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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
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![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...
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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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... MTs bind metals such as cadmium, zinc, and copper through metal-thiolate clusters [11,15,16]. This interaction results in the formation of metal-protein complexes that are stored in vacuoles and eventually expelled from the cell in non-toxic form [17][18][19]. Metal ions can trigger oxidative stress by generating reactive oxygen species (ROS). MTs function as antioxidants, effectively scavenging these harmful radicals at a rate significantly higher than glutathione [18], thus mitigating oxidative damage. ...
... Additionally, MTs can also be induced by a wide variety of stimuli or environmental stressors, including temperature shocks (heat or cold), pH fluctuations, hormones, cytokines, starvation, and various chemicals. Consequently, MTs are considered multistress proteins [13,18] The MT superfamily classification system recognizes ciliate MTs as family 7, further divided into subfamilies 7a (CdMTs) and 7b (CuMTs) [20,21]. These subfamilies are distinguished by their metal induction patterns (Cd/Zn or Cu) and cysteine residue clustering patterns [22]. ...
Metallothioneins (MTs) are low molecular weight cysteine rich proteins involved in detoxification of heavy metals. They are synthesized in response to metal exposure and can bind to various metals, thus reducing their toxicity and providing protection against oxidative stress. MTs are considered to be efficient bioremediators of heavy metal contaminated industrial wastewater. The present study was aimed at further enhancing the metal binding capacity of a cadmium metallothionein protein PMCd1, reported some time back from this laboratory in protozoan ciliate Paramecium, to equip them with more efficient system to deal with metal contaminated water bodies. Three additional cysteine residues were introduced at three different places of the protein by site directed mutagenesis, viz. S20C, R180C and Y185C. The wild type and each mutant of PMCd1 were expressed in E. coli BL21 cells. Metal uptake ability of each transformant was determined in the presence of 1 and 2mM Cd²⁺ in the medium. The three mutants showed enhanced metal uptake compared to the wild PMCd1 which underscored the role of additional cysteines in enhanced metal binding ability. Amongst the mutants, the genetically modified organism with S20C mutation exhibited 9.1 fold more metal uptake compared to the control ciliate. This mutant has great potential to clean the cadmium- contaminated water.
... Findings of the laboratory challenge also suggest that the oxidative stress response in Pacific oysters may be at least partially shaped by culture treatment. Temperature and culture treatment had a significant interactive effect on the expression of MT, a metal-binding protein that participates in a range of protective stress responses (Ruttkay-Nedecky et al. 2013), and Gpx, an antioxidant enzyme that combats ROS accumulation and is thus associated with aerobic recovery in bivalves (Pannunzio and Storey 1998;Trevisan et al. 2014). ...
In order to investigate how shellfish culture in the intertidal zone may serve as a means of conferring resilience prior to subtidal deployment for commercial grow-out, a common garden experiment was carried out with juvenile Pacific oysters. Individuals were cultured under intertidal or subtidal conditions for one year, following which intertidal animals were transplanted to the subtidal site and both treatment groups were cultured together under subtidal conditions for a period of five months. During that time, microbiome and gene expression were tracked in relation to a marine heatwave event. Multivariate analyses of samples indicated a significant effect of time on gene expression, but no significant effect of culture treatment prior to and during the heatwave. Significant differences in the expression of oxidative stress and immune response genes in post-heatwave samples in comparison to pre-heatwave and heatwave samples, and between culture treatment groups post-heatwave, were detected. Results also indicated significant differences in microbiome according to culture treatment and timepoint, with increased richness observed in intertidally-cultured oysters and over time. Similarly, while the overall composition of the oyster microbiome did not vary between culture treatments, changes were observed over time. At the end of the field trial, a laboratory-based temperature and Vibrio challenge experiment was conducted to compare genomic responses of both culture treatment groups following 24-h exposure to coinciding acute warming and pathogen stressor conditions. A significant interactive effect of temperature and culture treatment on gene expression was observed, further suggesting that stress response may be influenced by prior culture treatment.
... The different directions of changes may be connected with the roles of the groups of proteins in the organism. The protective molecules bind metals (Mts), participate in defensive red-ox processes (both), or play their role as chaperon proteins (HSP70) (Roesijadi, 1996;Ruttkay-Nedecky et al., 2013;Rosenzweig et al., 2019;Zhang et al., 2022). Usually, protective protein levels are up-regulated under stress conditions (Farahani et al., 2020;Fisker al., 2013;Zhou et al., 2020). ...
Airborne road and abrasive car parts particles penetrate into aquatic and soil environments, but also, settling on
vegetation along highways, enter trophic chains as a result of consumption by herbivorous invertebrates. The
effects of this exposure are poorly recognized. The study aimed to assess the toxicity of two traffic-connected
materials: tread rubber (TR) particles and environmentally relevant field-collected road dust (RD), to the Tenebrio molitor larvae under laboratory conditions using a set of protective (heat shock protein – HSP70, metallothionein – Mts levels), immunity (lysozyme – Lys, defensin – Def levels) and digestive (protease, amylase, and
celulase activities) biomarkers. ELISA assay was used for protein levels, while fluorimetric and spectrophotometric methods were used for enzymatic activity studies. RD and TR particles were characterized by SEM/EDS
techniques. The representative TR particle sizes were within the range of 31 µm and 274 µm. For the RD, the size
of the particles were 153–587 µm. Fat body HSP70 levels were, on average, twice lower in groups exposed to RD
particles. For fat body Mts, RD and TR caused the decrease while in the gut, the effect depended on the particle
type. Gut lysozyme levels increased for both particles while in fat body this effect was made by RD. Digestive
enzyme activity did not reflect exposure to TR and RD particles. RD induced changes in more experimental
groups than TR. This may be due to the greater complexity of their composition. Further studies focusing on
material type, concentration, exposure duration, and particle size are necessary to understand the effects of
traffic-connected material on terrestrial herbivores.
... Metallothioneins (MTs) are low-molecular-weight (6-7 kDa) metal-binding proteins [1,2] that have many essential biological functions [3][4][5]. MTs are significantly involved in the control and detoxification of heavy metals. Moreover, they have a protective role in oxidative stress, scavenging free radicals [6]. ...
Metallothioneins (MTs) are low-molecular-weight metal-binding proteins potentially involved in the detoxification of heavy metals, protection against oxidative stress, and other biological processes. This study examined progesterone’s influence on Mt gene expression in rat adipose tissue. Wistar rats (females and males) received 100 mg of progesterone per rat. MT mRNA and protein levels were quantified by real-time PCR and Western blotting methods. Using radioimmunoassay, the serum progesterone level was measured. In this study, progesterone administration to female rats led to a 2.5-fold increase in serum progesterone concentration and significant increases in MT-1, MT-2A mRNA, and protein levels in inguinal WAT (WATi), compared to untreated female rats. RU 486 (progesterone receptor antagonist) abolished progesterone’s influence on Mt-1 and Mt-2A gene expression in female WATi. Progesterone administration did not alter the level of Mt-3 gene expression in WATi or Mt-1 and Mt-2A in retroperitoneal WAT or brown adipose tissue in female rats.
... Metallothioneins are a family of small (~6 kDa) proteins containing stretches of 20 cysteine residues, which allow them to bind ions of heavy metals (gold, silver, cadmium, etc.) [54,55]. Metallothioneins have been found in different organisms [56]; they are involved in protection against the toxic effects of heavy metal salts [57] and oxidative stress [58]. ...
Electron microscopy (EM) is one of the most efficient methods for studying the fine structure of cells with a resolution thousands of times higher than that of visible light microscopy. The most advanced implementation of electron microscopy in biology is EM tomography of samples stabilized by freezing without water crystallization (cryoET). By circumventing the drawbacks of chemical fixation and dehydration, this technique allows investigating cellular structures in three dimensions at the molecular level, down to resolving individual proteins and their subdomains. However, the problem of efficient identification and localization of objects of interest has not yet been solved, thus limiting the range of targets to easily recognizable or abundant subcellular components. Labeling techniques provide the only way for locating the subject of investigation in microscopic images. CryoET imposes conflicting demands on the labeling system, including the need to introduce into a living cell the particles composed of substances foreign to the cellular chemistry that have to bind to the molecule of interest without disrupting its vital functions and physiology of the cell. This review examines both established and prospective methods for selective labeling of proteins and subcellular structures aimed to enable their localization in cryoET images.
... We also detected increased expression of sirtuin 2 (Sirt2), a fatty-acid oxidation sensitive enzyme that regulates NAD+ availability, for treated MuSCs when compared to controls ( Fig. 4H) (45,46). Conversely, upregulated genes in untreated cells included metallothioneins 1 and 2 (Mt1, Mt2), markers of oxidative stress, and Rock2, a negative regulator of mitophagy (47,48). GO Term enrichment analysis showed that treatment reduced apoptotic pathways, cell cycle entry, and TOR signaling (Supp. ...
Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.
... 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.
