Back to Nucleus: Combating with Cadmium Toxicity Using Nrf2 Signaling Pathway as a Promising Therapeutic Target

  • Milad Ashrafizadeh
  • Zahra Ahmadi
  • Tahereh Farkhondeh
  • Saeed SamarghandianEmail author


There are concerns about the spread of heavy metals in the environment, and human activities are one of the most important factors in their spread. These agents have the high half-life resulting in their persistence in the environment. So, prevention of their spread is the first step. However, heavy metals are an inevitable part of modern and industrial life and they are applied in different fields. Cadmium is one of the heavy metals which has high carcinogenesis ability. Industrial waste, vehicle emissions, paints, and fertilizers are ways of exposing human to cadmium. This potentially toxic agent harmfully affects the various organs and systems of body such as the liver, kidney, brain, and cardiovascular system. Oxidative stress is one of the most important pathways of cadmium toxicity. So, improving the antioxidant defense system can be considered as a potential target. On the other hand, the Nrf2 signaling pathway involves improving the antioxidant capacity by promoting the activity of antioxidant enzymes such as catalase and superoxide dismutase. At the present review, we demonstrate how Nrf2 signaling pathway can be modulated to diminish the cadmium toxicity.


Antioxidant Cadmium Nrf2 signaling pathway Oxidative stress Toxicity 



Agency for Toxic Substance and Disease Registry




Endoplasmic reticulum


Inducible nitric oxide synthase


Nuclear factor erythroid 2-related factor 2


Cap “n” Collar


Kelch-like ECH-associated protein 1


Antioxidant response element


Heme oxygenase-1


NADPH quinone oxidoreductase 1




Superoxide dismutase


Reactive oxygen species


Alzheimer’s disease


Parkinson’s disease


Protein kinase R-like ER kinase




Long non-coding RNA


Tumor necrosis factor-α


Kidney injury molecule-1










Mammalian target of rapamycin




Neurological disorders


Blood-brain barrier








Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ahmad M, Taweel GMA, Hidayathulla S (2018) Nano-composites chitosan-curcumin synergistically inhibits the oxidative stress induced by toxic metal cadmium. Int J Biol Macromol 108:591–597PubMedCrossRefGoogle Scholar
  2. 2.
    Ahmadi Z, Ashrafizadeh M (2018) Downregulation of osteocalcin gene in chickens treated with lead acetate II. Int Biol Biomed J 4(4):0–0Google Scholar
  3. 3.
    Ahmadi Z, Ashrafizadeh M (2019) Down regulation of osteocalcin gene in chickens treated with cadmium. Iranian Journal of Toxicology 13(1):1–4Google Scholar
  4. 4.
    Ahmadi Z, Ashrafizadeh M (2019) Melatonin as a potential modulator of Nrf2. Fundam Clin PharmacolGoogle Scholar
  5. 5.
    Ahmadi Z et al (2019) The targeting of autophagy and endoplasmic reticulum stress mechanisms by honokiol therapy. Rev Clin Med 6(2):66–73Google Scholar
  6. 6.
    Ahmadi Z, Mohammadinejad R, Ashrafizadeh M (2019) Drug delivery systems for resveratrol, a non-flavonoid polyphenol: emerging evidence in last decades. J Drug Deliv Sci Technol 51:591–604CrossRefGoogle Scholar
  7. 7.
    Akinyemi AJ, Onyebueke N, Faboya OA, Onikanni SA, Fadaka A, Olayide I (2017) Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney. J Food Drug Anal 25(2):438–446PubMedCrossRefGoogle Scholar
  8. 8.
    Aladaileh SH et al (2019) Formononetin upregulates Nrf2/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats. Antioxidants (Basel) 8(10). PubMedCentralCrossRefGoogle Scholar
  9. 9.
    Almeer RS, Alarifi S, Alkahtani S, Ibrahim SR, Ali D, Moneim A (2018) The potential hepatoprotective effect of royal jelly against cadmium chloride-induced hepatotoxicity in mice is mediated by suppression of oxidative stress and upregulation of Nrf2 expression. Biomed Pharmacother 106:1490–1498PubMedCrossRefGoogle Scholar
  10. 10.
    Almeer R et al (2018) Royal jelly abrogates cadmium-induced oxidative challenge in mouse testes: involvement of the Nrf2 pathway. Int J Mol Sci 19(12):3979PubMedCentralCrossRefGoogle Scholar
  11. 11.
    Almeer RS et al (2018) Royal jelly mitigates cadmium-induced neuronal damage in mouse cortex. Mol Biol Rep 46(1):119–131PubMedCrossRefGoogle Scholar
  12. 12.
    Almeer RS, AlBasher G, Alarifi S, Alkahtani S, Ali D, Abdel Moneim AE (2019) Royal jelly attenuates cadmium-induced nephrotoxicity in male mice. Sci Rep 9(1):5825PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Almeer RS, Kassab RB, AlBasher G, Alarifi S, Alkahtani S, Ali D, Abdel Moneim AE (2019) Royal jelly mitigates cadmium-induced neuronal damage in mouse cortex. Mol Biol Rep 46(1):119–131PubMedCrossRefGoogle Scholar
  14. 14.
    Asadi N, Kheradmand A, Gholami M, Saidi SH, Mirhadi SA (2019) Effect of royal jelly on testicular antioxidant enzymes activity, MDA level and spermatogenesis in rat experimental Varicocele model. Tissue Cell 57:70–77PubMedCrossRefGoogle Scholar
  15. 15.
    Ashrafizadeh M, Ahmadi Z (2019) Effects of statins on gut microbiota (microbiome). Rev Clin Med 6(2):55–59Google Scholar
  16. 16.
    Ashrafizadeh M, Ahmadi Z (2019) Effect of astaxanthin treatment on the sperm quality of the mice treated with nicotine. Rev Clin Med 6(1):1–5Google Scholar
  17. 17.
    Ashrafizadeh M, Rafiei H, Ahmadi Z (2018) Histological changes in the liver and biochemical parameters of chickens treated with lead acetate II. Iran J Toxicol 12(6):1–5Google Scholar
  18. 18.
    Ashrafizadeh M et al (2019) Autophagy, anoikis, ferroptosis, necroptosis, and endoplasmic reticulum stress: potential applications in melanoma therapy. J Cell Physiol 234(11):19471–19479PubMedCrossRefGoogle Scholar
  19. 19.
    Ashrafizadeh M et al (2019) Nanoparticles targeting STATs in cancer therapy. Cells 8(10):1158PubMedCentralCrossRefGoogle Scholar
  20. 20.
    Ashrafizadeh M et al (2019) Modulatory effects of statins on the autophagy: a therapeutic perspective. J Cell Physiol.
  21. 21.
    Ashrafizadeh M et al (2019) Autophagy as a molecular target of quercetin underlying its protective effects in human diseases. Arch Physiol Biochem:1–9.
  22. 22.
    Ashrafizadeh M et al (2019) Effects of newly introduced antidiabetic drugs on autophagy. Diabetes Metab Syndr 13(4):2445–2449CrossRefGoogle Scholar
  23. 23.
    Ashrafizadeh M et al (2019) MicroRNAs mediate the anti-tumor and protective effects of ginsenosides. Nutr Cancer:1–12.
  24. 24.
    Ashrafizadeh M et al Monoterpenes modulating autophagy: a review study. Basic Clin Pharmacol Toxicol
  25. 25.
    Ashrafizadeh M et al Therapeutic and biological activities of berberine: the involvement of Nrf2 signaling pathway. J Cell Biochem 0(0).
  26. 26.
    Samarghandian S et al Catechin treatment ameliorates diabetes and its complications in streptozotocin-induced diabetic rats. Dose-Response 15(1):1559325817691158CrossRefGoogle Scholar
  27. 27.
    Badisa VL et al (2007) Mechanism of DNA damage by cadmium and interplay of antioxidant enzymes and agents. Environ Toxicol 22(2):144–151PubMedCrossRefGoogle Scholar
  28. 28.
    Bahri S, Kaddour H, Karoui D, Bouraoui S, Amri M, Mokni M (2019) Protective role of vitamin E against cadmium induced oxidative stress into the rat liver. Tunis Med 97(1):100–105PubMedGoogle Scholar
  29. 29.
    Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, Chen Q, Tan Y, Cui T, Zheng Y, Cai L (2013) Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol 57:82–95PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Banik S et al (2019) Carvacrol inhibits cadmium toxicity through combating against caspase dependent/independent apoptosis in PC12 cells. Food Chem Toxicol 134:110835. PubMedCrossRefGoogle Scholar
  31. 31.
    Banni M, Chouchene L, Said K, Kerkeni A, Messaoudi I (2011) Mechanisms underlying the protective effect of zinc and selenium against cadmium-induced oxidative stress in zebrafish Danio rerio. Biometals 24(6):981–992PubMedCrossRefGoogle Scholar
  32. 32.
    Bashir N et al (2019) The molecular and biochemical insight view of grape seed proanthocyanidins in ameliorating cadmium-induced testes-toxicity in rat model: implication of PI3K/Akt/Nrf-2 signaling. Biosci Rep 39(1):BSR20180515PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Benvenga S et al (2019) Effects of Myo-inositol alone and in combination with Seleno-L-methionine on cadmium-induced testicular damage in mice. Curr Mol Pharmacol 12(4):311–323PubMedCrossRefGoogle Scholar
  34. 34.
    Beryllium I (1993) Cadmium, mercury, and exposures in the glass manufacturing industry. Working group views and expert opinions, Lyon, 9–16 February 1993. IARC Monogr Eval Carcinog Risks Hum 58:1–415Google Scholar
  35. 35.
    Branca JJV, Morucci G, Pacini A (2018) Cadmium-induced neurotoxicity: still much ado. Neural Regen Res 13(11):1879–1882PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Cai S-A et al (2018) Nrf2 is a key regulator on puerarin preventing cardiac fibrosis and upregulating metabolic enzymes UGT1A1 in rats. Front Pharmacol 9:540PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Cai Y et al (2019) Cadmium exposure affects growth performance, energy metabolism, and neuropeptide expression in Carassius auratus gibelio. Fish Physiol Biochem.
  38. 38.
    Caixeta DC, Teixeira RR, Peixoto LG, Machado HL, Baptista NB, de Souza AV, Vilela DD, Franci CR, Salmen Espindola F (2018) Adaptogenic potential of royal jelly in liver of rats exposed to chronic stress. PLoS One 13(1):e0191889PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Calderon-Garciduenas L, Reynoso-Robles R, Gonzalez-Maciel A (2019) Combustion and friction-derived nanoparticles and industrial-sourced nanoparticles: the culprit of Alzheimer and Parkinson’s diseases. Environ Res 176:108574PubMedCrossRefGoogle Scholar
  40. 40.
    Çavuşoğlu K, Yapar K, Yalçin E (2009) Royal jelly (honey bee) is a potential antioxidant against cadmium-induced genotoxicity and oxidative stress in albino mice. J Med Food 12(6):1286–1292PubMedCrossRefGoogle Scholar
  41. 41.
    Chen W-Y, Chen TY, Hsieh NH, Ju YT (2016) Site-specific water quality criteria for lethal/sublethal protection of freshwater fish exposed to zinc in southern Taiwan. Chemosphere 159:412–419PubMedCrossRefGoogle Scholar
  42. 42.
    Chhunchha B, Kubo E, Singh DP (2019) Sulforaphane-induced Klf9/Prdx6 Axis acts as a molecular switch to control redox signaling and determines fate of \cells. Cells 8(10). PubMedCentralCrossRefGoogle Scholar
  43. 43.
    Cho H-Y (2013) Genomic structure and variation of nuclear factor (erythroid-derived 2)-like 2. Oxidative Med Cell Longev 2013:286524. Google Scholar
  44. 44.
    Chouchene L, Banni M, Kerkeni A, Saïd K, Messaoudi I (2011) Cadmium-induced ovarian pathophysiology is mediated by change in gene expression pattern of zinc transporters in zebrafish (Danio rerio). Chem Biol Interact 193(2):172–179PubMedCrossRefGoogle Scholar
  45. 45.
    Chouchene L, Pellegrini E, Gueguen MM, Hinfray N, Brion F, Piccini B, Kah O, Saïd K, Messaoudi I, Pakdel F (2016) Inhibitory effect of cadmium on estrogen signaling in zebrafish brain and protection by zinc. J Appl Toxicol 36(6):863–871PubMedCrossRefGoogle Scholar
  46. 46.
    Cobb-Abdullah A et al (2019) Diallyl disulfide attenuation effect on transcriptome in rat liver cells against cadmium chloride toxicity. Environ Toxicol 34(8):950–957PubMedCrossRefGoogle Scholar
  47. 47.
    Deng Y, Tang K, Chen R, Nie H, Liang S, Zhang J, Zhang Y, Yang Q (2019) Berberine attenuates hepatic oxidative stress in rats with non-alcoholic fatty liver disease via the Nrf2/ARE signalling pathway. Exp Ther Med 17(3):2091–2098PubMedPubMedCentralGoogle Scholar
  48. 48.
    Driessnack MK, Jamwal A, Niyogi S (2017) Effects of chronic waterborne cadmium and zinc interactions on tissue-specific metal accumulation and reproduction in fathead minnow (Pimephales promelas). Ecotoxicol Environ Saf 140:65–75PubMedCrossRefGoogle Scholar
  49. 49.
    Faroon O, et al (2012) Toxicological profile for cadmium. Google Scholar
  50. 50.
    Filippini T, Malagoli C, Wise LA, Malavolti M, Pellacani G, Vinceti M (2019) Dietary cadmium intake and risk of cutaneous melanoma: an Italian population-based case-control study. J Trace Elem Med Biol 56:100–106PubMedCrossRefGoogle Scholar
  51. 51.
    Fırat Ö, Kargın F (2010) Effects of zinc and cadmium on erythrocyte antioxidant systems of a freshwater fish Oreochromis niloticus. J Biochem Mol Toxicol 24(4):223–229PubMedCrossRefGoogle Scholar
  52. 52.
    Fonseca LM, Cruxen CEDS, Bruni GP, Fiorentini ÂM, Zavareze EDR, Lim LT, Dias ARG (2019) Development of antimicrobial and antioxidant electrospun soluble potato starch nanofibers loaded with carvacrol. Int J Biol Macromol 139:1182–1190PubMedCrossRefGoogle Scholar
  53. 53.
    Fu C, Chen B, Jin X, Liu X, Wang F, Guo R, Chen Z, Zheng H, Wang L, Zhang Y (2018) Puerarin protects endothelial progenitor cells from damage of angiotensin II via activation of ERK1/2-Nrf2 signaling pathway. Mol Med Rep 17(3):3877–3883PubMedGoogle Scholar
  54. 54.
    Fujiki K et al (2019) Blockade of ALK4/5 signaling suppresses cadmium-and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms. Cell Death Differ 26(11):2371–2385CrossRefGoogle Scholar
  55. 55.
    Gabr SA, Alghadir AH, Ghoniem GA (2019) Biological activities of ginger against cadmium-induced renal toxicity. Saudi J Biol Sci 26(2):382–389PubMedCrossRefGoogle Scholar
  56. 56.
    Ge J, Zhang C, Sun YC, Zhang Q, Lv MW, Guo K, Li JL (2019) Cadmium exposure triggers mitochondrial dysfunction and oxidative stress in chicken (Gallus gallus) kidney via mitochondrial UPR inhibition and Nrf2-mediated antioxidant defense activation. Sci Total Environ 689:1160–1171PubMedCrossRefGoogle Scholar
  57. 57.
    Gong Z-G, Wang XY, Wang JH, Fan RF, Wang L (2019) Trehalose prevents cadmium-induced hepatotoxicity by blocking Nrf2 pathway, restoring autophagy and inhibiting apoptosis. J Inorg Biochem 192:62–71PubMedCrossRefGoogle Scholar
  58. 58.
    Gureev AP, Popov VN (2019) Nrf2/ARE pathway as a therapeutic target for the treatment of Parkinson diseases. Neurochem Res 157:84–104Google Scholar
  59. 59.
    Hassanein EHM, Shalkami AS, Khalaf MM, Mohamed WR, Hemeida RAM (2019) The impact of Keap1/Nrf2, P38MAPK/NF-kappaB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity. Biomed Pharmacother 109:47–56PubMedCrossRefGoogle Scholar
  60. 60.
    He L, Li P, Yu LH, Li L, Zhang Y, Guo Y, Long M, He JB, Yang SH (2018) Protective effects of proanthocyanidins against cadmium-induced testicular injury through the modification of Nrf2-Keap1 signal path in rats. Environ Toxicol Pharmacol 57:1–8PubMedCrossRefGoogle Scholar
  61. 61.
    Hou N et al (2019) Carvacrol attenuates diabetic cardiomyopathy by modulating the PI3K/AKT/GLUT4 pathway in diabetic mice. Front Pharmacol 10:998PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Huo L et al (2019) Sulforaphane protects the male reproductive system of mice from obesity-induced damage: involvement of oxidative stress and autophagy. Int J Environ Res Public Health 16(19). PubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hyder O, Chung M, Cosgrove D, Herman JM, Li Z, Firoozmand A, Gurakar A, Koteish A, Pawlik TM (2013) Cadmium exposure and liver disease among US adults. J Gastrointest Surg 17(7):1265–1273PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Järup L, Åkesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238(3):201–208PubMedCrossRefGoogle Scholar
  65. 65.
    Jiang C, Yuan Y, Hu F, Wang Q, Zhang K, Wang Y, Gu J, Liu X, Bian J, Liu Z (2014) Cadmium induces PC12 cells apoptosis via an extracellular signal-regulated kinase and c-Jun N-terminal kinase-mediated mitochondrial apoptotic pathway. Biol Trace Elem Res 158(2):249–258PubMedCrossRefGoogle Scholar
  66. 66.
    Jiang W, Li S, Chen X, Zhang W, Chang Y, He Y, Zhang S, Su X, Gao T, Li C, Jian Z (2019) Berberine protects immortalized line of human melanocytes from H2O2-induced oxidative stress via activation of Nrf2 and Mitf signaling pathway. J Dermatol Sci 94(1):236–243PubMedCrossRefGoogle Scholar
  67. 67.
    Jin A et al (2019) PHLPP2 downregulation protects cardiomyocytes against hypoxia-induced injury through reinforcing Nrf2/ARE antioxidant signaling. Chem Biol Interact 314:108848PubMedCrossRefGoogle Scholar
  68. 68.
    Ke Y et al (2019) Protective roles of Pyracantha fortuneana extract on acute renal toxicity induced by cadmium chloride in rats. Acta Cir Bras 34(7):e201900706Google Scholar
  69. 69.
    Kim J, Song H, Heo HR, Kim JW, Kim HR, Hong Y, Yang SR, Han SS, Lee SJ, Kim WJ, Hong SH (2017) Cadmium-induced ER stress and inflammation are mediated through C/EBP–DDIT3 signaling in human bronchial epithelial cells. Exp Mol Med 49(9):e372PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kim KS, Lim HJ, Lim JS, Son JY, Lee J, Lee BM, Chang SC, Kim HS (2018) Curcumin ameliorates cadmium-induced nephrotoxicity in Sprague-Dawley rats. Food Chem Toxicol 114:34–40PubMedCrossRefGoogle Scholar
  71. 71.
    Kirkham M (2006) Cadmium in plants on polluted soils: effects of soil factors, hyperaccumulation, and amendments. Geoderma 137(1–2):19–32CrossRefGoogle Scholar
  72. 72.
    Klaassen CD, Liu J, Choudhuri S (1999) METALLOTHIONEIN: an intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 39(1):267–294PubMedCrossRefGoogle Scholar
  73. 73.
    Kocovic DM et al (2019) Cadmium versus lanthanum effects on spontaneous electrical activity and expression of connexin isoforms Cx26, Cx36, and Cx45 in the human fetal cortex. Cereb Cortex.
  74. 74.
    Lanctôt CM, Cresswell T, Melvin SD (2017) Uptake and tissue distributions of cadmium, selenium and zinc in striped marsh frog tadpoles exposed during early post-embryonic development. Ecotoxicol Environ Saf 144:291–299PubMedCrossRefGoogle Scholar
  75. 75.
    Lee H-J, Yoon Y-S, Lee S-J (2018) Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction. Cell Death Dis 9(7):712PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Li H et al (2019) Piceatannol alleviates inflammation and oxidative stress via modulation of the Nrf2/HO-1 and NF-kappaB pathways in diabetic cardiomyopathy. Chem Biol Interact 310:108754PubMedCrossRefGoogle Scholar
  77. 77.
    Liang Y, Fan C, Yan X, Lu X, Jiang H, di S, Ma Z, Feng Y, Zhang Z, Feng P, Feng X, Feng J, Jin F (2019) Berberine ameliorates lipopolysaccharide-induced acute lung injury via the PERK-mediated Nrf2/HO-1 signaling axis. Phytother Res 33(1):130–148PubMedCrossRefGoogle Scholar
  78. 78.
    Liu Y, Zou J, Liu X, Zhang Q (2019) MicroRNA-138 attenuates myocardial ischemia reperfusion injury through inhibiting mitochondria-mediated apoptosis by targeting HIF1-alpha. Exp Ther Med 18(5):3325–3332PubMedPubMedCentralGoogle Scholar
  79. 79.
    Mahmoud AM et al (2019) Mesoporous silica nanoparticles trigger liver and kidney injury and fibrosis via altering TLR4/NF-kappaB, JAK2/STAT3 and Nrf2/HO-1 signaling in rats. Biomolecules 9(10):528. PubMedCentralCrossRefGoogle Scholar
  80. 80.
    Mao W, Zhang NN, Zhou FY, Li WX, Liu HY, Feng J, Zhou L, Wei CJ, Pan YB, He ZJ (2011) Cadmium directly induced mitochondrial dysfunction of human embryonic kidney cells. Hum Exp Toxicol 30(8):920–929PubMedCrossRefGoogle Scholar
  81. 81.
    Mohajeri M, Rezaee M, Sahebkar A (2017) Cadmium-induced toxicity is rescued by curcumin: a review. Biofactors 43(5):645–661PubMedCrossRefGoogle Scholar
  82. 82.
    Mohammadinejad R et al (2019) Shedding light on gene therapy: carbon dots for the minimally invasive image-guided delivery of plasmids and noncoding RNAs. J Adv Res 18:81–93Google Scholar
  83. 83.
    Mohammadinejad R et al (2019) Berberine as a potential autophagy modulator. J Cell Physiol. CrossRefGoogle Scholar
  84. 84.
    Mohebbati R et al (2019) Zataria multiflora and its main ingredient, carvacrol, affect on the renal function, histopathological, biochemical and antioxidant parameters in adriamycin-induced nephrotic rats. Arch Physiol Biochem:1–9.
  85. 85.
    Mostafa DG, Khaleel EF, Badi RM, Abdel-Aleem GA, Abdeen HM (2019) Rutin hydrate inhibits apoptosis in the brains of cadmium chloride-treated rats via preserving the mitochondrial integrity and inhibiting endoplasmic reticulum stress. Neurol Res 41(7):594–608PubMedCrossRefGoogle Scholar
  86. 86.
    Nakajima Y et al (2009) Comparison of bee products based on assays of antioxidant capacities. BMC Complement Altern Med 9(1):4PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Nasheed Hamad Almohammed Z et al (2020) The effect of melatonin on mitochondrial function and autophagy in in vitro matured oocytes of aged mice. Cell J 22(1):9–16PubMedGoogle Scholar
  88. 88.
    Oboh G, Adebayo AA, Ademosun AO, Olowokere OG (2019) Rutin alleviates cadmium-induced neurotoxicity in Wistar rats: involvement of modulation of nucleotide-degrading enzymes and monoamine oxidase. Metab Brain Dis 34(4):1181–1190PubMedCrossRefGoogle Scholar
  89. 89.
    Omotosho IO (2019) Oxidative stress indices as markers of lead and cadmium exposure toxicity in auto technicians in Ibadan, Nigeria. Oxidative Med Cell Longev 2019:3030614CrossRefGoogle Scholar
  90. 90.
    Pan Y et al (2018) Royal jelly reduces cholesterol levels, ameliorates Aβ pathology and enhances neuronal metabolic activities in a rabbit model of Alzheimer’s disease. Front Aging Neurosci 10:50PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Panel EC (2011) Scientific opinion on tolerable weekly intake for cadmium. EFSA J 9(2):19Google Scholar
  92. 92.
    Patel MS, Packer L (2008) Lipoic acid: energy production, antioxidant activity and health effects: CRC Press, 1st Edition: 556.
  93. 93.
    Patra R, Rautray AK, Swarup D (2011) Oxidative stress in lead and cadmium toxicity and its amelioration. Vet Med Int 2011:457327. CrossRefGoogle Scholar
  94. 94.
    Piotrowska H, Kucinska M, Murias M (2012) Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat Res 750(1):60–82PubMedCrossRefGoogle Scholar
  95. 95.
    Qu H (2014) Effects of sulforaphane combined with tea polyphenols on expression of protein kinase A anchorage protein 95 and cyclin E2 in lung cancer tissues. Mod Pharm Clin 10:1092–1095Google Scholar
  96. 96.
    Qu K-C, Wang ZY, Tang KK, Zhu YS, Fan RF (2019) Trehalose suppresses cadmium-activated Nrf2 signaling pathway to protect against spleen injury. Ecotoxicol Environ Saf 181:224–230PubMedCrossRefGoogle Scholar
  97. 97.
    Rafiei H, Ashrafizadeh M (2018) Expression of collagen type II and osteocalcin genes in mesenchymal stem cells from rats treated with lead acetate II. Iranian Journal of Toxicology 12(5):35–40Google Scholar
  98. 98.
    Rafiei H, Ahmadi Z, Ashrafizadeh M (2018) Effects of orally administered lead acetate II on rat femur histology, mineralization properties and expression of osteocalcin gene. Int Biol Biomed J 4(3):149–155Google Scholar
  99. 99.
    Rathi VK et al (2017) Naringin abates adverse effects of cadmium-mediated hepatotoxicity: an experimental study using HepG2 cells. J Biochem Mol Toxicol 31(8):e21915CrossRefGoogle Scholar
  100. 100.
    Raut GK et al (2019) Glucose starvation induced upregulation of Prohibitin 1 via ROS generation causes mitochondrial dysfunction and apoptosis in breast cancer cells. Free Radic Biol Med. CrossRefGoogle Scholar
  101. 101.
    Refaie MM et al (2019) Mechanisms mediating the cardioprotective effect of carvedilol in cadmium induced cardiotoxicity. Role of eNOS and HO1/Nrf2 pathway. Environ Toxicol Pharmacol:103198. PubMedCrossRefGoogle Scholar
  102. 102.
    Roumeliotis S, Eleftheriadis T, Liakopoulos V (2019) Is oxidative stress an issue in peritoneal dialysis? In Seminars in dialysis. Semin Dial 32(5):463–466PubMedCrossRefGoogle Scholar
  103. 103.
    Rudolf E, Červinka M (2011) Sulforaphane induces cytotoxicity and lysosome-and mitochondria-dependent cell death in colon cancer cells with deleted p53. Toxicol in Vitro 25(7):1302–1309PubMedCrossRefGoogle Scholar
  104. 104.
    Sabir S et al (2019) Role of cadmium and arsenic as endocrine disruptors in the metabolism of carbohydrates: inserting the association into perspectives. Biomed Pharmacother 114:108802PubMedCrossRefGoogle Scholar
  105. 105.
    Sajjad N et al (2019) Artemisia amygdalina Upregulates Nrf2 and Protects Neurons Against Oxidative Stress in Alzheimer Disease. Cell Mol Neurobiol 39(3):387–399PubMedCrossRefGoogle Scholar
  106. 106.
    Saleh HM, el-Sayed YS, Naser SM, Eltahawy AS, Onoda A, Umezawa M (2017) Efficacy of α-lipoic acid against cadmium toxicity on metal ion and oxidative imbalance, and expression of metallothionein and antioxidant genes in rabbit brain. Environ Sci Pollut Res 24(31):24593–24601CrossRefGoogle Scholar
  107. 107.
    Sarmiento-Ortega V et al (2018) The NOAEL metformin dose is ineffective against metabolic disruption induced by chronic cadmium exposure in Wistar rats. Toxics 6(3):55PubMedCentralCrossRefGoogle Scholar
  108. 108.
    Satarug S (2018) Dietary cadmium intake and its effects on kidneys. Toxics 6(1):15PubMedCentralCrossRefGoogle Scholar
  109. 109.
    Schmidt A, Bekeschus S (2018) Redox for repair: cold physical plasmas and nrf2 signaling promoting wound healing. Antioxidants 7(10):146PubMedCentralCrossRefGoogle Scholar
  110. 110.
    Setoguchi Y, Oritani Y, Ito R, Inagaki H, Maruki-Uchida H, Ichiyanagi T, Ito T (2014) Absorption and metabolism of piceatannol in rats. J Agric Food Chem 62(12):2541–2548PubMedCrossRefGoogle Scholar
  111. 111.
    Shati AA (2019) Resveratrol protects against cadmium chloride-induced hippocampal neurotoxicity by inhibiting ER stress and GAAD 153 and activating sirtuin 1/AMPK/Akt. Environ Toxicol 34(12):1340–1353PubMedCrossRefGoogle Scholar
  112. 112.
    Shi X, Fu L (2019) Piceatannol inhibits oxidative stress through modification of Nrf2-signaling pathway in testes and attenuates spermatogenesis and steroidogenesis in rats exposed to cadmium during adulthood. Drug Des Dev Ther 13:2811CrossRefGoogle Scholar
  113. 113.
    Shi C, Zhou X, Zhang J, Wang J, Xie H, Wu Z (2016) α-Lipoic acid protects against the cytotoxicity and oxidative stress induced by cadmium in HepG2 cells through regeneration of glutathione by glutathione reductase via Nrf2/ARE signaling pathway. Environ Toxicol Pharmacol 45:274–281PubMedCrossRefGoogle Scholar
  114. 114.
    Shila S, Kokilavani V, Subathra M, Panneerselvam C (2005) Brain regional responses in antioxidant system to α-lipoic acid in arsenic intoxicated rat. Toxicology 210(1):25–36PubMedCrossRefGoogle Scholar
  115. 115.
    Shin JH, Park SJ, Jo DS, Park NY, Kim JB, Bae JE, Jo YK, Hwang JJ, Lee JA, Jo DG, Kim JC, Jung YK, Koh JY, Cho DH (2019) Down-regulated TMED10 in Alzheimer disease induces autophagy via ATG4B activation. Autophagy 15(9):1495–1505PubMedCrossRefGoogle Scholar
  116. 116.
    Singh KB et al (2019) Reversal of the Warburg phenomenon in chemoprevention of prostate cancer by sulforaphane. Carcinogenesis.
  117. 117.
    Sobhani B et al (2019) Histopathological analysis of testis: effects of astaxanthin treatment against nicotine toxicity. Iranian Journal of Toxicology 13(1):41–44Google Scholar
  118. 118.
    Song X-B, Liu G, Wang ZY, Wang L (2016) Puerarin protects against cadmium-induced proximal tubular cell apoptosis by restoring mitochondrial function. Chem Biol Interact 260:219–231PubMedCrossRefGoogle Scholar
  119. 119.
    Spannhoff A, Kim YK, Raynal NJ, Gharibyan V, Su MB, Zhou YY, Li J, Castellano S, Sbardella G, Issa JP, Bedford MT (2011) Histone deacetylase inhibitor activity in royal jelly might facilitate caste switching in bees. EMBO Rep 12(3):238–243PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Sun Q, Dong M, Wang Z, Wang C, Sheng D, Li Z, Huang D, Yuan C (2016) Selenium-enriched polysaccharides from Pyracantha fortuneana (Se-PFPs) inhibit the growth and invasive potential of ovarian cancer cells through inhibiting β-catenin signaling. Oncotarget 7(19):28369–28383PubMedPubMedCentralGoogle Scholar
  121. 121.
    Sun Y, Han M, Shen Z, Huang H, Miao X (2018) Anti-hypertensive and cardioprotective effects of a novel apitherapy formulation via upregulation of peroxisome proliferator-activated receptor-α and-γ in spontaneous hypertensive rats. Saudi J Biol Sci 25(2):213–219PubMedCrossRefGoogle Scholar
  122. 122.
    Tao T et al (2019) The PERK/Nrf2 pathway mediates endoplasmic reticulum stress-induced injury by upregulating endoplasmic reticulophagy in H9c2 cardiomyoblasts. Life Sci 237:116944. PubMedCrossRefGoogle Scholar
  123. 123.
    Tavakol S et al (2019) Autophagy modulators: mechanistic aspects and drug delivery systems. Biomolecules 9(10):530PubMedCentralCrossRefGoogle Scholar
  124. 124.
    Theodore M, Kawai Y, Yang J, Kleshchenko Y, Reddy SP, Villalta F, Arinze IJ (2008) Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2. J Biol Chem 283(14):8984–8994PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Trindade GGG, Thrivikraman G, Menezes PP, França CM, Lima BS, Carvalho YMBG, Souza EPBSS, Duarte MC, Shanmugam S, Quintans-Júnior LJ, Bezerra DP, Bertassoni LE, Araújo AAS (2019) Carvacrol/beta-cyclodextrin inclusion complex inhibits cell proliferation and migration of prostate cancer cells. Food Chem Toxicol 125:198–209PubMedCrossRefGoogle Scholar
  126. 126.
    Turner A (2018) Cadmium pigments in consumer products and their health risks. Sci Total Environ 657:1409–1418PubMedCrossRefGoogle Scholar
  127. 127.
    Van Gelder CW, Flurkey WH, Wichers HJ (1997) Sequence and structural features of plant and fungal tyrosinases. Phytochemistry 45(7):1309–1323PubMedCrossRefGoogle Scholar
  128. 128.
    Vinas P et al (2009) Solid-phase microextraction on-fiber derivatization for the analysis of some polyphenols in wine and grapes using gas chromatography–mass spectrometry. J Chromatogr A 1216(9):1279–1284PubMedCrossRefGoogle Scholar
  129. 129.
    Viñas P, Martínez-Castillo N, Campillo N, Hernández-Córdoba M (2011) Directly suspended droplet microextraction with in injection-port derivatization coupled to gas chromatography–mass spectrometry for the analysis of polyphenols in herbal infusions, fruits and functional foods. J Chromatogr A 1218(5):639–646PubMedCrossRefGoogle Scholar
  130. 130.
    Wahdan SA et al (2019) Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-kappaB inflammatory cascade. Naunyn Schmiedebergs Arch Pharmacol 392(11):1331–1345PubMedCrossRefGoogle Scholar
  131. 131.
    Wang B, Du Y (2013) Cadmium and its neurotoxic effects. Oxidative Med Cell Longev 2013:898034. Google Scholar
  132. 132.
    Wang L, Wise JT, Zhang Z, Shi X (2016) Progress and prospects of reactive oxygen species in metal carcinogenesis. Curr Pharmacol Rep 2(4):178–186PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Wang XY et al (2018) Alleviation of cadmium-induced oxidative stress by trehalose via inhibiting the Nrf2-Keap1 signaling pathway in primary rat proximal tubular cells. J Biochem Mol Toxicol 32(1):e22011CrossRefGoogle Scholar
  134. 134.
    Wang Y, Mandal AK, Son YO, Pratheeshkumar P, Wise JTF, Wang L, Zhang Z, Shi X, Chen Z (2018) Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane. Toxicol Appl Pharmacol 353:23–30PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Wang L-Y, Fan RF, Yang DB, Zhang D, Wang L (2019) Puerarin reverses cadmium-induced lysosomal dysfunction in primary rat proximal tubular cells via inhibiting Nrf2 pathway. Biochem Pharmacol 162:132–141PubMedCrossRefGoogle Scholar
  136. 136.
    Wang C-C, Si LF, Guo SN, Zheng JL (2019) Negative effects of acute cadmium on stress defense, immunity, and metal homeostasis in liver of zebrafish: the protective role of environmental zinc dpre-exposure. Chemosphere 222:91–97PubMedCrossRefGoogle Scholar
  137. 137.
    Wang Y et al (2019) Autophagy suppression accelerates apoptosis induced by Norcantharidin in cholangiocarcinoma. Pathol Oncol Res.
  138. 138.
    Xiao Y, Li B, Liu J, Ma X (2018) Carvacrol ameliorates inflammatory response in interleukin 1beta-stimulated human chondrocytes. Mol Med Rep 17(3):3987–3992PubMedGoogle Scholar
  139. 139.
    Xu XZ, Tang Y, Cheng LB, Yao J, Jiang Q, Li KR, Zhen YF (2019) Targeting Keap1 by miR-626 protects retinal pigment epithelium cells from oxidative injury by activating Nrf2 signaling. Free Radic Biol Med 143:387–396PubMedCrossRefGoogle Scholar
  140. 140.
    Yang S-H, Long M, Yu LH, Li L, Li P, Zhang Y, Guo Y, Gao F, Liu MD, He JB (2016) Sulforaphane prevents testicular damage in Kunming mice exposed to cadmium via activation of Nrf2/ARE signaling pathways. Int J Mol Sci 17(10):1703PubMedCentralCrossRefGoogle Scholar
  141. 141.
    Yang S-H et al (2018) Protective mechanism of sulforaphane on cadmium-induced sertoli cell injury in mice testis via nrf2/are signaling pathway. Molecules 23(7):1774PubMedCentralCrossRefGoogle Scholar
  142. 142.
    Yang S-H et al (2019) Sulforaphane protect against cadmium-induced oxidative damage in mouse Leydigs cells by activating Nrf2/ARE signaling pathway. Int J Mol Sci 20(3):630PubMedCentralCrossRefGoogle Scholar
  143. 143.
    Yaribeygi H, Farrokhi FR, Rezaee R, Sahebkar A (2018) Oxidative stress induces renal failure: a review of possible molecular pathways. J Cell Biochem 119(4):2990–2998PubMedCrossRefGoogle Scholar
  144. 144.
    Yasuda S, Horinaka M, Sakai T (2019) Sulforaphane enhances apoptosis induced by Lactobacillus pentosus strain S-PT84 via the TNFalpha pathway in human colon cancer cells. Oncol Lett 18(4):4253–4261PubMedPubMedCentralGoogle Scholar
  145. 145.
    Yuan C, Wang C, Bu Y, Xiang T, Huang X, Wang Z, Yi F, Ren G, Liu G, Song F (2010) Antioxidative and immunoprotective effects of Pyracantha fortuneana (Maxim.) Li polysaccharides in mice. Immunol Lett 133(1):14–18PubMedCrossRefGoogle Scholar
  146. 146.
    Yuan C, Li Z, Yi M, Wang X, Peng F, Xiao F, Chen T, Wang C, Mushtaq G, Kamal MA (2015) Effects of polysaccharides from selenium-enriched Pyracantha fortuneana on mice liver injury. Med Chem 11(8):780–788PubMedCrossRefGoogle Scholar
  147. 147.
    Zarif Najafi P et al (2019) The protective effect of Zataria Multiflora on the embryotoxicity induced by bisphenol A in the brain of chicken embryos. Biointerface Res Appl Chem 9(5):4239–4242CrossRefGoogle Scholar
  148. 148.
    Zhai H, Pan T, Yang H, Wang H, Wang Y (2019) Cadmium induces A549 cell migration and invasion by activating ERK. Exp Ther Med 18(3):1793–1799PubMedPubMedCentralGoogle Scholar
  149. 149.
    Zhang S et al (2017) The effect of royal jelly on the growth of breast cancer in mice. Oncol Lett 14(6):7615–7621PubMedPubMedCentralGoogle Scholar
  150. 150.
    Zhang C, Lin J, Ge J, Wang LL, Li N, Sun XT, Cao HB, Li JL (2017) Selenium triggers Nrf2-mediated protection against cadmium-induced chicken hepatocyte autophagy and apoptosis. Toxicol in Vitro 44:349–356PubMedCrossRefGoogle Scholar
  151. 151.
    Zhang J et al (2017) Regeneration of glutathione by alpha-lipoic acid via Nrf2/ARE signaling pathway alleviates cadmium-induced HepG2 cell toxicity. Environ Toxicol Pharmacol 51:30–37PubMedCrossRefGoogle Scholar
  152. 152.
    Zhang T et al (2019) The effects of long-term exposure to low doses of cadmium on the health of the next generation of mice. Chem Biol Interact 312:108792PubMedCrossRefGoogle Scholar
  153. 153.
    Zhang HS et al (2019) Nrf2 promotes breast cancer cell migration via up-regulation of G6PD/HIF-1α/Notch1 axis. J Cell Mol Med 23(5):3451–3463PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Zhang Z et al (2019) LncRNA TUG1 promotes cisplatin resistance in esophageal squamous cell carcinoma cells by regulating Nrf2. Acta Biochim Biophys Sin Shanghai 51(8):826–833PubMedCrossRefGoogle Scholar
  155. 155.
    Zheng W, Li D, Gao X, Zhang W, Robinson BO (2019) Carvedilol alleviates diabetic cardiomyopathy in diabetic rats. Exp Ther Med 17(1):479–487PubMedGoogle Scholar
  156. 156.
    Zwolak I (2019) The role of selenium in arsenic and cadmium toxicity: an updated review of scientific literature. Biol Trace Elem Res:1–20.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Milad Ashrafizadeh
    • 1
  • Zahra Ahmadi
    • 2
  • Tahereh Farkhondeh
    • 3
  • Saeed Samarghandian
    • 4
    Email author
  1. 1.Department of Basic Science, Faculty of Veterinary MedicineUniversity of TabrizTabrizIran
  2. 2.Department of Basic Science, Shoushtar BranchIslamic Azad UniversityShoushtarIran
  3. 3.Cardiovascular Diseases Research CenterBirjand University of Medical SciencesBirjandIran
  4. 4.Department of Basic Medical SciencesNeyshabur University of Medical SciencesNeyshaburIran

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