1932

Abstract

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency.

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2021-10-11
2024-04-23
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Literature Cited

  1. 1. 
    Adachi Y, Yoshida J, Kodera Y, Kato A, Yoshikawa Y et al. 2004. A new insulin-mimetic bis(allixinato)zinc(II) complex: structure-activity relationship of zinc(II) complexes. J. Biol. Inorg. Chem. 9:7885–93
    [Google Scholar]
  2. 2. 
    Adjepong D, Jahangir S, Malik BH. 2020. The effect of zinc on post-neurosurgical wound healing: a review. Cureus 12:1e6770
    [Google Scholar]
  3. 3. 
    Agency for Toxic Substances and Disease Registry (ATSDR) 2005. Toxicological profile for zinc https://www.atsdr.cdc.gov/ToxProfiles/tp60.pdf
  4. 4. 
    Agnew UM, Slesinger TL. 2021. Zinc toxicity. StatPearls Treasure Island, FL: StatPearls https://www.ncbi.nlm.nih.gov/books/NBK554548/
    [Google Scholar]
  5. 5. 
    Ahmed T, Svennerholm A-M, Al Tarique A, Sultana GNN, Qadri F 2009. Enhanced immunogenicity of an oral inactivated cholera vaccine in infants in Bangladesh obtained by zinc supplementation and by temporary withholding breast-feeding. Vaccine 27:91433–39
    [Google Scholar]
  6. 6. 
    Aiuchi T, Mihara S, Nakaya M, Masuda Y, Nakajo S, Nakaya K. 1998. Zinc ions prevent processing of caspase-3 during apoptosis induced by geranylgeraniol in HL-60 cells. J. Biochem. 124:2300–3
    [Google Scholar]
  7. 7. 
    Allen JI, Perri RT, McClain CJ, Kay NE. 1983. Alterations in human natural killer cell activity and monocyte cytotoxicity induced by zinc deficiency. J. Lab. Clin. Med. 102:4577–89
    [Google Scholar]
  8. 8. 
    Alvarez-Collazo J, Díaz-García CM, López-Medina AI, Vassort G, Alvarez JL. 2012. Zinc modulation of basal and β-adrenergically stimulated L-type Ca2+ current in rat ventricular cardiomyocytes: consequences in cardiac diseases. Pflüg. Arch. 464:5459–70
    [Google Scholar]
  9. 9. 
    Amin N, Clark CCT, Taghizadeh M, Djafarnejad S. 2020. Zinc supplements and bone health: the role of the RANKL-RANK axis as a therapeutic target. J. Trace Elem. Med. Biol. 57:126417
    [Google Scholar]
  10. 10. 
    Andersson DA, Gentry C, Moss S, Bevan S 2009. Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+. PNAS 106:208374–79
    [Google Scholar]
  11. 11. 
    Andrews GK. 2001. Cellular zinc sensors: MTF-1 regulation of gene expression. Biometals 14:3–4223–37
    [Google Scholar]
  12. 12. 
    Andrulewicz-Botulińska E, Wiśniewska R, Brzóska MM, Rogalska J, Galicka A. 2018. Beneficial impact of zinc supplementation on the collagen in the bone tissue of cadmium-exposed rats. J. Appl. Toxicol. 38:7996–1007
    [Google Scholar]
  13. 13. 
    Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C et al. 2019. An essential role for the Zn2+ transporter ZIP7 in B cell development. Nat. Immunol. 20:3350–61
    [Google Scholar]
  14. 14. 
    Aster I, Barth L-M, Rink L, Wessels I. 2019. Alterations in membrane fluidity are involved in inhibition of GM-CSF-induced signaling in myeloid cells by zinc. J. Trace Elem. Med. Biol. 54:214–20
    [Google Scholar]
  15. 15. 
    Auld DS. 2001. Zinc coordination sphere in biochemical zinc sites. Biometals 14:3–4271–313
    [Google Scholar]
  16. 16. 
    Auld DS 2013. Zinc-binding sites in proteins. Encyclopedia of Metalloproteins RH Kretsinger, VN Uversky, EA Permyakov 2554–59 New York: Springer
    [Google Scholar]
  17. 17. 
    Auld DS, Falchuk KH, Zhang K, Montorzi M, Vallee BL 1996. X-ray absorption fine structure as a monitor of zinc coordination sites during oogenesis of Xenopus laevis. PNAS 93:83227–31
    [Google Scholar]
  18. 18. 
    Aydemir TB, Cousins RJ. 2018. The multiple faces of the metal transporter ZIP14 (SLC39A14). J. Nutr. 148:2174–84
    [Google Scholar]
  19. 19. 
    Aydemir TB, Sitren HS, Cousins RJ. 2012. The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology 142:71536–46.e5
    [Google Scholar]
  20. 20. 
    Banks L, Pim D, Thomas M. 2003. Viruses and the 26S proteasome: hacking into destruction. Trends Biochem. Sci. 28:8452–59
    [Google Scholar]
  21. 21. 
    Bao B, Ahmad A, Azmi A, Li Y, Prasad A, Sarkar FH 2014. The biological significance of zinc in inflammation and aging. Inflammation, Advancing Age and Nutrition I Rahman, D Bagchi 15–27 Amsterdam: Elsevier
    [Google Scholar]
  22. 22. 
    Bao B, Prasad AS, Beck FWJ, Fitzgerald JT, Snell D et al. 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. 91:61634–41
    [Google Scholar]
  23. 23. 
    Bao B, Prasad AS, Beck FWJ, Godmere M. 2003. Zinc modulates mRNA levels of cytokines. Am. J. Physiol. Endocrinol. Metab. 285:5E1095–1095
    [Google Scholar]
  24. 24. 
    Bao S, Knoell DL. 2006. Zinc modulates cytokine-induced lung epithelial cell barrier permeability. Am. J. Physiol. Lung Cell. Mol. Physiol. 291:6L1132–1132
    [Google Scholar]
  25. 25. 
    Bao S, Liu M-J, Lee B, Besecker B, Lai J-P et al. 2010. Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF-κB. Am. J. Physiol. Lung Cell. Mol. Physiol. 298:6L744–744
    [Google Scholar]
  26. 26. 
    Barnum KJ, O'Connell MJ. 2014. Cell cycle regulation by checkpoints. Methods Mol. Biol. 1170:29–40
    [Google Scholar]
  27. 27. 
    Bélanger LF. 1978. The influence of zinc-deprivation on the mast cell population of the bone marrow and other tissues. J. Nutr. 108:81315–21
    [Google Scholar]
  28. 28. 
    Bell SG, Vallee BL. 2009. The metallothionein/thionein system: an oxidoreductive metabolic zinc link. ChemBioChem 10:155–62
    [Google Scholar]
  29. 29. 
    Bellomo E, Massarotti A, Hogstrand C, Maret W. 2014. Zinc ions modulate protein tyrosine phosphatase 1B activity. Metallomics 6:71229–39
    [Google Scholar]
  30. 30. 
    Berg K, Bolt G, Andersen H, Owen TC. 2001. Zinc potentiates the antiviral action of human IFN-α tenfold. J. Interferon Cytokine Res. 21:7471–74
    [Google Scholar]
  31. 31. 
    Bertolo RFP, Bettger WJ, Atkinson SA. 2001. Calcium competes with zinc for a channel mechanism on the brush border membrane of piglet intestine. J. Nutr. Biochem. 12:266–72
    [Google Scholar]
  32. 32. 
    Beyersmann D, Haase H. 2001. Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 14:3–4331–41
    [Google Scholar]
  33. 33. 
    Bin B-H, Seo J, Kim ST. 2018. Function, structure, and transport aspects of ZIP and ZnT zinc transporters in immune cells. J. Immunol. Res. 2018 9365747
    [Google Scholar]
  34. 34. 
    Blanden AR, Yu X, Loh SN, Levine AJ, Carpizo DR. 2015. Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer. Drug Discov. Today 20:111391–97
    [Google Scholar]
  35. 35. 
    Botella H, Stadthagen G, Lugo-Villarino G, de Chastellier C, Neyrolles O. 2012. Metallobiology of host-pathogen interactions: an intoxicating new insight. Trends Microbiol 20:3106–12
    [Google Scholar]
  36. 36. 
    Boudreault F, Pinilla-Vera M, Englert JA, Kho AT, Isabelle C et al. 2017. Zinc deficiency primes the lung for ventilator-induced injury. JCI Insight 2:11e86507
    [Google Scholar]
  37. 37. 
    Braga CBM, Santos IKFM, Palmeira P, Peria FM, Ribeiro SMF et al. 2015. Effect of zinc supplementation on serological response to vaccination against Streptococcus pneumoniae in patients undergoing chemotherapy for colorectal cancer. Nutr. Cancer 67:6926–32
    [Google Scholar]
  38. 38. 
    Brieger A, Rink L, Haase H. 2013. Differential regulation of TLR-dependent MyD88 and TRIF signaling pathways by free zinc ions. J. Immunol. 191:41808–17
    [Google Scholar]
  39. 39. 
    Briffa J, Sinagra E, Blundell R. 2020. Heavy metal pollution in the environment and their toxicological effects on humans. Heliyon 6:9e04691
    [Google Scholar]
  40. 40. 
    Brito S, Lee M-G, Bin B-H, Lee J-S. 2020. Zinc and its transporters in epigenetics. Molecules Cells 43:4323–30
    [Google Scholar]
  41. 41. 
    Brough D, Pelegrin P, Rothwell NJ. 2009. Pannexin-1-dependent caspase-1 activation and secretion of IL-1β is regulated by zinc. Eur. J. Immunol. 39:2352–58
    [Google Scholar]
  42. 42. 
    Bundy DAP, Golden MHN. 1987. The impact of host nutrition on gastrointestinal helminth populations. Parasitology 95:3623–35
    [Google Scholar]
  43. 43. 
    Ceylan MN, Akdas S, Yazihan N. 2021. Is zinc an important trace element on bone-related diseases and complications? A meta-analysis and systematic review from serum level, dietary intake, and supplementation aspects. Biol. Trace Elem. Res. 199:535–49
    [Google Scholar]
  44. 44. 
    Chai F, Truong-Tran AQ, Evdokiou A, Young GP, Zalewski PD. 2000. Intracellular zinc depletion induces caspase activation and p21 Waf1/Cip1 cleavage in human epithelial cell lines. J. Infect. Dis. 182:Suppl. 185–92
    [Google Scholar]
  45. 45. 
    Cheknev SB, Apresova MA, Moryakova NA, Efremova IE, Mezdrokhina AS et al. 2014. Production of the growth factors GM-CSF, G-CSF, and VEGF by human peripheral blood cells induced with metal complexes of human serum γ-globulin formed with copper or zinc ions. Mediat. Inflamm. 2014 518265
    [Google Scholar]
  46. 46. 
    Chen Y-H, Jeng S-S, Hsu Y-C, Liao Y-M, Wang Y-X et al. 2020. In anemia zinc is recruited from bone and plasma to produce new red blood cells. J. Inorg. Biochem. 210:111172
    [Google Scholar]
  47. 47. 
    Chesters J. 1999. A possible role for cyclins in the zinc requirements during G1 and G2 phases of the cell cycle. J. Nutr. Biochem. 10:5279–90
    [Google Scholar]
  48. 48. 
    Chesters JK, Petrie L, Travis AJ. 1990. A requirement for Zn2+ for the induction of thymidine kinase but not ornithine decarboxylase in 3T3 cells stimulated from quiescence. Biochem. J. 272:2525–27
    [Google Scholar]
  49. 49. 
    Chesters JK, Petrie L, Vint H. 1989. Specificity and timing of the Zn2+ requirement for DNA synthesis by 3T3 cells. Exp. Cell Res. 184:2499–508
    [Google Scholar]
  50. 50. 
    Cho HM, Ryu JR, Jo Y, Seo TW, Choi YN et al. 2019. Drp1-Zip1 interaction regulates mitochondrial quality surveillance system. Mol. Cell 73:2364–76.e8
    [Google Scholar]
  51. 51. 
    Colomar-Carando N, Meseguer A, Company-Garrido I, Jutz S, Herrera-Fernández V et al. 2019. Zip6 transporter is an essential component of the lymphocyte activation machinery. J. Immunol. 202:2441–50
    [Google Scholar]
  52. 52. 
    Conti M, Beavo J. 2007. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu. Rev. Biochem. 76:481–511
    [Google Scholar]
  53. 53. 
    Cooper GS, Bynum MLK, Somers EC. 2009. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J. Autoimmun. 33:3–4197–207
    [Google Scholar]
  54. 54. 
    Curcio JS, Silva MG, Silva Bailão MG, Báo SN, Casaletti L et al. 2017. Identification of membrane proteome of Paracoccidioides lutzii and its regulation by zinc. Future Sci. OA 3:4FSO232
    [Google Scholar]
  55. 55. 
    Dai F-Z, Yang J, Chen X-B, Xu M-Q 2013. Zinc finger protein A20 inhibits maturation of dendritic cells resident in rat liver allograft. J. Surg. Res. 183:2885–93
    [Google Scholar]
  56. 56. 
    D'Amico E, Zanghì A, Romano A, Sciandra M, Palumbo GAM, Patti F 2019. The neutrophil-to-lymphocyte ratio is related to disease activity in relapsing remitting multiple sclerosis. Cells 8:101114
    [Google Scholar]
  57. 57. 
    Daniel AG, Farrell NP. 2014. The dynamics of zinc sites in proteins: electronic basis for coordination sphere expansion at structural sites. Metallomics 6:122230–41
    [Google Scholar]
  58. 58. 
    Dardenne M, Prasad A, Bach J-F. 2013. Zinc and thymulin. Trace Elements in Clinical Medicine [Proceedings of the Second Meeting of the International Society for Trace Element Research in Humans (ISTERH)] H Tomita 177–82 Tokyo: Springer
    [Google Scholar]
  59. 59. 
    DeRuisseau KC, Cheuvront SN, Haymes EM, Sharp RG. 2002. Sweat iron and zinc losses during prolonged exercise. Int. J. Sport Nutr. Exerc. Metab. 12:4428–37
    [Google Scholar]
  60. 60. 
    Dierichs L, Kloubert V, Rink L. 2018. Cellular zinc homeostasis modulates polarization of THP-1-derived macrophages. Eur. J. Nutr. 57:62161–69
    [Google Scholar]
  61. 61. 
    Dowd PS, Kelleher J, Guillou PJ. 1986. T-lymphocyte subsets and interleukin-2 production in zinc-deficient rats. Br. J. Nutr. 55:159–69
    [Google Scholar]
  62. 62. 
    Dubben S, Hönscheid A, Winkler K, Rink L, Haase H. 2010. Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1α,25-dihydroxyvitamin D3. J. Leukoc. Biol. 87:5833–44
    [Google Scholar]
  63. 63. 
    Duvall E, Wyllie AH. 1986. Death and the cell. Immunol. Today 7:4115–19
    [Google Scholar]
  64. 64. 
    Elmes ME. 1977. Apoptosis in the small intestine of zinc-deficient and fasted rats. J. Pathol. 123:4219–23
    [Google Scholar]
  65. 65. 
    Eron SJ, MacPherson DJ, Dagbay KB, Hardy JA. 2018. Multiple mechanisms of zinc-mediated inhibition for the apoptotic caspases-3, -6, -7, and -8. ACS Chem. Biol. 13:51279–90
    [Google Scholar]
  66. 66. 
    Fanzo JC, Reaves SK, Cui L, Zhu L, Lei KY. 2002. p53 protein and p21 mRNA levels and caspase-3 activity are altered by zinc status in aortic endothelial cells. Am. J. Physiol. Cell Physiol. 283:2C631–631
    [Google Scholar]
  67. 67. 
    Faure H, Peyrin JC, Richard MJ, Favier A. 1991. Parenteral supplementation with zinc in surgical patients corrects postoperative serum-zinc drop. Biol. Trace Elem. Res. 30:137–45
    [Google Scholar]
  68. 68. 
    Fenstermacher KJ, DeStefano JJ. 2011. Mechanism of HIV reverse transcriptase inhibition by zinc: formation of a highly stable enzyme-(primer-template) complex with profoundly diminished catalytic activity. J. Biol. Chem. 286:4740433–42
    [Google Scholar]
  69. 69. 
    Fenwick PK, Aggett PJ, Macdonald D, Huber C, Wakelin D. 1990. Zinc deficiency and zinc repletion: effect on the response of rats to infection with Trichinella spiralis. Am. J. Clin. Nutr. 52:1166–72
    [Google Scholar]
  70. 70. 
    Fischer HJ, Sie C, Schumann E, Witte A-K, Dressel R et al. 2017. The insulin receptor plays a critical role in T cell function and adaptive immunity. J. Immunol. 198:51910–20
    [Google Scholar]
  71. 71. 
    Fong LYY, Mancini R, Nakagawa H, Rustgi AK, Huebner K. 2003. Combined cyclin D1 overexpression and zinc deficiency disrupts cell cycle and accelerates mouse forestomach carcinogenesis. Cancer Res 63:144244–52
    [Google Scholar]
  72. 72. 
    Fosmire GJ. 1990. Zinc toxicity. Am. J. Clin. Nutr. 51:2225–27
    [Google Scholar]
  73. 73. 
    Fossati G, Mazzucchelli I, Gritti D, Ricevuti G, Edwards SW et al. 1998. In vitro effects of GM-CSF on mature peripheral blood neutrophils. Int. J. Mol. Med. 1:6943–51
    [Google Scholar]
  74. 74. 
    Fraker PJ, King LE. 2004. Reprogramming of the immune system during zinc deficiency. Annu. Rev. Nutr. 24:277–98
    [Google Scholar]
  75. 75. 
    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:Suppl. 51399–406
    [Google Scholar]
  76. 76. 
    Fraker PJ, Lill-Elghanian DA. 2004. The many roles of apoptosis in immunity as modified by aging and nutritional status. J. Nutr. Health Aging 8:156–63
    [Google Scholar]
  77. 77. 
    Franklin RB, Costello LC. 2009. The important role of the apoptotic effects of zinc in the development of cancers. J. Cell. Biochem. 106:5750–57
    [Google Scholar]
  78. 78. 
    Friedman RL, Manly SP, McMahon M, Kerr IM, Stark GR. 1984. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38:3745–55
    [Google Scholar]
  79. 79. 
    Fukada T, Kambe T 2019. Zinc Signaling Singapore: Springer. , 2nd ed..
  80. 80. 
    Fukushima T, Horike H, Fujiki S, Kitada S, Sasaki T, Kashihara N. 2009. Zinc deficiency anemia and effects of zinc therapy in maintenance hemodialysis patients. Ther. Apher. Dial. 13:3213–19
    [Google Scholar]
  81. 81. 
    Gammoh NZ, Rink L. 2017. Zinc in infection and inflammation. Nutrients 9:6624
    [Google Scholar]
  82. 82. 
    Ghaffari J, Khalilian A, Salehifar E, Khorasani E, Rezaii MS. 2014. Effect of zinc supplementation in children with asthma: a randomized, placebo-controlled trial in northern Islamic Republic of Iran. East. Mediterr. Health J. 20:6391–96
    [Google Scholar]
  83. 83. 
    Gore A, Moran A, Hershfinkel M, Sekler I. 2004. Inhibitory mechanism of store-operated Ca2+ channels by zinc. J. Biol. Chem. 279:1211106–11
    [Google Scholar]
  84. 84. 
    Grazioso CF, Isalgué M, de Ramírez I, Ruz M, Solomons NW. 1993. The effect of zinc supplementation on parasitic reinfestation of Guatemalan schoolchildren. Am. J. Clin. Nutr. 57:5673–78
    [Google Scholar]
  85. 85. 
    Green DR, Kroemer G. 2009. Cytoplasmic functions of the tumour suppressor p53. Nature 458:72421127–30
    [Google Scholar]
  86. 86. 
    Gruber K, Maywald M, Rosenkranz E, Haase H, Plumakers B, Rink L. 2013. Zinc deficiency adversely influences interleukin-4 and interleukin-6 signaling. J. Biol. Regul. Homeost. Agents 27:3661–71
    [Google Scholar]
  87. 87. 
    Günther V, Lindert U, Schaffner W. 2012. The taste of heavy metals: gene regulation by MTF-1. Biochim. Biophys. Acta 1823:91416–25
    [Google Scholar]
  88. 88. 
    Gupta P, Rapp F. 1976. Effect of zinc ions on synthesis of herpes simplex virus type 2–induced polypeptides. Proc. Soc. Exp. Biol. Med. 152:3455–58
    [Google Scholar]
  89. 89. 
    Haase H, Ellinger S, Linseisen J, Neuhäuser-Berthold M, Richter M. 2020. Revised D-A-CH-reference values for the intake of zinc. J. Trace Elem. Med. Biol. 61:126536
    [Google Scholar]
  90. 90. 
    Haase H, Hebel S, Engelhardt G, Rink L. 2015. The biochemical effects of extracellular Zn2+ and other metal ions are severely affected by their speciation in cell culture media. Metallomics 7:1102–11
    [Google Scholar]
  91. 91. 
    Haase H, Rink L. 2009. Functional significance of zinc-related signaling pathways in immune cells. Annu. Rev. Nutr. 29:133–52
    [Google Scholar]
  92. 92. 
    Haase H, Rink L. 2014. Zinc signals and immune function. Biofactors 40:127–40
    [Google Scholar]
  93. 93. 
    Hasan R, Rink L, Haase H. 2013. Zinc signals in neutrophil granulocytes are required for the formation of neutrophil extracellular traps. Innate Immun 19:3253–64
    [Google Scholar]
  94. 94. 
    Hasan R, Rink L, Haase H. 2016. Chelation of free Zn2+ impairs chemotaxis, phagocytosis, oxidative burst, degranulation, and cytokine production by neutrophil granulocytes. Biol. Trace Elem. Res. 171:179–88
    [Google Scholar]
  95. 95. 
    He L, He T, Farrar S, Ji L, Liu T, Ma X 2017. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell. Physiol. Biochem. 44:2532–53
    [Google Scholar]
  96. 96. 
    Heller RA, Sun Q, Hackler J, Seelig J, Seibert L et al. 2020. Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker. Redox Biol 38:101764
    [Google Scholar]
  97. 97. 
    Henderson LM, Chappell JB, Jones OT. 1988. Superoxide generation by the electrogenic NADPH oxidase of human neutrophils is limited by the movement of a compensating charge. Biochem. J. 255:1285–90
    [Google Scholar]
  98. 98. 
    Hennigar SR, Kelley AM, McClung JP. 2016. Metallothionein and zinc transporter expression in circulating human blood cells as biomarkers of zinc status: a systematic review. Adv. Nutr. 7:4735–46
    [Google Scholar]
  99. 99. 
    Hershfinkel M. 2018. The zinc sensing receptor, ZnR/GPR39, in health and disease. Int. J. Mol. Sci. 19:2439
    [Google Scholar]
  100. 100. 
    Higashimura Y, Takagi T, Naito Y, Uchiyama K, Mizushima K et al. 2020. Zinc deficiency activates the IL-23/Th17 axis to aggravate experimental colitis in mice. J. Crohns Colitis 14:6856–66
    [Google Scholar]
  101. 101. 
    Hoeger J, Simon T-P, Beeker T, Marx G, Haase H, Schuerholz T. 2017. Persistent low serum zinc is associated with recurrent sepsis in critically ill patients: a pilot study. PLOS ONE 12:5e0176069
    [Google Scholar]
  102. 102. 
    Hojyo S, Miyai T, Fujishiro H, Kawamura M, Yasuda T et al. 2014. Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. PNAS 111:3211786–91
    [Google Scholar]
  103. 103. 
    Hönscheid A, Rink L, Haase H. 2009. T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions. Endocr. Metab. Immune Disord. Drug Targets 9:2132–44
    [Google Scholar]
  104. 104. 
    Hou S, Vigeland LE, Zhang G, Xu R, Li M et al. 2010. Zn2+ activates large conductance Ca2+-activated K+ channel via an intracellular domain. J. Biol. Chem. 285:96434–42
    [Google Scholar]
  105. 105. 
    Hu H, Bandell M, Petrus MJ, Zhu MX, Patapoutian A. 2009. Zinc activates damage-sensing TRPA1 ion channels. Nat. Chem. Biol. 5:3183–90
    [Google Scholar]
  106. 106. 
    Hu J, Yang Z, Wang J, Yu J, Guo J et al. 2016. Zinc chloride transiently maintains mouse embryonic stem cell pluripotency by activating Stat3 signaling. PLOS ONE 11:2e0148994
    [Google Scholar]
  107. 107. 
    Huang T, Yan G, Guan M 2020. Zinc homeostasis in bone: zinc transporters and bone diseases. Int. J. Mol. Sci. 21:41236
    [Google Scholar]
  108. 108. 
    Huber KL, Hardy JA. 2012. Mechanism of zinc-mediated inhibition of caspase-9. Protein Sci 21:71056–65
    [Google Scholar]
  109. 109. 
    Hwang JJ, Kim HN, Kim J, Cho D-H, Kim MJ et al. 2010. Zinc(II) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line. Biometals 23:6997–1013
    [Google Scholar]
  110. 110. 
    Ishida T. 2019. Review on the role of Zn2+ ions in viral pathogenesis and the effect of Zn2+ ions for host cell–virus growth inhibition. Am. J. Biomed. Sci. Res. 2:128–37
    [Google Scholar]
  111. 111. 
    Jansen J, Karges W, Rink L. 2009. Zinc and diabetes—clinical links and molecular mechanisms. J. Nutr. Biochem. 20:6399–417
    [Google Scholar]
  112. 112. 
    Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi R, Constantine G, Katulanda P 2012. Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis. Diabetol. Metab. Syndr. 4:113
    [Google Scholar]
  113. 113. 
    Joisten N, Proschinger S, Rademacher A, Schenk A, Bloch W et al. 2021. High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation. Mult. Scler. 27:7113639
    [Google Scholar]
  114. 114. 
    Jörnvall H, Bergman T 2013. Zinc alcohol dehydrogenases. Encyclopedia of Metalloproteins RH Kretsinger, VN Uversky, EA Permyakov 2349–54 New York: Springer
    [Google Scholar]
  115. 115. 
    Kabu K, Yamasaki S, Kamimura D, Ito Y, Hasegawa A et al. 2006. Zinc is required for FcεRI-mediated mast cell activation. J. Immunol. 177:21296–305
    [Google Scholar]
  116. 116. 
    Kahmann L, Uciechowski P, Warmuth S, Plümäkers B, Gressner AM et al. 2008. Zinc supplementation in the elderly reduces spontaneous inflammatory cytokine release and restores T cell functions. Rejuvenation Res 11:1227–37
    [Google Scholar]
  117. 117. 
    Kaltenberg J, Plum LM, Ober-Blöbaum JL, Hönscheid A, Rink L, Haase H. 2010. Zinc signals promote IL-2-dependent proliferation of T cells. Eur. J. Immunol. 40:51496–503
    [Google Scholar]
  118. 118. 
    Kambe T, Matsunaga M, Takeda T-A. 2017. Understanding the contribution of zinc transporters in the function of the early secretory pathway. Int. J. Mol. Sci. 18:102179
    [Google Scholar]
  119. 119. 
    Karlsen TH, Sommerfelt H, Klomstad S, Andersen PK, Strand TA et al. 2003. Intestinal and systemic immune responses to an oral cholera toxoid B subunit whole-cell vaccine administered during zinc supplementation. Infect. Immun. 71:73909–13
    [Google Scholar]
  120. 120. 
    Keller SR, Scott HM, Mastick CC, Aebersold R, Lienhard GE. 1995. Cloning and characterization of a novel insulin-regulated membrane aminopeptidase from Glut4 vesicles. J. Biol. Chem. 270:4023612–18
    [Google Scholar]
  121. 121. 
    Kim JE, Yoo SR, Jeong MG, Ko JY, Ro YS. 2014. Hair zinc levels and the efficacy of oral zinc supplementation in patients with atopic dermatitis. Acta Derm. Venerol. 94:5558–62
    [Google Scholar]
  122. 122. 
    King JC, Brown KH, Gibson RS, Krebs NF, Lowe NM et al. 2015. Biomarkers of Nutrition for Development (BOND): zinc review. J. Nutr. 146:4S858–858
    [Google Scholar]
  123. 123. 
    King LE, Fraker PJ. 2000. Variations in the cell cycle status of lymphopoietic and myelopoietic cells created by zinc deficiency. J. Infect. Dis. 182:Suppl. 116–22
    [Google Scholar]
  124. 124. 
    King LE, Fraker PJ. 2002. Zinc deficiency in mice alters myelopoiesis and hematopoiesis. J. Nutr. 132:113301–7
    [Google Scholar]
  125. 125. 
    Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S et al. 2006. Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function. Nat. Immunol. 7:9971–77
    [Google Scholar]
  126. 126. 
    Kloubert V, Blaabjerg K, Dalgaard TS, Poulsen HD, Rink L, Wessels I. 2018. Influence of zinc supplementation on immune parameters in weaned pigs. J. Trace Elem. Med. Biol. 49:231–40
    [Google Scholar]
  127. 127. 
    Kloubert V, Rink L. 2015. Zinc as a micronutrient and its preventive role of oxidative damage in cells. Food Funct 6:103195–204
    [Google Scholar]
  128. 128. 
    Kloubert V, Wessels I, Wolf J, Blaabjerg K, Janssens V et al. 2021. Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREMα expression in T cells. Clin. Nutr. 40:5326378
    [Google Scholar]
  129. 129. 
    Knoell DL, Julian MW, Bao S, Besecker B, Macre JE et al. 2009. Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis. Crit. Care Med. 37:41380–88
    [Google Scholar]
  130. 130. 
    Kochańczyk T, Drozd A, Krężel A. 2015. Relationship between the architecture of zinc coordination and zinc binding affinity in proteins: insights into zinc regulation. Metallomics 7:2244–57
    [Google Scholar]
  131. 131. 
    Kocyła A, Adamczyk J, Krężel A. 2018. Interdependence of free zinc changes and protein complex assembly: insights into zinc signal regulation. Metallomics 10:1120–31
    [Google Scholar]
  132. 132. 
    Kocyła A, Tran JB, Krężel A. 2021. Galvanization of protein-protein interactions in a dynamic zinc interactome. Trends Biochem. Sci. 46:164–79
    [Google Scholar]
  133. 133. 
    Kogan S, Sood A, Garnick MS. 2017. Zinc and wound healing: a review of zinc physiology and clinical applications. Wounds 29:4102–6
    [Google Scholar]
  134. 134. 
    Kolenko V, Uzzo RG, Bukowski R, Bander NH, Novick AC et al. 1999. Dead or dying: necrosis versus apoptosis in caspase-deficient human renal cell carcinoma. Cancer Res 59:122838–42
    [Google Scholar]
  135. 135. 
    Kondaiah P, Yaduvanshi PS, Sharp PA, Pullakhandam R. 2019. Iron and zinc homeostasis and interactions: Does enteric zinc excretion cross-talk with intestinal iron absorption?. Nutrients 11:81885
    [Google Scholar]
  136. 136. 
    Korant BD, Kauer JC, Butterworth BE. 1974. Zinc ions inhibit replication of rhinoviruses. Nature 248:449588–90
    [Google Scholar]
  137. 137. 
    Krenn BM, Gaudernak E, Holzer B, Lanke K, van Kuppeveld FJM, Seipelt J. 2009. Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J. Virol. 83:158–64
    [Google Scholar]
  138. 138. 
    Kretsinger RH, Uversky VN, Permyakov EA 2013. Encyclopedia of Metalloproteins New York: Springer
  139. 139. 
    Krones C, Klosterhalfen B, Fackeldey V, Junge K, Rosch R et al. 2004. Deleterious effect of zinc in a pig model of acute endotoxemia. J. Investig. Surg. 17:5249–56
    [Google Scholar]
  140. 140. 
    Kulik L, Maywald M, Kloubert V, Wessels I, Rink L. 2019. Zinc deficiency drives Th17 polarization and promotes loss of Treg cell function. J. Nutr. Biochem. 63:11–18
    [Google Scholar]
  141. 141. 
    Lanke K, Krenn BM, Melchers WJG, Seipelt J, van Kuppeveld FJM. 2007. PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells. J. Gen. Virol. 88:Part 41206–17
    [Google Scholar]
  142. 142. 
    Lazarczyk M, Dalard C, Hayder M, Dupre L, Pignolet B et al. 2012. EVER proteins, key elements of the natural anti–human papillomavirus barrier, are regulated upon T-cell activation. PLOS ONE 7:6e39995
    [Google Scholar]
  143. 143. 
    Lazarczyk M, Pons C, Mendoza J-A, Cassonnet P, Jacob Y, Favre M. 2008. Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J. Exp. Med. 205:135–42
    [Google Scholar]
  144. 144. 
    Lee M-G, Choi M-A, Chae S, Kang M-A, Jo H et al. 2019. Loss of the dermis zinc transporter ZIP13 promotes the mildness of fibrosarcoma by inhibiting autophagy. Sci. Rep. 9:115042
    [Google Scholar]
  145. 145. 
    Lee S-J, Cho KS, Koh J-Y. 2009. Oxidative injury triggers autophagy in astrocytes: the role of endogenous zinc. Glia 57:121351–61
    [Google Scholar]
  146. 146. 
    Lee S-J, Koh J-Y. 2010. Roles of zinc and metallothionein-3 in oxidative stress–induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Mol. Brain 3:130
    [Google Scholar]
  147. 147. 
    Lee Y-M, Lim C. 2008. Physical basis of structural and catalytic Zn-binding sites in proteins. J. Mol. Biol. 379:3545–53
    [Google Scholar]
  148. 148. 
    Levaot N, Hershfinkel M. 2018. How cellular Zn2+ signaling drives physiological functions. Cell Calcium 75:53–63
    [Google Scholar]
  149. 149. 
    Li X, Chen S, Mao L, Li D, Xu C et al. 2019. Zinc improves functional recovery by regulating the secretion of granulocyte colony stimulating factor from microglia/macrophages after spinal cord injury. Front. Mol. Neurosci. 12:18
    [Google Scholar]
  150. 150. 
    Lienau S, Rink L, Wessels I. 2018. The role of zinc in calprotectin expression in human myeloid cells. J. Trace Elem. Med. Biol. 49:106–12
    [Google Scholar]
  151. 151. 
    Likoswe BH, Phiri FP, Broadley MR, Joy EJM, Patson N et al. 2020. Inflammation adjustment by two methods decreases the estimated prevalence of zinc deficiency in Malawi. Nutrients 12:61563
    [Google Scholar]
  152. 152. 
    Liu C, DeRoo EP, Stecyk C, Wolsey M, Szuchnicki M, Hagos EG. 2015. Impaired autophagy in mouse embryonic fibroblasts null for Krüppel-like factor 4 promotes DNA damage and increases apoptosis upon serum starvation. Mol. Cancer 14:101
    [Google Scholar]
  153. 153. 
    Liu M-J, Bao S, Gálvez-Peralta M, Pyle CJ, Rudawsky AC et al. 2013. ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell Rep 3:2386–400
    [Google Scholar]
  154. 154. 
    Liuzzi JP, Guo L, Chang S-M, Cousins RJ. 2009. Krüppel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 296:3G517–517
    [Google Scholar]
  155. 155. 
    Liuzzi JP, Guo L, Yoo C, Stewart TS. 2014. Zinc and autophagy. Biometals 27:61087–96
    [Google Scholar]
  156. 156. 
    Liuzzi JP, Lichten LA, Rivera S, Blanchard RK, Aydemir TB et al. 2005. Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. PNAS 102:196843–48
    [Google Scholar]
  157. 157. 
    Liuzzi JP, Narayanan V, Doan H, Yoo C. 2018. Effect of zinc intake on hepatic autophagy during acute alcohol intoxication. Biometals 31:2217–32
    [Google Scholar]
  158. 158. 
    Liuzzi JP, Pazos R. 2020. Interplay between autophagy and zinc. J. Trace Elem. Med. Biol. 62:126636
    [Google Scholar]
  159. 159. 
    Liuzzi JP, Yoo C. 2013. Role of zinc in the regulation of autophagy during ethanol exposure in human hepatoma cells. Biol. Trace Elem. Res. 156:1–3350–56
    [Google Scholar]
  160. 160. 
    Lo MN, Damon LJ, Wei Tay J, Jia S, Palmer AE 2020. Single cell analysis reveals multiple requirements for zinc in the mammalian cell cycle. eLife 9:e51107
    [Google Scholar]
  161. 161. 
    Loh SN. 2010. The missing zinc: p53 misfolding and cancer. Metallomics 2:7442–49
    [Google Scholar]
  162. 162. 
    Lowe NM, Fekete K, Decsi T. 2009. Methods of assessment of zinc status in humans: a systematic review. Am. J. Clin. Nutr. 89:6S2040–2040
    [Google Scholar]
  163. 163. 
    Ma H, Su Le, Yue H, Yin X, Zhao J et al. 2015. HMBOX1 interacts with MT2A to regulate autophagy and apoptosis in vascular endothelial cells. Sci. Rep. 5:15121
    [Google Scholar]
  164. 164. 
    Maares M, Haase H. 2016. Zinc and immunity: an essential interrelation. Arch. Biochem. Biophys. 611:58–65
    [Google Scholar]
  165. 165. 
    Maares M, Haase H. 2020. A guide to human zinc absorption: general overview and recent advances of in vitro intestinal models. Nutrients 12:3762
    [Google Scholar]
  166. 166. 
    Maares M, Keil C, Straubing S, Robbe-Masselot C, Haase H. 2020. Zinc deficiency disturbs mucin expression, O-glycosylation and secretion by intestinal goblet cells. Int. J. Mol. Sci. 21:176149
    [Google Scholar]
  167. 167. 
    Mahdaviroshan M, Golzarand M, Taramsari MR, Mahdaviroshan M. 2013. Effect of zinc supplementation on serum zinc and calcium levels in postmenopausal osteoporotic women in Tabriz, Islamic Republic of Iran. East. Mediterr. Health J. 19:3271–75
    [Google Scholar]
  168. 168. 
    Maret W. 2017. Zinc in cellular regulation: the nature and significance of “zinc signals.”. Int. J. Mol. Sci. 18:112285
    [Google Scholar]
  169. 169. 
    Maret W, Jacob C, Vallee BL, Fischer EH 1999. Inhibitory sites in enzymes: zinc removal and reactivation by thionein. PNAS 96:51936–40
    [Google Scholar]
  170. 170. 
    Martin SJ, Mazdai G, Strain JJ, Cotter TG, Hannigan BM. 1991. Programmed cell death (apoptosis) in lymphoid and myeloid cell lines during zinc deficiency. Clin. Exp. Immunol. 83:2338–43
    [Google Scholar]
  171. 171. 
    Mattingly PC, Mowat AG. 1982. Zinc sulphate in rheumatoid arthritis. Ann. Rheum. Dis. 41:5456–57
    [Google Scholar]
  172. 172. 
    Maywald M, Rink L. 2017. Zinc supplementation induces CD4+CD25+Foxp3+ antigen-specific regulatory T cells and suppresses IFN-γ production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1. Eur. J. Nutr. 56:51859–69
    [Google Scholar]
  173. 173. 
    Maywald M, Wang F, Rink L. 2018. The intracellular free zinc level is vital for Treg function and a feasible tool to discriminate between Treg and activated Th cells. Int. J. Mol. Sci. 19:113575
    [Google Scholar]
  174. 174. 
    Maywald M, Wessels I, Rink L. 2017. Zinc signals and immunity. Int. J. Mol. Sci. 18:102222
    [Google Scholar]
  175. 175. 
    McDonald CM, Suchdev PS, Krebs NF, Hess SY, Wessells KR et al. 2020. Adjusting plasma or serum zinc concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Am. J. Clin. Nutr. 111:4927–37
    [Google Scholar]
  176. 176. 
    Méplan C, Richard MJ, Hainaut P. 2000. Metalloregulation of the tumor suppressor protein p53: Zinc mediates the renaturation of p53 after exposure to metal chelators in vitro and in intact cells. Oncogene 19:465227–36
    [Google Scholar]
  177. 177. 
    Metz CHD, Schröder AK, Overbeck S, Kahmann L, Plümäkers B, Rink L. 2007. T-helper type 1 cytokine release is enhanced by in vitro zinc supplementation due to increased natural killer cells. Nutrition 23:2157–63
    [Google Scholar]
  178. 178. 
    Mir E, Hossein-Nezhad A, Bahrami A, Bekheirnia MR, Javadi E et al. 2007. Serum zinc concentration could predict bone mineral density and protect osteoporosis in healthy men. Iran. J. Public Health 36:Suppl. 130–36
    [Google Scholar]
  179. 179. 
    Miura Y, Endo T. 2016. Glycomics and glycoproteomics focused on aging and age-related diseases: glycans as a potential biomarker for physiological alterations. Biochim. Biophys. Acta 1860:81608–14
    [Google Scholar]
  180. 180. 
    Miyai T, Hojyo S, Ikawa T, Kawamura M, Irié T et al. 2014. Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development. PNAS 111:3211780–85
    [Google Scholar]
  181. 181. 
    Mnatsakanyan H, Sabater i Serra R, Salmeron-Sanchez M, Rico P 2019. Zinc maintains embryonic stem cell pluripotency and multilineage differentiation potential via AKT activation. Front. . Cell Dev. Biol. 7:180
    [Google Scholar]
  182. 182. 
    Mocchegiani E, Fabris N. 1995. Age-related thymus involution: Zinc reverses in vitro the thymulin secretion defect. Int. J. Immunopharmacol. 17:9745–49
    [Google Scholar]
  183. 183. 
    Mocchegiani E, Muzzioli M, Giacconi R, Cipriano C, Gasparini N et al. 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. 124:4459–68
    [Google Scholar]
  184. 184. 
    Muneoka S, Goto M, Nishimura T, Enomoto K, Kadoshima-Yamaoka K, Tomimori Y. 2019. G protein–coupled receptor 39 agonist improves concanavalin A–induced hepatitis in mice. Biol. Pharm. Bull. 42:81415–18
    [Google Scholar]
  185. 185. 
    Muzzioli M, Stecconi R, Moresi R, Provinciali M. 2009. Zinc improves the development of human CD34+ cell progenitors towards NK cells and increases the expression of GATA-3 transcription factor in young and old ages. Biogerontology 10:5593–604
    [Google Scholar]
  186. 186. 
    Nakashima-Kaneda K, Matsuda A, Mizuguchi H, Sasaki-Sakamoto T, Saito H et al. 2013. Regulation of IgE-dependent zinc release from human mast cells. Int. Arch. Allergy Immunol. 161:Suppl.44–51
    [Google Scholar]
  187. 187. 
    Noh S, Lee SR, Jeong YJ, Ko KS, Rhee BD et al. 2015. The direct modulatory activity of zinc toward ion channels. Integr. Med. Res. 4:3142–46
    [Google Scholar]
  188. 188. 
    Noulas C, Tziouvalekas M, Karyotis T. 2018. Zinc in soils, water and food crops. J. Trace Elem. Med. Biol. 49:252–60
    [Google Scholar]
  189. 189. 
    Ollig J, Kloubert V, Taylor KM, Rink L. 2019. B cell activation and proliferation increase intracellular zinc levels. J. Nutr. Biochem. 64:72–79
    [Google Scholar]
  190. 190. 
    Ollig J, Kloubert V, Weßels I, Haase H, Rink L. 2016. Parameters influencing zinc in experimental systems in vivo and in vitro. Metals 6:371
    [Google Scholar]
  191. 191. 
    Orlov AP, Orlova MA, Trofimova TP, Kalmykov SN, Kuznetsov DA. 2018. The role of zinc and its compounds in leukemia. J. Biol. Inorg. Chem. 23:3347–62
    [Google Scholar]
  192. 192. 
    Pawlitzki M, Uebelhör J, Sweeney-Reed CM, Stephanik H, Hoffmann J et al. 2018. Lower serum zinc levels in patients with multiple sclerosis compared to healthy controls. Nutrients 10:8967
    [Google Scholar]
  193. 193. 
    Pitt SJ, Stewart AJ. 2015. Examining a new role for zinc in regulating calcium release in cardiac muscle. Biochem. Soc. Trans. 43:3359–63
    [Google Scholar]
  194. 194. 
    Plum LM, Brieger A, Engelhardt G, Hebel S, Nessel A et al. 2014. PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation. Metallomics 6:71277–87
    [Google Scholar]
  195. 195. 
    Plum LM, Rink L, Haase H. 2010. The essential toxin: impact of zinc on human health. Int. J. Environ. Res. Public Health 7:41342–65
    [Google Scholar]
  196. 196. 
    Porter NJ, Christianson DW. 2019. Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases. Curr. Opin. Struct. Biol. 59:9–18
    [Google Scholar]
  197. 197. 
    Prasad AS. 1985. Clinical and biochemical manifestation zinc deficiency in human subjects. J. Pharmacol. 16:4344–52
    [Google Scholar]
  198. 198. 
    Prasad AS. 2000. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J. Infect. Dis. 182:Suppl. 162–68
    [Google Scholar]
  199. 199. 
    Prasad AS. 2014. Zinc: an antioxidant and anti-inflammatory agent: role of zinc in degenerative disorders of aging. J. Trace Elem. Med. Biol. 28:4364–71
    [Google Scholar]
  200. 200. 
    Prasad AS, Bao B, Beck FWJ, Kucuk O, Sarkar FH. 2004. Antioxidant effect of zinc in humans. Free Radic. Biol. Med. 37:81182–90
    [Google Scholar]
  201. 201. 
    Prasad AS, Beck FWJ, Bao B, Fitzgerald JT, Snell DC et al. 2007. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am. J. Clin. Nutr. 85:3837–44
    [Google Scholar]
  202. 202. 
    Prasad AS, Miale A, Farid Z, Sandstead HH, Schulert AR. 1963. Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism. J. Lab. Clin. Med. 61:537–49
    [Google Scholar]
  203. 203. 
    Qadri F, Ahmed T, Wahed MA, Ahmed F, Bhuiyan NA et al. 2004. Suppressive effect of zinc on antibody response to cholera toxin in children given the killed, B subunit–whole cell, oral cholera vaccine. Vaccine 22:3–4416–21
    [Google Scholar]
  204. 204. 
    Qi S, He J, Zheng H, Chen C, Jiang H, Lan S 2020. Zinc supplementation increased bone mineral density, improves bone histomorphology, and prevents bone loss in diabetic rat. Biol. Trace Elem. Res. 194:2493–501
    [Google Scholar]
  205. 205. 
    Qiu M, Chen Y, Chu Y, Song S, Yang N et al. 2013. Zinc ionophores pyrithione inhibits herpes simplex virus replication through interfering with proteasome function and NF-κB activation. Antiv. Res. 100:144–53
    [Google Scholar]
  206. 206. 
    Quintal SM, dePaula QA, Farrell NP. 2011. Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences. Metallomics 3:2121–39
    [Google Scholar]
  207. 207. 
    Rajagopalan S, Winter CC, Wagtmann N, Long EO. 1995. The Ig-related killer cell inhibitory receptor binds zinc and requires zinc for recognition of HLA-C on target cells. J. Immunol. 155:94143–46
    [Google Scholar]
  208. 208. 
    Ranasinghe P, Wathurapatha WS, Ishara MH, Jayawardana R, Galappatthy P et al. 2015. Effects of zinc supplementation on serum lipids: a systematic review and meta-analysis. Nutr. Metab. 12:26
    [Google Scholar]
  209. 209. 
    Rasker JJ, Kardaun SH. 1982. Lack of beneficial effect of zinc sulphate in rheumatoid arthritis. Scand. J. Rheumatol. 11:3168–70
    [Google Scholar]
  210. 210. 
    Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. 2019. The role of zinc in antiviral immunity. Adv. Nutr. 10:4696–710
    [Google Scholar]
  211. 211. 
    Reiterer G, MacDonald R, Browning JD, Morrow J, Matveev SV et al. 2005. Zinc deficiency increases plasma lipids and atherosclerotic markers in LDL-receptor-deficient mice. J. Nutr. 135:92114–18
    [Google Scholar]
  212. 212. 
    Rice JM, Zweifach A, Lynes MA. 2016. Metallothionein regulates intracellular zinc signaling during CD4+ T cell activation. BMC Immunol 17:113
    [Google Scholar]
  213. 213. 
    Rink L 2011. Zinc in Human Health Amsterdam: IOS Press
  214. 214. 
    Rolles B, Maywald M, Rink L. 2018. Influence of zinc deficiency and supplementation on NK cell cytotoxicity. J. Funct. Foods 48:322–28
    [Google Scholar]
  215. 215. 
    Roscioli E, Jersmann HP, Lester S, Badiei A, Fon A et al. 2017. Zinc deficiency as a codeterminant for airway epithelial barrier dysfunction in an ex vivo model of COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 12:3503–10
    [Google Scholar]
  216. 216. 
    Rosenkranz E, Maywald M, Hilgers R-D, Brieger A, Clarner T et al. 2016. Induction of regulatory T cells in Th1-/Th17-driven experimental autoimmune encephalomyelitis by zinc administration. J. Nutr. Biochem. 29:116–23
    [Google Scholar]
  217. 217. 
    Rosenkranz E, Metz CHD, Maywald M, Hilgers R-D, Weßels I et al. 2016. Zinc supplementation induces regulatory T cells by inhibition of Sirt-1 deacetylase in mixed lymphocyte cultures. Mol. Nutr. Food Res. 60:3661–71
    [Google Scholar]
  218. 218. 
    Rossi L, Migliaccio S, Corsi A, Marzia M, Bianco P et al. 2001. Reduced growth and skeletal changes in zinc-deficient growing rats are due to impaired growth plate activity and inanition. J. Nutr. 131:41142–46
    [Google Scholar]
  219. 219. 
    Sacan O, Turkyilmaz IB, Bayrak BB, Mutlu O, Akev N, Yanardag R. 2016. Zinc supplementation ameliorates glycoprotein components and oxidative stress changes in the lung of streptozotocin diabetic rats. Biometals 29:2239–48
    [Google Scholar]
  220. 220. 
    Sakakibara Y, Sato S, Kawashima Y, Someya Y, Shirato K et al. 2011. Different recovery responses from dietary zinc-deficiency in the distribution of rat granulocytes. J. Nutr. Sci. Vitaminol. 57:2197–201
    [Google Scholar]
  221. 221. 
    Sakurai H, Adachi Y. 2005. The pharmacology of the insulinomimetic effect of zinc complexes. Biometals 18:4319–23
    [Google Scholar]
  222. 222. 
    Salari S, Khomand P, Arasteh M, Yousefzamani B, Hassanzadeh K. 2015. Zinc sulphate: a reasonable choice for depression management in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Pharmacol. Rep. 67:3606–9
    [Google Scholar]
  223. 223. 
    Sandstead HH, Freeland-Graves JH. 2014. Dietary phytate, zinc and hidden zinc deficiency. J. Trace Elem. Med. Biol. 28:4414–17
    [Google Scholar]
  224. 224. 
    Sanna A, Firinu D, Zavattari P, Valera P. 2018. Zinc status and autoimmunity: a systematic review and meta-analysis. Nutrients 10:168
    [Google Scholar]
  225. 225. 
    Santos HO, Teixeira FJ, Schoenfeld BJ. 2020. Dietary versus pharmacological doses of zinc: a clinical review. Clin. Nutr. 39:51345–53
    [Google Scholar]
  226. 226. 
    Schubert C, Guttek K, Grüngreiff K, Thielitz A, Bühling F et al. 2014. Oral zinc aspartate treats experimental autoimmune encephalomyelitis. Biometals 27:61249–62
    [Google Scholar]
  227. 227. 
    Scott DA. 1934. Crystalline insulin. Biochem. J. 28:41592–1602.1
    [Google Scholar]
  228. 228. 
    Scott ME, Koski KG. 2000. Zinc deficiency impairs immune responses against parasitic nematode infections at intestinal and systemic sites. J. Nutr. 130:5S1412–1412
    [Google Scholar]
  229. 229. 
    Seo H-J, Cho Y-E, Kim T, Shin H-I, Kwun I-S. 2010. Zinc may increase bone formation through stimulating cell proliferation, alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells. Nutr. Res. Pract. 4:5356–61
    [Google Scholar]
  230. 230. 
    Seo H-M, Kim YH, Lee JH, Kim JS, Park YM, Lee JY. 2017. Serum zinc status and its association with allergic sensitization: the fifth Korea National Health and Nutrition Examination Survey. Sci. Rep. 7:112637
    [Google Scholar]
  231. 231. 
    Shalini S, Dorstyn L, Dawar S, Kumar S. 2015. Old, new and emerging functions of caspases. Cell Death Differ. 22:4526–39
    [Google Scholar]
  232. 232. 
    Shen H, MacDonald R, Bruemmer D, Stromberg A, Daugherty A et al. 2007. Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone. J. Nutr. 137:112339–45
    [Google Scholar]
  233. 233. 
    Solomons NW. 2001. Dietary sources of zinc and factors affecting its bioavailability. Food Nutr. Bull. 22:2138–54
    [Google Scholar]
  234. 234. 
    Stennicke HR, Salvesen GS. 1997. Biochemical characteristics of caspases-3, -6, -7, and -8. J. Biol. Chem. 272:4125719–23
    [Google Scholar]
  235. 235. 
    Stoncius LV, Ashrafi SH, Meyer J. 1985. Ultrastructure of mast cells in the hyperplastic buccal mucosa of the zinc-deficient rat. J. Oral Pathol. 14:5375–82
    [Google Scholar]
  236. 236. 
    Strand TA, Hollingshead SK, Julshamn K, Briles DE, Blomberg B, Sommerfelt H. 2003. Effects of zinc deficiency and pneumococcal surface protein A immunization on zinc status and the risk of severe infection in mice. Infect. Immun. 71:42009–13
    [Google Scholar]
  237. 237. 
    Strieder-Barboza C, Baker NA, Flesher CG, Karmakar M, Neeley CK et al. 2019. Advanced glycation end-products regulate extracellular matrix–adipocyte metabolic crosstalk in diabetes. Sci. Rep. 9:119748
    [Google Scholar]
  238. 238. 
    Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS Jr 2013. Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity 39:4697–710
    [Google Scholar]
  239. 239. 
    Suzuki T, Kajita Y, Katsumata S-I, Matsuzaki H, Suzuki K. 2015. Zinc deficiency increases serum concentrations of parathyroid hormone through a decrease in serum calcium and induces bone fragility in rats. J. Nutr. Sci. Vitaminol. 61:5382–90
    [Google Scholar]
  240. 240. 
    Taylor KM, Hiscox S, Nicholson RI, Hogstrand C, Kille P. 2012. Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. Sci. Signal. 5:210ra11
    [Google Scholar]
  241. 241. 
    te Velthuis AJW, van den Worm SHE, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. 2010. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLOS Pathog 6:11e1001176
    [Google Scholar]
  242. 242. 
    Trame S, Wessels I, Haase H, Rink L. 2018. A short 18 items food frequency questionnaire biochemically validated to estimate zinc status in humans. J. Trace Elem. Med. Biol. 49:285–95
    [Google Scholar]
  243. 243. 
    Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD. 2001. The role of zinc in caspase activation and apoptotic cell death. Biometals 14:3–4315–30
    [Google Scholar]
  244. 244. 
    Tupe R, Kulkarni A, Adeshara K, Sankhe N, Shaikh S et al. 2015. Zinc inhibits glycation induced structural, functional modifications in albumin and protects erythrocytes from glycated albumin toxicity. Int. J. Biol. Macromol. 79:601–10
    [Google Scholar]
  245. 245. 
    Uchida R, Xiang H, Arai H, Kitamura H, Nishida K. 2019. L-type calcium channel–mediated zinc wave is involved in the regulation of IL-6 by stimulating non-IgE with LPS and IL-33 in mast cells and dendritic cells. Biol. Pharm. Bull. 42:187–93
    [Google Scholar]
  246. 246. 
    Valés-Gómez M, Erskine RA, Deacon MP, Strominger JL, Reyburn HT 2001. The role of zinc in the binding of killer cell Ig-like receptors to class I MHC proteins. PNAS 98:41734–39
    [Google Scholar]
  247. 247. 
    Valko M, Morris H, Cronin MTD. 2005. Metals, toxicity and oxidative stress. Curr. Med. Chem. 12:101161–208
    [Google Scholar]
  248. 248. 
    Vallee BL, Auld DS 1993. Cocatalytic zinc motifs in enzyme catalysis. PNAS 90:72715–18
    [Google Scholar]
  249. 249. 
    Vallee BL, Galdes A. 1984. The metallobiochemistry of zinc enzymes. Adv. Enzymol. Relat. Areas Mol. Biol. 56:283–430
    [Google Scholar]
  250. 250. 
    Vogel-González M, Talló-Parra M, Herrera-Fernández V, Pérez-Vilaró G, Chillón M et al. 2021. Low zinc levels at clinical admission associates with poor outcomes in COVID-19. Nutrients 13:2562
    [Google Scholar]
  251. 251. 
    von Bülow V, Rink L, Haase H. 2005. Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-α and IL-1β production in monocytes by elevation of guanosine 3′,5′-cyclic monophosphate. J. Immunol. 175:74697–705
    [Google Scholar]
  252. 252. 
    Wan Y, Petris MJ, Peck SC. 2014. Separation of zinc-dependent and zinc-independent events during early LPS-stimulated TLR4 signaling in macrophage cells. FEBS Lett 588:172928–35
    [Google Scholar]
  253. 253. 
    Wang C, Zhang R, Wei X, Lv M, Jiang Z 2020. Metalloimmunology: the metal ion–controlled immunity. Advances in Immunology in China B C Dong, Z Jiang 187–241 Amsterdam: Elsevier
    [Google Scholar]
  254. 254. 
    Wang J, Zhao H, Xu Z, Cheng X. 2020. Zinc dysregulation in cancers and its potential as a therapeutic target. Cancer Biol. Med. 17:3612–25
    [Google Scholar]
  255. 255. 
    Wang L, Wang F-S, Gershwin ME. 2015. Human autoimmune diseases: a comprehensive update. J. Intern. Med. 278:4369–95
    [Google Scholar]
  256. 256. 
    Wang Z, Wang J, Cao D, Han L. 2020. Correlation of neutrophil-to-lymphocyte ratio with the prognosis of non-ST-segment elevation in patients with acute coronary syndrome undergoing selective percutaneous coronary intervention. J. Int. Med. Res. 48:100300060520959510
    [Google Scholar]
  257. 257. 
    Wei C-C, Luo Z, Hogstrand C, Xu Y-H, Wu L-X et al. 2018. Zinc reduces hepatic lipid deposition and activates lipophagy via Zn2+/MTF-1/PPARα and Ca2+/CaMKKβ/AMPK pathways. FASEB J 32:126666–80
    [Google Scholar]
  258. 258. 
    Wessels I 2017. Epigenetics and minerals: an overview. Handbook of Nutrition, Diet, and Epigenetics V Patel, V Preedy 1–19 Basel, Switz.: Springer
    [Google Scholar]
  259. 259. 
    Wessels I, Cousins RJ. 2015. Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation. Am. J. Physiol. Gastrointest. Liver Physiol. 309:9G768–768
    [Google Scholar]
  260. 260. 
    Wessels I, Haase H, Engelhardt G, Rink L, Uciechowski P. 2013. Zinc deficiency induces production of the proinflammatory cytokines IL-1β and TNFα in promyeloid cells via epigenetic and redox-dependent mechanisms. J. Nutr. Biochem. 24:1289–97
    [Google Scholar]
  261. 261. 
    Wessels I, Maywald M, Rink L. 2017. Zinc as a gatekeeper of immune function. Nutrients 9:121286
    [Google Scholar]
  262. 262. 
    Wessels I, Pupke JT, von Trotha K-T, Gombert A, Himmelsbach A et al. 2020. Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity. Thorax 75:3253–61
    [Google Scholar]
  263. 263. 
    Wessels I, Rink L. 2020. Micronutrients in autoimmune diseases: possible therapeutic benefits of zinc and vitamin D. J. Nutr. Biochem. 77:108240
    [Google Scholar]
  264. 264. 
    Wessels I, Rolles B, Rink L. 2020. The potential impact of zinc supplementation on COVID-19 pathogenesis. Front. Immunol. 11:1712
    [Google Scholar]
  265. 265. 
    Williams RB, Chesters JK. 1970. The effects of early zinc deficiency on DNA and protein synthesis in the rat. Br. J. Nutr. 24:41053–59
    [Google Scholar]
  266. 266. 
    Wilson M, Hogstrand C, Maret W. 2012. Picomolar concentrations of free zinc(II) ions regulate receptor protein–tyrosine phosphatase β activity. J. Biol. Chem. 287:129322–26
    [Google Scholar]
  267. 267. 
    Wong CP, Dashner-Titus EJ, Alvarez SC, Chase TT, Hudson LG, Ho E. 2019. Zinc deficiency and arsenic exposure can act both independently or cooperatively to affect zinc status, oxidative stress, and inflammatory response. Biol. Trace Elem. Res. 191:2370–81
    [Google Scholar]
  268. 268. 
    Wong CP, Rinaldi NA, Ho E. 2015. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Mol. Nutr. Food Res. 59:5991–99
    [Google Scholar]
  269. 269. 
    Wong SHK, Shih RSM, Schoene NW, Lei KY. 2008. Zinc-induced G2/M blockage is p53 and p21 dependent in normal human bronchial epithelial cells. Am. J. Physiol. Cell Physiol. 294:6C1342–1342
    [Google Scholar]
  270. 270. 
    World Health Organization (WHO) 2003. The World Health report 2002. Midwifery 19:172–73
    [Google Scholar]
  271. 271. 
  272. 272. 
    Xie W, Xue Q, Niu L, Wong K-W. 2020. Zinc transporter SLC39A7 relieves zinc deficiency to suppress alternative macrophage activation and impairment of phagocytosis. PLOS ONE 15:7e0235776
    [Google Scholar]
  273. 273. 
    Xie Z, Wu H, Zhao J. 2020. Multifunctional roles of zinc in Alzheimer's disease. NeuroToxicology 80:112–23
    [Google Scholar]
  274. 274. 
    Yakoob MY, Theodoratou E, Jabeen A, Imdad A, Eisele TP et al. 2011. Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health 11:Suppl. 323
    [Google Scholar]
  275. 275. 
    Yu M, Lee W-W, Tomar D, Pryshchep S, Czesnikiewicz-Guzik M et al. 2011. Regulation of T cell receptor signaling by activation-induced zinc influx. J. Exp. Med. 208:4775–85
    [Google Scholar]
  276. 276. 
    Zha Q-B, Wei H-X, Li C-G, Liang Y-D, Xu L-H et al. 2016. ATP-induced inflammasome activation and pyroptosis is regulated by AMP-activated protein kinase in macrophages. Front. Immunol. 7:597
    [Google Scholar]
  277. 277. 
    Zhao N, Wang X, Zhang Y, Gu Q, Huang F et al. 2013. Gestational zinc deficiency impairs humoral and cellular immune responses to hepatitis B vaccination in offspring mice. PLOS ONE 8:9e73461
    [Google Scholar]
  278. 278. 
    Zhu B, Wang J-Y, Zhou J-J, Zhou F, Cheng W et al. 2017. PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells. J. Inorg. Biochem. 175:92–100
    [Google Scholar]
  279. 279. 
    Zhuang X, Pang X, Zhang W, Wu W, Zhao J et al. 2012. Effects of zinc and manganese on advanced glycation end products (AGEs) formation and AGEs-mediated endothelial cell dysfunction. Life Sci 90:3–4131–39
    [Google Scholar]
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