The zinc transporter SLC39A7 (ZIP7) is essential for regulation of cytosolic zinc levels s

Zinc homeostasis is a highly regulated process in mammalian cells that is critical for normal growth and development. Movement of zinc across cell compartments is controlled by two classes of transporters: Slc39a family members transport zinc into the cytosol from either the extracellular space or intracellular stores such as the endoplasmic reticulum (ER), whereas the SLC30A family mediates zinc efflux from the cytosol. In this study, we report that genetic ablation of SLC39A7 (ZIP7) results in decreased cytosolic zinc levels, increased ER zinc levels, impaired cell prolif

Could plasma zinc be a predictor for mortality and severity in sepsis syndrome?

Background: While many factors are known to play a role in outcomes of sepsis, the role of micronutrients such as zinc remains a gray area. This study assesses the correlation of plasma zinc levels with mortality and severity of sepsis. Objective was to study the association between plasma zinc levels with mortality and severity of sepsis.Methods: Comparative prospective observational study which included 89 patients with proven sepsis according to the society of critical care medicine (SCCM) guidelines. The study was conducted at a tertiary care centre in South India. A total of 89 patients who were admitted into the medical ICU directly from ER, from December 2014 to August 2015 were chosen for the study after satisfying specific inclusion criteria and divided into 2 outcome groups based on mortality.Results: There was a significant association between plasma zinc (categorized as low, normal and high plasma zinc) and outcome. While the severity of sepsis as per SOFA score on admission did not have an association, there was a significant association between plasma zinc and the 48-hour SOFA score.Conclusions: Higher plasma zinc values had lower mortality and lower 48 hours SOFA score, strengthening the hypothesis regarding the role of zinc in the immune response to sepsis. More research is needed regarding the role of zinc in assessing the severity and predicting the mortality of patients with sepsis

Hepatic zinc deficiency in alcoholic liver disease: dysregulation of zinc transporters and activation of mitochondrial apoptotic cell death pathway

Excessive alcohol consumption exerts health concerns, and alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the United States. However, there is still lack of an effective treatment. Zinc deficiency has been found in alcoholics over a half century ago. Experimental animals chronically exposed to alcohol exhibit decreased zinc level in the liver as well. Therefore, it is critical to determine the role of zinc deficiency in the pathogenesis of ALD. Our laboratory has repeatedly demonstrated that alcohol feeding significantly decreased hepatic zinc levels in rodents. In addition, clinical studies have shown that the severity of zinc deficiency is positively correlated with the stage of ALD. However, the mechanism that underlies alcohol-induced hepatic zinc deficiency is still unclear. Therefore, we hypothesized that dysregulation of hepatic zinc transporters, ZIP and ZnT, result in alcohol-induced zinc deficiency in the liver and decreased zinc levels in the liver enhanced intrinsic apoptotic cell death pathway via endoplasmic reticulum (ER) and mitochondrial stress. Aim 1 of this project investigated the expression of zinc transporters in alcohol- and pair-fed mice at different time points, along with the effect of reactive oxygen species (ROS) on the expression of zinc transporters. The results indicate that increased ROS due to chronic alcohol exposure altered the expression of zinc transporters, which account for the decrease in hepatic zinc level. Our laboratory also demonstrated that zinc deficiency contributes to ALD by decreasing ß-oxidation and blunting very low density lipoprotein (VLDL) secretion. Furthermore, zinc deficiency is associated with increased oxidative stress. Zinc supplementation protects against alcohol-induced liver injury. Given the fact that increased oxidative stress and impaired mitochondrial functions are closely linked with the pathogenesis of apoptosis and increased hepatic apoptosis plays a critical role in the development of ALD, the role of zinc deficiency in the pathogenesis of apoptosis was assessed in Aims 2 and 3. In Aim 2, increased endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) expression after zinc deprivation was linked with the activation of mitochondrial apoptotic cell death pathway, which was partially dependent on oxidative stress. Data obtain in Aim 3 demonstrated that mitochondrial biogenesis regulators were downregulated by zinc deprivation, which resulted in defect of the mitochondrial electron transport chain. As a result, overproduction of ROS and decreased mitochondrial membrane potential occurred. Collectively, these findings provided critical insights into the molecular mechanisms of alcohol consumption-induced zinc deficiency and zinc deficiency-induced activation of apoptosis. However, we still need to investigate i) the direct effect of subcellular zinc deficiency on organelle functions, and ii) the beneficial effect of dietary zinc supplementation on subcellular zinc deficiency as well as organelle functions

Interplay between endoplasmic reticulum (ER) stress and autophagy induces mutant p53H273 degradation

The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins in order to survive bioenergetic stress and/or induce cell death. Oncosuppressor TP53 may undergo inactivation following missense mutations within the DNA-binding domain (DBD), and mutant p53 (mutp53) proteins may acquire a misfolded conformation, often due to the loss of the DBD-bound zinc ion, leading to accumulation of hyperstable mutp53 proteins that correlates with more aggressive tumors, resistance to therapies, and poorer outcomes. We previously showed that zinc supplementation induces mutp53 protein degradation by autophagy. Here, we show that mutp53 (i.e., Arg273) degradation following zinc supplementation is correlated with activation of ER stress and of the IRE1α/XBPI arm of the UPR. ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components

Cyclic AMP pathway activation and extracellular zinc induce rapid intracellular zinc mobilization in Candida albicans

LK was supported by Innovation Fund Denmark, DK (4019-00019B). Pcovery ApS received funding from Wellcome Trust, Research Councils, UK (100480/Z/12), Novo Seeds, DK and Boehringer Ingelheim Venture Fund, D. DW is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (102549/Z/13/Z), the Medical Research Council and University of Aberdeen (MR/N006364/1) and received support from a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z). The funders had no part in study design, data collection and interpretation, or the decision to submit the work for publication.Peer reviewedPublisher PD

ZNF93 Increases Resistance to ET-743 (Trabectedin; Yondelis®) and PM00104 (Zalypsis®) in Human Cancer Cell Lines

ET-743 (trabectedin, Yondelis) and PM00104 (Zalypsis) are marine derived compounds that have antitumor activity. ET-743 and PM00104 exposure over sustained periods of treatment will result in the development of drug resistance, but the mechanisms which lead to resistance are not yet understood.Human chondrosarcoma cell lines resistant to ET-743 (CS-1/ER) or PM00104 (CS-1/PR) were established in this study. The CS-1/ER and CS-1/PR exhibited cross resistance to cisplatin and methotrexate but not to doxorubicin. Human Affymetrix Gene Chip arrays were used to examine relative gene expression in these cell lines. We found that a large number of genes have altered expression levels in CS-1/ER and CS-1/PR when compared to the parental cell line. 595 CS-1/ER and 498 CS-1/PR genes were identified as overexpressing; 856 CS-1/ER and 874 CS-1/PR transcripts were identified as underexpressing. Three zinc finger protein (ZNF) genes were on the top 10 overexpressed genes list. These genes have not been previously associated with drug resistance in tumor cells. Differential expressions of ZNF93 and ZNF43 genes were confirmed in both CS-1/ER and CS-1/PR resistant cell lines by real-time RT-PCR. ZNF93 was overexpressed in two ET-743 resistant Ewing sarcoma cell lines as well as in a cisplatin resistant ovarian cancer cell line, but was not overexpressed in paclitaxel resistant cell lines. ZNF93 knockdown by siRNA in CS-1/ER and CS-1/PR caused increased sensitivity for ET-743, PM00104, and cisplatin. Furthermore, ZNF93 transfected CS-1 cells are relatively resistant to ET-743, PM00104 and cisplatin.This study suggests that zinc finger proteins, and ZNF93 in particular, are involved in resistance to ET-743 and PM00104

Bioavailability of Cu and Zn in raw and anaerobically digested pig slurry

The impact of anaerobic digestion on the bioavailability of copper and zinc from pig slurry was assessed. Both chemical and biological approaches were used independently on raw slurry (RS) and anaerobically digested pig slurry (DS). This work, using ultracentrifugation pellets from the same pig slurry before and after an anaerobic treatment, confirmed that Cu and Zn behave differently in terms of bioavailability, and contrasting results were obtained by chemical and biological assessments. A chemical approach combined a preliminary study of the pH effect on particulate/dissolved metal partitioning, sequential extraction, and biochemical fractionation. This approach tended to show a lower mobility of metals from digested slurry (DS). A biological approach was carried out with Zea mays and Vicia faba to study Cu and Zn uptake in soil amended with RS or DS. This assay could not differentiate the two slurries

Coulomb correlation effects in zinc monochalcogenides

Electronic structure and band characteristics for zinc monochalcogenides with zinc-blende- and wurtzite-type structures are studied by first-principles density-functional-theory calculations with different approximations. It is shown that the local-density approximation underestimates the band gap and energy splitting between the states at the top of the valence band, misplaces the energy levels of the Zn-3d states, and overestimates the crystal-field-splitting energy. Regardless of the structure type considered, the spin-orbit-coupling energy is found to be overestimated for ZnO and underestimated for ZnS with wurtzite-type structure, and more or less correct for ZnSe and ZnTe with zinc-blende-type structure. The order of the states at the top of the valence band is found to be anomalous for ZnO in both zinc-blende- and wurtzite-type structure, but is normal for the other zinc monochalcogenides considered. It is shown that the Zn-3d electrons and their interference with the O-2p electrons are responsible for the anomalous order. The typical errors in the calculated band gaps and related parameters for ZnO originate from strong Coulomb correlations, which are found to be highly significant for this compound. The LDA+U approach is by and large found to correct the strong correlation of the Zn-3d electrons, and thus to improve the agreement with the experimentally established location of the Zn-3d levels compared with that derived from pure LDA calculations