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Expert Opinion on Therapeutic Targets Jul 2020Coronary artery disease (CAD) poses significant morbidity and mortality globally. Despite significant advances in treatment interventions, residual cardiovascular risks... (Review)
Review
INTRODUCTION
Coronary artery disease (CAD) poses significant morbidity and mortality globally. Despite significant advances in treatment interventions, residual cardiovascular risks remain unchecked. Recent clinical trials have shed light on the potential therapeutic benefits of targeting anti-inflammatory pathways. Myeloperoxidase (MPO) plays an important role in atherosclerotic plaque formation and destabilization of the fibrous cap; both increase the risk of atherosclerotic cardiovascular disease and especially CAD.
AREAS COVERED
This article examines the role of MPO in the pathogenesis of atherosclerotic CAD and the mechanistic data from several key therapeutic drug targets. There have been numerous interesting studies on prototype compounds that directly or indirectly attenuate the enzymatic activities of MPO, and subsequently exhibit atheroprotective effects; these include aminobenzoic acid hydrazide, ferulic acid derivative (INV-315), thiouracil derivatives (PF-1355 and PF-06282999), 2-thioxanthines derivative (AZM198), triazolopyrimidines, acetaminophen, N-acetyl lysyltyrosylcysteine (KYC), flavonoids, and alternative substrates such as thiocyanate and nitroxide radical.
EXPERT OPINION
Future investigations must determine if the cardiovascular benefits of direct systemic inhibition of MPO outweigh the risk of immune dysfunction, which may be less likely to arise with alternative substrates or MPO inhibitors that selectively attenuate atherogenic effects of MPO.
Topics: Animals; Anti-Inflammatory Agents; Coronary Artery Disease; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Peroxidase; Plaque, Atherosclerotic
PubMed: 32336171
DOI: 10.1080/14728222.2020.1762177 -
International Journal of Molecular... Apr 2023Phenols are widely used in industries despite their toxicity, which requires governments to limit their concentration in water to 5 mg/L before discharge to the city...
Phenols are widely used in industries despite their toxicity, which requires governments to limit their concentration in water to 5 mg/L before discharge to the city sewer. Thus, it is essential to develop a rapid, simple, and low-cost detection method for phenol. This study explored two pathways of peroxidase immobilization to develop a phenol detection system: peroxidase encapsulation into polyelectrolyte microcapsules and peroxidase captured by CaCO. The encapsulation of peroxidase decreased enzyme activity by 96%; thus, this method cannot be used for detection systems. The capturing process of peroxidase by CaCO microspherulites did not affect the maximum reaction rate and the Michaelis constant of peroxidase. The native peroxidase-Vmax = 109 µM/min, Km = 994 µM; CaCO-peroxidase-Vmax = 93.5 µM/min, Km = 956 µM. Ultimately, a reusable phenol detection system based on CaCO microparticles with immobilized peroxidase was developed, capable of detecting phenol in the range of 700 ng/mL to 14 µg/mL, with an error not exceeding 5%, and having a relatively low cost and production time. The efficiency of the system was confirmed by determining the content of phenol in a paintwork product.
Topics: Phenol; Peroxidase; Phenols; Peroxidases; Enzymes, Immobilized; Horseradish Peroxidase
PubMed: 37047739
DOI: 10.3390/ijms24076766 -
Pharmacology & Therapeutics Aug 2022Myeloperoxidase is a heme-peroxidase which makes up approximately 5% of the total dry cell weight of neutrophils where it is predominantly found in the primary... (Review)
Review
Myeloperoxidase is a heme-peroxidase which makes up approximately 5% of the total dry cell weight of neutrophils where it is predominantly found in the primary (azurophilic) granules. Other cell types, such as monocytes and certain macrophage subpopulations also contain myeloperoxidase, but to a much lesser extent. Initially, the function of myeloperoxidase had been mainly associated with its ability as a catalyzer of reactive oxidants that help to clear pathogens. However, over the past years non-canonical functions of myeloperoxidase have been described both in health and disease. Attention has been specially focused on inflammatory diseases, in which an exacerbate infiltration of leukocytes can favor a poorly-controlled production and release of myeloperoxidase and its oxidants. There is compelling evidence that myeloperoxidase derived oxidants contribute to tissue damage and the development and propagation of acute and chronic vascular inflammation. Recently, neutrophils have attracted much attention within the large diversity of innate immune cells that are part of the tumor microenvironment. In particular, neutrophil-derived myeloperoxidase may play an important role in cancer development and progression. This review article aims to provide a comprehensive overview of the roles of myeloperoxidase in the development and progression of cancer. We propose future research approaches and explore prospects of inhibiting myeloperoxidase as a strategy to fight against cancer.
Topics: Humans; Inflammation; Neoplasms; Neutrophils; Oxidants; Peroxidase; Tumor Microenvironment
PubMed: 34890688
DOI: 10.1016/j.pharmthera.2021.108052 -
Biosensors Dec 2023Immunoassays based on antibodies as recognizing elements and enzymes as signal-generating modules are extensively used now in clinical lab diagnostics, food, and... (Review)
Review
Immunoassays based on antibodies as recognizing elements and enzymes as signal-generating modules are extensively used now in clinical lab diagnostics, food, and environmental analyses. However, the application of natural enzymes and antibodies has some drawbacks, such as relatively high manufacturing costs, thermal instability, and lot-to-lot variations that lower the reproducibility of results. Oligonucleotide aptamers are able to specifically bind their targets with high affinity and selectivity, so they represent a prospective alternative to protein antibodies for analyte recognition. Their main advantages include thermal stability and long shelf life, cost-efficient chemical synthesis, and negligible batch-to-batch variations. At the same time, a wide variety of non-protein peroxidase mimics are now available that show strong potential to replace protein enzymes. Here, we review and analyze non-protein biosensors that represent a nexus of these two concepts: aptamer-based sensors (aptasensors) with optical detection (colorimetric, luminescent, or fluorescent) based on different peroxidase mimics, such as DNAzymes, nanoparticles, or metal-organic frameworks.
Topics: Peroxidase; Prospective Studies; Reproducibility of Results; Peroxidases; Oligonucleotides; Biosensing Techniques; Antibodies; Aptamers, Nucleotide
PubMed: 38275302
DOI: 10.3390/bios14010001 -
Frontiers in Immunology 2021Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for... (Review)
Review
Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for many other autoimmune diseases, current treatments, which consist of general immunosuppressants, are partially effective, toxic and broadly immunosuppressive, causing significant and serious adverse effects in many patients. Therefore, there is an urgent need for more targeted and less harmful therapies. Tolerogenic dendritic cells, regulatory T cells and stem cells have emerged as attractive, new and safer options for the treatment for various autoimmune diseases due to their unique and selective immunosuppressive capacity. In this review, we will discuss how these cellular therapies offer potential to become novel and safer treatments for MPO-AAV.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Cell- and Tissue-Based Therapy; Humans; Peroxidase
PubMed: 34394071
DOI: 10.3389/fimmu.2021.642127 -
Free Radical Biology & Medicine Aug 2021The heme peroxidase family generates a battery of oxidants both for synthetic purposes, and in the innate immune defence against pathogens. Myeloperoxidase (MPO) is the... (Review)
Review
The heme peroxidase family generates a battery of oxidants both for synthetic purposes, and in the innate immune defence against pathogens. Myeloperoxidase (MPO) is the most promiscuous family member, generating powerful oxidizing species including hypochlorous acid (HOCl). Whilst HOCl formation is important in pathogen removal, this species is also implicated in host tissue damage and multiple inflammatory diseases. Significant oxidant formation and damage occurs extracellularly as a result of MPO release via phagolysosomal leakage, cell lysis, extracellular trap formation, and inappropriate trafficking. MPO binds strongly to extracellular biomolecules including polyanionic glycosaminoglycans, proteoglycans, proteins, and DNA. This localizes MPO and subsequent damage, at least partly, to specific sites and species, including extracellular matrix (ECM) components and plasma proteins/lipoproteins. Biopolymer-bound MPO retains, or has enhanced, catalytic activity, though evidence is also available for non-catalytic effects. These interactions, particularly at cell surfaces and with the ECM/glycocalyx induce cellular dysfunction and altered gene expression. MPO binds with higher affinity to some damaged ECM components, rationalizing its accumulation at sites of inflammation. MPO-damaged biomolecules and fragments act as chemo-attractants and cell activators, and can modulate gene and protein expression in naïve cells, consistent with an increasing cycle of MPO adhesion, activity, damage, and altered cell function at sites of leukocyte infiltration and activation, with subsequent tissue damage and dysfunction. MPO levels are used clinically both diagnostically and prognostically, and there is increasing interest in strategies to prevent MPO-mediated damage; therapeutic aspects are not discussed as these have been reviewed elsewhere.
Topics: Humans; Hypochlorous Acid; Inflammation; Oxidants; Oxidation-Reduction; Peroxidase
PubMed: 34246778
DOI: 10.1016/j.freeradbiomed.2021.07.007 -
Arthritis & Rheumatology (Hoboken, N.J.) Jan 2023Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be...
OBJECTIVE
Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis.
METHODS
Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization.
RESULTS
We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV.
CONCLUSION
These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Inflammation; Receptors, Fc; Immunoglobulin G; Immunity, Innate; Peroxidase; Syk Kinase
PubMed: 36428281
DOI: 10.1002/art.42321 -
The Journal of Biological Chemistry Aug 2022The protozoan parasite Trypanosoma cruzi is the causative agent of American trypanosomiasis, otherwise known as Chagas disease. To survive in the host, the T. cruzi...
The protozoan parasite Trypanosoma cruzi is the causative agent of American trypanosomiasis, otherwise known as Chagas disease. To survive in the host, the T. cruzi parasite needs antioxidant defense systems. One of these is a hybrid heme peroxidase, the T. cruzi ascorbate peroxidase-cytochrome c peroxidase enzyme (TcAPx-CcP). TcAPx-CcP has high sequence identity to members of the class I peroxidase family, notably ascorbate peroxidase (APX) and cytochrome c peroxidase (CcP), as well as a mitochondrial peroxidase from Leishmania major (LmP). The aim of this work was to solve the structure and examine the reactivity of the TcAPx-CcP enzyme. Low temperature electron paramagnetic resonance spectra support the formation of an exchange-coupled [Fe(IV)=O Trp] compound I radical species, analogous to that used in CcP and LmP. We demonstrate that TcAPx-CcP is similar in overall structure to APX and CcP, but there are differences in the substrate-binding regions. Furthermore, the electron transfer pathway from cytochrome c to the heme in CcP and LmP is preserved in the TcAPx-CcP structure. Integration of steady state kinetic experiments, molecular dynamic simulations, and bioinformatic analyses indicates that TcAPx-CcP preferentially oxidizes cytochrome c but is still competent for oxidization of ascorbate. The results reveal that TcAPx-CcP is a credible cytochrome c peroxidase, which can also bind and use ascorbate in host cells, where concentrations are in the millimolar range. Thus, kinetically and functionally TcAPx-CcP can be considered a hybrid peroxidase.
Topics: Antioxidants; Ascorbate Peroxidases; Ascorbic Acid; Chagas Disease; Cytochrome-c Peroxidase; Cytochromes c; Heme; Humans; Peroxidase; Peroxidases; Substrate Specificity; Trypanosoma cruzi
PubMed: 35772495
DOI: 10.1016/j.jbc.2022.102204 -
BMC Oral Health Jan 2021Disturbances in the levels of serum constituents occurring in chronic renal diseases can be reflected in the saliva composition. The aim of this study was to assess some...
BACKGROUND
Disturbances in the levels of serum constituents occurring in chronic renal diseases can be reflected in the saliva composition. The aim of this study was to assess some selected salivary components in children suffering from idiopathic steroid-sensitive nephrotic syndrome (iNS).
METHODS
A case-control study was performed on iNS and healthy participants. In unstimulated mixed saliva, pH, buffer capacity, total protein, α-amylase, peroxidase, calcium, magnesium, inorganic phosphate, fluoride, urea, uric acid and salivary flow rate were measured. Oral condition was assessed using dmft, DMFT, API and GI indices, usage of fluoride specimens and frequency of tooth brushing. Statistical analysis was performed by Shapiro-Wilk, Brown-Forsythe, Student's t, ANOVA, Tukey's and Pearson's chi-square tests, Pearson's and Spearman's correlations, logistic regression and receiver operating characteristic (ROC) curve analysis.
RESULTS
The study involved 94 participants of both genders aged 4-17 (47 cases in relapse or remission phase of iNS and 47 controls) who were treated in the clinic of pediatric nephrology or outpatient dental clinic. Neither group differed in the number of caries-affected primary and permanent teeth, gingival condition or use of fluoride specimens. The iNS group presented lower levels of magnesium (0.41 ± 0.34 vs. 0.60 ± 0.38 mg/dL, P < 0.05) and fluoride (0.15 ± 0.10 vs. 0.21 ± 0.10 ppm, P < 0.01) and higher contents of urea (35.19 ± 15.55 vs. 25.21 ± 10.78 mg/dL, P < 0.01) and uric acid (2.90 ± 1.23 vs. 2.34 ± 1.04 mg/dL, P < 0.05) than the controls. In the iNS participants with relapse, a higher peroxidase activity and lower magnesium content than in the remission phase were found. ROC analysis showed a weak discriminatory power of these salivary constituents for the differentiation of participants with and without disease (accuracy from 66.0 to 67.0%, area under the ROC curve (AUC) from 0.638 to 0.682) and the relapse and remission phases (accuracy 70.2% and 68.1% and AUC 0.717 and 0.675, respectively).
CONCLUSIONS
Levels of urea, uric acid, magnesium and fluoride in saliva can be associated with the course of iNS. Salivary levels of peroxidase and magnesium can be related to the phase of the disease. However, the measurements of these parameters cannot be useful as a noninvasive tool in diagnosing iNS and the phase of the disease.
Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Dental Caries; Female; Humans; Male; Nephrotic Syndrome; Peroxidase; Saliva
PubMed: 33413282
DOI: 10.1186/s12903-020-01375-1 -
Methods in Molecular Biology (Clifton,... 2021Neutrophils are innate immune cells that play important roles in many physiological and pathological processes, including immune defense and cancer metastasis. In...
Neutrophils are innate immune cells that play important roles in many physiological and pathological processes, including immune defense and cancer metastasis. In addition to the release of proinflammatory cytokines, chemokines, and cytoplasmic granules containing digestive proteins, in recent years, neutrophils have been observed to release neutrophil extracellular traps (NETs) that consist of extracellular DNA associated with antimicrobial proteins, such as histones and myeloperoxidase. These NETs are increasingly being recognized as an important mechanism of neutrophil host defense and function. This chapter will summarize the current literature on the known processes of NET formation and describe in detail an immunofluorescence approach that can be employed to visualize and quantify NETs in vitro.
Topics: DNA; Extracellular Traps; Histones; Humans; Image Processing, Computer-Assisted; Microscopy, Fluorescence; Peroxidase
PubMed: 34033097
DOI: 10.1007/978-1-0716-1162-3_9