Investigation of the effects of apilarnil and imatinib use on liver and kidney tissues in rats via PI3K/AKT/mTOR and JAK2/STAT3 pathways

Abstract

Imatinib, used in the field of molecular targeted therapy, has been reported to cause serious side effects, including liver and kidney failure. However, the mechanism of imatinib-induced liver and kidney toxicity remains unclear due to limited number of studies in this field. Apilarnil is a natural bee product produced from 3-7 day old drone larvae. The present study aimed to investigate the effects of apilarnil in rats with imatinib-induced liver and kidney toxicity using biochemical parameters. In the experiment, 35 wistar albino rats were divided into five groups (n=7): i) Control, ii) Apilarnil, iii) İmatinib, iv) İmatinib+Apilarnil-200, and v) İmatinib+Apilarnil-400. The rats were treated orally with İmatinib (100 mg/kg) alone or with apilarnil (200 and 400 mg/kg) for 14 consecutive days. Imatinib reduced PI3K, AKT and mTOR levels, while increasing JAK2 and STAT3 levels in liver and kidney tissues. Apilarnil given for treatment modulated these values and provided partial protection in liver and kidney tissue. In conclusion, it was determined that apilarnil has ameliorative effects against imatinib-induced liver and kidney damage.

Keywords

• Apilarnil
• İmatinib
• Liver
• Kidney
• Rat

References

1. Droogendijk HJ, Kluin Nelemans HJ, van Doormaal JJ, Oranje AP, Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis. Cancer. 2006;107:345-351.
2. Banka N, Aljurf M, Hamadah I. Imatinib (STI-571)-induced exfoliative dermatitis in a Saudi patient with deck chair sign. Dermatology. 2003;207:329-330.
3. Al-Allaf LI, Al-Ashoo HA Analysis of the Oxidative Stress Parameters in Testicular, Hepatic and Renal Tissues Homogenates of Albino Rats after Administration of Imatinib at Peripuberty. Zoology. 2018;27(5):26-33.
4. Herman EH, Knapton A, Rosen E, Thompson K, Rosenzweig B, Estis J, et al. A Multifaceted Evaluation of Imatinib-induced Cardiotoxicity in the Rat. Toxicol Pathol. 2011;39:1091-1106.
5. Al-Rasheed NM, El-Masry TA, Tousson E, Hassan HM, Al-Ghadeer A. Protective Potential of Grape Seed Proanthocyandins Extract against Glivec (Imatinib Mesylate) Induced Liver Toxicity and Oxidative Stress in Male Rats. Annu Res Rev Biol. 2017;20(6):1-9.
6. Liu L, Zhou J, Wang Y, Qi T, Wang Z, Chen L, et al. Imatinib inhibits oxidative stress response in spinal cord injury rats by activating Nrf2/HO‑1 signaling pathway. Exp Ther Med. 2020;(1):597-692.
7. Inci H., Izol E, Yilmaz MA, Ilkaya M, Bingöl Z, Gülçin I. Comprehensive phytochemical content by LC/MS/MS and anticholinergic, antiglaucoma, antiepilepsy, and antioxidant activity of apilarnil (drone larvae). Chem Biodiversity. 2023;20(10): e202300654.
8. Bărnuțiu LI, Mărghitaș LA, Dezmirean D, Bobiș O, Mihai C, Pavel C. Physico-chemical composition of apilarnil (bee drone larvae). Lucrari Stiintifice, Seria Zootehnie. 2013;59:199-202.

9. Sawczuk R, Karpinska J, Miltyk W. What do we need to know about drone brood homogenate and what is known. J Ethnopharmacol. 2019;245:111581.
10. Inandiklioglu N, Doganyigit Z, Okan A, Kayman E, Silici S. Nephroprotective effect of apilarnil in lipopolysaccharide-induced sepsis through TLR4/NF-κB signaling pathway. Life Sci. 2021;284:119875.
11. Emadi E, Abdoli N, Ghanbarinejad V, Mohammadi HR, Mobarakeh KM, Azarpira N, et al. The potential role of mitochondrial impairment in the pathogenesis of imatinib-induced renal injury. Heliyon. 2019;5(6):e01996.
12. Huang FR, Fang WT, Cheng ZP, Shen Y, Wang DJ, Wang YQ, et al. Imatinib-induced hepatotoxicity via oxidative stress and activation of NLRP3 inflammasome: an in vitro and in vivo study. Arch Toxicol. 2022;96(4):1075-1087.
13. Emadi E, Abdoli N, Ghanbarinejad V, Mohammadi HR, Mobarakeh KM, Azarpira N, et al. The potential role of mitochondrial impairment in the pathogenesis of imatinib-induced renal injury. Heliyon. 2019;5(6).
14. Sun EJ, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Biomedicines. 2021;9(11):1639.
15. Yang H, Wang H, Liu Y, Yang L, Sun L, Tian Y, et al. The PI3K/Akt/mTOR signaling pathway plays a role in regulating aconitine-induced autophagy in mouse liver. Res J Vet Sci. 2019;24:317-320.
16. Wang Y, Liu Z, Shu S, Cai J, Tang C, Dong Z. AMPK/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury. Front Physiol. 2020;11:619730.
17. Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell signal. 2014;26(12):2694-2701.
18. Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH, Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci. 2020;262:118513.
19. Ma L, Huang K, Zhang H, Kim E, Kim H, Liu Z, et al. Imatinib inhibits oral squamous cell carcinoma by suppressing the PI3K/AKT/mTOR signaling pathway. J Cancer 2024;15(3):659.
20. Doğanyiğit Z, Okan A, Kaymak E, Pandır D, Silici S. Investigation of protective effects of apilarnil against lipopolysaccharide induced liver injury in rats via TLR 4/HMGB-1/NF-κB pathway. Biomed Pharmacother. 2020;125:109967.
21. Zhang H, Liu Y, Wang LK, Wei N. Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway: An experimental study. Asian Pac J Trop Med. 2017;10(5):520-523.
22. Zai W, Chen W, Luan J, Fan J, Zhang X, Wu Z, et al. Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy. Appl Microbiol Biotechnol. 2018;102:1443-1453.
23. Wang M, Zhou Y, Hao G, Wu YE, Yin R, Zheng Y, et al. Recombinant Klotho alleviates vancomycin-induced acute kidney injury by upregulating anti-oxidative capacity via JAK2/STAT3/GPx3 axis. Toxicology. 2023;499:153657.
24. Shalaby M, Abdelaziz RR, Ghoneim HA, Suddek GM. Imatinib mitigates experimentally-induced ulcerative colitis: Possible contribution of NF-kB/JAK2/STAT3/COX2 signaling pathway. Life Sci. 2023;321:121596.