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12 pages, 1343 KiB

Open AccessArticle

Metabolic Reprogramming of Macrophages upon In Vitro Incubation with Aluminum-Based Adjuvant

by Ravi Danielsson, Nathan Ferey, Irene Mile and Håkan Eriksson

Int. J. Mol. Sci. 2023, 24(5), 4409; https://doi.org/10.3390/ijms24054409 - 23 Feb 2023

Cited by 1 | Viewed by 2016

Abstract

Aluminum-based adjuvants have been extensively used in vaccines. Despite their widespread use, the mechanism behind the immune stimulation properties of these adjuvants is not fully understood. Needless to say, extending the knowledge of the immune-stimulating properties of aluminum-based adjuvants is of utmost importance [...] Read more.

Aluminum-based adjuvants have been extensively used in vaccines. Despite their widespread use, the mechanism behind the immune stimulation properties of these adjuvants is not fully understood. Needless to say, extending the knowledge of the immune-stimulating properties of aluminum-based adjuvants is of utmost importance in the development of new, safer, and efficient vaccines. To further our knowledge of the mode of action of aluminum-based adjuvants, the prospect of metabolic reprogramming of macrophages upon phagocytosis of aluminum-based adjuvants was investigated. Macrophages were differentiated and polarized in vitro from human peripheral monocytes and incubated with the aluminum-based adjuvant Alhydrogel^®. Polarization was verified by the expression of CD markers and cytokine production. In order to recognize adjuvant-derived reprogramming, macrophages were incubated with Alhydrogel^® or particles of polystyrene as control, and the cellular lactate content was analyzed using a bioluminescent assay. Quiescent M0 macrophages, as well as alternatively activated M2 macrophages, exhibited increased glycolytic metabolism upon exposure to aluminum-based adjuvants, indicating a metabolic reprogramming of the cells. Phagocytosis of aluminous adjuvants could result in an intracellular depot of aluminum ions, which may induce or support a metabolic reprogramming of the macrophages. The resulting increase in inflammatory macrophages could thus prove to be an important factor in the immune-stimulating properties of aluminum-based adjuvants. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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24 pages, 3686 KiB

Open AccessArticle

Evidence and Metabolic Implications for a New Non-Canonical Role of Cu-Zn Superoxide Dismutase

by Ziqiao Sun and Xin-Gen Lei

Int. J. Mol. Sci. 2023, 24(4), 3230; https://doi.org/10.3390/ijms24043230 - 6 Feb 2023

Cited by 4 | Viewed by 2490

Abstract

Copper–zinc superoxide dismutase 1 (SOD1) has long been recognized as a major redox enzyme in scavenging superoxide radicals. However, there is little information on its non-canonical role and metabolic implications. Using a protein complementation assay (PCA) and pull-down assay, we revealed novel protein–protein [...] Read more.

Copper–zinc superoxide dismutase 1 (SOD1) has long been recognized as a major redox enzyme in scavenging superoxide radicals. However, there is little information on its non-canonical role and metabolic implications. Using a protein complementation assay (PCA) and pull-down assay, we revealed novel protein–protein interactions (PPIs) between SOD1 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) or epsilon (YWHAE) in this research. Through site-directed mutagenesis of SOD1, we studied the binding conditions of the two PPIs. Forming the SOD1 and YWHAE or YWHAZ protein complex enhanced enzyme activity of purified SOD1 in vitro by 40% (p < 0.05) and protein stability of over-expressed intracellular YWHAE (18%, p < 0.01) and YWHAZ (14%, p < 0.05). Functionally, these PPIs were associated with lipolysis, cell growth, and cell survival in HEK293T or HepG2 cells. In conclusion, our findings reveal two new PPIs between SOD1 and YWHAE or YWHAZ and their structural dependences, responses to redox status, mutual impacts on the enzyme function and protein degradation, and metabolic implications. Overall, our finding revealed a new unorthodox role of SOD1 and will provide novel perspectives and insights for diagnosing and treating diseases related to the protein. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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12 pages, 3084 KiB

Open AccessArticle

Effects of Salinomycin and Deferiprone on Lead-Induced Changes in the Mouse Brain

by Emilia Petrova, Yordanka Gluhcheva, Ekaterina Pavlova, Ivelin Vladov, Peter Dorkov, Martin Schaier, Irena Pashkunova-Martic, Thomas H. Helbich, Bernhard Keppler and Juliana Ivanova

Int. J. Mol. Sci. 2023, 24(3), 2871; https://doi.org/10.3390/ijms24032871 - 2 Feb 2023

Cited by 3 | Viewed by 1769

Abstract

Lead (Pb) is a highly toxic heavy metal that has deleterious effects on the central nervous system. This study aimed to investigate the effects of salinomycin (Sal) and deferiprone (DFP) on brain morphology and on the content of some essential elements in Pb-exposed [...] Read more.

Lead (Pb) is a highly toxic heavy metal that has deleterious effects on the central nervous system. This study aimed to investigate the effects of salinomycin (Sal) and deferiprone (DFP) on brain morphology and on the content of some essential elements in Pb-exposed mice. Adult male Institute of Cancer Research (ICR) mice were exposed to a daily dose of 80 mg/kg body weight ( b.w.) Pb(II) nitrate for 14 days and subsequently treated with Sal (16 mg/kg b.w.) or DFP (19 mg/kg b.w.) for another 14 days. At the end of the experimental protocol, the brains were processed for histological and inductively coupled plasma mass spectrometry (ICP-MS) analyses. Pb exposure resulted in a 50-fold increase in Pb concentration, compared with controls. Magnesium (Mg) and phosphorus (P) were also significantly increased by 22.22% and 17.92%, respectively. The histological analysis of Pb-exposed mice revealed brain pathological changes with features of neuronal necrosis. Brain Pb level remained significantly elevated in Sal- and DFP-administered groups (37-fold and 50-fold, respectively), compared with untreated controls. Treatment with Sal significantly reduced Mg and P concentrations by 22.56% and 18.38%, respectively, compared with the Pb-exposed group. Administration of Sal and DFP ameliorated brain injury in Pb-exposed mice and improved histological features. The results suggest the potential application of Sal and DFP for treatment of Pb-induced neurotoxicity. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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15 pages, 2163 KiB

Open AccessArticle

Can Zinc Supplementation Attenuate High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease?

by Oluwanifemi Esther Bolatimi, Kimberly Z. Head, Jianzhu Luo, Tyler C. Gripshover, Qian Lin, Ngozi V. Adiele, Walter H. Watson, Caitlin Wilkerson, Lu Cai, Matthew C. Cave and Jamie L. Young

Int. J. Mol. Sci. 2023, 24(2), 1763; https://doi.org/10.3390/ijms24021763 - 16 Jan 2023

Cited by 6 | Viewed by 5548

Abstract

The pathogenesis of non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is associated with zinc deficiency. Previous studies show zinc supplementation improves steatosis and glucose metabolism, but its therapeutic effects in patients with established NAFLD remain unclear. We developed an [...] Read more.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is associated with zinc deficiency. Previous studies show zinc supplementation improves steatosis and glucose metabolism, but its therapeutic effects in patients with established NAFLD remain unclear. We developed an in vivo model to characterize the effects of zinc supplementation on high-fat diet (HFD) induced NAFLD and hypothesized that the established NAFLD would be attenuated by zinc supplementation. Male C57BL/6J mice were fed a control diet or HFD for 12 weeks. Mice were then further grouped into normal and zinc-supplemented diets for 8 additional weeks. Body composition and glucose tolerance were determined before and after zinc supplementation. At euthanasia, plasma and liver tissue were collected for characterization and downstream analysis. As expected, 12 weeks of HFD resulted in reduced glucose clearance and altered body composition. Eight weeks of subsequent zinc supplementation did not alter glucose handling, plasma transaminases, steatosis, or hepatic gene expression. Results from our model suggest 8-week zinc supplementation cannot reverse established NAFLD. The HFD may have caused NAFLD disease progression beyond rescue by an 8-week period of zinc supplementation. Future studies will address these limitations and provide insights into zinc as a therapeutic agent for established NAFLD. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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11 pages, 2348 KiB

Open AccessArticle

Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution

by Wenlei Liu, Jana Jakobs and Lothar Rink

Int. J. Mol. Sci. 2023, 24(2), 1191; https://doi.org/10.3390/ijms24021191 - 7 Jan 2023

Cited by 6 | Viewed by 2796

Abstract

Proton-pump inhibitors (PPI), e.g., omeprazole or pantoprazole, are the most widely used drugs for various gastrointestinal diseases. However, more and more side effects, especially an increased risk of infections, have been reported in recent years. The underlying mechanism has still not yet been [...] Read more.

Proton-pump inhibitors (PPI), e.g., omeprazole or pantoprazole, are the most widely used drugs for various gastrointestinal diseases. However, more and more side effects, especially an increased risk of infections, have been reported in recent years. The underlying mechanism has still not yet been fully uncovered. Hence, in this study, we analyzed the T cell response after treatment with pantoprazole in vitro. Pantoprazole preincubation reduced the production and secretion of interferon (IFN)-γ and interleukin (IL)-2 after the T cells were activated with phytohemagglutinin (PHA)-L or toxic shock syndrome toxin-1 (TSST-1). Moreover, a lower zinc concentration in the cytoplasm and a higher concentration in the lysosomes were observed in the pantoprazole-treated group compared to the untreated group. We also tested the expression of the zinc transporter Zrt- and Irt-like protein (Zip)8, which is located in the lysosomal membrane and plays a key role in regulating intracellular zinc distribution after T cell activation. Pantoprazole reduced the expression of Zip8. Furthermore, we measured the expression of cAMP-responsive element modulator (CREM) α, which directly suppresses the expression of IL-2, and the expression of the phosphorylated cAMP response element-binding protein (pCREB), which can promote the expression of IFN-γ. The expression of CREMα was dramatically increased, and different isoforms appeared, whereas the expression of pCREB was downregulated after the T cells were treated with pantoprazole. In conclusion, pantoprazole downregulates IFN-γ and IL-2 expression by regulating the expression of Zip8 and pCREB or CREMα, respectively. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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10 pages, 1438 KiB

Open AccessArticle

Ratiometric Zinc Biosensor Based on Bioluminescence Resonance Energy Transfer: Trace Metal Ion Determination with Tunable Response

by Evgenia G. Matveeva, Andrea K. Stoddard, Hui-Hui Zeng, Graham Franke, Leslie Bourne, Carol A. Fierke and Richard B. Thompson

Int. J. Mol. Sci. 2022, 23(23), 14936; https://doi.org/10.3390/ijms232314936 - 29 Nov 2022

Cited by 3 | Viewed by 1741

Abstract

Determination of metal ions such as zinc in solution remains an important task in analytical and biological chemistry. We describe a novel zinc ion biosensing approach using a carbonic anhydrase–Oplophorus luciferase fusion protein that employs bioluminescence resonance energy transfer (BRET) to transduce [...] Read more.

Determination of metal ions such as zinc in solution remains an important task in analytical and biological chemistry. We describe a novel zinc ion biosensing approach using a carbonic anhydrase–Oplophorus luciferase fusion protein that employs bioluminescence resonance energy transfer (BRET) to transduce the level of free zinc as a ratio of emission intensities in the blue and orange portions of the spectrum. In addition to high sensitivity (below nanomolar levels) and selectivity, this approach allows both quantitative determination of “free” zinc ion (also termed “mobile” or “labile”) using bioluminescence ratios and determination of the presence of the ion above a threshold simply by the change in color of bioluminescence, without an instrument. The carbonic anhydrase metal ion sensing platform offers well-established flexibility in sensitivity, selectivity, and response kinetics. Finally, bioluminescence labeling has proven an effective approach for molecular imaging in vivo since no exciting light is required; the expressible nature of this sensor offers the prospect of imaging zinc fluxes in vivo. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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14 pages, 1553 KiB

Open AccessArticle

Chemical Element Profiling in the Sera and Brain of Bipolar Disorders Patients and Healthy Controls

by Vishnu Priya Sampath, Shiv Vardan Singh, Ilana Pelov, Ofir Tirosh, Yigal Erel and David Lichtstein

Int. J. Mol. Sci. 2022, 23(22), 14362; https://doi.org/10.3390/ijms232214362 - 18 Nov 2022

Cited by 3 | Viewed by 2212

Abstract

Bipolar Disorder (BD) is a severe recurrent affective mood disorder characterized by a wide range of lifelong mood swings, varying between depressive and manic states. BD affects more than 1% of the world’s population irrespective of nationality, ethnic origin, or socioeconomic status and [...] Read more.

Bipolar Disorder (BD) is a severe recurrent affective mood disorder characterized by a wide range of lifelong mood swings, varying between depressive and manic states. BD affects more than 1% of the world’s population irrespective of nationality, ethnic origin, or socioeconomic status and is one of the main causes of disability among young people, leading to cognitive and functional impairment and raised mortality, particularly death by suicide. Trace elements play a vital role in many biochemical and physiological processes. Compelling evidence shows that element toxicity might play a crucial role in the onset and progression of neurodegenerative disorders, but their involvement in mood disorders has been scarcely studied. In the present investigation, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of Al, B, Cu, K, Mg and V were significantly lower in the pre-frontal cortex of BD patients compared with those of the controls. A comparison of Spearman’s rank correlation coefficients between the elements in the serum and brain of BD patients and control groups pointed to boron and aluminum as being involved in the disease. These results suggest that there is a disturbance in the elements’ homeostasis and the inter-elements’ relationship in the brain of BD patients and advocate a thorough examination of the possible involvement of chemical elements in different stages of the disease. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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12 pages, 2227 KiB

Open AccessArticle

Vanadium in Bipolar Disorders—Reviving an Old Hypothesis

by Vishnu Priya Sampath, Shiv Vardan Singh, Ilana Pelov, Noa Horesh, Hiba Zannadeh, Ofir Tirosh, Yigal Erel and David Lichtstein

Int. J. Mol. Sci. 2022, 23(22), 13901; https://doi.org/10.3390/ijms232213901 - 11 Nov 2022

Cited by 4 | Viewed by 1825

Abstract

Bipolar disorder (BD) is a severe and common chronic mental illness. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Our previous studies supported the notion that alterations in Na⁺, K⁺-ATPase activity were involved [...] Read more.

Bipolar disorder (BD) is a severe and common chronic mental illness. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Our previous studies supported the notion that alterations in Na⁺, K⁺-ATPase activity were involved in the etiology of BD. As various chemical elements inhibit Na⁺, K⁺-ATPase, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients, and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of V was significantly lower in the pre-frontal cortex of BD patients compared with that of the controls. Intracerebroventricular administration of V in mice elicited anxiolytic and depressive activities, concomitantly inhibited brain Na⁺, K⁺-ATPase activity, and increased extracellular signal-regulated kinase phosphorylation. A hypothesis associating V with BD was set forth decades ago but eventually faded out. Our results are in accord with the hypothesis and advocate for a thorough examination of the possible involvement of chemical elements, V in particular, in BD. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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12 pages, 1921 KiB

Open AccessArticle

Manganese-Induced Toxicity in C. elegans: What Can We Learn from the Transcriptome?

by Merle M. Nicolai, Marcello Pirritano, Gilles Gasparoni, Michael Aschner, Martin Simon and Julia Bornhorst

Int. J. Mol. Sci. 2022, 23(18), 10748; https://doi.org/10.3390/ijms231810748 - 15 Sep 2022

Cited by 4 | Viewed by 2409

Abstract

Manganese (Mn) is an essential ubiquitous transition metal and, when occupationally or environmentally overexposed, a well-known risk factor for several neurological pathologies. However, the molecular mechanisms underlying Mn-induced neurotoxicity are largely unknown. In this study, addressing RNA-Seq analysis, bioavailability and survival assays, key [...] Read more.

Manganese (Mn) is an essential ubiquitous transition metal and, when occupationally or environmentally overexposed, a well-known risk factor for several neurological pathologies. However, the molecular mechanisms underlying Mn-induced neurotoxicity are largely unknown. In this study, addressing RNA-Seq analysis, bioavailability and survival assays, key pathways of transcriptional responses to Mn overexposure were investigated in the model organism Caenorhabditis elegans (C. elegans), providing insights into the Mn-induced cellular stress and damage response. Comparative transcriptome analyses identified a large number of differentially expressed genes (DEGs) in nematodes exposed to MnCl₂, and functional annotation suggested oxidative nucleotide damage, unfolded protein response and innate immunity as major damage response pathways. Additionally, a time-dependent increase in the transcriptional response after MnCl₂ exposure was identified by means of increased numbers of DEGs, indicating a time-dependent response and activation of the stress responses in Mn neurotoxicity. The data provided here represent a powerful transcriptomic resource in the field of Mn toxicity, and therefore, this study provides a useful basis for further planning of targeted mechanistic studies of Mn-induced neurotoxicity that are urgently needed in the face of increasing industrially caused environmental pollution with Mn. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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30 pages, 6970 KiB

Open AccessArticle

Copper Modulates Adult Neurogenesis in Brain Subventricular Zone

by Luke L. Liu, Richard M. van Rijn and Wei Zheng

Int. J. Mol. Sci. 2022, 23(17), 9888; https://doi.org/10.3390/ijms23179888 - 31 Aug 2022

Cited by 10 | Viewed by 3000

Abstract

The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator [...] Read more.

The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs). Applying D-Pen in cultured neurospheres significantly reduced intracellular Cu levels and reversed the Cu-induced suppression of NSPC’s differentiation and migration. An in vivo intracerebroventricular (ICV) infusion model was subsequently established to infuse D-Pen directly into the lateral ventricle. Metal analyses revealed a selective reduction of Cu in SVZ by 13.1% (p = 0.19) and 21.4% (p < 0.05) following D-Pen infusions at low (0.075 μg/h) and high (0.75 μg/h) doses for 28 days, respectively, compared to saline-infused controls. Immunohistochemical studies revealed that the 7-day, low-dose D-Pen infusion significantly increased Ki67(+)/Nestin(+) cell counts in SVZ by 28% (p < 0.05). Quantification of BrdU(+)/doublecortin (DCX)(+) newborn neuroblasts in the rostral migration stream (RMS) and olfactory bulb (OB) further revealed that the short-term, low-dose D-Pen infusion, as compared with saline-infused controls, resulted in more newborn neuroblasts in OB, while the high-dose D-Pen infusion showed fewer newborn neuroblasts in OB but with more arrested in the RMS. Long-term (28-day) infusion revealed similar outcomes. The qPCR data from neurosphere experiments revealed altered expressions of mRNAs encoding key proteins known to regulate SVZ adult neurogenesis, including, but not limited to, Shh, Dlx2, and Slit1, in response to the changed Cu level in neurospheres. Further immunohistochemical data indicated that Cu chelation also altered the expression of high-affinity copper uptake protein 1 (CTR1) and metallothionein-3 (MT3) in the SVZ as well as CTR1 in the choroid plexus, a tissue regulating brain Cu homeostasis. Taken together, this study provides first-hand evidence that a high Cu level in SVZ appears likely to maintain the stability of adult neurogenesis in this neurogenic zone. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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22 pages, 2895 KiB

Open AccessArticle

Zinc Status Impacts the Epidermal Growth Factor Receptor and Downstream Protein Expression in A549 Cells

by Emily Scheiermann, Mary-Ann Puppa, Lothar Rink and Inga Wessels

Int. J. Mol. Sci. 2022, 23(4), 2270; https://doi.org/10.3390/ijms23042270 - 18 Feb 2022

Cited by 4 | Viewed by 2627

Abstract

Zinc has been suggested to play a role in carcinogenesis and tumor progression. Serum zinc levels of lung cancer patients are for example lower than in healthy individuals. The activation and expression of the epidermal growth factor receptor (EGFR), which plays a role [...] Read more.

Zinc has been suggested to play a role in carcinogenesis and tumor progression. Serum zinc levels of lung cancer patients are for example lower than in healthy individuals. The activation and expression of the epidermal growth factor receptor (EGFR), which plays a role in tumor biology, are presumably influenced by zinc. EGFR activation influences cell adhesion and immune escape. This study provides insights into the impacts of zinc on the EGFR activation and expression of downstream proteins such as E-cadherin and PD-L1 in the alveolar carcinoma cell line A549. To model chronic changes in zinc homeostasis, A549 cells were cultured in media with different zinc contents. EGFR surface expression of unstimulated and stimulated A549 cells was determined by flow cytometry. EGFR phosphorylation as well as the protein expression of E-cadherin and PD-L1 were analyzed by Western blot. In our hands, chronic zinc deficiency led to increased EGFR surface expression, decreased E-cadherin protein expression and increased PD-L1 protein expression. Zinc supplementation decreased EGFR surface expression and PD-L1 protein expression. In summary, zinc-deficient A549 cells may display a more malignant phenotype. Thus, future clinical research should further focus on the possible benefits of restoring disturbed zinc homeostasis, especially in lung cancer patients. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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Review

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16 pages, 3237 KiB

Open AccessReview

Managing the Dual Nature of Iron to Preserve Health

by Laura Silvestri, Mariateresa Pettinato, Valeria Furiosi, Letizia Bavuso Volpe, Antonella Nai and Alessia Pagani

Int. J. Mol. Sci. 2023, 24(4), 3995; https://doi.org/10.3390/ijms24043995 - 16 Feb 2023

Cited by 13 | Viewed by 3683

Abstract

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly [...] Read more.

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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19 pages, 2998 KiB

Open AccessReview

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

by Josef Köhrle

Int. J. Mol. Sci. 2023, 24(4), 3393; https://doi.org/10.3390/ijms24043393 - 8 Feb 2023

Cited by 38 | Viewed by 13856

Abstract

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along [...] Read more.

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H₂O₂-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus–pituitary–thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H₂O₂ as cofactor. The latter is generated by the dual oxidase system organized as ‘thyroxisome’ at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H₂O₂ and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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18 pages, 5643 KiB

Open AccessReview

The LIV-1 Subfamily of Zinc Transporters: From Origins to Present Day Discoveries

by Kathryn M. Taylor

Int. J. Mol. Sci. 2023, 24(2), 1255; https://doi.org/10.3390/ijms24021255 - 9 Jan 2023

Cited by 8 | Viewed by 3768

Abstract

This review explains the origin of the LIV-1 family of zinc transporters, paying attention to how this family of nine human proteins was originally discovered. Structural and functional differences between these nine human LIV-1 family members and the five other ZIP transporters are [...] Read more.

This review explains the origin of the LIV-1 family of zinc transporters, paying attention to how this family of nine human proteins was originally discovered. Structural and functional differences between these nine human LIV-1 family members and the five other ZIP transporters are examined. These differences are both related to aspects of the protein sequence, the conservation of important motifs and to the effect this may have on their overall function. The LIV-1 family are dependent on various post-translational modifications, such as phosphorylation and cleavage, which play an important role in their ability to transport zinc. These modifications and their implications are discussed in detail. Some of these proteins have been implicated in cancer which is examined. Furthermore, some additional areas of potential fruitful discovery are discussed and suggested as worthy of examination in the future. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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22 pages, 1555 KiB

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Skin Minerals: Key Roles of Inorganic Elements in Skin Physiological Functions

by Marek Haftek, Rawad Abdayem and Pascale Guyonnet-Debersac

Int. J. Mol. Sci. 2022, 23(11), 6267; https://doi.org/10.3390/ijms23116267 - 3 Jun 2022

Cited by 10 | Viewed by 4704

Abstract

As odd as it may seem at first glance, minerals, it is what we are all about…or nearly. Although life on Earth is carbon-based, several other elements present in the planet’s crust are involved in and often indispensable for functioning of living organisms. [...] Read more.

As odd as it may seem at first glance, minerals, it is what we are all about…or nearly. Although life on Earth is carbon-based, several other elements present in the planet’s crust are involved in and often indispensable for functioning of living organisms. Many ions are essential, and others show supportive and accessory qualities. They are operative in the skin, supporting specific processes related to the particular situation of this organ at the interface with the environment. Skin bioenergetics, redox balance, epidermal barrier function, and dermal remodeling are amongst crucial activities guided by or taking advantage of mineral elements. Skin regenerative processes and skin ageing can be positively impacted by adequate accessibility, distribution, and balance of inorganic ions. Full article

(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)

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