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The Role of Trace Elements in Diseases
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The Role of Trace Elements in Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 61675

Special Issue Editors

Dr. Alexey A. Tinkov

E-Mail Website
Guest Editor
Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, Sovetskaya Str. 14, 150000 Yaroslavl, Russia
Interests: trace elements in metabolic syndrome; neurotoxicity; trace element biochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Anatoly Skalny

E-Mail Website
Guest Editor
Sechenov University, Moscow, Russia
Interests: trace elements in epidemiology; physiology; sport medicine; autism research

Special Issue Information

Dear Colleagues,

The involvement of trace elements (TE) in the pathogenesis of multiple diseases is of particular interest due to the high prevalence of TE deficiency and overload. A significant importance of trace elements for human health is mediated by their role in the regulation of multiple vital functions including development, immunity, and metabolism. Numerous epidemiological studies demonstrated the predictive role of TE in the incidence of certain diseases, as well as the effectiveness of TE supplementation in their management. Consequently, maintaining the adequate mineral status of the population significantly reduces economic losses.

Recent developments highlight the potential of trace element application in the diagnosis and treatment of neurological, endocrinological, and oncological diseases, as well as diet-related diseases. Trace element-containing supplements are considered important agents in management of a number of infectious diseases, including COVID-19 and other seasonal infections.

This Special Issue of IJMS includes topics presented below:

- Pathophysiological and molecular mechanisms of trace elements in health and disease;

- Trace elements and oncology;

- Trace elements in neurodevelopmental and neurological diseases;

- Trace elements and metabolic syndrome;

- Trace elements and seasonal infections, COVID-19, SARS, MERS and pneumonia.

Dr. Alexey A. Tinkov
Dr. Anatoly Skalny
Guest Editors

Manuscript Submission Information

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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

  • Trace elements
  • Trace element status of population
  • Trace element therapy
  • Diet-related diseases
  • TE in disease prevention
  • Trace element deficiency and overload

Published Papers (18 papers)

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Research

Jump to: Review

16 pages, 2158 KiB  
Article
Selenium-Rich Yeast Peptide Fraction Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis in Mice by Inhibiting Inflammation via MAPK and NF-κB Signaling Pathways
by Hengke Guo, Min Li and Hongmei Liu
Int. J. Mol. Sci. 2022, 23(4), 2112; https://doi.org/10.3390/ijms23042112 - 14 Feb 2022
Cited by 11 | Viewed by 2799
Abstract
Psoriasis, a chronic and immune-mediated inflammatory disease, adversely affects patients’ lives. We previously prepared selenium-rich yeast peptide fraction (SeP) from selenium-rich yeast protein hydrolysate and found that SeP could effectively alleviate ultraviolet radiation-induced skin damage in mice and inhibited H2O2 [...] Read more.
Psoriasis, a chronic and immune-mediated inflammatory disease, adversely affects patients’ lives. We previously prepared selenium-rich yeast peptide fraction (SeP) from selenium-rich yeast protein hydrolysate and found that SeP could effectively alleviate ultraviolet radiation-induced skin damage in mice and inhibited H2O2-induced cytotoxicity in cultured human epidermal keratinocyte (HaCaT) cells. This study aimed to investigate whether SeP had a protective effect on imiquimod (IMQ)-induced psoriasis-like dermatitis in mice and the underlying mechanisms. Results showed that SeP significantly ameliorated the severity of skin lesion in IMQ-induced psoriasis-like mouse model. Moreover, SeP treatment significantly attenuated the expression of key inflammatory cytokines, including interleukin (IL)-23, IL-17A, and IL-17F, in the dorsal skin of mice. Mechanistically, SeP application not only inhibited the activation of JNK and p38 MAPK, but also the translocation of NF-κB into the nucleus in the dorsal skin. Furthermore, SeP treatment inhibited the levels of inflammatory cytokines and the activation of MAPK and NF-κB signaling induced by lipopolysaccharide in HaCaT cells and macrophage cell line RAW264.7. Overall, our findings showed that SeP alleviated psoriasis-like skin inflammation by inhibiting MAPK and NF-κB signaling pathways, which suggested that SeP would have a potential therapeutic effect against psoriasis. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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22 pages, 2647 KiB  
Article
Zinc Exposure Promotes Commensal-to-Pathogen Transition in Pseudomonas aeruginosa Leading to Mucosal Inflammation and Illness in Mice
by Tong Wu, Annie Gagnon, Katherine McGourty, Rebecca DosSantos, Lucia Chanetsa, Boce Zhang, Dhimiter Bello and Shannon L. Kelleher
Int. J. Mol. Sci. 2021, 22(24), 13321; https://doi.org/10.3390/ijms222413321 - 11 Dec 2021
Cited by 6 | Viewed by 2504
Abstract
The opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa) is associated gastrointestinal (GI) inflammation and illness; however, factors motivating commensal-to-pathogen transition are unclear. Excessive zinc intake from supplements is common in humans. Due to the fact that zinc exposure enhances P. aeruginosa colonization [...] Read more.
The opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa) is associated gastrointestinal (GI) inflammation and illness; however, factors motivating commensal-to-pathogen transition are unclear. Excessive zinc intake from supplements is common in humans. Due to the fact that zinc exposure enhances P. aeruginosa colonization in vitro, we hypothesized zinc exposure broadly activates virulence mechanisms, leading to inflammation and illness. P. aeruginosa was treated with excess zinc and growth, expression and secretion of key virulence factors, and biofilm production were determined. Effects on invasion, barrier function, and cytotoxicity were evaluated in Caco-2 cells co-cultured with P. aeruginosa pre-treated with zinc. Effects on colonization, mucosal pathology, inflammation, and illness were evaluated in mice infected with P. aeruginosa pre-treated with zinc. We found the expression and secretion of key virulence factors involved in quorum sensing (QS), motility (type IV pili, flagella), biosurfactants (rhamnolipids), toxins (exotoxin A), zinc homeostasis (CzcR), and biofilm production, were all significantly increased. Zinc exposure significantly increased P. aeruginosa invasion, permeability and cytotoxicity in Caco-2 cells, and enhanced colonization, inflammation, mucosal damage, and illness in mice. Excess zinc exposure has broad effects on key virulence mechanisms promoting commensal-to-pathogen transition of P. aeruginosa and illness in mice, suggesting excess zinc intake may have adverse effects on GI health in humans. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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11 pages, 2934 KiB  
Article
A Potential New Role for Zinc in Age-Related Macular Degeneration through Regulation of Endothelial Fenestration
by Fiona Cunningham, Sabrina Cahyadi and Imre Lengyel
Int. J. Mol. Sci. 2021, 22(21), 11974; https://doi.org/10.3390/ijms222111974 - 5 Nov 2021
Cited by 4 | Viewed by 1984
Abstract
Age-related macular degeneration (AMD) is a common blinding disease in the western world that is linked to the loss of fenestration in the choriocapillaris that sustains the retinal pigment epithelium and photoreceptors in the back of the eye. Changes in ocular and systemic [...] Read more.
Age-related macular degeneration (AMD) is a common blinding disease in the western world that is linked to the loss of fenestration in the choriocapillaris that sustains the retinal pigment epithelium and photoreceptors in the back of the eye. Changes in ocular and systemic zinc concentrations have been associated with AMD; therefore, we hypothesized that these changes might be directly involved in fenestrae formation. To test this hypothesis, an endothelial cell (bEND.5) model for fenestrae formation was treated with different concentrations of zinc sulfate (ZnSO4) solution for up to 20 h. Fenestrae were visualized by staining for Plasmalemmal Vesicle Associated Protein-1 (PV-1), the protein that forms the diaphragms of the fenestrated endothelium. Size and distribution were monitored by transmission electron microscopy (TEM). We found that zinc induced the redistribution of PV-1 into areas called sieve plates containing ~70-nm uniform size and typical morphology fenestrae. As AMD is associated with reduced zinc concentrations in the serum and in ocular tissues, and dietary zinc supplementation is recommended to slow disease progression, we propose here that the elevation of zinc concentration may restore choriocapillaris fenestration resulting in improved nutrient flow and clearance of waste material in the retina. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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20 pages, 7362 KiB  
Article
Comparison of Selenium Nanoparticles and Sodium Selenite on the Alleviation of Early Atherosclerosis by Inhibiting Endothelial Dysfunction and Inflammation in Apolipoprotein E-Deficient Mice
by Junying Xiao, Na Li, Shengze Xiao, Yuzhou Wu and Hongmei Liu
Int. J. Mol. Sci. 2021, 22(21), 11612; https://doi.org/10.3390/ijms222111612 - 27 Oct 2021
Cited by 13 | Viewed by 2498
Abstract
Atherosclerosis and related cardiovascular diseases represent the greatest threats to human health, worldwide. Previous animal studies showed that selenium nanoparticles (SeNPs) and Na2SeO3 might have anti-atherosclerotic activity, but the underlying mechanisms are poorly elucidated. This study compared the anti-atherosclerotic activity [...] Read more.
Atherosclerosis and related cardiovascular diseases represent the greatest threats to human health, worldwide. Previous animal studies showed that selenium nanoparticles (SeNPs) and Na2SeO3 might have anti-atherosclerotic activity, but the underlying mechanisms are poorly elucidated. This study compared the anti-atherosclerotic activity of SeNPs stabilized with chitosan (CS-SeNPs) and Na2SeO3 and the related mechanism in a high-fat-diet-fed apolipoprotein E-deficient mouse model of atherosclerosis. The results showed that oral administration of both CS-SeNPs and Na2SeO3 (40 μg Se/kg/day) for 10 weeks significantly reduced atherosclerotic lesions in mouse aortae. Mechanistically, CS-SeNPs and Na2SeO3 not only alleviated vascular endothelial dysfunction, as evidenced by the increase of serum nitric oxide level and the decrease of aortic adhesion molecule expression, but also vascular inflammation, as evidenced by the decrease of macrophage recruitment as well as the expression of proinflammatory molecules. Importantly, these results were replicated within in-vivo experiments on the cultured human endothelial cell line EA.hy926. Overall, CS-SeNPs had a comparable effect with Na2SeO3 but might have more potential in atherosclerosis prevention due to its lower toxicity. Together, these results provide more insights into the mechanisms of selenium against atherosclerosis and further highlight the potential of selenium supplementation as a therapeutic strategy for atherosclerosis. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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15 pages, 2761 KiB  
Article
The Effect of Surface-Modified Gold Nanorods on the Early Stage of Embryonic Development and Angiogenesis: Insight into the Molecular Pathways
by Nouf N. Mahmoud, Zain Zaki Zakaria, Hadeel Kheraldine, Ishita Gupta, Semir Vranic, Maha Al-Asmakh and Ala-Eddin Al Moustafa
Int. J. Mol. Sci. 2021, 22(20), 11036; https://doi.org/10.3390/ijms222011036 - 13 Oct 2021
Cited by 1 | Viewed by 2063
Abstract
Gold nanorods have been implicated in several biomedical applications. Herein, the effect of two surface-modified gold nanorods on the early stages of embryogenesis and angiogenesis was investigated using avian embryos at three days and their chorioallantoic membrane (CAM) at five days of incubation. [...] Read more.
Gold nanorods have been implicated in several biomedical applications. Herein, the effect of two surface-modified gold nanorods on the early stages of embryogenesis and angiogenesis was investigated using avian embryos at three days and their chorioallantoic membrane (CAM) at five days of incubation. We found that gold nanorods (GNR) modified with PEGylated phospholipid moiety show a high mortality rate in embryos after four days of exposure compared to GNR modified with PEGylated cholesterol moiety. Meanwhile, our data revealed that surface modified-GNR significantly inhibit the formation of new blood vessels in the treated CAM model after 48 h of exposure. Moreover, we report that surface-modified GNR significantly deregulate the expression of several genes implicated in cell proliferation, invasion, apoptosis, cellular energy metabolism, and angiogenesis. On the other hand, our data point out that GNR treatments can modulate the expression patterns of JNK1/2/3, NF-KB/p38, and MAPK, which could be the main molecular pathways of the nanorods in our experimental models. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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16 pages, 13729 KiB  
Article
Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans
by Merle M. Nicolai, Ann-Kathrin Weishaupt, Jessica Baesler, Vanessa Brinkmann, Anna Wellenberg, Nicola Winkelbeiner, Anna Gremme, Michael Aschner, Gerhard Fritz, Tanja Schwerdtle and Julia Bornhorst
Int. J. Mol. Sci. 2021, 22(20), 10905; https://doi.org/10.3390/ijms222010905 - 9 Oct 2021
Cited by 4 | Viewed by 1945
Abstract
Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, [...] Read more.
Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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16 pages, 3148 KiB  
Article
Zinc Favors Triple-Negative Breast Cancer’s Microenvironment Modulation and Cell Plasticity
by Marina Vogel-González, Dunia Musa-Afaneh, Pilar Rivera Gil and Rubén Vicente
Int. J. Mol. Sci. 2021, 22(17), 9188; https://doi.org/10.3390/ijms22179188 - 25 Aug 2021
Cited by 13 | Viewed by 2731
Abstract
Triple-negative breast cancer (TNBC) tends to metastasize to the brain, a step that worsens the patient’s prognosis. The specific hallmarks that determine successful metastasis are motility and invasion, microenvironment modulation, plasticity, and colonization. Zinc, an essential trace element, has been shown to be [...] Read more.
Triple-negative breast cancer (TNBC) tends to metastasize to the brain, a step that worsens the patient’s prognosis. The specific hallmarks that determine successful metastasis are motility and invasion, microenvironment modulation, plasticity, and colonization. Zinc, an essential trace element, has been shown to be involved in all of these processes. In this work, we focus our attention on the potential role of zinc during TNBC metastasis. We used MDA-MB-BrM2 (BrM2) cells, a brain metastasis model derived from the parental TNBC cell line MDA-MB-231. Our studies show that BrM2 cells had double the zinc content of MDA-MB-231 cells. Moreover, exploring different metastatic hallmarks, we found that the zinc concentration is especially important in the microenvironment modulation of brain metastatic cells, enhancing the expression of SerpinB2. Furthermore, we show that zinc promotes the tumorigenic capacity of breast cancer stem cells. In addition, by causing a disturbance in MDA-MB-231 zinc homeostasis by overexpressing the Zip4 transporter, we were able to increase tumorigenicity. Nevertheless, this strategy did not completely recapitulate the BrM2 metastatic phenotype. Altogether, our work suggests that zinc plays an important role in the transformative steps that tumoral cells take to acquire tumorigenic potential and niche specificity. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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14 pages, 2064 KiB  
Article
Simultaneous Quantification and Speciation of Trace Metals in Paired Serum and CSF Samples by Size Exclusion Chromatography–Inductively Coupled Plasma–Dynamic Reaction Cell–Mass Spectrometry (SEC-DRC-ICP-MS)
by Bernhard Michalke, Achim Berthele and Vivek Venkataramani
Int. J. Mol. Sci. 2021, 22(16), 8892; https://doi.org/10.3390/ijms22168892 - 18 Aug 2021
Cited by 10 | Viewed by 2908
Abstract
Background: Transition metals play a crucial role in brain metabolism: since they exist in different oxidation states they are involved in ROS generation, but they are also co-factors of enzymes in cellular energy metabolism or oxidative defense. Methods: Paired serum and cerebrospinal fluid [...] Read more.
Background: Transition metals play a crucial role in brain metabolism: since they exist in different oxidation states they are involved in ROS generation, but they are also co-factors of enzymes in cellular energy metabolism or oxidative defense. Methods: Paired serum and cerebrospinal fluid (CSF) samples were analyzed for iron, zinc, copper and manganese as well as for speciation using SEC-ICP-DRC-MS. Brain extracts from Mn-exposed rats were additionally analyzed with SEC-ICP-DRC-MS. Results: The concentration patterns of transition metal size fractions were correlated between serum and CSF: Total element concentrations were significantly lower in CSF. Fe-ferritin was decreased in CSF whereas a LMW Fe fraction was relatively increased. The 400–600 kDa Zn fraction and the Cu-ceruloplasmin fraction were decreased in CSF, by contrast the 40–80 kDa fraction, containing Cu- and Zn-albumin, relatively increased. For manganese, the α-2-macroglobulin fraction showed significantly lower concentration in CSF, whereas the citrate Mn fraction was enriched. Results from the rat brain extracts supported the findings from human paired serum and CSF samples. Conclusions: Transition metals are strictly controlled at neural barriers (NB) of neurologic healthy patients. High molecular weight species are down-concentrated along NB, however, the Mn-citrate fraction seems to be less controlled, which may be problematic under environmental load. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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22 pages, 4309 KiB  
Article
Hepatic Proteomic Analysis of Selenoprotein T Knockout Mice by TMT: Implications for the Role of Selenoprotein T in Glucose and Lipid Metabolism
by Ke Li, Tiejun Feng, Leyan Liu, Hongmei Liu, Kaixun Huang and Jun Zhou
Int. J. Mol. Sci. 2021, 22(16), 8515; https://doi.org/10.3390/ijms22168515 - 7 Aug 2021
Cited by 8 | Viewed by 2691
Abstract
Selenoprotein T (SELENOT, SelT), a thioredoxin-like enzyme, exerts an essential oxidoreductase activity in the endoplasmic reticulum. However, its precise function remains unknown. To gain more understanding of SELENOT function, a conventional global Selenot knockout (KO) mouse model was constructed for the first time [...] Read more.
Selenoprotein T (SELENOT, SelT), a thioredoxin-like enzyme, exerts an essential oxidoreductase activity in the endoplasmic reticulum. However, its precise function remains unknown. To gain more understanding of SELENOT function, a conventional global Selenot knockout (KO) mouse model was constructed for the first time using the CRISPR/Cas9 technique. Deletion of SELENOT caused male sterility, reduced size/body weight, lower fed and/or fasting blood glucose levels and lower fasting serum insulin levels, and improved blood lipid profile. Tandem mass tag (TMT) proteomics analysis was conducted to explore the differentially expressed proteins (DEPs) in the liver of male mice, revealing 60 up-regulated and 94 down-regulated DEPs in KO mice. The proteomic results were validated by western blot of three selected DEPs. The elevated expression of Glycogen [starch] synthase, liver (Gys2) is consistent with the hypoglycemic phenotype in KO mice. Furthermore, the bioinformatics analysis showed that Selenot-KO-induced DEPs were mainly related to lipid metabolism, cancer, peroxisome proliferator-activated receptor (PPAR) signaling pathway, complement and coagulation cascades, and protein digestion and absorption. Overall, these findings provide a holistic perspective into SELENOT function and novel insights into the role of SELENOT in glucose and lipid metabolism, and thus, enhance our understanding of SELENOT function. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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Review

Jump to: Research

16 pages, 528 KiB  
Review
Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues
by Anatoly V. Skalny, Michael Aschner, Xin Gen Lei, Viktor A. Gritsenko, Abel Santamaria, Svetlana I. Alekseenko, Nagaraja Tejo Prakash, Jung-Su Chang, Elena A. Sizova, Jane C. J. Chao, Jan Aaseth and Alexey A. Tinkov
Int. J. Mol. Sci. 2021, 22(23), 13074; https://doi.org/10.3390/ijms222313074 - 3 Dec 2021
Cited by 33 | Viewed by 4691
Abstract
The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight [...] Read more.
The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight relationship between Zn metabolism and gut microbiota as demonstrated in Zn deficiency, supplementation, and toxicity studies. Generally, Zn was found to be a significant factor for gut bacteria biodiversity. The effects of physiological and nutritional Zn doses also result in improved gut wall integrity, thus contributing to reduced translocation of bacteria and gut microbiome metabolites into the systemic circulation. In contrast, Zn overexposure induced substantial alterations in gut microbiota. In parallel with intestinal effects, systemic effects of Zn-induced gut microbiota modulation may include systemic inflammation and acute pancreatitis, autism spectrum disorder and attention deficit hyperactivity disorder, as well as fetal alcohol syndrome and obesity. In view of both Zn and gut microbiota, as well as their interaction in the regulation of the physiological functions of the host organism, addressing these targets through the use of Zn-enriched probiotics may be considered an effective strategy for health management. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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16 pages, 875 KiB  
Review
Metals in ALS TDP-43 Pathology
by Lassi Koski, Cecilia Ronnevi, Elina Berntsson, Sebastian K. T. S. Wärmländer and Per M. Roos
Int. J. Mol. Sci. 2021, 22(22), 12193; https://doi.org/10.3390/ijms222212193 - 11 Nov 2021
Cited by 12 | Viewed by 4188
Abstract
Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are [...] Read more.
Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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17 pages, 5652 KiB  
Review
Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis
by Lichun Qiao, Xuan Liu, Yujie He, Jiaheng Zhang, Hao Huang, Wenming Bian, Mumba Mulutula Chilufya, Yan Zhao and Jing Han
Int. J. Mol. Sci. 2021, 22(21), 11932; https://doi.org/10.3390/ijms222111932 - 3 Nov 2021
Cited by 27 | Viewed by 4120
Abstract
Fluorine is widely dispersed in nature and has multiple physiological functions. Although it is usually regarded as an essential trace element for humans, this view is not held universally. Moreover, chronic fluorosis, mainly characterized by skeletal fluorosis, can be induced by long-term excessive [...] Read more.
Fluorine is widely dispersed in nature and has multiple physiological functions. Although it is usually regarded as an essential trace element for humans, this view is not held universally. Moreover, chronic fluorosis, mainly characterized by skeletal fluorosis, can be induced by long-term excessive fluoride consumption. High concentrations of fluoride in the environment and drinking water are major causes, and patients with skeletal fluorosis mainly present with symptoms of osteosclerosis, osteochondrosis, osteoporosis, and degenerative changes in joint cartilage. Etiologies for skeletal fluorosis have been established, but the specific pathogenesis is inconclusive. Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis. In recent years, researchers have conducted extensive studies in fields of signaling pathways (Wnt/β-catenin, Notch, PI3K/Akt/mTOR, Hedgehog, parathyroid hormone, and insulin signaling pathways), stress pathways (oxidative stress and endoplasmic reticulum stress pathways), epigenetics (DNA methylation and non-coding RNAs), and their inter-regulation involved in the pathogenesis of skeletal fluorosis. In this review, we summarised and analyzed relevant findings to provide a basis for comprehensive understandings of the pathogenesis of skeletal fluorosis and hopefully propose more effective prevention and therapeutic strategies. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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14 pages, 1032 KiB  
Review
Alzheimer’s Disease and Diabetes Mellitus in Comparison: The Therapeutic Efficacy of the Vanadium Compound
by Zhijun He, Guanying You, Qiong Liu and Nan Li
Int. J. Mol. Sci. 2021, 22(21), 11931; https://doi.org/10.3390/ijms222111931 - 3 Nov 2021
Cited by 9 | Viewed by 2814
Abstract
Alzheimer’s disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aβ) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have [...] Read more.
Alzheimer’s disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aβ) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have been proposed, including the amyloid cascade hypothesis, the oxidative stress hypothesis, the inflammatory hypothesis, the cholinergic hypothesis, et al. In the meantime, great efforts had been made in developing effective drugs for AD. However, the clinical efficacy of the drugs that were approved by the US Food and Drug Association (FDA) to date were determined only mild/moderate. We recently adopted a vanadium compound bis(ethylmaltolato)-oxidovanadium (IV) (BEOV), which was originally used for curing diabetes mellitus (DM), to treat AD in a mouse model. It was shown that BEOV effectively reduced the Aβ level, ameliorated the inflammation in brains of the AD mice, and improved the spatial learning and memory activities of the AD mice. These finding encouraged us to further examine the mechanisms underlying the therapeutic effects of BEOV in AD. In this review, we summarized the achievement of vanadium compounds in medical studies and investigated the prospect of BEOV in AD and DM treatment. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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12 pages, 1199 KiB  
Review
Antitumor Effects of Selenium
by Seung Jo Kim, Min Chul Choi, Jong Min Park and An Sik Chung
Int. J. Mol. Sci. 2021, 22(21), 11844; https://doi.org/10.3390/ijms222111844 - 31 Oct 2021
Cited by 42 | Viewed by 4432
Abstract
Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. [...] Read more.
Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. Hydrogen selenide from selenite, and methylselenol (MSeH) from Se-methylselenocyteine (MSeC) and methylseleninicacid (MSeA) are the most reactive metabolites produced reactive oxygen species (ROS); furthermore, these metabolites may involve in oxidizing sulfhydryl groups, including glutathione. Selenite also reacted with glutathione and produces hydrogen selenide via selenodiglutathione (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus. However, a more pronounced effect was shown in the subsequent treatment of sodium selenite with chemotherapy and radiation therapy. High doses of sodium selenite were effective to increase radiation therapy and chemotherapy, and further to reduce radiation side effects and drug resistance. In our study, advanced cancer patients can tolerate until 5000 μg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short, and, further, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells. Further clinical studies of high amount sodium selenite are required to treat advanced cancer patients. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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16 pages, 1105 KiB  
Review
Trace Element Selenium Effectively Alleviates Intestinal Diseases
by Ruihua Ye, Jiaqiang Huang, Zixu Wang, Yaoxing Chen and Yulan Dong
Int. J. Mol. Sci. 2021, 22(21), 11708; https://doi.org/10.3390/ijms222111708 - 28 Oct 2021
Cited by 33 | Viewed by 4087
Abstract
Selenium (Se) is an essential trace element in the body. It is mainly used in the body in the form of selenoproteins and has a variety of biological functions. Intestinal diseases caused by chronic inflammation are among the most important threats to human [...] Read more.
Selenium (Se) is an essential trace element in the body. It is mainly used in the body in the form of selenoproteins and has a variety of biological functions. Intestinal diseases caused by chronic inflammation are among the most important threats to human health, and there is no complete cure at present. Due to its excellent antioxidant function, Se has been proven to be effective in alleviating intestinal diseases such as inflammatory bowel diseases (IBDs). Therefore, this paper introduces the role of Se and selenoproteins in the intestinal tract and the mechanism of their involvement in the mediation of intestinal diseases. In addition, it introduces the advantages and disadvantages of nano-Se as a new Se preparation and traditional Se supplement in the prevention and treatment of intestinal diseases, so as to provide a reference for the further exploration of the interaction between selenium and intestinal health. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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16 pages, 4183 KiB  
Review
Brief Review of Endometriosis and the Role of Trace Elements
by Ida Osuchowska-Grochowska, Eliza Blicharska, Marek Gogacz, Agata Nogalska, Izabela Winkler, Agnieszka Szopa, Halina Ekiert, Barbara Tymczyna-Borowicz, Mansur Rahnama-Hezavah and Cezary Grochowski
Int. J. Mol. Sci. 2021, 22(20), 11098; https://doi.org/10.3390/ijms222011098 - 14 Oct 2021
Cited by 7 | Viewed by 3581
Abstract
Endometriosis is a chronic, estrogen-dependent, inflammatory condition that is defined as the presence of endometrial glands and stroma outside the uterine cavity. Despite the progress in research into the mechanisms leading to the development of endometriosis, its cause has not yet been established. [...] Read more.
Endometriosis is a chronic, estrogen-dependent, inflammatory condition that is defined as the presence of endometrial glands and stroma outside the uterine cavity. Despite the progress in research into the mechanisms leading to the development of endometriosis, its cause has not yet been established. It seems to be possible that the formation of oxidative stress may be one of the main causes of the development of endometriosis. There is much research that studies the potential role of trace elements in the appearance of endometrial-like lesions. Most studies focus on assessing the content of selected trace elements in the blood, urine, or peritoneal fluid in women with endometriosis. Meanwhile, little is known about the content of these elements in endometrial-like implants, which may be helpful in developing the theory of endometriosis. Investigations that are more comprehensive are needed to confirm a hypothesis that some trace elements play a role in the pathomechanism of endometriosis. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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27 pages, 936 KiB  
Review
Selected Essential and Toxic Chemical Elements in Hypothyroidism—A Literature Review (2001–2021)
by Anna Błażewicz, Patrycja Wiśniewska and Katarzyna Skórzyńska-Dziduszko
Int. J. Mol. Sci. 2021, 22(18), 10147; https://doi.org/10.3390/ijms221810147 - 20 Sep 2021
Cited by 14 | Viewed by 3850
Abstract
Thyroid hormones are known for controlling metabolism of lipids, carbohydrates, proteins, minerals, and electrolytes and for regulating body temperature. Normal thyroid status depends on the chemical/elemental composition of body fluids and tissues, which changes depending on physiological state, lifestyle and environment. A deficiency [...] Read more.
Thyroid hormones are known for controlling metabolism of lipids, carbohydrates, proteins, minerals, and electrolytes and for regulating body temperature. Normal thyroid status depends on the chemical/elemental composition of body fluids and tissues, which changes depending on physiological state, lifestyle and environment. A deficiency or excess of certain essential chemical elements (selenium, zinc, copper, iron or fluorine) or exposure to toxic (cadmium or lead) or potentially toxic elements (manganese or chromium) interacts with thyroid hormone synthesis and may disturb thyroid homeostasis. In our review, accessible databases (Scopus, PubMed and Web of Science) were searched for articles from 2001–2021 on the influence of selected chemical elements on the development of hypothyroidism. Our review adopted some of the strengths of a systematic review. After non-eligible reports were rejected, 29 remaining articles were reviewed. The review found that disruption of the physiological levels of elements in the body adversely affects the functioning of cells and tissues, which can lead to the development of disease. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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19 pages, 2966 KiB  
Review
Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer’s Disease
by Jan Aaseth, Anatoly V. Skalny, Per M. Roos, Jan Alexander, Michael Aschner and Alexey A. Tinkov
Int. J. Mol. Sci. 2021, 22(17), 9461; https://doi.org/10.3390/ijms22179461 - 31 Aug 2021
Cited by 28 | Viewed by 4654
Abstract
The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer’s disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced [...] Read more.
The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer’s disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aβ generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aβ cross-linking and up-regulation of RAGE expression. Moreover, Aβ glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting AGE accumulation and metal-induced neurotoxicity. Full article
(This article belongs to the Special Issue The Role of Trace Elements in Diseases)
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