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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (25 November 2019) | Viewed by 60790

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Prof. Dr. Toshiyuki Fukada

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Guest Editor

Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Interests: zinc signaling; Slc39a/ZIP and Slc30a/ZnT zinc transporters; signal transduction; physiology; disease
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Taiho Kambe

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Guest Editor

Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Interests: zinc transporter; zinc metabolism; cellular biochemistry; metal enzymes; metal biology; absorption of essential trace elements; nutrient deficiency (Fe, Zn, Cu)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The essential trace element zinc plays indispensable roles in multiple cellular processes. It regulates a great number of protein functions, including transcription factors, enzymes, adapters, and growth factors as a structural and/or catalytic factor. Zinc homeostasis is regulated by metal transporters and cation channels, and recent studies have highlighted zinc as an intra- and intercellular signaling mediator, “zinc signal”, which can regulate cellular signaling pathways and biological processes.

This Special Issue focuses on crucial roles of zinc homeostasis and zinc signaling in biology as regards the molecular and physiological bases, addressing the future directions and questions. Because there is growing interest and attention in the physiopathological contribution of zinc homeostasis and zinc signaling, we believe this Special Issue will provide very timely information on it and thus should appeal to a wide range of readers.

The International Society for Zinc Biology Conference 2019 (ISZB-2019, http://www.iszb2019.com) will be held in Kyoto, Japan, 9–13 September, 2019. All attendees presenting a paper at this conference are welcome to submit a manuscript for publication (Deadline: 25 November 2019). For further information, please contact the Editorial Office ([email protected] or [email protected]).

Prof. Toshiyuki Fukada
Prof. Taiho Kambe
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Zinc
Zinc biology
Zinc transporters
Metallothionein
receptors and channels
physiology
disease

Related Special Issue

Zinc Signaling in Physiology and Pathogenesis in International Journal of Molecular Sciences (19 articles)

Published Papers (12 papers)

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Research

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11 pages, 2218 KiB

Open AccessArticle

Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome

by Sara M. Hancock, Stuart D. Portbury, Adam P. Gunn, Blaine R. Roberts, Ashley I. Bush and Paul A. Adlard

Int. J. Mol. Sci. 2020, 21(3), 839; https://doi.org/10.3390/ijms21030839 - 28 Jan 2020

Cited by 9 | Viewed by 2684

Abstract

Metals are critical cellular elements that are involved in a variety of cellular processes, with recent literature demonstrating that zinc, and the synaptic zinc transporter (ZnT3), are specifically involved in learning and memory and may also be key players in age-related neurodegenerative disorders such as Alzheimer’s disease. Whilst the cellular content and location of metals is critical, recent data has demonstrated that the metalation state of proteins is a determinant of protein function and potential toxicity. As we have previously reported that ZnT3 knockout (KO) mice have deficits in total zinc levels at both 3 and 6 months of age, we were interested in whether there might be changes in the metalloproteomic profile in these animals. To do this, we utilised size exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS) and examined hippocampal homogenates from ZnT3 KO and age-matched wild-type mice at 3, 6 and 18 months of age. Our data suggest that there are alterations in specific metal binding proteins, for zinc, copper and iron all being modulated in the ZnT3 KO mice compared to wild-type (WT). These data suggest that ZnT3 KO mice may have impairments in the levels or localisation of multiple transition metals, and that copper- and iron-dependent cellular pathways may also be impacted in these mice. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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15 pages, 2201 KiB

Open AccessArticle

Elucidating the H⁺ Coupled Zn²⁺ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica

by Eitan Hoch, Moshe Levy, Michal Hershfinkel and Israel Sekler

Int. J. Mol. Sci. 2020, 21(3), 734; https://doi.org/10.3390/ijms21030734 - 22 Jan 2020

Cited by 21 | Viewed by 3587

Abstract

Cellular Zn²⁺ homeostasis is tightly regulated and primarily mediated by designated Zn²⁺ transport proteins, namely zinc transporters (ZnTs; SLC30) that shuttle Zn²⁺ efflux, and ZRT-IRT-like proteins (ZIPs; SLC39) that mediate Zn²⁺ influx. While the functional determinants of ZnT-mediated Zn²⁺ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3⁻ or (II) H⁺ coupled Zn²⁺ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn²⁺ and H⁺, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3⁻ failed to induce Zn²⁺ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn²⁺ uptake. Furthermore, Zn²⁺ uptake was coupled to enhanced H⁺ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H⁺ powered Zn²⁺ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis enteropathica, a rare condition of Zn²⁺ deficiency. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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15 pages, 3331 KiB

Open AccessArticle

Effect of Zinc Supplementation on Renal Anemia in 5/6-Nephrectomized Rats and a Comparison with Treatment with Recombinant Human Erythropoietin

by Hui-Lin Feng, Yen-Hua Chen and Sen-Shyong Jeng

Int. J. Mol. Sci. 2019, 20(20), 4985; https://doi.org/10.3390/ijms20204985 - 09 Oct 2019

Cited by 8 | Viewed by 3317

Abstract

Anemia is a severe complication in patients with chronic kidney disease (CKD). Treatment with exogenous erythropoietin (EPO) can correct anemia in many with CKD. We produced 5/6-nephrectomized rats that became uremic and anemic at 25 days post surgery. Injection of the anemic 5/6-nephrectomized rats with 2.8 mg zinc/kg body weight raised their red blood cell (RBC) levels from approximately 85% of the control to 95% in one day and continued for 4 days. We compared the effect of ZnSO₄ and recombinant human erythropoietin (rHuEPO) injections on relieving anemia in 5/6-nephrectomized rats. After three consecutive injections, both the ZnSO₄ and rHuEPO groups had significantly higher RBC levels (98 ± 6% and 102 ± 6% of the control) than the saline group (90 ± 3% of the control). In vivo, zinc relieved anemia in 5/6-nephrectomized rats similar to rHuEPO. In vitro, we cultured rat bone marrow cells supplemented with ZnCl₂, rHuEPO, or saline. In a 4-day suspension culture, we found that zinc induced erythropoiesis similar to rHuEPO. When rat bone marrow cells were supplement-cultured with zinc, we found that zinc stimulated the production of EPO in the culture medium and that the level of EPO produced was dependent on the concentration of zinc supplemented. The production of EPO via zinc supplementation was involved in the process of erythropoiesis. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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18 pages, 2731 KiB

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Mitochondria-Targeting Antioxidant Provides Cardioprotection through Regulation of Cytosolic and Mitochondrial Zn²⁺ Levels with Re-Distribution of Zn²⁺-Transporters in Aged Rat Cardiomyocytes

by Yusuf Olgar, Erkan Tuncay and Belma Turan

Int. J. Mol. Sci. 2019, 20(15), 3783; https://doi.org/10.3390/ijms20153783 - 02 Aug 2019

Cited by 18 | Viewed by 4163

Abstract

Aging is an important risk factor for cardiac dysfunction. Heart during aging exhibits a depressed mechanical activity, at least, through mitochondria-originated increases in ROS. Previously, we also have shown a close relationship between increased ROS and cellular intracellular free Zn²⁺ ([Zn²⁺]_i) in cardiomyocytes under pathological conditions as well as the contribution of some re-expressed levels of Zn²⁺-transporters for redistribution of [Zn²⁺]_i among suborganelles. Therefore, we first examined the cellular (total) [Zn²⁺] and then determined the protein expression levels of Zn²⁺-transporters in freshly isolated ventricular cardiomyocytes from 24-month rat heart compared to those of 6-month rats. The [Zn²⁺]_i in the aged-cardiomyocytes was increased, at most, due to increased ZIP7 and ZnT8 with decreased levels of ZIP8 and ZnT7. To examine redistribution of the cellular [Zn²⁺]_i among suborganelles, such as Sarco/endoplasmic reticulum, S(E)R, and mitochondria ([Zn²⁺]_SER and [Zn²⁺]_Mit), a cell model (with galactose) to mimic the aged-cell in rat ventricular cell line H9c2 was used and demonstrated that there were significant increases in [Zn²⁺]_Mit with decreases in [Zn²⁺]_SER. In addition, the re-distribution of these Zn²⁺-transporters were markedly changed in mitochondria (increases in ZnT7 and ZnT8 with no changes in ZIP7 and ZIP8) and S(E)R (increase in ZIP7 and decrease in ZnT7 with no changes in both ZIP8 and ZnT8) both of them isolated from freshly isolated ventricular cardiomyocytes from aged-rats. Furthermore, we demonstrated that cellular levels of ROS, both total and mitochondrial lysine acetylation (K-Acetylation), and protein-thiol oxidation were significantly high in aged-cardiomyocytes from 24-month old rats. Using a mitochondrial-targeting antioxidant, MitoTEMPO (1 µM, 5-h incubation), we provided an important data associated with the role of mitochondrial-ROS production in the [Zn²⁺]_i-dyshomeostasis of the ventricular cardiomyocytes from 24-month old rats. Overall, our present data, for the first time, demonstrated that a direct mitochondria-targeting antioxidant treatment can be a new therapeutic strategy during aging in the heart through a well-controlled [Zn²⁺] distribution among cytosol and suborganelles with altered expression levels of the Zn²⁺-transporters. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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17 pages, 2919 KiB

Open AccessArticle

Zinc Supplementation Stimulates Red Blood Cell Formation in Rats

by Yen-Hua Chen, Hui-Lin Feng and Sen-Shyong Jeng

Int. J. Mol. Sci. 2018, 19(9), 2824; https://doi.org/10.3390/ijms19092824 - 18 Sep 2018

Cited by 30 | Viewed by 7781

Abstract

In rats, mice, and humans, it is known that zinc deficiency may be related to anemia, and zinc supplementation influences hemoglobin production. Our previous studies indicate that in fish, zinc supplementation stimulates red blood cell (RBC) formation (erythropoiesis). However, it is not clear whether the mechanism of zinc-induced erythropoiesis stimulation in fish also occurs in rats. We induced anemia in rats using phenylhydrazine (PHZ) and injected either saline or ZnSO₄ solution. We found that an appropriate amount of zinc stimulated erythropoiesis in the PHZ-induced anemic rats. The effects of ZnSO₄ injection were dose-dependent. When the concentration of ZnSO₄ was higher than 2.8 mg zinc/kg body weight, the RBC level of the anemic rats increased from 60 ± 7% to 88 ± 10% that of the normal rats in two days. Rat bone marrow cells with or without ZnCl₂ supplementation were cultured in suspension in vitro. In the cell culture when the zinc concentration was at 0.3 mM, a 1.6-fold proliferation of nascent immature reticulocytes (new RBCs) was observed after one day. In the rat blood, zinc was combined with serum transferrin to induce erythropoiesis. The stimulation of RBC formation by zinc appears to be common among different animals. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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Review

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22 pages, 793 KiB

Open AccessReview

The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target

by Anna Laitakari, Lingzhi Liu, Thomas M. Frimurer and Birgitte Holst

Int. J. Mol. Sci. 2021, 22(8), 3872; https://doi.org/10.3390/ijms22083872 - 08 Apr 2021

Cited by 23 | Viewed by 5264

Abstract

The G-protein coupled receptor GPR39 is abundantly expressed in various tissues and can be activated by changes in extracellular Zn²⁺ in physiological concentrations. Previously, genetically modified rodent models have been able to shed some light on the physiological functions of GPR39, and more recently the utilization of novel synthetic agonists has led to the unraveling of several new functions in the variety of tissues GPR39 is expressed. Indeed, GPR39 seems to be involved in many important metabolic and endocrine functions, but also to play a part in inflammation, cardiovascular diseases, saliva secretion, bone formation, male fertility, addictive and depression disorders and cancer. These new discoveries offer opportunities for the development of novel therapeutic approaches against many diseases where efficient therapeutics are still lacking. This review focuses on Zn²⁺ as an endogenous ligand as well as on the novel synthetic agonists of GPR39, placing special emphasis on the recently discovered physiological functions and discusses their pharmacological potential. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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16 pages, 2681 KiB

Open AccessReview

Japan’s Practical Guidelines for Zinc Deficiency with a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis

by Hiroko Kodama, Makoto Tanaka, Yuji Naito, Kazuhiro Katayama and Mitsuhiko Moriyama

Int. J. Mol. Sci. 2020, 21(8), 2941; https://doi.org/10.3390/ijms21082941 - 22 Apr 2020

Cited by 64 | Viewed by 7770

Abstract

Zinc deficiency is common in Japan, yet awareness on this disorder is lacking. The Japanese Society of Clinical Nutrition recently issued the Japan’s Practical Guideline for Zinc Deficiency 2018 setting forth criteria for diagnosing zinc deficiency, i.e., (a) one or more symptoms of zinc deficiency or low serum alkaline phosphatase, (b) ruling out other diseases, (c) low serum zinc, and (d) alleviation of symptoms upon zinc administration. Serum zinc <60 μg/dL and 60–80 μg/dL indicate zinc deficiency and marginal deficiency, respectively. Zinc deficiency symptoms vary and include dermatitis and taste disorders among others. Zinc administration improves taste in 50–82% of patients suffering from taste disorders (a common symptom of zinc deficiency). Effects of zinc administration do not appear immediately, and therapy should be continued for at least three months. Zinc deficiency often accompanies various diseases and conditions. Here, we focus on inflammatory bowel diseases and liver cirrhosis. As zinc deficiency enhances intestinal inflammation via macrophage activation, we discuss the pathological mechanism for inflammation and zinc deficiency in the context of IBD. Zinc deficiency can also lead to a nitrogen metabolic disorder in patients with liver cirrhosis. Zinc supplementation can improve not only the ammonia metabolism, but also the protein metabolism. We also discuss directions for future studies of zinc deficiency. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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15 pages, 744 KiB

Open AccessReview

Zinc Finger Proteins in the Human Fungal Pathogen Cryptococcus neoformans

by Yuan-Hong Li and Tong-Bao Liu

Int. J. Mol. Sci. 2020, 21(4), 1361; https://doi.org/10.3390/ijms21041361 - 18 Feb 2020

Cited by 9 | Viewed by 6584

Abstract

Zinc is one of the essential trace elements in eukaryotes and it is a critical structural component of a large number of proteins. Zinc finger proteins (ZNFs) are zinc-finger domain-containing proteins stabilized by bound zinc ions and they form the most abundant proteins, serving extraordinarily diverse biological functions. In recent years, many ZNFs have been identified and characterized in the human fungal pathogen Cryptococcus neoformans, a fungal pathogen causing fatal meningitis mainly in immunocompromised individuals. It has been shown that ZNFs play important roles in the morphological development, differentiation, and virulence of C. neoformans. In this review, we, first, briefly introduce the ZNFs and their classification. Then, we explain the identification and classification of the ZNFs in C. neoformans. Next, we focus on the biological role of the ZNFs functionally characterized so far in the sexual reproduction, virulence factor production, ion homeostasis, pathogenesis, and stress resistance in C. neoformans. We also discuss the perspectives on future function studies of ZNFs in C. neoformans. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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12 pages, 621 KiB

Open AccessReview

Zinc Homeostasis in Bone: Zinc Transporters and Bone Diseases

by Tongling Huang, Guoyong Yan and Min Guan

Int. J. Mol. Sci. 2020, 21(4), 1236; https://doi.org/10.3390/ijms21041236 - 12 Feb 2020

Cited by 58 | Viewed by 4472

Abstract

Zinc is an essential micronutrient that plays critical roles in numerous physiological processes, including bone homeostasis. The majority of zinc in the human body is stored in bone. Zinc is not only a component of bone but also an essential cofactor of many proteins involved in microstructural stability and bone remodeling. There are two types of membrane zinc transporter proteins identified in mammals: the Zrt- and Irt-like protein (ZIP) family and the zinc transporter (ZnT) family. They regulate the influx and efflux of zinc, accounting for the transport of zinc through cellular and intracellular membranes to maintain zinc homeostasis in the cytoplasm and in intracellular compartments, respectively. Abnormal function of certain zinc transporters is associated with an imbalance of bone homeostasis, which may contribute to human bone diseases. Here, we summarize the regulatory roles of zinc transporters in different cell types and the mechanisms underlying related pathological changes involved in bone diseases. We also present perspectives for further studies on bone homeostasis-regulating zinc transporters. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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23 pages, 882 KiB

Open AccessReview

Advances of Zinc Signaling Studies in Prostate Cancer

by Dangdang Li, Daniel B. Stovall, Wenmeng Wang and Guangchao Sui

Int. J. Mol. Sci. 2020, 21(2), 667; https://doi.org/10.3390/ijms21020667 - 19 Jan 2020

Cited by 42 | Viewed by 7517

Abstract

Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer-related death among men worldwide. Despite progresses in early diagnosis and therapeutic strategies, prognosis for patients with advanced PCa remains poor. Noteworthily, a unique feature of healthy prostate is its highest level of zinc content among all soft tissues in the human body, which dramatically decreases during prostate tumorigenesis. To date, several reviews have suggested antitumor activities of zinc and its potential as a therapeutic strategy of PCa. However, an overview about the role of zinc and its signaling in PCa is needed. Here, we review literature related to the content, biological function, compounds and clinical application of zinc in PCa. We first summarize zinc content in prostate tissue and sera of PCa patients with their clinical relevance. We then elaborate biological functions of zinc signaling in PCa on three main aspects, including cell proliferation, death and tumor metastasis. Finally, we discuss clinical applications of zinc-containing compounds and proteins involved in PCa signaling pathways. Based on currently available studies, we conclude that zinc plays a tumor suppressive role and can serve as a biomarker in PCa diagnosis and therapies. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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15 pages, 998 KiB

Open AccessReview

Application of Acyzol in the Context of Zinc Deficiency and Perspectives

by Gjumrakch Aliev, Yi Li, Vladimir N. Chubarev, Svetlana A. Lebedeva, Lidiya N. Parshina, Boris A. Trofimov, Susanna S. Sologova, Alfiya Makhmutova, Marco F. Avila-Rodriguez, Sergey G. Klochkov, Pavel A. Galenko-Yaroshevsky and Vadim V. Tarasov

Int. J. Mol. Sci. 2019, 20(9), 2104; https://doi.org/10.3390/ijms20092104 - 29 Apr 2019

Cited by 11 | Viewed by 4213

Abstract

Zinc is one of the most important essential trace elements. It is involved in more than 300 enzyme systems and is an indispensable participant in many biochemical processes. Zinc deficiency causes a number of disorders in the human body, the main ones being the delay of growth and puberty, immune disorders, and cognitive dysfunctions. There are over two billion people in the world suffering from zinc deficiency conditions. Acyzol, a zinc-containing medicine, developed as an antidote against carbon monoxide poisoning, demonstrates a wide range of pharmacological activities: Anti-inflammatory, reparative, detoxifying, immunomodulatory, bacteriostatic, hepatoprotective, adaptogenic, antioxidant, antihypoxic, and cardioprotective. The presence of zinc in the composition of Acyzol suggests the potential of the drug in the treatment and prevention of zinc deficiency conditions, such as Prasad’s disease, immune system pathology, alopecia, allergodermatoses, prostate dysfunction, psoriasis, stomatitis, periodontitis, and delayed mental and physical development in children. Currently, the efficiency of Acyzol in the cases of zinc deficiency is shown in a large number of experimental studies. So, Acyzol can be used as a highly effective drug for pharmacologic therapy of a wide range of diseases and conditions and it opens up new perspectives in the treatment and prevention of zinc deficiency conditions. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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3 pages, 156 KiB

Open AccessMeeting Report

Report for the Sixth Meeting of the International Society for Zinc Biology (ISZB-2019)

by Toshiyuki Fukada and Taiho Kambe

Int. J. Mol. Sci. 2020, 21(2), 611; https://doi.org/10.3390/ijms21020611 - 17 Jan 2020

Cited by 1 | Viewed by 2402

Abstract

The sixth meeting of the International Society for Zinc Biology (ISZB-2019) was held on September 9–13, 2019 in Kyoto, Japan. The meeting attracted 215 participants, had four plenary speakers, ten scientific symposia, two oral sessions, and one poster discussion session. In this chapter, [...] Read more.

(This article belongs to the Special Issue Zinc Biology 2019)

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