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Zinc and human health: an update

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Abstract

The importance of micronutrients in health and nutrition is undisputable, and among them, zinc is an essential element whose significance to health is increasingly appreciated and whose deficiency may play an important role in the appearance of diseases. Zinc is one of the most important trace elements in the organism, with three major biological roles, as catalyst, structural, and regulatory ion. Zinc-binding motifs are found in many proteins encoded by the human genome physiologically, and free zinc is mainly regulated at the single-cell level. Zinc has critical effect in homeostasis, in immune function, in oxidative stress, in apoptosis, and in aging, and significant disorders of great public health interest are associated with zinc deficiency. In many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, autoimmune diseases, aging, age-related degenerative diseases, and Wilson’s disease, the concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress, and lead to the generation of inflammatory cytokines. In these diseases, oxidative stress and chronic inflammation may play important causative roles. It is therefore important that status of zinc is assessed in any case and zinc deficiency is corrected, since the unique properties of zinc may have significant therapeutic benefits in these diseases. In the present paper, we review the zinc as a multipurpose trace element, its biological role in homeostasis, proliferation and apoptosis and its role in immunity and in chronic diseases, such as cancer, diabetes, depression, Wilson’s disease, Alzheimer’s disease, and other age-related diseases.

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References

  • Adamo AM, Zago MP, Mackenzie GG, Aimo L, Keen CL, Keenan A, Oteiza PI (2010) The role of zinc in the modulation of neuronal proliferation and apoptosis. Neurotoxic Res 17:1–14

    CAS  Google Scholar 

  • Adlard PA, Parncutt JM, Finkelstein DI, Bush AI (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J Neurosci 30:1631–1636

    PubMed  CAS  Google Scholar 

  • Albrecht AL, Somji S, Sens MA, Sens DA, Garrett SH (2008) Zinc transporter mRNA expression in the RWPE-1 human prostate epithelial cell line. Biometals 4:405–416

    Google Scholar 

  • Amani R, Saeidi S, Nazari Z, Nematpour S (2010) Correlation between dietary zinc intakes and its serum levels with depression scales in young female students. Biol Trace Elem Res 137(2):150–158

    PubMed  CAS  Google Scholar 

  • Ando A, Kikuti YY, Shigenari A et al (1996) cDNA cloning of the human homologues of the mouse Ke4 and Ke6 genes at the centromeric end of the human MHC region. Genomics 35:600–602

    PubMed  CAS  Google Scholar 

  • Aschner M (1996) The functional significance of brain. Metallothionein. FASEB J 10:1129–1136

    PubMed  CAS  Google Scholar 

  • Atwood CS, Huang X, Moir RD, Tanzi RE, Bush AI (1999) Role of free radicals and metal ions in the pathogenesis of Alzheimer’s disease. Met Ions Biol Syst 36:309–364

    PubMed  CAS  Google Scholar 

  • Bao B, Prasad AS, Beck FW, Godmere M (2003) Zinc modulates mRNA levels of cytokines. Am J Physiol Endocrinol Metab 285:E1095–E1102

    PubMed  CAS  Google Scholar 

  • Bao B, Prasad AS, Beck FW, Fitzgerald JT, Snell D, Bao GW, Singh T, Cardozo LJ (2010) Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr 91(6):1634–1641

    PubMed  CAS  Google Scholar 

  • Barceloux DG (1999) Zinc. Clin Toxicol 37:279–292

    CAS  Google Scholar 

  • Barnham KJ, Bush AI (2008) Metals in Alzheimer’s and Parkinson’s diseases. Curr Opin Chem Biol 12:222–228

    PubMed  CAS  Google Scholar 

  • Beck FW, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ (1997) Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol 272:E1002–E1007

    PubMed  CAS  Google Scholar 

  • Beharier O, Etzion Y, Katz A, Friedman H, Tenbosh N, Zacharish S et al (2007) Crosstalk between L-type calcium channels and ZnT-1, a new player in rate-dependent cardiac electrical remodeling. Cell Calcium 42:71–82

    PubMed  CAS  Google Scholar 

  • Beyersmann D (2002) Homeostasis and cellular functions of zinc. Mat Wiss U Werkstofftech 33:764–769

    CAS  Google Scholar 

  • Bhowmik D, Chiranjib KP, Kumar KPS (2010) A potential medicinal importance of zinc in human health and chronic disease. Int J Pharm Biomed Sci 1(1):05–11

    Google Scholar 

  • Bravou V, Antonacopoulou A, Papadaki H, Floratou K, Stavropoulos M, Episkopou V, Petropoulou C, Kalofonos H (2009) TGF-beta repressors SnoN and Ski are implicated in human colorectal carcinogenesis. Cell Oncol 31(1):41–51

    PubMed  CAS  Google Scholar 

  • Bruinsma JJ, Jirakulaporn T, Muslin AJ, Kornfeld K (2002) Zinc ions and cation diffusion facilitator proteins regulate Ras-mediated signaling. Dev Cell 2:567–578

    PubMed  CAS  Google Scholar 

  • Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE (2001) Structure of a BRCA1-BARD1 heterodimeric RING–RING complex. Nat Struct Biol 10:833–837

    Google Scholar 

  • Brzovic PS, Keeffe JR, Nishikawa H, Miyamoto K, Fox D III, Fukuda M et al (2003) Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc Natl Acad Sci USA 100:5646–5651

    PubMed  CAS  Google Scholar 

  • Büntzel J, Bruns F, Glatzel M, Garayev A, Mücke R, Kisters K, Schäfer U, Schönekaes K, Micke O (2007) Zinc concentrations in serum during head and neck cancer progression. Anticancer Res 27(4A):1941–1943

    PubMed  Google Scholar 

  • Bush AI (2000) Metals and neuroscience. Curr Opin Chem Biol 4:184–191

    PubMed  CAS  Google Scholar 

  • Bush AI (2002) Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging 23:1031–1038

    PubMed  CAS  Google Scholar 

  • Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 5(3):421–432

    PubMed  CAS  Google Scholar 

  • Bussereau F, Lafay JF, Bolotin-Fukuhara M (2004) Zinc finger transcriptional activators of yeasts. FEMS Yeast Res 4(4–5):445–458

    PubMed  CAS  Google Scholar 

  • Calesnick B, Dinan AM (1988) Zinc deficiency and zinc toxicity. Am Fam Physician 37:267–270

    PubMed  CAS  Google Scholar 

  • Carroll RJ, Hammer RE, Chan SJ, Swift HH, Rubenstein AH, Steiner DF (1988) A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway. Proc Natl Acad Sci USA 85:8943–8947

    PubMed  CAS  Google Scholar 

  • Chakravarty PK, Ghosh A, Chowdhury JR (1985) Zinc in human malignancies. Neoplasma 33:85–90

    Google Scholar 

  • Chasapis CT, Spyroulias GA (2009) Ring finger E3 ubiquitin ligases: structure and drug discovery. Curr Pharm Des 15–31:3716–3731

    Google Scholar 

  • Chasapis CT, Loutsidou AK, Orkoula MG and Spyroulias GA (2010) Zinc binding properties of engineered RING finger domain of Arkadia E3 ubiquitin ligase. Bioinorg Chem Appl vol 2010, Article ID 323152, p 7

  • Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD et al (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits betaamyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676

    PubMed  CAS  Google Scholar 

  • Chimienti F, Aouffen M, Favier A, Seve M (2003) Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate. Curr Drug Targets 4:323–338

    PubMed  CAS  Google Scholar 

  • Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B et al (2006) In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci 119:4199–4206

    PubMed  CAS  Google Scholar 

  • Clegg MS, Hanna LA, Niles BJ, Momma TY, Keen CL (2005) Zinc deficiency-induced cell death. IUBMB Life 57:661–669

    PubMed  CAS  Google Scholar 

  • Cohen N, Golik A (2006) Zinc balance and medications commonly used in the management of heart failure. Heart Fail Rev 11:19–24

    PubMed  CAS  Google Scholar 

  • Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD (1999) Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci USA 96:1716–1721

    PubMed  CAS  Google Scholar 

  • Corniola RS, Tassabehji NM, Hare J, Sharma G, Levenson CW (2008) Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Res 1237:52–61

    PubMed  CAS  Google Scholar 

  • Costello LC, Franklin RB (2006) The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer 5:17

    PubMed  Google Scholar 

  • Coyle P, Philcox JC, Carey LC, Rofe AM (2002) Metallothionein: the multipurpose protein. Cell Mol Life Sci 59:627–647

    PubMed  CAS  Google Scholar 

  • Darling DS, Gaur NK, Zhu BA (1998) Zinc finger homeodomain transcription factor binds specific thyroid hormone response elements. Mol Cell Endocrinol 139:25–35

    PubMed  CAS  Google Scholar 

  • Davis SR, McMahon RJ, Cousins RJ (1998) Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1expression. J Nutr 128:825–831

    PubMed  CAS  Google Scholar 

  • DePasquale-Jardieu P, Fraker PJ (1980) Further characterization of the role of corticosterone in the loss of humoral immunity in zinc-deficient A/J mice as determined by adrenalectomy. J Immunol 124:2650–2655

    PubMed  CAS  Google Scholar 

  • Dhawan DK, Chadha VD (2010) Zinc: a promising agent in dietary chemoprevention of cancer. Indian J Med Res 132(6):676–682

    PubMed  CAS  Google Scholar 

  • Dodson G, Steiner D (1998) The role of assembly in insulin’s biosynthesis. Curr Opin Struct Biol 8:189–194

    PubMed  CAS  Google Scholar 

  • Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA et al (2003) Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 42:2768–2773

    PubMed  CAS  Google Scholar 

  • Dreosti IE (2001) Zinc and the gene. Mutat Res 475:161–167

    PubMed  CAS  Google Scholar 

  • Eide DJ (2006) Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta 1763(7):711–722

    PubMed  CAS  Google Scholar 

  • Etzion Y, Ganiel A, Beharier O, Shalev A, Novack V, Volvich L et al (2008) Correlation between atrial ZnT-1 expression and atrial fibrillation in humans: a pilot study. J Cardiovasc Electrophysiol 19:157–164

    PubMed  Google Scholar 

  • Fabris N, Mocchegiani E, Albertini G (1993) Psycoendocrine-immune interactions in Down’s syndrome: role of zinc. In: Castells S, Wisnieski KE (eds) Growth hormone treatment in Down’s syndrome. Wiley, New York, pp 203–218

    Google Scholar 

  • Fabris N, Mocchegiani E, Provinciali M (1997) Plasticity of neuroendocrine—thymus interactions during aging. Exp Gerontol 32:415–429

    PubMed  CAS  Google Scholar 

  • Faller P (2009) Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer. Chembiochem 10(18):2837–2845

    PubMed  CAS  Google Scholar 

  • Fernández-Gamba A, Leal MC, Morelli L, Castaño EM (2009) Insulin-degrading enzyme: structure-function relationship and its possible roles in health and disease. Curr Pharm Des 15(31):3644–3655

    PubMed  Google Scholar 

  • Fraker PJ (2005) Roles for cell death in zinc deficiency. J Nutr 135:359–362

    PubMed  CAS  Google Scholar 

  • Fraker PJ, King LE, Laakko T, Vollmer TL (2000) The dynamic link between the integrity of the immune system and zinc status. J Nutr 130(5S Suppl):1399S–1406S

    PubMed  CAS  Google Scholar 

  • Freedman DA, Wu L, Levine AJ (1999) Functions of the MDM2 oncoprotein. Cell Mol Life Sci 55:96–107

    PubMed  CAS  Google Scholar 

  • Friedlich AL, Lee JY, van Groen T, Cherny RA, Volitakis I et al (2004) Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer’s disease. J Neurosci 24:3453–3459

    PubMed  CAS  Google Scholar 

  • Giaccia AJ, Kastan MB (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12:2973–2983

    PubMed  CAS  Google Scholar 

  • Gilmore TD (2006) Introduction to NF-kB: players, pathways, perspectives. Oncogene 25:6680–6684

    PubMed  CAS  Google Scholar 

  • Golik A, Cohen N, Ramot Y, Maor J, Moses R, Weissgarten J et al (1993) Type II diabetes mellitus, congestive heart failure, and zinc metabolism. Biol Trace Elem Res 39:171–175

    PubMed  CAS  Google Scholar 

  • Gupta SK, Singh SP, Shukla VK (2005) Copper, zinc, and Cu/Zn ratio in carcinoma of the gallbladder. J Surg Oncol 91:204–208

    PubMed  CAS  Google Scholar 

  • Haase H, Maret W (2003) Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 291:289–298

    PubMed  CAS  Google Scholar 

  • Haase H, Rink L (2009) The immune system and the impact of zinc during aging. Immun Ageing 6:9

    PubMed  Google Scholar 

  • Holt D, Magos L, Webb M (1980) The interaction of cadium-induced rat renal metallothionein with bivalent mercury in vitro. Chem Biol Interact 32(1–2):125–135

    PubMed  CAS  Google Scholar 

  • Huster D (2010) Wilson disease. Best Pract Res Clin Gastroenterol 24(5):531–539

    PubMed  CAS  Google Scholar 

  • Issell BF, Macfadyen BV, Gum ET, Valdivieso M, Dudrick SJ, Bodey GP (2006) Serum zinc levels in lung cancer patients. Cancer 47:1845–1848

    Google Scholar 

  • Joazeiro CA, Weissman AM (2000) RING finger proteins: mediators of ubiquitin ligase activity. Cell 102(5):549–552

    PubMed  CAS  Google Scholar 

  • John E, Laskow TC, Buchser WJ, Pitt BR (2010) Zinc in innate and adaptive tumor immunity. J Transl Med 8:118

    PubMed  Google Scholar 

  • Jomovaa K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283(2–3):65–87

    Google Scholar 

  • Kabu K, Yamasaki S, Kamimura D, Ito Y, Hasegawa A, Sato E, Kitamura H, Nishida K, Hirano T (2006) Zinc is required for Fc epsilon RI-mediated mast cell activation. J Immunol 177(2):1296–1305

    PubMed  CAS  Google Scholar 

  • Kadrmas JL, Smith MA, Clark KA, Pronovost SM, Muster N, Yates JR III, Beckerle MC (2004) The integrin effector PINCH regulates JNK activity and epithelial migration in concert with Ras suppressor 1. J Cell Biol 167(6):1019–1024

    PubMed  CAS  Google Scholar 

  • Kagara N, Tanaka N, Noguchi S, Hirano T (2007) Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer Sci 98:692–697

    PubMed  CAS  Google Scholar 

  • Kandias NG, Chasapis CT, Episkopou V, Bentrop D, Spyroulias GA (2009) High yield expression and NMR characterization of Arkadia E3 ubiquitin ligase RING-H2 finger domain. Biochem Biophys Res Commun 378:498–502

    PubMed  CAS  Google Scholar 

  • Karagulova G, Yue Y, Moreyra A, Boutjdir M, Korichneva I (2007) Protective role of intracellular zinc in myocardial ischemia/reperfusion is associated with preservation of protein kinase C isoforms. J Pharmacol Exp Ther 321:517–525

    PubMed  CAS  Google Scholar 

  • Katoh S, Hong C, Tsunoda Y, Murata K, Takai R, Minami E, Yamazaki T, Katoh E (2003) High precision NMR structure and function of the RING-H2 finger domain of EL5, a rice protein whose expression is increased upon exposure to pathogen-derived oligosaccharides. J Biol Chem 278:15341–15348

    PubMed  CAS  Google Scholar 

  • Keen CL, Gershwin ME (1990) Zinc deficiency and immune function. Annu Rev Nutr 10:415–431

    PubMed  CAS  Google Scholar 

  • Kelly EJ, Quaife CJ, Froelick GJ, Palmiter RD (1996) Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice. J Nutr 126(7):1782–1790

    PubMed  CAS  Google Scholar 

  • Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S, Fukada T, Yamashita S, Kaisho T, Akira S, Murakami M, Hirano T (2006) Toll-like receptormediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7:971–977

    PubMed  CAS  Google Scholar 

  • Kondoh M, Imada N, Kamada K, Tsukahara R, Higashimoto M, Takiguchi M, Watanabe Y, Sato M (2003) Property of metallothionein as a Zn pool differs depending on the induced condition of metallothionein. Toxicol Lett 142(1–2):11–18

    PubMed  CAS  Google Scholar 

  • Koropatnick J, Cherian MG (1993) A mutant mouse (tx) with increased hepatic metallothionein stability and accumulation. Biochem J 296(Pt 2):443–449

    PubMed  CAS  Google Scholar 

  • Kovalovsky D, Uche OU, Eladad S, Hobbs RM, Yi W, Alonzo E, Chua K, Eidson M, Kim H-J, Im JS, Pandolfi PP, Sant’Angelo DB (2008) The BTB-zinc finger transcriptional regulator, PLZF, controls the development of iNKT cell effector functions. Nat Immunol 9:1055–1064

    PubMed  CAS  Google Scholar 

  • Krezel A, Maret W (2007) Dual nanomolar and picomolar Zn(II) binding properties of metallothionein. J Am Chem Soc 129:10911–10921

    PubMed  CAS  Google Scholar 

  • Kumar V, Cotran R, Robbins SL (2003) Cell injury, adaptation, and death. In: Robbins basic pathology, 7th edn. Saunders, An Imprint of Elsevier, Philadelphia

    Google Scholar 

  • Küry S, Kharfi M, Kamoun R et al (2003) Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica. Hum Mutat 22:337–338

    PubMed  Google Scholar 

  • Lai JL, Preudhomme C, Zandecki M et al (1994) Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations. Leukemia 9:370–381

    Google Scholar 

  • Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY (2002) Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci USA 99:7705–7710

    PubMed  CAS  Google Scholar 

  • Lee JY, Friedman JE, Angel I, Kozak A, Koh JY (2004) The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein transgenic mice. Neurobiol Aging 25:1315–1321

    PubMed  CAS  Google Scholar 

  • Levy S, Beharier O, Etzion Y, Mor M, Buzaglo L, Shaltiel L et al (2009) Molecular basis for zinc transporter 1 action as an endogenous inhibitor of L-type calcium channels. J Biol Chem 284:32434–32443

    PubMed  CAS  Google Scholar 

  • Lichten LA, Cousins RJ (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29:153–176

    PubMed  Google Scholar 

  • Little PJ, Bhattacharya R, Moreyra AE, Korichneva IL (2010) Zinc and cardiovascular disease. Nutrition 26:1050–1057

    PubMed  CAS  Google Scholar 

  • MacDonald RS (2000) The role of zinc in growth and cell proliferation. J Nutr 130:1500S–1508S

    PubMed  CAS  Google Scholar 

  • Maret W (2003) Cellular zinc and redox states converge in the metallothionein/thionein pair. J Nutr 133(5 Suppl 1):S1460–S1462

    Google Scholar 

  • Maret W (2008) Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol 43:363–369

    PubMed  CAS  Google Scholar 

  • Margalioth EJ, Schenker JG, Chevion M (1983) Copper and zinc levels in normal and malignant tissues. Cancer Sci 52:868–872

    CAS  Google Scholar 

  • Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX (2005) Metals and amyloid-beta in Alzheimer’s disease. Int J Exp Pathol 86:147–159

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Fabris N (1995) Age-related thymus involution: zinc reverses in vitro the thymulin secretion effect. Int J Immunopharmacol 17:745–749

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M (2000a) Zinc, metallothioneins, immune responses, survival and ageing. Biogerontology 1:133–143

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M (2000b) Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections. J Nutr 130(Suppl 5):S1424–S1431

    Google Scholar 

  • Mocchegiani E, Muzzioli M, Giacconi R (2000) Zinc and immunoresistance to infections in ageing: new biological tools. Trends Pharmacol Sci 21:205–208

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Giacconi R, Cipriano C, Muzzioli M, Fattoretti P, Bertoni-Freddari C, Isani G, Zambenedetti P, Zatta P (2001) Zinc-bound metallothioneins as potential biological markers of ageing. Brain Res Bull 55:147–153

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Giacconi R, Cipriano C, Gasparini N, Orlando F, Stecconi R, Muzzioli M, Isani G, Carpene E (2002) Metallothioneins (I+II) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply. Mech Ageing Dev 123:675–694

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M, Giacconi R, Cipriano C, Gasparini N, Franceschi C, Gaettic R, Cavalierid E, Suzukid H (2003) Metallothioneins/PARP-1/IL-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply. Mech Ageing Dev 124:459–468

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Costarelli L, Giacconi R, Piacenza F, Basso A, Malavolta M. (2011) Zinc, metallothioneins and immunosenescence: effect of zinc supply as nutrigenomic approach. Biogerontology. [Epub ahead of print] PMID: 21503725

  • Murakami M, Hirano T (2008) Intracellular zinc homeostasis and zinc signaling. Cancer Sci 99:1515–1522

    PubMed  CAS  Google Scholar 

  • Muzzioli M, Stecconi R, Moresi R, Provinciali M (2009) Zinc improves the development of human CD34+ cell progenitors towards NK cells andincreases the expression of GATA-3 transcription factor in young and old ages. Biogerontology 10(5):593–604

    PubMed  CAS  Google Scholar 

  • Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, Yuki K, Isogaya K, Saitoh M, Imamura T, Episkopou V, Miyazono K, Miyazawa K (2007) Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling. J Biol Chem 282:20492–20501

    PubMed  CAS  Google Scholar 

  • Nath R, Kumar D, Li T, Singal KP (2000) Metallothioneins, oxidative stress and the cardiovascular system. Toxicology 155:17–26

    PubMed  CAS  Google Scholar 

  • Ninh NX, Maiter D, Verniers J, Lause P, Ketelslegers JM, Thissen JP (1998) Failure of exogenous IGF-I to restore normal growth in rats submitted to dietary zinc deprivation. J Endocrinol 159:211–217

    PubMed  CAS  Google Scholar 

  • Nowak G, Siwek M, Dudek D, Ziêba A, Pilc A (2003) Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol 55:1143–1147

    PubMed  CAS  Google Scholar 

  • Nowak G, Szewczyk B, Pilc A (2005) Zinc and depression. An update. Pharmacol Rep 57:713–718

    PubMed  CAS  Google Scholar 

  • Pagani A, Villarreal L, Capdevila M, Atrian S (2007) The saccharomyces cerevisiae Crs5 metallothionein metal-binding abilities and its role in the response to zinc overload. Mol Microbiol 1:256–269

    Google Scholar 

  • Palecek E, Brazdova M, Cernocka H, Vlk D, Brazda V, Vojtesek B (1999) Effect of transition metals on binding of p53 protein to supercoiled DNA and to consensus sequence in DNA fragments. Oncogene 18(24):3617–3625

    PubMed  CAS  Google Scholar 

  • Pittenger C, Sanacora G, Krystal JH (2007) The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disord Drug Targets 2:101–115

    Google Scholar 

  • Plum LM, Rink L, Haase H (2010) The essential toxin: impact of zinc on human health. Int J Environ Res Public Health 7:1342–1365

    PubMed  CAS  Google Scholar 

  • Prasad AS (1998) Zinc in human health: an update. J Trace Elem Exp Med 11:63–87

    CAS  Google Scholar 

  • Prasad AS (2009) Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opinion Clin Nutr Metab Care 12:646–652

    CAS  Google Scholar 

  • Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, Cardozo LJ (2007) Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr 85(3):837–844

    PubMed  CAS  Google Scholar 

  • Puertollano MA, Puertollano E, de Cienfuegos GÁ, de Pablo MA (2011) Dietary antioxidants: immunity and host defense. Curr Top Med Chem 11(14):1752–1766

    PubMed  CAS  Google Scholar 

  • Rahman K (2007) Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging 2:219–236

    PubMed  CAS  Google Scholar 

  • Rink L, Gabriel P (2000) Zinc and the immune system. Proc Nutr Soc 4:541–552

    Google Scholar 

  • Rutter GA (2010) Think zinc, new roles for zinc in the control of insulin secretion. Islets 2(1):49–50

    PubMed  Google Scholar 

  • Sato M (1992) Biological antioxidant defense system and metallothionein. Jpn J Toxicol Environ Health 38:228–239

    CAS  Google Scholar 

  • SCF (2003) Opinion of the Scientific Committee on Food on the tolerable upper intake level of zinc. European Commission

  • Schlag P, Seeling W, Merkle P, Betzler M (1978) Changes of serum-zinc in breast cancer. Langenbecks Arch Chir 2:129–133

    Google Scholar 

  • Scully R, Livingston DM (2000) In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408:429–432

    PubMed  CAS  Google Scholar 

  • Seve M, Chimienti F, Favier A (2002) Role of intracellular zinc in programmed cell death. Pathol Biol (Paris) 50:212–221 Sheikh et al. 2010

    CAS  Google Scholar 

  • Sheikh A, Shamsuzzaman S, Ahmad SM, Nasrin D, Nahar S, Alam MM, Al Tarique A, Begum YA, Qadri SS, Chowdhury MI, Saha A, Larson CP, Qadri F (2010) Zinc influences innate immune responses in children with enterotoxigenic Escherichia coli-induced diarrhea. J Nutr 140(5):1049–1056

    PubMed  CAS  Google Scholar 

  • Shimizu N, Fujiwara J, Ohnishi S, Sato M, Kodama H, Kohsaka T, Inui A, Fujisawa T, Tamai H, Ida S, Itoh S, Ito M, Horiike N, Harada M, Yoshino M, Aoki T (2010) Effects of long-term zinc treatment in Japanese patients with Wilson disease: efficacy, stability, and copper metabolism. Transl Res 156(6):350–357

    PubMed  CAS  Google Scholar 

  • Shokrzadeh M, Ghaemian A, Salehifar E, Aliakbari S, Saravi SS, Ebrahimi P (2009) Serum zinc and copper levels in ischemic cardiomyopathy. Biol Trace Elem Res 127:116–123

    PubMed  CAS  Google Scholar 

  • Singh RB, Niaz MA, Rastogi SS, Bajaj S, Gaoli Z, Shoumin Z (1998) Current zinc intake and risk of diabetes and coronary artery disease and factors associated with insulin resistance in rural and urban populations of North India. J Am Coll Nutr 17:564–570

    PubMed  CAS  Google Scholar 

  • Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

    PubMed  CAS  Google Scholar 

  • Stefanidou M, Maravelias C (2004) Metallothioneins in toxicology. Curr Top Toxicol 1:161–167

    CAS  Google Scholar 

  • Stefanidou M, Maravelias C, Dona A, Spiliopoulou C (2006) Zinc: a multipurpose trace element. Arch Toxicol 80(1):1–9 Review

    PubMed  CAS  Google Scholar 

  • Stoltenberg M, Bruhn M, Sondergaard C, Doering P, West MJ et al (2005) Immersion autometallographic tracing of zinc ions in Alzheimer beta-amyloid plaques. Histochem Cell Biol 123:605–611

    PubMed  CAS  Google Scholar 

  • Szewczyk B, Poleszak E, Wlaź P, Wróbel A, Blicharska E, Cichy A, Dybała M, Siwek A, Pomierny-Chamioło L, Piotrowska A, Brański P, Pilc A, Nowak G (2009) The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test. Prog Neuropsychopharmacol Biol Psychiatry 33(2):323–329

    PubMed  CAS  Google Scholar 

  • Takeda A (2000) Movement of zinc and its functional significance in the brain. Brain Res Bull 34:137–148

    CAS  Google Scholar 

  • Taniguchi M, Seino K, Nakayama T (2003) The NKT cell system: bridging innate and acquired immunity. Nat Immunol 4:1164–1165

    PubMed  CAS  Google Scholar 

  • Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555

    PubMed  CAS  Google Scholar 

  • Tapiero H, Tew KD (2003) Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother 57:399–411

    PubMed  CAS  Google Scholar 

  • Taylor KM (2008) A distinct role in breast cancer for two LIV-1 family zinc transporters. Biochem Soc Trans 36(Pt 6):1247–1251

    PubMed  CAS  Google Scholar 

  • Taylor KM, Vichova P, Jordan N, Hiscox S, Hendley R, Nicholson RI (2008) ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer cells. Endocrinology 149:4912–4920

    PubMed  CAS  Google Scholar 

  • Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    PubMed  CAS  Google Scholar 

  • Trasobares E, Corbaton A, Gonzalez-Estecha M, Lopez-Colon JL, Prats P, Olivan P et al (2007) Effects of angiotensin-converting enzyme inhibitors (ACE i) on zinc metabolism in patients with heart failure. J Trace Elem Med Biol 21:53–55

    PubMed  CAS  Google Scholar 

  • Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD (2001) The role of zinc in caspase activation and apoptotic cell death. Biometals 14:315–330

    PubMed  CAS  Google Scholar 

  • Truong-Tran AQ, Grosser D, Ruffin RE, Murgia C, Zalewski PD (2003) Apoptosis in the normal and inflamed airway epithelium: role of zinc in epithelial protection and procaspase-3 regulation. Biochem Pharmacol 66:1459–1468

    PubMed  CAS  Google Scholar 

  • Vallee BL (1995) The function of metallothionein. Neurochem Int 27:23–33

    PubMed  CAS  Google Scholar 

  • Vallee BL, Auld DS (1993) New perspective on zinc biochemistry: cocatalytic sites in multi-zinc enzymes. Biochemistry 32(26):6493–6500

    PubMed  CAS  Google Scholar 

  • Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118

    PubMed  CAS  Google Scholar 

  • Vara H, Martinez B, Santos A, Colino A (2002) Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 110:19–28

    PubMed  CAS  Google Scholar 

  • Vasak M, Hasler DW (2000) Metallothioneins: new functional and structural insights. Curr Opin Chem Biol 4:177–183

    PubMed  CAS  Google Scholar 

  • Verhaegh GW, Parat MO, Richard MJ, Hainaut P (1998) Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc. Mol Carcinog 21:205–214

    PubMed  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    PubMed  CAS  Google Scholar 

  • Walker CL, Black RE (2010) Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes. Int J Epidemiol 39(Suppl 1):63–69

    Google Scholar 

  • Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71:66–73

    PubMed  CAS  Google Scholar 

  • Wang CY, Wang T, Zheng W, Zhao BL, Danscher G, Chen Y, Wang Z (2010) Zinc overload enhances APP cleavage and Ab deposition in the Alzheimer mouse brain. PLoS One 5(12):e15349

    PubMed  Google Scholar 

  • Weiss JH, Sensi SL, Koh JY (2000) Zinc(2+): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 21:395–401

    PubMed  CAS  Google Scholar 

  • Wellinghausen N, Rink L (1998) The significance of zinc for leukocyte biology. J Leukoc Biol 64:571–577

    PubMed  CAS  Google Scholar 

  • Wellinghausen N, Martin M, Rink L (1997) Zinc inhibits interleukin-1- dependent T cell stimulation. Eur J Immunol 27:2529–2535

    PubMed  CAS  Google Scholar 

  • Whittle N, Lubec G, Singewald N (2009) Zinc deficiency induces enhanced depression-like behaviour and altered limbic activation reversed by antidepressant treatment in mice. Amino Acids 36(1):147–158

    PubMed  CAS  Google Scholar 

  • Witte KK, Clark AL, Cleland JG (2001) Chronic heart failure and micronutrients. J Am Coll Cardiol 37:1765–1774

    PubMed  CAS  Google Scholar 

  • Wong SH, Zhao Y, Schoene NW, Han CT, Shih RS, Lei KY (2007) Zinc deficiency depresses p21 gene expression: inhibition of cell cycle progression is independent of the decrease in p21 protein level in HepG2 cells. Am J Physiol Cell Physiol 292:C2175–C2184

    PubMed  CAS  Google Scholar 

  • Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL et al (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14:430–440

    PubMed  CAS  Google Scholar 

  • Xia Y, Pao GM, Chen HW, Verma IM, Hunter T (2003) Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein. J Biol Chem 278:5255–5263

    PubMed  CAS  Google Scholar 

  • Yamasaki S, Sakata-Sogawa K, Hasegawa A, Suzuki T, Kabu K, Sato E, Kurosaki T, Yamashita S, Tokunaga M, Nishida K, Hirano T (2007) Zinc is a novel intracellular second messenger. J Cell Biol 177:637–645

    PubMed  CAS  Google Scholar 

  • Yary T, Aazami S (2011) Dietary intake of zinc was inversely associated with depression. Biol Trace Elem Res. [Epub ahead of print] PMID:21932045

  • Zhang R, Wang H (2000) MDM2 oncogene as a novel target for human cancer therapy. Curr Pharm Des 6:393–416

    Google Scholar 

  • Zhang LH, Wang X, Zheng ZH, Ren H, Stoltenberg M et al (2010) Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain. Neurobiol Aging 31:74–87

    PubMed  Google Scholar 

  • Zhao XQ, Bai FW (2011) Zinc and yeast stress tolerance: micronutrient plays a big role. J Biotechnol. [Epub ahead of print] PMID:21763361

  • Zhao H, Eide D (1996) The yeast ZRT1 gene encodes the zinc transporter protein of a high-affinity uptake system induced by zinc limitation. Proc Natl Acad Sci USA 93:2454–2458

    PubMed  CAS  Google Scholar 

  • Zheng W, Xin N, Chi ZH, Zhao BL, Zhang J et al (2009) Divalent metal transporter 1 is involved in amyloid precursor protein processing and Abeta generation. FASEB J 23:4207–4217

    PubMed  CAS  Google Scholar 

  • Zheng W, Wang T, Yu D, Feng WY, Nie YX et al (2010) Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AbetaPP/PS1 transgenic mouse. J Alzheimers Dis 20:323–331

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece

    Christos T. Chasapis & Ariadni C. Loutsidou

  2. Department of Forensic Medicine and Toxicology, School of Medicine, University of Athens, 75, Mikras Asias street, 11527, Goudi, Athens, Greece

    Chara A. Spiliopoulou & Maria E. Stefanidou

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  1. Christos T. Chasapis
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  2. Ariadni C. Loutsidou
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  3. Chara A. Spiliopoulou
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  4. Maria E. Stefanidou
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Correspondence to Maria E. Stefanidou.

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Chasapis, C.T., Loutsidou, A.C., Spiliopoulou, C.A. et al. Zinc and human health: an update. Arch Toxicol 86, 521–534 (2012). https://doi.org/10.1007/s00204-011-0775-1

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