Biometals最新文献

The substantial anticancer potential of inexpensive trace metal-based coordination compounds has been seen to convey enormous significance in the area of cancer therapy. Herein, the present work portrays the synthesis of four new Cd(II) and Zn(II) complexes of general formula, ([{text{M}}({text{L}}_{{text{R}}}^{{text{p}}} )left( {text{X}} right)_{2} ]), where M = Zn(II) or Cd(II) and X = I⁻ or Cl⁻, encompassing the pincer-shaped pyridylidene amide derivatives of ({text{L}}_{{text{Me }}}^{{text{p}}}) = N²,N⁶-bis(1-methylpyridin-4(1H)-ylidene)pyridine-2,6-dicarboxamide and ({text{L}}_{{{text{Bn}}}}^{{text{p}}}) = N²,N⁶-bis(1-benzylpyridin-4(1H)-ylidene)pyridine-2,6-dicarboxamide. The synthesized drug candidates were characterized through NMR (¹H and ¹³C), FT-IR spectroscopy and elemental analysis. Geometry optimization, frontier orbital analysis and electronic characteristics were investigated by DFT studies. Compounds 1–7 interacted with DNA, showing moderate binding affinity to CT DNA (K_b = 1.8 to 9.4 × 10⁴ M⁻¹) and stabilizing the duplex through mixed binding mechanisms, supported by molecular docking studies. Complexes (4–7) were determined to be stable during the examined time by using electronic spectroscopy and ¹HNMR analysis of their solutions. The MTT assay was used to evaluate the cytotoxicity of ligands and complexes. The Annexin V-FITC apoptosis detection and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were used to assess early apoptosis and DNA fragmentation, respectively. By employing the Caspase-Glo™ assay to investigate pro-apoptotic caspase activation, the fundamental mechanism of DNA fragmentation was further clarified. The in vitro cytotoxicity of the compounds was evaluated against breast cancer cell lines (MCF-7, T47D) and the Vero cell line as a representative of normal cells. Complexes 6 (12.2 ± 0.3 µM) and 7 (10.0 ± 3.6 µM) exhibited remarkable anticancer activity compared to complexes 4 (40.0 ± 0.8 µM), 5 (29.0 ± 2.8 µM), and cisplatin (25.1 ± 1.1 µM) against the T47D cell line. Furthermore, complexes 6 and 7 induced DNA fragmentation through the initiation of early and late apoptosis, accompanied by the activation of apoptotic signaling cascades (caspase-3/7 and caspase-9), thereby confirming apoptosis as the underlying mechanism of cell death in the breast cancer cell line.

Graphical Abstract

Neurodegenerative disorders (NDs), exemplified by Alzheimer’s disease (AD), present a global health challenge driven by oxidative stress, with current therapies hampered by poor blood–brain barrier (BBB) permeability. In this study, green-synthesized rutin hydrate (RH)-capped metallic gold nanoparticles (RH-AuNPs) were developed and, for the first time, evaluated for stability, biocompatibility, and antioxidant potential in SH-SY5Y cells under oxidative stress, compared to conventional gold NPs (AuNPs) and free RH. Nanoparticles (NPs) were characterized using UV–Visible spectroscopy, dynamic light scattering for particle size and distribution and surface charge, Fourier transform infrared spectroscopy (FTIR) and scanning transmission electron microscopy (STEM). Their in chemico antioxidant potential was assessed via DPPH assay, while in vitro biocompatibility was evaluated using WST-1, and cellular antioxidant activity was determined using both plate-based DCF assay, fluorescence DCF microscopy, and MitoSOX microscopy to assess intracellular and mitochondrial ROS. The RH-AuNPs exhibited favourable physicochemical traits (λmax = 523 nm, size = 34.043 ± 0.041 nm, polydispersity index (PDI) = 0.391 ± 0.003, and zetapotential (ZP) = -30.23 ± 0.569 mV) and robust biocompatibility (> 80% cell viability). Their antioxidant activity matched established antioxidants and significantly surpassed conventional AuNPs. Critically, in vitro studies demonstrated RH-AuNPs’ potent antioxidant radical scavenging, outperforming both AuNPs and the RH, thereby inferring their neuroprotective capabilities. RH-AuNPs represent a promising green-synthesized neurotherapeutic platform that combines antioxidant potency, biocompatibility, and ideal characteristics, which would enable downstream potential for effective BBB penetration and neuronal protection against oxidative stress.

Selenium (Se) is an essential metalloid, possessing not only antioxidant but also anti-inflammatory effects. Recent studies have shown that the latter may be mediated by modulation of NLRP3 inflammasome activation, although the exact mechanisms have yet to be fully characterized. Therefore, the objective of this review is to discuss the molecular mechanisms by which Se modulates NLRP3 inflammasome activation and to examine the downstream effects on NLRP3-mediated inflammation and pyroptotic cell death. The selenoproteins S, O, M, W, and especially glutathione peroxidase (GPX) and thioredoxin reductase (TXNRD) are involved in regulation of the NLRP3 inflammasome machinery through modulation of redox homeostasis. In contrast, Se deficiency has been shown to aggravate NLRP3 inflammasome activation induced by lipopolysaccharide (LPS) treatment or exposure to organic pollutant bisphenol A (BPA). In addition to increased reactive oxygen species (ROS) generation, Se deficiency contributes to NLRP3-mediated inflammation and pyroptosis through modulation of non-coding RNA expression. In turn, Se supplementation mitigates NLRP3 inflammasome activation in liver, heart, kidneys, intestine, brain, and certain other tissues induced by LPS exposure, ischemia/reperfusion (I/R), and various xenobiotics including heavy metals and organic pollutants. This effect appears to be mediated by modulation of various components of Toll-like receptor (TLR)/nuclear factor κB (NF-κB)/NRLP3, nuclear factor erythroid 2-related factor 2 (Nrf2)/ROS/NLRP3, thioredoxin-interacting protein (TXNIP)/NLRP3 pathways, and several other mechanisms including modulation of gut microbiota with subsequent reduction of circulating LPS levels. Collectively, these findings demonstrate that the anti-inflammatory and cytoprotective effects of Se supplementation may be mediated by modulation of NLRP3 inflammasome activation.

Structural and quantitative changes in lipid and osmolyte profiles can serve as markers of technogenic stress caused by heavy metal pollution. This study investigates the biochemical responses of common soil filamentous fungi (Alternaria septospora, Cladosporium halotolerans, Fusarium equiseti, Trichoderma harzianum, and Clonostachys farinosa) to copper (Cu) exposure, focusing on changes in lipids (membrane and storage lipids) and specific osmolytes (polyols and certain carbohydrates). Based on effective concentration values, A. septospora and C. farinosa proved to be the most Cu-resistant species. Under Cu stress, we observed an increased phosphatidylcholines/phosphatidylethanolamines (PC/PE) ratio in the melanized A. septospora, C. halotolerans, and the resistant C. farinosa. Conversely, Cu exposure led to an increased proportion of phosphatidic acids in T. harzianum. Changes in osmolyte composition included elevated mannitol levels, alongside reduced levels of low molecular weight polyols (arabitol, erythritol) and carbohydrates, primarily trehalose. The increased PC/PE ratio, elevated mannitol, and reduced low molecular weight polyols may serve as reliable indicators of Cu-induced stress. These findings underscore the pivotal role of lipid and osmolyte remodeling in fungal tolerance to copper stress and suggest their potential utility as biochemical markers for assessing environmental heavy metal contamination and guiding bioremediation strategies.

With aging and environmental pollution, heavy metal exposure has become a growing concern for age-related eye diseases. However, the relationship between heavy metals and age-related macular degeneration (AMD), cataracts, glaucoma, and diabetic retinopathy (DR) remains unclear. This study investigates the association between urinary heavy metals and these eye diseases, focusing on the molecular mechanisms of cadmium (Cd) in driving AMD. Data from the 2005–2008 NHANES (n = 1865) were analyzed using multivariable logistic regression, weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), restricted cubic spline (RCS) modeling, and sensitivity analyses. Potential molecular mechanisms of Cd in AMD were explored via intersection gene screening, protein–protein interaction network construction, and GO/KEGG enrichment analyses. In single-metal exposure models, Cd was significantly associated with AMD (OR = 1.563, 95% CI: 1.177–2.077, P = 0.00205), Co with cataract (OR = 1.386), U with glaucoma (OR = 1.300), and As with DR (OR = 1.214). In the WQS model, only AMD remained significantly associated with the overall metal mixture (OR = 1.89, 95% CI: 1.22–2.91, P = 0.0041). BKMR identified Cd as the most influential contributor to AMD (PIP = 0.523). The exposure–response curve for Cd and AMD demonstrated an upward trend, with the risk of AMD increasing as Cd exposure levels rose. Additionally, the overall metal mixture was positively associated with AMD risk. Subgroup and RCS analyses confirmed the stability of results, with no significant interaction across demographic subgroups. Sensitivity analyses further validated the findings: the highest quartile of Cd exposure was associated with increased AMD risk (OR = 2.45), and a significant dose–response trend was observed (P for trend = 0.0187). The association remained robust after excluding outliers (OR = 1.31, P = 0.0483).Mechanistically, Cd may induce retinal pigment epithelium damage via oxidative stress (SIRT1/TP53 axis), inflammation (TLR4/NF-κB pathway and pro-inflammatory cytokines), dysregulated apoptosis (BCL2/BAX imbalance), and hypoxia-induced metabolic disruption (HIF-1 signaling). Cd is an independent risk factor for AMD, likely acting through multiple toxic pathways. The effects of U, Co, and As may depend on exposure thresholds or confounders. These findings highlight the need for stricter Cd control and targeted antioxidant or anti-inflammatory strategies for age-related eye disease prevention and treatment.

Graphical Abstract

The formation and maintenance of a biological seal between the peri-implant soft tissue and the titanium (Ti) abutment are critical for preventing peri-implant disease and ensuring implant longevity. However, this seal is fragile and prone to breakdown, particularly under inflammatory conditions. This study aimed to investigate the potential of a polyethylene glycol (PEG) coating associated to a bioactive flavonoid naringenin (NA) to enhance human gingival fibroblast (HGF) functions related to biological sealing on Ti surfaces. Initially, the effects of NA (10 µg/mL) on HGF proliferation, adhesion, and collagen synthesis were assessed under tumor necrosis factor alpha (TNF-α)-induced inflammatory challenge. Subsequently, Ti discs were coated with PEG or PEG incorporated with 10 µg/mL (v/v) of NA, and their surface morphology, chemical composition, and NA release profiles were evaluated. HGF responses, including viability, adhesion/spreading, matrix metalloproteinases (MMPs) and collagen production, were analyzed on the coated discs in the presence or absence of TNF-α-challenge. The results demonstrated that NA enhanced critical cellular processes underlying biological seal formation, including cell proliferation, adhesion, and collagen synthesis, while Ti discs were successfully coated with PEG-NA, which enabled rapid NA release. Moreover, the Ti/PEG-NA coating improved HGF viability and collagen synthesis while reducing TNF-α-induced MMP-2 and MMP-9 production. These in vitro findings underscore the potential of the PEG-NA coating to modulate HGF adhesion and metabolism, representing a promising strategy to enhance soft tissue integration and, consequently, long-term implant stability.

Manganese is an essential trace element for the human body, yet its role in heart function remains inadequately understood, this study aimed to reveal the influence of Mn deficiency on the heart, and uncover underlying mechanisms involved. A manganese-deficient diet was provided to weaned mice, to which manganese chloride (MnCl₂) was administered intraperitoneally to correct Mn deficiency. The pathological changes in the heart were evaluated through histological examination. Cardiac oxidative stress levels were assessed using flow cytometry and biochemical assay kits. The adenosine triphosphate (ATP) content and the levels of mitochondrial respiratory chain (MRC) complexes I-IV were measured with biochemical assay kits. Real-time PCR and Western blotting were performed to determine protein expression related to the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Mn deficiency induced significant cardiac structural damage and elevated serum levels of cardiac injury markers. It also promoted oxidative stress and compromised antioxidant defenses. Mitochondrially, Mn deficiency impaired function, evidenced by reduced ATP levels and suppressed activities of MRC complexes I-IV. Crucially, Mn deficiency inhibited the Nrf2 pathway, demonstrated by decreased Nrf2, HO-1, and NQO1 expression and increased Keap1 expression. However, MnCl₂ supplementation significantly improved these alterations. Research results indicated the association of myocardial damage caused by Mn deficiency with mitochondrial dysfunction and oxidative damage, both of which show close correlations with the Nrf2 signaling pathway.

Breast cancer remains one of the most common and lethal malignancies among women worldwide. Although conventional treatment approaches—including surgery, radiotherapy, chemotherapy, and targeted therapy—have achieved substantial progress, clinical outcomes are still severely limited by issues such as drug resistance, recurrence, and metastasis. In this context, metal-based immunotherapy has emerged as a novel and highly promising strategy, gaining increasing attention for its unique advantages in enhancing anti-tumor immune responses and remodeling the tumor immune microenvironment. In recent years, mounting evidence has demonstrated that metal nanoparticles, metal–organic frameworks (MOFs), and metal complexes hold great potential in breast cancer immunotherapy. These agents exert immunotherapeutic effects through mechanisms such as immune activation, modulation of immunosuppressive cells, and synergistic enhancement of immune checkpoint blockade. Despite these encouraging developments, several critical challenges remain, including systemic toxicity, limited clinical translation, and insufficient understanding of their immunomodulatory mechanisms. This review provides a comprehensive summary of recent advances in metal-based immunotherapy for breast cancer, with a particular focus on the applications of metal nanoparticles, metal complexes, and metal-based nanocarriers. The mechanisms of action, therapeutic advantages, and existing limitations are thoroughly discussed, and future directions are proposed to facilitate further research and clinical translation in this emerging field.

Major depressive disorder (MDD) is a prevalent psychiatric condition associated with increased oxidative stress, which may contribute to its pathophysiology. Elevated malondialdehyde (MDA) levels and reduced total antioxidant capacity (TAC) and glutathione peroxidase (GPX) activity have been observed in individuals with MDD. Nano-selenium, a novel formulation with enhanced bioavailability and antioxidant potency compared to conventional selenium, may help modulate these oxidative stress biomarkers. In this randomized, triple-blind, placebo-controlled trial, 50 adults newly diagnosed with MDD received either nano-selenium (55 µg/day) or placebo, both alongside sertraline (50 mg/day), over a 12-week period. A total of 42 participants (21 per group) completed the study. Depressive symptoms were measured using the Hamilton Depression Rating Scale (HDRS), and serum levels of GPX, TAC, and MDA were assessed at baseline and post-intervention. Compared to placebo, nano-selenium significantly reduced depressive symptoms (mean change: −5.09 ± 4.94; P < 0.001) and increased TAC (mean change: 0.03 ± 0.04 mmol/L; P = 0.003) and GPX levels (median change: 9.56 U/L; IQR: −7.86 to 30.31; P = 0.044). While MDA levels decreased significantly in both groups, between-group differences were not statistically significant. These findings suggest that nano-selenium may serve as a safe and effective adjunctive therapy for reducing depressive symptoms and improving antioxidant status in MDD. However, the short duration and modest sample size of this study limit generalizability. Larger, multicenter trials with extended follow-up are recommended to confirm and expand upon these results. This study was approved by the Research Ethics Committee of Iran University of Medical Sciences (IR.IUMS.REC.1402.206; June 13, 2023) and registered with the Iranian Registry of Clinical Trials (IRCT20091114002709N62; July 29, 2023). Written informed consent was obtained from all participants.

Graphical abstract

The chemotaxis response of E. coli to metal cations is less understood than their response to organic molecules. Using dark-field videomicroscopy, E. coli behavior was analyzed in a 17 mm-long microfluidic channel exposed to a Zn(NO₃)₂ chemorepellent gradient, generated by a 250 mM solution placed in a well at the channel extremity, with or without prior Zn²⁺ pre-exposure of the cultures (10 µM). The bacteria exhibited an escape wave away from the zinc source. Compared to unexposed cultures, zinc pre-exposure resulted in a constant and shorter passage time at a given position of the wave peak, despite unchanged growth and swimming speed. The time lag decreased with growth duration. Given the one-dimensional gradient setup, this decrease is associated to a reduced diffusion duration from the Zn²⁺ source. The content of Zn²⁺ in the extracellular medium at the peak of the wave is therefore lower, but allows bacteria to escape more rapidly. These findings suggested an increase in bacterial Zn²⁺ sensitivity. By analogy to Ni²⁺ binding to the cytoplasmic HAMP domain of the Tar receptor, Zn²⁺ likely triggers a chemorepellent response through a cytoplasmic receptor. The activation of this receptor relies on the available zinc pool, which is specifically buffered by substantial other intracellular zinc reservoirs. In this model, saturating the reservoirs in pre-exposed cultures would enable the fastest response time, and a gradual filling of the reservoirs in unexposed cells would reduce a delay in chemotactic escape.