Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Naringenin suppresses aluminum-induced experimental hepato-nephrotoxicity in mice through modulation of oxidative stress and inflammation

  • Ravina Rai (Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University) ;
  • Zaved Ahmad (Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University) ;
  • Subodh Kumar Jain (Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University) ;
  • Deepali Jat (Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University) ;
  • Siddhartha Kumar Mishra (Department of Biochemistry, University of Lucknow)
  • Received : 2022.11.30
  • Accepted : 2023.08.17
  • Published : 2024.01.15
⟨ Previous Next ⟩

Abstract

Aluminum is a widely used metal substance in daily life activities that has been shown to cause severe hepato-nephrotoxicity with long-term exposure. Natural dietary flavonoids are being utilized as a newer pharmaceutical approach against various acute and chronic diseases. Naringenin (NAR) has shown efficient therapeutic properties, including effects against metal toxicities. However, the protective efficacy of NAR on aluminum chloride (AlCl3)-induced hepato-renal toxicity needs investigation as aluminum has shown serious environmental toxicity and bioaccumulation behavior. In this study, mice were treated with AlCl3 (10 mg/kg b.w./day) to assess toxicities, and a group of mice were co-treated with NAR (10 mg/kg b.w./day) to assess the protective effects of NAR against hepato-nephrotoxicity. The levels of blood serum enzymes, oxidative stress biomarkers, inflammatory cytokines, and the apoptosis marker caspase-3 were measured using histological examinations. NAR treatment in AlCl3-treated mice resulted in maintained levels of liver and kidney function enzymes and lipid profiles. NAR treatment attenuated oxidative stress by regulating the levels of nitric oxide, advance oxidation of protein products, protein carbonylation, and lipid peroxidation. NAR also replenished reduced antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and reduced the levels of glutathione and oxidized glutathione. NAR regulated the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and elevated the levels of anti-inflammatory cytokines (IL-4, IL-10, and IFN-γ). The histological study further confirmed the protective effects of NAR against AlCl3-induced hepato-renal alterations. NAR decreased the expression of caspase-3 as a mechanism of protective effects against apoptotic damage in the liver and kidney of AlCl3-treated mice. In summary, this study demonstrated the antioxidant and anti-inflammatory properties of NAR, leading to the suppression of AlCl3-triggered hepato-renal apoptosis and histological alterations. The results suggest that aluminum toxicity needs to be monitored in daily life usage, and supplementation of the natural dietary flavonoid naringenin may help maintain liver and kidney health.

Keywords

Acknowledgement

The authors would like to extend their sincere thanks to the Department of Zoology and Sophisticated Instrumentation Center (SIC), Dr. Harisingh Gour Central University, Sagar, India for proving laboratory and instrumental facilities. The authors are thankful for the DST-FIST Grant (DST, Govt. of India) to the Department.

References

  1. Ahmed WMS, Ibrahim MA, Helmy NA, ElKashlan AM, Elmaidomy AH, Zaki AR (2022) Amelioration of aluminum-induced hepatic and nephrotoxicity by Premna odorata extract is mediated by lowering MMP9 and TGF-β gene alterations in Wistar rat. Environ Sci Pollut Res 29:72827-72838. https://doi.org/10.1007/s11356-022-20735-8
  2. Dordevic D, Buchtova H, Jancikova S, Macharackova B, Jarosova M, Vitez T, Kushkevych I (2019) Aluminum contamination of food during culinary preparation: case study with aluminum foil and consumers' preferences. Food Sci Nutr 7:3349-3360. https://doi.org/10.1002/fsn3.1204
  3. Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, Kacew S, Lindsay J, Mahfouz AM, Rondeau V (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 10 Suppl 1:1-269. https://doi.org/10.1080/10937400701597766
  4. Geyikoglu F, Turkez H, Bakir TO, Cicek M (2013) The genotoxic, hepatotoxic, nephrotoxic, haematotoxic and histopathological effects in rats after aluminium chronic intoxication. Toxicol Ind Health 29:780-791. https://doi.org/10.1177/0748233712440140
  5. Gameiro J, Fonseca JA, Outerelo C, Lopes JA (2020) Acute kidney injury: from diagnosis to prevention and treatment strategies. J Clin Med 9:1704. https://doi.org/10.3390/jcm9061704
  6. Carbone F, Montecucco F, Mach F, Pontremoli R, Viazzi F (2013) The liver and the kidney: two critical organs infuencing the atherothrombotic risk in metabolic syndrome. Thromb Haemost 110:940-958. https://doi.org/10.1160/TH13-06-0499
  7. Mohamed B, Fares NH, Ashaat NA, Abozeid F (2022) Biochemical, histological, and immunohistochemical changes associated with Alcl3-induced hepatic injury in rats: protective effects of L-carnitine. Egypt J Histol 45:90-100. https://doi.org/10.21608/EJH.2021.52300.1395
  8. Yousef MI (2004) Aluminium-induced changes in hemato-biochemical parameters, lipid peroxidation and enzyme activities of male rabbits: protective role of ascorbic acid. Toxicology 199:47-57. https://doi.org/10.1016/j.tox.2004.02.014
  9. Paz LNF, Moura LM, Feio DCA, Cardoso MdSG, Ximenes WLO, Montenegro RC, Alves APN, Burbano RR, Lima PDL (2017) Evaluation of in vivo and in vitro toxicological and genotoxic potential of aluminum chloride. Chemosphere 175:130-137. https://doi.org/10.1016/j.chemosphere.2017.02.011
  10. Tan P, Jin L, Qin X, He B (2022) Natural flavonoids: potential therapeutic strategies for non-alcoholic fatty liver disease. Front Pharmacol 13:1005312. https://doi.org/10.3389/fphar.2022.1005312
  11. Ammar NM, Hassan HA, Abdallah HMI, Aff SM, Elgamal AM, Farrag ARH, El-Gendy AEG, Farag MA, Elshamy AI (2022) Protective effects of Naringenin from Citrus sinensis (var. Valencia) peels against CCl(4)-induced hepatic and renal injuries in rats assessed by metabolomics, histological and biochemical analyses. Nutrients 14:841. https://doi.org/10.3390/nu14040841
  12. Hernandez-Aquino E, Muriel P (2018) Beneficial effects of naringenin in liver diseases: molecular mechanisms. World J Gastroenterol 24:1679-1707. https://doi.org/10.3748/wjg.v24.i16.1679
  13. Mershiba SD, Dassprakash MV, Saraswathy SD (2013) Protective effect of naringenin on hepatic and renal dysfunction and oxidative stress in arsenic intoxicated rats. Mol Biol Rep 40:3681-3691. https://doi.org/10.1007/s11033-012-2444-8
  14. Sahu N, Mishra G, Chandra HK, Nirala SK, Bhadauria M (2020) Naringenin mitigates antituberculosis drugs induced hepatic and renal injury in rats. J Traditional Complement Med 10:26-35. https://doi.org/10.1016/j.jtcme.2019.01.001
  15. Rai R, Jat D, Mishra SK (2023) Naringenin ameliorates aluminum toxicity-induced testicular dysfunctions in mice by suppressing oxidative stress and histopathological alterations. Syst Biol Reprod Med. https://doi.org/10.1080/19396368.2023.2203794 [Online ahead of print]
  16. Roy A, Das A, Das R, Haldar S, Bhattacharya S, Haldar PK (2014) Naringenin, a citrus flavonoid, ameliorates arsenic-induced toxicity in swiss albino mice. J Environ Pathol Toxicol Oncol 33:195-204. https://doi.org/10.1615/jenvironpatholtoxicoloncol.2014010317
  17. Ishfaq PM, Mishra S, Mishra A, Ahmad Z, Gayen S, Jain SK, Tripathi S, Mishra SK (2022) Inonotus obliquus aqueous extract prevents histopathological alterations in liver induced by environmental toxicant Microcystin. Curr Res Pharmacol Drug Discov 3:100118. https://doi.org/10.1016/j.crphar.2022.100118
  18. Ishfaq PM, Mishra A, Mishra S, Ahmad Z, Gayen S, Jain SK, Tripathi S, Mishra SK (2021) Inonotus obliquus aqueous extract suppresses carbon tetrachloride-induced hepatic injury through modulation of antioxidant enzyme system and anti-inflammatory mechanism. Clin Cancer Drugs 8:122-136. https://doi.org/10.2174/2212697X08666211130130119
  19. Dhar D, Baglieri J, Kisseleva T, Brenner DA (2020) Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood) 245:96-108. https://doi.org/10.1177/1535370219898141
  20. Bryan NS, Rassaf T, Maloney RE, Rodriguez CM, Saijo F, Rodriguez JR, Feelisch M (2004) Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A 101:4308-4313. https://doi.org/10.1073/pnas.0306706101
  21. Ito F, Sono Y, Ito T (2019) Measurement and clinical significance of lipid peroxidation as a biomarker of oxidative stress: oxidative stress in diabetes, atherosclerosis, and chronic inflammation. Antioxidants (Basel) 8:72. https://doi.org/10.3390/antiox8030072
  22. Witko-Sarsat V, Friedlander M, Capeillere-Blandin C, NguyenKhoa T, Nguyen AT, Zingraf J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304-1313. https://doi.org/10.1038/ki.1996.186
  23. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329:23-38. https://doi.org/10.1016/s0009-8981(03)00003-2
  24. Marrocco I, Altieri F, Peluso I (2017) Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxidative Med Cell Longev 2017:6501046. https://doi.org/10.1155/2017/6501046
  25. Zhang H, Wang P, Yu H, Yu K, Cao Z, Xu F, Yang X, Song M, Li Y (2018) Aluminum trichloride-induced hippocampal inflammatory lesions are associated with IL-1β-activated IL-1 signaling pathway in developing rats. Chemosphere 203:170-178. https://doi.org/10.1016/j.chemosphere.2018.03.162
  26. Al Dera HS (2016) Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats. Saudi Med J 37:369-378. https://doi.org/10.15537/smj.2016.4.13611
  27. Mannaa FA, Abdel-Wahhab KG (2016) Physiological potential of cytokines and liver damages. Hepatoma Res 2:131-143. https://doi.org/10.20517/2394-5079.2015.58
  28. Ramesh G, Reeves WB (2004) Inflammatory cytokines in acute renal failure. Kidney Int 66:S56-S61. https://doi.org/10.1111/j.1523-1755.2004.09109.x
  29. Fischer WJ, Dietrich DR (2000) Pathological and biochemical characterization of microcystin-induced hepatopancreas and kidney damage in carp (Cyprinus carpio). Toxicol Appl Pharmcol 164:73-81. https://doi.org/10.1006/taap.1999.8861
  30. Li S, Hong M, Tan H-Y, Wang N, Feng Y (2016) Insights into the role and interdependence of oxidative stress and inflammation in Liver Diseases. Oxidative Med Cell Longev 2016:4234061. https://doi.org/10.1155/2016/4234061
  31. Eckle VS, Buchmann A, Bursch W, Schulte-Hermann R, Schwarz M (2004) Immunohistochemical detection of activated caspases in apoptotic hepatocytes in rat liver. Toxicol Pathol 32:9-15. https://doi.org/10.1080/01926230490260673
  32. Yang B, El Nahas AM, Thomas GL, Haylor JL, Watson PF, Wagner B, Johnson TS (2001) Caspase-3 and apoptosis in experimental chronic renal scarring. Kidney Int 60:1765-1776. https://doi.org/10.1046/j.1523-1755.2001.00013.x
  33. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495-516. https://doi.org/10.1080/01926230701320337
  34. Ferrell L (2000) Liver pathology: cirrhosis, Hepatitis, and primary liver tumors. Update and diagnostic problems. Mod Pathol 13:679-704. https://doi.org/10.1038/modpathol.3880119
  35. Tsai MH, Fang YW, Liou HH, Leu JG, Lin BS (2018) Association of serum aluminum levels with mortality in patients on chronic hemodialysis. Sci Rep 8:16729. https://doi.org/10.1038/s41598-018-34799-5
  36. Musso CG, Alvarez Gregori J, Jauregui JR, Macias Nunez JF (2012) Creatinine, urea, uric acid, water and electrolytes renal handling in the healthy oldest old. World J Nephrol 1:123-126. https://doi.org/10.5527/wjn.v1.i5.123
  37. Al-Kahtani M, Morsy K (2019) Ameliorative effect of selenium nanoparticles against aluminum chloride-induced hepatorenal toxicity in rats. Environ Sci Pollut Res Int 26:32189-32197. https://doi.org/10.1007/s11356-019-06417-y
  38. Al-Otaibi SS, Arafah MM, Sharma B, Alhomida AS, Siddiqi NJ (2018) Synergistic effect of quercetin and α-lipoic acid on aluminium chloride induced neurotoxicity in rats. J Toxicol 2018:2817036. https://doi.org/10.1155/2018/2817036
  39. Amini N, Maleki M, Badavi M (2022) Nephroprotective activity of naringin against chemical-induced toxicity and renal ischemia/reperfusion injury: a review. Avicenna J Phytomed 12:357-370. https://doi.org/10.22038/ajp.2022.19620
  40. Marcellinus AE, Onitsha EN (2022) Nephroprotective potential of Spondias mombin against aluminum chloride induced-renal injury in female albino rats. World J Adv Sci Technol 2:1-10. https://doi.org/10.53346/wjast.2022.2.1.0033
  41. Balgoon MJ (2019) Assessment of the protective effect of Lepidium sativum against Aluminum-induced liver and kidney effects in albino rat. Biomed Res Int 2019:4516730. https://doi.org/10.1155/2019/4516730
  42. Elsawy H, Alzahrani AM, Alfwuaires M, Abdel-Moneim AM, Khalil M (2021) Nephroprotective effect of naringin in methotrexate induced renal toxicity in male rats. Biomed Pharmacother 143:112180. https://doi.org/10.1016/j.biopha.2021.112180
  43. Amudha K, Pari L (2011) Beneficial role of naringin, a flavanoid on nickel induced nephrotoxicity in rats. Chem Biol Interact 193:57-64. https://doi.org/10.1016/j.cbi.2011.05.003
  44. Kany S, Vollrath JT, Relja B (2019) Cytokines in inflammatory disease. Int J Mol Sci 20:6008. https://doi.org/10.3390/ijms20236008
  45. Ghorbel I, Maktouf S, Fendri N, Jamoussi K, Ellouze Chaabouni S, Boudawara T, Zeghal N (2016) Co-exposure to aluminum and acrylamide disturbs expression of metallothionein, proinflammatory cytokines and induces genotoxicity: biochemical and histopathological changes in the kidney of adult rats. Environ Toxicol 31:1044-1058. https://doi.org/10.1002/tox.22114
  46. Wu LH, Lin C, Lin HY, Liu YS, Wu CY, Tsai CF, Chang PC, Yeh WL, Lu DY (2016) Naringenin suppresses neuroinflammatory responses through inducing suppressor of cytokine signaling 3 expression. Mol Neurobiol 53:1080-1091. https://doi.org/10.1007/s12035-014-9042-9
  47. Mai M, Jiang Y, Wu X, Liu G, Zhu Y, Zhu W (2020) Association of TGF-β1, IL-4, and IL-10 polymorphisms with chronic kidney disease susceptibility: a meta-analysis. Front Genet 11:79. https://doi.org/10.3389/fgene.2020.00079
  48. Wang J, Niu X, Wu C, Wu D (2018) Naringenin modifies the development of lineage-specific effector CD4(+) T cells. Front Immunol 9:2267. https://doi.org/10.3389/fmmu.2018.02267
  49. Sirovina D, Orsolic N, Gregorovic G, Koncic MZ (2016) Naringenin ameliorates pathological changes in liver and kidney of diabetic mice: a preliminary study. Arh Hig Rada Toksikol 67:19-24. https://doi.org/10.1515/aiht-2016-67-2708
  50. Adil M, Kandhare AD, Visnagri A, Bodhankar SL (2015) Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1, Caspase-3, TGF-β, and TNF-α. Ren Fail 37:1396-1407. https://doi.org/10.3109/0886022x.2015.1074462