Figure 2 - available via license: Creative Commons Attribution 3.0 Unported
Content may be subject to copyright.
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
Source publication
![Table 1 . Summary of reactive oxygen and nitrogen species [10,11].](publication/236055564/figure/tbl1/AS:670524560646157@1536876921566/Summary-of-reactive-oxygen-and-nitrogen-species-10-11_Q320.jpg)
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...
Context in source publication
Context 1
... 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 ...
Similar publications
Apoptosis, also known as programmed cell death is a highly regulated and fundamental process found in all multicellular organisms. It is not only implicated in regulatory mechanisms of cells, but has been attributed to a number of diseases, like inflammation, malignancy, autoimmunity and neuro-degeneration. A variability of pollutants can persuade...
Parenthood is a fundamental feature of all known life. However, infertility has been recognized as a public health issue worldwide. But even when the offspring are conceived, in utero problems can lead to immediate (abortion), early (birth), and late (adulthood) consequences. One of the most studied factors is stress. However, stress response is, p...
In the present work, Petunia × hybrida leaf discs maintained on regeneration medium for 8 days were used to assess the effects of genotoxic stress induced by in vitro culture. The investigation was carried out by comparing the response of intact leaves excised from Petunia × hybrida plantlets grown in vitro and the regenerating leaf discs. In situ...
Citations
... 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. ...
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. ...
Background
Airborne fine particulate matter with diameter < 2.5 μm (PM2.5), can reach the alveolar regions of the lungs, and is associated with over 4 million premature deaths per year worldwide. However, the source-specific consequences of PM2.5 exposure remain poorly understood. A major, but unregulated source is car brake wear, which exhaust emission reduction measures have not diminished.
Methods
We used an interdisciplinary approach to investigate the consequences of brake-wear PM2.5 exposure upon lung alveolar cellular homeostasis using diesel exhaust PM as a comparator. This involved RNA-Seq to analyse global transcriptomic changes, metabolic analyses to investigate glycolytic reprogramming, mass spectrometry to determine PM composition, and reporter assays to provide mechanistic insight into differential effects.
Results
We identified brake-wear PM from copper-enriched non-asbestos organic, and ceramic brake pads as inducing the greatest oxidative stress, inflammation, and pseudohypoxic HIF activation (a pathway implicated in diseases associated with air pollution exposure, including cancer, and pulmonary fibrosis), as well as perturbation of metabolism, and metal homeostasis compared with brake wear PM from low- or semi-metallic pads, and also, importantly, diesel exhaust PM. Compositional and metal chelator analyses identified that differential effects were driven by copper.
Conclusions
We demonstrate here that brake-wear PM may perturb cellular homeostasis more than diesel exhaust PM. Our findings demonstrate the potential differences in effects, not only for non-exhaust vs exhaust PM, but also amongst different sources of non-exhaust PM. This has implications for our understanding of the potential health effects of road vehicle-associated PM. More broadly, our findings illustrate the importance of PM composition on potential health effects, highlighting the need for targeted legislation to protect public health.
... More specifically, genes encoding Metallothioneins (MT1E, MT2A, and MT1X) were among the top six genes that significantly upregulated following FOS upregulation (FDR < 1e-50) ( Fig. 3i and Supplementary Data 1). Metallothioneins have been wellknown for their antioxidant and antiapoptotic effects, and their role in T2D has gained increasing attention in recent years [34][35][36] . A previous study also reported the function of FOS and JUND in preventing cell death from oxidative stress 37 , consistent with regX's interpretations (Table 1 and Fig. 3f, g). ...
Cells are regulated at multiple levels, from regulations of individual genes to interactions across multiple genes. Some recent neural network models can connect molecular changes to cellular phenotypes, but their design lacks modeling of regulatory mechanisms, limiting the decoding of regulations behind key cellular events, such as cell state transitions. Here, we present regX, a deep neural network incorporating both gene-level regulation and gene-gene interaction mechanisms, which enables prioritizing potential driver regulators of cell state transitions and providing mechanistic interpretations. Applied to single-cell multi-omics data on type 2 diabetes and hair follicle development, regX reliably prioritizes key transcription factors and candidate cis-regulatory elements that drive cell state transitions. Some regulators reveal potential new therapeutic targets, drug repurposing possibilities, and putative causal single nucleotide polymorphisms. This method to analyze single-cell multi-omics data demonstrates how the interpretable design of neural networks can better decode biological systems.
... 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]. ...
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.
... 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]. ...
... 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]. ...
Background/Objectives: All 11 metallothionein protein-coding genes are located on human chromosome 16q13. It is unique among human genetics to have an entire pathway’s genes clustered in a short chromosomal region. Since solid tumors, particularly high-grade serous ovarian cancer (HGSC), exhibit high rates of monoallelic aneuploidy, this region is commonly lost. Studies have not yet been performed to determine what vulnerability may be created in cancer cells with low metallothionein expression. Here, a screen of FDA-approved cancer small molecule drugs for those best targeting low metallothionein ovarian cancer was completed. Methods: Screening methods were tested and compared using vehicle-treated negative controls and cadmium chloride, a positive control for cell loss selective for low metallothionein cells. CAOV3 cells, which are unique in their expression of only two metallothionein isoforms, were used, with or without shRNA knockdown of the predominantly expressed MT2A gene. A library of FDA-approved molecules was then screened. Results: The optimal assay utilized Hoechst 33342 nuclear staining and mechanized fluorescent microscope counting of cell content. Encorafenib, an RAF inhibitor, was identified as the most selective for enhanced cytotoxicity in MT2A knockdown cells compared to scrambled controls. Conclusions: The nuclear stain Hoechst 33342, assessed by fluorescence microscopy, provides a low variance, moderate throughput platform for cancer cell loss screens. Low metallothionein ovarian cancer cells exhibit a vulnerability to the RAF inhibitor encorafenib.
... 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. ...
Pharmacological reactivation of the tumor suppressor p53 remains a key challenge for the treatment of cancer. Acetylation Targeting Chimera (AceTAC), a novel technology is previously reported that hijacks lysine acetyltransferases p300/CBP to acetylate the p53Y220C mutant. However, p300/CBP are the only acetyltransferases harnessed for AceTAC development to date. In this study, it is demonstrated for the first time that the TAF1 acetyltransferase can be recruited to acetylate p53Y220C. A novel TAF1‐recruiting AceTAC, MS172 is discovered, which effectively acetylates p53Y220C lysine 382 in a concentration‐, time‐ and TAF1‐dependent manner via inducing the ternary complex formation between p53Y220C and TAF1. Notably, MS172 suppresses the proliferation in multiple p53Y220C‐harboring cancer cell lines more potently than the previously reported p300/CBP‐recruiting p53Y220C AceTAC MS78 with little toxicity in p53 WT and normal cells. Additionally, MS172 is bioavailable in mice and suitable for in vivo efficacy studies. Lastly, novel upregulation of metallothionine proteins by MS172‐induced p53Y220C acetylation is discovered using RNA‐seq and RT‐qPCR studies. This work demonstrates that TAF1 can be harnessed for AceTAC development and expands the very limited repertoire of the acetyltransferases that can be leveraged for developing AceTACs, thus advancing the targeted protein acetylation field.
... Metallothioneins, on the other hand, are small cysteine-rich proteins that play a crucial role in Cd detoxification. Metallothioneins scavenge Cd ions and mitigate oxidative damage by serving as sacrificial targets for ROS (Ruttkay-Nedecky et al. 2013). Dynamic changes in the synthesis and accumulation of phytochelatins and metallothioneins reflect the adaptive responses of cereal crops to Cd stress and their ability to maintain cellular integrity under adverse conditions (Sharma et al. 2015). ...
Heavy metal cadmium (Cd) is hazardous and naturally occurs in the environment. It is also produced by various anthropogenic activities and is a contaminant. Since food is the primary source of Cd consumption for the non-smoking population, soil pollution has an impact on human health. Cd poisoning in crops can be caused by disruptions in the uptake and transport of mineral nutrients and disruptions in plant metabolism, which can impede plant development and evolution. Nonetheless, plants possess ways to withstand Cd, such as limited absorption of cadmium, reduced translocation from the root to the shoot, heightened activity of antioxidant enzymes and elevated phytochelatin synthesis. There are various molecular, biochemical, metabolic, genetic and exogenous factors that crops can employ to mitigate either the uptake of Cd or enhance their tolerance levels during severe Cd stress. In this chapter, we have intricately discussed the toxic effects of Cd on some of the most staple cereal crops prevalent in Indian subcontinent and other parts of Asia, as well as the different types of mitigation strategies used by them and from outside sources (exogenous agents), including the examples of natural hyperaccumulators used extensively for bioremediation purposes. The ecological significance of Cd stress in multidisciplinary research and crucial remediation techniques to address Cd contamination in agricultural soil will be addressed in this chapter.
... Evaluation of antioxidant, apoptotic, and sphingolipid pathway genes ( Figure 6) and selective proteins (Figure 7) immediately after light damage provides insights into the impact of light and L-Cycloserine treatment on these pathways. Light-induced stress conditions (VLD) significantly upregulate the expression of Fosl (p < 0.05), Mt2 (p < 0.01), and Lcn2 (p < 0.05), which are all associated with antioxidant and/or apoptotic pathways [58][59][60] (Figure 6). However, the precise mechanisms behind these actions and the exact role of ceramide in these processes require further experimentation. ...
Retinal degenerative diseases lead to irreversible vision loss due to photoreceptor cell death, driven by complex genetic and environmental factors. Ceramide, a sphingolipid metabolite, emerges as a critical mediator in the apoptotic cascade associated with retinal degeneration. Our previous work demonstrated L-Cycloserine’s ability to protect photoreceptor-derived cells from oxidative stress by inhibiting the de novo ceramide pathway and thus prompting further investigation on its effect in the in vivo retina. This study investigates the potential of L-Cycloserine to protect albino BALB/c mice against light-induced retinal degeneration (LIRD). L-Cycloserine, in an optimal dose, administered systemically 30 min before LIRD, was found to prevent photoreceptor cell death significantly from light-induced degeneration. We further determined the retinal bioavailability and pharmacokinetic behavior of L-Cycloserine, its effect on sphingolipid profile, expression of sphingolipid biosynthetic, and cell death-promoting genes and proteins from the retina to understand the underlying mechanisms. This study lays the groundwork for further preclinical and clinical investigations into L-Cycloserine’s potential as a novel therapeutic in treating retinal degenerative diseases.
