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1
Martinez-Finley, Ebany J., e Michael Aschner. "Revelations from the NematodeCaenorhabditis eleganson the Complex Interplay of Metal Toxicological Mechanisms". Journal of Toxicology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/895236.
Abstract (sommario):
Metals have been definitively linked to a number of disease states. Due to the widespread existence of metals in our environment from both natural and anthropogenic sources, understanding the mechanisms of their cellular detoxification is of upmost importance. Organisms have evolved cellular detoxification systems including glutathione, metallothioneins, pumps and transporters, and heat shock proteins to regulate intracellular metal levels. The model organism,Caenorhabditis elegans(C. elegans), contains these systems and provides several advantages for deciphering the mechanisms of metal detoxification. This review provides a brief summary of contemporary literature on the various mechanisms involved in the cellular detoxification of metals, specifically, antimony, arsenic, cadmium, copper, manganese, mercury, and depleted uranium using theC. elegansmodel system for investigation and analysis.
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Hall, J. L. "Cellular mechanisms for heavy metal detoxification and tolerance". Journal of Experimental Botany 53, n. 366 (1 gennaio 2002): 1–11. http://dx.doi.org/10.1093/jexbot/53.366.1.
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Hall, J. L. "Cellular mechanisms for heavy metal detoxification and tolerance". Journal of Experimental Botany 53, n. 366 (1 gennaio 2002): 1–11. http://dx.doi.org/10.1093/jxb/53.366.1.
4
Storz, Peter, Heike Döppler e Alex Toker. "Protein Kinase D Mediates Mitochondrion-to-Nucleus Signaling and Detoxification from Mitochondrial Reactive Oxygen Species". Molecular and Cellular Biology 25, n. 19 (1 ottobre 2005): 8520–30. http://dx.doi.org/10.1128/mcb.25.19.8520-8530.2005.
Abstract (sommario):
ABSTRACT Efficient elimination of mitochondrial reactive oxygen species (mROS) correlates with increased cellular survival and organism life span. Detoxification of mitochondrial ROS is regulated by induction of the nuclear SOD2 gene, which encodes the manganese-dependent superoxide dismutase (MnSOD). However, the mechanisms by which mitochondrial oxidative stress activates cellular signaling pathways leading to induction of nuclear genes are not known. Here we demonstrate that release of mROS activates a signal relay pathway in which the serine/threonine protein kinase D (PKD) activates the NF-κB transcription factor, leading to induction of SOD2. Conversely, the FOXO3a transcription factor is dispensable for mROS-induced SOD2 induction. PKD-mediated MnSOD expression promotes increased survival of cells upon release of mROS, suggesting that mitochondrion-to-nucleus signaling is necessary for efficient detoxification mechanisms and cellular viability.
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Sabbatino, Francesco, Valeria Conti, Luigi Liguori, Giovanna Polcaro, Graziamaria Corbi, Valentina Manzo, Vincenzo Tortora et al. "Molecules and Mechanisms to Overcome Oxidative Stress Inducing Cardiovascular Disease in Cancer Patients". Life 11, n. 2 (30 gennaio 2021): 105. http://dx.doi.org/10.3390/life11020105.
Abstract (sommario):
Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells. ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities. In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems. In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death. In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease. Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease. Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments.
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Black, William C., Trey K. Snell, Karla Saavedra-Rodriguez, Rebekah C. Kading e Corey L. Campbell. "From Global to Local—New Insights into Features of Pyrethroid Detoxification in Vector Mosquitoes". Insects 12, n. 4 (24 marzo 2021): 276. http://dx.doi.org/10.3390/insects12040276.
Abstract (sommario):
The threat of mosquito-borne diseases continues to be a problem for public health in subtropical and tropical regions of the world; in response, there has been increased use of adulticidal insecticides, such as pyrethroids, in human habitation areas over the last thirty years. As a result, the prevalence of pyrethroid-resistant genetic markers in natural mosquito populations has increased at an alarming rate. This review details recent advances in the understanding of specific mechanisms associated with pyrethroid resistance, with emphasis on features of insecticide detoxification and the interdependence of multiple cellular pathways. Together, these advances add important context to the understanding of the processes that are selected in resistant mosquitoes. Specifically, before pyrethroids bind to their targets on motoneurons, they must first permeate the outer cuticle and diffuse to inner tissues. Resistant mosquitoes have evolved detoxification mechanisms that rely on cytochrome P450s (CYP), esterases, carboxyesterases, and other oxidation/reduction (redox) components to effectively detoxify pyrethroids to nontoxic breakdown products that are then excreted. Enhanced resistance mechanisms have evolved to include alteration of gene copy number, transcriptional and post-transcriptional regulation of gene expression, as well as changes to cellular signaling mechanisms. Here, we outline the variety of ways in which detoxification has been selected in various mosquito populations, as well as key gene categories involved. Pathways associated with potential new genes of interest are proposed. Consideration of multiple cellular pathways could provide opportunities for development of new insecticides.
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Perelman, Alexander, Avraham Uzan, Dalia Hacohen e Rakefet Schwarz. "Oxidative Stress in Synechococcus sp. Strain PCC 7942: Various Mechanisms for H2O2 Detoxification with Different Physiological Roles". Journal of Bacteriology 185, n. 12 (15 giugno 2003): 3654–60. http://dx.doi.org/10.1128/jb.185.12.3654-3660.2003.
Abstract (sommario):
ABSTRACT This study focuses on the mechanisms for hydrogen peroxide detoxification in Synechococcus sp. strain PCC 7942. To gain better understanding of the role of different routes of hydrogen peroxide detoxification, we inactivated tplA (thioredoxin-peroxidase-like), which we recently identified. In addition, we inactivated the gene encoding catalase-peroxidase and examined the ability to detoxify H2O2 and to survive oxidative stress in both of the single mutants and in the double mutant. Surprisingly, we observed that the double mutant survived H2O2 concentrations that the single catalase-peroxidase mutant could not tolerate. This phenotype correlated with an increased ability of the double mutant to detoxify externally added H2O2 compared to the catalase-peroxidase mutant. Therefore, our studies suggested the existence of a hydrogen peroxide detoxification activity in addition to catalase-peroxidase and thioredoxin-peroxidase. The rate of detoxification of externally added H2O2 was similar in the wild-type and the TplA mutant cells, suggesting that, under these conditions, catalase-peroxidase activity was essential for this process and TplA was dispensable. However, during excessive radiation, conditions under which the cell might experience oxidative stress, TplA appears to be essential for growth, and cells lacking it cannot compete with the wild-type strain. Overall, these studies suggested different physiological roles for various cellular hydrogen peroxide detoxification mechanisms in Synechococcus sp. strain PCC 7942.
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Zbieralski, Kacper, Jacek Staszewski, Julia Konczak, Natalia Lazarewicz, Malgorzata Nowicka-Kazmierczak, Donata Wawrzycka e Ewa Maciaszczyk-Dziubinska. "Multilevel Regulation of Membrane Proteins in Response to Metal and Metalloid Stress: A Lesson from Yeast". International Journal of Molecular Sciences 25, n. 8 (18 aprile 2024): 4450. http://dx.doi.org/10.3390/ijms25084450.
Abstract (sommario):
In the face of flourishing industrialization and global trade, heavy metal and metalloid contamination of the environment is a growing concern throughout the world. The widespread presence of highly toxic compounds of arsenic, antimony, and cadmium in nature poses a particular threat to human health. Prolonged exposure to these toxins has been associated with severe human diseases, including cancer, diabetes, and neurodegenerative disorders. These toxins are known to induce analogous cellular stresses, such as DNA damage, disturbance of redox homeostasis, and proteotoxicity. To overcome these threats and improve or devise treatment methods, it is crucial to understand the mechanisms of cellular detoxification in metal and metalloid stress. Membrane proteins are key cellular components involved in the uptake, vacuolar/lysosomal sequestration, and efflux of these compounds; thus, deciphering the multilevel regulation of these proteins is of the utmost importance. In this review, we summarize data on the mechanisms of arsenic, antimony, and cadmium detoxification in the context of membrane proteome. We used yeast Saccharomyces cerevisiae as a eukaryotic model to elucidate the complex mechanisms of the production, regulation, and degradation of selected membrane transporters under metal(loid)-induced stress conditions. Additionally, we present data on orthologues membrane proteins involved in metal(loid)-associated diseases in humans.
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Preziosi, Morgan, e Satdarshan Monga. "Update on the Mechanisms of Liver Regeneration". Seminars in Liver Disease 37, n. 02 (maggio 2017): 141–51. http://dx.doi.org/10.1055/s-0037-1601351.
Abstract (sommario):
AbstractLiver possesses many critical functions such as synthesis, detoxification, and metabolism. It continually receives nutrient-rich blood from gut, which incidentally is also toxin-rich. That may be why liver is uniquely bestowed with a capacity to regenerate. A commonly studied procedure to understand the cellular and molecular basis of liver regeneration is that of surgical resection. Removal of two-thirds of the liver in rodents or patients instigates alterations in hepatic homeostasis, which are sensed by the deficient organ to drive the restoration process. Although the exact mechanisms that initiate regeneration are unknown, alterations in hemodynamics and metabolism have been suspected as important effectors. Key signaling pathways are activated that drive cell proliferation in various hepatic cell types through autocrine and paracrine mechanisms. Once the prehepatectomy mass is regained, the process of regeneration is adequately terminated. This review highlights recent discoveries in the cellular and molecular basis of liver regeneration.
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Kushwaha, Anamika, Radha Rani, Sanjay Kumar e Aishvarya Gautam. "Heavy metal detoxification and tolerance mechanisms in plants: Implications for phytoremediation". Environmental Reviews 24, n. 1 (marzo 2016): 39–51. http://dx.doi.org/10.1139/er-2015-0010.
Abstract (sommario):
Heavy metals, such as cobalt, copper, manganese, molybdenum, and zinc, are essential in trace amounts for growth by plants and other living organisms. However, in excessive amounts these heavy metals have deleterious effects. Like other organisms, plants possess a variety of detoxification mechanisms to counter the harmful effects of heavy metals. These include the restriction of heavy metals by mycorrhizal association, binding with plant cell wall and root excretions, metal efflux from the plasma membrane, metal chelation by phytochelatins and metallothioneins, and compartmentalization within the vacuole. Phytoremediation is an emerging technology that uses plants and their associated rhizospheric microorganisms to remove pollutants from contaminated sites. This technology is inexpensive, efficient, and ecofriendly. This review focuses on potential cellular and molecular adaptations by plants that are necessary to tolerate heavy metal stress.
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De Francisco, Patricia, Ana Martín-González, Daniel Rodriguez-Martín e Silvia Díaz. "Interactions with Arsenic: Mechanisms of Toxicity and Cellular Resistance in Eukaryotic Microorganisms". International Journal of Environmental Research and Public Health 18, n. 22 (21 novembre 2021): 12226. http://dx.doi.org/10.3390/ijerph182212226.
Abstract (sommario):
Arsenic (As) is quite an abundant metalloid, with ancient origin and ubiquitous distribution, which represents a severe environmental risk and a global problem for public health. Microbial exposure to As compounds in the environment has happened since the beginning of time. Selective pressure has induced the evolution of various genetic systems conferring useful capacities in many microorganisms to detoxify and even use arsenic, as an energy source. This review summarizes the microbial impact of the As biogeochemical cycle. Moreover, the poorly known adverse effects of this element on eukaryotic microbes, as well as the As uptake and detoxification mechanisms developed by yeast and protists, are discussed. Finally, an outlook of As microbial remediation makes evident the knowledge gaps and the necessity of new approaches to mitigate this environmental challenge.
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Genath, Antonia, Hannes Petruschke, Martin von Bergen e Ralf Einspanier. "Influence of formic acid treatment on the proteome of the ectoparasite Varroa destructor". PLOS ONE 16, n. 10 (26 ottobre 2021): e0258845. http://dx.doi.org/10.1371/journal.pone.0258845.
Abstract (sommario):
The ectoparasite Varroa destructor Anderson and Trueman is the most important parasites of the western honey bee, Apis mellifera L. The most widely currently used treatment uses formic acid (FA), but the understanding of its effects on V. destructor is limited. In order to understand the mechanism of action of FA, its effect on Varroa mites was investigated using proteomic analysis by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). V. destructor was collected from honey bee colonies with natural mite infestation before and 24 h after the initiation of FA treatment and subjected to proteome analysis. A total of 2637 proteins were identified. Quantitative analysis of differentially expressed candidate proteins (fold change ≥ 1.5; p ≤ 0.05) revealed 205 differentially expressed proteins: 91 were induced and 114 repressed in the FA-treated group compared to the untreated control group. Impaired protein synthesis accompanied by increased protein and amino acid degradation suggest an imbalance in proteostasis. Signs of oxidative stress included significant dysregulation of candidate proteins of mitochondrial cellular respiration, increased endocytosis, and induction of heat shock proteins. Furthermore, an increased concentration of several candidate proteins associated with detoxification was observed. These results suggest dysregulated cellular respiration triggered by FA treatment as well as an increase in cellular defense mechanisms, including induced heat shock proteins and detoxification enzymes.
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Basu, Alakananda, e Soumya Krishnamurthy. "Cellular Responses to Cisplatin-Induced DNA Damage". Journal of Nucleic Acids 2010 (2010): 1–16. http://dx.doi.org/10.4061/2010/201367.
Abstract (sommario):
Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.
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Klimova, Nina, Adam Fearnow e Tibor Kristian. "Role of NAD+—Modulated Mitochondrial Free Radical Generation in Mechanisms of Acute Brain Injury". Brain Sciences 10, n. 7 (14 luglio 2020): 449. http://dx.doi.org/10.3390/brainsci10070449.
Abstract (sommario):
It is commonly accepted that mitochondria represent a major source of free radicals following acute brain injury or during the progression of neurodegenerative diseases. The levels of reactive oxygen species (ROS) in cells are determined by two opposing mechanisms—the one that produces free radicals and the cellular antioxidant system that eliminates ROS. Thus, the balance between the rate of ROS production and the efficiency of the cellular detoxification process determines the levels of harmful reactive oxygen species. Consequently, increase in free radical levels can be a result of higher rates of ROS production or due to the inhibition of the enzymes that participate in the antioxidant mechanisms. The enzymes’ activity can be modulated by post-translational modifications that are commonly altered under pathologic conditions. In this review we will discuss the mechanisms of mitochondrial free radical production following ischemic insult, mechanisms that protect mitochondria against free radical damage, and the impact of post-ischemic nicotinamide adenine mononucleotide (NAD+) catabolism on mitochondrial protein acetylation that affects ROS generation and mitochondrial dynamics. We propose a mechanism of mitochondrial free radical generation due to a compromised mitochondrial antioxidant system caused by intra-mitochondrial NAD+ depletion. Finally, the interplay between different mechanisms of mitochondrial ROS generation and potential therapeutic approaches are reviewed.
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Meng, Xiaoqian, Jun Zhou e Na Sui. "Mechanisms of salt tolerance in halophytes: current understanding and recent advances". Open Life Sciences 13, n. 1 (18 maggio 2018): 149–54. http://dx.doi.org/10.1515/biol-2018-0020.
Abstract (sommario):
AbstractHalophytes are plants that exhibit high salt tolerance, allowing them to survive and thrive under extremely saline conditions. The study of halophytes advances our understanding about the important adaptations that are required for survival in high salinity conditions, including secretion of salt through the salt glands, regulation of cellular ion homeostasis and osmotic pressure, detoxification of reactive oxygen species, and alterations in membrane composition. To explore the mechanisms that contribute to tolerance to salt stress, salt-responsive genes have been isolated from halophytes and expressed in non-salt tolerant plants using targeted transgenic technologies. In this review, we discuss the mechanisms that underpin salt tolerance in different halophytes.
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Sauer, Martin, Sandra Doß, Johannes Ehler, Thomas Mencke e Nana-Maria Wagner. "Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?" BioMed Research International 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/6130725.
Abstract (sommario):
Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability.Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for2×72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey’s test.Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P<0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (allP<0.001). Comparable effects were obtained employing L929 fibroblasts.Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro.Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.
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Vojvodić, Snežana, Marina Stanić, Bernd Zechmann, Tanja Dučić, Milan Žižić, Milena Dimitrijević, Jelena Danilović Luković, Milica R. Milenković, Jon K. Pittman e Ivan Spasojević. "Mechanisms of detoxification of high copper concentrations by the microalga Chlorella sorokiniana". Biochemical Journal 477, n. 19 (5 ottobre 2020): 3729–41. http://dx.doi.org/10.1042/bcj20200600.
Abstract (sommario):
Microalgae have evolved mechanisms to respond to changes in copper ion availability, which are very important for normal cellular function, to tolerate metal pollution of aquatic ecosystems, and for modulation of copper bioavailability and toxicity to other organisms. Knowledge and application of these mechanisms will benefit the use of microalgae in wastewater processing and biomass production, and the use of copper compounds in the suppression of harmful algal blooms. Here, using electron microscopy, synchrotron radiation-based Fourier transform infrared spectroscopy, electron paramagnetic resonance spectroscopy, and X-ray absorption fine structure spectroscopy, we show that the microalga Chlorella sorokiniana responds promptly to Cu2+ at high non-toxic concentration, by mucilage release, alterations in the architecture of the outer cell wall layer and lipid structures, and polyphosphate accumulation within mucilage matrix. The main route of copper detoxification is by Cu2+ coordination to polyphosphates in penta-coordinated geometry. The sequestrated Cu2+ was accessible and could be released by extracellular chelating agents. Finally, the reduction in Cu2+ to Cu1+ appears also to take place. These findings reveal the biochemical basis of the capacity of microalgae to adapt to high external copper concentrations and to serve as both, sinks and pools of environmental copper.
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Ducic, Tanja, e Andrea Polle. "Transport and detoxification of manganese and copper in plants". Brazilian Journal of Plant Physiology 17, n. 1 (marzo 2005): 103–12. http://dx.doi.org/10.1590/s1677-04202005000100009.
Abstract (sommario):
Heavy metals like Mn and Cu, though essential for normal plant growth and development, can be toxic when present in excess in the environment. For normal plant growth maintenance of metal homeostasis is important. Excess uptake of redox active elements causes oxidative destruction. Thus, uptake, transport and distribution within the plant must be strongly controlled. Regulation includes precisely targeted transport from the macro-level of the tissue to the micro-level of the cell and organelles. Membrane transport systems play very important roles in metal trafficking. This review provides a broad overview of the long distance and cellular transport as well as detoxification and homeostasis mechanisms of Mn and Cu, which are essential micronutrients but extremely toxic at elevated concentrations.
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Reddy, Narsa M., Steven R. Kleeberger, Masayuki Yamamoto, Thomas W. Kensler, Catherine Scollick, Shyam Biswal e Sekhar P. Reddy. "Genetic dissection of the Nrf2-dependent redox signaling-regulated transcriptional programs of cell proliferation and cytoprotection". Physiological Genomics 32, n. 1 (dicembre 2007): 74–81. http://dx.doi.org/10.1152/physiolgenomics.00126.2007.
Abstract (sommario):
The beta zipper (bZip) transcription factor, nuclear factor erythroid 2, like 2 (Nrf2), acting via an antioxidant/electrophile response element, regulates the expression of several antioxidant enzymes and maintains cellular redox homeostasis. Nrf2 deficiency diminishes pulmonary expression of several antioxidant enzymes, rendering them highly susceptible to various mouse models of prooxidant-induced lung injury. We recently demonstrated that Nrf2 deficiency impairs primary cultured pulmonary epithelial cell proliferation and greatly enhances sensitivity to prooxidant-induced cell death. Glutathione (GSH) supplementation rescued cells from these defects associated with Nrf2 deficiency. To further delineate the mechanisms by which Nrf2, via redox signaling, regulates cellular protection and proliferation, we compared the global expression profiling of Nrf2-deficient cells with and without GSH supplementation. We found that GSH regulates the expression of various networks of transcriptional programs including 1) several antioxidant enzymes involved in cellular detoxification of reactive oxygen species and recycling of thiol status and 2) several growth factors, growth factor receptors, and integrins that are critical for cell growth and proliferation. We also found that Nrf2 deficiency enhances the expression levels of several genes encoding proinflammatory cytokines; however, GSH supplementation markedly suppressed their expression. Collectively, these findings uncover an important insight into the nature of genes regulated by Nrf2-dependent redox signaling through GSH that are involved in cellular detoxification and proliferation.
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Ni, Yingqian, Peibo Shen, Xingchen Wang, He Liu, Huiyuan Luo e Xiuzhen Han. "The roles of IDH1 in tumor metabolism and immunity". Future Oncology 18, n. 35 (novembre 2022): 3941–53. http://dx.doi.org/10.2217/fon-2022-0583.
Abstract (sommario):
IDH1 is a key metabolic enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle that can convert isocitrate into α-ketoglutarate (α-KG) and generate NADPH. The reduction of IDH1 may affect dioxygenase activity and damage the body's detoxification mechanism. Many studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 expression levels or gene mutations have appeared in many tumor tissues and produced a series of metabolic and immunity changes at the same time. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors.
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Afjei, Rayhaneh, Negar Sadeghipour, Sukumar Uday Kumar, Mallesh Pandrala, Vineet Kumar, Sanjay V. Malhotra, Tarik F. Massoud e Ramasamy Paulmurugan. "A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations". Cancers 14, n. 24 (12 dicembre 2022): 6120. http://dx.doi.org/10.3390/cancers14246120.
Abstract (sommario):
TP53 tumor suppressor gene is a commonly mutated gene in cancer. p53 mediated senescence is critical in preventing oncogenesis in normal cells. Since p53 is a transcription factor, mutations in its DNA binding domain result in the functional loss of p53-mediated cellular pathways. Similarly, nuclear factor erythroid 2–related factor 2 (Nrf2) is another transcription factor that maintains cellular homeostasis by regulating redox and detoxification mechanisms. In glioblastoma (GBM), Nrf2-mediated antioxidant activity is upregulated while p53-mediated senescence is lost, both rendering GBM cells resistant to treatment. To address this, we identified novel Nrf2 inhibitors from bioactive compounds using a molecular imaging biosensor-based screening approach. We further evaluated the identified compounds for their in vitro and in vivo chemotherapy enhancement capabilities in GBM cells carrying different p53 mutations. We thus identified an Nrf2 inhibitor that is effective in GBM cells carrying the p53 (R175H) mutation, a frequent clinically observed hotspot structural mutation responsible for chemotherapeutic resistance in GBM. Combining this drug with low-dose chemotherapies can potentially reduce their toxicity and increase their efficacy by transiently suppressing Nrf2-mediated detoxification function in GBM cells carrying this important p53 missense mutation.
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Molina, Lázaro, e Ana Segura. "Biochemical and Metabolic Plant Responses toward Polycyclic Aromatic Hydrocarbons and Heavy Metals Present in Atmospheric Pollution". Plants 10, n. 11 (26 ottobre 2021): 2305. http://dx.doi.org/10.3390/plants10112305.
Abstract (sommario):
Heavy metals (HMs) and polycyclic aromatic hydrocarbons (PAHs) are toxic components of atmospheric particles. These pollutants induce a wide variety of responses in plants, leading to tolerance or toxicity. Their effects on plants depend on many different environmental conditions, not only the type and concentration of contaminant, temperature or soil pH, but also on the physiological or genetic status of the plant. The main detoxification process in plants is the accumulation of the contaminant in vacuoles or cell walls. PAHs are normally transformed by enzymatic plant machinery prior to conjugation and immobilization; heavy metals are frequently chelated by some molecules, with glutathione, phytochelatins and metallothioneins being the main players in heavy metal detoxification. Besides these detoxification mechanisms, the presence of contaminants leads to the production of the reactive oxygen species (ROS) and the dynamic of ROS production and detoxification renders different outcomes in different scenarios, from cellular death to the induction of stress resistances. ROS responses have been extensively studied; the complexity of the ROS response and the subsequent cascade of effects on phytohormones and metabolic changes, which depend on local concentrations in different organelles and on the lifetime of each ROS species, allow the plant to modulate its responses to different environmental clues. Basic knowledge of plant responses toward pollutants is key to improving phytoremediation technologies.
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Damodaran, Dilna, Raj Mohan Balakrishnan e Vidya K. Shetty. "The Uptake Mechanism of Cd(II), Cr(VI), Cu(II), Pb(II), and Zn(II) by Mycelia and Fruiting Bodies ofGalerina vittiformis". BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/149120.
Abstract (sommario):
Optimum concentrations of heavy metals like copper, cadmium, lead, chromium, and zinc in soil are essential in carrying out various cellular activities in minimum concentrations and hence help in sustaining all life forms, although higher concentration of these metals is lethal to most of the life forms.Galerina vittiformis, a macrofungus, was found to accumulate these heavy metals into its fleshy fruiting body in the order Pb(II) > Cd(II) > Cu(II) > Zn(II) > Cr(VI) from 50 mg/kg soil. It possesses various ranges of potential cellular mechanisms that may be involved in detoxification of heavy metals and thus increases its tolerance to heavy metal stress, mainly by producing organic acids and phytochelatins (PCs). These components help in repairing stress damaged proteins and compartmentalisation of metals to vacuoles. The stress tolerance mechanism can be deduced by various analytical tools like SEM-EDX, FTIR, and LC-MS. Production of two kinds of phytochelatins was observed in the organism in response to metal stress.
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Kursov, S. V., V. V. Nikonov, O. V. Biletskyi, O. E. Feskov e S. M. Skoroplit. "Physiology of magnesium metabolism and the use of magnesium in intensive care (part 2)". EMERGENCY MEDICINE 17, n. 6 (10 gennaio 2022): 17–27. http://dx.doi.org/10.22141/2224-0586.17.6.2021.242323.
Abstract (sommario):
In the second part of the review, aspects of changes in magnesium metabolism under conditions of severe stress, mechanisms of anti-stress protection of the body with the participation of magnesium, features of magnesium participation in water-electrolyte metabolism at the cellular level, the anti-inflammatory effect of magnesium and the role of magnesium in the processes of detoxification of the body in acute poisoning with certain poisons are consi-dered. The main mechanisms of the body’s magnesium defence are to suppress the mechanisms of oxidative stress by limiting the production of stress hormones, the intake of ionized calcium and sodium into cells with a decrease in the severity of transmineralization and sodium retention in the body, suppressing the action of factors that initiate the development of inflammation and reducing the production of pro-inflammatory mediators, in blocking and protecting glutamate receptors. Magnesium therapy can help keep effective energy production in the body in critical conditions by maintaining the functioning of the Na+/K+-ATPase, the work of the Na+/H+-exchanger, helping reduce the severity of cellular acidosis. The mechanisms of functioning and the prescription of the sodium-magnesium antiporter are discussed. Hypertonic solutions of magnesium sulfate are being injected at a high rate to create the effect of rapid low-volume fluid resuscitation, thereby eliminating the dangerous effects of severe hyperchloremia and hypernatremia that occur when using hypertonic sodium chloride solutions. In toxico-logy, magnesium preparations are used to protect the body when exposed to heavy metals, organophosphorus compounds. They also help reduce the severity of oxidative stress caused by heavy metals, inhibit excess production of endogenous carbon monoxide, and limit free radical damage in its pathological effect. During detoxification, magnesium prevents depletion of the antioxidant system by helping maintain sufficient levels of glutathione and other antioxidants in cells.
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Virmani, Mohamed Ashraf, e Maria Cirulli. "The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation". International Journal of Molecular Sciences 23, n. 5 (28 febbraio 2022): 2717. http://dx.doi.org/10.3390/ijms23052717.
Abstract (sommario):
Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.
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Vayalil, Praveen K., Girija Kuttan e Ramadasan Kuttan. "Rasayanas: Evidence for the Concept of Prevention of Diseases". American Journal of Chinese Medicine 30, n. 01 (gennaio 2002): 155–71. http://dx.doi.org/10.1142/s0192415x02000168.
Abstract (sommario):
Rasayanas are non-toxic Ayurvedic complex herbal preparations or individual herbs used to rejuvenate or attain the complete potential of an individual in order to prevent diseases and degenerative changes that leads to disease. The present paper reviews various activities of Rasayanas to support the above concept, its role as a prophylactic medication and significance in the prevention of diseases in both healthy as well as diseased individuals. The emerging data suggest that the possible mechanisms may be by immunostimulation, quenching free radicals, enhancing cellular detoxification mechanisms, repair damaged non-proliferating cells, inducing cell proliferation and self-renewal of damaged proliferating tissues, and replenishing them by eliminating damaged or mutated cells with fresh cells.
27
Van Breusegem, Frank, Marc Van Montagu e Dirk Inzé. "Engineering Stress Tolerance in Maize". Outlook on Agriculture 27, n. 2 (giugno 1998): 115–24. http://dx.doi.org/10.1177/003072709802700209.
Abstract (sommario):
A wide range of environmental stresses (such as chilling, ozone, high light, drought, and heat) can damage crop plants, with consequent high annual yield losses. A common factor in all these unrelated adverse conditions, called oxidative stress, is the enhanced production of active oxygen species (AOS) within several subcellular compartments of the plant. AOS can react very rapidly with DNA, lipids and proteins, causing severe cellular damage. Under normal growth conditions, AOS are efficiently scavenged by both enzymatic and non-enzymatic detoxification mechanisms. Nevertheless, during prolonged stress conditions such detoxification systems get saturated and damage occurs. The main players within the defence system are superoxide dismutases, ascorbate peroxidase, and catalases. These enzymes directly eliminate the harmful AOS. By enhancing the levels of these proteins in transgenic plants via transformation technology the improvement of tolerance against oxidative stress is being attempted. In our research, we are generating transgenic maize lines that overproduce various antioxidative stress enzymes and we are assessing the performance of these plants during chilling stress.
28
Brown-Borg, Holly. "SOMATOTROPIC SIGNALING IN HEALTH AND LONGEVITY". Innovation in Aging 6, Supplement_1 (1 novembre 2022): 91. http://dx.doi.org/10.1093/geroni/igac059.361.
Abstract (sommario):
Abstract The endocrine system is highly integrated and regulates growth, reproduction, metabolism, and stress responses that influence aging. Reduced growth hormone (GH) signaling extends health and lifespan in part, by altering metabolism maintaining enhanced insulin sensitivity and defense mechanisms. Diet composition affects metabolism and GH status integrates these nutrient signals, modulating metabolic responses that result in age-related disease susceptibility. Two pathways affected by somatotropic signaling include methionine and lipid metabolism. GH appears to regulate oxidative defense and the methionine pathway via enzymes that affect S-adenosyl-methionine, glutathione, DNA methylation, and detoxification activities. We also have evidence that GH deficient mice escape fatty liver disease when fed high-fat diets. Together our work and others indicate that GH plays a significant role in an organism’s ability to respond to nutrients and cellular stressors by regulating factors that counter stress, modulating metabolic responsiveness to nutrients, and detoxification of endogenous and exogenous compounds.
29
Garcia-Ortega, Dorian Yarih, Sara Aileen Cabrera-Nieto, Haydee Sarai Caro-Sánchez e Marlid Cruz-Ramos. "An overview of resistance to chemotherapy in osteosarcoma and future perspectives". Cancer Drug Resistance 5, n. 2 (2022): 762–93. http://dx.doi.org/10.20517/cdr.2022.18.
Abstract (sommario):
Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.
30
Chung, Kuang-Ren. "Stress Response and Pathogenicity of the Necrotrophic Fungal PathogenAlternaria alternata". Scientifica 2012 (2012): 1–17. http://dx.doi.org/10.6064/2012/635431.
Abstract (sommario):
The production of host-selective toxins by the necrotrophic fungusAlternaria alternatais essential for the pathogenesis.A. alternatainfection in citrus leaves induces rapid lipid peroxidation, accumulation of hydrogen peroxide (H2O2), and cell death. The mechanisms by whichA. alternataavoids killing by reactive oxygen species (ROS) after invasion have begun to be elucidated. The ability to coordinate of signaling pathways is essential for the detoxification of cellular stresses induced by ROS and for pathogenicity inA. alternata. A low level of H2O2, produced by the NADPH oxidase (NOX) complex, modulates ROS resistance and triggers conidiation partially via regulating the redox-responsive regulators (YAP1 and SKN7) and the mitogen-activated protein (MAP) kinase (HOG1) mediated pathways, which subsequently regulate the genes required for the biosynthesis of siderophore, an iron-chelating compound. Siderophore-mediated iron acquisition plays a key role in ROS detoxification because of the requirement of iron for the activities of antioxidants (e.g., catalase and SOD). Fungal strains impaired for the ROS-detoxifying system severely reduce the virulence on susceptible citrus cultivars. This paper summarizes the current state of knowledge of signaling pathways associated with cellular responses to multidrugs, oxidative and osmotic stress, and fungicides, as well as the pathogenicity/virulence in the tangerine pathotype ofA. alternata.
31
Rejano-Gordillo, Claudia M., Beatriz Marín-Díaz, Ana Ordiales-Talavero, Jaime M. Merino, Francisco J. González-Rico e Pedro M. Fernández-Salguero. "From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms". International Journal of Molecular Sciences 23, n. 23 (29 novembre 2022): 14919. http://dx.doi.org/10.3390/ijms232314919.
Abstract (sommario):
The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.
32
Martel, Cécile, Le Ha Huynh, Anne Garnier, Renée Ventura-Clapier e Catherine Brenner. "Inhibition of the Mitochondrial Permeability Transition for Cytoprotection: DirectversusIndirect Mechanisms". Biochemistry Research International 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/213403.
Abstract (sommario):
Mitochondria are fascinating organelles, which fulfill multiple cellular functions, as diverse as energy production, fatty acidβoxidation, reactive oxygen species (ROS) production and detoxification, and cell death regulation. The coordination of these functions relies on autonomous mitochondrial processes as well as on sustained cross-talk with other organelles and/or the cytosol. Therefore, this implies a tight regulation of mitochondrial functions to ensure cell homeostasis. In many diseases (e.g., cancer, cardiopathies, nonalcoholic fatty liver diseases, and neurodegenerative diseases), mitochondria can receive harmful signals, dysfunction and then, participate to pathogenesis. They can undergo either a decrease of their bioenergetic function or a process called mitochondrial permeability transition (MPT) that can coordinate cell death execution. Many studies present evidence that protection of mitochondria limits disease progression and severity. Here, we will review recent strategies to preserve mitochondrial functions via direct or indirect mechanisms of MPT inhibition. Thus, several mitochondrial proteins may be considered for cytoprotective-targeted therapies.
33
Potęga, Agnieszka. "Glutathione-Mediated Conjugation of Anticancer Drugs: An Overview of Reaction Mechanisms and Biological Significance for Drug Detoxification and Bioactivation". Molecules 27, n. 16 (17 agosto 2022): 5252. http://dx.doi.org/10.3390/molecules27165252.
Abstract (sommario):
The effectiveness of many anticancer drugs depends on the creation of specific metabolites that may alter their therapeutic or toxic properties. One significant route of biotransformation is a conjugation of electrophilic compounds with reduced glutathione, which can be non-enzymatic and/or catalyzed by glutathione-dependent enzymes. Glutathione usually combines with anticancer drugs and/or their metabolites to form more polar and water-soluble glutathione S-conjugates, readily excreted outside the body. In this regard, glutathione plays a role in detoxification, decreasing the likelihood that a xenobiotic will react with cellular targets. However, some drugs once transformed into thioethers are more active or toxic than the parent compound. Thus, glutathione conjugation may also lead to pharmacological or toxicological effects through bioactivation reactions. My purpose here is to provide a broad overview of the mechanisms of glutathione-mediated conjugation of anticancer drugs. Additionally, I discuss the biological importance of glutathione conjugation to anticancer drug detoxification and bioactivation pathways. I also consider the potential role of glutathione in the metabolism of unsymmetrical bisacridines, a novel prosperous class of anticancer compounds developed in our laboratory. The knowledge on glutathione-mediated conjugation of anticancer drugs presented in this review may be noteworthy for improving cancer therapy and preventing drug resistance in cancers.
34
Lamas, J., P. Morais, J. A. Arranz, M. L. Sanmartín, F. Orallo e J. Leiro. "Resveratrol promotes an inhibitory effect on the turbot scuticociliate parasite Philasterides dicentrarchi by mechanisms related to cellular detoxification". Veterinary Parasitology 161, n. 3-4 (maggio 2009): 307–15. http://dx.doi.org/10.1016/j.vetpar.2008.12.025.
35
Reid, Linzi, Nancy Khammo e Richard H. Clothier. "An Evaluation of the Effects of Photoactivation of Bithionol, Amiodarone and Chlorpromazine on Human Keratinocytes In Vitro". Alternatives to Laboratory Animals 35, n. 5 (ottobre 2007): 471–85. http://dx.doi.org/10.1177/026119290703500513.
Abstract (sommario):
Human skin is a continual target for chemical toxicity, due to its constant exposure to xenobiotics. The skin possesses a number of protective antioxidant systems, including glutathione and enzymic pathways, which are capable of neutralising reactive oxygen species (ROS). In combination with certain chemicals, the presence of ROS might augment the levels of toxicity, due to photoactivation of the chemical or, alternatively, due to an oxidatively-stressed state in the skin which exisited prior to exposure to the chemical. Bithionol is a phototoxic anti-parasitic compound. The mechanism of its toxicity and the possible methods of protection from its damaging effects have been explored. The capacity of keratinocytes to protect themselves from bithionol and other phototoxic chemicals has been investigated. In addition, the potential of endogenous antioxidants, such as vitamin C and E, to afford protection to the cells, has been evaluated. The intracellular glutathione stores of HaCaT keratinocytes were reduced following treatment with biothionol. Following photoactivation, both bithionol and chlorpromazine had similar effects, which suggests that glutathione is important in the detoxification pathway of these chemicals. This was confirmed by means of the visual identification of fluorescently-labelled glutathione. Endogenous antioxidants were unable to protect the HaCaT keratinocytes from bithionol toxicity or chlorpromazine phototoxicity. Amiodarone was shown to have no effect on cellular glutathione levels, which suggests that an alternative mechanism of detoxification was occurring in this case. This was supported by evidence of the protection of HaCaT cells from amiodarone phototoxicity via endogenous antioxidants. Thus, it appears that amiodarone toxicity is dependent on the levels of non-gluathione antioxidants present, whilst bithionol and chlorpromazine detoxification relies on the glutathione antioxidant system. This type of approach could indicate the likely mechanisms of phototoxicity of chemicals in vitro, with relevance to potential effects in vivo.
36
Grüning, Nana-Maria, e Markus Ralser. "Monogenic Disorders of ROS Production and the Primary Anti-Oxidative Defense". Biomolecules 14, n. 2 (9 febbraio 2024): 206. http://dx.doi.org/10.3390/biom14020206.
Abstract (sommario):
Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular anti-oxidant defense mechanisms, plays a critical role in the pathogenesis of various human diseases. Redox metabolism, comprising a network of enzymes and genes, serves as a crucial regulator of ROS levels and maintains cellular homeostasis. This review provides an overview of the most important human genes encoding for proteins involved in ROS generation, ROS detoxification, and production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), and the genetic disorders that lead to dysregulation of these vital processes. Insights gained from studies on inherited monogenic metabolic diseases provide valuable basic understanding of redox metabolism and signaling, and they also help to unravel the underlying pathomechanisms that contribute to prevalent chronic disorders like cardiovascular disease, neurodegeneration, and cancer.
37
Hess, David A., e Michael J. Rieder. "The Role of Reactive Drug Metabolites in Immune-Mediated Adverse Drug Reactions". Annals of Pharmacotherapy 31, n. 11 (novembre 1997): 1378–87. http://dx.doi.org/10.1177/106002809703101116.
Abstract (sommario):
OBJECTIVE: To highlight recent advances in the understanding of adverse drug reactions (ADRs), with a focus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific mechanisms that identify the metabolic pathways responsible for drug bioactivation to reactive drug metabolites (RDMs) involved in the initiation and propagation of specific immune-mediated hypersensitivity reactions are discussed. Drug classes well known to be associated with immune-mediated ADRs are reviewed and the clinical implications of current research are discussed. DATA SOURCES: Original experimental research and immunologic review articles relevant to ADR diagnosis and etiology. DATA EXTRACTION: Results of relevant in vitro experiments and clinical reactions to drug therapy were compiled and reviewed. Critical discoveries concerning the identification of RDMs involved in ADRs were highlighted, with respect to RDM involvement in the production of an immune response to drug haptens. DATA SYNTHESIS: Drug adverse effects are classified according to clinical characteristics, immune interactions, and mechanistic similarities. Cytochrome P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An electrophilic metabolite may react with cellular macromolecules (i.e., lipids, proteins, nucleic acids), resulting in direct cellular damage and organ toxicity. Covalent binding of an RDM to cellular macromolecules may also result in the formation of a hapten that is capable of eliciting a cellular or humoral immune response against drug or protein epitopes, culminating in the characteristic symptoms of hypersensitivity reactions. Mechanistic details concerning the identification of stable protein-metabolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pathways, as well as reduced cellular defense against RDMs due to disease or concomitant drug therapy, act as risk factors to the onset and severity of ADRs. CONCLUSIONS: Adverse reactions to drug therapy cause significant morbidity and mortality. Identification of the pathways involved in drug bioactivation and detoxification may elucidate the potential of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the prevention and management of ADRs, and may prove useful in the design of novel therapeutic agents with reduced incidence of severe adverse events.
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Russi, Sabino, Henu Kumar Verma, Simona Laurino, Pellegrino Mazzone, Giovanni Storto, Anna Nardelli, Pietro Zoppoli et al. "Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells". International Journal of Molecular Sciences 20, n. 15 (31 luglio 2019): 3736. http://dx.doi.org/10.3390/ijms20153736.
Abstract (sommario):
Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.
39
Sullivan, Matthew J., Kelvin G. K. Goh e Glen C. Ulett. "Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus". PLOS Pathogens 18, n. 7 (21 luglio 2022): e1010607. http://dx.doi.org/10.1371/journal.ppat.1010607.
Abstract (sommario):
Metals such as copper (Cu) and zinc (Zn) are important trace elements that can affect bacterial cell physiology but can also intoxicate bacteria at high concentrations. Discrete genetic systems for management of Cu and Zn efflux have been described in several bacteria pathogens, including streptococci. However, insight into molecular cross-talk between systems for Cu and Zn management in bacteria that drive metal detoxification, is limited. Here, we describe a biologically consequential cross-system effect of metal management in group B Streptococcus (GBS) governed by the Cu-responsive copY regulator in response to Zn. RNAseq analysis of wild-type (WT) and copY-deficient GBS subjected to metal stress revealed unique transcriptional links between the systems for Cu and Zn detoxification. We show that the Cu-sensing role of CopY extends beyond Cu and enables CopY to regulate Cu and Zn stress responses that effect changes in gene function for central cellular processes, including riboflavin synthesis. CopY also supported GBS intracellular survival in human macrophages and virulence during disseminated infection in mice. In addition, we show a novel role for CovR in modulating GBS resistance to Zn intoxication. Identification of the Zn resistome of GBS using TraDIS revealed a suite of genes essential for GBS growth in metal stress. Several of the genes identified are novel to systems that support bacterial survival in metal stress and represent a diverse set of mechanisms that underpin microbial metal homeostasis during cell stress. Overall, this study reveals a new and important mechanism of cross-system complexity driven by CopY in bacteria to regulate cellular management of metal stress and survival.
40
Zhang, Jiayuan, Zhiming Bao, Jieyu Guo, Xianbin Su, Yongfeng Zou e Hui Guo. "Comparative Transcriptome Analysis of the Hepatopancreas from Macrobrachium rosenbergii Exposed to the Heavy Metal Copper". Animals 14, n. 7 (5 aprile 2024): 1117. http://dx.doi.org/10.3390/ani14071117.
Abstract (sommario):
The contamination of aquatic ecosystems by the heavy metal copper (Cu) is an important environmental issue and poses significant risks to the physiological functions of aquatic organisms. Macrobrachium rosenbergii is one of the most important freshwater-cultured prawns in the world. The hepatopancreas of crustaceans is a key organ for immune defense, heavy metal accumulation, and detoxification, playing a pivotal role in toxicological research. However, research on the molecular response of the hepatopancreas in M. rosenbergii to Cu exposure is still lacking. In this study, the transcriptomic response in the hepatopancreas of M. rosenbergii was studied after Cu exposure for 3 and 48 h. Compared with the control group, 11,164 (7288 up-regulated and 3876 down-regulated genes) and 10,937 (6630 up-regulated and 4307 down-regulated genes) differentially expressed genes (DEGs) were identified after 3 and 48 h exposure, respectively. Most of these DEGs were up-regulated, implying that gene expressions were largely induced by Cu. Functional enrichment analysis of these DEGs revealed that immunity, copper homeostasis, detoxification, DNA damage repair, and apoptosis were differentially regulated by Cu. Seven genes involved in immunity, detoxification, and metabolism were selected for validation by qRT-PCR, and the results confirmed the reliability of RNA-Seq. All these findings suggest that M. rosenbergii attempts to resist the toxicity of Cu by up-regulating the expression of genes related to immunity, metabolism, and detoxification. However, with the excessive accumulation of reactive oxygen species (ROS), the antioxidant enzyme system was destroyed. As a result, DNA damage repair and the cellular stress response were inhibited, thereby exacerbating cell damage. In order to maintain the normal function of the hepatopancreas, M. rosenbergii removes damaged cells by activating the apoptosis mechanism. Our study not only facilitates an understanding of the molecular response mechanisms of M. rosenbergii underlying Cu toxicity effects but also helps us to identify potential biomarkers associated with the stress response in other crustaceans.
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Shangari, N., W. R. Bruce, R. Poon e P. J. O'Brien. "Toxicity of glyoxals – role of oxidative stress, metabolic detoxification and thiamine deficiency". Biochemical Society Transactions 31, n. 6 (1 dicembre 2003): 1390–93. http://dx.doi.org/10.1042/bst0311390.
Abstract (sommario):
Glyoxals are reactive α-oxoaldehydes that are formed endogenously from sugars, the levels of which are increased in various pathological conditions associated with hyperglycaemia and thiamine deficiency. However, the molecular cytotoxic mechanisms of glyoxal are not known. Results presented here and in the other studies cited provide a glimpse into the cytotoxicity mechanisms involved and their pathological implications. We found that glyoxal (10 μM) markedly increased the susceptibility of hepatocyte glutathione (GSH) to oxidation by hydrogen peroxide (H2O2) and markedly increased cytotoxicity by compromising the cellular antioxidant enzyme system. At higher concentrations, glyoxal was cytotoxic towards hepatocytes, which can be attributed to GSH depletion, oxidative stress and mitochondrial toxicity. Aminoguanidine or penicillamine protected the hepatocytes. Glyoxal cytotoxicity was prevented by increasing glyoxal metabolism with thiamine or NAD(P)H generators, and was increased in GSH- or thiamine-deficient hepatocytes. It was also found that feeding rats reduced thiamine levels in a diet high in simple sugars increased the number of aberrant crypt foci/colon in the absence of clinical evidence of beriberi. This was associated with decreased plasma thiamine and low erythrocyte transketolase activity. Western diets, which are frequently poor in thiamine and high in sugars, could result in increased levels of endogenous glyoxals, which in turn may lead to a predisposition to AGE (advanced glycation end-product)-related pathologies and neoplastic conditions.
42
Fruth, K., N. Best, M. Amro, K. Ingel, J. Gosepath, W. J. Mann e J. Brieger. "No evidence for a correlation of glutathione S-tranferase polymorphisms and chronic rhinosinusitis". Rhinology journal 49, n. 2 (1 giugno 2011): 180–84. http://dx.doi.org/10.4193/rhino10.064.
Abstract (sommario):
OBJECTIVE: Cellular detoxification mechanisms are mandatory for cellular protection against oxidative stress and reactive oxygen species. One major group of antioxidative active enzymes involved in cellular detoxification are the Glutathione S-Transferases (GST). Multiple subtypes like GSTM1, GSTP1, and GSTT1 and variants of them are known, arising from allelic variations of the GST loci. Moreover, functional variants occur in high percentages and have been associated with diseases like bronchial asthma and bronchial hyperresponsiveness. The interplay of oxidative stress, detoxifying genes like GSTs and the genesis of respiratory tract illness is under contradictory debate. In this study, we analysed the potential association of GST-polymorphisms and chronic rhinosinusitis (CRS). METHODS: In total 170 nasal tissue samples, 49 tissue samples from patients with CRS without nasal polyps, 69 tissue samples from CRS with nasal polyps and 52 healthy tissue controls of the inferior turbinate were analysed for their individual GST-status. Genotypes for GSTM1 (null versus present), GSTT1 (null versus present), and GSTP1 (Ile105Val) were determined by Polymerase Chain Reaction. The respective genotypes were correlated to the incidence of CRS with and without nasal polyps in aspirin-tolerant and intolerant patients and to the individual health status concerning asthma and allergies. RESULTS: No correlation between any GST-polymorphism and CRS with and without nasal polyps or allergies or asthma or aspirin-intolerance was observed. CONCLUSION: Our results do not suggest that there is a relevant genetic predisposition considering the individual GST-status for the susceptibility of nasal respiratory epithelia leading to CRS.
43
AL-Ishaq, Raghad Khalid, Anthony J. Overy e Dietrich Büsselberg. "Phytochemicals and Gastrointestinal Cancer: Cellular Mechanisms and Effects to Change Cancer Progression". Biomolecules 10, n. 1 (8 gennaio 2020): 105. http://dx.doi.org/10.3390/biom10010105.
Abstract (sommario):
Gastrointestinal (GI) cancer is a prevailing global health disease with a high incidence rate which varies by region. It is a huge economic burden on health care providers. GI cancer affects different organs in the body such as the gastric organs, colon, esophagus, intestine, and pancreas. Internal and external factors like smoking, obesity, urbanization, genetic mutations, and prevalence of Helicobacter pylori and Hepatitis B and Hepatitis C viral infections could increase the risk of GI cancer. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in fruits, grains, and vegetables. Consumption of phytochemicals may protect against chronic diseases like cardiovascular disease, neurodegenerative disease, and cancer. Multiple studies have assessed the chemoprotective effect of selected phytochemicals in GI cancer, offering support to their potential towards reducing the pathogenesis of the disease. The aim of this review was to summarize the current knowledge addressing the anti-cancerous effects of selected dietary phytochemicals on GI cancer and their molecular activities on selected mechanisms, i.e., nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), detoxification enzymes, adenosine monophosphate activated protein kinase (AMPK), wingless-related integration site/β-catenin (wingless-related integration site (Wnt) β-catenin, cell apoptosis, phosphoinositide 3-kinases (PI3K)/ protein kinase B AKT/ mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK). In this review phytochemicals were classified into four main categories: (i) carotenoids, including lutein, lycopene, and β-carotene; (ii) proanthocyanidins, including quercetin and ellagic acid; (iii) organosulfur compounds, including allicin, allyl propyl disulphide, asparagusic acid, and sulforaphane; and (iv) other phytochemicals including pectin, curcumins, p-coumaric acid and ferulic acid. Overall, phytochemicals improve cancer prognosis through the downregulation of β-catenin phosphorylation, therefore enhancing apoptosis, and upregulation of the AMPK pathway, which supports cellular homeostasis. Nevertheless, more studies are needed to provide a better understanding of the mechanism of cancer treatment using phytochemicals and possible side effects associated with this approach.
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Elsayed Azab, Azab, Almokhtar A Adwas, Ata Sedik Ibrahim Elsayed, Almokhtar A Adwas, Ata Sedik Ibrahim Elsayed e Fawzia Amhimmid Quwaydir. "Oxidative stress and antioxidant mechanisms in human body". Journal of Applied Biotechnology & Bioengineering 6, n. 1 (21 febbraio 2019): 43–47. http://dx.doi.org/10.15406/jabb.2019.06.00173.
Abstract (sommario):
The present review aims to high light on the oxidative stress, and prevention by internal antioxidants and external antioxidants by some natural products possessing antioxidant properties. Oxidative stress occurs when the balance between reactive oxygen species (ROS) formation and detoxification favors an increase in ROS levels, leading to disturbed cellular function. ROS causes damage to cellular macromolecules causing lipid peroxidation, nucleic acid, and protein alterations. Their formation is considered as a pathobiochemical mechanism involved in the initiation or progression phase of various diseases such as atherosclerosis, ischemic heart diseases, diabetes, and initiation of carcinogenesis or liver diseases. In order to maintain proper cell signaling, it is likely that a number of radical scavenging enzymes maintain a threshold level of ROS inside the cell. However, when the level of ROS exceeds this threshold, an increase in ROS production may lead to excessive signals to the cell, in addition to direct damage to key components in signaling pathways. ROS can also irreversibly damage essential macromolecules. Protein-bound thiol and non-protein-thiol are the major cytosolic low molecular weight sulfhydryl compound that acts as a cellular reducing and a protective reagent against numerous toxic substances including most inorganic pollutants, through the –SH group. Hence, thiol is often the first line of defense against oxidative stress. Flavonoids have been found to play important roles in the non-enzymatic protection against oxidative stress, especially in the case of cancer. Flavonoids have occurred widely in tea, fruit, red wine, vegetables, and cocoas. Flavonoids, including flavones, flavanone, flavonols, and isoflavones, are polyphenolic compounds which are widespread in foods and beverages, and possess a wide range of biological activities, of which anti-oxidation has been extensively explored. It can be concluded that oxidative stress causes irreversible damage in cellular macromolecules that leads to initiation of various diseases such as atherosclerosis, ischemic heart diseases, liver diseases, diabetes, and initiation of carcinogenesis. Antioxidants inhibit reactive oxygen species production and scavenging of free radicals. Therefore, the review recommends that high consumption of natural foods that are rich in antioxidants will provide more protection against toxic agents and related diseases.
45
Elsayed Azab, Azab, Almokhtar A Adwas, Ata Sedik Ibrahim Elsayed, Almokhtar A Adwas, Ata Sedik Ibrahim Elsayed e Fawzia Amhimmid Quwaydir. "Oxidative stress and antioxidant mechanisms in human body". Journal of Applied Biotechnology & Bioengineering 6, n. 1 (21 febbraio 2019): 43–47. http://dx.doi.org/10.15406/jabb.2019.06.00173.
Abstract (sommario):
The present review aims to high light on the oxidative stress, and prevention by internal antioxidants and external antioxidants by some natural products possessing antioxidant properties. Oxidative stress occurs when the balance between reactive oxygen species (ROS) formation and detoxification favors an increase in ROS levels, leading to disturbed cellular function. ROS causes damage to cellular macromolecules causing lipid peroxidation, nucleic acid, and protein alterations. Their formation is considered as a pathobiochemical mechanism involved in the initiation or progression phase of various diseases such as atherosclerosis, ischemic heart diseases, diabetes, and initiation of carcinogenesis or liver diseases. In order to maintain proper cell signaling, it is likely that a number of radical scavenging enzymes maintain a threshold level of ROS inside the cell. However, when the level of ROS exceeds this threshold, an increase in ROS production may lead to excessive signals to the cell, in addition to direct damage to key components in signaling pathways. ROS can also irreversibly damage essential macromolecules. Protein-bound thiol and non-protein-thiol are the major cytosolic low molecular weight sulfhydryl compound that acts as a cellular reducing and a protective reagent against numerous toxic substances including most inorganic pollutants, through the –SH group. Hence, thiol is often the first line of defense against oxidative stress. Flavonoids have been found to play important roles in the non-enzymatic protection against oxidative stress, especially in the case of cancer. Flavonoids have occurred widely in tea, fruit, red wine, vegetables, and cocoas. Flavonoids, including flavones, flavanone, flavonols, and isoflavones, are polyphenolic compounds which are widespread in foods and beverages, and possess a wide range of biological activities, of which anti-oxidation has been extensively explored. It can be concluded that oxidative stress causes irreversible damage in cellular macromolecules that leads to initiation of various diseases such as atherosclerosis, ischemic heart diseases, liver diseases, diabetes, and initiation of carcinogenesis. Antioxidants inhibit reactive oxygen species production and scavenging of free radicals. Therefore, the review recommends that high consumption of natural foods that are rich in antioxidants will provide more protection against toxic agents and related diseases.
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Grosjean, Nicolas, Marie Le Jean, Jordan Ory e Damien Blaudez. "Yeast Deletomics to Uncover Gadolinium Toxicity Targets and Resistance Mechanisms". Microorganisms 11, n. 8 (19 agosto 2023): 2113. http://dx.doi.org/10.3390/microorganisms11082113.
Abstract (sommario):
Among the rare earth elements (REEs), a crucial group of metals for high-technologies. Gadolinium (Gd) is the only REE intentionally injected to human patients. The use of Gd-based contrasting agents for magnetic resonance imaging (MRI) is the primary route for Gd direct exposure and accumulation in humans. Consequently, aquatic environments are increasingly exposed to Gd due to its excretion through the urinary tract of patients following an MRI examination. The increasing number of reports mentioning Gd toxicity, notably originating from medical applications of Gd, necessitates an improved risk–benefit assessment of Gd utilizations. To go beyond toxicological studies, unravelling the mechanistic impact of Gd on humans and the ecosystem requires the use of genome-wide approaches. We used functional deletomics, a robust method relying on the screening of a knock-out mutant library of Saccharomyces cerevisiae exposed to toxic concentrations of Gd. The analysis of Gd-resistant and -sensitive mutants highlighted the cell wall, endosomes and the vacuolar compartment as cellular hotspots involved in the Gd response. Furthermore, we identified endocytosis and vesicular trafficking pathways (ESCRT) as well as sphingolipids homeostasis as playing pivotal roles mediating Gd toxicity. Finally, tens of yeast genes with human orthologs linked to renal dysfunction were identified as Gd-responsive. Therefore, the molecular and cellular pathways involved in Gd toxicity and detoxification uncovered in this study underline the pleotropic consequences of the increasing exposure to this strategic metal.
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Fu, Bing, Kushal Sengupta, Lauren A. Genova, Ace George Santiago, Won Jung, Łukasz Krzemiński, Udit Kumar Chakraborty, Wenyao Zhang e Peng Chen. "Metal-induced sensor mobilization turns on affinity to activate regulator for metal detoxification in live bacteria". Proceedings of the National Academy of Sciences 117, n. 24 (28 maggio 2020): 13248–55. http://dx.doi.org/10.1073/pnas.1919816117.
Abstract (sommario):
Metal detoxification is essential for bacteria’s survival in adverse environments and their pathogenesis in hosts. Understanding the underlying mechanisms is crucial for devising antibacterial treatments. In the Gram-negative bacteriumEscherichia coli, membrane-bound sensor CusS and its response regulator CusR together regulate the transcription of thecusoperon that plays important roles in cells’ resistance to copper/silver, and they belong to the two-component systems (TCSs) that are ubiquitous across various organisms and regulate diverse cellular functions. In vitro protein reconstitution and associated biochemical/physical studies have provided significant insights into the functions and mechanisms of CusS–CusR and related TCSs. Such studies are challenging regarding multidomain membrane proteins like CusS and also lack the physiological environment, particularly the native spatial context of proteins inside a cell. Here, we use stroboscopic single-molecule imaging and tracking to probe the dynamic behaviors of both CusS and CusR in live cells, in combination with protein- or residue-specific genetic manipulations. We find that copper stress leads to a cellular protein concentration increase and a concurrent mobilization of CusS out of clustered states in the membrane. We show that the mobilized CusS has significant interactions with CusR for signal transduction and that CusS’s affinity toward CusR switches on upon sensing copper at the interfacial metal-binding sites in CusS’s periplasmic sensor domains, prior to ATP binding and autophosphorylation at CusS’s cytoplasmic kinase domain(s). The observed CusS mobilization upon stimulation and its surprisingly early interaction with CusR likely ensure an efficient signal transduction by providing proper conformation and avoiding futile cross talks.
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Nguyen, Hoa Quynh, Yuseob Kim e Yikweon Jang. "De Novo Transcriptome Analysis Reveals Potential Thermal Adaptation Mechanisms in the Cicada Hyalessa fuscata". Animals 11, n. 10 (24 settembre 2021): 2785. http://dx.doi.org/10.3390/ani11102785.
Abstract (sommario):
In metropolitan Seoul, populations of the cicada Hyalessa fuscata in hotter urban heat islands (“high UHIs”) exhibit higher thermal tolerance than those in cooler UHIs (“low UHIs”). We hypothesized that heat stress may activate the expression of genes that facilitate greater thermal tolerance in high-UHI cicadas than in those from cooler areas. Differences in the transcriptomes of adult female cicadas from high-UHI, low-UHI, and suburban areas were analyzed at the unheated level, after acute heat stress, and after heat torpor. No noticeable differences in unheated gene expression patterns were observed. After 10 min of acute heat stress, however, low-UHI and suburban cicadas expressed more heat shock protein genes than high-UHI counterparts. More specifically, remarkable changes in the gene expression of cicadas across areas were observed after heat torpor stimulus, as represented by a large number of up- and downregulated genes in the heat torpor groups compared with the 10 min acute heat stress and control groups. High-UHI cicadas expressed the most differentially expressed genes, followed by the low-UHI and suburban cicadas. There was a notable increase in the expression of heat shock, metabolism, and detoxification genes; meanwhile, immune-related, signal transduction, and protein turnover genes were downregulated in high-UHI cicadas versus the other cicada groups. These results suggested that under heat stress, cicadas inhabiting high-UHIs could rapidly express genes related to heat shock, energy metabolism, and detoxification to protect cells from stress-induced damage and to increase their thermal tolerance toward heat stress. The downregulation of apoptosis mechanisms in high-UHI cicadas suggested that there was less cellular damage, which likely contributed to their high tolerance of heat stress.
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Georgiou-Siafis, Sofia K., e Asterios S. Tsiftsoglou. "The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates". Antioxidants 12, n. 11 (1 novembre 2023): 1953. http://dx.doi.org/10.3390/antiox12111953.
Abstract (sommario):
Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1–5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts’ formation enhances our knowledge of the human metabolome. GSH–hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.
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Köhler, Bianca, Sviatlana Dubovik, Elisa Hörterer, Ulrich Wilk, Jan Bernd Stöckl, Hande Tekarslan-Sahin, Bojan Ljepoja et al. "Combating Drug Resistance by Exploiting miRNA−200c-Controlled Phase II Detoxification". Cancers 14, n. 22 (11 novembre 2022): 5554. http://dx.doi.org/10.3390/cancers14225554.
Abstract (sommario):
Acquired drug resistance constitutes a serious obstacle to the successful therapy of cancer. In the process of therapy resistance, microRNAs can play important roles. In order to combat resistance formation and to improve the efficacy of chemotherapeutics, the mechanisms of the multifaceted hsa-miR−200c on drug resistance were elucidated. Upon knockout of hsa-miR−200c in breast carcinoma cells, a proteomic approach identified altered expression of glutathione S-transferases (GSTs) when cells were treated with the chemotherapeutic drug doxorubicin. In different hsa-miR−200c expression systems, such as knockout, inducible sponge and inducible overexpression, the differential expression of all members of the GST family was evaluated. Expression of hsa-miR−200c in cancer cells led to the repression of a multitude of these GSTs and as consequence, enhanced drug-induced tumor cell death which was evaluated for two chemotherapeutic drugs. Additionally, the influence of hsa-miR−200c on the glutathione pathway, which is part of the phase II detoxification mechanism, was investigated. Finally, the long-term effects of hsa-miR−200c on drug efficacy were studied in vitro and in vivo. Upon doxycycline induction of hsa-miR−200c, MDA-MB 231 xenograft mouse models revealed a strongly reduced tumor growth and an enhanced treatment response to doxorubicin. A combined treatment of these tumors with hsa-miR−200c and doxorubicin resulted in complete regression of the tumor in 60% of the animals. These results identify hsa-miR−200c as an important player regulating the cellular phase II detoxification, thus sensitizing cancer cells not expressing this microRNA to chemotherapeutics and reversing drug resistance through suppression of GSTs.