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International Journal of Molecular... Sep 2022This review discusses the formation of hypochlorous acid HOCl and the role of reactive chlorinated species (RCS), which are catalysed by the enzyme myeloperoxidase MPO,... (Review)
Review
This review discusses the formation of hypochlorous acid HOCl and the role of reactive chlorinated species (RCS), which are catalysed by the enzyme myeloperoxidase MPO, mainly located in leukocytes and which in turn contribute to cellular oxidative stress. The reactions of RCS with various organic molecules such as amines, amino acids, proteins, lipids, carbohydrates, nucleic acids, and DNA are described, and an attempt is made to explain the chemical mechanisms of the formation of the various chlorinated derivatives and the data available so far on the effects of MPO, RCS and halogenative stress. Their presence in numerous pathologies such as atherosclerosis, arthritis, neurological and renal diseases, diabetes, and obesity is reviewed and were found to be a feature of debilitating diseases.
Topics: Amines; Amino Acids; Animals; Carbohydrates; Hypochlorous Acid; Lipids; Mammals; Nucleic Acids; Peroxidase
PubMed: 36142645
DOI: 10.3390/ijms231810735 -
Frontiers in Immunology 2023Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, is...
BACKGROUND
Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between and with susceptibility to, and with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of , which is in strong linkage disequilibrium with and , with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether is associated with the risk of relapse in MPO-AAV.
METHODS
First, the association of with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported and were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (P) were corrected for multiple comparisons in each analysis using the false discovery rate method.
RESULTS
The association of with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: P=5.8x10, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: P=1.1x10, OR 1.71, 95%CI 1.34-2.17). was in strong linkage disequilibrium with and , and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of (P=0.049, Q=0.42, hazard ratio [HR]:1.87), (P=0.020, Q=0.22, HR:2.11) and (P=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including carriers, showed longer relapse-free survival with nominal significance (P=0.010, Q=0.42, HR:0.31). By combining and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (P=0.0055, Q=0.033, HR:4.02).
CONCLUSION
is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Peroxidase; East Asian People; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis; Myeloblastin
PubMed: 36969218
DOI: 10.3389/fimmu.2023.1119064 -
Gut Microbes 2022This study investigates the interplay between Lon protease and catalase-peroxidase (KatG) in relation to virulence modulation and the response to oxidative stress in...
This study investigates the interplay between Lon protease and catalase-peroxidase (KatG) in relation to virulence modulation and the response to oxidative stress in Typhimurium (ST). Proteomic comparison of ST wild-type and deletion mutant led to the recognition of a highly expressed KatG protein product among five other protein candidates that were significantly affected by deletion. By employing a bacterium two-hybrid assay (B2H), we demonstrated that the catalytic domain of Lon protease potentially interacts with the KatG protein that leads to proteolytic cleavage. Assessment of virulence gene expression in single and double and mutants revealed to be a potential positive modulator of both pathogenicity Island-1 (SPI-1) and -2, while significantly affected SPI-1 genes. ST double deletion mutant, ∆ was more susceptible to survival defects within macrophage-like cells and exhibited meager colonization of the mouse spleen compared to the single deletion mutants. The findings reveal a previously unknown function of Lon and KatG interaction in virulence. Taken together, our experiments demonstrate the importance of Lon and KatG to cope with oxidative stress, for intracellular survival and virulence of .
Topics: Animals; Bacterial Proteins; Catalase; Gastrointestinal Microbiome; Gene Expression Regulation, Bacterial; Mice; Oxidative Stress; Peroxidase; Protease La; Proteomics; Salmonella Infections; Salmonella typhimurium; Virulence
PubMed: 35438052
DOI: 10.1080/19490976.2022.2064705 -
International Journal of Molecular... Dec 2021The treatment of environmental pollutants such as synthetic dyes and lignin has received much attention, especially for biotechnological treatments using both native and...
The treatment of environmental pollutants such as synthetic dyes and lignin has received much attention, especially for biotechnological treatments using both native and artificial metalloenzymes. In this study, we designed and engineered an efficient peroxidase using the O carrier myoglobin (Mb) as a protein scaffold by four mutations (F43Y/T67R/P88W/F138W), which combines the key structural features of natural peroxidases such as the presence of a conserved His-Arg pair and Tyr/Trp residues close to the heme active center. Kinetic studies revealed that the quadruple mutant exhibits considerably enhanced peroxidase activity, with the catalytic efficiency (/) comparable to that of the most efficient natural enzyme, horseradish peroxidase (HRP). Moreover, the designed enzyme can effectively decolorize a variety of synthetic organic dyes and catalyze the bioconversion of lignin, such as Kraft lignin and a model compound, guaiacylglycerol-β-guaiacyl ether (GGE). As analyzed by HPLC and ESI-MS, we identified several bioconversion products of GGE, as produced via bond cleavage followed by dimerization or trimerization, which illustrates the mechanism for lignin bioconversion. This study indicates that the designed enzyme could be exploited for the decolorization of textile wastewater contaminated with various dyes, as well as for the bioconversion of lignin to produce more value-added products.
Topics: Animals; Chromatography, High Pressure Liquid; Color; Coloring Agents; Guaifenesin; Heme; Hydrogen Peroxide; Kinetics; Lignin; Myoglobin; Oxidation-Reduction; Peroxidase; Polymerization; Protein Engineering; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Sperm Whale
PubMed: 35008837
DOI: 10.3390/ijms23010413 -
Journal of Neurotrauma Aug 2022Advanced age at the time of spinal cord injury (SCI) exacerbates damage from reactive oxygen species (ROS). Mechanisms underlying this age-dependent response are not...
Advanced age at the time of spinal cord injury (SCI) exacerbates damage from reactive oxygen species (ROS). Mechanisms underlying this age-dependent response are not well understood and may arise from decreased antioxidant defense. We investigated how spinal cord levels of the antioxidant glutathione (GSH), and its regulation, change with age and SCI. GSH is used by GSH peroxidase to sequester ROS and is recycled by GSH reductase. Male and female, 4- and 14-month-old (MO) mice received a 60 kDyn contusion SCI, and the levels of GSH and its regulatory enzymes were evaluated at one and three days post-injury (dpi). The mice with SCI were treated with N-acetylcysteine-amide (NACA; 150 mg/kg), a cysteine supplement that increases GSH, to determine effects on functional and histological outcomes. GSH was decreased with older age in sham mice, and an SCI-dependent depletion was observed in 4-MO mice by three dpi. Neither age nor injury affected the abundance of proteins regulating GSH synthesis or recycling. GSH peroxidase activity, however, increased after SCI only in 4-MO mice. In contrast, GSH peroxidase activity was increased in 14-MO sham mice, indicating that spinal cords of older mice have an elevated oxidative state. Indeed, 14-MO sham mice had more oxidized protein (3-nitrotyrosine [3-NT]) within their spinal cords compared with 4-MO sham mice. Only 4-MO mice had significant injury-induced increases in 3-NT at three dpi. NACA treatment restored GSH and improved the redox environment in injured 4- and 14-MO mice at one dpi; however, three days of NACA delivery did not improve motor, sensory, or anatomical deficits at 28 dpi in 4-MO mice and trended toward toxicity in all outcomes in 14-MO mice. Our observation suggests that GSH levels at acute stages of SCI play a minimal role in age-dependent outcomes reported after SCI in mice. Collective results implicate elements of injury occurring after three dpi, such as inflammation, as key regulators of age-dependent effects.
Topics: Animals; Antioxidants; Female; Glutathione; Male; Mice; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Spinal Cord; Spinal Cord Injuries
PubMed: 35373589
DOI: 10.1089/neu.2022.0010 -
Biochimica Et Biophysica Acta. Proteins... Jan 2020Human peroxidasin 1 is a multidomain peroxidase situated in the basement membrane. The iron enzyme with covalently bound heme oxidizes bromide to hypobromous acid which...
Human peroxidasin 1 is a multidomain peroxidase situated in the basement membrane. The iron enzyme with covalently bound heme oxidizes bromide to hypobromous acid which facilitates the formation of distinct sulfilimine cross-links in the collagen IV network and therefore contributes to its mechanical stability. Additional to the catalytically active peroxidase domain peroxidasin comprises a leucine rich repeat domain, four Ig domains and a C-terminal von Willebrand factor type C module (VWC). Peroxidasin has been shown to form homotrimers involving two redox-sensitive cysteine residues and to undergo posttranslational C-terminal proteolytic cleavage. The present study on several recombinantly produced truncated peroxidasin variants showed that the VWC is not required for trimer formation whereas the alpha-helical linker region located between the peroxidase domain and the VWC is crucial for trimerization. Our data furthermore implies that peroxidasin oligomerization occurs intracellularly before C-terminal cleavage. For the first time we present overall solution structures of monomeric and trimeric truncated peroxidasin variants which were determined by rotary shadowing combined with transmission electron microscopy and by small-angle X-ray scattering (SAXS). A triangular arrangement of the peroxidase domains to each other within the homotrimer was revealed and this structure was confirmed by a model of trimeric peroxidase domains. Our SAXS data showed that the Ig domains are highly flexible and interact with the peroxidase domain and that within the homotrimer each alpha-helical linker region interacts with the respective adjacent peroxidase domain. The implications of our findings on the structure-function relationship of peroxidasin are discussed.
Topics: Extracellular Matrix Proteins; Humans; Models, Molecular; Peroxidase; Protein Multimerization; Recombinant Proteins; Peroxidasin
PubMed: 31295557
DOI: 10.1016/j.bbapap.2019.07.002 -
International Journal of Molecular... Oct 2022Myeloperoxidase (MPO) is one of the most abundantly expressed proteins in neutrophils. It serves as a critical component of the antimicrobial defense system,... (Review)
Review
Myeloperoxidase (MPO) is one of the most abundantly expressed proteins in neutrophils. It serves as a critical component of the antimicrobial defense system, facilitating microbial killing via generation of reactive oxygen species (ROS). Interestingly, emerging evidence indicates that in addition to the well-recognized canonical antimicrobial function of MPO, it can directly or indirectly impact immune cells and tissue responses in homeostatic and disease states. Here, we highlight the emerging non-canonical functions of MPO, including its impact on neutrophil longevity, activation and trafficking in inflammation, its interactions with other immune cells, and how these interactions shape disease outcomes. We further discuss MPO interactions with barrier forming endothelial and epithelial cells, specialized cells of the central nervous system (CNS) and its involvement in cancer progression. Such diverse function and the MPO association with numerous inflammatory disorders make it an attractive target for therapies aimed at resolving inflammation and limiting inflammation-associated tissue damage. However, while considering MPO inhibition as a potential therapy, one must account for the diverse impact of MPO activity on various cellular compartments both in health and disease.
Topics: Humans; Peroxidase; Reactive Oxygen Species; Inflammation; Neutrophils; Neoplasms
PubMed: 36293108
DOI: 10.3390/ijms232012250 -
Signal Transduction and Targeted Therapy Mar 2022The current feasibility of nanocatalysts in clinical anti-infection therapy, especially for drug-resistant bacteria infection is extremely restrained because of the...
The current feasibility of nanocatalysts in clinical anti-infection therapy, especially for drug-resistant bacteria infection is extremely restrained because of the insufficient reactive oxygen generation. Herein, a novel Ag/BiMoO (Ag/BMO) nanozyme optimized by charge separation engineering with photoactivated sustainable peroxidase-mimicking activities and NIR-II photodynamic performance was synthesized by solvothermal reaction and photoreduction. The Ag/BMO nanozyme held satisfactory bactericidal performance against methicillin-resistant Staphylococcus aureus (MRSA) (~99.9%). The excellent antibacterial performance of Ag/BMO NPs was ascribed to the corporation of peroxidase-like activity, NIR-II photodynamic behavior, and acidity-enhanced release of Ag. As revealed by theoretical calculations, the introduction of Ag to BMO made it easier to separate photo-triggered electron-hole pairs for ROS production. And the conduction and valence band potentials of Ag/BMO NPs were favorable for the reduction of O to ·O. Under 1064 nm laser irradiation, the electron transfer to BMO was beneficial to the reversible change of Mo/Mo, further improving the peroxidase-like catalytic activity and NIR-II photodynamic performance based on the Russell mechanism. In vivo, the Ag/BMO NPs exhibited promising therapeutic effects towards MRSA-infected wounds. This study enriches the nanozyme research and proves that nanozymes can be rationally optimized by charge separation engineering strategy.
Topics: Anti-Bacterial Agents; Bacteria; Hydrogen-Ion Concentration; Methicillin-Resistant Staphylococcus aureus; Peroxidase; Photochemotherapy
PubMed: 35342192
DOI: 10.1038/s41392-022-00900-8 -
Redox Biology Oct 2021This review provides a practical guide to myeloperoxidase (MPO) and presents to the reader the diversity of its presence in biology. The review provides a historical... (Review)
Review
This review provides a practical guide to myeloperoxidase (MPO) and presents to the reader the diversity of its presence in biology. The review provides a historical background, from peroxidase activity to the discovery of MPO, to its role in disease and drug development. MPO is discussed in terms of its necessity, as specific individuals lack MPO expression. An underlying theme presented throughout brings up the question of the benefit and burden of MPO activity. Enzyme structure is discussed, including accurate masses and glycosylation sites. The catalytic cycle of MPO and its corresponding pathways are presented, with a discussion of the importance of the redox couples of the different states of MPO. Cell lines expressing MPO are discussed and practically summarized for the reader, and locations of MPO (primary and secondary) are provided. Useful methods of MPO detection are discussed, and how these can be used for studying disease processes are implied through the presentation of MPO as a biomarker. The presence of MPO in neutrophil extracellular traps is presented, and the activators of the former are provided. Lastly, the transition from drug metabolism to a target for drug development is where the review concludes.
Topics: Biomarkers; Drug Discovery; Humans; Inflammation; Neutrophils; Peroxidase; Pharmaceutical Preparations
PubMed: 34455146
DOI: 10.1016/j.redox.2021.102109 -
Free Radical Biology & Medicine Sep 2023Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous...
Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br), or thiocyanate (SCN) as substrates. AECs exposed to GOX/MPO/SCN (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br diverged significantly from GOX/MPO/SCN for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br-treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.
Topics: Humans; Child, Preschool; Thiocyanates; Peroxidase; Cystic Fibrosis; Bromides; Chlorides; Oxidants; Antioxidants; Hypochlorous Acid; Epithelial Cells; Metabolomics
PubMed: 37356776
DOI: 10.1016/j.freeradbiomed.2023.06.021