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Curcumin confers hepatoprotection against AFB1-induced toxicity via activating autophagy and ameliorating inflammation involving Nrf2/HO-1 signaling pathway

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Abstract

The current study demonstrated curcumin intervention against AFB1-indeuced hepatotoxicity. The hallmarks of autophagy and inflammation were assessed by transmission electron microscopy, RT-PCR and western blot. Besides, normal cellular morphology, autophagosomes were found in control and curcumin control group. In contrast, fragmented and swollen mitochondria, irregular shaped nuclei and fat droplets were visible but autophagosomes disappear in AFB1-treated group. The mRNA and protein expression levels of autophagy-related genes indicated that AFB1 significantly inhibited autophagy and induced inflammation. In addition, Nrf2 and HO-1 mRNA and protein level was significantly (p < 0.05) reduced in AFB1-fed group. Intriguingly, dietary curcumin supplementation modulated autophagy through the activation of beclin-1, ATG5, Dynein, LC3a, LC3b-I/II and downregulation of p53 & mTOR expression level. Curcumin significantly ameliorated AFB1-induced inflammation. Moreover, curcumin treatment significantly (p < 0.05) elevated AFB1-induced decrease in Nrf2 and HO-1 mRNA and protein expression level. In summary, curcumin activated autophagy and ameliorated inflammation involving Nrf2 signaling pathway which may become a new targeted therapy to prevent AFB1-induced hepatotoxicity.

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References

  1. Sridhar M, Suganthi RU, Thammiaha V (2015) Effect of dietary resveratrol in ameliorating aflatoxin B1-induced changes in broiler birds. J Anim Physiol Anim Nutr. https://doi.org/10.1111/jpn.12260

    Article  Google Scholar 

  2. Liu Y, Wu F (2010) Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 118(6):818–824

    Article  CAS  Google Scholar 

  3. Diaz G, Murcia H, Cepeda S (2010) Cytochrome P450 enzymes involved in the metabolism of aflatoxin B1 in chickens and quail. Poult Sci 89(11):2461–2469

    Article  CAS  Google Scholar 

  4. Wang X, Muhammad I, Sun X, Han M, Hamid S, Zhang X (2018) Protective role of curcumin in ameliorating AFB1-induced apoptosis via mitochondrial pathway in liver cells. Mol Biol Rep. https://doi.org/10.1007/s11033-018-4234-4

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oguz H, Kurtoglu V, Coskun B (2000) Preventive efficacy of clinoptilolite in broilers during chronic aflatoxin (50 and 100 ppb) and clinoptilolite exposure. Res Vet Sci 69:197–201

    Article  CAS  Google Scholar 

  6. Ferenčík M, Ebringer L (2003) Modulatory effects of selenium and zinc on the immune system. Folia Microbiol 48:417–426. https://doi.org/10.1007/BF02931378

    Article  Google Scholar 

  7. Stettler P, Sengstag C (2001) Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell line. Mol Carcinog 31:125–138. https://doi.org/10.1002/mc.1047

    Article  CAS  PubMed  Google Scholar 

  8. Saini SS, Kaur A (2012) Aflatoxin B1: toxicity, characteristics and analysis: mini review. Glob Adv Res J Chem Mater Sci 1:63–70

    Google Scholar 

  9. Corcuera L-A, Vettorazzi A, Arbillaga L, Pérez N, Gil AG, Azqueta A, González-Peñas E, García-Jalón JA, de Cerain AL (2015) Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay. Food Chem Toxicol 76:116–124. https://doi.org/10.1016/j.fct.2014.12.003

    Article  CAS  PubMed  Google Scholar 

  10. Muhammad I, Sun X, Wang H, Li W, Wang X, Cheng P, Li S, Zhang X, Hamid S (2017) Curcumin successfully inhibited the computationally identified CYP2A6 enzyme mediated bioactivation of aflatoxin B1 in arbor acres broiler. Front Pharmacol 8:143. https://doi.org/10.3389/fphar.2017.00143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mughal MJ, Peng X, Zhou Y, Fang J (2017) Aflatoxin B1 invokes apoptosis via death receptor pathway in hepatocytes. Oncotarget 8(5):8239–8249. https://doi.org/10.18632/oncotarget.14158

    Article  PubMed  Google Scholar 

  12. Peng X, Yu Z, Liang N, Chi X, Li X, Jiang M, Fang J, Cui H, Lai W, Zhou Y (2016) The mitochondrial and death receptor pathways involved in the thymocytes apoptosis induced by aflatoxin B1. Oncotarget 7:12222–12234. https://doi.org/10.18632/oncotarget.7731

    Article  PubMed  PubMed Central  Google Scholar 

  13. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16(7):966–975. https://doi.org/10.1038/cdd.2009.33

    Article  CAS  PubMed  Google Scholar 

  14. He Z1, Simon HU (2013) Autophagy protects from liver injury. Cell Death Differ 20:850–851; https://doi.org/10.1038/cdd.2013.43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mihalache CC, Simon HU (2012) Autophagy regulation in macrophages and neutrophils. Exp Cell Res 318:1187–1192. https://doi.org/10.1016/j.yexcr.2011.12.021

    Article  CAS  PubMed  Google Scholar 

  16. Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signaling. Biochem J 441:523–540. https://doi.org/10.1042/BJ20111451

    Article  CAS  PubMed  Google Scholar 

  17. Paul S, Jakhar R, Bhardwaj M, Kang SC (2015) Glutathione-S-transferase omega 1 (GSTO1-1) acts as mediator of signaling pathways involved in aflatoxin B1-induced apoptosis-autophagy crosstalk in macrophages. Free Radic Biol Med 89:1218–1230. https://doi.org/10.1016/j.freeradbiomed.2015.11.006

    Article  CAS  PubMed  Google Scholar 

  18. An Y, Shi X, Tang X, Wang Y, Shen F, Zhang Q, Wang C, Jiang M, Liu M, Yu L (2017) Aflatoxin B1 induces reactive oxygen species-mediated autophagy and extracellular trap formation in macrophages. Front Cell Infect Microbiol 7:53. https://doi.org/10.3389/fcimb.2017.00053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim SH, Jeong H, Kim YK, Cho SH, Min KU, Kim YY (2001) IgE mediated occupational asthma induced by herbal medicine, Banha (Pinellia ternata). Clin Exp Allergy 31:779–781. https://doi.org/10.1046/j.1365-2222.2001.01067.x

    Article  CAS  PubMed  Google Scholar 

  20. Tacchini L, Pogliaghi G, Radice L, Anzon E, Bernelli-Zazzera A (1995) Differential activation of heat-shock and oxidation-specific stress genes in chemically induced oxidative stress. Biochem J 309(Pt 2):453–459

    Article  CAS  Google Scholar 

  21. Chawanthayatham S, Valentine CC, Fedeles BI et al (2017) Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma. Proc Natl Acad Sci USA 114(15):E3101–E3109. https://doi.org/10.1073/pnas.1700759114

    Article  CAS  PubMed  Google Scholar 

  22. Long M, Zhang Y, Li P et al (2016) Intervention of grape seed proanthocyanidin extract on the subchronic immune injury in mice induced by aflatoxin B1. Int J Mol Sci 17(4):516. https://doi.org/10.3390/ijms17040516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yarru LP, Settivari RS, Gowda NK, Antoniou E, Ledoux DR, Rottinghaus GE (2009) Effects of turmeric (Curcuma longa) on the expression of hepatic genes associated with biotransformation, antioxidant, and immune systems in broiler chicks fed aflatoxin. Poult Sci 88:2620–2627

    Article  CAS  Google Scholar 

  24. Li Y, Ma Q-G, Zhao L-H et al (2014) Effects of lipoic acid on immune function, the antioxidant defense system, and inflammation-related genes expression of broiler chickens fed aflatoxin contaminated diets. Int J Mol Sci 15(4):5649–5662. https://doi.org/10.3390/ijms15045649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aggarwal BB, Sundaram C, Malani N et al (2007) Curcumin: the Indian solid gold. Adv Exp Med Biol 595:1–75

    Article  Google Scholar 

  26. Ahsan H, Parveen N, Khan NU et al (1999) Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 121(2):161–175

    Article  CAS  Google Scholar 

  27. Sreejayan N, Rao MN (1996) Free radical scavenging activity of curcuminoids. Arzneimittelforschung 46(2):169–171

    CAS  PubMed  Google Scholar 

  28. Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as Curecumin: from kitchen to clinic. Biochem Pharmacol 75(4):787–809

    Article  CAS  Google Scholar 

  29. Anand P, Sundaram C, Jhurani S et al (2008) Curcumin and cancer: an ‘‘old-age” disease with an ‘‘age-old” solution. Cancer Lett 267(1):133–164

    Article  CAS  Google Scholar 

  30. Wang XS, Liu C, Khoso PA et al (2017) Autophagy response in the liver of pigeon exposed to avermectin. Environ Sci Pollut Res 24:12767. https://doi.org/10.1007/s11356016-6209-0

    Article  CAS  Google Scholar 

  31. Cheng P, Wang T, Li W, Muhammad I, Wang H, Sun X, Yang Y, Li J, Xiao T, Zhang X (2017) Baicalin alleviates Lipopolysaccharide-induced liver inflammation in chicken by suppressing TLR4-mediated NF-κB pathway. Front Pharmacol 8:547. https://doi.org/10.3389/fphar.2017.00547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang J, Yi M, Chen X, Muhammad I, Liu F, Li R, Li J, Li J (2106) Effects of colistin on amino acid neurotransmitters and blood-brain barrier in the mouse brain. Neurotoxicol Teratol 55:32–37

    Article  Google Scholar 

  33. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real time quantitative PCR and the 2−ΔΔC t method. Methods 25(4):402–408

    Article  CAS  Google Scholar 

  34. Lu Z, Miao Y, Muhammad I, Tian E, Hu W, Wang J, Wang B, Li R, Li J (2017) Colistin-induced autophagy and apoptosis involves the JNK-Bcl2-Bax signaling pathway and JNK-p53-ROS positive feedback loop in PC-12 cells. Chem Biol Interact 277:62–73. https://doi.org/10.1016/j.cbi.2017.08.011

    Article  CAS  PubMed  Google Scholar 

  35. Kobayashi M, Yamamoto M (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 46:113–140

    Article  CAS  Google Scholar 

  36. Xu W, Zheng D, Liu Y, Li J, Yang L, Shang X, Glaucocalyxin B (2017) Alleviates Lipopolysaccharide-induced Parkinson’s disease by inhibiting TLR/NF-κB and activating Nrf2/HO-1 pathway. Cell Physiol Biochem 44:2091–2104

    Article  CAS  Google Scholar 

  37. Labban L (2014) Medicinal and pharmacological properties of Turmeric (Curcuma longa): a review. Int J Pharm Biomed Sci 5(1):17–23

    Google Scholar 

  38. Bundy R, Walker AF, Middleton RW, Booth J (2004) Turmeric extract mayimprove irritable bowel syndrome symptomology in otherwise healthyadults: a pilot study. J Altern Complement Med 10:1015–1018

    Article  Google Scholar 

  39. Park EJ, Jeon CH, Ko G, Kim J, Sohn DH (2000) Protective effect of curcumin in rat liver injury induced by carbon tetrachloride. J Pharm Pharmacol 52:437–440

    Article  CAS  Google Scholar 

  40. Maiuri C, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Rev Mol Cell Biol 8:741–752

    Article  CAS  Google Scholar 

  41. Jewell JL, Russell RC, Guan KL (2013) Amino acid signaling upstream of mTOR. Nat Rev Mol Cell Biol 14:133–139

    Article  CAS  Google Scholar 

  42. Matsunaga K, Saitoh T, Tabata K et al (2009) Two Beclin 1-binding proteins, ATG14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396

    Article  CAS  Google Scholar 

  43. Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM (2016) LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J 30(12):3961–3978

    Article  CAS  Google Scholar 

  44. Shah SZA, Zhao D, Hussain T, Yang L (2017) Role of the AMPK pathway in promoting autophagic flux via modulating mitochondrial dynamics in neurodegenerative diseases: insight into prion diseases. Ageing Res Rev 40:51–63. https://doi.org/10.1016/j.arr.2017.09.004

    Article  CAS  PubMed  Google Scholar 

  45. Naoki Shinojima T, Yokoyama YK, Kondo S (2007) Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3(6):635–637. https://doi.org/10.4161/auto.4916

    Article  PubMed  Google Scholar 

  46. Loft S, Poulsen HE (1996) Cancer risk and oxidative DNA damage in man. J Mol Med (Berl) 74:297–312

    Article  CAS  Google Scholar 

  47. Mohajeri M, Behnam B, Cicero AFG, Sahebkar A (2018) Protective effects of curcumin against aflatoxicosis: a comprehensive review. J Cell Physiol 233:3552–3577. https://doi.org/10.1002/jcp.26212

    Article  CAS  PubMed  Google Scholar 

  48. Aggarwal BB, Sung B (2009) Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 30(2):85–94

    Article  CAS  Google Scholar 

  49. Nahar PP, Slitt AL, Seeram NP (2015) Anti-inflammatory effects of novel standardized solid lipid curcumin formulations. J Med Food 18(7):786–792. https://doi.org/10.1089/jmf.2014.0053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sahin K, Orhan C, Tuzcu Z, Tuzcu M, Sahin N (2012) Curcumin ameloriates heat stress via inhibition of oxidative stress and modulation of Nrf2/HO-1 pathway in quail. Food Chem Toxicol 50(11):4035–4041. https://doi.org/10.1016/j.fct.2012.08.029

    Article  CAS  PubMed  Google Scholar 

  51. Calabrese V, Signorile A, Cornelius C, Mancuso C, Scapagnini G, Ventimiglia B, Ragusa N, Dinkova-Kostova A (2008) Practical approaches to investigate redox regulation of heat shock protein expression and intracellular glutathione redox state. Methods Enzymol 441:83–110

    Article  CAS  Google Scholar 

  52. Mancuso C, Barone E (2009) The heme oxygenase/biliverdin reductase pathway in drug research and development. Curr Drug Metab 10:579–594

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the National Natural Science Foundation of China (Registration Number: 31172369) and the Natural Science Foundation of Heilongjiang Province (Registration Number: ZD201405) for providing financial funding.

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Author notes

  1. Ishfaq Muhammad and Xinghe Wang have contributed equally to this work.

Authors and Affiliations

  1. Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, People’s Republic of China

    Ishfaq Muhammad, Sihong Li, Rui Li & Xiuying Zhang

  2. Laboratory of Veterinary Pathology, Faculty of Basic Veterinary Science, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, People’s Republic of China

    Xinghe Wang

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  1. Ishfaq Muhammad
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Correspondence to Xiuying Zhang.

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All the experimental protocols were approved by Harbin Veterinary Research Institute Animal Ethics Committee (No. SYXK (Hei) 2012-2067) working under the guidelines and supervision of Chinese Academy of Agricultural Sciences (China).

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Muhammad, I., Wang, X., Li, S. et al. Curcumin confers hepatoprotection against AFB1-induced toxicity via activating autophagy and ameliorating inflammation involving Nrf2/HO-1 signaling pathway. Mol Biol Rep 45, 1775–1785 (2018). https://doi.org/10.1007/s11033-018-4323-4

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