scholarly journals The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease

2020 ◽  
Vol 21 (17) ◽  
pp. 6450 ◽  
Author(s):  
Patrick San Gabriel ◽  
Yuyang Liu ◽  
Angie Schroder ◽  
Hans Zoellner ◽  
Belal Chami
Keyword(s):  
Patient Outcomes ◽  
Hypochlorous Acid ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Rheumatic Arthritis ◽  
Protein Residues ◽  
Hypohalous Acids ◽  
Pathophysiological Role ◽  
Oxidative Species

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.

scholarly journals Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model

2019 ◽  
Vol 316 (2) ◽  
pp. F360-F371 ◽  
Author(s):  
Selene Colon ◽  
Haiyan Luan ◽  
Yan Liu ◽  
Cameron Meyer ◽  
Leslie Gewin ◽  
...  
Keyword(s):  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Hypochlorous Acid ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Renal Inflammation ◽  
Eosinophil Peroxidase ◽  
Hypohalous Acids ◽  
Heme Peroxidases

Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (H2O2). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize H2O2 into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.

The Need for Consensus About Liver Transplantation For Patients With Neuropsychiatric Wilson’s Disease

2021 ◽  
pp. 152692482110028
Author(s):  
Alberto Ferrarese ◽  
Patrizia Burra
Keyword(s):  
Liver Transplantation ◽  
Patient Outcomes ◽  
Wilson’S Disease ◽  
Therapeutic Option ◽  
Copper Metabolism ◽  
Wilson's Disease ◽  
Published Data ◽  
Neurological Improvement ◽  
Effective Therapeutic Option

Liver transplantation is considered an effective therapeutic option for Wilson’s disease (WD) patients with hepatic phenotype, since it removes the inherited defects of copper metabolism, and is associated with excellent graft and patient outcomes. The role of liver transplantation in WD patients with mixed hepatic and neuropsychiatric phenotype has remained controversial over time, mainly because of high post-operative complications, reduced survival and a variable, unpredictable rate of neurological improvement. This article critically discusses the recently published data in this field, focussing in more detail on isolated neuropsychiatric phenotype as a potential indication for liver transplantation in WD patients.

scholarly journals Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence

2021 ◽  
Vol 22 (6) ◽  
pp. 3059
Author(s):  
Corrado Pelaia ◽  
Cecilia Calabrese ◽  
Eugenio Garofalo ◽  
Andrea Bruni ◽  
Alessandro Vatrella ◽  
...  
Keyword(s):  
Review Article ◽  
Lung Damage ◽  
Current Evidence ◽  
Therapeutic Effects ◽  
Cytokine Storm ◽  
Future Perspectives ◽  
Pathogenic Role ◽  
Refractory Rheumatoid Arthritis ◽  
Life Threatening

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab’s therapeutic effects in patients with life-threatening SARS-CoV-2 infection.

scholarly journals Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 767
Author(s):  
Courtney Davis ◽  
Sean I. Savitz ◽  
Nikunj Satani
Keyword(s):  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Culture Conditions ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
Inflammatory Molecules ◽  
The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

The Role of Uric Acid in the Acute Myocardial Infarction: A Narrative Review

Angiology ◽  
2021 ◽  
pp. 000331972110125
Author(s):  
Atalay Demiray ◽  
Baris Afsar ◽  
Adrian Covic ◽  
Masanari Kuwabara ◽  
Charles J. Ferro ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Uric Acid ◽  
Adverse Outcomes ◽  
Narrative Review ◽  
Background Information ◽  
Pathophysiological Role ◽  
Artery Disease ◽  
Pathologic Processes

Increased serum uric acid (SUA) levels have been associated with various pathologic processes such as increased oxidative stress, inflammation, and endothelial dysfunction. Thus, it is not surprising that increased SUA is associated with various adverse outcomes including cardiovascular (CV) diseases. Recent epidemiological evidence suggests that increased SUA may be related to acute myocardial infarction (AMI). Accumulating data also showed that elevated UA has pathophysiological role in the development of AMI. However, there are also studies showing that SUA is not related to the risk of AMI. In this narrative review, we summarized the recent literature data regarding SUA and AMI after providing some background information for the association between UA and coronary artery disease. Future studies will show whether decreasing SUA levels is beneficial for outcomes related to AMI and the optimum SUA levels for best outcomes in CV diseases.

THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S4-S4
Author(s):  
Belal Chami ◽  
Gulfam Ahmad ◽  
Angie Schroder ◽  
Patrick San Gabriel ◽  
Paul Witting
Keyword(s):  
Disease Severity ◽  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Activity Index ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Sodium Sulphate ◽  
Host Tissue ◽  
Neutrophil Extracellular Trap

Abstract Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury. We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut. Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.

scholarly journals Lifestyle Modification for Enhancing Autonomic Cardiac Regulation in Children: The Role of Exercise

Children ◽  
2019 ◽  
Vol 6 (11) ◽  
pp. 127
Author(s):  
Kathryn E Speer ◽  
Nenad Naumovski ◽  
Stuart Semple ◽  
Andrew J McKune
Keyword(s):  
Exercise Prescription ◽  
Lifestyle Modification ◽  
Exercise Duration ◽  
Population Characteristics ◽  
Cardiometabolic Health ◽  
Therapeutic Effects ◽  
Global Concern ◽  
Underlying Mechanisms ◽  
Autonomic Cardiac Regulation

Decreased physical activity (PA) is a global concern contributing to the rise in cardiometabolic diseases. One potential mechanism linking insufficient PA and poor health is dysregulated autonomic nervous system (ANS) activity. This relationship is established in adults and PA recommendations, with specific exercise prescription guidelines, have been proposed to overcome this societal health burden. However, research on the benefits and underlying mechanisms of exercise on ANS activity in children <18 years old is limited. This review aimed to describe the optimal exercise “dose” and potential mechanisms of action that exercise may pose on enhancing child ANS activity, represented by heart rate variability (HRV). PubMed, Web of Science and Google Scholar were searched for articles examining the influence of exercise on child HRV. Various exercise duration and frequency combinations appear to improve HRV indices, primarily those representing parasympathetic influence. Furthermore, both aerobic and resistance training benefit HRV through potentially different mechanisms with intensity proposed to be important for exercise prescription. Findings indicate that exercise is a crucial lifestyle modification with protective and therapeutic effects on cardiometabolic health associated with improvements in child ANS activity. Exercise programming must consider the various components including mode, intensity and population characteristics to optimize ANS health.

scholarly journals Pathophysiological Role of Autophagy: Lesson from Autophagy-Deficient Mouse Models

2011 ◽  
Vol 60 (4) ◽  
pp. 329-345 ◽  
Author(s):  
Yoshinobu ICHIMURA ◽  
Masaaki KOMATSU
Keyword(s):  
Mouse Models ◽  
Deficient Mouse ◽  
Pathophysiological Role
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