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Iron and its alloys are attractive as biodegradable materials because of their low toxicity and suitable mechanical properties; however, they generally have a slow degradation rate. Given that corrosion is an electrochemical phenomenon where an exchange of electrons takes place, the application of magnetic fields from outside the body may accelerate the degradation of a ferrous temporary implant. In the present study, we have investigated the effect of alternating and direct low magnetic field (H = 6.5 kA/m) on the corrosion process of pure iron (Fe) and an iron-manganese alloy (FeMnC) in modified Hanks' solution. A 14-day static immersion test was performed on the materials. The corrosion rate was assessed by mass and cross-sectional loss measurements, scanning electron microscopy, X-ray diffractometry, Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy before and after degradation. The results show that the presence of magnetic fields significantly accelerates the degradation rate of both materials, with the corrosion rate being twice as high in the case of Fe and almost three times as high for FeMnC. In addition, a homogenous degradation layer is formed over the entire surface and the chemical composition of the degradation products is the same regardless of the presence of a magnetic field.

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Iron is one of the essential metals required by almost all living organisms. However, nature has certain constraints in distributing this element among tissues. Since polymeric oxide-bridged Fe (III) is the prominent source of Fe (III) ions, the insolubility of Fe (III) ions in aqueous systems reduces the direct uptake by cells. Secondly, the free-Fe entities which generate .OH radicals pave the way to the destruction of the cells. Hence, a protective coordination environment via sophisticated chemical systems is required for the acquisition of Fe, its successive transport, storage, and effective utilization in various tissues. Siderophores are polydentate ligands used by bacterial cells for Fe acquisition, with a relatively high affinity for Fe (III) ions. Secreted from the bacterial cells into the external aqueous medium, they sequester Fe to give a soluble complex which re-enters the organism at a specific receptor. Once it gets inside the cell, the Fe is released from the complex and utilized for essential biochemical reactions. The medicinal applications of these natural ligands, developing progressively in various research groups, necessitate the theoretical aspects of their coordination chemistry. This research paper deals with the coordination chemistry of one of the siderophores, cepabactin (Cep). The chemical computations confirm that the FeIII(Cep)3 complex is octahedral and high spin. The oxygen atoms of Cep, which are hard and negatively charged, thus act as electron donors in the FeIII(Cep)3 complex formation. This in turn makes the siderophores relatively less attractive towards Fe (II) ions.

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BACKGROUND: Despite the agreed principle that access to food is a human right, undernourishment and metal ion deficiencies are public health problems worldwide, exacerbated in impoverished or war-affected areas. It is known that maternal malnutrition causes growth retardation and affects behavioral and cognitive development of the newborn. Here we ask whether severe caloric restriction leads per se to disrupted metal accumulation in different organs of the Wistar rat. METHODS: Inductively coupled plasma optical emission spectroscopy was used to determine the concentration of multiple elements in the small and large intestine, heart, lung, liver, kidney, pancreas, spleen, brain, spinal cord, and three skeletal muscles from control and calorically restricted Wistar rats. The caloric restriction protocol was initiated from the mothers prior to mating and continued throughout gestation, lactation, and post-weaning up to sixty days of age. RESULTS: Both sexes were analyzed but dimorphism was rare. The pancreas was the most affected organ presenting a higher concentration of all the elements analyzed. Copper concentration decreased in the kidney and increased in the liver. Each skeletal muscle responded to the treatment differentially: Extensor Digitorum Longus accumulated calcium and manganese, gastrocnemius decreased copper and manganese, whereas soleus decreased iron concentrations. Differences were also observed in the concentration of elements between organs independently of treatment: The soleus muscle presents a higher concentration of Zn compared to the other muscles and the rest of the organs. Notably, the spinal cord showed large accumulations of calcium and half the concentration of zinc compared to brain. X-ray fluorescence imaging suggests that the extra calcium is attributable to the presence of ossifications whereas the latter finding is attributable to the low abundance of zinc synapses in the spinal cord. CONCLUSION: Severe caloric restriction did not lead to systemic metal deficiencies but caused instead specific metal responses in few organs.

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BACKGROUND/AIM: Metal-containing compounds (e.g., platinum complexes) belong to the standard armamentarium of cancer chemotherapy. Copper N-(2-hydroxy acetophenone) glycinate (CuNG) exerts anticancer activity in vitro and in vivo and modulates drug resistance related to glutathione or P-glycoprotein. The potential of CuNG to interact with ATP-binding cassette (ABC) transporters has not been fully explored yet. This study focused on the modulatory effects of CuNG on four ABC transporters (MRP1, MRP1, BCRP, and P-glycoprotein). MATERIALS AND METHODS: Cell viability, drug uptake and ABC transporter expression were measured by resazurin assays, flow cytometry, and ELISA in HL60AR, MDCKII-hBCRP, and Caco-2 cells. RESULTS: CuNG increased doxorubicin sensitivity of MRP1-over-expressing HL60AR with a similar efficacy as the control MRP1 inhibitor MK571. CuNG also increased MRP1's efflux activity. Comparable results were obtained with MDCKII cells over-expressing hBCRP. ELISA assays revealed that the expression of MRP1 in HL60AR cells and BCRP in MDCKII- cells was predominant but other ABC-transporters were also expressed at lower levels. Caco-2 cells expressed high levels of MRP2, but MRP1, BCRP, and P-glycoprotein were also expressed. In contrast to the two former cell lines, CuNG increased doxorubicin resistance and decreased efflux activity in Caco-2 cells. CONCLUSION: CuNG exerted different modulatory activities towards ABC-transporter-expressing cells. While CuNG-mediated ABC-transporter inhibition may improve tumor chemotherapy (like in HL60AR and MDCKII-hBCRP cells), CuNG-mediated enhanced ABC-transport (like in Caco-2 cells) may be a new strategy to ameliorate inflammatory diseases associated with decreased ABC-transporter expression such as ulcerative colitis.

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Biometals are all metal ions that are essential for all living organisms. About 40% of all enzymes with known structures require biometals to function correctly. The main target of damage by biometals is the central nervous system (CNS). Biometal dysregulation (metal deficiency or overload) is related to pathological processes. Chronic occupational and environmental exposure to biometals, including iron and copper, is related to an increased risk of developing Parkinson's disease (PD). Indeed, biometals have been shown to induce a dopaminergic neuronal loss in the substantia nigra. Although the etiology of PD is still unknown, oxidative stress dysregulation, mitochondrial dysfunction, and inhibition of both the ubiquitin-proteasome system (UPS) and autophagy are related to dopaminergic neuronal death. Herein, we addressed the involvement of redox-active biometals, iron, and copper, as oxidative stress and neuronal death inducers, as well as the current metal chelation-based therapy in PD.

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Inadequate mechanical compliance of orthopedic implants can result in excessive strain of the bone interface, and ultimately, aseptic loosening. It is hypothesized that a fiber-based biometal with adjustable anisotropic mechanical properties can reduce interface strain, facilitate continuous remodeling, and improve implant survival under complex loads. The biometal is based on strategically layered sintered titanium fibers. Six different topologies are manufactured. Specimens are tested under compression in three orthogonal axes under 3-point bending and torsion until failure. Biocompatibility testing involves murine osteoblasts. Osseointegration is investigated by micro-computed tomography and histomorphometry after implantation in a metaphyseal trepanation model in sheep. The material demonstrates compressive yield strengths of up to 50 MPa and anisotropy correlating closely with fiber layout. Samples with 75% porosity are both stronger and stiffer than those with 85% porosity. The highest bending modulus is found in samples with parallel fiber orientation, while the highest shear modulus is found in cross-ply layouts. Cell metabolism and morphology indicate uncompromised biocompatibility. Implants demonstrate robust circumferential osseointegration in vivo after 8 weeks. The biometal introduced in this study demonstrates anisotropic mechanical properties similar to bone, and excellent osteoconductivity and feasibility as an orthopedic implant material.

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Alzheimer's disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24-0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036-0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced ß-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.

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Direct analysis of biometals in biomedical samples by energy dispersive X-ray fluorescence (EDXRF) for disease diagnostics has hardly been fully explored due to dark matrix analytical challenges. In this study, we exploited multivariate chemometrics modeling of cancer diagnostics in model human tissue simulates and cultures using selected biometals' (Mn, Fe, Cu, Zn and Se) fluorescence and Compton scatter profiles. PCA successfully reduced the correlated data dimension to uncorrelated datasets for the characterization of the cell cultures. Artificial neural network (ANN) enhanced the classification of cancer staging and the development of a multivariate calibration strategy for the quantification of trace elements. ANN characterized cancer into early, intermediate, and advanced stages of development. Low concentrations of Fe (101 ± 28 ppm), Zn (59 ± 4 ppm) and Cu (21 ± 1 ppm) were evident in SV10 due to the lag phase stage of cancer development. Further, strong correlation (0.976) was evident in early-stage cancer between Zn and Se but with strong negative correlations between Mn and Se (-0.973) and between Mn and Zn (-0.900) probably due to their antioxidant effects. The results show predictable and systematic associations between the concentrations of Fe, Cu, Zn, Se and Mn as cancer biomarkers with the potential to be used for cancer diagnosis at the early stage of development.

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As a neuromodulator, zinc regulates synaptic plasticity, learning and memory. Synaptic zinc is also a crucial factor in the development of toxic forms of amyloid beta protein and, subsequently, of Alzheimer's dementia (AD). Therefore, efforts to pinpoint mechanisms underlying zinc-dependent cognitive functions might aid AD research, by providing potential novel targets for drugs. One of the most understudied proteins in this regard is a zinc-sensing metabotropic receptor: GPR39. In this study we investigated the impact of GPR39 knock-out (KO) on age-related memory decline in mice of both sexes, by comparing them to age-matched wild-type (WT) littermates. We also tested the effects of a GPR39 agonist (TC-G 1008) on declarative memory of old animals, and its disruption in adult mice. We observed episodic-like memory (ELM) and spatial memory (SM) deficits in male GPR39 KO mice, as well as intact procedural memory in GPR39 KO mice regardless of age and sex. ELM was also absent in old WT male mice, and all female mice regardless of their genotype. Acute application of TC-G 1008 (10 mg/kg) reversed a deficit in two of three ELM components in old WT male mice, and had no promnesic effect on consolidation interference of ELM in adult WT mice. We discuss the possible neurobiological mechanisms and the translational value of these results for potential add-on pharmacotherapy of AD aimed at the zinc-sensing receptor.

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Metals serve important roles in the human body, including the maintenance of cell structure and the regulation of gene expression, the antioxidant response, and neurotransmission. High metal uptake in the nervous system is harmful because it can cause oxidative stress, disrupt mitochondrial function, and impair the activity of various enzymes. Metal accumulation can cause lifelong deterioration, including severe neurological problems. There is a strong association between accidental metal exposure and various neurodegenerative disorders, including Alzheimer's disease (AD), the most common form of dementia that causes degeneration in the aged. Chronic exposure to various metals is a well-known environmental risk factor that has become more widespread due to the rapid pace at which human activities are releasing large amounts of metals into the environment. Consequently, humans are exposed to both biometals and heavy metals, affecting metal homeostasis at molecular and biological levels. This review highlights how these metals affect brain physiology and immunity and their roles in creating harmful proteins such as ß-amyloid and tau in AD. In addition, we address findings that confirm the disruption of immune-related pathways as a significant toxicity mechanism through which metals may contribute to AD.

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Recent advances fascinated the use of biological resources in combination with metals to obtain high quality biometals and apply its advantages in different fields. Endophytic mediated Zinc oxide nanoparticles (ZnO-NPs) is an economical and ecofriendly way for farmers to avoid Zn deficiency in rice crop and obtain high yield. Here we synthesized ZnO-NPs utilizing endophytic bacterial strain of Enterobacter hormaechei (E. hormaechei). The physiochemical properties of the prepared NPs were determined through UV-Vis spectroscopy, XRD, FT-IR, SEM and TEM. The prepared NPs revealed surface plasmon resonance (SPR) at 320 nm (nm) and crystalline structure with 21 nm average crystalline size. FT-IR spectra showed the presence of carboxylic, alcohol and amine functional groups, which confirm the biometallic assembling of the ZnO and endophytic bacterial functional groups. SEM showed pyramidal symmetry whereas TEM revealed poly dispersed spherical shape with particle size distribution 18-48 nm. Our results showed that prepared NPs possess significant antifungal, antibacterial and antioxidant potential at 25, 50 and 100 µg/mL concentrations. Moreover, Cytotoxic and hemolytic assay showed significant results (less % viability and hemolysis activity) at 50 and 100 µg/mL (ZnO-NP's) concentrations as compared to control. The prepared ZnO-NPs were used as bio fertilizer in various concentrations as a foliar spray, which showed significant enhancement of the rice plant growth, along with chlorophyll, proteins and carotenoid contents. These results recommend that endophytic mediated ZnO-NPs are biocompatible and possess significant potential for agricultural applications.

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Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of ASD behavior. From these studies, a complex pathology emerges, with alterations in the gastrointestinal and immune system and synaptic signaling in the brain, as a major consequence of prenatal zinc deficiency. The features represent a critical link in a causal chain that leads to various neuronal dysfunctions and behavioral phenotypes observed in prenatal zinc deficient (PZD) mice and probably other mouse models for ASD. Given that the complete phenotype of PZD mice may be key to understanding how non-genetic factors can modify the clinical features and severity of autistic patients and explain the observed heterogeneity, here, we summarize published data on PZD mice. We critically review the emerging evidence that prenatal zinc deficiency is at the core of several environmental risk factors associated with ASD, being mechanistically linked to ASD-associated genetic factors. In addition, we highlight future directions and outstanding questions, including potential symptomatic, disease-modifying, and preventive treatment strategies.

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Biodegradable metals have gained vast attention as befitting candidates for developing degradable metallic implants. Such implants are primarily employed for temporary applications and are expected to degrade or resorbed after the tissue is healed. Fe-based materials have generated considerable interest as one of the possible biodegradable metals. Like other biometals such as Mg and Zn, Fe exhibits good biocompatibility and biodegradability. The versatility in the mechanical behaviour of Fe-based materials makes them a better choice for load-bearing applications. However, the very low degradation rate of Fe in the physiological environment needs to be improved to make it compatible with tissue growth. Several studies on tailoring the degradation behaviour of Fe in the human body are already reported. Majority of these works include studies on the effect of manufacturing and processing techniques on biocompatibility and biodegradability. This article focuses on a comprehensive review and analysis of the various manufacturing and processing techniques so far reported for developing biodegradable iron-based orthopaedic implants. The current status of research in the field is neatly presented, and a summary of the works is included in the article for the benefit of researchers in the field to contextualise their research and effectively find the lacunae in the existing scholarship.

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Hydrogenases and ureases play vital metabolic functions in all three domains of life. However, nickel ions are cytotoxic because they can inactivate enzymes that require less competitive ions (e.g. Mg2+) in the Irving-Williams series to function. Life has evolved elegant mechanisms to solve the problem of delivering the toxic metal to the active site of nickel-containing enzymes inside the cells. Here, we review our current understanding of nickel trafficking along the hydrogenase and urease maturation pathways. Metallochaperones and accessory proteins (SlyD, HypA, HypB, UreD, UreE, UreF, and UreG) form specific protein complexes to allow the transfer of nickel from one protein to another without releasing the toxic metal into the cytoplasm. The role of SlyD is not fully understood, but it can interact with and transfer its nickel to HypB. In the hydrogenase maturation pathway, nickel is transferred from HypB to HypA, which can then deliver its nickel to the hydrogenase large subunit precursor. In Helicobacter pylori, the urease maturation pathway receives its nickel from HypA of the hydrogenase maturation pathway via the formation of a HypA/UreE2 complex. Guanosine triphosphate (GTP) binding promotes the formation of a UreE2G2 complex, where UreG receives a nickel from UreE. In the final step of the urease maturation, nickel/GTP-bound UreG forms an activation complex with UreF, UreD, and apo-urease. Upon GTP hydrolysis, nickel is released from UreG to the urease. Finally, some common themes learned from the hydrogenase-urease maturation pathway are discussed.

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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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Biometals are essential during the development of the central nervous system (CNS) since they participate in the organization and regulation of multiple processes related with the proper organization and functioning of brain structures. Neuronal differentiation is a specialized and complex process that occurs actively from embryonic development to the first years of life and is even maintained in specific areas of the mammalian adult brain. In this review, we focus on describing the cellular and molecular mechanisms of trace biometals such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) on neuronal specialization, comprising from brain uptake to effects on synaptogenesis, axonal outgrowth, myelination, and cellular and neurochemical phenotype determination. We highlight the relevance of biometals in the proper brain functioning by discussing some of the potentially detrimental effects when biometal dyshomeostasis occurs in the brain. Finally, future directions are proposed for exploring the relevance of biometals in brain function using pharmacological, molecular, and analytical approaches.

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[This corrects the article DOI: 10.3389/fnmol.2021.665686.].