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Overview of metallothionein (MT) gene regulation and function. The MT promoter has many response elements that upregulate transcription. These include the following: (1) metal response elements (MRE), which are activated by the metal-responsive transcription factor (MTF-1) after zinc occupancy, which is a function of the dietary zinc supply; (2) glucocorticoid response elements (GRE); (3) elements activated by STAT (signal transducers and activators of transcription) proteins through cytokine signaling; and 4) the antioxidant (or electrophile) response element (ARE), activated in response to redox status. Methylation may downregulate expression in some tumor cells. Cellular zinc pools are influenced by dietary zinc intake and zinc transporter activity and serve as the source of zinc bound to MT. Zinc bound to MT exhibits high thermodynamic stability. Apo-MT (thionein) and Zn 7 -MT (all coordination sites occupied) may serve to 

Overview of metallothionein (MT) gene regulation and function. The MT promoter has many response elements that upregulate transcription. These include the following: (1) metal response elements (MRE), which are activated by the metal-responsive transcription factor (MTF-1) after zinc occupancy, which is a function of the dietary zinc supply; (2) glucocorticoid response elements (GRE); (3) elements activated by STAT (signal transducers and activators of transcription) proteins through cytokine signaling; and 4) the antioxidant (or electrophile) response element (ARE), activated in response to redox status. Methylation may downregulate expression in some tumor cells. Cellular zinc pools are influenced by dietary zinc intake and zinc transporter activity and serve as the source of zinc bound to MT. Zinc bound to MT exhibits high thermodynamic stability. Apo-MT (thionein) and Zn 7 -MT (all coordination sites occupied) may serve to 

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Free radicals are chemical particles containing one or more unpaired electrons, which may be part of the molecule. They cause the molecule to become highly reactive. The free radicals are also known to play a dual role in biological systems, as they can be either beneficial or harmful for living systems. It is clear that there are numerous mechanis...

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... gene expression and activity of proteins, such as metalloproteins and metal-dependent transcription factors, as shown in Figure 2 and discussed in the following papers [79,80]. The binding of zinc to MTs is thermodynamically stable, which makes MTs an ideal zinc reservoir in vivo . The question is how MTs make zinc available for other molecules, including transcription factors and metalloproteins. Maret et al. [76] showed that there is fast zinc exchange between MT isoforms 1 and 2 and also between MT2 and the zinc cluster in the Gal4 transcription factor [76]. Moreover, Jacob et al. found zinc transfer between MT and the apo-forms of zinc proteins E. coli alkaline phosphatase and bovine carboxypeptidase A [80]. Reduced glutathione (GSH) and glutathione disulfide (GSSG) are critical modulators of both the rate of zinc transfer and the ultimate number of zinc atoms transferred [79,81,82]. GSH inhibits zinc release in the absence of GSSG, indicating that MT is stabilized at relatively high cellular GSH concentrations. The presence of GSSG results in zinc release ...

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... It is known that their reactivity can be significantly changed in the presence of vitamins C and E [36]. Selenium compounds can reduce peroxides and have a great influence on the release of zinc by metallothionein [22,34,37]. However, the lowest OS value was calculated for the sample with BiVits® ACTIVA Recovery, which possesses the strongest antioxidant effect. ...
... In addition, due to their high thiol content, these proteins were involved in quenching hydroxyl (OH . ) and superoxide radicals (O 2 -. ) [107]. Under our experimental conditions, the significant increase of MT levels in PEN-exposed clams reflected probably an adaptive approach adopted by R. decussates to reduce this fungicide. ...
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The baleful effect of penconazole fungicide on clam Ruditapes decussatus gills: fatty acids composition, redox status and histological features, Chemistry and Ecology, ABSTRACT Penconazole is a widely used fungicide to control critical fungal diseases of crops. This study aimed to elucidate the effects of PEN exposure, for 96 h, on fatty acids composition, redox status, and histopathological injuries in Ruditapes decussatus gills under different concentrations (4, 40, and 400 µg/L). Compared to the control group, our results showed an increase in saturated and monounsaturated fatty acids. However, the levels of polyunsaturated fatty acids were diminished, mainly those of eicosapentaenoic, docosahexaenoic, and arachidonic acids upon exposure to PEN. Depletion of PUFAs' levels, particularly the long-chain and double-bond-rich ones, can affect membrane fluidity, and disrupt membranes' biological functions, such as cell signalling, membrane transport, and protection against other environmental stresses. Herein, PEN uptake also results in enhanced oxidative stress by increasing levels of the ferric-reducing antioxidant power, hydrogen peroxidase, malondialdehyde, advanced oxidation protein products, and protein carbonyls. Moreover, changes in both enzymatic and non-enzymatic antioxidants were noticeable, indicating the stimulation of the antioxidant defense system. Adverse histological alterations were detected in PEN-treated specimens' gill tissues, supporting our biochemical findings. Overall, in the current study, redox status was related to changes in fatty acid composition, contributing to a better understanding of the PEN-toxicity mechanism in clams.
... The main difference in elemental composition between diesel PM and brake-wear PM measured here is the enrichment of metals in the latter. Consistent with this difference, we demonstrated that all brake-wear PM types could upregulate the expression of genes encoding metallothioneins, cysteine-rich metal-chelating proteins [49]. Metallothioneins are canonically described as zinc-binding proteins [50], which play an important role in regulating the intracellular free concentration of zinc [49]. ...
... Consistent with this difference, we demonstrated that all brake-wear PM types could upregulate the expression of genes encoding metallothioneins, cysteine-rich metal-chelating proteins [49]. Metallothioneins are canonically described as zinc-binding proteins [50], which play an important role in regulating the intracellular free concentration of zinc [49]. When intracellular free zinc concentrations increase, zinc binds to metal regulatory transcription factor 1 (MTF1), promoting nuclear translocation and binding to and Oxidative Stress Score. ...
... In C and D, a Pearson's correlation was used. In F and G, and two-tailed paired t-test was used promoter sequences on metallothionein genes, increasing their expression to maintain zinc homeostasis [49]. In this context, it is notable that SemiMxCu-derived brakewear PM contained more zinc than any of the other vehicle-derived PM types examined, however, NAO and ceramic brake-wear PM still induced the highest magnitude response in metallothionein gene expression. ...
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... For instance, z plays a key role in antioxidant defense systems, DNA repair, and enzyme functio However, Cd disrupts Zn homeostasis in astrocytes by competing with Zn for sites, thereby displacing Zn and perturbing its normal functions [204,205]. This eve weakens the antioxidant defense of glial cells and causes CNS disease susceptibilit Also, considering that Zn is responsible for the functioning of metallothioneins (a that catalyzes the detoxification of metals against oxidative stress), the Cd-indu homeostasis imbalance can further lead to uncontrolled cellular damage that is imp in many neurodegenerative diseases [207,208]. ...
... This eventually weakens the antioxidant defense of glial cells and causes CNS disease susceptibility [206]. Also, considering that Zn is responsible for the functioning of metallothioneins (a protein that catalyzes the detoxification of metals against oxidative stress), the Cd-induced Zn homeostasis imbalance can further lead to uncontrolled cellular damage that is implicated in many neurodegenerative diseases [207,208]. ...
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Citation: Ijomone, O.K.; Ukwubile, I.I.; Aneke, V.O.; Olajide, T.S.; Inyang, H.O.; Omotosho, O.I.; Oyerinde, T.O.; Anadu, V.E.; Gbayisomore, T.J.; Okeowo, O.M.; et al. Glial Perturbation in Metal Neurotoxicity: Implications for Brain Disorders. Neuroglia 2025, 6, 4. https://doi. Abstract: Overexposure of humans to heavy metals and essential metals poses a significant risk for the development of neurological and neurodevelopmental disorders. The mechanisms through which these metals exert their effects include the generation of reactive oxygen species, mitochondrial dysfunction, activation of inflammatory pathways, and disruption of cellular signaling. The function of glial cells in brain development and in the maintenance of homeostasis cannot be overlooked. The glial cells are particularly susceptible to metal-induced neurotoxicity. Accumulation of metals in the brain promotes microglial activation, triggering inflammatory responses that can coincide with other mechanisms of neurotoxicity, inducing alteration in synaptic transmission, cognitive deficit, and neuronal damage. In this review, we highlighted the role of glial dysfunction in some selected neurodegenerative diseases and neurodevelopmental disorders. We further dive into how exposure to metals such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, and lead affect the functions of the microglia, astrocytes, and oligodendrocytes and the mechanisms through which they exert the effects on the brain in relation to some selected neurodegenerative diseases and neurodevelopmental disorders. Potential therapeutic interventions such as the use of new and improved chelating agents and antioxidant therapies might be a significant approach to alleviating these metal-induced glial perturbations.
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... Given the robust recapitulation of shMT2A sensitivity using encorafenib, it was of interest to evaluate the mechanistic connection to metallothioneins. Metallothioneins regulate reactive oxygen species (ROS) through regulation of zinc-finger transcription factors [32], mobilization of zinc [33], and contributing to the redox cycle of glutathione [34], the primary cytoplasmic antioxidant. ROS signals through the BRAF/CRAF-MEK-MAPK pathway, often upstream of RAF through RAS activation [35]. ...
... Scavenging ROS with NAC abolished the shMT2A selectivity of encorafenib and reduced cell loss ( Figure 7C). zinc-finger transcription factors [32], mobilization of zinc [33], and contributing to the redox cycle of glutathione [34], the primary cytoplasmic antioxidant. ROS signals through the BRAF/CRAF-MEK-MAPK pathway, often upstream of RAF through RAS activation [35]. ...
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... These results are consistent with previous studies which showed that metallothionine proteins are involved in oxidative stress and inhibition of metallothionine proteins can increase cancer cell growth by regulating zinc-finger proteins. [25,26] To validate the RNA-seq results, we performed a subsequent RT-qPCR study in BxPC3 cells treated with DMSO, PK9328, or MS172 at different concentrations (Figure 5e). We observed a concentration-dependent upregulation of MT1X and MT1N genes and a simultaneous downregulation of ZNF391 and ZNF778 genes at 4 h time point induced by MS172, while PK9328 treatment led to no changes compared to the DMSO control. ...
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