Aim: This research studied the effects of glycyrrhizic acid (GA) on apoptosis induced with by titanium dioxide (NTiO2) in the liver of rats.
Background: It is widely accepted that the contamination resulting from nanoparticles (NPs) is an emerging dangerous issue. Metal oxide nanoparticles have high environmental stability and cause toxicity in the food chain. Thus, the present study investigated the anti-apoptotic effects of glycyrrhizic acid (GA) on the hepatotoxicity generated by titanium dioxide (NTiO2) NPs in the liver tissue.
Methods: Thirty-two male Wistar rats were randomly divided into four groups. NTiO2-treated rats were given 300 mg / kg of NTiO2 solution via gavage for 14 days; GA-treated were administered 100 mg/kg GA for 14 days; protection group was pre-treated with GA before NTiO2 administration for 7 days. Then, apoptotic index was evaluated through immunolocalization of Bax and Bcl-2 and TUNEL assay.
Results: we found that HSCORE of Bax expression and apoptotic index experienced a significant increase with NTiO2 (P <0.001), while Bcl-2 expression significantly diminished in NTiO2-treated rats (P <0.001). The results revealed that the increased Bax expression and apoptotic index were reversed by GA and enhanced the activities of Bcl2.
Conclusion: The results revealed that GA effectively attenuated apoptosis against NTiO2 in rats.
Keywords: NTiO2, Immunohistochemistry, TUNEL, Apoptosis, Histopathological.
(Please cite as: Orazizadeh M, Khorsandi LS, Mansouri E, Fakhredini FS. The effect of glycyrrhizin acid on Bax and Bcl2 expression in hepatotoxicity induced by Titanium dioxide nanoparticles in rats. Gastroenterol Hepatol Bed Bench 2020;13(2):168-176).
McGill MR, Du K, Weemhoff JL, Jaeschke H. Critical review of resveratrol in xenobiotic-induced hepatotoxicity. Food Chem Toxicol 2015;86:309-18.
Borm PJ, Kreyling W. Toxicological hazards of inhaled nanoparticles potentialimplications for drug delivery. J Nanosci Nanotechnol 2004;4:521-31.
Chen Y, Xue Z, Zheng D, Xia K, Zhao Y, Liu T, et al. Sodium chloridemodified silica nanoparticles as a non-viral vector with a high efficiency of DNA transfer into cells. Curr Gene Ther 2003;3:273-9.
Fisher J, Egerton TA. Encyclopedia of Chemical Technology. Wiley & Sons, New York 2001.
Kaida T, Kobayashi K, Adachi M, Suzuki F. Optical characteristics of titanium oxide interference film and the film laminated with oxides and their applications for cosmetics. J Cosmet Sci 2004;55:219-20.
Matteo C, Andrea P, Marcella M, Marco P, Chiara F, Francesca B, et al. Titanium Dioxide Nanoparticle Penetration into the Skin and Effects on HaCaT Cells. Int J Environ Res Public Health 2015;12:9282-97.
Schulz J, Hohenberg H, Pflücker F, Gärtner E, Will T, Pfeiffer S, et al. Wittern, Distribution of sunscreens on skin. Adv Drug Deliv Rev 2002;54:157-63.
Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, et al. Extrapulmonary translocation of ultrafine carbon particles followingwhole-body inhalation exposure of rats. J Toxicol Environ Health A 2002; 65:1531-43.
Fabian E, Landsiedel R, Ma-Hock L, Wiench K, Wohlleben W, van Ravenzwaay B. Tissue distribution and toxicity of intravenously administeredtitanium dioxide nanoparticles in rats. Arch Toxicol 2008;82:151-7.
Sugibayashi K, Todo H, Kimura E. Safety evaluation of titanium dioxidenanoparticles by their absorption and elimination profiles. J Toxicol Sci 2008;33:293-8.
Long TC, Tajuba J, Sama P, Saleh N, Swartz C, Parker J, et al. Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro. Health Perspect 2007;115:1631-7.
Wang J, Li N, Zheng L, Wang S, Wang Y, Zhao X, et al. P38-Nrf-2 Signaling Pathway of Oxidative Stress in Mice Caused by Nanoparticulate TiO2. Biol Trace Elem Res 2011; 140:186-97.
Osano E, Kishi J, Takahashi Y. Phagocytosis of titanium particles and necrosis in TNF-alpha-resistant mouse sarcoma L929 cells. Toxicol In Vitro 2003;17:41-7.
Liu HT, Ma LL, Zhao JF, Liu J, Yan JY, Ruan J, et al. Biochemical toxicity of mice caused by nano-anatase TiO2 particles. Biol Trace Elem Res 2009;129:170-80.
Ma LL, Zhao JF, Wang J, Duan YM, Liu J, Li N, et al. The acute liver injury in mice caused by nano-anatase TiO2. Nanoscale Res Lett 2009;4:1275-85.
Li JJ, Muralikrishnan S, Ng CT, Yung LY, Bay BH. Nanoparticle-induced pulmonary toxicity. Exp Biol Med 2012;235:1025-33.
Cui Y, Gong X, Duan Y, Li N, Hu R, Liu H, et al. Hepatocyte apoptosis and its molecular mechanisms in micecaused by titanium dioxide nanoparticles. J Hazard Mater 2010;183:874-80.
Frei B, Higdon JV. Antioxidant activity of tea polyphenols in vivo: evidencefrom animal studies. J Nutr 2003;133:3275-84.
Mehana EE, Meki AR, Fazili KM. Ameliorated effects of green tea extract onlead induced liver toxicity in rats, Exp. Toxicol Pathol 2012; 64:291-5.
Armanini D, De Palo CB, Mattarello MJ, Spinella P, Zaccaria M, Ermolao A, et al. Effect oflicorice on reduction of body fat mass in healthy subjects. J Endocrinol Invest 2003;26:646-50.
Fenwick GR, Lutomski J, Nieman C. Glycyrrhizaglabra L-composition,uses and analysis. Food Chem 1990;38:119-43.
Ma SK, Bae EH, Kim IJ, Choi KC, Kim SH, Lee J, et al. Increased renalexpression of nitric oxide synthase and atrial natriuretic peptide in rats withglycyrrhizic-acid-induced hypertension. Phytother Res 2009;23:206-11.
Racková L, Jancinová V, Petríková M, Drábiková K, Nosál R, Stefek M, et al. Mechanism of anti-inflammatory actionof liquorice extract and glycyrrhizin. Nat Prod Res 2007;21:1234-41.
Kim SW, Jin Y, Shin JH, Kim ID, Lee HK, Park S, et al. Glycyrrhizic acid affords robust neuroprotection in the postischemic brain viaanti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion. Neurobiol Dis 2012;46:147-56.
Ni B, Cao Z, Liu Y. Glycyrrhizin protects spinal cord and reducesinflammation in spinal cord ischemia-reperfusion injury. Int J Neurosci 2013;123:745-51.
Fiore C, Eisenhut M, Krausse R, Ragazzi E, Pellati D, Armanini D, et al. Antiviral effects of Glycyrrhiza species. Phytother Res 2008;22:141-8.
Smolarczyk R, Cichoń T, Matuszczak S, Mitrus I, Lesiak M, Kobusińska M, et al. The role of Glycyrrhizin, an inhibitor ofHMGB1 protein, in anticancer therapy. Arch Immunol Ther Exp 2012;60:391-9.
Li XL, Zhou AG, Zhang L, Chen WJ. Antioxidant status and immune activityof Glycyrrhizin in allergic rhinitis mice. Int J Mol Sci 2011;12:905-16.
Wan XY, Luo M, Li XD, He P. Hepatoprotective and anti-hepatocarcinogeniceffects of glycyrrhizin and matrine. Chem Biol Interact 2009;181:15-9.
Mabuchi A, Wake K, Marlini M, Watanabe H, Wheatley AM. Protection byglycyrrhizin against warm ischemia-reperfusion-induced cellular injury andderangement of the microcirculatory blood flow in the rat liver. Microcirculation 2009;16:364-76.
Lee CH, Park SW, Kim YS, Kang SS, Kim JA, Lee SH, et al. Protectivemechanism of Glycyrrhizin on acute liver injury induced by carbontetrachloride in mice. Biol Pharm Bull 2007; 30:1898-904.
Guo XL, Liang B, Wang XW, Fan FG, Jin J, Lan R, et al. Glycyrrhizic acid attenuates CCl4-induced hepatocyte apoptosis in ratsvia a p53-mediated pathway. World J Gastroenterol 2013;19:3781-91.
Krutovskikh VA, Piccoli C, Yamasaki H. Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene 2002;21:1989-99.
Soufy H, Yassein S, Ahmed AR, Khodier MH, Kutkat MA, Nasr SM, et al. Antiviral and immune stimulant activities of glycyrrhizin against duck hepatitis virus. Afr J Tradit Complement Altern Med 2012;9:389-95.
Tsai JJ, Kuo HC, Lee KF, Tsai TH. Glycyrrhizin represses total parenteralnutrition-associated acute liver injury in rats by suppressing endoplasmicreticulum stress. Int J Mol Sci 2013;14:12563-80.
Zhang R, Niu Y, Li Y, Zhao C, Song B, Li Y, et al. Acute toxicitystudy of the interaction between titanium dioxide nanoparticles and leadacetate in mice, Environ. Toxicol Pharmacol 2010;30:52-60.
Liang XJ, Chen C, Zhao Y, Jia L, Wang PC. Biopharmaceutics andtherapeutic potential of engineered nanomaterials, Curr. Drug Metab 2008;9:697-709.
Khorsandi LS, Hashemitabar M, Orazizadeh M, Albughobeish N. Dexamethasone effects on Fas ligand expression in mouse testicular germ cells. Pak J Biol 2008;11:2231-6.
Orazizadeh M, Khorsandi LS, Hashemitabar M. Toxic effects of dexamethasone on mouse testicular germ cells. Andrologia 2010;42:247-53.
Afkhami-Ardakani M, Shirband A, Golzadeh J, Asadi-Samani M, Latifi E, Kheylapour M, et al. The effect of iron oxide nanoparticles on liver enzymes (ALT, AST and ALP), thyroid hormones (T3 and T4) and TSH in rats. J Shahrekord Univ Med Sci 2013;14:82-8.
Olmedo D, Guglielmotti MB, Cabrini RL. An experimental study of thedissemination of titanium and zirconium in the body. J Mater Sci Mater Med 2002;13:793-6.
Shukla RK, Kumar A, Pandey AK, Singh SS, DhawanA. Titanium dioxide nanoparticles induce oxidative stress-mediated apoptosis in human HepG2 cells. J Biomed Nanotechnol 2011;7:100-1.
Li N, Duan Y, Hong M, Zheng L, Fei M, Zhao X, et al. Spleen injury and apoptotic pathway in mice caused by titanium dioxide nanoparticles. Toxicol Lett 2010;195:161-8.
Kang BPS, Urbonas A, Baddoo A, Baskin S, Malhotra A, Meggs LG. IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose. Am J Physiol Renal Physiol 2003;285:1013-24.
Sohaebuddin SK, Thevenot PT, Baker D, Eaton JW, Tang L. Nanomaterial cytotoxicity is composition, size, and cell type dependent. Part Fibre Toxicol 2010;7:22.
Lemasters JJ. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. Am J Physiol 1999;276:1-6.
Levin S, Bucci TJ, Cohen SM, Fix AS, Hardisty JF, LeGrand EK, et al. The nomenclature of cell death: recommendations of an ad hoc Committee of the Society of Toxicologic Pathologists. Toxicol Pathol 1999;27:484-90.
Gwak GY, Moon TG, Lee DH, Yoo BC. Glycyrrhizin attenuates HMGB1- induced hepatocyte apoptosis by inhibiting the p38-dependent mitochondrial pathway. World J Gastroenterol 2012;18:679-84.
Tang B, Qiao H, Meng F, Sun X. Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats. Braz J Med Biol Res 2007;40:1637-46.
Sadauskas E, Wallin H, Stoltenberg M, Vogel U, Doering P, Larsen A, et al. Kupffer cells are central in the removal of nanoparticles from the organism. Part Fibre Toxicol 2007;4:1-10.
Möller W, Hofer T, Ziesenis A, Karg E, Heyder J. Ultrafine particles cause cytoskeletal dysfunctions in macrophages. Toxicol Appl Pharmacol 2002;182:197-207.
Sun SJ, Yu WQ, Zhang YL, Jiang XQ, Zhang FQ. Effects of TiO2 nanotube layers on RAW 264.7 macrophage behaviour and bone morphogenetic protein-2 expression. Cell Prolif 2013;46:685-94.
Duan Y, Li N, Hong M, Zheng L, Fei M, Zhao X, et al. Spleen injury and apoptotic pathway in mice caused by titanium dioxide nanoparticles .Toxicol Lett 2010;195:161-8.
Kim YA, Lee WH, Choi YH. Involvment of p21WAF1/CIPI, pRB, bax and NF-kappaB in induction of growth arrest and apoptosis by resveratrol in human lung carcinoma A549 cells. Int J Oncol 2010;23:1143-9.