Metallomics最新文献

Inorganic drugs have a huge impact in medicine, yet their solution behavior in presence of solvents for biological testing is often underestimated, even for clinically established agents. Speciation, hydrolysis, and redox processes can profoundly affect efficacy, safety, and reproducibility, with direct implications for both in vitro and in vivo testing. Here we present a proof-of-concept study highlighting the importance of systematic stability assessment prior to biological evaluation. Four representative metallodrugs were selected to capture diverse oxidation states, coordination geometries, and activation mechanisms: the ruthenium(III) complex NAMI-A, the platinum(II) drug oxaliplatin, the platinum(IV) derivative Hex-Pt, and the experimental gold(I) complex Npx-Au. Although limited in number, this panel demonstrates that meaningful insights can only be obtained through an integrated, multi-technique approach. By combining methods such as NMR spectroscopy, UV-Vis spectroscopy, and HPLC-MS, early degradation events can be reliably detected, optimal storage conditions defined, and misleading experimental outcomes avoided. Our findings emphasize that rigorous stability profiling over time is not optional but essential for accurate dosing, reproducibility, and correct interpretation of preclinical assays. This work establishes a framework for incorporating systematic solution stability evaluation into the development and experimental use of metallodrugs, ensuring more reliable translation from bench to clinic.

X-ray absorption spectroscopy (XAS) is a technique which is frequently used in metallomics research, providing a valuable tool for the elucidation of element-specific electronic and geometric structural information. Recent decades have seen the development of related synchrotron-based X-ray techniques with enhanced analytical capabilities, including X-ray emission spectroscopy (XES), resonant inelastic X-ray scattering (RIXS), and high energy resolution fluorescence detected X-ray absorption spectroscopy (HERFD-XAS). With appropriate experimental configuration, HERFD-XAS can generate spectra with significantly improved spectroscopic resolution and background rejection compared to conventional XAS, providing a substantial advantage in the analysis of dilute analytes in biological samples. These improvements arise from the capability to interrogate selected fluorescence lines with the use of multiple crystal analyzers, minimizing the effects of core-hole lifetime broadening. Herein, we review a range of existing and emerging applications of HERFD-XAS for the study of metals and metalloids in biology and medicine. Direct comparisons of conventional XAS and HERFD-XAS spectra highlight the substantial improvements in resolution, and greater potential for the interpretation of metal speciation in complex and dilute biological samples. We also discuss current challenges with the design of HERFD-XAS experiments.

Iron is an essential metal for almost all living organisms. The major 'consumers' of intracellular iron content are a group of proteins that require an iron-sulfur cluster for their functions. It has been shown that iron-sulfur clusters in proteins are assembled by a set of highly conserved proteins using intracellular free iron and L-cysteine as iron and sulfide sources, respectively. Ironically, excess iron is detrimental to cells as free ferrous iron promotes the production of reactive oxygen species via the Fenton reaction. In Escherichia coli, intracellular iron homeostasis is regulated primarily by a global transcription factor Fur (ferric uptake regulator). Since its discovery, it had been assumed that Fur binds ferrous iron to regulate intracellular iron homeostasis, oxidative stress response, and bacterial virulence, among others. However, the proposed 'iron-bound' Fur had never been identified in E. coli or any other bacteria. Recent studies have revealed that E. coli Fur binds a unique [2Fe-2S] cluster in response to elevation of intracellular free iron content, and that the [2Fe-2S] cluster in Fur is enzymatically assembled by the iron-sulfur cluster biogenesis machinery. Because Fur also regulates the expression of the genes encoding the iron-sulfur cluster assembly machinery, Fur represents a key link between biogenesis of iron-sulfur clusters and regulation of intracellular iron homeostasis in bacteria.

Oral leukoplakia is oral potentially malignant disorder with an unclear etiology. Emerging evidence indicates a link between metal dyshomeostasis and carcinogenesis. This study is the first to compare serum concentrations of calcium (Ca), magnesium (Mg), selenium (Se), copper (Cu), zinc (Zn), iron (Fe), lead (Pb) and manganese (Mn), as well as the peripheral blood immunological characteristics, between patients with oral leukoplakia and healthy controls, aiming to explore the potential association between metal dyshomeostasis and oral leukoplakia. This cross-sectional-case-control study recruited 89 participants at West China Hospital of Stomatology, including 59 patients with oral leukoplakia and 30 healthy controls. The concentrations of Ca, Mg, Se, Cu, Zn, Fe, Pb and Mn were measured by inductively coupled plasma-mass spectrometry (ICP-MS), and peripheral blood immunological characteristics were quantified using standard clinical chemistry methods. Compared with the control group, the serum Se level in oral leukoplakia patients was significantly decreased and negatively correlated with the degree of dysplasia. However, the Pb level was significantly increased. Patients with oral leukoplakia had abnormal immune function, with significantly decreased percentages of CD3 + T cell and CD8 + T cells, and significantly increased levels of IgA and antinuclear antibodies. Moreover, the Pb was significantly negatively correlated with cellular immunity, while Se was positively correlated with the count of CD8 + T cells. This study indicates a potential association between metal dyshomeostasis and oral leukoplakia, which may be mediated through the immune function, especially abnormal cellular immunity. These findings provide new insights into the etiology and treatment of oral leukoplakia.

Iron is an essential micronutrient and plays a vital role in human nutrition and plant development. In this report, we investigated iron-binding proteins (IBPs) of bread wheat at the sequence and structure levels, utilizing high-throughput systematic computational biology and bioinformatic approaches. We found that out of 133 346 wheat proteins, at least 0.97% could bind with iron ions. The analysis revealed numerous significant differences among these IBPs, which are involved in various biological functions. Most of these proteins are localized in plastids, followed by the endoplasmic reticulum, cell membrane and nucleus. But the most diverse group of IBPs are localized in the nucleus and cytoplasm region, being functionally associated with various biological processes. Out of 321 IBP unique domains, most proteins fall under GT1-Gtf-like, protein kinase domain, secretory peroxidases and CYP1. Further categorization and classification of these shortlisted IBPs revealed that most of these proteins are involved in metabolic processes, with oxidoreductase activity being the most prominent gene ontology molecular function (GO: MF), whereas biological process (GO: BP) enrichment highlighted the involvement of these IBPs in the management of reactive oxygen species. Protein interaction and identification of hub genes revealed further important IBP genes that have the potential to be used as a reference sheet for wet-lab work in the development of molecular markers for biofortification and understanding iron homeostasis in wheat.

Novel monoribbed-functionalized iron(II) cage complexes with optically active and/or terminal biorelevant group(s) were designed and prepared by two-step nucleophilic substitution of their mono- and dichloroclathrochelate precursors. The single-crystal XRD structures of all of them and those of known leader iron(II)-centered cage bioeffector and of its reactive monochloroclathrochelate precursor were solved. These experimental data were used for theoretical quantum chemical calculations of electrostatic potentials for their 3D-shaped molecules. This allowed to localize the peripheral (exterior) biorelevant group(s), which are responsible for supramolecular binding of thus designed clathrochelate guests to globular proteins as the hosts. Host-guest binding in aqueous solutions between the unfolded protein macromolecules and all the aforementioned iron(II) complexes was studied by the circular dichroism method. An inherent chirality of the metalloclathrochelates with optically active ribbed substituent and a metal-centered chirality of all the prepared macrobicyclic compounds, induced by their supramolecular clathrochelate-to-protein binding, were observed.

Iron (Fe) and copper (Cu) are crucial micronutrients for plant growth and development. The yellow stripe-like (YSL) proteins play a vital role in the absorption and transport of metal chelates in plants. The YSL genes in tobacco have not been systematically identified and characterized. This study aims to explore the YSL genes in Nicotiana tabacum. A comprehensive set of 17 NtYSL genes were identified and classified into four distinct clades on the phylogenetic tree. The gene structures, characterized by the length and distribution of exons and introns, and protein motifs are relatively conserved. Genomic localization analysis revealed that the NtYSL genes are unevenly distributed across 15 chromosomes, with 11 pairs of homeologous loci identified within the genome. To investigate the functionality of these genes, we analyzed their expression levels in shoots and roots under Fe- and Cu-deficient conditions by real-time quantitative reverse transcription PCR (qRT-PCR), finding that several NtYSL genes are responsive to Cu deficiency or Fe deficiency. This study provides a systematic characterization of the NtYSL gene family in Nicotiana tabacum and offers insights into their potential roles in Fe and Cu homeostasis.

The complex interplay between metal abundance, transport mechanisms, cell distribution, and tumor progression-related biological pathways (e.g. metabolism, collagen remodeling) remains poorly understood. Traditionally, genes and metals have been studied in isolation, limiting insights into their interactions. Recent advances in spatial transcriptomics and elemental profiling now enable comprehensive exploration of tissue-wide metal-gene interactions, though integration remains challenging. In this proof-of-concept study, we investigated metal-dependent signaling within the tumor microenvironment of a unique colorectal cancer (CRC) tumor. We implemented a spatial multimodal workflow which integrated elemental imaging, gene expression, cellular composition, and histopathological features to uncover metals-related pathways through spatially resolved gene expression correlation analyses. Preliminary findings revealed significant associations, for instance: elevated iron correlated with mesenchymal phenotypes located at the tumor's proliferative front, correlating with expression of genes involved in the epithelial-to-mesenchymal transition pathways, and extracellular matrix remodeling. Preliminary observations from this single sample revealed that high copper concentrations were localized to regions of active tumor growth and were associated with increased expression of immune response genes. This proof-of-concept workflow demonstrates the feasibility of integrating elemental imaging with spatial transcriptomics to identify metals-based gene correlates. Future application of this workflow to larger patient cohorts will pave the way for expansive comparisons across the metallome and transcriptome, ultimately identifying novel targets for tumor progression biomarkers and therapeutic interventions.

Manganese (Mn) plays a dual role in the body, acting as an essential trace element and a potential toxicant, the effects of which depend on its levels. In addition to food, exposure can occur through polluted air and contaminated water. Animal studies suggest that increased retention and absorption of Mn might result from iron deficiency, as both share similar physicochemical properties. However, human evidence is incomplete. This study aimed to confirm and expand upon prior findings that iron status influences Mn kinetics in the U.S. female population. The analysis included 1255 non-pregnant females aged 12-49 years with valid urinary and blood Mn and iron measurements as part of the 2015-2018 National Health and Nutrition Examination Survey. Iron status was assessed with a total body iron (TBI) score calculated from measured serum ferritin and the transferrin receptor. Iron deficiency was defined as a TBI score < 0. Demographic and laboratory characteristics (e.g. age and kidney function) were recorded. Among the study participants, roughly 8.8% were found to have iron deficiency. Conversely, 16.9% of participants exhibited blood Mn levels exceeding 1.5 µg/dL, a commonly used reference. On average, blood Mn was approximately 40% higher in subjects considered iron deficient than in their counterparts after controlling for covariates such as race. Those with iron deficiency also had a lower urine-to-blood Mn ratio. The findings suggest that iron-deficient females may have greater Mn accumulation, increasing the risk of Mn toxicity. Further investigations should include male populations to complement the current findings.