Biometals最新文献

Chronic, sub-toxic, multi-metal accumulation stemming from environmental exposure in daily life is a common phenomenon in modern humans and has been linked to numerous diseases. Toxic metals found in leukemia patients have recently been linked to chemoresistance and poor survival. To reverse chemoresistance, depletion of metal ions by chelators has been suggested as a possible adjuvant to chemotherapy. However, existing animal models for metal accumulation are largely unsuitable for this type of cancer research. We developed a novel accelerated model for chronic, sub-toxic, multi-metal accumulation in rats, in which a mixture of 11 metals was administered orally, followed by an equilibration period of at least five weeks to allow the metal ions to settle into their target organs in a chronic-like distribution, without overt toxicity. The model was characterized in terms of metal ion levels in urine, feces, serum, and organs. We surveyed seven chelators with different properties, seeking a compound that would specifically remove highly toxic metals, while exerting a minimal effect on essential elements. Our studies pointed to Monoisoamyl-dimercaptosuccinic acid (MiADMSA), an exploratory chelator with promising properties, as the most suitable for this purpose. Different treatment regimens, aimed at optimizing the clinical application of the chelator, were explored and characterized. Repeated monthly cycles of 5 treatments per cycle led to efficient removal of inorganic arsenic, cadmium, vanadium, and cobalt from rat organs. Our study shows that MiADMSA is a promising chelator that may be efficient in treating chronic metal accumulation, and potentially as an adjuvant to chemotherapy.

Graphical abstract

Physiological and metabolic responses of the Pb-tolerant Brassicaceae Hirschfeldia incana to short-term (3 days) and medium-term (15 days) Pb exposure were evaluated. Physiological traits revealed an early and sustained control of oxidative stress. By day 3, non-enzymatic antioxidants and soluble sugars increased to support ROS quenching and promote osmotic adjustment. By day 15, POD activity further increased, while phenolic and soluble sugar contents remained elevated and chl b decreased selectively. Non-targeted metabolomics revealed a stronger response in roots than in shoots, highlighting the organ-specific nature of Pb tolerance in H. incana. Constitutive metabolic features were distinguished from time-dependent induced ones. Roots displayed a constitutive antioxidant defense driven by metabolic diversion from tryptophan and glucosinolates. Over time, this constitutive strategy was strengthened by an expansion of phenolics, particularly ferulic acid and sinapic acid to enhanced cell wall lignification. By day 15, the marked depletion of soluble non-enzymatic antioxidants (ascorbate and glutathione) likely reflected the sustained ROS turnover under elevated H₂O₂ levels. Although shoots accumulated less Pb, they still mounted an antioxidant response centered on anthocyanins and phenolics, along with an increase in small dipeptides, consistent with peptide-mediated nitrogen shuttling and repair. These data provide a comprehensive insight into the overall Pb stress response mechanisms in H. incana. These findings also support the potential use of this species as a model for understanding Pb tolerance and for developing phytoremediation-oriented strategies in contaminated environments.

Iron overload (IO) is a harmful condition in humans that promotes oxidative damage to DNA and lipids. As IO has been associated with the onset of neurodegenerative diseases (NDs), chelation therapy has been extensively used for treating IO and considered potentially suitable for NDs treatment. Desferrioxamine (DFO) presents high affinity and selectivity for iron(III), however, its clinical use as chelator is limited due to its low cell permeability. To circumvent this limitation, synthetic routes and conditions were selected for conjugating DFO to 5-aminolevulinic acid (5-ALA) or γ-aminobutyric acid (GABA), non-proteinogenic amino acids previously reported as permeable to the blood–brain barrier (BBB). Once obtained and purified, the conjugates 5-ALA-DFO and GABA-DFO were characterized by LC/ESI–MS and ¹H and ¹³C NMR. Both exhibited iron binding abilities comparable to that of DFO, displayed identical antioxidant activity, weak interactions with human serum albumin, and were unable to remove iron from transferrin (Tf). Based on DFT calculations, a theoretical model was developed that allows to predict the efficiency of iron chelation with DFO and its conjugates, in good agreement with experimental results. In assays with human colorectal adenocarcinoma (Caco-2) cells, a model for the blood–brain barrier (BBB), both chelators were non-toxic, and unlike DFO or 5-ALA-DFO, GABA-DFO was able to bind intracellular iron. Altogether, these results demonstrate that the chemical conjugation proposed here was highly effective and that GABA-DFO is a promising intracellular iron chelator.

Alzheimer’s disease (AD), a leading cause of dementia, remains incurable, necessitating novel insights into its pathogenesis and therapeutic strategies. Recent studies highlight cuproptosis—a copper (Cu)-dependent mitochondrial cell death pathway—as a critical player in AD progression. Cuproptosis is triggered by Cu overload, which disrupts mitochondrial tricarboxylic acid cycle enzymes, resulting in toxic aggregation of lipoylated proteins and iron-sulfur cluster destabilization. This process exacerbates mitochondrial dysfunction, oxidative stress, and neuronal loss, synergizing with hallmark AD pathologies like Aβ deposition and Tau hyperphosphorylation. Unlike ferroptosis or apoptosis, cuproptosis uniquely involves mitochondrial protein lipoylation and Cu homeostasis imbalance. Therapeutic strategies targeting cuproptosis include Cu chelators, inhibitors of Cu transporters, antioxidants, and gene editing approaches to restore Cu homeostasis or mitigate protein aggregation. Immunotherapy and neuroprotective agents further show promise in alleviating cuproptosis-driven neuroinflammation. Despite preclinical advancements, challenges remain in balancing Cu’s essential roles with therapeutic interventions. This review underscores cuproptosis as a pivotal mechanism in AD and outlines emerging therapeutic avenues, emphasizing the ncessity for precision in targeting Cu dysregulation to halt neurodegeneration.

Metal complexes are well known for their DNA cleavage activity. Copper is a metal that stands out for this purpose because it is able to perform cleavage through oxidative mechanisms using the Haber–Weiss cycle. We report two unprecedented copper(II) complexes (2 and 3) with long-chain ligands and compare the results with those of a previously reported complex (1), which we use as a reference in our studies. They were all properly characterized using a set of physicochemical methods, including elemental analysis, electron paramagnetic resonance, spectroscopic and electrochemical analysis. Density functional theory (DFT) modeling revealed a pseudo-octahedral environment where the ligands are trans to each other. The interaction of 1, 2, and 3 with salmon sperm DNA was monitored spectrophotometrically, and the binding constants (K_b) were 4.24 × 10⁴ L mol⁻¹, 1.92 × 10⁴ L mol⁻¹, and 1.15 × 10⁴ L mol⁻¹, respectively. The interactions were supported by docking studies conducted with the CCDC GOLD® docking suite. Finally, all complexes exhibited DNA binding and cleavage properties, but 2 stood out as the most active one (2, k_obs = 0.88 ± 0.09 h⁻¹ > 1, k_obs = 0.54 ± 0.06 h⁻¹ > 3, k_obs = 0.50 ± 0.03 h⁻¹). These results support the idea that fine-tuning the length of the alkyl chain can enhance DNA-targeting activity and contribute to the development of efficient strategies for catalytic cleavage of nucleic acids.

Hypothyroidism is a common endocrine disorder associated with widespread disturbances in essential and toxic trace elements. This study aimed to evaluate the serum levels of selected trace and toxic elements in Iraqi hypothyroid patients, both newly diagnosed and under levothyroxine therapy, to identify potential metabolic imbalances on trace element homeostasis. A total of 120 participants were enrolled and divided into three groups: healthy controls, untreated hypothyroid patients, and levothyroxine-treated hypothyroid patients. Serum concentrations of (Cu, Zn, Mg, Ni, Mn, Co, Cr, Al, Fe, Pb, and Cd) were measured using atomic absorption spectrophotometry. Results showed that the untreated patients had significantly lower levels of (Zn: 70.3 ± 9.1 vs 101.1 ± 14.6, Mg: 1.09 ± 0.23 vs 1.57 ± 0.21, Mn: 0.018 ± 0.003 vs 0.186 ± 0.028, Cr: 0.138 ± 0.041 vs 0.167 ± 0.024 and Fe: 73.50 ± 14.70 vs 104.13 ± 16.98, respectively, p < 0.05) compared to controls, while levothyroxine therapy restored Cr and Fe only. In contrast, other elements including Cu, Ni, Al, Pb and Cd remained elevated in both treated and untreated patients (p < 0.05). Correlation analyses revealed antagonistic and synergistic relationships among essential and toxic elements, suggesting complex interactions influencing thyroid function. These findings indicate that trace element dysregulation persists despite hormonal therapy and highlight the importance of monitoring both essential and toxic metals to optimize hypothyroidism management and prevent ongoing metabolic disturbances.

Obesity is more prevalent in women worldwide and has been associated with low-grade inflammation, oxidative stress, and alterations in the homeostasis of trace elements, such as zinc (Zn) and copper (Cu). The aim of this study was to evaluate the association between nutritional status and cardiometabolic traits, inflammatory biomarkers, oxidative stress markers, and serum concentrations of Zn and Cu in adult women. In this observational cross-sectional study, anthropometric data and cardiometabolic traits from 123 adult women in Mexico City were analyzed. Inflammatory biomarkers (leptin and resistin) were quantified by enzyme-linked immunosorbent assay (ELISA). Oxidative stress markers were evaluated by serum total antioxidant capacity (sTAC) using the DPPH radical scavenging method (2,2-diphenyl-1-picrylhydrazyl) and lipid peroxidation via thiobarbituric acid reactive substances (TBARS). Serum Zn and Cu concentrations were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Overweight and obesity were associated with increased lipid peroxidation (p = 0.013) and the Cu/Zn ratio (p = 0.021) and negatively associated with sTAC (p = 0.030) and Zn concentrations (p = 0.003). A positive association was observed between serum Cu concentrations and total cholesterol (TC; p = 0.045). Leptin and resistin concentrations were higher in the overweight and obesity groups. In conclusion, our findings suggest that higher body weight in Mexican adult women is associated with a deregulated redox status and trace elements homeostasis, particularly reduced Zn levels and an increased Cu/Zn ratio. Additionally, the observed association between serum Cu concentrations and TC may highlight a potential mechanism linking adiposity, oxidative stress, and lipid metabolism.

Plant Growth Promoting Rhizobacteria (PGPR) offer a cost-effective, eco-friendly solution for Cr(VI) bioremediation. This study evaluates the medicinal plants Justicia adhatoda and Solanum trilobatum as novel candidates for Cr(VI) bioremediation. We investigated the ameliorative effects of two PGPR, Bacillus altitudinis M1 (BaM1) and Bacillus flexus M2 (BfM2), isolated from tannery effluent contaminated soil. Both strains significantly improved plants’ biomass in soil containing 300 mg/kg Cr(VI). Inoculation of the PGPR markedly mitigated physiological stress, significantly lowering concentrations of proline, hydrogen peroxide (H₂O₂), and malondialdehyde (MDA) compared to Cr(VI)-only treatments by enhancing the plants phytostabilization potential.While Cr(VI) stress initially triggered a robust antioxidant response, PGPR application attenuated the oxidative pressure, where superoxide dismutase (SOD) and catalase (CAT) activities decreased by up to 66.74% in S. trilobatum and 56.97% in J. adhatoda, respectively. PGPR application significantly reduced Cr(VI) translocation to aerial tissues of both medicinal species, shifting the plants’ strategy toward superior rhizostabilization. This minimizes metal mobility and supports the long-term bioremediation capacity of the medicinal plant–microbe consortium. Our findings establish this approach as a highly efficient, sustainable, and novel strategy for the restoration of Cr(VI) contaminated industrial environments.

Titanium (Ti-6Al-4 V) alloys are widely utilized in dental and orthopedic implants for their strength, corrosion resistance, and biocompatibility. However, the oral environment’s corrosive conditions can promote ion release, raising concerns regarding potential long-term public health risks. In this investigation, samples of titanium alloy were submerged in artificial saliva for six months to simulate long-term oral exposure. The concentrations of corrosion derived metal ions were subsequently determined using Inductively Coupled Plasma Mass Spectrometry. Cytotoxicity, inflammatory, and apoptotic responses were assessed in fibroblast cell lines. Additionally, an in vivo study in male mice assessed systemic oxidative stress, antioxidant defense mechanisms, and liver and kidney function. Titanium alloy released ions treated cells showed a marked decline in fibroblast viability and a significant elevation (p < 0.05) in pro-apoptotic and inflammatory markers, including Bax, TNF-α, and IL-6, compared with untreated cells. In vivo findings demonstrated significant increases in TBARS and DNA fragmentation, accompanied by a depletion of antioxidant enzymes, particularly in renal tissues. Biochemical evaluation of serum samples demonstrated significant changes in lipid profiles and marked impairments in liver and kidney function. Histopathological assessments confirmed these findings, showing inflammatory infiltration and degenerative changes in hepatic and renal tissues. Overall, ions released from the titanium alloy induced pronounced cytotoxicity accompanied by increased oxidative imbalance and inflammatory reactions, emphasizing the need for developing safer biomaterials and implementing long-term patient monitoring to mitigate chronic complications.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with type 2 diabetes mellitus, which is characterized by hepatic steatosis. Vanadium compounds have the potential to prevent hyperlipidemia. However, whether vanadium compound supplementation could rescue hepatic steatosis in NAFLD remains uncertain. We sought to investigate the molecular mechanisms by which vanadium(IV)-chlorodipicolinate (VOdipic-Cl) ameliorated hepatic steatosis in obesity. The therapeutic effect of VOdipic-Cl was evaluated using high-fat diet (HFD)-induced C57BL/6 mice and palmitic acid/oleic acid (PO)-treated L02 hepatocytes, respectively. Lipidomic analysis, RNA-sequencing (RNA-seq), Western blotting, and molecular dynamics simulation were employed to elucidate the molecular mechanism of VOdipic-Cl in regulating lipid metabolism in liver and hepatocytes. VOdipic-Cl treatment effectively reduced hepatic lipid accumulation and improved hepatic function in HFD-fed mice. Lipidomic analysis showed that the primary differential lipid metabolites were mainly associated with glycerophospholipid metabolism pathway. Transcriptomic analysis revealed that adenosine monophosphate-activated protein kinase (AMPK) signaling pathway was involved in the regulation of hepatic lipid metabolism by VOdipic-Cl treatment. Moreover, VOdipic-Cl-induced AMPK activation significantly restored hepatic mitochondrial homeostasis and reduced lipid accumulation through upregulating transcription factor peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and carnitine palmitoyltransferase 1 (CPT1) in hepatocytes, respectively. Our findings suggest that VOdipic-Cl triggers the activation of AMPK, leading to the upregulation of PGC-1α and CPT1 expression, ultimately improving mitochondrial homeostasis and decreasing lipid accumulation. Collectively, these molecular cascades contribute to the ameliorating effect of VOdipic-Cl on HFD-induced hepatic steatosis. This study also provides evidence supporting the potential utilization of VOdipic-Cl for the treatment of NAFLD.