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Hepatotoxic mechanism of diclofenac sodium on broiler chicken revealed by iTRAQ-based proteomics analysis

  • Sun, Chuanxi (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Zhu, Tianyi (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Zhu, Yuwei (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Li, Bing (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Zhang, Jiaming (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Liu, Yixin (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Juan, Changning (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Yang, Shifa (Institute of Poultry Science, Shandong Academy of Agricultural Sciences) ;
  • Zhao, Zengcheng (Institute of Poultry Science, Shandong Academy of Agricultural Sciences) ;
  • Wan, Renzhong (College of Animal Science and Veterinary Medicine, Shandong Agricultural University) ;
  • Lin, Shuqian (Institute of Poultry Science, Shandong Academy of Agricultural Sciences) ;
  • Yin, Bin (Institute of Poultry Science, Shandong Academy of Agricultural Sciences)
  • Received : 2022.01.19
  • Accepted : 2022.04.05
  • Published : 2022.07.31

Abstract

Background: At the therapeutic doses, diclofenac sodium (DFS) has few toxic side effects on mammals. On the other hand, DFS exhibits potent toxicity against birds and the mechanisms remain ambiguous. Objectives: This paper was designed to probe the toxicity of DFS exposure on the hepatic proteome of broiler chickens. Methods: Twenty 30-day-old broiler chickens were randomized evenly into two groups (n = 10). DFS was administered orally at 10mg/kg body weight in group A, while the chickens in group B were perfused with saline as a control. Histopathological observations, serum biochemical examinations, and quantitative real-time polymerase chain reaction were performed to assess the liver injury induced by DFS. Proteomics analysis of the liver samples was conducted using isobaric tags for relative and absolute quantification (iTRAQ) technology. Results: Ultimately, 201 differentially expressed proteins (DEPs) were obtained, of which 47 were up regulated, and 154 were down regulated. The Gene Ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to screen target DEPs associated with DFS hepatotoxicity. The regulatory relationships between DEPs and signaling pathways were embodied via a protein-protein interaction network. The results showed that the DEPs enriched in multiple pathways, which might be related to the hepatotoxicity of DFS, were "protein processing in endoplasmic reticulum," "retinol metabolism," and "glycine, serine, and threonine metabolism." Conclusions: The hepatotoxicity of DFS on broiler chickens might be achieved by inducing the apoptosis of hepatocytes and affecting the metabolism of retinol and purine. The present study could provide molecular insights into the hepatotoxicity of DFS on broiler chickens.

Keywords

Acknowledgement

The current research was supported by Innovation Ability Promotion Project for Technology-based Small and Medium Enterprise in Shandong Province (2021TSGC1271, 2021TSGC1275), Shandong Provincial Central Government Guides Local Technology Development Fund Projects (YDZX20203700003775).

References

  1. Ertekin T, Bilir A, Aslan E, Koca B, Turamanlar O, Ertekin A, et al. The effect of diclofenac sodium on neural tube development in the early stage of chick embryos. Folia Morphol (Warsz). 2019;78(2):307-313. https://doi.org/10.5603/fm.a2018.0080
  2. Bertocchi P, Antoniella E, Valvo L, Alimonti S, Memoli A. Diclofenac sodium multisource prolonged release tablets--a comparative study on the dissolution profiles. J Pharm Biomed Anal. 2005;37(4):679-685. https://doi.org/10.1016/j.jpba.2004.11.041
  3. Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 2010;26(7):1715-1731. https://doi.org/10.1185/03007995.2010.486301
  4. Sharma S, Setia H, Toor AP. Assessing the bioremediation potential of indigenously isolated Klebsiella sp. WAH1 for diclofenac sodium: optimization, toxicity and metabolic pathway studies. World J Microbiol Biotechnol. 2021;37(2):33. https://doi.org/10.1007/s11274-021-02998-4
  5. Menasse R, Hedwall PR, Kraetz J, Pericin C, Riesterer L, Sallmann A, et al. Pharmacological properties of diclofenac sodium and its metabolites. Scand J Rheumatol Suppl. 1978;7(22):5-16.
  6. Swan GE, Cuthbert R, Quevedo M, Green RE, Pain DJ, Bartels P, et al. Toxicity of diclofenac to Gyps vultures. Biol Lett. 2006;2(2):279-282. https://doi.org/10.1098/rsbl.2005.0425
  7. Green RE, Taggart MA, Das D, Pain DJ, Sashi Kumar C, Cunningham AA, et al. Collapse of Asian vulture populations: risk of mortality from residues of the veterinary drug diclofenac in carcasses of treated cattle. J Appl Ecol. 2006;43(5):949-956. https://doi.org/10.1111/j.1365-2664.2006.01225.x
  8. Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, et al. Diclofenac residues as the cause of vulture population decline in Pakistan. Nature. 2004;427(6975):630-633. https://doi.org/10.1038/nature02317
  9. Galligan TH, Mallord JW, Prakash VM, Bhusal KP, Alam AS, Anthony FM, et al. Trends in the availability of the vulture-toxic drug, diclofenac, and other NSAIDs in South Asia, as revealed by covert pharmacy surveys. Bird Conserv Int. 2021;31(3):337-353. https://doi.org/10.1017/S0959270920000477
  10. Paudel K, Amano T, Acharya R, Chaudhary A, Baral HS, Bhusal KP, et al. Population trends in Himalayan Griffon in Upper Mustang, Nepal, before and after the ban on diclofenac. Bird Conserv Int. 2016;26(3):286-292. https://doi.org/10.1017/S0959270915000192
  11. Hussain I, Khan MZ, Khan A, Javed I, Saleemi MK. Toxicological effects of diclofenac in four avian species. Avian Pathol. 2008;37(3):315-321. https://doi.org/10.1080/03079450802056439
  12. Naidoo V, Swan GE. Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction. Comp Biochem Physiol C Toxicol Pharmacol. 2009;149(3):269-274. https://doi.org/10.1016/j.cbpc.2008.07.014
  13. Nethathe B, Chipangura J, Hassan IZ, Duncan N, Adawaren EO, Havenga L, et al. Diclofenac toxicity in susceptible bird species results from a combination of reduced glomerular filtration and plasma flow with subsequent renal tubular necrosis. PeerJ. 2021;9:e12002. https://doi.org/10.7717/peerj.12002
  14. Sun C, Lin S, Li Z, Liu H, Liu Y, Wang K, et al. iTRAQ-based quantitative proteomic analysis reveals the toxic mechanism of diclofenac sodium on the kidney of broiler chicken. Comp Biochem Physiol C Toxicol Pharmacol. 2021;249:109129. https://doi.org/10.1016/j.cbpc.2021.109129
  15. Xie J, Dong W, Liu R, Wang Y, Li Y. Research on the hepatotoxicity mechanism of citrate-modified silver nanoparticles based on metabolomics and proteomics. Nanotoxicology. 2018;12(1):18-31. https://doi.org/10.1080/17435390.2017.1415389
  16. Aslam B, Basit M, Nisar MA, Khurshid M, Rasool MH. Proteomics: technologies and their applications. J Chromatogr Sci. 2017;55(2):182-196. https://doi.org/10.1093/chromsci/bmw167
  17. Akter R, Sarker M. Effect of diclofenac sodium in broilers. Bangladesh J Vet Med. 2015;13(1):19-24. https://doi.org/10.3329/bjvm.v13i1.23710
  18. Ramzan M, Ashraf M, Hashmi H, Iqbal Z, Anjum A. Evaluation of diclofenac sodium toxicity at different concentrations in relation to time using broiler chicken model. J Anim Plant Sci. 2015;25(2):357-365.
  19. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology. 2000;7(3):153-163. https://doi.org/10.1016/S0928-4680(00)00053-5
  20. Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V. Role of apoptosis in disease. Aging (Albany NY). 2012;4(5):330-349. https://doi.org/10.18632/aging.100459
  21. Hassan IZ, Duncan N, Adawaren EO, Naidoo V. Could the environmental toxicity of diclofenac in vultures been predictable if preclinical testing methodology were applied? Environ Toxicol Pharmacol. 2018;64:181-186. https://doi.org/10.1016/j.etap.2018.10.006
  22. Naidoo V, Duncan N, Bekker L, Swan G. Validating the domestic fowl as a model to investigate the pathophysiology of diclofenac in Gyps vultures. Environ Toxicol Pharmacol. 2007;24(3):260-266. https://doi.org/10.1016/j.etap.2007.06.003
  23. Cuthbert RJ, Taggart MA, Saini M, Sharma A, Das A, Kulkarni MD, et al. Continuing mortality of vultures in India associated with illegal veterinary use of diclofenac and a potential threat from nimesulide. Oryx. 2016;50(1):104-112. https://doi.org/10.1017/S003060531500037X
  24. Goda K, Takahashi T, Kobayashi A, Shoda T, Kuno H, Sugai S. Usefulness of in vitro combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury. J Toxicol Sci. 2016;41(5):605-615. https://doi.org/10.2131/jts.41.605
  25. Boonyong C, Vardhanabhuti N, Jianmongkol S. Natural polyphenols prevent indomethacin-induced and diclofenac-induced Caco-2 cell death by reducing endoplasmic reticulum stress regardless of their direct reactive oxygen species scavenging capacity. J Pharm Pharmacol. 2020;72(4):583-591. https://doi.org/10.1111/jphp.13227
  26. Fecker LF, Stockfleth E, Braun FK, Rodust PM, Schwarz C, Kohler A, et al. Enhanced death ligandinduced apoptosis in cutaneous SCC cells by treatment with diclofenac/hyaluronic acid correlates with downregulation of c-FLIP. J Invest Dermatol. 2010;130(8):2098-2109. https://doi.org/10.1038/jid.2010.40
  27. Yamazaki T, Muramoto M, Oe T, Morikawa N, Okitsu O, Nagashima T, et al. Diclofenac, a non-steroidal anti-inflammatory drug, suppresses apoptosis induced by endoplasmic reticulum stresses by inhibiting caspase signaling. Neuropharmacology. 2006;50(5):558-567. https://doi.org/10.1016/j.neuropharm.2005.10.016
  28. Huang Z, Liu Y, Qi G, Brand D, Zheng SG. Role of vitamin A in the immune system. J Clin Med. 2018;7(9):258. https://doi.org/10.3390/jcm7090258
  29. Khillan JS. Vitamin A/retinol and maintenance of pluripotency of stem cells. Nutrients. 2014;6(3):1209-1222. https://doi.org/10.3390/nu6031209
  30. Tanumihardjo SA, Russell RM, Stephensen CB, Gannon BM, Craft NE, Haskell MJ, et al. Biomarkers of nutrition for development (BOND)-vitamin A review. J Nutr. 2016;146(9):1816S-1848S. https://doi.org/10.3945/jn.115.229708
  31. Ford ES, Mokdad AH, Giles WH, Brown DW. The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey. Diabetes. 2003;52(9):2346-2352. https://doi.org/10.2337/diabetes.52.9.2346
  32. Jin L, Yan S, Shi B, Shi H, Guo X, Li J. Retinoic acid attenuates oxidative injury in bovine mammary epithelial cells induced by hydrogen peroxide. Czech J Anim Sci. 2017;62(12):539-548. https://doi.org/10.17221/42/2016-CJAS
  33. Shi HY, Yan SM, Guo YM, Zhang BQ, Guo XY, Shi BL. Vitamin A pretreatment protects NO-induced bovine mammary epithelial cells from oxidative stress by modulating Nrf2 and NF-κB signaling pathways. J Anim Sci. 2018;96(4):1305-1316. https://doi.org/10.1093/jas/sky037
  34. Jiang H, Dan Z, Wang H, Lin J. Effect of ATRA on contents of liver retinoids, oxidative stress and hepatic injury in rat model of extrahepatic cholestasis. J Huazhong Univ Sci Technolog Med Sci. 2007;27(5):491-494. https://doi.org/10.1007/s11596-007-0503-5
  35. Dal-Pizzol F, Klamt F, Benfato MS, Bernard EA, Moreira JC. Retinol supplementation induces oxidative stress and modulates antioxidant enzyme activities in rat Sertoli cells. Free Radic Res. 2001;34(4):395-404. https://doi.org/10.1080/10715760100300331
  36. Borghi C, Virdis A. Serum urate, uricase, and blood pressure control in gout. Hypertension. 2019;74(1):23-25. https://doi.org/10.1161/hypertensionaha.119.12831
  37. Werner AK, Witte CP. The biochemistry of nitrogen mobilization: purine ring catabolism. Trends Plant Sci. 2011;16(7):381-387. https://doi.org/10.1016/j.tplants.2011.03.012
  38. Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8-14. https://doi.org/10.1016/j.ijcard.2015.08.109
  39. Krebs HA. Regulatory mechanisms in purine biosynthesis. Adv Enzyme Regul. 1977;16:409-422. https://doi.org/10.1016/0065-2571(78)90086-9
  40. Zhang Y, Morar M, Ealick SE. Structural biology of the purine biosynthetic pathway. Cell Mol Life Sci. 2008;65(23):3699-3724. https://doi.org/10.1007/s00018-008-8295-8