2,113 research outputs found

    Analysis of Zinc Transporters in C. elegans

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    Zinc is a trace element essential for organisms, and organisms have homeostatic mechanisms to control zinc metabolism. Zinc metabolism is mediated by numerous proteins including zinc transporters, zinc-responsive transcription factors and zinc-binding proteins. Of these proteins, zinc transporters, composed of CDF and ZIP families, play a major role and are implicated in a variety of human diseases. However, the mechanisms by which zinc transporters coordinate to regulate zinc homeostasis in whole animals and by which they are related to human diseases are not well understood. To address these questions, we used C. elegans as a model system. While three C. elegans cdf genes have been characterized previously, the majority of zinc transporters remain to be studied. Here, we characterized cdf-2 and ttm-1 and conducted initial studies of other zinc transporters. We demonstrated that lysosome-related organelles in intestinal cells, termed gut granules, function as a major site of zinc storage. Gut granules were important for detoxification of excess zinc as well as mobilization of zinc in response to low-zinc environments, and CDF-2 was necessary for these processes. In high zinc conditions, gut granules displayed morphological changes characterized by a bilobed morphology with asymmetric distributions of molecules. These findings suggest novel mechanisms of zinc storage, detoxification and mobilization in C. elegans. ttm-1 encodes two isoforms, ttm-1a and ttm-1b, by using different transcription start sites. TTM-1 plays a role in the excretion of zinc and is involved in zinc detoxification via the action of TTM-1B which localizes to the apical membrane of intestinal cells. These functions of TTM-1 are critical specifically in the absence of CDF-2, suggesting that TTM-1coordinates with CDF-2 to regulate zinc homeostasis of whole animals. Studies of other zinc transporters including expression pattern analysis suggested novel functions of zinc transporters in biological processes. These results suggest that further studies of C. elegans zinc transporters may contribute to understanding of sophisticated networks of zinc transporters in zinc metabolism and elucidate physiological functions of zinc transporters

    A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models

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    Zinc absorption in the small intestine is one of the main mechanisms regulating the systemic homeostasis of this essential trace element. This review summarizes the key aspects of human zinc homeostasis and distribution. In particular, current knowledge on human intestinal zinc absorption and the influence of diet-derived factors on bioaccessibility and bioavailability as well as intrinsic luminal and basolateral factors with an impact on zinc uptake are discussed. Their investigation is increasingly performed using in vitro cellular intestinal models, which are continually being refined and keep gaining importance for studying zinc uptake and transport via the human intestinal epithelium. The vast majority of these models is based on the human intestinal cell line Caco-2 in combination with other relevant components of the intestinal epithelium, such as mucin-secreting goblet cells and in vitro digestion models, and applying improved compositions of apical and basolateral media to mimic the in vivo situation as closely as possible. Particular emphasis is placed on summarizing previous applications as well as key results of these models, comparing their results to data obtained in humans, and discussing their advantages and limitations.DFG, 316442145, FOR 2558: Interaktionen von essenziellen Spurenelementen in gesunden und erkrankten 盲lteren Menschen (TraceAge)DFG, 414044773, Open Access Publizieren 2019 - 2020 / Technische Universit盲t Berli

    Maternal zinc intakes and homeostatic adjustments during pregnancy and lactation.

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    Zinc plays critical roles during embryogenesis, fetal growth, and milk secretion, which increase the zinc need for pregnancy and lactation. Increased needs can be met by increasing the dietary zinc intake, along with making homeostatic adjustments in zinc utilization. Potential homeostatic adjustments include changes in circulating zinc, increased zinc absorption, decreased zinc losses, and changes in whole body zinc kinetics. Although severe zinc deficiency during pregnancy has devastating effects, systematic reviews and meta-analysis of the effect of maternal zinc supplementation on pregnancy outcomes have consistently shown a limited benefit. We hypothesize, therefore, that zinc homeostatic adjustments during pregnancy and lactation improve zinc utilization sufficiently to provide the increased zinc needs in these stages and, therefore, mitigate immediate detrimental effects due to a low zinc intake. The specific questions addressed are the following: How is zinc utilization altered during pregnancy and lactation? Are those homeostatic adjustments influenced by maternal zinc status, dietary zinc, or zinc supplementation? These questions are addressed by critically reviewing results from published human studies on zinc homeostasis during pregnancy and lactation carried out in different populations worldwide

    An evolutionary perspective on zinc uptake by human fungal pathogens

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    DW is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 102549/Z/13/Z).Peer reviewedPublisher PD

    Zinc transporters and their functional integration in mammalian cells

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    Zinc is a ubiquitous biological metal in all living organisms. The spatiotemporal zinc dynamics in cells provide crucial cellular signaling opportunities, but also challenges intracellular zinc homeostasis with broad disease implications. Zinc transporters play a central role in regulating cellular zinc balance and subcellular zinc distributions. The discoveries of two complementary families of mammalian zinc transporters (ZnTs and ZIPs) in the mid-1990s spurred much speculation on their metal selectivity and cellular functions. After two decades of research, we have arrived at a biochemical description of zinc transport. However, in vitro functions are fundamentally different from those in living cells, where mammalian zinc transporters are directed to specific subcellular locations, engaged in dedicated macromolecular machineries and connected with diverse cellular processes. Hence, the molecular functions of individual zinc transporters are reshaped and deeply integrated in cells to promote the utilization of zinc chemistry to perform enzymatic reactions, tune cellular responsiveness to pathophysiologic signals and safeguard cellular homeostasis. At present, the underlying mechanisms driving the functional integration of mammalian zinc transporters are largely unknown. This knowledge gap has motivated a shift of the research focus from in vitro studies of purified zinc transporters to in cell studies of mammalian zinc transporters in the context of their subcellular locations and protein interactions. In this review, we will outline how knowledge of zinc transporters has been accumulated from in-test-tube to in-cell studies, highlighting new insights and paradigm shifts in our understanding of the molecular and cellular basis of mammalian zinc transporter functions

    Zinc inhibits TRPV1 to alleviate chemotherapy-induced neuropathic pain

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    Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1

    Analysis Expression of ZIP1 and Caspase-3 Protein in Adenocarsinoma of the Prostate

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    Background: Carcinogenesis of adenocarcinoma of the prostate occurs due to dysregulation of zinc level within the cells. Intracellular zinc molecules influx is regulated by a transporter protein ZIP1, whose non-presence is predicted to inhibit apoptosis, thus leads to the development of prostate adenocarcinoma. Methods: This study was aimed to analyse the correlation of ZIP1 and Caspase-3 expression in prostate adenocarcinoma on its grading as represented by Gleason Score. This was a cross-sectional, retrospective analytical study on 31 Formalin-fixed, paraffin-embedded tissue that meets inclusion criteria. The specimen was stained using the immune-histochemistry technique for ZIP1 and Caspase-3. Protein expression of each case was counted using ImageJ analysis. Gleason score was acquired as secondary data from the cases' reports. The correlation of their expression with respect to Gleason score was analysed with Pearson's correlation using SPSS 11.5. Results: Mean expression level of ZIP1 and Caspase-3 in prostate adenocarcinoma were 35% and 33%, respectively. There was a significantly positive correlation between ZIP1 and Caspase-3 expression (r=0.379; p=0.018). However, their correlation was stronger in intermediate-grade group (r=0.73; p=0.01) and the correlation was much weaker in high-grade group (r=0.04; p=0.48). Conclusions: There was a positive correlation between ZIP1 and Caspase-3 expression in prostate adenocarcinoma.&nbsp

    The effect of maternal iron deficiency on zinc and copper levels and on genes of zinc and copper metabolism during pregnancy in the rat

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    Fe deficiency is relatively common in pregnancy and has both short- and long-term consequences. However, little is known about the effect on the metabolism of other micronutrients. A total of fifty-four female rats were fed control (50 mg Fe/kg) or Fe-deficient diets (7路5 mg/kg) before and during pregnancy. Maternal liver, placenta and fetal liver were collected at day 21 of pregnancy for Cu and Zn analysis and to measure expression of the major genes of Cu and Zn metabolism. Cu levels increased in the maternal liver (P=0路002) and placenta (P=0路018) of Fe-deficient rats. Zn increased (P&lt;0路0001) and Cu decreased (P=0路006) in the fetal liver. Hepatic expression of the Cu chaperones antioxidant 1 Cu chaperone (P=0路042) and cytochrome c oxidase Cu chaperone (COX17, P=0路020) decreased in the Fe-deficient dams, while the expression of the genes of Zn metabolism was unaltered. In the placenta, Fe deficiency reduced the expression of the chaperone for superoxide dismutase 1, Cu chaperone for superoxide dismutase (P=0路030), ceruloplasmin (P=0路042) and Zn transport genes, ZRT/IRT-like protein 4 (ZIP4, P=0路047) and Zn transporter 1 (ZnT1, P=0路012). In fetal liver, Fe deficiency increased COX17 (P=0路020), ZRT/IRT-like protein 14 (P=0路036) and ZnT1 (P=0路0003) and decreased ZIP4 (P=0路004). The results demonstrate that Fe deficiency during pregnancy has opposite effects on Cu and Zn levels in the fetal liver. This may, in turn, alter metabolism of these nutrients, with consequences for development in the fetus and the neonate.</p

    Essential metals at the host-pathogen interface : nutritional immunity and micronutrient assimilation by human fungal pathogens

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    AC and DW are supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 102549/Z/13/Z).Peer reviewedPublisher PD