Chrysanthemum extract attenuates hepatotoxicity via inhibiting oxidative stress in vivo and in vitro
Background: ‘Bianliang ziyu’, a famous chrysanthemum variety commonly planted in Kaifeng, China, is often consumed by local residents. However, the hepatoprotective effects of Bianliang ziyu and their underlying mechanisms are not clear.
Objective: In this study, we investigated the hepatoprotective and antioxidative effects of Bianliang ziyu extract (BZE) on liver injury and explored its molecular mechanisms.
Design: Sprague-Dawley rats were administered BZE by intragastric administration for 8–9 days, and then alcohol or carbon tetrachloride (CCl4) was administered by gavage to induce acute liver injury. The activities of serum alanine aminotransferase, aspartate aminotransferase, superoxide dismutase, and malondialdehyde in the rats were measured, and the liver of each rat was examined for histopathological changes. In vitro, HL-7702 cells were pretreated with BZE for 24 h and then exposed to 30 mmol•L−1 acetaminophen (APAP) for 12 h. The survival rate of the cells and the alanine aminotransferase and aspartate aminotransferase activities were determined. Then, we investigated the effects of BZE on oxidative stress, apoptosis, and the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling in HL-7702 cells induced by APAP.
Results: The results showed that BZE prevented alcohol-, CCl4-, and APAP-induced liver injury and suppressed hepatic oxidative stress in vitro and in vivo. BZE was also observed to significantly inhibit the reduction of mitochondrial membrane potential and regulate the expression of Bcl-2, Bax and Caspase-3 in APAP-induced HL-7702 cells. In addition, BZE significantly promoted nuclear translocation and the expression of Nrf2 as well as its downstream gene hemeoxygenase-1 (HO-1) in vitro. Furthermore, the findings showed that Nrf2 siRNA reversed the effects of BZE on cell survival and apoptosis-related protein expression in APAP-induced HL-7702 cells.
Conclusions: BZE plays an important role in preventing hepatotoxicity by inhibiting oxidative stress and apoptosis through activation of Nrf2 signaling. BZE could be developed as an effective functional food for protecting the liver.
- Hamid M, Liu D, Abdulrahim Y, Liu Y, Qian G, Khan A, et al. Amelioration of CCl4-induced liver injury in rats by selenizing Astragalus polysaccharides: Role of proinflammatory cytokines, oxidative stress and hepatic stellate cells. Res Vet Sci 2017; 11(4): 202–211. DOI: 10.1016/j.rvsc.2017.05.002.
- Sánchez-Valle V, Chávez-Tapia NC, Uribe M, Méndez-Sánchez N. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem 2012; 19(28): 4850–4860. DOI: 10.2174/092986712803341520.
- Ibrahim SRM, Elagamy DS, Mohamed H, Ahmed N, Elkablawy M, Mohamed G. Protective activity of tovophyllin A, a xanthone isolated from Garcinia mangostana pericarps against acetaminophen-induced hepatic damage: Role of Nrf2 activation. Food & Function 2018; 9(6): 3291–3300. DOI: 10.1039/c8fo00378e.
- Teschke R, Danan G. systematic review: Drug induced liver injury: Alternative causes in case series as confounding variables. Br J Clin Pharmacol 2018; 84(7): 1467–1477. DOI: 10.1111/bcp.13593.
- Elgawish RAR, Rahman HGA, Abdelrazek HMA. Green tea extract attenuates CCl4-induced hepatic injury in male hamsters via inhibition of lipid peroxidation and p53-mediated apoptosis. Toxicology Reports 2015; 2(C): 1149–1156. DOI: 10.1016/j.toxrep.2015.08.001.
- Gesslbauer B, Bochkov V. Biochemical targets of drugs mitigating oxidative stress via redox-independent mechanisms. Biochem Soc T 2017; 45(6): 1225–1252. DOI: 10.1042/BST20160473.
- Marotta F, Yadav H, Gumaste U, Helmy A, Jain S, Minelli E. Protective effect of a phytocompound on oxidative stress and DNA fragmentation against paracetamol-induced liver damage. Annals of Hepatology 2009; 8(1): 50–56. DOI: 10.0000/PMID19221534.
- Bartosz G. Reactive oxygen species: Destroyers or messengers?. Biochem Pharmacol 2009; 77(8): 1303–1315. DOI: 10.1016/j.bcp.2008.11.009.
- Shi J, Aisaki K, Ikawa Y, Wake K. Evidence of Hepatocyte Apoptosis in Rat Liver after the Administration of Carbon Tetrachloride. Am J Pathol 1998; 153(2): 515–525. DOI: 10.1016/s0002–9440(10)65594–0.
- Volkmann N, Marassi F M, Newmeyer D D, Hanein D. The rheostat in the membrane: BCL-2 family proteins and apoptosis. Cell Death & Differentiation 2014; 21(2): 206–215. DOI: 10.1038/cdd.2013.153.
- Khan RA, Khan MR, Sumaira S. CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. Bmc Complementary & Alternative Medicine 2012; 12(1): 178–184. DOI: 10.1186/1472-6882-12-178.
- Cong P, Liu Y, Liu N, Zhang Y, Tong C, Shi L, et al. Cold exposure induced oxidative stress and apoptosis in the myocardium by inhibiting the Nrf2-Keap1 signaling pathway. Bmc Cardiovascular Disorders 2018; 18(1): 36. DOI: 10.1186/s12872-018-0748-x.
- Ji LL, Sheng YC, Zheng ZY, Shi L, Wang ZT. The involvement of p62-Keap1-Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radical Biology & Medicine 2015; 8512–23. DOI: 10.1016/j.freeradbiomed.2015.03.035.
- Shi L, Hao Z, Zhang S, Wei M, Lu B, Wang Z, et al. Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: the involvement of ERK1/2 and PKC. Biochem Pharmacol 2018; 1509–23. DOI: 10.1016/j.bcp.2018.01.026.
- Xie ZY, Xiao ZH, Wang FF. Inhibition of autophagy reverses alcohol-induced hepatic stellate cells activation through activation of Nrf2-Keap1-ARE signaling pathway. Biochimie 2018; 14755–62. DOI: 10.1016/j.biochi.2017.12.013.
- Hajra S, Patra AR, Basu A, Bhattacharya S. Prevention of doxorubicin (DOX)-induced genotoxicity and cardiotoxicity: Effect of plant derived small molecule indole-3-carbinol (I3C) on oxidative stress and inflammation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 10(1): 228–243. DOI: 10.1016/j.biopha.2018.02.088.
- Wang M, Zhang XJ, Feng R, Jiang Y, Zhang DY, He C, et al. Hepatoprotective properties of Penthorum chinense Pursh against carbon tetrachloride-induced acute liver injury in mice. Chinese Medicine 2017; 12(1): 32–43. DOI: 10.1186/s13020-017-0153-x.
- Wang Y, Li L, Wang Y, Zhu X, Jiang M, Song E, et al. New application of the commercial sweetener rebaudioside a as a hepatoprotective candidate: induction of the Nrf2 signaling pathway. Eur J Pharmacol 2018; 82(2): 128–137. DOI: 10.1016/j.ejphar.2018.01.020.
- Jing J, Teschke R. Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury. Journal of Clinical & Translational Hepatology 2018; 6(1): 57–68. DOI: 10.14218/JCTH.2017.00033.
- Wu WH, Tsai PJ, Chang ML, Chuang CC, Hsin CM, Chuang LT. Antilipotoxicity Activity of Osmanthus fragransand Chrysanthemum morifolium Flower Extracts in Hepatocytes and Renal Glomerular Mesangial Cells. Mediators Inflamm. 2017; 2017(23): 1–12. DOI: 10.1155/2017/4856095.
- Wang P, Pan X, Chen G, Li J, Liu L, Liu X, et al. Increased exposure of vitamin A by Chrysanthemum morifolium Ramat extract in rat was not via induction of CYP1A1, CYP1A2, and CYP2B1. J Food Sci 2012; 77(6): H121–H127. DOI: 10.1111/j.1750-3841.2012.02732.x.
- Cui Y, Wang X, Xue J, Liu J, Xie M. Chrysanthemum morifolium extract attenuates high-fat milk-induced fatty liver through peroxisome proliferator-activated receptor α-mediated mechanism in mice. Nutr Res 2014; 34(3): 268–275. DOI: 10.1016/j.nutres.2013.12.010.
- Gildawie KR, Galli RL, Shukitt-Hale B, Carey AN. Protective Effects of Foods Containing Flavonoids on Age-Related Cognitive Decline. Current Nutrition Reports 2018; 7(2): 1–10. DOI: 10.1007/s13668-018-0227-0.
- Sultana B, Yaqoob S, Zafar Z, Bhatti H N. Escalation of liver malfunctioning: A step toward Herbal Awareness. J Ethnopharmacol 2018; 21(6): 104–119. DOI: 10.1016/j.jep.2018.01.002.
- Uchida NS, Silvafilho SE, Cardia GFE, Cremer E, Silva EL, Bersaniamado C A, et al. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice. Evidence-Based Complementray and Alternative Medicine 2017; 2017: 1–9. DOI: 10.1155/2017/1796209.
- Lugohuitrón R, Blancoayala T, Ugaldemuñiz P, Carrillomora P, Pedrazachaverrí J, Silvaadaya D, et al. On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicology & Teratology 2011; 33(5): 538–547. DOI: 10.1016/j.ntt.2011.07.002.
- Dwivedi S, Saquib Q, Al-Khedhairy AA, Ahmad J, Siddiqui MA, Musarrat J. Rhamnolipids functionalized AgNPs-induced oxidative stress and modulation of toxicity pathway genes in cultured MCF-7 cells. Colloids & Surfaces B Biointerfaces 2015; 132: 290–298. DOI: 10.1016/j.colsurfb.2015.05.034.
- Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkovakostova A T, et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radical Biology & Medicine 2015; 88(Pt B): 108–146. DOI: 10.1016/j.freeradbiomed.2015.06.021.
- Gong G, Yin L, Yuan L, Sui D, Sun Y, Fu H, et al. Ganglioside GM1 protects against high altitude cerebral edema in rats by suppressing the oxidative stress and inflammatory response via the PI3K/AKT-Nrf2 pathway. Mol Immunol 2018; 9591–98. DOI: 10.1016/j.molimm.2018.02.001.
- Wu T, Li J, Li Y, Song H. Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon Tetrachloride-Induced Hepatotoxicity via the Nrf2/HO-1 Pathway. Cellular Physiology & Biochemistry International Journal of Experimental Cellular Physiology Biochemistry & Pharmacology 2017; 41(6): 2242–2254. DOI: 10.1159/000475639.
- Adachi M, Ishii H. Role of mitochondria in alcoholic liver injury. Free Radical Biology & Medicine 2002; 32(6): 487–491. DOI: org/10.1093/alcalc/agm089.
- Ma JQ, Liu CM, Wei Y. Protective effect of rutin against carbon tetrachloride-induced oxidative stress, inflammation and apoptosis in mouse kidney associated with the ceramide, MAPKs, p53 and calpain activities. Chem-Biol Interact 2018; 286: 26–33. DOI: 10.1016/j.cbi.2018.03.003.
- Ma JQ, Ding J, Zhang L, Liu CM. Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. Clinics & Research in Hepatology & Gastroenterology 2015; 39(2): 188–197. DOI: 10.1016/j.clinre.2014.09.007.
- Ma JQ, Ding J, Xiao ZH, Liu CM. Puerarin ameliorates carbon tetrachloride-induced oxidative DNA damage and inflammation in mouse kidney through ERK/Nrf2/ARE pathway. Food & Chemical Toxicology 2014; 71: 264–271. DOI: 10.1016/j.fct.2014.06.017.
- Mahmoud AM, Mohammed HM, Khadrawy SM, Galaly SR. Hesperidin protects against chemically induced hepatocarcinogenesis via modulation of Nrf2/ARE/HO-1, PPARγ and TGF-β1/Smad3 signaling, and amelioration of oxidative stress and inflammation. Chem-Biol Interact 2017; 277: 146–158. DOI: 10.1016/j.cbi.2017.09.015.
- Ming K, Chen Y, Shi J, Yang J, Yao F, Du H, et al. Effects of Chrysanthemum indicum polysaccharide and its phosphate on anti-duck hepatitis a virus and alleviating hepatic injury. Int J Biol Macromol 2017; 102: 813–821. DOI: 10.1016/j.ijbiomac.2017.04.093.
- Tetuya S, Kiharu I. Identification of major flavonoids in petals of edible chrysanthemum flowers and their suppressive effect on carbon tetrachloride-induced liver injury in mice. Food Science & Technology Research 2009; 15(5): 499–506. DOI: 10.3136/fstr.15.499.
- Lozovoy MA, Simão AN, Panis C, Rotter MA, Reiche EM, Morimoto HK, et al. Oxidative stress is associated with liver damage, inflammatory status, and corticosteroid therapy in patients with systemic lupus erythematosus. Lupus 2011; 20(12): 1250–1259. DOI: 10.1177/0961203311411350.
- Adewusi EA, Afolayan AJ. Effect of Pelargonium reniforme roots on alcohol-induced liver damage and oxidative stress. Pharm Biol 2010; 48(9): 980–987. DOI: 10.3109/13880200903410354.
- Liu Z, Meng F, Li C, Zhou X, Zeng X, He Y, et al. Human umbilical cord mesenchymal stromal cells rescue mice from acetaminophen-induced acute liver failure. Cytotherapy 2014; 16(9): 1207–1219. DOI: 10.1016/j.jcyt.2014.05.018.
- Lavrik IN. Systems biology of apoptosis signaling networks. Curr Opin Biotech 2010; 21(4): 551–555. DOI: 10.1016/j.copbio.2010.07.001.
- Ferrín G, Linares CI, Muntané J. Mitochondrial drug targets in cell death and cancer. Curr Pharm Design 2011; 17(20): 2002–2016. DOI: 10.2174/138161211796904803.
- Reusche N, Beineke A, Urhausen C, Beyerbach M, Schmicke M, Kramer S, et al. Proliferative and apoptotic changes in the healthy canine endometrium and in cystic endometrial hyperplasia. Theriogenology 2018; 114: 14–24. DOI: 10.1016/j.theriogenology.2018.03.018.
- Birkinshaw RW, Czabotar PE. The BCL-2 family of proteins and mitochondrial outer membrane permeabilisation. Semin Cell Dev Biol 2017; 72: 152–162. DOI: 10.1016/j.semcdb.2017.04.001.
- Peñablanco A, Garcíasáez AJ. Bax, Bak and beyond: mitochondrial performance in apoptosis. Febs Journal 2017; 285(3): 416–431. DOI: 10.1111/febs.14186.
- Reisman SA, Aleksunes LM, Klaassen CD. Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. Biochem Pharmacol 2009; 77(7): 1273–1282. DOI: org/10.1016/j.bcp.2008.12.028.
- Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, et al. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 2001; 59(1): 169–177. DOI: 10.1137/S0363012903428664.
- Sompakdee V, Prawan A, Senggunprai L, Kukongviriyapan U, Samathiwat P, Wandee J, et al. Suppression of Nrf2 confers chemosensitizing effect through enhanced oxidant-mediated mitochondrial dysfunction. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 101: 627–634. DOI: 10.1016/j.biopha.2018.02.112.
- Steel RJ, O’Connell MA, Searcey M. Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction. Bioorg Med Chem Lett 2018; 255: 23–30. DOI: 10.1016/j.bmcl.2018.03.003.
- Zou B, Xiao G, Xu Y, Wu J, Yu Y, Fu M. Persimmon vinegar polyphenols protect against hydrogen peroxide-induced cellular oxidative stress via Nrf2 signalling pathway. Food Chem 2018; 255: 23–30. DOI: 10.1016/j.foodchem.2018.02.028.
- Verma AK, Yadav A, Singh SV, Mishra P, Rath SK. Isoniazid induces apoptosis: Role of oxidative stress and inhibition of nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Life Sci 2018; 199: 23–33. DOI: 10.1016/j.lfs.2018.02.037.
- Zhang HJ, Chen RC, Sun GB, Yang LP, Zhu YD, Xu XD, et al. Protective effects of total flavonoids from Clinopodium chinense (Benth.) O. Ktze on myocardial injury in vivo and in vitro via regulation of Akt/Nrf2/HO-1 pathway. Phytomedicine International Journal of Phytotherapy & Phytopharmacology 2018; 40: 88–97. DOI: 10.1016/j.phymed.2018.01.004.
- Qu LL, Yu B, Li Z, Jiang WX, Jiang JD, Kong WJ. Gastrodin Ameliorates Oxidative Stress and Proinflammatory Response in Nonalcoholic Fatty Liver Disease through the AMPK/Nrf2 Pathway. Phytother Res 2016; 30(3): 402–411. DOI: 10.1002/ptr.5541.
- Zhang Y, Qiao R, He D, Zhao Z, Yang S, Zou H, et al. Indazolo[3,2-b]quinazolinones attack hepatocellular carcinoma Hep3B cells by inducing mitochondrial-dependent apoptosis and inhibition of Nrf2/ARE signaling pathway. Current Molecular Medicine 2016; 16(9): 820–828. DOI: 10.2174/1566524016666161128114444.
- Lin G, Luo D, Liu J, Wu X, Chen J, Huang Q, et al. Hepatoprotective Effect of Polysaccharides Isolated fromDendrobium officinaleagainst Acetaminophen-Induced Liver Injury in Mice via Regulation of the Nrf2-Keap1 Signaling Pathway. Oxidative Medicine & Cellular Longevity 2018; 2018: 1–10. DOI: 10.1155/2018/6962439.
- Pang C, Zheng Z, Shi L, Sheng Y, Wei H, Wang Z, et al. Caffeic acid prevents acetaminophen-induced liver injury by activating the Keap1-Nrf2 antioxidative defense system. Free Radical Biology & Medicine 2016; 91: 236–246. DOI: 10.1016/j.freeradbiomed.2015.12.024.
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