Metallothionein Expression Research Articles

Effects of Waterborne Cadmium Exposure on Its Internal Distribution in Meretrix meretrix and Detoxification by Metallothionein and Antioxidant Enzymes

Cadmium (Cd), one of the most toxic metals found in inshore sediments of China, is a persistent environmental contaminant capable of exerting irreversible toxic effect on aquatic organisms and their associated ecosystems. Although Cd is known to be toxic to marine animals, the underlying mechanism of this toxicity is not clear. In this study, Meretrix meretrix, a commercially and ecologically important species of clam, was exposed to different concentrations of cadmium chloride (0, 1.5, 3, 6, 12 mg L-1) for 5 days, and the levels of Cd accumulation, antioxidant enzyme activity and expression of metallothionein (MT) in the hepatopancreas, gill, foot and mantle were evaluated. The results revealed a sharp increase in Cd accumulation in the tissues in response to increased Cd2+ concentrations in the water, and significant differences in Cd accumulation were observed among the different tissues. Increased Cd2+ level in the tissues also led to a significant increase in malonaldehyde (MDA) content, caused by increased lipid peroxidation. The activities of superoxide dismutase (SOD) and catalase (CAT) also increased, peaking at different Cd2+ concentrations, depending on the tissue. Glutathione peroxidases (GPx) activity in the gill and mantle initially increased, but then decreased with increasing external Cd2+ concentration. In the hepatopancreas and foot, GPx activity was inhibited by Cd2+, even at low concentrations. Furthermore, Cd2+ also stimulated the expression of MT in all four tissues. However, the levels of reduced glutathione (GSH) andoxidized glutathione (GSSG) in the gill and mantle, as well as the GSH/GSSG ratios in all four tissues decreased with increasing external Cd2+ concentrations. Taken together, the results suggested that in M. meretrix, response to the toxic effect of Cd2+ might occur through a combination of mechanisms, which involve both enhanced antioxidant enzyme activities and the ability to bind and sequester Cd2+ via cysteine-rich molecules such as GSH and MT, both of which would eventually lead to the reduction of heavy metal-induced oxidative stress.

Influence of calcium and EDTA on copper ion bioavailability in copper nanoparticle toxicity tests improves understanding of nano-specific effects.

Metal-based nanoparticles (NPs) can release metal ions that are toxic to aquatic organisms; however, whether the toxicity is from metal ions rather than unique "nano-scale" effects of the NPs is unresolved. The present study aimed to compare the toxicity of Cu2+ and Cu-NPs in larval zebrafish (Danio rerio) to clarify whether toxic effects are attributable to release of Cu ions and to determine the effect of the chelating agent ethylenediaminetetraacetic acid (EDTA) and calcium hardness (as CaCO3) on the Cu toxicity. First, the acute toxicity (96-h lethality) of Cu-NPs was determined in comparison to aqueous Cu in larvae exposed to CuSO4, and subsequently, sublethal tests with Cu-NPs and CuSO4 were conducted with additions of EDTA or calcium ions to evaluate alterations in expression of metallothionein-2 (MT2) gene transcripts (quantitative real-time polymerase chain reaction). Acute toxicity of Cu in larvae exposed to CuSO4 was greater (LC50 = 226 µg Cu/L) than for larvae exposed to Cu-NPs (LC50 = 648 µg Cu/L). The expression of MT2 increased with Cu concentration (p < 0.05), and the slope of the linear regression was significantly greater in fish exposed to CuSO4 (slope = 0.090) compared to Cu-NPs (slope = 0.011). Cu2+ was 2.9-fold more toxic than Cu-NPs. The presence of 5 mg/L EDTA and 220 mg/L CaCO3 significantly reduced the expression of MT2 (1.8-fold for EDTA, 2.3-fold for CaCO3) in larvae exposed to CuSO4. For larvae exposed to Cu-NPs, the presence of EDTA reduced the expression of MT2 (1.7-fold) relative to Cu-NP concentration. While Cu-NPs induced MT2 expression, the differences in concentration relationships of MT2 expression between Cu-NPs and CuSO4 indicated that factors other than release of Cu ions from Cu-NPs influenced acute toxicity of Cu-NPs. The conclusion drawn from this ecotoxicological risk assessment was that EDTA and calcium significantly decreased Cu toxicity in freshwater fish.

Metal induced non-metallothionein protein in earthworm: A new pathway for cadmium detoxification in chloragogenous tissue

Earthworms neutralize toxic metals by a small (∼13 kDa) cysteine rich metal binding protein, metallothionein (MT). Although the rate of metal accumulation and MT expression does not correlate well, the reason behind such inconsistency has not yet been deciphered. The present investigation clearly demonstrates that expression of some non-MT metal induced proteins is responsible for such incongruity. Applying selective protein isolation techniques in fluorescence tagged cadmium exposed (135 mg/kg) earthworms we were able to purify a 150 kDa metal induced protein (MIP) among others. After 60 days of exposure cadmium accumulation in earthworm intestines was significant. Immunofluorescence staining followed by confocal microscopy exhibited that MIP accumulates ingested cadmium in the intestinal region and eventually deposits the metal in the chloragogenous tissue. We determined the N-terminal sequence of 15 amino acid residues and after bioinformatics analysis, it was concluded that MIP is most probably a glutamic acid rich, novel cadmium binding protein. To further validate the binding mechanism, we conducted paper chromatography and continuous variation experiments which evidenced that cadmium readily binds to glutamic acid. The present finding is the first in-vivo evidence of a non-metallothionein cadmium binding protein induced in the intestines of earthworm exposed to a cadmium rich environment.

Evaluation of Lactobacillus rhamnosus Antioxidant Effects on Survival of Human Mesenchymal Stem Cells

Introduction: Multipotent mesenchymal stromal cells (MSCs) have novel therapeutic potential to treat a wide variety of diseases but they have poor survival in oxidative stress conditions. Probiotics are one of the most effective antioxidant substances in the improvement of cell resistance to oxidative environments. The main purpose of this study was to evaluate the protective effects of Lactobacillus rhamnosus on MSCs viability in stressful conditions. Materials and Methods: The MSCs were exposed to live or killed L. rhamnosus in oxidative-stress conditions to evaluate the expression of antioxidant genes; heme oxygenase (HO1), metallothionein 1 (MT1), superoxide dismutase 1 (SOD1) and 2 (SOD2). Also, the antioxidant activity was assessed. Results: In harmful conditions (H2O2) and serum deprivation, killed L. rhamnosus not only increased the expression of HO-1, MT1, SOD1 and SOD2 genes of the MSCs (P ≤ 0.001) but also enhanced the antioxidant activity of MSCs (P ≤ 0.001), leading to a better survival under oxidative stress conditions. The synergism effect of killed L. rhamnosus increased the antioxidant potential of MSCs to resist oxidative stress conditions. Conclusions: The killed L. rhamnosus has protective effects on the survival of MSCs in stress conditions.

Endothelial Overexpression of Metallothionein Prevents Diabetes-Induced Impairment in Ischemia Angiogenesis Through Preservation of HIF-1α/SDF-1/VEGF Signaling in Endothelial Progenitor Cells.

Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high-fat diet- and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in db/db mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from patients with diabetes exhibited decreased MT expression, increased cell apoptosis, and impaired tube formation, while cultured JTMT EPCs had enhanced cell survival, migration, and tube formation in hypoxic/hyperglycemic conditions compared with WT EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1), and vascular endothelial growth factor (VEGF) expression and reduced oxidative stress in ischemic tissues. MT's pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting its antioxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC function, most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.

Ex-situ induction of Metallothionein gene in Lybiodrilus violaceous post cadmium and zinc exposure

BackgroundEarthworms are good indicators used in evaluating the health status of the terrestrial ecosystem and metallothionein (Mt) is a biomarker monitored during environmental studies. There is however a dearth of information on metallothioneins in African earthworms. Libyodrilus violaceous is a West African earthworm well investigated and reported including its tolerance to metal pollution but the presence of Mt gene in L. violaceous is not established. MethodsThe presence of Mt. in L. violaceous was determined to validate its potential role in metal tolerance. L. violaceous sampled from Ije-Ododo soil were exposed to varying concentrations of Cadmium (Cd) and Zinc (Zn) in a potted experimental set-up and the metallothionein (MT) expressions were determined. The presence of Mt gene and metallothionein expression were determined using whole transcriptome sequencing and real-time polymerase chain reaction (PCR), respectively after extracting Ribonucleic acid (RNA) from samples on the 1 st, 3rd and 7th days. The genetic relationship of the detected MT protein sequence was compared to existing MT protein sequences and a phylogenetic tree was constructed. ResultsWe established the presence of the MT gene and the phylogenetic tree showed that it had a relationship with other earthworms' MTs. Up-regulation of Mt. expression was observed on the 7th day in L.violaceous exposed to concentrations of Cd and Zn. ConclusionOne of the modes of survival of L. violaceous to metal pollution is by the up-regulation of metallothioneins. This earthworm metallothionein protein sequence is the first report of species in the Eudriloides family and the first report in African earthworms deposited in the GenBank repository for reference. The use of L.violaceous for Cd and Zn remediation in soils could be exploited.

Protective effects of zinc L-carnosine against hydrogen peroxide-induced DNA damage and micronucleus formation in CCD-18co human colon fibroblast cells

Zinc L-carnosine (ZnC) is a chelated compound of zinc and L-carnosine. The present study aims to determine the protective effects of ZnC against hydrogen peroxide (H2O2)-induced oxidative stress and genomic damage in CCD-18co human normal colon fibroblast cells. Generally, cells were pretreated with ZnC (0–100 µM) for 24 h before challenged with 20 µM of H2O2 for 1 h to induce oxidative damage. Results showed that pretreatment with ZnC was able to reduce the intracellular ROS level in CCD-18co cells after being challenged with H2O2. Moreover, pretreatment with ZnC demonstrated protection from H2O2-induced DNA strand breaks and micronucleus formation. Our current findings revealed that pretreatment with ZnC could induce the activation of MTF-1 signaling pathway and expression of metallothionein (MT) in a dose-dependent manner. However, ZnC did not have any effects on Nrf2 signaling pathway and the expression of glutathione, superoxide dismutase 1, and glutamate-cysteine ligase catalytic subunit (GCLC). Furthermore, pretreatment with ZnC did not induce the expression of OGG1 and PARP-1 in CCD-18co cells, suggesting that these two DNA repairing enzymes are not related to the genoprotective effects of ZnC. Since the expression of MT has been demonstrated to protect cells from oxidative DNA damage induced by various genotoxic agents, the genoprotective effects of ZnC might be due to the ability of ZnC to induce the expression of MT. In conclusion, ZnC pretreatment was able to protect CCD-18co cells from H2O2-induced genomic damage via the activation of the MTF-1 signalling pathway and the induction of MT expression.

Type I Interferons Ameliorate Zinc Intoxication of Candida glabrata by Macrophages and Promote Fungal Immune Evasion.

SummaryHost and fungal pathogens compete for metal ion acquisition during infectious processes, but molecular mechanisms remain largely unknown. Here, we show that type I interferons (IFNs-I) dysregulate zinc homeostasis in macrophages, which employ metallothionein-mediated zinc intoxication of pathogens as fungicidal response. However, Candida glabrata can escape immune surveillance by sequestering zinc into vacuoles. Interestingly, zinc-loading is inhibited by IFNs-I, because a Janus kinase 1 (JAK1)-dependent suppression of zinc homeostasis affects zinc distribution in macrophages as well as generation of reactive oxygen species (ROS). In addition, systemic fungal infections elicit IFN-I responses that suppress splenic zinc homeostasis, thereby altering macrophage zinc pools that otherwise exert fungicidal actions. Thus, IFN-I signaling inadvertently increases fungal fitness both in vitro and in vivo during fungal infections. Our data reveal an as yet unrecognized role for zinc intoxication in antifungal immunity and suggest that interfering with host zinc homeostasis may offer therapeutic options to treat invasive fungal infections.

Metallothionein expression on oysters ( Crassostrea cuculata and Crassostrea glomerata) from the southern coastal region of East Java.

Background: This study aimed to analyse levels of heavy metals (Pb, Hg and Cd) in the aquatic body, gills and stomach of the oysters Crassostrea cuculata and Crassostrea glomerata, the metallothionein (MT) level in the gills and stomach of both oysters, and relationships between heavy metals level (Pb, Hg and Cd) in the gills and stomach to MT level in both species of oysters. Methods: The research method utilized was a descriptive method. The oyster samples were taken from three stations: Sendang Biru, Popoh and Prigi beaches. MT values were assessed using confocal laser scanning microscopy. The heavy metal levels were assessed using atomic absorption spectrophotometry method. Results: Both oyster heavy metal content obtained in the southern coastal waters exceeded the safe limit set by the State Minister of Environment No. 51 of 2004. In general, the expression of MT was found to be higher in stomach tissue compared to gill tissue. Conclusions: The levels of the heavy metals Pb, Hg, and has a strong relationship with MT levels in the gills and stomach in both types of oysters.

Biochemical profile and gene expression of Clarias gariepinus as a signature of heavy metal stress

Heavy metals have been found in increasing concentrations in the aquatic environment. Fishes exposed to such metals have altered gene expression, serum profiles, tissue histology and bioindices that serve as overall health biomarkers. The heavy metals (Ni, Cd, and Cr) accumulated in water and fish tissues, were beyond the permissible limits defined by the Central Pollution Control Board/World Health Organization. Metallothionein (MT) and glutathione peroxidase (GPX) genes expression patterns highlighted the metal-specific exposure of fish. An increased fold change of genes against beta-actin serves as a potential feature for toxicity. Metal toxicity is also reflected by an increased level of digestive enzymes (amylase and lipase) in the serum and alterations in values of reproductive hormones (11-Ketotestosterone and progesterone). Total serum bilirubin attribute to the liver and biliary tract disease in fishes. Histopathological studies show cellular degeneration, breakage, vacuolization signifying the chronic stress.

Multi-omic profiling reveals associations between the gut mucosal microbiome, the metabolome, and host DNA methylation associated gene expression in patients with colorectal cancer

BackgroundThe human gut microbiome plays a critical role in the carcinogenesis of colorectal cancer (CRC). However, a comprehensive analysis of the interaction between the host and microbiome is still lacking.ResultsWe found correlations between the change in abundance of microbial taxa, butyrate-related colonic metabolites, and methylation-associated host gene expression in colonic tumour mucosa tissues compared with the adjacent normal mucosa tissues. The increase of genus Fusobacterium abundance was correlated with a decrease in the level of 4-hydroxybutyric acid (4-HB) and expression of immune-related peptidase inhibitor 16 (PI16), Fc Receptor Like A (FCRLA) and Lymphocyte Specific Protein 1 (LSP1). The decrease in the abundance of another potentially 4-HB-associated genus, Prevotella 2, was also found to be correlated with the down-regulated expression of metallothionein 1 M (MT1M). Additionally, the increase of glutamic acid-related family Halomonadaceae was correlated with the decreased expression of reelin (RELN). The decreased abundance of genus Paeniclostridium and genus Enterococcus were correlated with increased lactic acid level, and were also linked to the expression change of Phospholipase C Beta 1 (PLCB1) and Immunoglobulin Superfamily Member 9 (IGSF9) respectively. Interestingly, 4-HB, glutamic acid and lactic acid are all butyrate precursors, which may modify gene expression by epigenetic regulation such as DNA methylation.ConclusionsOur study identified associations between previously reported CRC-related microbial taxa, butyrate-related metabolites and DNA methylation-associated gene expression in tumour and normal colonic mucosa tissues from CRC patients, which uncovered a possible mechanism of the role of microbiome in the carcinogenesis of CRC. In addition, these findings offer insight into potential new biomarkers, therapeutic and/or prevention strategies for CRC.

Assessment of metallothionein expression in Biomphalaria alexandrina snails and Oreochromis niloticus Fish as a biomarker for water pollution with heavy metals.

Assessment of metallothionein expression in Biomphalaria alexandrina snails and Oreochromis niloticus Fish as a biomarker for water pollution with heavy metals.

Polyvinyl chloride (PVC) plastic fragments release Pb additives that are bioavailable in zebrafish

Plastic polymers such as polyvinyl chloride (PVC) may contain chemical additives, such as lead (Pb), that are leachable in aqueous solution. The fragmentation into microplastics (MPs) of plastics such as PVC may facilitate desorption of chemical additives and increase exposure of aquatic animals. In this study, the role of chemical additives in the aqueous toxicity of PVC, high-density polyethylene (HDPE) and polyethylene terephthalate (PET) MPs were investigated in early-life stage zebrafish (Danio rerio) by assessment of changes in expression of biomarkers. Exposure of zebrafish larvae to PVC for 24 h increased expression of metallothionein 2 (mt2), a metal-binding protein, but no changes in expression of biomarkers of estrogenic (vtg1) or organic (cyp1a) contaminants were observed. HDPE and PET caused no changes in expression of any biomarkers. A filtered leachate of the PVC also caused a significant increase in expression of mt2 and indicated that a desorbed metal additive likely elicited the response in zebrafish. Metal release was confirmed by acid-washing the MPs which mitigated the response in mt2. Metal analysis showed Pb leached from PVC into water during exposures; at 500 mg PVC L−1 in water, 84.3 ± 8.7 μg Pb L−1 was measured after 24 h. Exposure to a Pb-salt at this concentration caused a comparable mt2 increase in zebrafish as observed in exposures to PVC. These data indicated that PVC MPs elicited a response in zebrafish but the effect was indirect and mediated through desorption of Pb from PVC into the exposure water. Data also indicated that PVC MPs may act as longer-term environmental reservoirs of Pb for exposure of aquatic animals; the Pb leached from PVC in 24 h in freshwater equated to 2.52% of total Pb in MPs leachable by the acid-wash. Studies of MPs should consider the potential role of chemical additives in toxicity observed.

Exposure to Dichlorodiphenyldichloroethylene (DDE) and Metallothionein Levels in Rats Fed with Normocaloric or High-Fat Diet: A Review

The growing number of studies on metallothioneins (MTs), cysteine-rich metal-binding proteins, have been disclosing new functions of these proteins. Thanks to their inducibility, they were considered to play a pivotal role in regulating trace metals homeostasis and in detoxification from heavy metals; nowadays, it is known that they are involved in various physiological and pathological processes, such as regulation of apoptosis, elimination of free radicals, and protection of nucleic acids against toxic insults. MT induction has been demonstrated following stress factors other than heavy metals, such as endocrine-disrupting chemicals, insecticides, and herbicides. However, retrieved data are often controversial: in some cases, xenobiotics elicit MT expression and synthesis; under different conditions, they lead to a decrease in cellular MT content. This review describes the MT response to dichlorodiphenyltrichloroethane (DDT) contamination in mammalian tissues. In particular, attention focuses on changes in MT expression, synthesis, and localization in rat liver, kidneys, and testes following oral administration of dichlorodiphenyldichloroethylene (DDE), the main metabolite of DDT, under normal dietary conditions or in combination with a high fat diet potentially able to increase the cellular uptake of this lipophilic pesticide. The potential connection between MT expression and synthesis, lipophilic substances and trace metals availability is also discussed.

Zinc L-Carnosine Protects CCD-18co Cells from L-Buthionine Sulfoximine-Induced Oxidative Stress via the Induction of Metallothionein and Superoxide Dismutase 1 Expression.

Zinc L-carnosine (ZnC) is the chelate form of zinc and L-carnosine and is one of the zinc supplements available in the market. This study aims to determine the protective effects of ZnC against L-buthionine sulfoximine (BSO)-induced oxidative stress in CCD-18co human normal colon fibroblast cell line. CCD-18co cells were pretreated with ZnC (0-100μM) for 24h before the induction of oxidative stress by BSO (1mM) for another 24h. Results from this present study demonstrated that ZnC up to the concentration of 100μM was not cytotoxic to CCD-18co cells. Induction with BSO significantly increased the intracellular reactive oxygen species (ROS) levels and reduced the intracellular glutathione (GSH) levels in CCD-18co cells. Pretreatment with ZnC was able to attenuate the increment in intracellular ROS level in CCD-18co cells significantly in a concentration-dependent manner. However, ZnC did not have any effects on intracellular GSH levels and Nrf2 activation. Mechanistically, pretreatment with ZnC was able to upregulate the expression of metallothionein (MT) and superoxide dismutase 1 (SOD1) in CCD-18co cells. Results from dual-luciferase reporter gene assay reported that ZnC was able to increase the MRE-mediated relative luciferase activities in a concentration-dependent manner, suggesting that the induction of MT expression by ZnC was due to the activation of MTF-1 signaling pathway. Taken together, our current findings suggest that ZnC can protect CCD-18co cells from BSO-induced oxidative stress via the induction of MT and SOD1 expression.

Heavy metal toxicity has an immunomodulatory effect on metallothionein and glutathione peroxidase gene expression in Cyprinus carpio inhabiting a wetland lake and a culture pond.

The study provides cumulative data on the status of the two water bodies. The study designed revealed physicochemical properties (temperature, dissolved oxygen, pH, total dissolved solids and conductivity) to be in the desirable range, however, amongst the heavy metals excepting for Cd all were found to be higher than the permissible limits set by WHO and USEPA. It was observed that these elements cast their impact on bioindices (hepatosomatic index, condition factor, spleenosomatic index and kidney somatic index), renal marker enzyme (creatine kinase), hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase), histology of immune organs (liver, spleen, head-kidney and thymus) and level of serum immunoglobulin (IgM). Further, expression levels of Metallothionein (MT) and Glutathione peroxidase (GPX) genes in immune-related tissues (liver, spleen, head-kidney, thymus and blood) observed indicates metal pollution and abiotic stresses. These alterations are reliable indicators of the cellular and humoral immune response in Cyprinus carpio.

Metallothionein isoforms as double agents - Their roles in carcinogenesis, cancer progression and chemoresistance.

Metallothioneins (MTs) are small cysteine-rich intracellular proteins with four major isoforms identified in mammals, designated MT-1 through MT-4. The best known biological functions of MTs are their ability to bind and sequester metal ions as well as their active role in redox homeostasis. Despite these protective roles, numerous studies have demonstrated that changes in MT expression could be associated with the process of carcinogenesis and participation in cell differentiation, proliferation, migration, and angiogenesis. Hence, MTs have the role of double agents, i.e., working with and against cancer. In view of their rich biochemical properties, it is not surprising that MTs participate in the emergence of chemoresistance in tumor cells. Many studies have demonstrated that MT overexpression is involved in the acquisition of resistance to anticancer drugs including cisplatin, anthracyclines, tyrosine kinase inhibitors and mitomycin. The evidence is gradually increasing for a cellular switch in MT functions, showing that they indeed have two faces: protector and saboteur. Initially, MTs display anti-oncogenic and protective roles; however, once the oncogenic process was launched, MTs are utilized by cancer cells for progression, survival, and contribution to chemoresistance. The duality of MTs can serve as a potential prognostic/diagnostic biomarker and can therefore pave the way towards the development of new cancer treatment strategies. Herein, we review and discuss MTs as tumor disease markers and describe their role in chemoresistance to distinct anticancer drugs.

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.

Metallothionein 2A gene polymorphisms in relation to diseases and trace element levels in humans.

Human metallothioneins are a superfamily of low molecular weight intracellular proteins, whose synthesis can be induced by essential elements (primarily Zn and Cu), toxic elements and chemical agents, and stress-producing conditions. Of the four known isoforms in the human body MT2 is the most common. The expression of metallothioneins is encoded by a multigene family of linked genes and can be influenced by single nucleotide polymorphisms (SNPs) in these genes. To date, 24 SNPs in the MT2A gene have been identified with the incidence of about 1 % in various population groups, and three of them were shown to affect physiological and pathophysiological processes. This review summarises current knowledge about these three SNPs in the MT2A gene and their associations with element concentrations in the body of healthy and diseased persons. The most investigated SNP is rs28366003 (MT2A −5 A/G). Reports associate it with longevity, cancer (breast, prostate, laryngeal, and in paranasal sinuses), and chronic renal disease. The second most investigated SNP, rs10636 (MT2A +838G/C), is associated with breast cancer, cardiovascular disease, and type 2 diabetes. Both are also associated with several metal/metalloid concentrations in the organism. The third SNP, rs1610216 (MT2A −209A/G), has been studied for association with type 2 diabetes, cardiomyopathy, hyperglycaemia, and Zn concentrations. Metallothionein concentrations and MT2A polymorphisms have a potential to be used as biomarkers of metal exposure and clinical markers of a number of chronic diseases. This potential needs to be studied and verified in a large number of well-defined groups of participants (several hundreds and thousands) with a focus on particular physiological or pathological condition and taking into consideration other contributing factors, such as environmental exposure and individual genetic and epigenetic makeup.

Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity

IntroductionZinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury...