, et al: Forsythiae fructus inhibits B16 melanoma growth involving MAPKs/Nrf2/HO-1 mediated anti-oxidation and anti-inflammation. Am J Chin Med. 44:1043–1061. 2016. View Article : Google Scholar : PubMed/NCBI
8	Liu C, Xu H, Fu S, Chen Y, Chen Q, Cai Z, Zhou J and Wang Z: Sulforaphane ameliorates bladder dysfunction through activation of the Nrf2-ARE pathway in a rat model of partial bladder outlet obstruction. Oxid Med Cell Longev. 2016:75982942016. View Article : Google Scholar : PubMed/NCBI
9	Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, Engel JD and Yamamoto M: Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 40:10228–10239. 2012. View Article : Google Scholar : PubMed/NCBI
10	Liu D, Duan X, Dong D, Bai C, Li X, Sun G and Li B: Activation of the Nrf2 pathway by inorganic arsenic in human hepatocytes and the role of transcriptional repressor Bach1. Oxid Med Cell Longev. 2013:9845462013. View Article : Google Scholar : PubMed/NCBI
11	Zhao HJ, Li MJ, Zhang MP, Wei MK, Shen LP, Jiang M and Zeng T: Allyl methyl trisulfide protected against acetaminophen (paracetamol)-induced hepatotoxicity by suppressing CYP2E1 and activating Nrf2 in mouse liver. Food Funct. 10:2244–2253. 2019. View Article : Google Scholar : PubMed/NCBI
12	Nepka C, Sivridis E, Antonoglou O, Kortsaris A, Georgellis A, Taitzoglou I, Hytiroglou P, Papadimitriou C, Zintzaras I and Kouretas D: Chemopreventive activity of very low dose dietary tannic acid administration in hepatoma bearing C3H male mice. Cancer Lett. 141:57–62. 1999. View Article : Google Scholar : PubMed/NCBI
13	Gray JP, Mishin V, Heck DE and Laskin JD: Dietary tannic acid stimulates production of reactive oxygen intermediates and growth factor and inflammatory gene expression in human colon tumor cells. Cancer Rese. 65:12232005.
14	Ninan N, Forget A, Shastri VP, Voelcker NH and Blencowe A: Antibacterial and anti-inflammatory pH-responsive tannic acid-carboxylated agarose composite hydrogels for wound healing. ACS Appl Mater Interfaces. 8:28511–28521. 2016. View Article : Google Scholar : PubMed/NCBI
15	Jin W, Xue Y, Xue Y, Han X, Song Q, Zhang J, Li Z, Cheng J, Guan S, Sun S and Chu L: Tannic acid ameliorates arsenic trioxide-induced nephrotoxicity, contribution of NF-κB and Nrf2 pathways. Biomed Pharmacother. 126:1100472020. View Article : Google Scholar : PubMed/NCBI
16	Chu X, Wang H, Jiang YM, Zhang YY, Bao YF, Zhang X, Zhang JP, Guo H, Yang F, Luan YC and Dong YS: Ameliorative effects of tannic acid on carbon tetrachloride-induced liver fibrosis in vivo and in vitro. J Pharmacol Sci. 130:15–23. 2016. View Article : Google Scholar : PubMed/NCBI
17	Zhang J, Song Q, Han X, Zhang Y, Zhang Y, Zhang X, Chu X, Zhang F and Chu L: Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid. Int Immunopharmacol. 47:95–105. 2017. View Article : Google Scholar : PubMed/NCBI
18	Chung MY, Song JH, Lee J, Shin EJ, Park JH, Lee SH, Hwang JT and Choi HK: Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. Mol Metab. 9:34–48. 2019. View Article : Google Scholar
19	Krajka-Kuźniak V, Paluszczak J, Szaefer H and Baer-Dubowska W: The activation of the Nrf2/ARE pathway in HepG2 hepatoma cells by phytochemicals and subsequent modulation of phase II and antioxidant enzyme expression. J Physiol Biochem. 71:227–238. 2015. View Article : Google Scholar : PubMed/NCBI
20	Zhang J, Cui L, Han X, Zhang Y, Zhang X, Chu X, Zhang F, Zhang Y and Chu L: Protective effects of tannic acid on acute doxorubicin-induced cardiotoxicity: Involvement of suppression in oxidative stress, inflammation, and apoptosis. Biomed Pharmacother. 93:1253–1260. 2017. View Article : Google Scholar : PubMed/NCBI
21	Hemmati AA, Olapour S, Varzi HN, Khodayar MJ, Dianat M, Mohammadian B and Yaghooti H: Ellagic acid protects against arsenic trioxide-induced cardiotoxicity in rat. Hum Exp Toxicol. 37:412–419. 2017. View Article : Google Scholar : PubMed/NCBI
22	Singh AP, Goel RK and Kaur T: Mechanisms pertaining to arsenic toxicity. Toxicol Int. 18:87–93. 2011. View Article : Google Scholar : PubMed/NCBI
23	Messarah M, Saoudi M, Boumendjel A, Kadeche L, Boulakoud MS and Feki AE: Green tea extract alleviates arsenic-induced biochemical toxicity and lipid peroxidation in rats. Toxicol Ind Health. 29:349–359. 2013. View Article : Google Scholar : PubMed/NCBI
24	Vermeulen NP, Bessems JG and Van De Straat R: Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism-based prevention. Drug Metab Rev. 24:367–407. 1992. View Article : Google Scholar : PubMed/NCBI
25	Basu T, Panja S, Shendge AK, Das A and Mandal N: A natural antioxidant, tannic acid mitigates iron-overload induced hepatotoxicity in swiss albino mice through ROS regulation. Environ Toxicol. 33:603–618. 2018. View Article : Google Scholar : PubMed/NCBI
26	Ahmed SM, Luo L, Namani A, Wang XJ and Tang X: Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Di. 1863:585–597. 2017. View Article : Google Scholar
27	Lushchak IV: Free radicals, reactive oxygen species, oxidative stress and its classification. Chem Biol Interact. 224:164–175. 2014. View Article : Google Scholar : PubMed/NCBI
28	Sumedha NC and Miltonprabu S: Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. Hum Exp Toxicol. 34:506–525. 2015. View Article : Google Scholar : PubMed/NCBI
29	Adedara IA, Adebowale AA, Atanda OE, Fabunmi AT, Ayenitaju AC, Rocha JBT and Farombi EO: Selenium abates reproductive dysfunction via attenuation of biometal accumulation, oxido-inflammatory stress and caspase-3 activation in male rats exposed to arsenic. Environ Pollut. 254:113079–113090. 2019. View Article : Google Scholar : PubMed/NCBI
30	Imam F, Al-Harbi NO, Al-Harbi MM, Ansari MA, Al-Asmari AF, Ansari MN, Al-Anazi WA, Bahashwan S, Almutairi MM, Alshammari M, et al: Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-κB signaling pathways. Pharmacol Rep. 70:993–1000. 2018. View Article : Google Scholar
31	Dash SK, Chattopadhyay S, Ghosh T, Dash SS, Tripathy S, Das B, Bag BG, Das D and Roy S: Self-assembled betulinic acid protects doxorubicin induced apoptosis followed by reduction of ROS-TNF-α-caspase-3 activity. Biomed Pharmacother. 72:144–157. 2015. View Article : Google Scholar : PubMed/NCBI
32	Van Opdenbosch N and Lamkanfi M: Caspases in cell death, inflammation, and disease. Immunity. 50:1352–1364. 2019. View Article : Google Scholar : PubMed/NCBI
33	Oliveira PJ, Santos MS and Wallace KB: Doxorubicin-induced thiol-dependent alteration of cardiac mitochondrial permeability transition and respiration. Biochemistry (Mosc). 71:194–199. 2006. View Article : Google Scholar : PubMed/NCBI
34	Liu W, Gao FF, Li Q, Lv JW, Wang Y, Hu PC, Xiang QM and Wei L: Protective effect of Astragalus polysaccharides on liver injury induced by several different chemotherapeutics in mice. Asian Pac J Cancer Prev. 15:10413–10420. 2014. View Article : Google Scholar : PubMed/NCBI
35	Wu Z, Zhang Y, Song T, Song Q, Zhang Y, Zhang X, Han X, Zhang J and Chu L: Magnesium isoglycyrrhizinate ameliorates doxorubicin-induced acute cardiac and hepatic toxicity via antio-xidant and anti-apoptotic mechanisms in mice. Exp Ther Med. 15:1005–1012. 2018.PubMed/NCBI
36	Miltonprabu S, Sumedha NC and Senthilraja P: Diallyl trisulfide, a garlic polysulfide protects against As-induced renal oxidative nephrotoxicity, apoptosis and inflammation in rats by activating the Nrf2/ARE signaling pathway. Int Immunopharmacol. 50:107–120. 2017. View Article : Google Scholar : PubMed/NCBI
37	Singh S, Vrishni S, Singh BK, Rahman I and Kakkar P: Nrf2-ARE stress response mechanism: A control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases. Free Radic Res. 44:1267–1288. 2010. View Article : Google Scholar : PubMed/NCBI
38	Niture SK and Jaiswal AK: Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 287:9873–9886. 2012. View Article : Google Scholar : PubMed/NCBI
39	Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K and Yamamoto M: Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 7:116242016. View Article : Google Scholar : PubMed/NCBI
40	Katsuragi Y, Ichimura Y and Komatsu M: Regulation of the Keap1-Nrf2 pathway by p62/SQSTM1. Oxidative Toxicology. Johnson J, Puga A, Wallace KB and Zhang D: 1. Current Opinion in Toxicology; pp. 54–61. 2016
41	Shi L, Hao Z, Zhang S, Wei M, Lu B, Wang Z and Ji L: Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: The involvement of ERK1/2 and PKC. Biochem Pharmacol. 150:9–23. 2018. View Article : Google Scholar : PubMed/NCBI
42	Shafik NM and El Batsh MM: Protective effects of combined selenium and punica granatum treatment on some inflammatory and oxidative stress markers in arsenic-induced hepatotoxicity in rats. Biol Trace Elem Res. 169:121–128. 2016. View Article : Google Scholar : PubMed/NCBI
43	Vineetha RC, Archana V, Binu P, Arathi P and Nair RH: L-ascorbic acid and α-Tocopherol reduces hepatotoxicity associated with arsenic trioxide chemotherapy by modulating Nrf2 and Bcl2 transcription factors in chang liver cells. Nutr Cancer. 70:684–696. 2018. View Article : Google Scholar : PubMed/NCBI
44	Ugun-Klusek A, Tatham MH, Elkharaz J, Constantin-Teodosiu D, Lawler K, Mohamed H, Paine SM, Anderson G, John Mayer R, Lowe J, et al: Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway. Cell Death Dis. 8:e25312017. View Article : Google Scholar : PubMed/NCBI
45	Baird L and Dinkova-Kostova AT: The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol. 85:241–272. 2011. View Article : Google Scholar : PubMed/NCBI
46	Takahashi T, Morita K, Akagi R and Sassa S: Heme oxygenase-1: A novel therapeutic target in oxidative tissue injuries. Curr Med Chem. 11:1545–1561. 2004. View Article : Google Scholar : PubMed/NCBI
47	Xu D, Hu L, Xia X, Song J, Li L, Song E and Song Y: Tetrachlorobenzoquinone induces acute liver injury, up-regulates HO-1 and NQO1 expression in mice model: The protective role of chlorogenic acid. Environ Toxicol Pharmacol. 37:1212–1220. 2014. View Article : Google Scholar : PubMed/NCBI
48	Liu X, Chen K, Zhu L, Liu H, Ma T, Xu Q and Xie T: Soyasaponin Ab protects against oxidative stress in HepG2 cells via Nrf2/HO-1/NQO1 signaling pathways. J Functional Foods. 45:110–117. 2018. View Article : Google Scholar
49	Aaseth J, Skaug MA, Cao Y and Andersen O: Chelation in metal intoxication-Principles and paradigms. J Trace Elem Med Biol. 31:260–266. 2015. View Article : Google Scholar : PubMed/NCBI
50	Lau A, Whitman SA, Jaramillo MC and Zhang DD: Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway. J Biochem Mol Toxicol. 27:99–105. 2013. View Article : Google Scholar : PubMed/NCBI