Metallomics最新文献

Zinc is essential for cellular homeostasis and acts both as a structural element and a secondary messenger in intracellular signalling. While the role of SLC39 (former ZIP) family transporters in breast cancer biology is intensively studied, the signalling function of SLC30 family transporters (former ZnT) remains insufficiently explored. This study investigates the involvement of SLC30 transporters in oestrogen receptor-positive (ER+) breast cancer. Bioinformatic and experimental analyses revealed that SLC30 transporters, particularly SLC30A1, SLC30A5, and SLC30A9, regulate the PTP/AKT/ESR1 pathway, contributing to hormone-independent ESR1 activation. Zn-dependent inhibition of PTP phosphatases modulates kinase signalling, promoting proliferation. Notably, high SLC30 expression correlates with improved survival, but serves as a negative prognostic marker under tamoxifen treatment. Here, we evidence that ESR1 directly represses SLC30 transcription and that zinc transporters form a regulatory feedback loop sustaining ER+ breast tumour progression. These findings position SLC30 transporters as active participants in signalling cascades, offering novel targets for therapeutic intervention in ER+ breast cancer.

In this study, we report the synthesis and detailed characterization of four novel bidentate (N, N) ligands incorporating a 2-(methylthio)pyrimidine moiety and their fac-tricarbonylrhenium(I) complexes (ReB1-ReB4 and ReB1Aq) with the general formula fac-[Re(CO)3(N,N)X]n+, with X = Cl- or H2O and n = 0 or 1. Designed to integrate biologically relevant functionalities, these complexes exhibited promising multifunctional bioactivity. Cytotoxicity assays demonstrated moderate activity (IC50 = 11-78 µM) on various human cancer cell lines, with certain derivatives showing notable selectivity toward the Colo205 line. Most of the chlorido complexes effectively inhibited the replication of Herpes simplex virus type 2, while ReB4 displayed significant antibacterial activity against Staphylococcus aureus, including methicillin-resistant strains (MIC = 12.5-25 µM), and demonstrated biofilm inhibition. Aqueous stability of these organometallic complexes was thoroughly investigated, and complexes ReB2 and ReB3 containing a pyrimidine and a thiazole ring, respectively, gradually decompose in aqueous media, correlating with a decline in anticancer activity. Ligand-exchange processes were observed, in which the chlorido co-ligands were replaced by water, thus affecting the solubility and lipophilicity. The aqua complex ReB1Aq exhibited a low chloride affinity, and the pKa of the coordinated water molecule was obtained to be ∼8. Its interaction with human serum albumin was investigated in detail and was found to be dominated by non-covalent interactions, indicating that no coordination bond formation occurs with the protein.

Knee osteoarthritis (OA) is a leading cause of disability worldwide. Oxidative stress (OS), enhanced by exposure to heavy metals such as cadmium (Cd), may contribute to its progression. Cd, present in tobacco smoke, disrupts chondrocyte viability, redox balance, and essential metal homeostasis. This study aimed to determine whether Cd exposure, particularly through smoking, influences the development and severity of knee OA by affecting antioxidant defense, metallothioneins (MTs) expression, arginase II activity, and trace metal levels in blood, synovial fluid (SF), and cartilage. Fifty-one OA patients were stratified by smoking status (non-smokers, ex-smokers, smokers). Cd and other metals were quantified by ICP-MS, along with OS markers (MDA, MGO, AOPPs), antioxidant enzymes (GST, GGT, CAT), prooxidant enzymes (MPO, arginase II), and metallothinein-1A and 2A (MT-1A/2A) levels. Non-parametric tests assessed correlations between Cd and redox markers. Smokers exhibited higher Cd in blood (0.34 ng/mL) and cartilage (26.07 ng/g), with increased GST, GGT, MDA, and AOPPs. Cd correlated positively with MDA (rho = 0.319, P = 0.033). In SF, elevated CAT, GGT, and arginase II activity were found in patients with high Cd levels (Q3), alongside increased MT-2A expression in smokers (P = 0.018). Cd exposure was also linked to an imbalance of essential metals such as selenium (Se). These findings suggest that Cd, mainly from smoking, exacerbates OS, alters redox enzyme activity, induces MT-2A, and disrupts metal homeostasis, potentially mediating OA pathogenesis. Longitudinal studies are warranted to confirm its causal role in disease progression.

Mine tailings contribute to environmental heavy metal contamination through the formation of acid mine drainage. Microbially-mediated processes such as iron and sulfur redox cycling influence metal mobility. Here, we applied an integrated metagenomic and metaproteomic approach to profile microbial communities across vertical geochemical gradients in legacy copper/nickel tailings in Sudbury, Ontario, Canada. From 43 samples, we recovered 454 non-redundant metagenome-assembled genomes (MAGs), revealing diverse populations within the Actinobacteriota, Desulfobacterota, and uncultured lineages such as Candidatus Eremiobacterota and SZUA-79. Functional profiling identified 301 putative iron- and sulfur-cycling MAGs, including those within the Ca. Eremiobacterota and SZUA-79 phyla. A custom set of Hidden Markov Models (HMMs) was used to annotate metal resistance genes, which were widespread and diverse, but whose abundances did not correlate with measured Cu, Ni, or Fe concentrations. This observation suggests that resistance traits are broadly encoded in these microbial communities regardless of environmental metal concentrations. Proteomic data confirmed in situ expression of selected metal resistance genes and iron/sulfur metabolism genes, although protein recovery was limited due to the difficult nature of mine tailings as an extraction matrix. Our findings highlight both the depth of microbial diversity in metal resistance and metal biogeochemical cycling in mining waste, as well as the technical challenges that currently limit genomic and proteomic sequencing coverage in low-biomass, metal-rich matrices.

Zinc (Zn) is a trace element essential for the function of over 10% of the human proteome, yet the average adult body contains only about two grams. Despite its trace status, Zn plays an indispensable role in immune regulation, inflammation control, and redox signalling. Low Zn status is associated with impaired immune function and increased oxidative stress-factors that critically contribute to the pathogenesis of cardiac inflammatory diseases (CIDs), including myocarditis and pericarditis. These conditions are rising in incidence globally, particularly in younger adults, and are linked to viral infections, autoimmune triggers, and post-vaccination inflammatory responses. Zn not only protects cysteine thiol groups from oxidation but also acts as a redox-sensitive secondary messenger via the "Redox Zinc Switch" mechanism-a key process in modulating cellular responses to oxidative stress. In the cardiovascular system, Zn influences antioxidant defence, cytokine regulation, and membrane repair pathways, including cellular responses that are regulated by protein kinase C and metallothioneins. Emerging evidence supports Zn supplementation as a strategy to mitigate myocardial inflammation, reduce cardiac remodelling, and improve outcomes in oxidative stress driven heart diseases. This review synthesizes current knowledge on Zn's biochemical, immunological, and therapeutic roles in cardiac inflammation. We argue that maintaining optimal Zn levels through diet or supplementation represents a promising, accessible intervention to reduce the burden of CIDs and improve cardiovascular resilience in at-risk populations.

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.

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.

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.

The molecular mechanism of aluminum toxicity in biological systems remains poorly understood. In this study, the relationship between aluminum and intracellular calcium was investigated in Saccharomyces cerevisiae model cells. Genetic analysis demonstrated that deletion mutants of plasma membrane calcium transport cch1Δ and mid1Δ, as well as the Golgi calcium pump deletion mutant pmr1Δ, increased the sensitivity to aluminum, while their sensibility could be compensated by exogenous calcium. Strains of cch1Δ and mid1Δ treated by Ca2+ chelator EGTA was more sensitive to aluminum compared with BY4741 and pmc1Δ. Further ICP-AES analysis showed that calcium uptake through both CCH1 and MID1 did not detoxify by inhibiting aluminum absorption. Meanwhile, aluminum treatment did not change the intracellular calcium uptake in cch1Δ, and mid1Δ, although it increased the mRNA levels of CCH1 or MID1 in all tested strains. It suggests that the increase in intracellular calcium induced by aluminum is CCH1 and MID1-dependent. Subsequently, the intracellular calcineurin-CRZ1 pathway was activated under aluminum stress to promote the expression of CCH1, MID1 and PMR1. Notably, overexpression of PMR1 significantly reduced intracellular aluminum levels and enhanced aluminum tolerance in both wild-type and mutant strains (cch1Δ, cnb1Δ, and crz1Δ). Furthermore, another vesicle transport deletion mutant gos1Δ or the strains (WT and gos1Δ) treated by BFA (a vesicle transport inhibitor) showed enhanced sensitivity to aluminum stress. However, exogenous calcium and/or PMR1 overexpression could reverse this sensitivity. Altogether, increasing intracellular calcium serves as a protective response to aluminum stress. The calcium-related signaling, particularly PMR1-mediated vesicle transport, plays a crucial role in aluminum detoxification.

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.