Review Article
Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus
重新评价金属硫蛋白:对糖尿病患者的临床意义
Yongsoo Park,
Jian Zhang,
Lu Cai,
Yongsoo Park
Department of Pediatrics, Pediatrics Research Institute, University of Louisville, Louisville, Kentucky, USA
Hanyang University, College of Medicine and Engineering, Seoul, South Korea
Search for more papers by this authorJian Zhang
Department of Pediatrics, Pediatrics Research Institute, University of Louisville, Louisville, Kentucky, USA
The Center of Cardiovascular Disorders, The First Hospital of Jilin University, Changchun, China
Search for more papers by this authorCorresponding Author
Lu Cai
Department of Pediatrics, Pediatrics Research Institute, University of Louisville, Louisville, Kentucky, USA
Department of Radiation Oncology, University of Louisville, Louisville, Kentucky, USA
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
Correspondence
Lu Cai, Children's Hospital Research Institute, University of Louisville, 570 S. Preston Street, Donald Baxter Building, Suite 321A, Louisville, KY 40202, USA.
Tel: +1 502 852 2214
Fax: +1 502 852 5634
Email: [email protected]
Search for more papers by this authorYongsoo Park,
Jian Zhang,
Lu Cai,
Yongsoo Park
Department of Pediatrics, Pediatrics Research Institute, University of Louisville, Louisville, Kentucky, USA
Hanyang University, College of Medicine and Engineering, Seoul, South Korea
Search for more papers by this authorJian Zhang
Department of Pediatrics, Pediatrics Research Institute, University of Louisville, Louisville, Kentucky, USA
The Center of Cardiovascular Disorders, The First Hospital of Jilin University, Changchun, China
Search for more papers by this authorCorresponding Author
Lu Cai
Department of Pediatrics, Pediatrics Research Institute, University of Louisville, Louisville, Kentucky, USA
Department of Radiation Oncology, University of Louisville, Louisville, Kentucky, USA
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
Correspondence
Lu Cai, Children's Hospital Research Institute, University of Louisville, 570 S. Preston Street, Donald Baxter Building, Suite 321A, Louisville, KY 40202, USA.
Tel: +1 502 852 2214
Fax: +1 502 852 5634
Email: [email protected]
Search for more papers by this authorAbstract
enReactive oxygen and nitrogen species (ROS and RNS, respectively) are byproducts of cellular physiological processes of the metabolism of intermediary nutrients. Although physiological defense mechanisms readily convert these species into water or urea, an improper balance between their production and removal leads to oxidative stress (OS), which is harmful to cellular components. This OS may result in uncontrolled growth or, ultimately, cell death. In addition, ROS and RNS are closely related to the development of diabetes and its complications. Therefore, numerous researchers have proposed the development of strategies for the removal of ROS/RNS to prevent or treat diabetes and its complications. Some molecules that are synthesized in the body or obtained from food participate in the removal and neutralization of ROS and RNS. Metallothionein, a cysteine-rich protein, is a metal-binding protein that has a wide range of functions in cellular homeostasis and immunity. Metallothionein can be induced by a variety of conditions, including zinc supplementation, and plays a crucial role in mediating anti-OS, anti-apoptotic, detoxification, and anti-inflammatory effects. Metallothionein can modulate various stress-induced signaling pathways (mitogen-activated protein kinase, Wnt, nuclear factor-κB, phosphatidylinositol 3-kinase, sirtuin 1/AMP-activated protein kinase and fibroblast growth factor 21) to alleviate diabetes and diabetic complications. However, a deeper understanding of the functional, biochemical, and molecular characteristics of metallothionein is needed to bring about new opportunities for OS therapy. This review focuses on newly proposed functions of a metallothionein and their implications relevant to diabetes and its complications.
摘要
zh活性氧以及活性氮(Reactive oxygen species, ROS;Reactive nitrogen species, RNS)是细胞中间营养物质生理代谢过程中的副产品。虽然生理防御机制可以迅速将这类物资转化成水或者尿素氮, 但是如果合成与清除之间失衡就会导致氧化应激(oxidative stress, OS), 这对细胞成分是有害的。这种OS可以导致生长失控, 或最终导致细胞死亡。另外, ROS和RNS都与糖尿病及其并发症的发生密切相关。因此, 许多学者都提出了通过清除ROS/RNS来预防或者治疗糖尿病及其并发症的治疗策略。一些在身体中合成或从食物中获得的分子参与了ROS与RNS的清除及中和过程。金属硫蛋白, 一种富含半胱氨酸的蛋白质, 它是一种金属结合蛋白, 在细胞内稳态以及免疫方面都有广泛的功能。许多状态下都可以诱导产生金属硫蛋白, 包括补充锌治疗, 它在介导抗OS、抗细胞凋亡、解毒以及抗炎等方面都有着极其重要的作用。金属硫蛋白能够通过调节多种应激诱导的信号通路(丝裂原活化蛋白激酶、Wnt、核因子-κB、磷脂酰肌醇3激酶、去乙酰化酶1/AMP活化的蛋白激酶以及成纤维细胞生长因子21)来缓解糖尿病以及其并发症。然而, 为了给OS治疗带来新的机遇, 需要我们更深入地了解金属硫蛋白的功能、生化以及分子特征。这篇综述聚焦于新近提出的金属硫蛋白功能以及它们与糖尿病及其并发症的关系。
References
- 1Park Y. Oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress. Biodesign. 2014; 2: 12–20.
- 2Grattagliano I, Palmieri VO, Portincasa P, Moschetta A, Palasciano G. Oxidative stress-induced risk factors associated with the metabolic syndrome: A unifying hypothesis. J Nutr Biochem. 2008; 19: 491–504.
- 3Brownlee M. The pathobiology of diabetic complications. A unifying mechanism. Diabetes. 2005; 54: 1615–1625.
- 4Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017; 13: 36–49.
- 5Ghanim H, Abuaysheh S, Sia CL et al. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: Implications for insulin resistance. Diabetes Care. 2009; 32: 2281–2287.
- 6Deopurkar R, Ghanim H, Friedman J et al. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care. 2010; 33: 991–997.
- 7Dandona P, Mohanty P, Ghanim H et al. The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation. J Clin Endocrinol Metab. 2001; 86: 355–362.
- 8Matsuzawa A, Ichijo H. Redox control of cell fate by MAP kinase: Physiological roles of ASK1/MAP kinase pathway in stress signaling. Biochim Biophys Acta. 1780; 2008: 1325–1336.
- 9Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organiz J. 2012; 5: 9–19.
- 10Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med. 2000; 28: 1456–1462.
- 11Bartz RR, Piantadosi CA. Clinical review: Oxygen as a signaling molecule. Crit Care. 2010; 14: 234–242.
- 12Katsuyama M, Matsuno K, Yabe-Nishimura C. Physiological roles of NOX/NADPH oxidase, the superoxide generating enzyme. J Clin Biochem Nutr. 2012; 50: 9–22.
- 13Preiser JC. Oxidative stress. JPEN J Parenter Enteral Nutr. 2012; 36: 147–154.
- 14Laskin DL. Oxidative/Nitrosative Stress and Disease. Blackwell Publishing, Boston, 2010.
- 15Kohen R, Nyska A. Oxidation of biologic systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol. 2002; 30: 620–650.
- 16Pan JS, Hong MZ, Ren JL. Reactive oxygen species: A double-edged sword in oncogenesis. World J Gastroenterol. 2009; 15: 1702–1707.
- 17Runchel C, Matsuzawa A, Ichijo H. Mitogen-activated protein kinases in mammalian oxidative stress responses. Antioxid Redox Signal. 2011; 15: 205–218.
- 18Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. J Biomed Biotechnol. 2012; 2012: 936486.
- 19Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD. Free radicals and antioxidants in human health: Current status and future prospects. J Assoc Physicians India. 2004; 52: 794–804.
- 20Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. 2006; 28: 219–242.
- 21Katunga LA, Gudimella P, Efird JT et al. Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy. Mol Metab. 2015; 4: 493–506.
- 22Vasak M. Advances in metallothionein structure and functions. J Trace Elem Med Biol. 2005; 19: 13–17.
- 23Takahashi S. Positive and negative regulators of the metallothionein gene. Mol Med Rep. 2015; 12: 795–799.
- 24Miles AT, Hawksworth GM, Beattie JH, Rodilla V. Induction, regulation, degradation, and biological significance of mammalian metallothioneins. Crit Rev Biochem Mol Biol. 2000; 35: 35–70.
- 25Kimura T, Kambe T. The functions of metallothionein and ZIP and ZnT transporters: An overview and perspective. Int J Mol Sci. 2016; 17: 336–359.
- 26Monia BP, Butt TR, Ecker DJ, Mirabelli CK, Crooke ST. Metallothionein turnover in mammalian cells. Implications in metal toxicity. J Biol Chem. 1986; 261: 10957–10959.
- 27Klaassen CD, Choudhuri S, JM MK Jr, LD L-MK, Kershaw WC. In vitro and in vivo studies on the degradation of metallothionein. Environ Health Perspect. 1994; 102 (Suppl. 3): 141–146.
- 28Rice JM, Zweifach A, Lynes MA. Metallothionein regulates intracellular zinc signaling during CD4(+) T cell activation. BMC Immunol. 2016; 17: 13.
- 29Cherian MG. The significance of the nuclear and cytoplasmic localization of metallothionein in human liver and tumor cells. Environ Health Perspect. 1994; 102 (Suppl. 3): 131–135.
- 30Cherian MG, Apostolova MD. Nuclear localization of metallothionein during cell proliferation and differentiation. Cell Mol Biol (Noisy-le-Grand). 2000; 46: 347–356.
- 31De Lisle RC, Sarras MP Jr, Hidalgo J, Andrews GK. Metallothionein is a component of exocrine pancreas secretion: Implications for zinc homeostasis. Am J Physiol. 1996; 271: C1103–C1110.
- 32Yin X, Knecht DA, Lynes MA. Metallothionein mediates leukocyte chemotaxis. BMC Immunol. 2005; 15: 21.
10.1186/1471-2172-6-21 Google Scholar
- 33Chen L, Jin T, Huang B et al. Plasma metallothionein antibody and cadmium-induced renal dysfunction in an occupational population in China. Toxicol Sci. 2006; 91: 104–112.
- 34Ye B, Maret W, Vallee BL. Zinc metallothionein imported into liver mitochondria modulates respiration. Proc Natl Acad Sci U S A. 2001; 98: 2317–2322.
- 35Gonçalves I, Quintela T, Baltazar G, Almeida MR, Saraiva MJ, Santos CR. Transthyretin interacts with metallothionein 2. Biochemistry. 2008; 47: 2244–2251.
- 36Lynes MA, Zaffuto K, Unfricht DW, Marusov G, Samson JS, Yin X. The physiological roles of extracellular metallothionein. Exp Biol Med (Maywood). 2006; 231: 1548–1554.
- 37Armario A, Hidalgo J, Bas J, Restrepo C, Dingman A, Garvey JS. Age-dependent effects of acute and chronic intermittent stresses on serum metallothionein. Physiol Behav. 1987; 39: 277–279.
- 38Hidalgo J, Giralt M, Garvey JS, Armario A. Physiological role of glucocorticoids on rat serum and liver metallothionein in basal and stress conditions. Am J Physiol. 1988; 254: E71–E78.
- 39Bremner I, Mehra RK, Sato M. Metallothionein in blood, bile and urine. Experientia Suppl. 1987; 52: 507–517.
- 40Garvey JS. Metallothionein: Structure/antigenicity and detection/quantitation in normal physiological fluids. Environ Health Perspect. 1984; 54: 117–127.
- 41West AK, Leung JY, Chung RS. Neuroprotection and regeneration by extracellular metallothionein via lipoprotein-receptor-related proteins. J Biol Inorg Chem. 2011; 16: 1115–1122.
- 42Bhandari S, Melchiorre C, Dostie K et al. Detection and manipulation of the stress response protein metallothionein. Curr Protoc Toxicol. 2017; 71: 17.19.1–17.19.28.
10.1002/cptx.17 Google Scholar
- 43Lynes MA, Hidalgo J, Manso Y, Devisscher L, Laukens D, Lawrence DA. Metallothionein and stress combine to affect multiple organ systems. Cell Stress Chaperones. 2014; 19: 605–611.
- 44Vašák M, Meloni G. Mammalian metallothionein-3: New functional and structural insights. Int J Mol Sci. 2017; 18: 1117.
- 45Jin R, Chow VT, Tan PH, Dheen ST, Duan W, Bay BH. Metallothionein 2A expression is associated with cell proliferation in breast cancer. Carcinogenesis. 2002; 23: 81–86.
- 46Crèvecoeur I, Gudmundsdottir V, Vig S et al. Early differences in islets from prediabetic NOD mice: Combined microarray and proteomic analysis. Diabetologia. 2017; 60: 475–489.
- 47Nielsen AE, Bohr A, Penkowa M. The balance between life and death of cells: Roles of metallothioneins. Biomark Insights. 2007; 1: 99–111.
- 48Dong F, Li Q, Sreejayan N, Nunn JM, Ren J. Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: Role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis. Diabetes. 2007; 56: 2201–2212.
- 49Kumar H, Koppula S, Kim IS, More SV, Kim BW, Choi DK. Nuclear factor erythroid 2 related factor 2 signaling in Parkinson disease: A promising multi therapeutic target against oxidative stress, neuroinflammation and cell death. CNS Neurol Disord Drug Targets. 2012; 11: 1015–1029.
- 50Levin ED, Perraut C, Pollard N, Freedman JH. Metallothionein expression and neurocognitive function in mice. Physiol Behav. 2006; 87: 513–518.
- 51Swindell WR. Metallothionein and the biology of aging. Ageing Res Rev. 2011; 10: 132–145.
- 52Wu MT, Demple B, Bennett RA, Christiani DC, Fan R, Hu H. Individual variability in the zinc inducibility of metallothionein-IIA mRNA in human lymphocytes. J Toxicol Environ Health A. 2000; 61: 553–567.
- 53Xue W, Liu Q, Cai L, Wang Z, Feng W. Stable overexpression of human metallothionein IIA in a heart-derived cell line confers oxidative protection. Toxicol Lett. 2009; 188: 70–76.
- 54Zhang N, Wang L, Duan Q et al. Metallothionein-I/II knockout mice aggravate mitochondrial superoxide production and peroxiredoxin 3 expression in thyroid after excessive iodide exposure. Oxid Med Cell Longev. 2015; 2015: 267027.
- 55Artells E, Palacios O, Capdevila M, Atrian S. Mammalian MT1 and MT2 metallothioneins differ in their metal binding abilities. Metallomics. 2013; 5: 1397–1410.
- 56Coyle P, Philcox JC, Carey LC, Rofe AM. Metallothionein: The multipurpose protein. Cell Mol Life Sci. 2002; 59: 627–647.
- 57Lee SR, Noh SJ, Pronto JR et al. The critical roles of zinc: Beyond impact on myocardial signaling. Korean J Physiol Pharmacol. 2015; 19: 389–399.
- 58Kukic I, Lee JK, Coblentz J, Kelleher SL, Kiselyov K. Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. Biochem J. 2013; 451: 155–163.
- 59Miao X, Sun W, Fu Y, Miao L, Cai L. Zinc homeostasis in the metabolic syndrome and diabetes. Front Med. 2013; 7: 31–52.
- 60Hojyo S, Fukada T. Zinc transporters and signaling in physiology and pathogenesis. Arch Biochem Biophys. 2016; 611: 43–50.
- 61Huang L. Zinc and its transporters, pancreatic β-cells, and insulin metabolism. Vitam Horm. 2014; 95: 365–390.
- 62Myers SA. Zinc transporters and zinc signaling: New insights into their role in type 2 diabetes. Int J Endocrinol. 2015; 2015: 167503.
- 63Hara T, Takeda TA, Takagishi T, Fukue K, Kambe T, Fukada T. Physiological roles of zinc transporters: Molecular and genetic importance in zinc homeostasis. J Physiol Sci. 2017; 67: 283–301.
- 64Cai L, Wang J, Li Y et al. Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Diabetes. 2005; 54: 1829–1837.
- 65Summers KL, Sutherland DE, Stillman MJ. Single-domain metallothioneins: Evidence of the onset of clustered metal binding domains in Zn-rhMT 1a. Biochemistry. 2013; 52: 2461–2471.
- 66Mocchegiani E, Giacconi R, Muti E et al. Zinc-bound metallothioneins and immune plasticity: Lessons from very old mice and humans. Immun Ageing. 2007; 4: 7–14.
- 67Zheng J, Zhang Y, Xu W et al. Zinc protects HepG2 cells against the oxidative damage and DNA damage induced by ochratoxin A. Toxicol Appl Pharmacol. 2013; 268: 123–131.
- 68He K, Aizenman E. ERK signaling leads to mitochondrial dysfunction in extracellular zinc-induced neurotoxicity. J Neurochem. 2010; 114: 452–461.
- 69Lim KS, Won YW, Park YS, Kim YH. Preparation and functional analysis of recombinant protein transduction domain–metallothionein fusion proteins. Biochimie. 2010; 92: 964–970.
- 70Park LJ, Min DS, Kim HO et al. TAT-enhanced delivery of metallothionein can partially prevent the development of diabetes. Free Radic Biol Med. 2011; 51: 1666–1674.
- 71Eum WS, Choung IS, Li MZ et al. HIV-1 Tat-mediated protein transduction of Cu,Zn-superoxide dismutase into pancreatic beta cells in vitro and in vivo. Free Radic Biol Med. 2004; 37: 339–349.
- 72Min D, Kim H, Park L et al. Amelioration of diabetic neuropathy by TAT-mediated enhanced delivery of metallothionein and SOD. Endocrinology. 2012; 153: 81–91.
- 73Park Y, Park Y, Kim H et al. Effective delivery of endogenous antioxidants ameliorates diabetic nephropathy. PLOS ONE. 2015; 10: e0130815.
- 74Shen X, Zheng S, Metreveli NS, Epstein PN. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 2006; 55: 798–805.
- 75Thornalley PJ, Vasák M. Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta. 1985; 827: 36–44.
- 76Abel J, de Ruiter N. Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein. Toxicol Lett. 1989; 47: 191–196.
- 77Quesada AR, Byrnes RW, Krezoski SO, Petering DH. Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: Zinc-metallothionein and other sites. Arch Biochem Biophys. 1996; 334: 241–250.
- 78Cai L, Klein JB, Kang YJ. Metallothionein inhibits peroxynitrite-induced DNA and lipoprotein damage. J Biol Chem. 2000; 275: 38957–38960.
- 79Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011; 16: 123–140.
- 80Yang M, Chitambar CR. Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008; 45: 763–772.
- 81Qu W, Pi J, Waalkes MP. Metallothionein blocks oxidative DNA damage in vitro. Arch Toxicol. 2013; 87: 311–321.
- 82Hwang YP, Kim HG, Han EH, Jeong HG. Metallothionein-III protects against 6-hydroxydopamine induced oxidative stress by increasing expression of hemeoxygenase-1 in a PI3K and ERK/Nrf2-dependent manner. Toxicol Appl Pharmacol. 2008; 231: 318–327.
- 83Purves T, Middlemas A, Agthong S et al. A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB J. 2001; 15: 2508–2514.
- 84Wu F, Wang B, Zhang S et al. FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK–paraoxonase 1 signaling axis in mice. Clin Sci (Lond). 2017; 131: 1877–1893.
- 85Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR. Cell Signaling through protein kinase C oxidation and activation. Int J Mol Sci. 2012; 13: 10697–10721.
- 86Roel M, Rubiolo JA, Ternon E, Thomas OP, Vieytes MR, Botana LM. Crambescinc1 exerts a cytoprotective effect on HepG2 cells through metallothionein induction. Mar Drugs. 2015; 13: 4633–4653.
- 87Miao X, Tang Z, Wang Y et al. Metallothionein prevention of arsenic trioxide-induced cardiac cell death is associated with its inhibition of mitogen-activated protein kinases activation in vitro and in vivo. Toxicol Lett. 2013; 220: 277–285.
- 88Yang L, Wang J, Yang J et al. Antioxidant metallothionein alleviates endoplasmic reticulum stress-induced myocardial apoptosis and contractile dysfunction. Free Radic Res. 2015; 49: 1187–1198.
- 89Shimoda R, Achanzar WE, Qu W et al. Metallothionein is a potential negative regulator of apoptosis. Toxicol Sci. 2003; 73: 294–300.
- 90Ma H, Su L, Yue H et al. HMBOX1 interacts with MT2A to regulate autophagy and apoptosis in vascular endothelial cells. Sci Rep. 2015; 5: 15121.
- 91Oikonomou N, Harokopos V, Zalevsky J et al. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis. PLoS ONE. 2006; 1: e108.
- 92Guijarro C, Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int. 2001; 59: 415–424.
- 93Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP. The role of oxidative stress and NF-κB activation in the late diabetic complications. BioFactors. 1999; 10: 157–167.
- 94Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB. Role of high glucose induced nuclear factor-κB activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol. 2002; 13: 894–902.
- 95Vermeulen L, DeWilde G, Notebaert S, VandenBerghe W, Haegeman G. Regulation of the transcriptional activity of the nuclear factor kappa B p65 subunit. Biochem Pharmacol. 2002; 64: 963–970.
- 96Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress–activated signalingpathways: A unifying hypothesis of type 2 diabetes. Endocr Rev. 2002; 23: 599–622.
- 97Stankovic RK, Chung RS, Penkowa M. Metallothioneins I and II: Neuroprotective significance during CNS pathology. Int J Biochem Cell Biol. 2007; 39: 484–489.
- 98Wu H, Zhou S, Kong L et al. Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice. Toxicol Lett. 2015; 232: 340–348.
- 99Leung JY, Bennett WR, Herbert RP et al. Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy. Cell Mol Life Sci. 2012; 69: 809–817.
- 100Youn J, Hwang SH, Ryoo ZY et al. Metallothionein suppresses collagen-induced arthritis via induction of TGF-beta and down-regulation of proinflammatory mediators. Clin Exp Immunol. 2002; 129: 232–239.
- 101Devisscher L, Hindryckx P, Lynes MA et al. Role of metallothioneins as danger signals in the pathogenesis of colitis. J Pathol. 2014; 233: 89–100.
- 102Abdel-Mageed AB, Agrawal KC. Activation of nuclear factor κB: Potential role in metallothionein-mediated mitogenic response. Cancer Res. 1998; 58: 2335–2338.
- 103Sakurai A, Hara S, Okano N, Kondo Y, Inoue J, Imura N. Regulatory role of metallothionein in NF-kappaB activation. FEBS Lett. 1999; 455: 55–58.
- 104Cohen DM. Mitogen-activated protein kinase cascades and the signaling of hyperosmotic stress to immediate early genes. Comp Biochem Physiol A Physiol. 1997; 117: 291–299.
- 105Kultz D, Burg M. Evolution of osmotic stress signaling via map kinase cascades. J Exp Biol. 1998; 201: 3015–3021.
- 106Wang XT, Martindale JL, Liu YS, Holbrook NJ. The cellular response to oxidative stress: Influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J. 1998; 333: 291–300.
- 107Tomlinson DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia. 1999; 42: 1271–1281.
- 108Thornalley PJ. Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Neurobiol. 1998; 44: 1013–1023.
- 109Igarashi M, Wakasaki H, Takahara N et al. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest. 1999; 103: 185–195.
- 110Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem. 1997; 272: 17810–17814.
- 111Simm A, Munch G, Seif F et al. Advanced glycation end products stimulate the MAP-kinase pathway in tubulus cell line LLC-PK1. FEBS Lett. 1997; 410: 481–484.
- 112Gallo S, Sala V, Gatti S, Crepaldi T. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clin Sci (Lond). 2015; 129: 1173–1193.
- 113Javadov S, Jang S, Agostini B. Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: Therapeutic perspectives. Pharmacol Ther. 2014; 144: 202–225.
- 114Wang S, Luo M, Zhang Z et al. Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling. Toxicol Lett. 2016; 258: 134–146.
- 115Wei WY, Ma ZG, Xu SC, Zhang N, Tang QZ. Pioglitazone protected against cardiac hypertrophy via inhibiting AKT/GSK3beta and MAPK signaling pathways. PPAR Res. 2016; 2016: 9174190.
- 116Zhang N, Yang Z, Yuan Y et al. Naringenin attenuates pressure overload-induced cardiac hypertrophy. Exp Ther Med. 2015; 10: 2206–2212.
- 117Zhang L, Ding WY, Wang ZH et al. Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy. J Transl Med. 2016; 14: 109.
- 118Fei AH, Wang FC, ZB W, Pan SM. Phosphocreatine attenuates angiotensin II-induced cardiac fibrosis in rat cardiomyocytes through modulation of MAPK and NF-kappaB pathway. Eur Rev Med Pharmacol Sci. 2016; 20: 2726–2733.
- 119Jiang S, Jiang D, Zhao P et al. Activation of AMP-activated protein kinase reduces collagen production via p38 MAPK in cardiac fibroblasts induced by coxsackievirus B3. Mol Med Rep. 2016; 14: 989–994.
- 120Sager HB, Hulsmans M, Lavine KJ et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res. 2016; 119: 853–864.
- 121Martinez PF, Bonomo C, Guizoni DM et al. Modulation of MAPK and NF-κB signaling pathways by antioxidant therapy in skeletal muscle of heart failure rats. Cell Physiol Biochem. 2016; 39: 371–384.
- 122Thandavarayan RA, Giridharan VV, Arumugam S et al. Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling. PLoS ONE. 2015; 10: e0119214.
- 123Ceylan-Isik AF, Zhao P, Zhang B, Xiao X, Su G, Ren J. Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis. J Mol Cell Cardiol. 2010; 48: 367–378.
- 124Qu W, Fuquay R, Sakurai T, Waalkes MP. Acquisition of apoptotic resistance in cadmium-induced malignant transformation: Specific perturbation of JNK signal transduction pathway and associated metallothionein overexpression. Mol Carcinog. 2006; 45: 561–571.
- 125Papouli E, Defais M, Larminat F. Overexpression of metallothionein-II sensitizes rodent cells to apoptosis induced by DNA cross-linking agent through inhibition of NF-kappa B activation. J Biol Chem. 2002; 277: 4764–4769.
- 126Cong W, Niu C, Lv L et al. Metallothionein prevents age-associated cardiomyopathy via inhibiting NF-κB pathway activation and associated nitrative damage to 2-OGD. Antioxid Redox Signal. 2016; 25: 936–952.
- 127Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ. Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury. Am J Pathol. 2004; 164: 1547–1556.
- 128Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004; 350: 664–671.
- 129Duan Q, Wang T, Zhang N et al. Propylthiouracil, perchlorate, and thyroid-stimulating hormone modulate high concentrations of iodide instigated mitochondrial superoxide production in the thyroids of metallothionein I/II knockout mice. Endocrinol Metab. 2016; 31: 174–184.
10.3803/EnM.2016.31.1.174 Google Scholar
- 130Bragina O, Gurjanova K, Krishtal J et al. Metallothionein 2A affects the cell respiration by suppressing the expression of mitochondrial protein cytochrome c oxidase subunit II. J Bioenerg Biomembr. 2015; 47: 209–216.
- 131Kang YJ, Li Y, Sun X, Sun X. Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice. Am J Pathol. 2003; 163: 1579–1586.
- 132Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008; 29: 42–61.
- 133Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev Mol Cell Biol. 2007; 8: 519–529.
- 134Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999; 397: 271–274.
- 135Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003; 23: 7448–7459.
- 136Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell. 2002; 3: 99–111.
- 137Haberzettl P, Hill BG. Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response. Redox Biol. 2013; 26: 56–64.
10.1016/j.redox.2012.10.003 Google Scholar
- 138Xu J, Wang G, Wang Y et al. Diabetes- and angiotensin II-induced cardiac endoplasmic reticulum stress and cell death: Metallothionein protection. J Cell Mol Med. 2009; 13: 1499–1512.
- 139Liang T, Zhang Q, Sun W et al. Zinc treatment prevents type 1 diabetes-induced hepatic oxidative damage, endoplasmic reticulum stress, and cell death, and even prevents possible steatohepatitis in the OVE26 mouse model: Important role of metallothionein. Toxicol Lett. 2015; 233: 114–124.
- 140Yang L, Hu N, Jiang S et al. Heavy metal scavenger metallothionein attenuates ER stress-induced myocardial contractile anomalies: Role of autophagy. Toxicol Lett. 2014; 225: 333–341.
- 141Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008; 7: 1013–1030.
- 142Gardner OS, Shiau CW, Chen CS, Graves LM. Peroxisome proliferator-activated receptor γ-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: Correlation with endoplasmic reticulum stress. J Biol Chem. 2005; 280: 10109–10118.
- 143Eno CO, Zhao G, Venkatanarayan A, Wang B, Flores ER, Li C. Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress. Free Radic Biol Med. 2013; 65: 26–37.
- 144Baird SK, Kurz T, Brunk UT. Metallothionein protects against oxidative stress-induced lysosomal destabilization. Biochem J. 2006; 394: 275–283.
- 145Ullio C, Brunk UT, Urani C et al. Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells. Autophagy. 2015; 11: 2184–2198.
- 146Diaz-Ruiz A, Vacio-Adame P, Monroy-Noyola A et al. Metallothionein-II inhibits lipid peroxidation and improves functional recovery after transient brain ischemia and reperfusion in rats. Oxid Med Cell Longev. 2014; 2014: 436429.
- 147Rahman MT, Haque N, Abu Kasim NH, De Ley M. Origin, function, and fate of metallothionein in human blood. Rev Physiol Biochem Pharmacol. 2017; 173: 41–62.
- 148Giacconi R, Cipriano C, Muti E et al. Novel –209A/G MT2A polymorphism in old patients with type 2 diabetes and atherosclerosis: Relationship with inflammation (IL-6) and zinc. Biogerontology. 2005; 6: 407–413.
- 149Giacconi R, Bonfigli AR, Testa R et al. +647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications. Mol Genet Metab. 2008; 94: 98–104.
- 150Yang L, Li H, Yu T et al. Polymorphisms in metallothionein-1 and -2 genes associated with the risk of type 2 diabetes mellitus and its complications. Am J Physiol Endocrinol Metab. 2008; 294: E987–E992.
- 151Hattori Y, Naito M, Satoh M et al. Metallothionein MT2A A-5G polymorphism as a risk factor for chronic kidney disease and diabetes: Cross-sectional and cohort studies. Toxicol Sci. 2016; 152: 181–193.
- 152Yang XY, Sun JH, Ke HY, Chen YJ, Xu M, Luo GH. Metallothionein 2A genetic polymorphism and its correlation to coronary heart disease. Eur Rev Med Pharmacol Sci. 2014; 18: 3747–3753.
- 153Zhang C, Huang Z, Gu J et al. Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway. Diabetologia. 2015; 58: 1937–1948.
- 154Yang X, Doser TA, Fang CX et al. Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: Role of oxidative stress. FASEB J. 2006; 20: 1024–1026.
- 155Ren J. Endoplasmic reticulum stress impairs murine cardiomyocyte contractile function via an Akt-dependent mechanism. Circulation. 2007; 116: 189–190.
- 156Guo R, Ma H, Gao F, Zhong L, Ren J. Metallothionein alleviates oxidative stress-induced endoplasmic reticulum stress and myocardial dysfunction. J Mol Cell Cardiol. 2009; 47: 228–237.
- 157Yang J, Cherian MG. Protective effects of metallothionein on streptozotocin-induced diabetes in rats. Life Sci. 1994; 55: 43–51.
- 158Park L, Min D, Kim H, Park J, Choi S, Park Y. The combination of metallothionein and superoxide dismutase protects pancreatic β cells from oxidative damage. Diabetes Metab Res Rev. 2011; 27: 802–808.
- 159Obrosova IG, Mabley JG, Zsengeller Z et al. Role for nitrosative stress in diabetic neuropathy: Evidence from studies with a peroxynitrite decomposition catalyst. FASEB J. 2005; 19: 401–403.
- 160Chander PN, Gealekman O, Brodsky SV et al. Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: Prevention by chronic therapy with a peroxynitrite scavenger ebselen. J Am Soc Nephrol. 2004; 15: 2391–2403.
- 161Cruz KJ, de Oliveira AR, Marreiro Ddo N. Antioxidant role of zinc in diabetes mellitus. World J Diabetes. 2015; 6: 333–337.
- 162Soinio M, Marniemi J, Laakso M, Pyörälä K, Lehto S, Rönnemaa T. Serum zinc level and coronary heart disease events in patients with type 2 diabetes. Diabetes Care. 2007; 30: 523–528.
- 163Miao X, Wang Y, Sun J et al. Zinc protects against diabetes-induced pathogenic changes in the aorta: Roles of metallothionein and nuclear factor (erythroid-derived 2)-like 2. Cardiovasc Diabetol. 2013; 12: 54–65.
- 164Jansen J, Karges W, Rink L. Zinc and diabetes – clinical links and molecular mechanisms. J Nutr Biochem. 2009; 20: 399–417.
- 165Cai L. Metallothionein as an adaptive protein prevents diabetes and its toxicity. Nonlinearity Biol Toxicol Med. 2004; 2: 89–103.
- 166Capdor J, Foster M, Petocz P, Samman S. Zinc and glycemic control: A meta-analysis of randomised placebo controlled supplementation trials in humans. J Trace Elem Med Biol. 2013; 27: 137–142.
- 167Jayawardena R, Ranasinghe P, Galappatthy P, Malkanthi R, Constantine G, Katulanda P. Effects of zinc supplementation on diabetes mellitus: A systematic review and meta-analysis. Diabetol Metab Syndr. 2012; 4: 13.
- 168Wang J, Song Y, Elsherif L et al. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation. 2006; 113: 544–554.
- 169Tang Y, Yang Q, Lu J et al. Zinc supplementation partially prevents renal pathological changes in diabetic rats. J Nutr Biochem. 2010; 21: 237–246.
- 170Noyan H, El-Mounayri O, Isserlin R et al. Cardioprotective signature of short-term caloric restriction. PLoS ONE. 2015; 10: e0130658.
- 171Han X, Ren J. Caloric restriction and heart function: Is there a sensible link? Acta Pharmacol Sin. 2010; 31: 1111–1117.
- 172Li C, Feng F, Xiong X, Li R, Chen N. Exercise coupled with dietary restriction reduces oxidative stress in male adolescents with obesity. J Sports Sci. 2017; 35: 663–668.
Citing Literature
