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1.
An Evaluation of Oxidative Stress With Thiol/Disulfide Homeostasis in Patients With Persistent Allergic Rhinitis.
Göker, AE, Alagöz, MH, Kumral, TL, Karaketir, S, Yilmazer, AB, Tutar, B, Ahmed, EA, Biçer, C, Uyar, Y
Ear, nose, & throat journal. 2022;(1):NP13-NP17
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Abstract
BACKGROUND We evaluated the efficacy of medical treatment on thiol-disulfide balance despite ongoing allergic stimulation. METHODS The research design was a prospective observational study that included 35 persistent allergic rhinitis (AR) patients. All patients who were diagnosed with persistent AR were included. A skin prick test was applied to all patients, and the Sino-nasal Outcome Test-22 was used to evaluate sinonasal symptoms. Thiol/disulfide homeostasis balance parameters were measured using a novel automatic and spectrophotometric method and compared statistically. Serum total thiol (TT), native thiol (SH), disulphide (SS), disulphide/native thiol (SS/SH), disulphide/total thiol (SS/TT), and native thiol/total thiol (SH/TT) ratios were measured after the second month of the treatment. RESULTS The 35 patients included 20 (58%) females and 15 (42%) males. The mean age of the patients was 33.17 ± 9.9 years. Disulphide, SS/SH, and SS/TT ratios decreased significantly after the treatment (P < .05), while SH and SH/TT increased significantly (P < .05). The mean SH measurement increased significantly in the second month (P = .001), but TT mean measurements showed no difference after the treatment (P = .058). The mean SS measurements, on the other hand, decreased significantly in the second month (P = .003). CONCLUSION Thiol/disulfide homeostasis may be used as a marker to evaluate the efficacy of persistent AR treatments. After the treatment, the increase in SH levels suggested the decrease in oxidative stress, even though allergen exposure continued.
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2.
Use of Thiols in the Treatment of COVID-19: Current Evidence.
Cazzola, M, Rogliani, P, Salvi, SS, Ora, J, Matera, MG
Lung. 2021;(4):335-343
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Abstract
There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients.
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Superoxide Oxidation by a Thiolate-Ligated Iron Complex and Anion Inhibition.
Dedushko, MA, Pikul, JH, Kovacs, JA
Inorganic chemistry. 2021;(10):7250-7261
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Abstract
Superoxide (O2•-) is a toxic radical, generated via the adventitious reduction of dioxygen (O2), which has been implicated in a number of human disease states. Nonheme iron enzymes, superoxide reductase (SOR) and superoxide dismutase (SOD), detoxify O2•- via reduction to afford H2O2 and disproportionation to afford O2 and H2O2, respectively. The former contains a thiolate in the coordination sphere, which has been proposed to prevent O2•- oxidation to O2. The work described herein shows that, in contrast to this, oxidized thiolate-ligated [FeIII(SMe2N4(tren)(THF)]2+ (1ox-THF) is capable of oxidizing O2•- to O2. Coordinating anions, Cl- and OAc-, are shown to inhibit dioxygen evolution, implicating an inner-sphere mechanism. Previously we showed that the reduced thiolate-ligated [FeII(SMe2N4(tren))]+ (1) is capable of reducing O2•- via a proton-dependent inner-sphere mechanism involving a transient Fe(III)-OOH intermediate. A transient ferric-superoxo intermediate, [FeIII(SMe2N4(tren))(O2)]+ (3), is detected by electronic absorption spectroscopy at -130 °C in the reaction between 1ox-THF and KO2 and shown to evolve O2 upon slight warming to -115 °C. The DFT calculated O-O (1.306 Å) and Fe-O (1.943 Å) bond lengths of 3 are typical of ferric-superoxo complexes, and the time-dependent DFT calculated electronic absorption spectrum of 3 reproduces the experimental spectrum. The electronic structure of 3 is shown to consist of two antiferromagnetically coupled (Jcalc = -180 cm-1) unpaired electrons, one in a superoxo π*(O-O) orbital and the other in an antibonding π*(Fe(dyz)-S(py)) orbital.
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Redox regulation in host-pathogen interactions: thiol switches and beyond.
Varatnitskaya, M, Degrossoli, A, Leichert, LI
Biological chemistry. 2021;(3):299-316
Abstract
Our organism is exposed to pathogens on a daily basis. Owing to this age-old interaction, both pathogen and host evolved strategies to cope with these encounters. Here, we focus on the consequences of the direct encounter of cells of the innate immune system with bacteria. First, we will discuss the bacterial strategies to counteract powerful reactive species. Our emphasis lies on the effects of hypochlorous acid (HOCl), arguably the most powerful oxidant produced inside the phagolysosome of professional phagocytes. We will highlight individual examples of proteins in gram-negative bacteria activated by HOCl via thiol-disulfide switches, methionine sulfoxidation, and N-chlorination of basic amino acid side chains. Second, we will discuss the effects of HOCl on proteins of the host. Recent studies have shown that both host and bacteria address failing protein homeostasis by activation of chaperone-like holdases through N-chlorination. After discussing the role of individual proteins in the HOCl-defense, we will turn our attention to the examination of effects on host and pathogen on a systemic level. Recent studies using genetically encoded redox probes and redox proteomics highlight differences in redox homeostasis in host and pathogen and give first hints at potential cellular HOCl signaling beyond thiol-disulfide switch mechanisms.
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Electrostatic interactions contribute to the control of intramolecular thiol-disulfide isomerization in a protein.
Maag, D, Putzu, M, Gómez-Flores, CL, Gräter, F, Elstner, M, Kubař, T
Physical chemistry chemical physics : PCCP. 2021;(46):26366-26375
Abstract
The roles of structural factors and of electrostatic interactions with the environment on the outcome of thiol-disulfide exchange reactions were investigated in a mutated immunoglobulin domain (I27*) under mechanical stress. An extensive ensemble of molecular dynamics trajectories was generated by means of QM/MM simulations for a total sampling of 5.7 μs. A significant number of thiol-disulfide exchanges were observed, and the Cys32 thiolate preferred to attack Cys55 over Cys24, in agreement with previous experimental and computational studies. The structural features as well as electronic structures of the thiol-disulfide system along the reaction were analyzed, as were the electrostatic interactions with the environment. The previous findings of better accessibility of Cys55 were confirmed. Additionally, the reaction was found to be directed by the electrostatic interactions of the involved sulfur atoms with the molecular environment. The relationships of atomic charges, which stem from the electrostatic interactions, lead to the kinetic preference of the attack on Cys55. Further, QM/MM metadynamics simulations of thiol-disulfide exchange in a small model system with varied artificial external electric potentials revealed changes in reaction kinetics of the same magnitude as in I27*. Therefore, the electrostatic interactions are confirmed to play a role in the regioselectivity of the thiol-disulfide exchange reactions in the protein.
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Neuroprotective effects of disubstituted dithiolethione ACDT against manganese-induced toxicity in SH-SY5Y cells.
Kulkarni, N, Gadde, R, Gugnani, KS, Vu, N, Yoo, C, Zaveri, R, Betharia, S
Neurochemistry international. 2021;:105052
Abstract
Dithiolethiones are lipophilic, organosulfur compounds that activate the Nrf2 transcription factor causing an upregulation of various phase II antioxidant enzymes. A disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) retains the functional pharmacophore while also containing modifiable functional groups. Neuroprotection against autoimmune encephalomyelitis in vivo and 6-hydroxy dopamine (a model for Parkinson's disease) in vitro have been previously reported with ACDT. Manganese (Mn) is a metal essential for metabolic processes at low concentrations. Overexposure and accumulation of Mn leads to a neurological condition called manganism which shares pathophysiological sequelae with parkinsonism. Here we hypothesized ACDT to be protective against manganese-induced cytotoxicity. SH-SY5Y human neuroblastoma cells exposed to 300 μM MnCl2 displayed approximately 50% cell death, and a 24-h pretreatment with 75 μM ACDT significantly reversed this cytotoxicity. ACDT pretreatment was also found to increase total GSH levels (2.18-fold) and the protein levels of NADPHquinone oxidoreductase-1 (NQO1) enzyme (6.33-fold), indicating an overall increase in the cells' antioxidant defense stores. A corresponding 2.32-fold reduction in the level of Mn-induced reactive oxygen species was also observed in cells pretreated with ACDT. While no changes were observed in the protein levels of apoptotic markers Bax and Bcl-2, pretreatment with 75 μM ACDT led to a 2.09-fold downregulation of ZIP14 import transporter, indicating a potential reduction in the cellular uptake of Mn as an additional neuroprotective mechanism. These effects did not extend to other transporters like the divalent metal transporter 1 (DMT1) or ferroportin. Collectively, ACDT showed substantial neuroprotection against Mn-induced cytotoxicity, opening a path for dithiolethiones as a potential novel therapeutic option against heavy metal neurotoxicity.
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Thiol-based redox switches in the major pathogen Staphylococcus aureus.
Linzner, N, Loi, VV, Fritsch, VN, Antelmann, H
Biological chemistry. 2021;(3):333-361
Abstract
Staphylococcus aureus is a major human pathogen, which encounters reactive oxygen, nitrogen, chlorine, electrophile and sulfur species (ROS, RNS, RCS, RES and RSS) by the host immune system, during cellular metabolism or antibiotics treatments. To defend against redox active species and antibiotics, S. aureus is equipped with redox sensing regulators that often use thiol switches to control the expression of specific detoxification pathways. In addition, the maintenance of the redox balance is crucial for survival of S. aureus under redox stress during infections, which is accomplished by the low molecular weight (LMW) thiol bacillithiol (BSH) and the associated bacilliredoxin (Brx)/BSH/bacillithiol disulfide reductase (YpdA)/NADPH pathway. Here, we present an overview of thiol-based redox sensors, its associated enzymatic detoxification systems and BSH-related regulatory mechanisms in S. aureus, which are important for the defense under redox stress conditions. Application of the novel Brx-roGFP2 biosensor provides new insights on the impact of these systems on the BSH redox potential. These thiol switches of S. aureus function in protection against redox active desinfectants and antimicrobials, including HOCl, the AGXX® antimicrobial surface coating, allicin from garlic and the naphthoquinone lapachol. Thus, thiol switches could be novel drug targets for the development of alternative redox-based therapies to combat multi-drug resistant S. aureus isolates.
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Effects of antiviral drug therapy on dynamic thiol/disulphide homeostasis and nitric oxide levels in COVID-19 patients.
Mete, AÖ, Koçak, K, Saracaloglu, A, Demiryürek, S, Altınbaş, Ö, Demiryürek, AT
European journal of pharmacology. 2021;:174306
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Abstract
The novel coronavirus disease 2019 (COVID-19) has led to a serious global pandemic. Although an oxidative stress imbalance occurs in COVID-19 patients, the contributions of thiol/disulphide homeostasis and nitric oxide (NO) generation to the pathogenesis of COVID-19 have been poorly identified. Therefore, the aim of this study was to evaluate the effects of antiviral drug therapy on the serum dynamics of thiol/disulphide homeostasis and NO levels in COVID-19 patients. A total of 50 adult patients with COVID-19 and 43 sex-matched healthy control subjects were enrolled in this prospective study. Venous blood samples were collected immediately on admission to the hospital within 24 h after the diagnosis (pre-treatment) and at the 15th day of drug therapy (post-treatment). Serum native thiol and total thiol levels were measured, and the amounts of dynamic disulphide bonds and related ratios were calculated. The average pre-treatment total and native thiol levels were significantly lower than the post-treatment values (P < 0.001 for all). We observed no significant changes in disulphide levels or disulphide/total thiol, disulphide/native thiol, or native thiol/total thiol ratios between pre- and post-treatments. There was also a significant increase in serum NO levels in the pre-treatment values when compared to control (P < 0.001) and post-treatment measurements (P < 0.01). Our results strongly suggest that thiol/disulphide homeostasis and nitrosative stress can contribute to the pathogenesis of COVID-19. This study was the first to show that antiviral drug therapy can prevent the depletion in serum thiol levels and decrease serum NO levels in COVID-19 patients.
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Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition.
Black, DM, Miller, M, Heinonen, TM, Zhang, G
Journal of cardiovascular pharmacology. 2021;(4):496-500
Abstract
Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.
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Measuring Reactive Sulfur Species and Thiol Oxidation States: Challenges and Cautions in Relation to Alkylation-Based Protocols.
Nagy, P, Dóka, É, Ida, T, Akaike, T
Antioxidants & redox signaling. 2020;(16):1174-1189
Abstract
Significance: Redox biology is gaining ground in research related to human physiology (metabolism, signaling), pathophysiology (cancer, cardiovascular disease, neurodegeneration), and toxicology (radiation- or xenobiotic-induced damage). A major hurdle in advancing redox medicine is the current lack of understanding the mechanisms underpinning the observed detrimental or beneficial in vivo effects. To gain deeper insights into the underlying molecular pathways of redox regulation, we need to appreciate the strengths and limitations of the currently available methods. Recent Advances: Reactive sulfur species (RSS), including cysteine derivatives of peptides and proteins along with small molecules such as hydrogen sulfide or inorganic polysulfides, are major players in redox biology. RSS-mediated regulation of protein functions is a widely studied mechanism in the field, and considerable efforts have been devoted to the development of selective detection methods. Critical Issues: A large number of available methods rely on an alkylation step to freeze the dynamism of consecutive oxidation and reduction events among RSS at a particular time point inside the cell. This process uses the assumption that alkylation blocks all redox events instantaneously. We argue that unfortunately this is often not the case, which could have serious impacts on detected sulfur species speciation and confound experimental results. Future Directions: Novel technologies and prudent optimization of existing methods to accurately characterize the dynamic redox status of the thiol proteome as well as detailed understanding of regulatory and signaling capacities of protein polysulfidation are crucial to open new routes toward therapeutic interventions.