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Fungal pathogens now account for an unprecedented burden on human health. Like all microorganisms, these fungi must successfully forage for essential micronutrients such as zinc in order to proliferate. However, pathogenic microbes face an additional hurdle in securing zinc from their environment: the action of host nutritional immunity which strictly manipulates microbial access to this essential, but also potentially toxic trace metal. This review introduces the relevant pathogenic species and goes on to cover the molecular mechanisms of zinc uptake by human fungal pathogens. Fungi scavenge zinc from their environment via two basic mechanisms: via a family of cellular zinc importers--the ZIP transporters; and via a unique secreted zinc binding protein--the zincophore. However the genetic requirement of these systems for fungal virulence is highly species-specific. As well as zinc scarcity, potential intoxification with this heavy metal can occur and, unlike bacteria, fungi deal with environmental insult this via intraorganellar compartmentalization. Zinc availability also modulates the morphogenic behavior of a subset of pathogenic yeast species. This chapter will cover these different aspects of zinc availability on the physiology of human fungal pathogens with emphasis on the major pathogenic species Candida albicans. [ABSTRACT FROM AUTHOR]

Introduction Dysregulation of both, systemic zinc levels and tissue-specific zinc transporters, is reported in chronic inflammatory and malignant liver disease (hepatocellular carcinoma, HCC). Aim of this study is to assess the expression level of three zinc transporters in liver tissue and HCC: ZIP4, ZIP14 and ZnT9. Methods The study is based on tissue samples obtained from 138 patients with histologically proven HCC. Tissue specimens from tumor (n = 138) and extra-lesional specimens (n = 72) were assessed immunohistochemically for the expression of the three zinc transporters. Expression levels were semi-quantitatively scored and statistically analyzed with respect to the etiology of HCC (alcohol, AFLD; non-alcoholic fatty liver disease, NAFLD; virus-hepatitis, VH) and survival. Results Overall, expression levels of ZIP4, ZIP14 and ZnT9 were significantly higher in HCC tissue than in adjacent extra-lesional liver tissue. Expression levels in tumor tissue and survival time revealed a negative correlation for ZIP4 and ZIP14, and in part for ZnT9 (nuclear staining) (p < 0.05), whereas cytoplasmic staining of ZnT9 did not correlate with survival. Furthermore, the expression level of ZIP4 in extra-lesional tissue showed inverse correlation with survival time. Conclusion The upregulation of zinc transporters in hepatic carcinogenesis and its negative correlation with survival time implies a regulatory/functional link between zinc-homeostasis and development/progression of HCC that deserves to be further explored. [ABSTRACT FROM AUTHOR]

Osteoclasts are bone‐resorbing cells that play an essential role in maintaining bone homeostasis. Zinc (Zn) has been reported to inhibit osteoclast‐mediated bone resorption, but the mechanism of this action has not been clarified. Zn homeostasis is tightly controlled by the coordinated actions of many Zn transporters. The Zn transporter ZIP14/Slc39a14 is involved in various physiological functions; hence, Zip14‐knockout (KO) mice exhibit multiple phenotypes. In this study, we thoroughly investigated the bone phenotypes of Zip14‐KO mice, demonstrating that the KO mice exhibited osteopenia in both trabecular and cortical bones. In Zip14‐KO mice, bone resorption was increased, whereas the bone formation rate was unchanged. Zip14mRNA was expressed in normal osteoclasts both in vivo and in vitro, but receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis was not impaired in bone marrow‐derived macrophages prepared from Zip14‐KO mice. These results suggest that ZIP14 regulates bone homeostasis by inhibiting bore resorption and that in Zip14‐KO mice, bone resorption is increased due to the elimination of this inhibitory regulation. Further studies are necessary to conclude whether the enhancement of bone resorption in Zip14‐KO mice is due to a cell‐autonomous or a non‐cell‐autonomous osteoclast defect. [ABSTRACT FROM AUTHOR]

The common C-allele of rs13266634 (c.973C>T or p.Arg325Trp) in SLC30A8 (ZNT8) is associated with increased risk of type 2 diabetes. While previous studies have examined the correlation of the variant with insulin and glucose metabolism, the effects of this variant on insulin and lipid responses after a lipid challenge in humans remain elusive. The goal of this study was to determine whether the C-allele had an impact on an individual's risk to metabolic syndromes in U.S. adults. We studied the genotypes of rs13266634 in 349 individuals aged between 18 and 65 y with BMI ranging from 18.5 to 45 kg/m2. The subjects were evaluated for insulin, glucose, HbA1c, ghrelin, and lipid profiles before and after a high-fat mixed macronutrient tolerance test (MMTT). We found that the effects of variants rs13266634 on glucose and lipid metabolism were sex-dimorphic, greater impact on males than on females. Insulin incremental area under the curve (AUC) after MMTT was significantly decreased in men with the CC genotype (p < 0.05). Men with the CC genotype also had the lowest fasting non-esterified fatty acid (NEFA) concentrations. On the other hand, the TT genotype was associated with a slower triglyceride removal from the circulation in men after MMTT. The reduced triglyceride removal was also observed in subjects with BMI ≥ 30 carrying either the heterozygous or homozygous T-allele. Nevertheless, the SNP had little effect on fasting or postprandial blood glucose and cholesterol concentrations. We conclude that the CC genotype negatively affects insulin response after MMTT while the T-allele may negatively influence lipolysis during fasting and postprandial blood triglyceride removal in men and obese subjects, a novel finding in this study. • SNP rs13266634 in SLC30A8 is associated with postprandial insulin secretion in men. • Fasting free fatty acid levels relate to the genotypes of rs1326664 in healthy men. • BMI is a cofactor with rs1326664 affecting postprandial blood triglyceride removal. [ABSTRACT FROM AUTHOR]

Abstract: The vacuolar Zn2+/H+ antiporter of Arabidopsis thaliana, AtMTP1, has a cytosolic histidine-rich loop (His-loop). We characterized the structures and Zn2+-binding properties of the His-loop and other domains. Circular dichroism analyses revealed that the His-loop partly consists of a polyproline type II structure and that its conformational change is induced by Zn2+ as well as the C-terminal domain. Isothermal titration calorimetry of the His-loop revealed a binding number of four Zn2+ per molecule. Numbers of Ni and Co associated with the His-loop were approximately one ion per molecule and the thermodynamic parameters of the association with these ions were different from that of Zn2+. These results suggest the involvement of the His-loop in sensing cytosolic Zn2+ and in the regulation of zinc transport activity through Zn2+-induced structural change. [Copyright &y& Elsevier]

The vacuolar Zn2+/H+ antiporter of Arabidopsis thaliana, AtMTP1, has a cytosolic histidine‐rich loop (His‐loop). We characterized the structures and Zn2+‐binding properties of the His‐loop and other domains. Circular dichroism analyses revealed that the His‐loop partly consists of a polyproline type II structure and that its conformational change is induced by Zn2+ as well as the C‐terminal domain. Isothermal titration calorimetry of the His‐loop revealed a binding number of four Zn2+ per molecule. Numbers of Ni and Co associated with the His‐loop were approximately one ion per molecule and the thermodynamic parameters of the association with these ions were different from that of Zn2+. These results suggest the involvement of the His‐loop in sensing cytosolic Zn2+ and in the regulation of zinc transport activity through Zn2+‐induced structural change. [ABSTRACT FROM AUTHOR]

We investigated the effects of a short-term dietary zinc deficiency on bone metabolism. Zinc deficiency increased the mRNA expression of zinc uptake transporters such as Zip1, Zip13, and Zip14 in bone. However, zinc deficiency might not maintain zinc storage in bone, resulting in a decrease in bone formation through downregulation of the expression levels of osteoblastogenesis-related genes. [ABSTRACT FROM AUTHOR]

Regulation of the zinc ion concentration is physiologically important to control the activities of a variety of cellular molecules. A BLAST search against a conserved domain of known zinc transporters identified twelve putative zinc transporter family genes in the Dictyostelium genome. Phylogenetic analysis revealed the presence of three zinc transporter subfamilies in Dictyostelium. One subfamily of proteins, consisting of the ZntA-D proteins, has weak homology to the STAT3-inducible LIV-1 protein. In addition, in situ hybridization revealed that the zntA-D genes are expressed in the pstAB cells, this expression being absent in the Dd-STATa null mutant. Thus, Dd-STATa may control stalk cell differentiation through some members of the zinc transporter family genes during Dictyostefium development. [ABSTRACT FROM AUTHOR]

Abstract: The accumulation of zinc in the cell is a sum of influx and efflux processes via transporter proteins, like the four Zn transporters (ZnT1–4), the divalent cation transporter 1 (DCT1) and of storage processes mainly bound to metallothionein (MT). To study the effect of Zn deficiency on mRNA expression levels, adult rats were used as an animal model. Food intake was restricted to 8 g/day containing 2 g Zn/g fortified with pure phytate in Zn deficiency rats and 58 g Zn/g in controls (n = 7). At day 1, 2, 4, 7, 11, 16, 22, and 29 of Zn deficiency, 3 animals were sacrificed, respectively (n = 24). Zn deficiency was evident from reduced plasma Zn, plasma alkaline phosphatase activity and severe mobilization of Zn from tissue stores (mainly skeleton), while food intake and body weight remained unaffected. Tissues representing Zn absorption (jejunum, colon), Zn storage and utilization (muscle, liver), and Zn excretion (kidney) were retrieved. Total RNA contents increased in colon (p = 0.003) and trend to decrease in liver (p = 0.086). Zn deficiency was without effect on tissue total RNA concentrations in muscle tissue and kidney. Real-time reverse transcription (RT) polymerase chain reaction (PCR) assays were developed and a relative quantification on the basis of GAPDH was applied. Assays allowed a relative and accurate quantification of mRNA molecules with a sufficiently high sensitivity and repeatability. All known Zn transporter subtypes were found in the tissues. ZnT3 was newly elucidated and sequenced in rat tissues. Expression patterns and reactions to Zn deficiency were specific for the tissue analysed. Expression results imply that some transporters are expressed constitutively, whereas others are highly regulated in tissues responsible for Zn homeostasis. The most distinct changes of expression levels were shown in colon which can therefore be postulated as a highly Zn sensitive tissue. MT was down-regulated in all tissues, massively in liver (p < 0.001) and in colon (p = 0.002) and in tendency also in the jejunum and kidney. In parallel with intracellular Zn status it is a potent candidate gene for Zn deficiency. ZnT1 and ZnT2 showed a significant up-regulation of mRNA expression in colon (p = 0.032 and p = 0.026) and for ZnT2 a trend of down regulation in jejunum (p = 0.098). This study provides the first comparative view of regulation of gene expression and fully quantitative expression analysis of all known Zn transporters in a non growing adult rat model on a constant platform and therefore allows a direct comparison. [Copyright &y& Elsevier]

Zinc transporters are thought to facilitate the mobilization of zinc (Zn) and the role of Zn as a signaling mediator during cellular events. Little is known about the response of Zn movement and zinc transporters during muscle proliferation and differentiation processes after damage. After rats were subjected to one 90-min session of downhill running to cause muscle damage, the gastrocnemius muscles were harvested to assess the expression of zinc transporters SLC39A/ZIP7, ZIP8, ZIP14 and myogenic regulatory factors at the 0 h, 6 h, 12 h, 1 d, 2 d, 3 d, 1 w and 2 w time points after exercise. SLC39A/ZIP7, ZIP8 and ZIP14 had translocated to different compartments of the cell following damage, and they exhibited differential expression profiles after eccentric exercise. The results regarding the myogenetic regulators showed that nf-κb was upregulated 2 d after exercise, and STAT3 and Akt1 mRNA levels were mostly expressed 2 w after exercise. The upregulation of phosphatidylinositol 3-kinase, catalytic subunit gamma (pik3cg), erk1 and erk2 mostly occurred at the early stage (6 h or 12 h) after exercise. In addition, we found that zip7 , zip8 and zip14 expression was moderately correlated with certain markers of muscle regeneration. The zinc transporters SLC39A/ZIP7, ZIP8 and ZIP14 have differential expression profiles upon eccentric exercise, and they might regulate muscle proliferation or differentiation processes through different cellular pathways after exercise-induced muscle damage. [ABSTRACT FROM AUTHOR]

The Zrt/Irt-like proteins (ZIP, SLC39A) and zinc transporters (ZnT, SLC30A) are the two major gene families responsible for the import/export of Zn and other metals. In this study, the mRNA expression levels and genetic variations of eight ZnTs and 14 ZIPs were identified in Crassostrea gigas after exposure to Zn, Cd, Cu, Hg, and Pb. Metal exposure induced reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation and antioxidant enzyme expression. The expanded gene numbers of superoxide dismutase (SOD) in the oysters exhibited diverse expression under exposure to the five metals, and the contrasting expressions of both ZnTs and ZIPs under different metal exposures were observed, revealing their ion-specific responses. Zn and Cu have similar transporters and induce high expression levels of ZnT1, 2, 7, and 9 and ZIP1, 3, 6, 9, 10, 11, and 14. Pb induced high expression levels of ZIP7, and 13 and ZnT5, 6, and 7, which are mainly expressed in the endoplasmic reticulum (ER). Cd induced high expression levels of ZnT1, 2, and 7 and ZIP1, 6, 9, 10, 11, and 13. Hg exposure was found to have little effect on the ZIP and ZnT expression levels. Based on 3784 single nucleotide polymorphisms (SNPs) within the ZnTs and ZIPs, genetic association analysis for Zn accumulation was conducted on 427 oyster samples. The 38 SNPs, which were located within 12 genes, were identified to be associated with Zn content (p < 0.01), explaining the phenotypic variation from 1.61% to 3.37%. One nonsynonymous mutation and related haplotypes were identified within ZIP1, explaining 1.69% of the variation in Zn. Its high expression under Zn exposure revealed its important role in Zn transportation. To the best of our knowledge, this study is the first comprehensive investigation of the transportation mechanisms of ZIPs and ZnTs under different metal exposures and the genetic effect of Zn accumulation in oysters, and provides valuable biomarkers and genetic resources to evaluate environmental metal pollution. [Display omitted] • Gene numbers of SOD expanded and functional diversity under metals exposure. • ZnTs and ZIPs displayed ion-specific responses under metals exposure. • ZIP4 has one special mutation in marine bivalves. • Non-synonymous SNP mutation was identified within ZIP1 for Zn accumulation. [ABSTRACT FROM AUTHOR]

The SARS-CoV binds its spike (S) proteins to host angiotensin-converting enzyme 2 (ACE2). Following entry, the viral RNA is released in the cytoplasm - a potential site of thymoquinone to stop the release. ORF1a and ORF1ab are translated to RdRP which eventually synthesizes mediate both replication and transcription. The Zn2+ can stop viral replication by inactivating (―|) RdRP. Another bioactive component of black seed i.e. , nigellimine might have dual actions working as ionophore (→) to enhance Zn entry into the infected cells as well as to inhibit (―|) the uncoating of the virus inside the infected cells. However, if allowed to continue, replication, full-length (−) RNA copies of the genome are produced and used as templates for full-length (+) RNA genomes. During transcription, sub-genomic RNAs are produced through discontinuous transcription which are eventually translated to synthesize viral proteins. Generally, viral nucleocapsids are assembled from genomic RNA and N protein in the cytoplasm, followed by budding into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Virions are then released from the infected cell through exocytosis. (→, activation or stimulation; ―| , inhibition) (modified from (Rahman and Idid, 2020). • The COVID-19 has been declared a pandemic while there is no specific medicine against its causative agent SARS-CoV-2. • As an complementary medicine Nigella sativa (black seed) could be considered for its bioactive components such as thymoquinone which was proven to have anti-viral activity. • Further benefits to use N. sativa could be augmented by Zn supplement. Notably, Zn has been proven to improve innate and adaptive immunity in course of microbial infection. • The effectiveness of the Zn salt supplement can be enhanced with N. sativa as its major bioactive component might work as ionophore to allow Zn2+ to enter pneumocytes and inhibit SARS-CoV-2 replication by stopping its replicase enzyme system. An effective vaccine to prevent the SARS-CoV-2 causing COVID-19 is yet to be approved. Further there is no drug that is specific to treat COVID-19. A number of antiviral drugs such as Ribavirin, Remdesivir, Lopinavir/ritonavir, Azithromycin and Doxycycline have been recommended or are being used to treat COVID-19 patients. In addition to these drugs, rationale and evidence have been presented to use chloroquine to treat COVID-19, arguably with certain precautions and criticism. In line with the proposed use of chloroquine, Nigella sativa (black seed) could be considered as a natural substitute that contains a number of bioactive components such as thymoquinone, dithymoquinone, thymohydroquinone, and nigellimine. Further benefits to use N. sativa could be augmented by Zn supplement. Notably, Zn has been proven to improve innate and adaptive immunity in the course of any infection, be it by pathogenic virus or bacteria. The effectiveness of the Zn salt supplement could also be enhanced with N. sativa as its major bioactive component might work as ionophore to allow Zn2+ to enter pneumocytes – the target cell for SARSCoV-2. Given those benefits, this review paper describes how N. sativa in combination with Zn could be useful as a complement to COVID-19 treatment. [ABSTRACT FROM AUTHOR]

• Nutritional zinc deficits lead to increased alveolar tissue loss in response to prolonged cigarette smoke exposure. • Alteration of ZIP8 causes increased alveolar tissue loss in response to prolonged cigarette smoke exposure. • Imbalance in zinc intake ZIP8 may be a critical determinant of susceptibility to COPD following cigarette smoke exposure. • Zinc homeostasis is an important factor in host defense against cadmium, a leading toxicant found in tobacco smoke. Cigarette smoke exposure is a major cause of chronic obstructive pulmonary disease. Cadmium is a leading toxic component of cigarette smoke. Cadmium and zinc are highly related metals. Whereas, zinc is an essential metal required for normal health, cadmium is highly toxic. Zrt- and Irt-like protein 8 (ZIP8) is an avid transporter of both zinc and cadmium into cells and is abundantly expressed in the lung of smokers compared to nonsmokers. Our objective was to determine whether disturbed zinc homeostasis through diet or the zinc transporter ZIP8 increase susceptibility to lung damage following prolonged cigarette smoke exposure. Cigarette smoke exposure was evaluated in the lungs of mice subject to insufficient and sufficient zinc intakes, in transgenic ZIP8 overexpressing mice, and a novel myeloid-specific ZIP8 knockout strain. Moderate depletion of zinc intakes in adult mice resulted in a significant increase in lung cadmium burden and permanent lung tissue loss following prolonged smoke exposure. Overexpression of ZIP8 resulted in increased lung cadmium burden and more extensive lung damage, whereas cigarette smoke exposure in ZIP8 knockout mice resulted in increased lung tissue loss without a change in lung cadmium content, but a decrease in zinc. Overall, findings were consistent with past human studies. Imbalance in Zn homeostasis increases susceptibility to permanent lung injury following prolonged cigarette smoke exposure. Based on animal studies, both increased and decreased ZIP8 expression enhanced irreversible tissue damage in response to prolonged tobacco smoke exposure. We believe these findings represent an important advancement in our understanding of how imbalance in zinc homeostasis and cadmium exposure via tobacco smoke may increase susceptibility to smoking-induced lung disease. [ABSTRACT FROM AUTHOR]