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![Schematic presentation of the stimuli that induce MT and the downstream effects of MT overexpression. MT can be activated by a variety of stimuli, including metal ions, cytokines, growth factors, oxidative stress and radiation. Downstream effects of MT overexpression are modulation of transcription of both tumor suppressor protein p53 and nuclear transcription factor NF- κ B. Another downstream effect of MT overexpression is free radical scavenging activity. All these downstream MT effects influence cell survival, cell growth, drug resistance and differentiation. Adopted and modified according to [107].](publication/236055564/figure/fig3/AS:299359037083656@1448384164572/Schematic-presentation-of-the-stimuli-that-induce-MT-and-the-downstream-effects-of-MT.png)
Schematic presentation of the stimuli that induce MT and the downstream effects of MT overexpression. MT can be activated by a variety of stimuli, including metal ions, cytokines, growth factors, oxidative stress and radiation. Downstream effects of MT overexpression are modulation of transcription of both tumor suppressor protein p53 and nuclear transcription factor NF- κ B. Another downstream effect of MT overexpression is free radical scavenging activity. All these downstream MT effects influence cell survival, cell growth, drug resistance and differentiation. Adopted and modified according to [107].
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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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... stress conditions, zinc release from MT occurs when the levels of nitric oxide or reactive oxygen species increase [83–86]. Treatment of lung fibroblasts with the NO donor, S-nitrosocysteine, resulted in an increase in intracellular labile zinc, as detected by a zinc-specific fluorophore, Zinquin, in wild-type, but not MT-null, fibroblasts [84]. Additional data obtained in sheep pulmonary artery endothelial cells suggested a role for the apo form of MT, thionein (T), as a Zn 2+ -binding protein in intact cells [84]. Collectively, these data showed that MT mediates NO-induced changes in intracellular Zn(II). Furthermore, in another study, Pearce et al. have shown that, in cultured pulmonary artery endothelial cells, a MT-green fluorescent fusion protein (FRET-MT) undergoes conformational changes in the presence of NO [87]. These conformational changes are consistent with the release of metals from the thiolate clusters of MT [88–90]. MT can be activated by a variety of stimuli, including metal ions, cytokines and growth factors [91–93], as shown in Figure 3. In a number of experiments, the synthesis of MT was shown to be increased by several-fold during oxidative stress [94,95] to protect the cells against cytotoxicity [96,97], radiation and DNA damage [98–100]. The stimuli that induce MT and the downstream effects of MT overexpression are summarized in Figure 3. A lot of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder [91]. MT expression in tumor tissues is mainly correlated with the proliferative capacity of tumor cells [101]. However, there are few exceptional cases, like downregulation of MT-I and -II in hepatocellular carcinoma [102] and also a reduced level of intracellular zinc, resulting in the increase of granulocytes, but a decreased number of lymphocytes [103]. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. Downregulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes, such as the p53 tumor suppressor gene. Mao et al. [104] identified a member of the MT family, termed MT1M , which is expressed in various normal tissues, with the highest level in the liver. However, MT1M expression markedly decreased in human hepatocellular carcinoma specimens. A methylation profiling analysis indicated that the MT1M promoter is methylated in the majority of hepatocellular carcinoma tumors examined. Moreover, restored expression of MT1M in the hepatocellular carcinoma cell line, Hep3B, which lacks endogenous MT1M expression, suppressed cell growth in vitro and in vivo and augmented apoptosis induced by tumor necrosis factor [104]. Similarly, Yan et al. [105] observed downregulation of MT1F by loss of heterozygosity in colon cancer tissue. Furthermore, exogenous MT1F expression increased colon cancer cell line (RKO) apoptosis and inhibited RKO cell migration, invasion and adhesion, as well as in vivo tumorigenicity. From this study, it could be concluded that MT1F is a putative tumor suppressor gene in colon carcinogenesis [105]. In another study, Faller et al. [106] observed DNA methylation in MT1E in malignant melanoma, which suggests that MT1E is also a potential tumor suppressor ...
Context 2
... stress conditions, zinc release from MT occurs when the levels of nitric oxide or reactive oxygen species increase [83–86]. Treatment of lung fibroblasts with the NO donor, S-nitrosocysteine, resulted in an increase in intracellular labile zinc, as detected by a zinc-specific fluorophore, Zinquin, in wild-type, but not MT-null, fibroblasts [84]. Additional data obtained in sheep pulmonary artery endothelial cells suggested a role for the apo form of MT, thionein (T), as a Zn 2+ -binding protein in intact cells [84]. Collectively, these data showed that MT mediates NO-induced changes in intracellular Zn(II). Furthermore, in another study, Pearce et al. have shown that, in cultured pulmonary artery endothelial cells, a MT-green fluorescent fusion protein (FRET-MT) undergoes conformational changes in the presence of NO [87]. These conformational changes are consistent with the release of metals from the thiolate clusters of MT [88–90]. MT can be activated by a variety of stimuli, including metal ions, cytokines and growth factors [91–93], as shown in Figure 3. In a number of experiments, the synthesis of MT was shown to be increased by several-fold during oxidative stress [94,95] to protect the cells against cytotoxicity [96,97], radiation and DNA damage [98–100]. The stimuli that induce MT and the downstream effects of MT overexpression are summarized in Figure 3. A lot of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder [91]. MT expression in tumor tissues is mainly correlated with the proliferative capacity of tumor cells [101]. However, there are few exceptional cases, like downregulation of MT-I and -II in hepatocellular carcinoma [102] and also a reduced level of intracellular zinc, resulting in the increase of granulocytes, but a decreased number of lymphocytes [103]. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. Downregulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes, such as the p53 tumor suppressor gene. Mao et al. [104] identified a member of the MT family, termed MT1M , which is expressed in various normal tissues, with the highest level in the liver. However, MT1M expression markedly decreased in human hepatocellular carcinoma specimens. A methylation profiling analysis indicated that the MT1M promoter is methylated in the majority of hepatocellular carcinoma tumors examined. Moreover, restored expression of MT1M in the hepatocellular carcinoma cell line, Hep3B, which lacks endogenous MT1M expression, suppressed cell growth in vitro and in vivo and augmented apoptosis induced by tumor necrosis factor [104]. Similarly, Yan et al. [105] observed downregulation of MT1F by loss of heterozygosity in colon cancer tissue. Furthermore, exogenous MT1F expression increased colon cancer cell line (RKO) apoptosis and inhibited RKO cell migration, invasion and adhesion, as well as in vivo tumorigenicity. From this study, it could be concluded that MT1F is a putative tumor suppressor gene in colon carcinogenesis [105]. In another study, Faller et al. [106] observed DNA methylation in MT1E in malignant melanoma, which suggests that MT1E is also a potential tumor suppressor ...
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... On the other hand, metallothioneins are small, cysteine-rich proteins that bind heavy metals and exert key cell protective actions against oxidative stress. In the liver homeostasis, metallothionein 1 (Mt1) and metallothionein 3 (Mt3) have an important control of the hepatic metal detoxification [54]. Both genes are downregulated at 8:00 h and Mt3 at 11:00 h in TRF, which could contribute to an oxidized environment early before food access. ...
Daytime-restricted feeding (TRF) exerts outstanding effects on circadian physiology, nutrient utilization, and energy metabolism. Limiting feeding access to two hours during the daytime (12:00–14:00 h) for three weeks promotes food-anticipatory activity (FAA). FAA encompasses not only behaviors related to meal expectations but also includes diurnal fluctuations in liver metabolic responses, including distinct redox handling. Hepatic microarray profiles of genes associated with redox response processes were analyzed at three crucial time points: at the beginning of the light period or before FAA (08:00 h), during the expression of FAA (11:00 h), and after feeding (14:00 h). Data on fasting and nutrient processing were integrated, whereas circadian implications were extrapolated by comparing the TRF transcriptional output with a one-day fasting group. Transcripts of redox reactions, such as reactive oxygen species (ROS) generation, antioxidant defenses, NAD+/NADH equilibrium, and glutathione, hydrogen peroxide (H2O2), arginine, nitric oxide (NO), and hydrogen sulfide (H2S) metabolism, were analyzed. Results showed a decline in antioxidant defenses at 08:00 h, followed by a burst of pro-oxidant reactions, preparation of glutathione metabolism factors, and a tendency to decrease H2O2 and increase NO and H2S during the FAA. Most of the findings observed during the FAA were absent in response to one-day fasting. Hence, TRF involves concerted and sequential responses in liver pro-oxidant and antioxidant reactions, facilitating a redox-related circadian control that optimizes the metabolic utilization of nutrients, which differs from a response to a simple fast-feed cycle.
... 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.
... Zinc plays a crucial role in functioning of MTs owing to their close association. Zinc stimulates increased expression of Zn-binding MTs via metal regulatory transcription factor 1 (MTF-1) that specifically responds to elevated levels of Zn (Dumanović et al. 2021;Ruttkay-Nedecky et al. 2013). During Magnaporthe grisea infection, MTs-1 and four pathogenesis-linked genes were strongly induced in rice to provide defense against the pathogen (Kim et al. 2001). ...
Zinc (Zn) is an essential nutrient for plants as well as animals. It is required for diverse critical plant physiological and metabolic processes, for instance, photosynthesis, chlorophyll synthesis, carbohydrate metabolism, and starch and sucrose synthesis. Zinc plays a key role in gene expression and regulation, protein synthesis, nitrogen fixation, and plant defense against numerous biotic and abiotic stressors. Even though the food availability has increased, its nutritional characteristics have decreased. In this context, the significance of micronutrients, including Zn, in dietary food has become a subject of universal interest having health-related issues. There are several important animal and human physiological processes involving Zn. Zn deficiency leads to loss of several millions of dollars every year in the form of additional medical expenses and claims lives of millions of people, mostly affecting kids. It is believed that around 17% of the human population on earth are facing the threat of Zn deficiency. Zinc deficit is linked to difficulty in pregnancy, under-developed growth, early deaths, immune system impairment, and several neurobehavioral ailments in human beings. The present chapter highlights the significance of Zn in several metabolic processes of plants and animals (including humans) in order to understand the problem of Zn paucity with respect to its influence on crop growing and human well-being, taking into account the available literature.
... 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.
