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Redox Biology Sep 2020Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational... (Review)
Review
Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational modifications. The type III IFs, vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP), are targets for diverse modifications by oxidants and electrophiles, for which their conserved cysteine residue emerges as a hot spot. Pathophysiological examples of these modifications include lipoxidation in cell senescence and rheumatoid arthritis, disulfide formation in cataracts and nitrosation in endothelial shear stress, although some oxidative modifications can also be detected under basal conditions. We previously proposed that cysteine residues of vimentin and GFAP act as sensors for oxidative and electrophilic stress, and as hinges influencing filament assembly. Accumulating evidence indicates that the structurally diverse cysteine modifications, either per se or in combination with other posttranslational modifications, elicit specific functional outcomes inducing distinct assemblies or network rearrangements, including filament stabilization, bundling or fragmentation. Cysteine-deficient mutants are protected from these alterations but show compromised cellular performance in network assembly and expansion, organelle positioning and aggresome formation, revealing the importance of this residue. Therefore, the high susceptibility to modification of the conserved cysteine of type III IFs and its cornerstone position in filament architecture sustains their role in redox sensing and integration of cellular responses. This has deep pathophysiological implications and supports the potential of this residue as a drug target.
Topics: Cytoskeleton; Glial Fibrillary Acidic Protein; Intermediate Filaments; Oxidants; Vimentin
PubMed: 32711378
DOI: 10.1016/j.redox.2020.101582 -
Redox Biology Jul 2023Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells... (Review)
Review
Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells generally represent a higher oxidant level, which suggests a dual therapeutic strategy by regulating redox status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, pro-oxidant therapy exhibits a great anti-cancer capability, attributing to a higher oxidant accumulation within cancer cells, whereas antioxidant therapy to restore redox homeostasis has been claimed to fail in several clinical practices. Targeting the redox vulnerability of cancer cells by pro-oxidants capable of generating excessive reactive oxygen species (ROS) has surfaced as an important anti-cancer strategy. However, multiple adverse effects caused by the indiscriminate attacks of uncontrolled drug-induced OS on normal tissues and the drug-tolerant capacity of some certain cancer cells greatly limit their further applications. Herein, we review several representative oxidative anti-cancer drugs and summarize their side effects on normal tissues and organs, emphasizing that seeking a balance between pro-oxidant therapy and oxidative damage is of great value in exploiting next-generation OS-based anti-cancer chemotherapeutics.
Topics: Humans; Antioxidants; Reactive Oxygen Species; Oxidative Stress; Oxidation-Reduction; Oxidants; Neoplasms
PubMed: 37224697
DOI: 10.1016/j.redox.2023.102754 -
Cells Jun 2020Severe burn injury initiates a feedback cycle of inflammation, fibrosis, oxidative stress and cardiac mitochondrial damage via the PDE5A-cGMP-PKG pathway. To test if...
Severe burn injury initiates a feedback cycle of inflammation, fibrosis, oxidative stress and cardiac mitochondrial damage via the PDE5A-cGMP-PKG pathway. To test if the PDE5A-cGMP-PKG pathway may contribute to burn-induced heart dysfunction. Sprague-Dawley rats were divided four groups: sham; sham/sildenafil; 24 h post burn (60% total body surface area scald burn, harvested at 24 h post burn); and 24 h post burn/sildenafil. We monitored heart function and oxidative adducts, as well as cardiac inflammatory, cardiac fibrosis and cardiac remodeling responses in vivo. Sildenafil inhibited the burn-induced PDE5A mRNA level and increased the cGMP level and PKG activity, leading to the normalization of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), a decreased ROS level (HO), decreased oxidatively modified adducts (malonyldialdehyde [MDA], carbonyls), attenuated fibrogenesis as well as fibrosis gene expression (ANP, BNP, COL1A2, COL3A2, αSMA and αsk-Actin), and reduced inflammation and related gene expression (RELA, IL-18 and TGF-β) after the burn. Additionally, sildenafil treatment preserved left ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and recovered the oxidant/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity). The PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction. Sildenafil treatment recovers burn-induced cardiac dysfunction.
Topics: Animals; Antioxidants; Burns; Cardiomyopathies; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Gene Expression Regulation; Male; Myocardium; Myocytes, Cardiac; Oxidants; Rats, Sprague-Dawley; Signal Transduction; Sildenafil Citrate
PubMed: 32503314
DOI: 10.3390/cells9061393 -
Redox Biology Oct 2019Motile cilia on airway cells are necessary for clearance of mucus-trapped particles out of the lung. Ciliated airway epithelial cells are uniquely exposed to oxidants... (Review)
Review
Motile cilia on airway cells are necessary for clearance of mucus-trapped particles out of the lung. Ciliated airway epithelial cells are uniquely exposed to oxidants through trapping of particles, debris and pathogens in mucus and the direct exposure to inhaled oxidant gases. Dynein ATPases, the motors driving ciliary motility, are sensitive to the local redox environment within each cilium. Several redox-sensitive cilia-localized proteins modulate dynein activity and include Protein Kinase A, Protein Kinase C, and Protein Phosphatase 1. Moreover, cilia are rich in known redox regulatory proteins and thioredoxin domain-containing proteins that are critical in maintaining a balanced redox environment. Importantly, a nonsense mutation in TXNDC3, which contains a thioredoxin motif, has recently been identified as disease-causing in Primary Ciliary Dyskinesia, a hereditary motile cilia disease resulting in impaired mucociliary clearance. Here we review current understanding of the role(s) oxidant species play in modifying airway ciliary function. We focus on oxidants generated in the airways, cilia redox targets that modulate ciliary beating and imbalances in redox state that impact health and disease. Finally, we review disease models such as smoking, asthma, alcohol drinking, and infections as well as the direct application of oxidants that implicate redox balance as a modulator of cilia motility.
Topics: Animals; Cilia; Cyclic AMP-Dependent Protein Kinases; Humans; Oxidants; Oxidation-Reduction; Protein Kinase C; Protein Phosphatase 1; Respiratory Tract Diseases; Thioredoxins
PubMed: 30833143
DOI: 10.1016/j.redox.2019.101146 -
Nature Communications Jul 2022The direct hydroxylation of arene C-H bonds is a highly sought-after transformation but remains an unsolved challenge due to the difficulty in efficient and...
The direct hydroxylation of arene C-H bonds is a highly sought-after transformation but remains an unsolved challenge due to the difficulty in efficient and regioselective C-H oxygenation and high reactivity of the phenolic products leading to overoxidation. Herein we report electrochemical C-H hydroxylation of arenes in continuous flow for the synthesis of phenols. The method is characterized by broad scope (compatible with arenes of diverse electronic properties), mild conditions without any catalysts or chemical oxidants, and excellent scalability as demonstrated by the continuous production of 1 mol (204 grams) of one of the phenol products.
Topics: Catalysis; Hydroxylation; Oxidants; Phenols
PubMed: 35803941
DOI: 10.1038/s41467-022-31634-4 -
Nature Communications Aug 2022Genomic reconstructions of the common ancestor to all life have identified genes involved in HO and O cycling. Commonly dismissed as an artefact of lateral gene transfer...
Genomic reconstructions of the common ancestor to all life have identified genes involved in HO and O cycling. Commonly dismissed as an artefact of lateral gene transfer after oxygenic photosynthesis evolved, an alternative is a geological source of HO and O on the early Earth. Here, we show that under oxygen-free conditions high concentrations of HO can be released from defects on crushed silicate rocks when water is added and heated to temperatures close to boiling point, but little is released at temperatures <80 °C. This temperature window overlaps the growth ranges of evolutionary ancient heat-loving and oxygen-respiring Bacteria and Archaea near the root of the Universal Tree of Life. We propose that the thermal activation of mineral surface defects during geological fault movements and associated stresses in the Earth's crust was a source of oxidants that helped drive the (bio)geochemistry of hot fractures where life first evolved.
Topics: Biological Evolution; Earth, Planet; Hydrogen Peroxide; Oxidants; Oxygen; Photosynthesis
PubMed: 35941147
DOI: 10.1038/s41467-022-32129-y -
Oxidative Medicine and Cellular... 2019Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a... (Review)
Review
Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a result of hypermetabolism, but the redox balance is maintained in cancer cells due to their marked antioxidant capacity. Recently, anticancer therapies that induce oxidative stress by increasing ROS and/or inhibiting antioxidant processes have received significant attention. The acceleration of accumulative ROS disrupts redox homeostasis and causes severe damage in cancer cells. In this review, we describe ROS-inducing cancer therapy and the anticancer mechanism employed by prooxidative agents. To understand the comprehensive biological response to certain prooxidative anticancer drugs such as 2-methoxyestradiol, buthionine sulfoximine, cisplatin, doxorubicin, imexon, and motexafin gadolinium, we propose and visualize the drug-gene, drug-cell process, and drug-disease interactions involved in oxidative stress induction and antioxidant process inhibition as well as specific side effects of these drugs using pathway analysis with a big data-based text-mining approach. Our review will be helpful to improve the therapeutic effects of anticancer drugs by providing information about biological changes that occur in response to prooxidants. For future directions, there is still a need for pharmacogenomic studies on prooxidative agents as well as the molecular mechanisms underlying the effects of the prooxidants and/or antioxidant-inhibitor agents for effective anticancer therapy through selective killing of cancer cells.
Topics: 2-Methoxyestradiol; Animals; Antineoplastic Agents; Homeostasis; Humans; Neoplasms; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 31929855
DOI: 10.1155/2019/5381692 -
The Journal of Biological Chemistry Oct 2019The free radical nitric oxide (NO) exerts biological effects through the direct and reversible interaction with specific targets ( soluble guanylate cyclase) or through... (Review)
Review
The free radical nitric oxide (NO) exerts biological effects through the direct and reversible interaction with specific targets ( soluble guanylate cyclase) or through the generation of secondary species, many of which can oxidize, nitrosate or nitrate biomolecules. The NO-derived reactive species are typically short-lived, and their preferential fates depend on kinetic and compartmentalization aspects. Their detection and quantification are technically challenging. In general, the strategies employed are based either on the detection of relatively stable end products or on the use of synthetic probes, and they are not always selective for a particular species. In this study, we describe the biologically relevant characteristics of the reactive species formed downstream from NO, and we discuss the approaches currently available for the analysis of NO, nitrogen dioxide (NO), dinitrogen trioxide (NO), nitroxyl (HNO), and peroxynitrite (ONOO/ONOOH), as well as peroxynitrite-derived hydroxyl (HO) and carbonate anion (CO) radicals. We also discuss the biological origins of and analytical tools for detecting nitrite (NO), nitrate (NO), nitrosyl-metal complexes, -nitrosothiols, and 3-nitrotyrosine. Moreover, we highlight state-of-the-art methods, alert readers to caveats of widely used techniques, and encourage retirement of approaches that have been supplanted by more reliable and selective tools for detecting and measuring NO-derived oxidants. We emphasize that the use of appropriate analytical methods needs to be strongly grounded in a chemical and biochemical understanding of the species and mechanistic pathways involved.
Topics: Free Radicals; Humans; Hydroxyl Radical; Nitrates; Nitric Oxide; Oxidants; Oxidation-Reduction; Peroxynitrous Acid; Reactive Nitrogen Species; Systems Biology
PubMed: 31409645
DOI: 10.1074/jbc.REV119.006136 -
International Journal of Molecular... Mar 2020Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine... (Review)
Review
Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species).
Topics: Animals; Catalytic Domain; Cathepsins; Cysteine; Cysteine Endopeptidases; Humans; Oxidants; Oxidation-Reduction; Papain; Proteolysis
PubMed: 32178437
DOI: 10.3390/ijms21061944 -
Nutrients Sep 2022Iodide is an antioxidant, oxidant and thyroid hormone constituent. Selenoproteins are needed for triiodothyronine synthesis, its deactivation and iodine release. They... (Review)
Review
Iodide is an antioxidant, oxidant and thyroid hormone constituent. Selenoproteins are needed for triiodothyronine synthesis, its deactivation and iodine release. They also protect thyroidal and extrathyroidal tissues from hydrogen peroxide used in the 'peroxidase partner system'. This system produces thyroid hormone and reactive iodine in exocrine glands to kill microbes. Exocrine glands recycle iodine and with high urinary clearance require constant dietary supply, unlike the thyroid. Disbalanced iodine-selenium explains relations between thyroid autoimmune disease (TAD) and cancer of thyroid and exocrine organs, notably stomach, breast, and prostate. Seafood is iodine unconstrained, but selenium constrained. Terrestrial food contains little iodine while selenium ranges from highly deficient to highly toxic. Iodine vs. TAD is U-shaped, but only low selenium relates to TAD. Oxidative stress from low selenium, and infection from disbalanced iodine-selenium, may generate cancer of thyroid and exocrine glands. Traditional Japanese diet resembles our ancient seashore-based diet and relates to aforementioned diseases. Adequate iodine might be in the milligram range but is toxic at low selenium. Optimal selenoprotein-P at 105 µg selenium/day agrees with Japanese intakes. Selenium upper limit may remain at 300-400 µg/day. Seafood combines iodine, selenium and other critical nutrients. It brings us back to the seashore diet that made us what we currently still are.
Topics: Antioxidants; Hashimoto Disease; Humans; Hydrogen Peroxide; Iodides; Iodine; Male; Oxidants; Peroxidases; Selenium; Selenoproteins; Thyroid Hormones; Thyroid Neoplasms; Triiodothyronine
PubMed: 36235539
DOI: 10.3390/nu14193886