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Rutin Ameliorates Cadmium-Induced Necroptosis in the Chicken Liver via Inhibiting Oxidative Stress and MAPK/NF-κB Pathway

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Abstract

Cadmium (Cd) is a recognized toxic metal and exerts serious hepatotoxicity in animals and humans. Rutin (RUT) is a dietary bioflavonoid with strong antioxidant and anti-inflammatory potential. However, little is known about the alleviating effect of RUT against Cd-induced liver necroptosis. The aim of this study was to ascertain the ameliorative mechanism of RUT on necroptosis triggered by Cd in chicken liver. One hundred twenty-eight 100-day-old Isa hens were randomly divided into four groups: the control group, RUT group, Cd + RUT cotreated group, and Cd group. Cd exposure prominently elevated Cd accumulation and the activities of liver function indicators (ALT and AST). Furthermore, the histopathological results, the overexpression of genes (RIPK1, RIPK3, and MLKL) related to the necroptosis pathway, and low Caspase 8 levels in Cd-exposed chicken liver indicated that Cd intoxication induced necroptosis in chicken liver. Meanwhile, Cd administration drastically increased the levels of oxidizing stress biomarkers (ROS production, MDA content, iNOS activity, and NO generation), and obviously reduced the activities of antioxidant enzymes (SOD, GPx, and CAT) and total antioxidant capacity (T-AOC) in chicken liver. Cd treatment promoted the expression of the main members of the MAPK and NF-κB pathways (JNK, ERK, P38, NF-κB, and TNF-α) and activated heat shock proteins (HSP27, HSP40, HSP60, HSP70, and HSP90). However, RUT application remarkably alleviated these Cd-induced variations and necroptosis injury. Overall, our study demonstrated that RUT might prevent Cd-induced necroptosis in the chicken liver by inhibiting oxidative stress and MAPK/NF-κB pathway.

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References

  1. Zhang J, Wang Y, Fu L, Wang B, Ji Y, Wang H, Xu D (2019) Chronic cadmium exposure induced hepatic cellular stress and inflammation in aged female mice. J Appl Toxicol 39(3):498–509

    Article  CAS  PubMed  Google Scholar 

  2. Wu C, Zhang Y, Chai L, Wang H (2017) Histological changes, lipid metabolism and oxidative stress in the liver of Bufo gargarizans exposed to cadmium concentrations. Chemosphere 179:337–346

    Article  CAS  PubMed  Google Scholar 

  3. Wang J, Zhu H, Liu X, Liu Z (2014) Oxidative stress and Ca(2+) signals involved on cadmium-induced apoptosis in rat hepatocyte. Biol Trace Elem Res 161(2):180–189

    Article  CAS  PubMed  Google Scholar 

  4. Linkermann A, Green D (2014) Necroptosis. N Engl J Med 370(5):455–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Saeed W, Jun D, Jang K, Koh D (2019) Necroptosis signaling in liver diseases: an update. Pharmacol Res 148:104439

    Article  CAS  PubMed  Google Scholar 

  6. Zhang S, Che L, He C, Huang J, Guo N, Shi J, Lin Y, Lin Z (2019) Drp1 and RB interaction to mediate mitochondria-dependent necroptosis induced by cadmium in hepatocytes. Cell Death Dis 10(7):523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. VandenBerghe T, Vanlangenakker N, Parthoens E, Deckers W, Devos M, Festjens N, Guerin C, Brunk U, Declercq W, Vandenabeele P (2010) Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ 17(6):922–930

    Article  CAS  Google Scholar 

  8. Lu B, Gong X, Wang Z, Ding Y, Wang C, Luo T, Piao M, Meng F, Chi G, Luo Y, Ge P (2017) Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation. Acta Pharmacol Sin 38(11):1543–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Raha S, Yumnam S, Hong G, Lee H, Saralamma V, Park H, Heo J, Lee S, Kim E, Kim J, Kim G (2015) Naringin induces autophagy-mediated growth inhibition by downregulating the PI3K/Akt/mTOR cascade via activation of MAPK pathways in AGS cancer cells. Int J Oncol 47(3):1061–1069

    Article  CAS  PubMed  Google Scholar 

  10. Yang T, Cao C, Yang J, Liu T, Lei X, Zhang Z, Xu S (2018) miR-200a-5p regulates myocardial necroptosis induced by Se deficiency via targeting RNF11. Redox Biol 15:159–169

    Article  CAS  PubMed  Google Scholar 

  11. Oliver Metzig M, Fuchs D, Tagscherer K, Gröne H, Schirmacher P, Roth W (2016) Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene 35(26):3399–3409

    Article  CAS  PubMed  Google Scholar 

  12. Khandia R, Munjal A, Iqbal H, Dhama K (2017) Heat shock proteins: therapeutic perspectives in inflammatory disorders. Recent Pat Inflamm Allergy Drug Discov 10(2):94–104

    Article  PubMed  Google Scholar 

  13. Wang W, Shi Q, Wang S, Zhang H, Xu S (2020) Ammonia regulates chicken tracheal cell necroptosis via the LncRNA-107053293/MiR-148a-3p/FAF1 axis. J Hazard Mater 386:121626

    Article  CAS  PubMed  Google Scholar 

  14. Qianru C, Xueyuan H, Bing Z, Qing Z, Kaixin Z, Shu L (2021) Regulation of HS-induced necroptosis and inflammation in broiler bursa of Fabricius by the miR-15b-5p/TGFBR3 axis and the involvement of oxidative stress in this process. J Hazard Mater 406:124682

    Article  CAS  PubMed  Google Scholar 

  15. Zhang J, Zheng S, Wang S, Liu Q, Xu S (2020) Cadmium-induced oxidative stress promotes apoptosis and necrosis through the regulation of the miR-216a-PI3K/AKT axis in common carp lymphocytes and antagonized by selenium. Chemosphere 258:127341

    Article  CAS  PubMed  Google Scholar 

  16. Jiang S, Shang L, Xue L, Ding W, Chen S, Ma R, Huang J, Xiong K (2014) The effect and underlying mechanism of Timosaponin B-II on RGC-5 necroptosis induced by hydrogen peroxide. BMC Complement Altern Med 14:459

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Liu L, Liu Y, Cheng X, Qiao X (2021) The alleviative effects of quercetin on cadmium-induced necroptosis via inhibition ROS/iNOS/NF-κB pathway in the chicken brain. Biol Trace Elem Res 199(4):1584–1594. https://doi.org/10.1007/s12011-020-02563-4

  18. Xin C, Guangliang S, Qing Z, Qingqing L, Hang Y, Yiming Z, Shu L (2020) Astilbin protects chicken peripheral blood lymphocytes from cadmium-induced necroptosis via oxidative stress and the PI3K/Akt pathway. Ecotoxicol Environ Saf 190:110064

    Article  CAS  PubMed  Google Scholar 

  19. Wang X, Wang T, Pan T, Huang M, Ren W, Xu G, Amin H, Kassab R, Abdel Moneim A (2020) Senna alexandrina extract supplementation reverses hepatic oxidative, inflammatory, and apoptotic effects of cadmium chloride administration in rats. Environ Sci Pollut Res Int 27(6):5981–5992

    Article  CAS  PubMed  Google Scholar 

  20. Zhou X, Wan X, Fu X, Xie C (2019) Puerarin prevents cadmium-induced hepatic cell damage by suppressing apoptosis and restoring autophagic flux. Biomed Pharmacother 115:108929

    Article  CAS  PubMed  Google Scholar 

  21. Sanjeev S, Bidanchi R, Murthy M, Gurusubramanian G, Roy V (2019) Influence of ferulic acid consumption in ameliorating the cadmium-induced liver and renal oxidative damage in rats. Environ Sci Pollut Res Int 26(20):20631–20653

    Article  CAS  PubMed  Google Scholar 

  22. Elsawy H, Badr G, Sedky A, Abdallah B, Alzahrani A, Abdel-Moneim A (2019) Rutin ameliorates carbon tetrachloride (CCl)-induced hepatorenal toxicity and hypogonadism in male rats. PeerJ 7:e7011

    Article  PubMed  PubMed Central  Google Scholar 

  23. Londero É, Bressan C, Pês T, Saccol E, Baldisserotto B, Finamor I, Pavanato M (2021) Rutin-added diet protects silver catfish liver against oxytetracycline-induced oxidative stress and apoptosis. Comp Biochem Physiol Toxicol Pharmacol 239:108848

    Article  CAS  Google Scholar 

  24. Caglayan C, Kandemir F, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak M (2019) Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. J Trace Elem Med Biol 56:60–68

    Article  CAS  PubMed  Google Scholar 

  25. Jin X, Jia T, Liu R, Xu S (2018) The antagonistic effect of selenium on cadmium-induced apoptosis via PPAR-γ/PI3K/Akt pathway in chicken pancreas. J Hazard Mater 357:355–362

    Article  CAS  PubMed  Google Scholar 

  26. Hassan F, Roushdy E, Kishawy A, Zaglool A, Tukur H, Saadeldin I (2018) Growth performance, antioxidant capacity, lipid-related transcript expression and the economics of broiler chickens fed different levels of rutin. Animals 9(1):7

  27. Liu Y, Wu S, Sun W, Chen S, Yang X, Yang X (2018) Variation in proteomics and metabolomics of chicken hepatocytes exposed to medium with or without folic acid. J Cell Biochem 119(7):6113–6124

    Article  CAS  PubMed  Google Scholar 

  28. Yang F, Liao J, Pei R, Yu W, Han Q, Li Y, Guo J, Hu L, Pan J, Tang Z (2018) Autophagy attenuates copper-induced mitochondrial dysfunction by regulating oxidative stress in chicken hepatocytes. Chemosphere 204:36–43

    Article  CAS  PubMed  Google Scholar 

  29. Zhang C, Lin J, Ge J, Wang L, Li N, Sun X, Cao H, Li J (2017) Selenium triggers Nrf2-mediated protection against cadmium-induced chicken hepatocyte autophagy and apoptosis. Toxicol In Vitro 44:349–356

    Article  CAS  PubMed  Google Scholar 

  30. Dai Z, Cheng J, Bao L, Zhu X, Li H, Chen X, Zhang Y, Zhang J, Chu W, Pan Y, Huang H (2020) Exposure to waterborne cadmium induce oxidative stress, autophagy and mitochondrial dysfunction in the liver of Procypris merus. Ecotoxicol Environ Saf 204:111051

    Article  CAS  PubMed  Google Scholar 

  31. Oboh G, Adebayo A, Ademosun A, Olowokere O (2019) Rutin alleviates cadmium-induced neurotoxicity in Wistar rats: involvement of modulation of nucleotide-degrading enzymes and monoamine oxidase. Metab Brain Dis 34(4):1181–1190

    Article  CAS  PubMed  Google Scholar 

  32. Li J, Jiang C, Li S, Xu S (2013) Cadmium induced hepatotoxicity in chickens (Gallus domesticus) and ameliorative effect by selenium. Ecotoxicol Environ Saf 96:103–109

    Article  CAS  PubMed  Google Scholar 

  33. Fang J, Yin H, Yang Z, Tan M, Wang F, Chen K, Zuo Z, Shu G, Cui H, Ouyang P, Guo H, Chen Z, Huang C, Geng Y, Liu W (2021) Vitamin E protects against cadmium-induced sub-chronic liver injury associated with the inhibition of oxidative stress and activation of Nrf2 pathway. Ecotoxicol Environ Saf 208:111610

    Article  CAS  PubMed  Google Scholar 

  34. Abdel-Rahim E, Abdel-Mobdy Y, Ali R, Mahmoud H (2014) Hepatoprotective effects of Solanum nigrum Linn fruits against cadmium chloride toxicity in albino rats. Biol Trace Elem Res 160(3):400–408

    Article  CAS  PubMed  Google Scholar 

  35. Jiayong Z, Shengchen W, Xiaofang H, Gang S, Shiwen X (2020) The antagonistic effect of selenium on lead-induced necroptosis via MAPK/NF-κB pathway and HSPs activation in the chicken spleen. Ecotoxicol Environ Saf 204:111049

    Article  PubMed  CAS  Google Scholar 

  36. Kandemir F, Caglayan C, Aksu E, Yildirim S, Kucukler S, Gur C, Eser G (2020) Protective effect of rutin on mercuric chloride-induced reproductive damage in male rats. Andrologia 52(3):e13524

    Article  PubMed  Google Scholar 

  37. Topal İ, Özbek Bilgin A, Keskin Çimen F, Kurt N, Süleyman Z, Bilgin Y, Özçiçek A, Altuner D (2018) The effect of rutin on cisplatin-induced oxidative cardiac damage in rats. Anatol J Cardiol 20(3):136–142

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang L, Wang L, Shi X, Xu S (2020) Chlorpyrifos induces the apoptosis and necroptosis of L8824 cells through the ROS/PTEN/PI3K/AKT axis. J Hazard Mater 398:122905

    Article  CAS  PubMed  Google Scholar 

  39. Chtourou Y, Slima A, Makni M, Gdoura R, Fetoui H (2015) Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats. Pharmacol Rep 67(6):1090–1097

    Article  CAS  PubMed  Google Scholar 

  40. Tian Q, Qin B, Gu Y, Zhou L, Chen S, Zhang S, Zhang S, Han Q, Liu Y, Wu X (2020) ROS-mediated necroptosis is involved in iron overload-induced osteoblastic cell death. Oxid Med Cell Longev 2020:1295382

    PubMed  PubMed Central  Google Scholar 

  41. Yu W, Lai Y, Ma J, Ho C, Hung S, Chen Y, Chen C, Kao J, Way T (2019) viaCitronellol induces necroptosis of human lung cancer cells TNF-α pathway and reactive oxygen species accumulation. In Vivo (Athens, Greece) 33(4):1193–1201

    CAS  Google Scholar 

  42. Han Q, Zhang J, Sun Q, Xu Y, Teng X (2020) Oxidative stress and mitochondrial dysfunction involved in ammonia-induced nephrocyte necroptosis in chickens. Ecotoxicol Environ Saf 203:110974

    Article  CAS  PubMed  Google Scholar 

  43. Han C, Guan Z, Zhang P, Fang H, Li L, Zhang H, Zhou F, Mao Y, Liu W (2018) Oxidative stress induced necroptosis activation is involved in the pathogenesis of hyperoxic acute lung injury. Biochem Biophys Res Commun 495(3):2178–2183

    Article  CAS  PubMed  Google Scholar 

  44. Wang J, Zhu H, Liu X, Liu Z (2014) N-acetylcysteine protects against cadmium-induced oxidative stress in rat hepatocytes. J Vet Sci 15(4):485–493

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhang Y, Liu Q, Yin H, Li S (2020) Cadmium exposure induces pyroptosis of lymphocytes in carp pronephros and spleens by activating NLRP3. Ecotoxicol Environ Saf 202:110903

    Article  CAS  PubMed  Google Scholar 

  46. Nkpaa K, Onyeso G, Kponee K (2019) Rutin abrogates manganese-Induced striatal and hippocampal toxicity via inhibition of iron depletion, oxidative stress, inflammation and suppressing the NF-κB signaling pathway. J Trace Elem Med Biol 53:8–15

    Article  CAS  PubMed  Google Scholar 

  47. Al-Harbi N, Imam F, Al-Harbi M, Al-Shabanah O, Alotaibi M, As Sobeai H, Afzal M, Kazmi I, Al Rikabi A (2019) Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway. Inflammopharmacology 27(4):817–827

    Article  CAS  PubMed  Google Scholar 

  48. Wang L, Li X, Yang Z, Pan X, Liu X, Zhu M, Xie J (2017) Crotonaldehyde induces autophagy-mediated cytotoxicity in human bronchial epithelial cells via PI3K, AMPK and MAPK pathways. Environ Pollut 228:287–296

    Article  CAS  PubMed  Google Scholar 

  49. Zhirong Z, Qiaojian Z, Chunjing X, Shengchen W, Jiahe L, Zhaoyi L, Shu L (2021) Methionine selenium antagonizes LPS-induced necroptosis in the chicken liver via the miR-155/TRAF3/MAPK axis. J Cell Physiol 236(5):4024–4035. https://doi.org/10.1002/jcp.30145

  50. Jia X, Zhang Q, Niu Q (2014) MAPK signaling pathways involved in aluminum-induced apoptosis and necroptosis in SH-SY5Y cells. Wei Sheng Yan Jiu 43(6):917–922

  51. Wang L, Shi X, Zheng S, Xu S (2020) Selenium deficiency exacerbates LPS-induced necroptosis by regulating miR-16-5p targeting PI3K in chicken tracheal tissue. Metallomics 12(4):562–571

    Article  CAS  PubMed  Google Scholar 

  52. Qin S, Yang C, Huang W, Du S, Mai H, Xiao J, Lü T (2018) Sulforaphane attenuates microglia-mediated neuronal necroptosis through down-regulation of MAPK/NF-κB signaling pathways in LPS-activated BV-2 microglia. Pharmacol Res 133:218–235

    Article  CAS  PubMed  Google Scholar 

  53. Yuan L, Wu Y, Ren X, Liu Q, Wang J, Liu X (2014) Isoorientin attenuates lipopolysaccharide-induced pro-inflammatory responses through down-regulation of ROS-related MAPK/NF-κB signaling pathway in BV-2 microglia. Mol Cell Biochem 386:153–165

    Article  CAS  PubMed  Google Scholar 

  54. Chi Q, Wang D, Hu X, Li S, Li S (2019) κHydrogen sulfide gas exposure induces necroptosis and promotes inflammation through the MAPK/NF-B pathway in broiler spleen. Oxid Med Cell Longev 2019:8061823

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Yu X, Ruan Y, Huang X, Dou L, Lan M, Cui J, Chen B, Gong H, Wang Q, Yan M, Sun S, Qiu Q, Zhang X, Man Y, Tang W, Li J, Shen T (2020) Dexrazoxane ameliorates doxorubicin-induced cardiotoxicity by inhibiting both apoptosis and necroptosis in cardiomyocytes. Biochem Biophys Res Commun 523(1):140–146

    Article  CAS  PubMed  Google Scholar 

  56. Qin L, Zhang Y, Wan C, Wang Z, Cong Y, Li S (2020) MiR-196-5p involvement in selenium deficiency-induced immune damage via targeting of NFκBIA in the chicken trachea. Metallomics 12(11):1679–1692

    Article  CAS  PubMed  Google Scholar 

  57. Zhang Y, Su S, Zhao S, Yang Z, Zhong C, Chen X, Cai Q, Yang Z, Huang D, Wu R, Han J (2017) RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat Commun 8:14329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Huang W, Xie W, Gong J, Wang W, Cai S, Huang Q, Chen Z, Liu Y (2020) Heat stress induces RIP1/RIP3-dependent necroptosis through the MAPK, NF-κB, and c-Jun signaling pathways in pulmonary vascular endothelial cells. Biochem Biophys Res Commun 528(1):206–212

    Article  CAS  PubMed  Google Scholar 

  59. Nafees S, Rashid S, Ali N, Hasan S, Sultana S (2015) Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact 231:98–107

    Article  CAS  PubMed  Google Scholar 

  60. Na J, Song K, Kim S, Kwon J (2016) Rutin protects rat articular chondrocytes against oxidative stress induced by hydrogen peroxide through SIRT1 activation. Biochem Biophys Res Commun 473(4):1301–1308

    Article  CAS  PubMed  Google Scholar 

  61. Zhao Y, Zhang C, Wei X, Li P, Cui Y, Qin Y, Wei X, Jin M, Kohama K, Gao Y (2015) Heat shock protein 60 stimulates the migration of vascular smooth muscle cells via Toll-like receptor 4 and ERK MAPK activation. Sci Rep 5:15352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Johnston A, Wang Z (2020) HSP70 promotes MLKL polymerization and necroptosis. Mol Cell Oncol 7(5):1791561

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhao X, Chen Z, Zhao J, Zhang P, Pu Y, Jiang S, Hou J, Cui Y, Jia X, Zhang S (2016) Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis. Cell Death Dis 7:e2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jacobsen A, Lowes K, Tanzer M, Lucet I, Hildebrand J, Petrie E, van Delft M, Liu Z, Conos S, Zhang J, Huang D, Silke J, Lessene G, Murphy J (2016) HSP90 activity is required for MLKL oligomerisation and membrane translocation and the induction of necroptotic cell death. Cell Death Dis 7:e2051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the Elsevier English Language Editing System for correcting grammatical, spelling, and other common errors.

Funding

This study was supported by the Foundation Item of Heilongjiang University of Chinese Medicine (Project No.15041200003).

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Authors and Affiliations

  1. College of Pharmacy, Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Harbin, 150040, China

    Lili Liu & Yuan Liu

  2. Drug Safety Evaluation Center, Heilongjiang University of Chinese Medicine, Harbin, 150040, China

    Liangyou Zhao

  3. Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary, College of Veterinary, Northeast Agricultural University, No. 600 Changjiang Street, Harbin, 150030, China

    Xiaoli Yu & Xinyuan Qiao

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  1. Lili Liu
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  3. Yuan Liu
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Liu, L., Zhao, L., Liu, Y. et al. Rutin Ameliorates Cadmium-Induced Necroptosis in the Chicken Liver via Inhibiting Oxidative Stress and MAPK/NF-κB Pathway. Biol Trace Elem Res 200, 1799–1810 (2022). https://doi.org/10.1007/s12011-021-02764-5

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