This study investigated whether long-term methylmercury exposure aggravates apical periodontitis in Wistar rats. Thirty-two male rats (90 days old) were randomized into four groups (n = 8): control, methylmercury, apical periodontitis, and methylmercury + apical periodontitis. Methylmercury was administered daily by intragastric gavage (0.04 mg/kg/day) for 60 days, while apical periodontitis was induced on day 32 by pulp exposure to the oral cavity for 28 days. After euthanasia, total mercury levels and systemic oxidative stress markers were analyzed in blood; additionally, mandibles were evaluated for lesion volume and alveolar bone quality using micro-computed tomography and histological analysis. Data were analyzed using the Shapiro–Wilk test, followed by two-way ANOVA and Tukey’s post hoc test (p < 0.05). The methylmercury + apical periodontitis group showed significantly larger periapical lesions and reduced alveolar bone quality compared to non-exposed animals (p < 0.05), with decreased trabecular thickness, lower bone volume/tissue volume ratio, and increased tissue destruction. Moreover, this group exhibited more intense oxidative alterations, including reduced antioxidant defenses (reduced glutathione and total antioxidant capacity equivalent to Trolox) and increased lipid peroxidation. Therefore, under the conditions of the present experimental model, long-term methylmercury exposure preceding and overlapping with apical periodontitis development resulted in increased lesion volume, impaired alveolar bone quality, and more pronounced systemic oxidative alterations, indicating an aggravation of apical periodontitis.
Copper (Cu) is essential to life as an enzymatic cofactor, powering a plethora of biological processes. However, cells teeter on a delicate balance where both too much and too little Cu can lead to dysfunction. These risks are exemplified by Menkes disease patients, where Cu deficiency leads to neurodevelopmental delay and early childhood mortality, and those affected by Wilson's disease, where Cu overload results in liver damage, behavioural changes and movement disorders. Cu is also a major cellular stressor, with roles in many other pathologies including neurodegeneration and cancer. Consequently, cells tightly regulate Cu load by highly conserved import, export, and distribution mechanisms. While these have been well documented, less is known about how cells sense and respond to Cu deviations. This function may lie in the extensive post-translational modifications (PTMs) that control the Cu transport proteins, where a chorus of glycosylation, phosphorylation, and ubiquitination affects their activity, intracellular trafficking, and stability. Cu also affects the machinery that applies these PTMs, providing a potential mechanism by which cells 'sense' Cu levels. This review explores this hypothesis, examining our current knowledge of how PTMs are modulated by Cu, and how they control the responses of the Cu transporters to fluctuating Cu load. Further probing of how cells sense and respond to Cu deviations may aid the pursuit of effective diagnosis and treatment of the many disorders associated with mismanaged Cu levels.
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Trace elements such as selenium (Se) and zinc (Zn) play important roles in the development of hypertension and cardiovascular diseases through direct effects on the vascular system and indirect effects on lipoprotein metabolism. Se and Zn are essential components of the antioxidant defense system that help reduce oxidative stress associated with cardiac disorders. In this study, serum Se and Zn levels were evaluated in patients undergoing coronary artery bypass surgery and compared with those of healthy controls. The study population comprised patients diagnosed with coronary heart disease and a control group of healthy individuals. Serum Zn concentrations were measured using flame atomic absorption spectrometry (AAS), while Se levels were determined by graphite furnace atomic absorption spectrometry (GFAAS). Statistical analysis was performed using analysis of variance (ANOVA), followed by Bonferroni-adjusted pairwise test. The mean preoperative serum Se concentration in patients was 25.49 ± 16.83 µg/L, which increased postoperatively to 31.55 ± 22.19 µg/L and to 40.97 ± 30.17 µg/L pre-discharge. In contrast, the control group had a significantly higher Se level of 70.88 ± 13.18 µg/L. Similarly, Zn levels in patients were 116.53 ± 27.85 µg/L preoperatively, decreased to 88.43 ± 23.32 µg/L postoperatively, and increased to 98.43 ± 21.53 µg/L pre-discharge, while controls had 120.46 ± 17.58 µg/L. Both Se and Zn levels were significantly lower in patients compared to controls (p < 0.0001). Based on these findings, we highlight that low Se and Zn levels are associated with coronary heart disease; therefore, randomized controlled trials are needed to determine whether Se and Zn supplementation under medical supervision provides clinically significant benefits.
Auranofin (AF) is a clinically approved gold(I) complex used for the treatment of rheumatoid arthritis and currently under investigation for drug repurposing in oncology. Its anticancer activity has been mainly associated with the inhibition of thioredoxin reductase (TrxR), an enzyme crucial for the maintenance of the redox balance of cell. Accordingly, this triggered intense research in the development of novel AF-analogues. Herein, a new series of AF-inspired gold(I) complexes (1–4) was designed and synthesized by replacing the thiosugar moiety with ligands targeting the translocator protein (TSPO), a mitochondrial protein overexpressed in several cancers, including ovarian cancer. The new complexes showed strong TrxR inhibition and sub/low-nanomolar TSPO affinity. All compounds exhibited low-micromolar cytotoxicity in ovarian cancer cells, including cisplatin- and AF-resistant variants, with a milder reduction in activity than AF and cisplatin in resistant models. Computational studies indicated that replacement of the thiosugar moiety with TSPO ligands affects the stability of the Au–S and Au–P bonds, leading to a different activation mode compared with AF. In parallel, ICP-AES analysis revealed comparable intracellular gold accumulation for complexes 1–4 and AF, indicating that differences in biological activity are not mainly driven by cellular uptake, but rather by distinct intracellular processing and target engagement. Overall, these findings support the conjugation of the [Au(PEt3)]+ fragment with mitochondria-targeting ligands as a promising strategy for developing multifunctional Au-based complexes.
Exposure to metals is an important cause of anemia. The effects of mixed metal exposure on hemoglobin have been less studied, and the existing research conclusions are inconsistent. Body mass index (BMI) is associated with both metal levels and hemoglobin and may play a mediating role in the association between metals and hemoglobin. This study selected 832 children from the National Health and Nutrition Examination Survey database and further analyzed the association between metals and hemoglobin, an indicator of anemia. We found that zinc (Zn), selenium (Se) and thallium (Tl) were associated with increased hemoglobin levels in children. Copper (Cu), cobalt (Co), and lead (Pb) were associated with decreased hemoglobin levels. Both Bayesian kernel machine regression (BKMR) and Quantile g-computation (Qgcomp) analysis showed that mixed metal exposure levels were positively correlated with hemoglobin levels, and both found that Zn played a major role in this relationship. Stratified analysis showed that mixed metal exposure had a more significant effect on older children and boys. Our analysis suggested BMI as an intermediary in the associations of Pb, Mn, and Tl with hemoglobin, with mediating proportions being 100, 12.6, and 14
Advancements in human activities lead to the widespread release of heavy metals into the environment. Zinc, iron, and nickel are heavy metals (HMs) that are teratogenic, carcinogenic, mutagenic, and endocrine disruptors when present at elevated concentrations. A greenhouse study was conducted in a hydroponic setup to investigate the phytoremediation potential of Chrysopogon zizanioides for the removal of zinc, iron, and nickel from aqueous media. The Vetiver grass was exposed to different concentrations of HMs for 15 days, and the samples were collected on the 3rd, 6th, 9th, 12th, and 15th days. The HM accumulation along with the biochemical variation was analysed to assess the plant stress and tolerance. The Vetiver grass shows an average absorption percentage of 52.91
A series of organotin(IV) complexes (2a–2d) derived from 2-hydroxy-1-naphthaldehyde and pyridoxamine were obtained in good yields via a one-pot strategy. 119Sn NMR confirmed hexacoordinated species in solution, and single-crystal X-ray diffraction of 2d revealed a distorted trigonal–bipyramidal geometry (τ = 0.65) with a C2NO2 donor set. UV–Vis and fluorescence titrations with CT-DNA demonstrated intercalative binding (Kb = 7.66–11.0 × 104 M−1), and isothermal titration calorimetry confirmed spontaneous, exothermic binding to ssDNA, with complex 2c showing stronger affinity than 2b due to combined enthalpic and entropic contributions. All complexes exhibited significantly higher cytotoxicity than cisplatin against MCF-7 and MDA-MB-231 breast cancer cell lines; 2c and 2d were the most potent (IC50 = 0.06–0.26 μM), with 2d showing the best selectivity index (SI = 2.33 for MCF-7). Flow cytometry revealed cell-line-dependent mechanisms: MDA-MB-231 cells underwent cytostatic mitotic blockade, with suppression of S and G2/M phases, whereas MCF-7 cells exhibited features of apoptosis and G1 accumulation. Molecular docking against CDK2/cyclin A showed binding energies of −9.31 to −10.27 kcal/mol, substantially higher than cisplatin (− 4.09 kcal/mol), with 2d displaying the strongest affinity, consistent with its higher biological activity.
Medicinal plants have served as the foundation of healthcare across cultures for centuries, yet their safety is increasingly undermined by heavy metal and pesticide contamination driven by industrial growth, agrochemical misuse and environmental degradation. Despite widespread concern, the field remains fragmented. Contamination data are scattered across taxa and regions. The link between pollutant bioaccumulation and loss of medicinal potency is rarely explored mechanistically. Moreover, human health risk assessments tailored to herbal consumers remain largely absent from regulatory conversations. This review brings these threads together. It traces how heavy metals including Pb, Cd, As, Hg, Cr and Ni along with pesticide residues enter medicinal plants, disrupt their physiology, impair secondary metabolite production and ultimately reach human consumers. "Five widely consumed medicinal genera Ocimum, Mentha, Glycyrrhiza, Catharanthus and Withania are examined as illustrative models". Each offers a distinct perspective on species-specific bioaccumulation patterns, providing a comparative framework rarely found in existing literature. Crucially, this review connects plant level stress responses to real world health outcomes, critically evaluating risk assessment tools such as EDI, HQ, HI and Cancer Risk models within the underexplored context of habitual herbal product use. Detection technologies, regulatory standards and mitigation strategies are assessed with equal rigor. The need for this review is urgent. The absence of unified monitoring frameworks and taxon-specific safety thresholds leaves billions of herbal medicine users inadequately protected. This work provides a consolidated, actionable foundation for researchers, regulators and clinicians working toward safer, evidence-based herbal therapeutics.
Root exudates help plants mitigate heavy metal stress. This study investigated organic acid changes in Medicago sativa L root exudates under lead (Pb) stress and the mechanisms by which exogenous oxalic acid alleviates Pb toxicity. Hydroponic experiments were conducted with Pb concentrations of 0, 5, 50, and 150 mg·L−1. Organic acids were analyzed via High-Performance Liquid Chromatography. Seedling growth, physiological indices (chlorophyll, root viability, malondialdehyde, reactive oxygen species, antioxidant enzymes, osmolytes), and subcellular Pb distribution were measured. Pb stress dose-dependently enhanced oxalic acid secretion. Exogenous oxalic acid (especially 5 mM) significantly increased seed germination, root viability. Compared with Pb alone, 5 mM oxalic acid increased vigor index by 316
To investigate essential metals’ association with anxiety/depression symptoms in the elderly, and explore serum thyroid hormones’ potential mediating role in this association. Study included 416 Shenzhen elderly. The Hamilton Anxiety Scale (HAMA) and the Geriatric Depression Scale (GDS) were utilized to evaluate symptoms of anxiety and depression. Essential metals in urine were measured using inductively coupled plasma mass spectrometry (ICP-MS), while thyroid hormone information was sourced from medical records. Mediation analysis assessed serum thyroid hormones’ mediating effect in the link between essential metals and anxiety/depression. Urinary zinc (Zn) level was negatively linked to the risk of anxiety symptoms [odds ratio (OR) = 0.308, 95
Due to the poor solubility of iron (III) and strong regional differences in terrestrial, riverine or airborne input, iron is a limiting micronutrient in much of the world ocean. Because of increasing living standards and climate change, rainfall is becoming more intermittent, which exacerbates drought conditions. As a result, seawater desalination has a vital and growing role in providing drinking water in many hot and arid regions of the world. Most seawater desalination plants use ferric or ferrate salts as flocculants for removing phyto- and bacterioplankton and suspended organic matter prior to the actual desalination process. Consequently, such seawater desalination plants release large amounts of suspended iron in conjunction with organic matter into coastal waters, with potentially significant consequences for the availability of this micronutrient in coastal marine ecosystems. This review paper provides important background information about the role of iron as a micronutrient in marine ecosystems, its role in the inorganic biochemistry of marine life, as well as key features of its use in seawater desalination, before providing a perspective by exploring potential implications for the physiology and biochemistry of marine life and marine ecosystem functioning.
Notwithstanding progress in chemotherapy, cancer recurrence resulting from metastasis continues to be a significant challenge. Consequently, targeting the epithelial–mesenchymal transition (EMT) has emerged as a viable approach to impede metastasis and enhance therapy success. In colorectal cancer, current initiatives focus on discovering new agents that are both efficacious and less harmful to normal cells. Plant-derived flavonoids and metal-based compounds exhibit significant medicinal potential. This research examined the anticancer efficacy of a Cu(II)-flavonoid complex comprising quercetin and 1,10-phenanthroline ligands in colorectal cancer cell lines HCT-116 and HT-29. The sulforhodamine B (SRB) assay assessed cell viability, yielding IC₅₀ values of 3.19 μM for HCT-116 and 1.81 μM for HT-29 after 48 h, but the individual ligands demonstrated no similar cytotoxicity. The compound exhibited lower cytotoxicity to normal colon cells (CCD-18Co) than toward colorectal cancer cells (HCT-116 and HT-29). Apoptosis induction was verified with Hoechst 33342, Annexin-V-FITC, and propidium Iodide staining, supplemented by M30-antigen ELISA, and further corroborated by the pan-caspase inhibitor Z-VAD-FMK and elevated levels of apoptotic protein markers such as cleaved caspase-8 and parp-1. Flow cytometry revealed G₀/G₁ phase arrest, indicating caspase-dependent apoptotic cell death. The compound also impeded epithelial-mesenchymal transition, as demonstrated by a dose-dependent reduction in migration and invasion in wound healing and Matrigel invasion experiments. Western blot analysis revealed elevated levels of E-cadherin and reduced levels of N-cadherin, vimentin, and snail. The Cu(II)-flavonoid combination demonstrates significant anti-proliferative, pro-apoptotic, and anti-metastatic properties in colorectal cancer cells, while exhibiting lower cytotoxic effects in normal colon cells. This underscores its potential as a viable candidate for additional molecular and in vivo assessment of the complex in colorectal cancer.
Zinc (Zn) is essential for immune cell function, while mesenchymal stem cells (MSCs) exert immunomodulatory effects primarily through the secretion of soluble factors. Considering the ability of MSCs and Zn to modulate the immune and inflammatory systems, this study investigated, in vitro, the effects of Zn supplementation on MSC responses to inflammatory stimuli and the subsequent modulation of macrophages and lymphocytes. Using the C3H10T1/2 line as a MSC model, we determined that 1 µM ZnSO4 enhanced MSC metabolic activity without affecting viability or cell-cycle distribution, whereas higher concentrations reduced cell viability. Under lipopolysaccharide (LPS) stimulation, Zn inhibited NFκB phosphorylation and increased AMPK phosphorylation, indicating anti-inflammatory and adaptive metabolic responses. Similarly, under TNF-α stimulation, Zn also reduced NFκB phosphorylation. Zn supplementation altered MSC secretory profiles, reducing IL-6, IL-10, and nitric oxide (NO) production while increasing TGF-β and prostaglandin E2 (PGE2) levels, indicating that Zn modifies MSC-derived soluble factor production under inflammatory conditions. Conditioned media from Zn-treated MSCs attenuated IL-6 and IL-12 production in macrophages, indicating a reduced pro-inflammatory cytokine response, whereas lymphocyte responses were unaffected. Importantly, Zn modulation of cytokine production was observed under LPS stimulation but not under TNF-α exposure, suggesting that Zn preferentially interferes with signaling pathways triggered by microbial stimuli. Overall, this study provides mechanistic insight into how Zn affects the secretory profile and inflammatory signaling pathways of C3H10T1/2 cells. These findings support further studies in primary MSCs to determine whether Zn supplementation may represent a useful strategy for modulating MSC-mediated immune regulation in therapeutic settings.
Lead is a persistent environmental heavy metal and a potent neurotoxin that continues to threaten global public health despite regulatory restrictions. Chronic and developmental exposure, particularly during early life, leads to persistent structural and functional disturbances in the central nervous system. This review provides a comprehensive analysis of the mechanisms underlying lead-induced neurotoxicity, integrating molecular, cellular, histopathological, and behavioral evidence from both rodent and zebrafish models. The review further summarizes blood–brain barrier disruption, oxidative stress, mitochondrial dysfunction, synaptic impairment, neuroinflammation, apoptosis, neurotransmitter dysregulation, and neurodevelopmental alterations associated with lead exposure in experimental animal models. Lead crosses the blood–brain barrier by mimicking essential divalent cations such as Ca2⁺, Zn2⁺, and Fe2⁺, thereby disrupting calcium signalling and impairing neuronal communication. Once in the brain, lead induces oxidative stress through excessive reactive oxygen species generation, mitochondrial dysfunction, lipid peroxidation, DNA damage, and depletion of antioxidant defenses. Lead also impairs synaptic plasticity by altering NMDA receptor subunit composition, reducing synaptic protein expression, and dysregulating genes involved in neurodevelopment. In parallel, it activates both intrinsic and extrinsic apoptotic pathways and enhances neuroinflammatory signaling through microglial and astrocytic activation, further contributing to neuronal injury. Experimental studies demonstrate hippocampal degeneration, Purkinje cell loss, synaptic ultrastructural alterations, impaired long-term potentiation, and cognitive dysfunction in rodents. Zebrafish models reveal disrupted neurodevelopment, altered expression of gfap, huC, neurexin, and antioxidant-related genes, behavioral abnormalities, and circadian rhythm disturbances. Overall, the study indicates that lead neurotoxicity arises from interconnected mechanisms involving oxidative stress, synaptic dysfunction, apoptosis, mitochondrial impairment, and neuroinflammation. A comprehensive understanding of these pathways is essential for early risk assessment, therapeutic target identification, and the development of effective neuroprotective interventions against lead-induced brain injury.
Pseudomonas aeruginosa employs a repertoire of TonB-dependent transporters (TBDTs) to acquire essential nutrients, such as iron-siderophore complexes, enabling its adaptation to diverse and often hostile environments. While the roles of some TBDTs in virulence and metal acquisition are well-established, many remain poorly characterized, despite their potential contributions to pathogenicity. Using a domain-based detection approach, we show that TBDTs are broadly conserved across diverse P. aeruginosa isolates and remain highly prevalent in multidrug-resistant (MDR) strains, further highlighting their clinical relevance. Notably, these transporters can be exploited as gateways for antibiotic delivery, as exemplified by the siderophore-antibiotic conjugate cefiderocol. To identify metal specificity TBDTs, we combined bioinformatic promoter analysis with fluorescent transcriptional reporters to validate their response to iron and zinc limitation. This approach identified 19 iron-responsive (bringing it to 21 iron-responsive TBDTs with previously published data) and 4 zinc-responsive TBDTs, including transporters with previously unknown substrates, and revealed that promoter-associated regulatory motifs, rather than protein homology, predict metal-specific regulation. Beyond this initial classification, the reporter library serves as a versatile tool for exogenous siderophore detection by monitoring transporter activity in response to their presence. Furthermore, single-cell analysis of TBDT promoter activity during co-culture with an enterobactin-producing Klebsiella pneumoniae strain revealed homogeneous expression of key TBDTs in P. aeruginosa populations, suggesting coordinated metal acquisition strategies under competitive conditions.
Lead (Pb) exposure is still a major public health concern in southern Nigeria’s urban and industrial areas. This study examined the relationship between blood lead levels (BLLs) and biomarkers related to oxido-inflammatory, antioxidant, renal, and apoptosis in adult residents of Port Harcourt, Aba, and Owerri. Atomic absorption spectrophotometry was used in this cross-sectional study to detect lead in venous blood samples. Biomarkers, including malondialdehyde (MDA), heme oxygenase-1 (HO-1), reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), interferon-gamma (IFN-γ), kidney injury molecule-1 (KIM-1), and caspase-3 (CASP3), were quantified using standard spectrophotometric and enzyme-linked immunosorbent assay (ELISA) methods. ANOVA, t-tests, Kruskal–Wallis tests with post-hoc comparisons, and Spearman correlation (α = 0.05) were among the statistical analyses performed. Aba had higher mean BLLs (2.8–4.2 µg/dL), which varied significantly between cities (p < 0.05). BLLs showed significant positive correlations with MDA (ρ = 0.39), HO-1 (ρ = 0.41), IFN-γ (ρ = 0.36), and KIM-1 (ρ = 0.42) (p < 0.05), suggesting increased oxidative stress, inflammatory response, and early renal involvement. The majority of sex-based differences were not statistically significant (p > 0.05), while antioxidant indicators showed inconsistent patterns. In regions with greater BLLs, CASP3 levels were slightly elevated. Measurable changes in oxidative, inflammatory, and renal indicators were linked to elevated BLLs. These results highlight the necessity of more stringent environmental monitoring and focused public health initiatives to lower lead exposure in Nigerian urban populations.
Iron deficiency and iron deficiency anemia (IDA) remain highly prevalent worldwide and are associated with substantial morbidity, especially among infants, children, women of reproductive age, and individuals with chronic diseases. Conventional oral iron salts and food fortification strategies are often limited by gastrointestinal side effects, poor adherence, and unfavorable sensory changes in fortified foods. Nano-enabled iron formulations have been proposed to overcome these limitations by improving bioavailability while preserving tolerability and product quality. This narrative review summarizes in vitro, in vivo and human studies on iron oxide, iron oxyhydroxide, ferric phosphate, ferric pyrophosphate and ferrous sulfate nanoparticles used for oral supplementation or food fortification in the context of iron deficiency and IDA. Overall, nano-sized iron sources tend to show improved iron bioaccessibility and relative bioavailability than their bulk or conventional counterparts, particularly for poorly soluble compounds, and several preparations appear to reduce gastrointestinal intolerance and sensory changes in foods. Early human data suggest that selected nano-iron formulations can approach the hematological efficacy of ferrous sulfate while offering technological advantages for incorporation into complex food matrices. However, most evidence still derives from short-term or preclinical studies, and important gaps remain regarding long-term safety, organ-specific accumulation, effects on the gut microbiota and performance in diverse at-risk populations. Future work should prioritize well-designed clinical trials, standardized physicochemical and toxicological characterization, and clear regulatory guidance to support the safe and effective integration of nano-enabled iron formulations into nutritional strategies against iron deficiency.
Iron is essential for neuronal metabolism, neurotransmitter synthesis, and enzymatic function; however, dysregulated accumulation contributes to oxidative stress and neurodegeneration. The basal ganglia, particularly the globus pallidus, represent a hotspot for iron deposition, yet the precise structural forms and their implications remain incompletely understood. Here, a multimodal approach was applied combining Raman microspectroscopy, light microscopy, transmission (TEM) and scanning electron microscopy coupled with energy-dispersive X-ray analysis (SEM–EDX) to characterise iron-rich deposits in post-mortem human globus pallidus. Tissue samples from six individuals without neurological disease were examined. Perls’ staining revealed iron-positive, spherical inclusions 10–20 µm in diameter. Raman spectroscopy revealed bands at 268–278, 490, 526, and 603 cm−1, as well as broader signals at 1259–1349 cm−1, consistent with magnetite, maghemite, hematite, and ferritin-like structures. Additional vibrations in the 682–1532 cm−1 range indicated interactions with organic matrices, such as protein or lipid components. SEM–EDX identified both regular and irregular iron-rich particles with multielemental composition, including C, O, Al, Si, P, S, Ca, Cr, and Ni, in addition to Fe. TEM examination showed the micrometre-sized particles of hematite and aggregation of ferrihydrite. These findings suggest that iron deposits in the globus pallidus comprise heterogeneous mixtures of oxides and hydroxides with variable crystallinity. Depending on their crystallinity and surface reactivity, such phases may represent a potential pool of redox-active iron; however, the present study did not assess markers of oxidative stress, and their physiological versus pathological significance remains to be established.
Trace metal ions regulate enzymatic catalysis, redox homeostasis, and xenobiotic metabolism across biological systems. This article examines the role of metal ions in governing sesquiterpene biosynthesis and redox signalling in Santalum album from a bioinorganic perspective. Current evidence in this review indicates that the formation of α- and β-santalol depends on magnesium-coordinated terpene synthases and iron-containing cytochrome P450 monooxygenases. In these systems, Mg2⁺ stabilizes diphosphate leaving groups during carbocation formation, while heme-bound Fe mediates oxygen activation and regioselective hydroxylation. Variations in Mg2⁺ and Fe availability may influence metabolic flux through the mevalonate pathway and alter essential oil composition. In addition, trace metals including Fe, Zn, Cu, Se, and Mg regulate antioxidant defence systems, mitochondrial respiration, apoptosis signalling, and inflammatory pathways that intersect with reported biological effects of santalol. Toxic elements such as Pb and Cd can disrupt metalloprotein function and are subject to regulatory limits under ICH Q3D guidelines. Analytical approaches including ICP-MS and laser ablation ICP-MS provide quantitative and spatial insight into elemental distribution in plant tissues. Integration of metallomic data with biochemical and molecular evidence offers a framework for understanding metal-dependent regulation of plant secondary metabolism.
