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  1. Article ; Online: Myeloperoxidase Gene Deletion Causes Drastic Microbiome Shifts in Mice and Does Not Mitigate Dextran Sodium Sulphate-Induced Colitis.

    San Gabriel, Patrick T / O'Neil, Thomas R / Au, Alice / Tan, Jian K / Pinget, Gabriela V / Liu, Yuyang / Fong, Genevieve / Ku, Jacqueline / Glaros, Elias / Macia, Laurence / Witting, Paul K / Thomas, Shane R / Chami, Belal

    International journal of molecular sciences

    2024  Volume 25, Issue 8

    Abstract: Neutrophil-myeloperoxidase (MPO) is a heme-containing peroxidase which produces excess amounts of hypochlorous acid during inflammation. While pharmacological MPO inhibition mitigates all indices of experimental colitis, no studies have corroborated the ... ...

    Abstract Neutrophil-myeloperoxidase (MPO) is a heme-containing peroxidase which produces excess amounts of hypochlorous acid during inflammation. While pharmacological MPO inhibition mitigates all indices of experimental colitis, no studies have corroborated the role of MPO using knockout (KO) models. Therefore, we investigated MPO deficient mice in a murine model of colitis. Wild type (Wt) and MPO-deficient mice were treated with dextran sodium sulphate (DSS) in a chronic model of experimental colitis with three acute cycles of DSS-induced colitis over 63 days, emulating IBD relapse and remission cycles. Mice were immunologically profiled at the gut muscoa and the faecal microbiome was assessed via 16S rRNA amplicon sequencing. Contrary to previous pharmacological antagonist studies targeting MPO, MPO-deficient mice showed no protection from experimental colitis during cyclical DSS-challenge. We are the first to report drastic faecal microbiota shifts in MPO-deficient mice, showing a significantly different microbiome profile on Day 1 of treatment, with a similar shift and distinction on Day 29 (half-way point), via qualitative and quantitative descriptions of phylogenetic distances. Herein, we provide the first evidence of substantial microbiome shifts in MPO-deficiency, which may influence disease progression. Our findings have significant implications for the utility of MPO-KO mice in investigating disease models.
    MeSH term(s) Animals ; Dextran Sulfate ; Peroxidase/metabolism ; Peroxidase/genetics ; Mice ; Colitis/microbiology ; Colitis/chemically induced ; Colitis/genetics ; Mice, Knockout ; Gastrointestinal Microbiome ; Disease Models, Animal ; Feces/microbiology ; Gene Deletion ; RNA, Ribosomal, 16S/genetics ; Mice, Inbred C57BL
    Chemical Substances Dextran Sulfate (9042-14-2) ; Peroxidase (EC 1.11.1.7) ; RNA, Ribosomal, 16S
    Language English
    Publishing date 2024-04-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25084258
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  2. Article ; Online: The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease.

    San Gabriel, Patrick T / Liu, Yuyang / Schroder, Angie L / Zoellner, Hans / Chami, Belal

    International journal of molecular sciences

    2020  Volume 21, Issue 17

    Abstract: Thiocyanate ( ... ...

    Abstract Thiocyanate (SCN
    MeSH term(s) Animals ; Humans ; Peroxidase/metabolism ; Rheumatic Fever/drug therapy ; Rheumatic Fever/enzymology ; Rheumatic Fever/pathology ; Thiocyanates/pharmacology
    Chemical Substances Thiocyanates ; Peroxidase (EC 1.11.1.7)
    Keywords covid19
    Language English
    Publishing date 2020-09-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21176450
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  3. Article: The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease

    San Gabriel, Patrick T / Liu, Yuyang / Schroder, Angie L / Zoellner, Hans / Chami, Belal

    Abstract: Thiocyanate (SCN-) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F-, Br-, I-) as ... ...

    Abstract Thiocyanate (SCN-) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F-, Br-, I-) as substrates for myeloperoxidase by undergoing two-electron oxidation with hydrogen peroxide. This forms their respective hypohalous acids (HOX where X- = halides) and in the case of thiocyanate, hypothiocyanous acid (HOSCN), which is also a bactericidal oxidative species involved in the regulation of commensal and pathogenic microflora. Disease may dysregulate redox processes and cause imbalances in the oxidative profile, where typically favoured oxidative species, such as hypochlorous acid (HOCl), result in an overabundance of chlorinated protein residues. As such, the pharmacological capacity of thiocyanate has been recently investigated for its ability to modulate myeloperoxidase activity for HOSCN, a less potent species relative to HOCl, although outcomes vary significantly across different disease models. To date, most studies have focused on therapeutic effects in respiratory and cardiovascular animal models. However, we note other conditions such as rheumatic arthritis where SCN- administration may worsen patient outcomes. Here, we discuss the pathophysiological role of SCN- in diseases where MPO is implicated.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #32899436
    Database COVID19

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  4. Article ; Online: The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease

    San Gabriel, Patrick T. / Liu, Yuyang / Schroder, Angie L. / Zoellner, Hans / Chami, Belal

    2020  

    Abstract: Thiocyanate (SCN-) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F-, Br-, I-) as ... ...

    Abstract Thiocyanate (SCN-) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F-, Br-, I-) as substrates for myeloperoxidase by undergoing two-electron oxidation with hydrogen peroxide. This forms their respective hypohalous acids (HOX where X- = halides) and in the case of thiocyanate, hypothiocyanous acid (HOSCN), which is also a bactericidal oxidative species involved in the regulation of commensal and pathogenic microflora. Disease may dysregulate redox processes and cause imbalances in the oxidative profile, where typically favoured oxidative species, such as hypochlorous acid (HOCl), result in an overabundance of chlorinated protein residues. As such, the pharmacological capacity of thiocyanate has been recently investigated for its ability to modulate myeloperoxidase activity for HOSCN, a less potent species relative to HOCl, although outcomes vary significantly across different disease models. To date, most studies have focused on therapeutic effects in respiratory and cardiovascular animal models. However, we note other conditions such as rheumatic arthritis where SCN- administration may worsen patient outcomes. Here, we discuss the pathophysiological role of SCN- in diseases where MPO is implicated.
    Keywords COVID-19 ; Coronavirus ; covid19
    Language English
    Publishing date 2020-01-01
    Publishing country au
    Document type Article ; Online
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  5. Article ; Online: The nitroxide 4-methoxy-tempo inhibits the pathogenesis of dextran sodium sulfate-stimulated experimental colitis.

    Chami, Belal / San Gabriel, Patrick T / Kum-Jew, Stephen / Wang, XiaoSuo / Dickerhof, Nina / Dennis, Joanne M / Witting, Paul K

    Redox biology

    2019  Volume 28, Page(s) 101333

    Abstract: Inflammatory bowel disease (IBD) is a chronic condition characterised by leukocyte recruitment to the gut mucosa. Leukocyte myeloperoxidase (MPO) produces the two-electron oxidant hypochlorous acid (HOCl), damaging tissue and playing a role in cellular ... ...

    Abstract Inflammatory bowel disease (IBD) is a chronic condition characterised by leukocyte recruitment to the gut mucosa. Leukocyte myeloperoxidase (MPO) produces the two-electron oxidant hypochlorous acid (HOCl), damaging tissue and playing a role in cellular recruitment, thereby exacerbating gut injury. We tested whether the MPO-inhibitor, 4-Methoxy-TEMPO (MetT), ameliorates experimental IBD. Colitis was induced in C57BL/6 mice by 3% w/v dextran-sodium-sulfate (DSS) in drinking water ad libitum over 9-days with MetT (15 mg/kg; via i. p. injection) or vehicle control (10% v/v DMSO+90% v/v phosphate buffered saline) administered twice daily during DSS challenge. MetT attenuated body-weight loss (50%, p < 0.05, n = 6), improved clinical score (53%, p < 0.05, n = 6) and inhibited serum lipid peroxidation. Histopathological damage decreased markedly in MetT-treated mice, as judged by maintenance of crypt integrity, goblet cell density and decreased cellular infiltrate. Colonic Ly6C
    MeSH term(s) Animals ; Biopsy ; Colitis/diagnostic imaging ; Colitis/drug therapy ; Colitis/etiology ; Colitis/pathology ; Cyclic N-Oxides/pharmacology ; Dextran Sulfate/adverse effects ; Disease Models, Animal ; Disease Susceptibility ; Immunohistochemistry ; Inflammatory Bowel Diseases/etiology ; Inflammatory Bowel Diseases/metabolism ; Inflammatory Bowel Diseases/pathology ; Mice ; Optical Imaging ; Oxidation-Reduction ; Oxidative Stress ; Phenotype ; Protective Agents/pharmacology
    Chemical Substances Cyclic N-Oxides ; Protective Agents ; Dextran Sulfate (9042-14-2) ; 4-methoxy-2,2,6,6-tetramethylpiperidinyl-1-oxy (95407-69-5)
    Language English
    Publishing date 2019-09-28
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701011-9
    ISSN 2213-2317 ; 2213-2317
    ISSN (online) 2213-2317
    ISSN 2213-2317
    DOI 10.1016/j.redox.2019.101333
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  6. Article: The role of sodium thiocyanate supplementation during dextran sodium sulphate-stimulated experimental colitis

    Liu, Yuyang / Burton, Thomas / Rayner, Benjamin Saul / San Gabriel, Patrick T / Shi, Han / El Kazzi, Mary / Wang, XiaoSuo / Dennis, Joanne M / Ahmad, Gulfam / Schroder, Angie L / Gao, Antony / Witting, Paul Kenneth / Chami, Belal

    Archives of biochemistry and biophysics. 2020 Oct. 15, v. 692

    2020  

    Abstract: Ulcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride (Cl⁻) and thiocyanous (SCN⁻) ... ...

    Abstract Ulcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride (Cl⁻) and thiocyanous (SCN⁻) anions, respectively. While HOCl indiscriminately oxidises biomolecules, HOSCN primarily targets low-molecular weight protein thiols. Oxidative damage mediated by HOSCN may be reversible, potentially decreasing MPO-associated host tissue destruction. This study investigated the effect of SCN⁻ supplementation in a model of acute colitis. Female mice were supplemented dextran sodium sulphate (DSS, 3% w/v) in the presence of 10 mM Cl⁻ or SCN⁻ in drinking water ad libitum, or with salts (NaCl and NaSCN only) or water only (controls). Behavioural studies showed mice tolerated NaSCN and NaCl-treated water with water-seeking frequency. Ion-exchange chromatography showed increased fecal and plasma SCN⁻ levels in thiocyanate supplemented mice; plasma SCN⁻ reached similar fold-increase for smokers. Overall there was no difference in weight loss and clinical score, mucin levels, crypt integrity and extent of cellular infiltration between DSS/SCN⁻ and DSS/Cl⁻ groups. Neutrophil recruitment remained unchanged in DSS-treated mice, as assessed by fecal calprotectin levels. Total thiol and tyrosine phosphatase activity remained unchanged between DSS/Cl⁻ and DSS/SCN⁻ groups, however, colonic tissue showed a trend in decreased 3-chlorotyrosine (1.5-fold reduction, p < 0.051) and marked increase in colonic GCLC, the rate-limiting enzyme in glutathione synthesis. These data suggest that SCN⁻ administration can modulate MPO activity towards a HOSCN-specific pathway, however, this does not alter the development of colitis within a DSS murine model.
    Keywords animal models ; biophysics ; dextran ; enzymes ; females ; gastrointestinal system ; glutathione ; ion exchange chromatography ; mucins ; neutrophils ; sodium ; sodium sulfate ; thiocyanates ; thiols ; tyrosine ; ulcerative colitis ; weight loss
    Language English
    Dates of publication 2020-1015
    Publishing place Elsevier Inc.
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1016/j.abb.2020.108490
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  7. Article: The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis.

    Ahmad, Gulfam / Chami, Belal / Liu, Yuyang / Schroder, Angie L / San Gabriel, Patrick T / Gao, Antony / Fong, Genevieve / Wang, XiaoSuo / Witting, Paul K

    Frontiers in pharmacology

    2020  Volume 11, Page(s) 556020

    Abstract: Chronic inflammatory bowel disease (IBD) is a condition with multifactorial pathophysiology. To date, there is no permanent cure and the disease is primarily managed by immunosuppressive drugs; long-term use promotes serious side effects including ... ...

    Abstract Chronic inflammatory bowel disease (IBD) is a condition with multifactorial pathophysiology. To date, there is no permanent cure and the disease is primarily managed by immunosuppressive drugs; long-term use promotes serious side effects including increased risk malignancies. The current study aimed to target neutrophil-myeloperoxidase, a key contributor to the pathogenesis of IBD, through the use of AZD3241that inhibits extracellular myeloperoxidase. Experimental colitis was induced in C57BL/6 male mice by 2% dextran sodium sulfate in drinking water
    Language English
    Publishing date 2020-09-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2020.556020
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  8. Article ; Online: The role of sodium thiocyanate supplementation during dextran sodium sulphate-stimulated experimental colitis.

    Liu, Yuyang / Burton, Thomas / Rayner, Benjamin Saul / San Gabriel, Patrick T / Shi, Han / El Kazzi, Mary / Wang, XiaoSuo / Dennis, Joanne M / Ahmad, Gulfam / Schroder, Angie L / Gao, Antony / Witting, Paul Kenneth / Chami, Belal

    Archives of biochemistry and biophysics

    2020  Volume 692, Page(s) 108490

    Abstract: Ulcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride ( ... ...

    Abstract Ulcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride (Cl
    MeSH term(s) Animals ; Colitis/chemically induced ; Colitis/drug therapy ; Colitis/enzymology ; Colitis/pathology ; Colon/enzymology ; Colon/pathology ; Dextran Sulfate/toxicity ; Disease Models, Animal ; Female ; Mice ; Peroxidase/metabolism ; Thiocyanates/pharmacology
    Chemical Substances Thiocyanates ; sodium thiocyanate (5W0K9HKA05) ; Dextran Sulfate (9042-14-2) ; Peroxidase (EC 1.11.1.7)
    Language English
    Publishing date 2020-07-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1016/j.abb.2020.108490
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    In stock of ZB MED Cologne/Königswinter

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