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Biometal ions are crucial in the structure and function of living organisms and have extensively been employed to promote bone tissue regeneration. Nevertheless, the biological functions of biometal ions and the underlying mechanisms responsible for their pro-regenerative effects remain incompletely understood, since bone repair is an intricate physiological process involving multiple cell types and signals. Recent accomplishments in the osteoimmunological field have revealed the momentous involvement of the immune system in mediating the therapeutic effects of biometal ions. The inflammatory factors secreted by immune cells contribute to bone cell migration, activation, and proliferation. This review summarizes the immune system and its constituent cells, followed by the current perspective on immunomodulation during bone healing. Next, the physicochemical and physiological properties of various biometal ions, including lithium, sodium, potassium, magnesium, calcium, strontium, vanadium, iron, cobalt, copper, and zinc, are thoroughly reviewed. In addition, the interactions between biometal ions, immune cells, and bone tissue are discussed, aiming to provide insights into the prospective development of novel approaches to bone tissue regeneration by harnessing the therapeutic potential of these biometal ions.

The current ageing trend of the world population has, in part, accounted for Alzheimer disease (AD) being a public health issue in recent times. Although some progress has been made in clarifying AD-related pathophysiological mechanisms, effective intervention is still elusive. Biometals are indispensable to normal physiological functions of the human body-for example, neurogenesis and metabolism. However, their association with AD remains highly controversial. Copper (Cu) and zinc (Zn) are biometals that have been investigated at great length in relation to neurodegeneration, whereas less attention has been afforded to other trace biometals, such as molybdenum (Mo), and iodine. Given the above context, we reviewed the limited number of studies that have evidenced various effects following the usage of these two biometals in different investigative models of AD. Revisiting these biometals via thorough investigations, along with their biological mechanisms may present a solid foundation for not only the development of effective interventions, but also as diagnostic agents for AD.

Many neurodegenerative and neuropsychiatric disorders have been reported to coincide with the dysregulation of metal ions in the body and central nervous system. However, in most cases, it is not the imbalance of a single divalent metal ion but a plethora of metal ions reported to be altered. Given that different divalent metal ions are often able to bind to a protein in a competitive manner, although with different affinities, and that they might use similar transporters for uptake and regulation, it is likely that the imbalance of one metal ion will downstream affect the homeostasis of other metal ions. Thus, based on this assumption, we hypothesize that the dysregulation of a specific metal ion will lead to a characteristic biometal profile. Similar profiles might therefore be detected in various neurological disorders. Moreover, if such shared biometal profiles exist across different neurological disorders, it is possible that shared behavioural impairments in these disorders result from the imbalance in metal ion homeostasis. Thus, here, we evaluate the reported excess or deficiency of metal ions in various neurological disorders and aim to integrate reported alterations in metal ions to generate a characteristic biometal profile for the disorder. Based on this, we try to predict which alterations in biometals will be caused by the overload or deficiency of one particular metal ion. Moreover, investigating the behavioural phenotypes of rodent models suffering from alterations in biometals, we assess whether a shared behavioural phenotype exists for disorders with similar biometal profiles. Our results show that observed behavioural aspects of some neurological disorders are reflected in their specific biometal profile and mirrored by mouse models suffering from similar biometal deregulations.

BACKGROUND: Aberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease. RESULTS: We observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes. CONCLUSIONS: This study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.

Numerous physiological processes happening in the human body, including cerebral development and function, require the participation of biometal ions such as iron, copper, and zinc. Their dyshomeostasis may, however, contribute to the onset of Alzheimer's disease (AD) and potentially other neurodegenerative diseases. Chelation of biometal ions is therefore a therapeutic strategy against AD. This review provides a survey of natural and synthetic chelating agents that are or could potentially be used to target the metal hypothesis of AD. Since metal dyshomeostasis is not the only pathological aspect of AD, and the nature of this disorder is very complex and multifactiorial, the most efficient therapeutics should target as many neurotoxic factors as possible. Various coumarin derivatives match this description and apart from being able to chelate metal ions, they exhibit the capacity to inhibit cholinesterases (ChEs) and monoamine oxidase B (MAO-B) while also possessing antioxidant, anti-inflammatory, and numerous other beneficial effects. Compounds based on the coumarin scaffold therefore represent a desirable class of anti-AD therapeutics.

Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.

Neuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6 Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.

Biometal dyshomeostasis and toxic metal accumulation are common features in many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. The neurotoxic effects of metal imbalance are generally associated with reduced enzymatic activities, elevated protein aggregation and oxidative stress in the central nervous system, in which a cascade of events lead to cell death and neurodegeneration. Although the links between biometal imbalance and neurodegenerative disorders remain elusive, a major class of endogenous proteins involved in metal transport has been receiving increasing attention over recent decades. The abnormal expression of these proteins has been linked to biometal imbalance and to the pathogenesis of AD. Here, we present a brief overview of the physiological roles of biometals including iron, zinc, copper, manganese, magnesium and calcium, and provide a detailed description of their transporters and their synergistic involvement in the development of AD. In addition, we also review the published data relating to neurotoxic metals in AD, including aluminum, lead, cadmium, and mercury.

BACKGROUND: Distraction osteogenesis (DO) is a functional tissue engineering approach that applies gradual mechanical traction on the bone tissues after osteotomy to stimulate bone regeneration. However, DO still has disadvantages that limit its clinical use, including long treatment duration. METHODS: Review the current methods of promoting bone formation and consolidation in DO with particular interest on biometal. RESULTS: Numerous approaches, including physical therapy, gene therapy, growth factor-based therapy, stem-cell-based therapy, and improved distraction devices, have been explored to reduce the DO treatment duration with some success. Nevertheless, no approach to date is widely accepted in clinical practice due to various reasons, such as high expense, short biologic half-life, and lack of effective delivery methods. Biometals, including calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), manganese (Mn), and cobalt (Co) have attracted attention in bone regeneration attributed to their biodegradability and bioactive components released during in vivo degradation. CONCLUSION: This review summarizes the current therapies accelerating bone formation in DO and the beneficial role of biometals in bone regeneration, particularly focusing on the use of biometal Mg and its alloy in promoting bone formation in DO. Translational potential: The potential clinical applications using Mg-based devices to accelerate DO are promising. Mg stimulates expression of multiple intrinsic biological factors and the development of Mg as an implantable component in DO may be used to argument bone formation and consolidation in DO.

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer's disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients.

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Increased interest regarding the biometal mechanisms of action and the pathways in which they have regulatory roles was lately observed. Particularly, it was shown that biometal homeostasis dysregulation may lead to neurodegeneration including Alzheimer’s disease, Parkinson disease, or prion protein disease, since important molecular signaling mechanisms in brain functions implicate both oxidative stress and redox active biometals. Oxidative stress could be a result of a breakdown in metal‐ion homeostasis which leads to abnormal metal protein chelation. In our previous work, we reported a strong correlation between Alzheimer’s disease and oxidative stress. Consequently, the aim of the present work was to evaluate some of the biometals’ levels (magnesium, manganese, and iron), the specific activity of some antioxidant enzymes (superoxide dismutase and glutathione peroxidase), and a common lipid peroxidation marker (malondialdehyde concentration), in mild cognitive impairment ( n = 15) and Alzheimer’s disease ( n = 15) patients, compared to age‐matched healthy subjects ( n = 15). We found increased lipid peroxidation effects, low antioxidant defense, low magnesium and iron concentrations, and high manganese levels in mild cognitive impairment and Alzheimer’s disease patients, in a gradual manner. These data could be relevant for future association studies regarding the prediction of Alzheimer’s disease development risk or circling through stages by analyzing both active redox metals, oxidative stress markers, and the correlations in between.

The cations of biometals in biological systems easily interact with various moieties of organic and inorganic biomolecules, either as natural constituents or after introduction into the body via O-, N- and S- donor atoms. Study of the interaction between M(II) biometal–O-donor ligand (drug) is of interest for various reasons: more evenly dosing of medicine and biodistribution of medicine; monitoring of its pharmacokinetics including excretion; reduction of unwanted effects of the medicine; greater antimicrobial activity; synergistic effect of the metal and medicine; and improved anti-ulcerous, antitumor and anti-bacterial activity. This paper offers an overview of the literature of published research on coordination between biometals and anti-inflammatory drugs of the acid type. The metals that the subject of focus in this review are d-metals with M(II) ions, namely, copper (Cu), zinc (Zn), cobalt (Co) and manganese (Mn).Those containing molecules with carboxyl functional groups can build complexes with coordinated number of metals of 4 and 6, of various stoichiometric structures, simple or complex, and also behave as monodentate, bidentate or bridge ligands in polynuclear complexes.Keywords: Biometals M(II), Anti-inflammatory medicine, Coordination, O-Donor ligands, Copper, Cobalt, Manganese, Zinc

In this in vitro study, we compared the cytocompatibility and osteoblast promoting potency on human bone marrow cell culture with three different alloys (surgical steel, CoCr, Ti6Al4V) and three different surface structures (polished, sandblasted, porous coated). These biometals were specifically chosen because of their current applications in clinical orthopedic practices. Human mononuclear bone marrow cells were cultivated onto the surface of the different biomaterials and stimulated by dexamethasone, L-ascorbic-acid-2-phoshpate and beta-glycerolphosphate over a 3-week period. Immunofluorescent stainings against several antigens (ALP, RANKL, osteopontin, collagen I), mRNA-expression of collagen (Col) I/II, BSP, osteopontin, osteocalcin, TRAP, light and scanning electron microscopy evaluation were used to evaluate cellular growth and osteoblast differentiation. For surface roughness and energy analysis of the specimen, roughness profile (Ra, Rz) and contact angle (CA) measurements were performed. We found differences between the different biometals and surface structures. Steel showed potential cytotoxic effects whereas CoCr and more Ti6Al4V showed an excellent cytocompatibility. There were no qualitative differences in mRNA expression between each of the tested biomaterials. In terms of antigen expression, a sandblasted Ti6Al4V surface showed enhanced osteoblastic differentiation. A porous-coated surface improved the osteoconductivity of CoCr when compared to a polished surface. In contrast to controls all cells cultivated with biometals induced a RANKL expression. Cells increased the implant roughness with the exception of sandblasted Ti6Al4V. Our data show that surface topography and physicochemical properties of biometals influence osteoblast differentiation in vitro.

Preface Zinc, Copper or Magnesium Supplementation against Cadmium Toxicity: An Experimental Study Nickel: Molecular Diversity, Application, Essentiality & Toxicity in Human Health Redox-Active Antimicrobial Metal Complexes with Sterically Hindered O-Diphenol & O-Aminophenol Derivatives Copper as a Biometal: An Insight on Transport, Toxicity & Tolerance in Photosynthetic Organisms Beneficial & Advserse Effects of Phytic Acid Extract from Sweet Potato FUR (Ferric Uptake Regulation) Proteins in Cyanobacteria Pentavalent Antimonials: Chemistry, Biochemistry & Therapeutic Perspectives Methods for the Detection & Quantitation of Phytochelatins: A Class of Heavy Metal-Binding Peptides Produced by Higher Plants, Algae, & Some Fungi Comparative Analysis of Metal Transportomes in Helicobacter Species: Modeling the Molecular Structures of Nickel Transporters Copper, Silver & Bacteria -- Does Resistance Pose a Threat to our Health Care System? Important Biometals in Human: Transporter & Transporter Receptor Biometals Research in Thailand Metallomics: A New Tool for Studying on Biometals Index.

Development of probes for accurate sensing and imaging of biometals in situ is still a growing interest owing to their crucial roles in cellular metabolism, neurotransmission, and apoptosis. Among them, Zn 2+ and Cu 2+ are two important cooperative biometals closely related to Alzheimer’s disease (AD). Herein, we developed a multifunctional probe based on self-assembling peptide nanoribbon for ratiometric sensing of Zn 2+, Cu 2+, or Zn 2+ and Cu 2+ simultaneously. Uniform peptide nanoribbon (AQZ@NR) was rationally designed by coassembling a Zn 2+ -specific ligand AQZ-modified peptide (AQZKL-7) with peptide KL-7. The nanoribbon further combined with Cu 2+ -sensitive near-infrared quantum dots (NIR QDs) and Alexa Fluor 633 as an inner reference molecule, which was endowed with the capability for ratiometric Zn 2+ and Cu 2+ imaging at the same time. The peptide-based probe exhibited good specificity to Zn 2+ and Cu 2+ without interference from other ions. Importantly, the nanoprobe was successfully applied for noninvasive Zn 2+ and Cu 2+ monitoring in both living cells and zebrafish via multicolor fluorescence imaging. This gives insights into the dynamic Zn 2+ and Cu 2+ distribution in an intracellular and in vivo mode, as well as understanding the neurotoxicity of high concentration of Zn 2+ and Cu 2+ . Therefore, the self-assembled nanoprobe shows great promise in multiplexed detection of many other biometals and biomolecules, which will benefit the diagnosis and treatment of AD in clinical applications.

Zn(II) and Cu(II) precipitate Abeta in vitro into insoluble aggregates that are dissolved by metal chelators. We now report evidence that these biometals also mediate the deposition of Abeta amyloid in Alzheimer's disease, since the solubilization of Abeta from post-mortem brain tissue was significantly increased by the presence of chelators, EGTA, N,N,N',N'-tetrakis(2-pyridyl-methyl) ethylene diamine, and bathocuproine. Efficient extraction of Abeta also required Mg(II) and Ca(II). The chelators were more effective in extracting Abeta from Alzheimer's disease brain tissue than age-matched controls, suggesting that metal ions differentiate the chemical architecture of amyloid in Alzheimer's disease. Agents that specifically chelate copper and zinc ions but preserve Mg(II) and Ca(II) may be of therapeutic value in Alzheimer's disease.

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