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Toxic and Essential Metals in Human Health and Disease 2022-2023

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 54776

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Prof. Dr. Valeria M. Nurchi

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Department of Environmental and Life Science, Università degli Studi di Cagliari, Cagliari, Italy
Interests: analytical chemistry; solution equilibria; bioinorganic chemistry; chelating agents; toxic metal ions; environmental chemistry
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Prof. Dr. Jan Aaseth

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Department of Research, Innlandet Hospital, N-2381 Brumunddal, Norway
Interests: internal medicine; endocrinology; toxicology; neurodegenerative diseases; neuroimaging; bioinorganic chemistry; environmental chemistry; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of Biomolecules called “Toxic and Essential Metals in Human Health and Disease 2022” represents a follow-up of our previous Special Issue with the name of “Toxic and Essential Metals in Human Health and Disease” and “Toxic and Essential Metals in Human Health and Disease 2021”. We would like to further explore the physicochemical and biological aspects of the elements, both in terms of the expanding appreciation of the essentiality of individual elements and the toxicity

of excessive amounts of each element. Molecular biologists and enzyme chemists share with clinicians and toxicologists an appreciation of these substances. The nutritional and metabolic complexities of the trace and mineral elements are reflected by the diversity of conditions recognized as being affected by derangements or deficiencies of these substances, such as neurodegenerative diseases, dermatological conditions, carcinogenic processes, cancer, osteoporosis, cardiovascular diseases, and endocrine dysfunctions. The ability of some trace elements to interfere with the biochemical and physiological utilization of molecular oxygen continues to sustain considerable research interest.

The journal Biomolecules welcomes researchers and clinicians around the world to submit for online presentation their results or reviews within this field of toxic and essential metals in human health and disease in this Special Issue.

Two previous Special Issues on “Toxic and Essential Metals in Human Health and Disease” already appeared in 2020 and 2021 (see: https://www.mdpi.com/journal/biomolecules/special_issues/Toxic_essential_metals, https://www.mdpi.com/journal/biomolecules/special_issues/Toxic_Essential_Metals_2021). Both of these issues were quite successful, with numerous interesting articles submitted, accepted, and published. Our team did its best to simplify and speed up the processing of articles, and the comments of our invited reviewers helped to improve their quality. Many of them were accepted for

publication no later than a month after their initial submission. We will aim to provide the same level of service this time.

Prof. Dr. Valeria M. Nurchi
Prof. Dr. Jan Aaseth
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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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.

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Published Papers (9 papers)

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Research

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19 pages, 2944 KiB

Open AccessCommunication

Neuroprotective Strategies and Cell-Based Biomarkers for Manganese-Induced Toxicity in Human Neuroblastoma (SH-SY5Y) Cells

by Catherine M. Cahill, Sanjan S. Sarang, Rachit Bakshi, Ning Xia, Debomoy K. Lahiri and Jack T. Rogers

Biomolecules 2024, 14(6), 647; https://doi.org/10.3390/biom14060647 - 31 May 2024

Viewed by 1236

Abstract

Manganese (Mn) is an essential heavy metal in the human body, while excess Mn leads to neurotoxicity, as observed in this study, where 100 µM of Mn was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to Mn exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at p < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate Mn-induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, Mn activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated Mn-losses of viability in SH-SY5Y cells. We discuss Mn as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. Mn induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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15 pages, 1706 KiB

Open AccessEditor’s ChoiceArticle

Multipurpose Iron-Chelating Ligands Inspired by Bioavailable Molecules

by Elena Cini, Guido Crisponi, Alessandra Fantasia, Rosita Cappai, Sofia Siciliano, Giuseppe Di Florio, Valeria M. Nurchi and Maddalena Corsini

Biomolecules 2024, 14(1), 92; https://doi.org/10.3390/biom14010092 - 11 Jan 2024

Cited by 2 | Viewed by 1587

Abstract

Because of their capacity to bind metals, metal chelators are primarily employed for therapeutic purposes, but they can also find applications as colorimetric reagents and cleaning solutions as well as in soil remediation, electroplating, waste treatment, and so on. For instance, iron-chelation therapy, which is used to treat iron-overload disorders, involves removing excess iron from the blood through the use of particular molecules, like deferoxamine, that have the ability to chelate the metal. The creation of bioinspired and biodegradable chelating agents is a crucial objective that draws inspiration from natural products. In this context, starting from bioavailable molecules such as maltol and pyrogallol, new molecules have been synthetized and characterized by potentiometry, infrared spectroscopy and cyclic voltammetry. Finally, the ability of these to bind iron has been investigated, and the stability constants of ferric complexes are measured using spectrophotometry. These compounds offer intriguing scaffolds for an innovative class of versatile, multipurpose chelating agents. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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10 pages, 1311 KiB

Open AccessArticle

Non-Uniform Bioaccumulation of Lead and Arsenic in Two Remote Regions of the Human Heart’s Left Ventricle: A Post-Mortem Study

by Ana Cirovic, Orish E. Orisakwe, Aleksandar Cirovic, Jovan Jevtic, Danijela Tasic and Nebojsa Tasic

Biomolecules 2023, 13(8), 1232; https://doi.org/10.3390/biom13081232 - 10 Aug 2023

Cited by 3 | Viewed by 1686

Abstract

The extent of heavy-metal-induced cardiotoxicity is proportional to the levels of metal bioaccumulation, and it was previously assumed that heavy metals accumulate uniformly in the myocardium. Therefore, the aim of this study was to investigate concentrations of metals and metalloids in two distant regions of the left ventricle (LV), the base of the LV, and apex of the LV using inductively coupled plasma mass spectrometry (ICP-MS). We also examined the potential correlation between metal levels and the thickness of the interventricular septum in twenty LV specimens (ten from the base of LV and ten from the apex of LV) from 10 individuals (mean age 75 ± 6 years). We found significantly higher concentrations of arsenic and lead in the LV apex compared to the base of the LV. We also found a positive correlation between the concentrations of arsenic in the myocardium of LV and the thickness of the interventricular septum. Our results indicate that arsenic and lead accumulate to a higher extent in the apex of the LV compared to the base of the LV. Therefore, future studies designed to measure levels of metals in heart muscle should consider non-uniform accumulation of metals in the myocardium. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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16 pages, 2355 KiB

Open AccessArticle

Joint Action Toxicity of Arsenic (As) and Lead (Pb) Mixtures in Developing Zebrafish

by Keturah Kiper and Jennifer L. Freeman

Biomolecules 2022, 12(12), 1833; https://doi.org/10.3390/biom12121833 - 8 Dec 2022

Cited by 7 | Viewed by 2234

Abstract

Arsenic (As) and lead (Pb) are environmental pollutants found in common sites and linked to similar adverse health effects. Multiple studies have investigated the toxicity of each metal individually or in complex mixtures. Studies defining the joint interaction of a binary exposure to As and Pb, especially during the earliest stages of development, are limited and lack confirmation of the predicted mixture interaction. We hypothesized that a mixture of As (iAsIII) and Pb will have a concentration addition (CA) interaction informed by common pathways of toxicity of the two metals. To test this hypothesis, developing zebrafish (1–120 h post fertilization; hpf) were first exposed to a wide range of concentrations of As or Pb separately to determine 120 hpf lethal concentrations. These data were then used in the CA and independent action (IA) models to predict the type of mixture interaction from a co-exposure to As and Pb. Three titration mixture experiments were completed to test prediction of observed As and Pb mixture interaction by keeping the Pb concentration constant and varying As concentrations in each experiment. The prediction accuracy of the two models was then calculated using the prediction deviation ratio (PDR) and Chi-square test and regression modeling applied to determine type of interaction. Individual metal exposures determined As and Pb concentrations at which 25% (39.0 ppm Pb, 40.2 ppm As), 50% (73.8 ppm Pb, 55.4 ppm As), 75% (99.9 ppm Pb, 66.6 ppm As), and 100% (121.7 ppm Pb, 77.3 ppm As) lethality was observed at 120 hpf. These data were used to graph the predicted mixture interaction using the CA and IA models. The titration experiments provided experimental observational data to assess the prediction. PDR values showed the CA model approached 1, whereas all PDR values for the IA model had large deviations from predicted data. In addition, the Chi-square test showed most observed results were significantly different from the predictions, except in the first experiment (Pb LC₂₅ held constant) with the CA model. Regression modeling for the IA model showed primarily a synergistic response among all exposure scenarios, whereas the CA model indicated additive response at lower exposure concentrations and synergism at higher exposure concentrations. The CA model was a better predictor of the Pb and As binary mixture interaction compared to the IA model and was able to delineate types of mixture interactions among different binary exposure scenarios. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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19 pages, 1931 KiB

Open AccessEditor’s ChoiceReview

Biological Effects of Human Exposure to Environmental Cadmium

by Massimiliano Peana, Alessio Pelucelli, Christos T. Chasapis, Spyros P. Perlepes, Vlasoula Bekiari, Serenella Medici and Maria Antonietta Zoroddu

Biomolecules 2023, 13(1), 36; https://doi.org/10.3390/biom13010036 - 24 Dec 2022

Cited by 88 | Viewed by 11293

Abstract

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin; chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd²⁺ can also replace essential metal ions, including redox-active ones. A total of 12 cancer types associated with specific genes coding for the Cd-metalloproteome were identified in this work. In addition, we summarize the proper treatments of Cd poisoning, based on the use of selected Cd detoxifying agents and chelators, and the potential for preventive approaches to counteract its chronic exposure. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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13 pages, 596 KiB

Open AccessFeature PaperReview

Chelation Combination—A Strategy to Mitigate the Neurotoxicity of Manganese, Iron, and Copper?

by Jan O. Aaseth and Valeria M. Nurchi

Biomolecules 2022, 12(11), 1713; https://doi.org/10.3390/biom12111713 - 18 Nov 2022

Cited by 4 | Viewed by 3266

Abstract

The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox–DFOA and the tetrathiomolybdate–DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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17 pages, 1386 KiB

Open AccessReview

Caenorhabditis elegans as a Model to Study Manganese-Induced Neurotoxicity

by Airton C. Martins, Priscila Gubert, Jung Li, Tao Ke, Merle M. Nicolai, Alexandre Varão Moura, Julia Bornhorst, Aaron B. Bowman and Michael Aschner

Biomolecules 2022, 12(10), 1396; https://doi.org/10.3390/biom12101396 - 29 Sep 2022

Cited by 16 | Viewed by 3918

Abstract

Caenorhabditis elegans (C. elegans) is a nematode present worldwide. The worm shows homology to mammalian systems and expresses approximately 40% of human disease-related genes. Since Dr. Sydney Brenner first proposed C. elegans as an advantageous experimental worm-model system for genetic approaches, increasing numbers of studies using C. elegans as a tool to investigate topics in several fields of biochemistry, neuroscience, pharmacology, and toxicology have been performed. In this regard, C. elegans has been used to characterize the molecular mechanisms and affected pathways caused by metals that lead to neurotoxicity, as well as the pathophysiological interrelationship between metal exposure and ongoing neurodegenerative disorders. Several toxic metals, such as lead, cadmium, and mercury, are recognized as important environmental contaminants, and their exposure is associated with toxic effects on the human body. Essential elements that are required to maintain cellular homeostasis and normal physiological functions may also be toxic when accumulated at higher concentrations. For instance, manganese (Mn) is a trace essential element that participates in numerous biological processes, such as enzymatic activities, energy metabolism, and maintenance of cell functions. However, Mn overexposure is associated with behavioral changes in C. elegans, which are consistent with the dopaminergic system being the primary target of Mn neurotoxicity. Caenorhabditis elegans has been shown to be an important tool that allows for studies on neuron morphology using fluorescent transgenic worms. Moreover, behavioral tests may be conducted using worms, and neurotransmitter determination and related gene expression are likely to change after Mn exposure. Likewise, mutant worms may be used to study molecular mechanisms in Mn toxicity, as well as the expression of proteins responsible for the biosynthesis, transport, storage, and uptake of dopamine. Furthermore, this review highlights some advantages and limitations of using the experimental model of C. elegans and provides guidance for potential future applications of this model in studies directed toward assessing for Mn neurotoxicity and related mechanisms. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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38 pages, 1515 KiB

Open AccessEditor’s ChoiceReview

Cerebral Iron Deposition in Neurodegeneration

by Petr Dusek, Tim Hofer, Jan Alexander, Per M. Roos and Jan O. Aaseth

Biomolecules 2022, 12(5), 714; https://doi.org/10.3390/biom12050714 - 17 May 2022

Cited by 66 | Viewed by 24246

Abstract

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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25 pages, 5467 KiB

Open AccessReview

Quantitative Analysis of the Interactions of Metal Complexes and Amphiphilic Systems: Calorimetric, Spectroscopic and Theoretical Aspects

by Rossella Migliore, Tarita Biver, Giampaolo Barone and Carmelo Sgarlata

Biomolecules 2022, 12(3), 408; https://doi.org/10.3390/biom12030408 - 7 Mar 2022

Cited by 4 | Viewed by 3479

Abstract

Metals and metal-based compounds have many implications in biological systems. They are involved in cellular functions, employed in the formation of metal-based drugs and present as pollutants in aqueous systems, with toxic effects for living organisms. Amphiphilic molecules also play important roles in the above bio-related fields as models of membranes, nanocarriers for drug delivery and bioremediating agents. Despite the interest in complex systems involving both metal species and surfactant aggregates, there is still insufficient knowledge regarding the quantitative aspects at the basis of their binding interactions, which are crucial for extensive comprehension of their behavior in solution. Only a few papers have reported quantitative analyses of the thermodynamic, kinetic, speciation and binding features of metal-based compounds and amphiphilic aggregates, and no literature review has yet addressed the quantitative study of these complexes. Here, we summarize and critically discuss the recent contributions to the quantitative investigation of the interactions of metal-based systems with assemblies made of amphiphilic molecules by calorimetric, spectrophotometric and computational techniques, emphasizing the unique picture and parameters that such an analytical approach may provide, to support a deep understanding and beneficial use of these systems for several applications. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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