Zuhal UÇKUN ŞAHİNOĞULLARI, Sevda GÜZEL, Necmiye CANACANKATAN, Cem YALAZA, Deniz KİBAR, Gulsen BAYRAK

Naringenin Reduces Hepatic Inflammation and Apoptosis Induced by Vancomycin in Rats

Objective: This investigation aimed to detect the possible protective impacts of naringenin (NAR) on vancomycin (VCM)-induced liver toxicity through measuring caspase-3, -8 and -9 activities as markers of apoptosis and the levels of tumor necrosis factor-alpha, cyclooxygenase-2 and vascular endothelial growth factor as inflammation markers and assessing the histopathological alterations in rats. Methods: The rats were allocated into seven groups as, the control group (saline, intraperitoneally (i.p.)), VCM group (400 mg/kg/day, i.p.), Carboxymethyl cellulose group (0.5% CMC, orally), NAR100 group (100 mg/kg/day, orally), VCM+NAR25 group (25 mg/kg/day, orally), VCM+NAR50 group (50 mg/kg/day, orally), VCM+NAR100 group (100 mg/kg/day, orally). The caspase enzyme activities and inflammation markers were measured using colorimetric methods and ELISA, respectively. Histopathological examinations were performed. Results: The caspase activities and levels of inflammation markers were significantly higher in the VCM group as opposed to the other groups. The caspase activities were significantly ameliorated in the VCM+NAR25 group compared to the VCM+NAR50 and VCM+NAR100 groups, but the levels of inflammation markers were significantly attenuated in VCM+NAR50 group and, especially, VCM+NAR100 group compared to VCM+NAR25 group. Conclusion: NAR has potential protective impact on liver injury caused by VCM, and the protective impacts of NAR at distinct doses may occur via different molecular mechanisms.

Keywords:

Vancomycin, Naringenin, Liver, Apoptosis, Inflammation,

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Ponte ML, Flores Lazdin C, Fernandez Acuña JM, Noferi LN, Tosi EJ, Manzano DC, et al. Drug-Induced Hepatotoxicity. ECGDS 2017;2:440-443.
David S, Hamilton JP. Drug-induced Liver Injury. US Gastroenterol Hepatol Rev 2010; 6:73-80.
Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB. Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother 2018;105:981-991.
Bruniera FR, Ferreira FM, Savioli LR, Bacci MR, Feder D, Pereira EC, et al. Endothelial, renal and hepatic variables in wistar rats treated with vancomycin. An Acad Bras Cienc 2014;86:1963-1972.
Uckun Z, Guzel S, Canacankatan N, Yalaza C, Kibar D, Coskun Yilmaz B. Potential protective effects of naringenin against vancomycin-induced nephrotoxicity via reduction on apoptotic and oxidative stress markers in rats. Drug Chem Toxicol 2020;43(1):104-111.
Sahin M, Cam H, Olgar S, Tunc SE, Arslan C, Uz E, et al. Protective role of erdosteine on vancomycin-induced oxidative stress in rat liver. Mol Cell Biochem 2006;291:155-160.
Cano A, Cifuentes L, Amariles P. Structured Literature Review of Hepatic Toxicity Caused by Medicines. Rev Colomb Gastroenterol 2017;32(4):337-348.
Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, et al. The Role of Oxidative Stress and Antioxidants in Liver Diseases. Int J Mol Sci 2015;16:26087-26124.
Wang C, Fan RQ, Zhang YX, Nie H, Li K. Naringenin protects against isoniazid-and rifampicin-induced apoptosis in hepatic injury. World J Gastroenterol 2016;22:9775-9783.
Renugadevi J, Prabu SM. Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol 2010;62:171-181.
Jayaraman J, Namasivayam N. Naringenin modulates circulatory lipid peroxidation, anti-oxidant status and hepatic alcohol metabolizing enzymes in rats with ethanol induced liver injury. Fundam Clin Pharmacol 2011;25:682-689.
Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J Gastroenterol 2018; 24:1679-1707.
Esmaeili MA, Alilou M. Naringenin attenuates CCl4 -induced hepatic inflammation by the activation of an Nrf2-mediated pathway in rats. Clin Exp Pharmacol Physiol 2014; 41:416-422.
Mershiba SD, Dassprakash MV, Saraswathy SD. Protective effect of naringenin on hepatic and renal dysfunction and oxidative stress in arsenic intoxicated rats. Mol Biol Rep 2013; 40:3681-3691.
Wang J, Yang Z, Lin L, Zhao Z, Liu Z, Liu X. Protective effect of naringenin against lead-induced oxidative stress in rats. Biol Trace Elem Res 2012;146:354-359.
Lv Y, Zhang B, Xing G, Wang F, Hu Z. Protective effect of naringenin against acetaminophen-induced acute liver injury in metallothionein (MT)-null mice. Food Funct 2013;4:297-302.
Fouad AA, Albuali WH, Zahran A, Gomaa W. Protective effect of naringenin against gentamicin-induced nephrotoxicity in rats. Environ Toxicol Pharmacol 2014;38:420-429.
Gnanasoundari M, Pari L. Impact of naringenin on oxytetracycline-mediated oxidative damage in kidney of rats. Ren Fail 2006;28:599-605.
Konishi H, Morita Y, Mizumura M, Iga I, Nagai K. Difference in nephrotoxicity of vancomycin administered once daily and twice Daily in rats. J Chemother 2013;25:273-278.
Nishino Y, Takemura S, Minamiyama Y, Hirohashi K, Tanaka H, Inoue M, et al. Inhibition of vancomycin-induced nephrotoxicity by targeting superoxide dismutase to renal proximal tubule cells in the rat. Redox Rep 2002;7:317-319.
Sahu BD, Tatireddy S, Koneru M, Borkar RM, Kumar JM, Kuncha M, et al. Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection. Toxicol Appl Pharmacol 2014;277:8-20.
Guzel S, Uckun Sahinogullari Z, Canacankatan N, Antmen SE, Kibar D, Bayrak G. The ameliorating effect of silymarin against vancomycin-induced apoptosis and inflammation in rat liver. J Res Pharm 2019;23:719-728.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265-275.
Guicciardi ME, Malhi H, Mott JL, Gores GJ. Apoptosis and necrosis in the liver. Compr Physiol 2013;3:977-1010.
Sak K. Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn Rev 2014;8:122-146.
Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol 2013;59:583-594.
Chtourou Y, Fetoui H, Jemai R, Ben Slima A, Makni M, Gdoura R. Naringenin reduces cholesterol-induced hepatic inflammation in rats by modulating matrix metalloproteinases-2, 9 via inhibition of nuclear factor κB pathway. Eur J Pharmacol 2015;746:96-105.
Dou W, Zhang J, Sun A, Zhang E, Ding L, Mukherjee S, et al. Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4/NF-κB signalling. Br J Nutr 2013;110: 599–608.
Aristatile B, Al-Assaf AH, Pugalendi KV. Carvacrol suppresses the expression of inflammatory marker genes in D-galactosamine-hepatotoxic rats. Asian Pac J Trop Med 2013;6(3):205-211.
Martín-Sanz P, Casado M, Boscá L. Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives. World J Gastroenterol 2017;23:3572-3580.
Jayaraman J, Jesudoss VA, Menon VP, Namasivayam N. Anti-inflammatory role of naringenin in rats with ethanol induced liver injury. Toxicol Mech Methods 2012; 22:568–576.
Dong D, Xu L, Yin L, Qi Y, Peng J. Naringin prevents carbon tetrachloride-induced acute liver injury in mice. J Funct Foods 2015;12:179-191.
Reinders ME, Sho M, Izawa A, Wang P, Mukhopadhyay D, Koss KE, et al. Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J Clin Invest 2003; 112:1655-1665.
Chen HJ, Hu MH, Xu FG, Xu HJ, She JJ, Xia HP. Understanding the inflammation-cancer transformation in the development of primary liver cancer. Hepatoma Res 2018;4:29.
Cao L, Quan XB, Zeng WJ, Yang XO, Wang MJ. Mechanism of Hepatocyte Apoptosis. J Cell Death 2016;9:19-29.
Subramanian P, Arul D. Attenuation of NDEA-induced hepatocarcinogenesis by naringenin in rats. Cell Biochem Funct 2013;31:511-517.
Hernández-Aquino E, Zarco N, Casas-Grajales S, Ramos-Tovar E, Flores-Beltrán RE, Arauz J, et al. Naringenin prevents experimental liver fibrosis by blocking TGFβ-Smad3 and JNK-Smad3 pathways. World J Gastroenterol 2017;23:4354-4368.
Yilma AN, Singh SR, Morici L, Dennis VA. Flavonoid naringenin: a potential immunomodulatory for Chlamydia trachomatis inflammation. Mediators Inflamm 2013; 2013:102457.
Del Campo JA, Gallego P, Grande L. Role of inflammatory response in liver diseases: Therapeutic strategies. World J Hepatol 2018;10:1-7.
Azam S, Jakaria M, Kim IS, Kim IS, Kim J, Haque ME, et al. Regulation of Toll-Like Receptor (TLR) Signaling Pathway by Polyphenols inthe Treatment of Age-Linked Neurodege- nerative Diseases: Focus on TLR4 Signaling. Front Immunol 2019;10:1000.
Humanes B, Jado JC, Camaño S, López-Parra V, Torres AM, Álvarez-Sala LA, et al. Protective effects of cilastatin against vancomycin-induced nephrotoxicity. Biomed Res Int 2015;704382.
Gupta A, Biyani M, Khaira A. Vancomycin nephrotoxicity: myths and facts. Neth J Med 2011;69:379-383.
Chen Y, Yang XY, Zeckel M, Killian C, Hornbuckle K, Regev A, Voss S. Risk of hepatic events in patients treated with vancomycin in clinical studies: a systematic review and meta-analysis. Drug Saf 2011;34:73-82.