Muhammad Fauzan LUBIS, Hafid SYAHPUTRA, Didi Nurhadi ILLIAN, Vera Estefania KABAN

Antioxidant activity and nephroprotective effect of Lansium parasiticum leaves in doxorubicin-induced rats

Doxorubicin is an important drug, especially in the treatment of cancer. But the effectiveness of its use is inseparable from its side effects, such as nephrotoxicity. This study aimed to examine the protective effect in doxorubicin-induced rats of Extract Ethanol of Lansium parasiticum leaves (EELP). The antioxidant activity of EELP was identified using the DPPH method and traced the total phenol content using the Folin-Ciocalteu method and total flavonoids using the colorimetry method. Oxidative stress and renal injury induced in doxorubicin treated rats were proved by the significant elevation of urea and creatinine and alteration in oxidative stress markers [MDA and GSH levels]. Histopathology of organs was examined under a microscope to see the damage that occurs in the tissue. The measurement results of antioxidant activity showed that EELP had a strong activity with an IC50 value of 14.8±0.7 μg/mL, 107.5±0.8 μg GAEs/mg extract for phenol content, and 33.6±0.3 μg quercetin/mg extract for flavonoid content. EELP was able to reduce MDA, urea, creatinine and increase GSH level. Observation of kidney tissues revealed a protective effect of EELP. This was characterized by a reduction in the type of damage that occurs in the kidney tissue of doxorubicin-induced rats. This study suggests that EELP through its antioxidant properties has a protective effect against doxorubicin-induced nephrotoxicity.

PDF

___

[1] Franco YL, Vaidya TR, Ait-Oudhia S. Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. Breast Cancer Targets Ther. 2018;10:131–41. [CrossRef]
[2] Yang F, Teves SS, Kemp CJ, Henikoff S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta - Rev Cancer [Internet]. 2014;1845(1):84–9. [CrossRef]
[3] Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB. Doxorubicin pathways. Pharmacogenet Genomics. 2011;21(7):440–6. [CrossRef]
[4] Rafiee Z, Moaiedi MZ, Gorji AV, Mansouri E. p-Coumaric Acid Mitigates Doxorubicin-Induced Nephrotoxicity Through Suppression of Oxidative Stress, Inflammation and Apoptosis. Arch Med Res [Internet]. 2020;51(1):32–40. [CrossRef]
[5] Prasanna PL, Renu K, Valsala Gopalakrishnan A. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sci [Internet]. 2020;250(March):117599. [CrossRef]
[6] Najafi M, Hooshangi Shayesteh MR, Mortezaee K, Farhood B, Haghi-Aminjan H. The role of melatonin on doxorubicininduced cardiotoxicity: A systematic review. Life Sci [Internet]. 2020;241:117173. [CrossRef]
[7] Liu LL, Li QX, Xia L, Li J, Shao L. Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Toxicology. 2007;231(1):81–90. [CrossRef]
[8] Aiswarya N, Rashmi RR, Preethi SJ, Chandran V, Teerthanath S, Sunil PB, Rakesh KB, Aiswarya N, Rashmi RR, Preethi SJ, Chandran V, Teerthanath S, Sunil PB, Rakesh KB. Nephroprotective effect of aqueous extract of Pimpinella anisum in gentamicin induced nephrotoxicity in wistar rats. Pharmacogn J. 2018;10(3):403–7.
[9] Hussain MA, Abogresha NM, Abdelkader G, Hassan R, Abdelaziz EZ, Greish SM. Antioxidant and Anti-Inflammatory Effects of Crocin Ameliorate Doxorubicin-Induced Nephrotoxicity in Rats. Oxid Med Cell Longev. 2021;2021:7–9. [CrossRef]
[10] Moneim AA. Protective Effect of Propolis on Doxorubicin Induced Cardio- and Nephrotoxicity. Ann Cardiol Vasc Med. 2020;3(1):1028.
[11] Elsayed Azab A, A Adwas Almokhtar, Ibrahim Elsayed AS, A Adwas A, Ibrahim Elsayed Ata Sedik, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human body. J Appl Biotechnol Bioeng. 2019;6(1):43–7.
[12] Sutrisno IH, Akob B, Navia ZI, Nuraini, Suwardi AB. Documentation of ritual plants used among the aceh tribe in Peureulak, East Aceh District, Indonesia. Biodiversitas. 2020;21(11):4990–8. [CrossRef]
[13] Syamsuardi S, Chairul C, Murni P. Analysis of Genetic Impurity of An Original Cultivar Duku (Lansium parasiticum (Osbeck.) K.C. Sahni & Bennet.), from Jambi, Indonesia Using ITS and MatK Gene. Int J Environ Agric Biotechnol. 2018;3(2):441–6. [CrossRef]
[14] Klungsupya P, Suthepakul N, Muangman T, Rerk-Am U, Thongdon-A. J. Determination of free radical scavenging, antioxidative DNA damage activities and phytochemical components of active fractions from Lansium domesticum corr. Fruit. Nutrients. 2015;7(8):6852–73. [CrossRef]
[15] Li AL, Li GH, Li YR, Wu XY, Ren DM, Lou HX, Wang XN, Shen T. Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases. Phytomedicine [Internet]. 2019;53:143–53. [CrossRef]
[16] Tong J, Yao X, Zeng H, Zhou G, Chen Y, Ma B, Wang Y. Hepatoprotective activity of flavonoids from Cichorium glandulosum seeds in vitro and in vivo carbon tetrachloride-induced hepatotoxicity. J Ethnopharmacol [Internet]. 2015;174:355–63. [CrossRef]
[17] Rosidah, Hasibuan PAZ, Haro G, Masri P, Satria D. Antioxidant activity of alkaloid fractions of Zanthoxylum acanthopodium DC. Fruits with 1,1-diphenyl-2-picrylhydrazyl assay. Asian J Pharm Clin Res. 2018;11(Special Issue 1):33– 4. [CrossRef]
[18] Alide T, Wangila P, Kiprop A. Effect of cooking temperature and time on total phenolic content, total flavonoid content and total in vitro antioxidant activity of garlic. BMC Res Notes [Internet]. 2020;13(1):1–7. [CrossRef]
[19] Afshar FH, Delazar A, Nazemiyeh H, Esnaashari S, Moghadam SB. Comparison of the total phenol, flavonoid contents and antioxidant activity of methanolic extracts of Artemisia spicigera and A. splendens growing in Iran. Pharm Sci. 2012;18(3):165–70.
[20] Kumar S, Sandhir R, Ojha S. Evaluation of antioxidant activity and total phenol in different varieties of Lantana camara leaves. BMC Res Notes. 2014;7(1):1–9. [CrossRef]
[21] Banjarnahor SDS, Artanti N. Antioxidant properties of flavonoids. Med J Indones. 2014;23(4):239–44. [CrossRef]
[22] Panis C, Herrera ACSA, Victorino VJ, Campos FC, Freitas LF, De Rossi T, Colado Simão AN, Cecchini AL, Cecchini R. Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. Breast Cancer Res Treat. 2012;133(1):89–97. [CrossRef]
[23] Gharib OA. Effects of Kombucha on oxidative stress induced nephrotoxicity in rats. Chin Med. 2009;4:2–7. [CrossRef]
[24] Zhang Y, Chi X, Wang Z, Bi S, Wang Y, Shi F, Hu S, Wang H. Protective effects of Panax notoginseng saponins on PMEInduced nephrotoxicity in mice. Biomed Pharmacother [Internet]. 2019;116(May):108970. [CrossRef]
[25] Jiang X, Ren Z, Zhao B, Zhou S, Ying X, Tang Y. Ameliorating Effect of Pentadecapeptide Derived from Cyclina sinensis on Cyclophosphamide-Induced Nephrotoxicity. Marine Drugs. 2020; 18(9):462. [CrossRef]
[26] Arnold N. Onyango, Naomichi Baba. New hypotheses on the pathways of formation of malondialdehyde and isofurans. Free Radical Biology and Medicine. 2010; 49(10):1594-1600. [CrossRef]
[27] Sadeghi H, Mansourian M, Panahi kokhdan E, Salehpour Z, Sadati I, Abbaszadeh-Goudarzi K, Asfaram A, Doustimotlagh AH. Antioxidant and protective effect of Stachys pilifera Benth against nephrotoxicity induced by cisplatin in rats. J Food Biochem. 2020;44(5):1–10. [CrossRef]
[28] Bellomo R, Ronco C, Mehta RL, Asfar P, Boisramé-Helms J, Darmon M, Diehl JL, Duranteau J, Hoste EAJ, Olivier JB, Legrand M, Lerolle N, Malbrain MLNG, Mårtensson J, Oudemans-van Straaten HM, Parienti JJ, Payen D, Perinel S, Peters E, Pickkers P, Rondeau E, Schetz M, Vinsonneau C, Wendon J, Zhang L, Laterre PF. Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference. Ann Intensive Care. 2017;7(1):1–40. [CrossRef]
[29] Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AYM, Yang CW. Chronic kidney disease: Global dimension and perspectives. Lancet [Internet]. 2013;382(9888):260–72. [CrossRef]
[30] Waikar SS, Bonventre J V. Biomarkers for the diagnosis of acute kidney injury. Curr Opin Nephrol Hypertens. 2007;16(6):557–64. [CrossRef]
[31] Alatriste PVM, Arronte RU, Espinosa COG, Cuevas M de los ÁE. Efecto de lactobacillus casei shirota sobre concentraciones de urea en la enfermedad renal crónica. Nutr Hosp. 2014;29(3):582–90.
[32] El-Sayed SM, El-Naggar ME, Hussein J, Medhat D, El-Banna M. Effect of Ficus carica L. leaves extract loaded gold nanoparticles against cisplatin-induced acute kidney injury. Colloids Surfaces B Biointerfaces [Internet]. 2019;184(August):110465. [CrossRef]
[33] Tousson E, El-Atrsh A, Mansour M, Abdallah A. Modulatory effects of Saussurea lappa root aqueous extract against ethephon-induced kidney toxicity in male rats. Environ Toxicol. 2019;34(12):1277–84. [CrossRef]
[34] El-Sheikh AAK, Morsy MA, Mahmoud MM, Rifaai RA, Abdelrahman AM. Effect of coenzyme-Q10 on doxorubicininduced nephrotoxicity in rats. Adv Pharmacol Sci. 2012;2012. [CrossRef]
[35] Refaie MMM, Amin EF, El-Tahawy NF, Abdelrahman AM. Possible protective effect of diacerein on doxorubicininduced nephrotoxicity in rats. J Toxicol. 2016;2016. [CrossRef]
[36] Beyrami-Miavagi A, Farokhi F, Asadi-Samani M. A study of the effect of prostodin and hydroalcoholic extract of Malva neglecta on kidney histopathology and renal factors in female rats. Adv Environ Biol. 2014;8(9 SPEC. ISSUE 4):942–7.
[37] Albrakati A. Aged garlic extract rescues ethephon-induced kidney damage by modulating oxidative stress, apoptosis, inflammation, and histopathological changes in rats. Environ Sci Pollut Res. 2021;28(6):6818–29. [CrossRef]
[38] Aydinoz S, Uzun G, Cermik H, Atasoyu EM, Yildiz S, Karagoz B, Evrenkaya R. Effects of different doses of hyperbaric oxygen on cisplatin-induced nephrotoxicity. Ren Fail. 2007;29(3):257–63. [CrossRef]
[39] Tonomura Y, Tsuchiya N, Torii M, Uehara T. Evaluation of the usefulness of urinary biomarkers for nephrotoxicity in rats. Toxicology [Internet]. 2010;273(1–3):53–9. [CrossRef]
[40] Yaman I, Balikci E. Protective effects of Nigella sativa against gentamicin-induced nephrotoxicity in rats. Exp Toxicol Pathol. 2010;62(2):183–90. [CrossRef]
[41] Li B, Kim DS, Yadav RK, Kim HR, Chae HJ. Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells. Int J Mol Med. 2015;36(1):53–64. [CrossRef]
[42] Asensio-López MC, Soler F, Pascual-Figal D, Fernández-Belda F, Lax A. Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes. PLoS One. 2017;12(2):1–21. [CrossRef]
[43] Afsar T, Razak S, Almajwal A, Al-Disi D. Doxorubicin-induced alterations in kidney functioning, oxidative stress, DNA damage, and renal tissue morphology; Improvement by Acacia hydaspica tannin-rich ethyl acetate fraction. Saudi J Biol Sci [Internet]. 2020;27(9):2251–60. [CrossRef]
[44] Ren Q, Guo F, Tao S, Huang R, Ma L, Fu P. Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice. Biomed Pharmacother [Internet]. 2020;122(37):109772. [CrossRef]
[45] Wang S, Fang Y, Yu X, Guo L, Zhang X, Xia D. The flavonoid-rich fraction from rhizomes of Smilax glabra Roxb. ameliorates renal oxidative stress and inflammation in uric acid nephropathy rats through promoting uric acid excretion. Biomed Pharmacother [Internet]. 2019;111(May 2018):162–8. [CrossRef]
[46] Wang HY, Zhao JG, Wei ZG, Zhang YQ. The renal protection of flavonoid-rich ethanolic extract from silkworm green cocoon involves in inhibiting TNF-α-p38 MAP kinase signalling pathway in type 2 diabetic mice. Biomed Pharmacother [Internet]. 2019;118(August):109379. Available from: [CrossRef]
[47] Rosidah, Yuandani, Widjaja SS, Auliafendri N, Lubis MF, Muhammad M, Satria D. Phytochemıcals analysis and immunomodulatory actıvıty of Saurauia vulcani Korth. leaves extracts towards raw 264.7 CELL. Rasayan J Chem. 2021;14(02):1378–83. [CrossRef]
[48] Dalimunthe A, Hasibuan PAZ, Silalahi J, Satria D. Antioxidant activity of alkaloid fractions of Litsea cubeba lour. Fruits. Asian J Pharm Clin Res. 2018;11(Special Issue 1):31–2. [CrossRef]
[49] Nazliniwaty, Hanafiah OA, Pertiwi D, Satria D, Muhammad M. Antioxidant activity, total phenolic and total flavonoid content of hydroalcoholic extract of Artocarpus lacucha Buch-Ham. Leaves. AIP Conf Proc. 2021;2342(April). [CrossRef]
[50] Do QD, Angkawijaya AE, Tran-Nguyen PL, Huynh LH, Soetaredjo FE, Ismadji S, Ju YH. Effect of extraction solvent on total phenol content, total flavonoid content, and antioxidant activity of Limnophila aromatica. J Food Drug Anal [Internet]. 2014;22(3):296–302. [CrossRef]
[51] Mohan M, Kamble S, Gadhi P, Kasture S. Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats. Food Chem Toxicol [Internet]. 2010;48(1):436–40. [CrossRef]
[52] Hamzeh M, Talebpour Amiri F, Yaghubi Beklar S, Hosseinimehr SJ. Nephroprotective effect of cerium oxide nanoparticles on cyclophosphamide-induced nephrotoxicity via anti-apoptotic and antioxidant properties in BALB/c mice. Marmara Pharm J. 2018;22(2):180–9. [CrossRef]
[53] Randjelovic P, Veljkovic S, Stojiljkovic N, Jankovic-Velickovic L, Sokolovic D, Stoiljkovic M, Ilic I. Salicylic acid attenuates gentamicin-induced nephrotoxicity in rats. Sci World J. 2012;2012. [CrossRef]
[54] Boroushaki MT, Asadpour E, Sadeghnia HR, Dolati K. Effect of pomegranate seed oil against gentamicin -induced nephrotoxicity in rat. J Food Sci Technol. 2014;51(11):3510–4. [CrossRef]
[55] Demirbag S, Uysal B, Guven A, Cayci T, Ozler M, Ozcan A, Kaldirim U, Surer I, Korkmaz A. Effects of medical ozone therapy on acetaminophen-induced nephrotoxicity in rats. Ren Fail. 2010;32(4):493–7. [CrossRef]