Abstract:Myeloperoxidase (MPO), an oxidant-producing enzyme, stored in azurophilic granules of neutrophils has been recently shown to inluence red blood cell (RBC) deformability leading to abnormalities in blood microcirculation. Native MPO is a homodimer, consisting of two identical protomers (monomeric MPO) connected by a single disulide bond but in inlammatory foci as a result of disulide cleavage monomeric MPO (hemi-MPO) can also be produced. This study investigated if two MPO isoforms have distinct efects on bioph… Show more
“…Hemi-MPO, as well as the dimeric form, bind to the glycophorins A/B and band three protein on RBCs’ plasma membrane, which lead to reduced cell resistance to osmotic and acidic hemolysis, a reduction in cell elasticity, significant changes in cell volume, morphology, and the conductance of RBC plasma membrane ion channels. MPO, an oxidant-producing enzyme, was shown to cause RBC deformability, leading to abnormalities in the blood microcirculation [ 82 ]. Abnormalities in blood microcirculation in inflammatory foci can be induced by hemi-MPO and homodimers.…”
The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.
“…Hemi-MPO, as well as the dimeric form, bind to the glycophorins A/B and band three protein on RBCs’ plasma membrane, which lead to reduced cell resistance to osmotic and acidic hemolysis, a reduction in cell elasticity, significant changes in cell volume, morphology, and the conductance of RBC plasma membrane ion channels. MPO, an oxidant-producing enzyme, was shown to cause RBC deformability, leading to abnormalities in the blood microcirculation [ 82 ]. Abnormalities in blood microcirculation in inflammatory foci can be induced by hemi-MPO and homodimers.…”
The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.
“…Two types of MPO bind to the RBCs' plasma membranes, which leads to reduced cell resistance to osmotic and acidic hemolysis, a reduction in cell elasticity, and significant changes in cell volume, morphology, and the conductance of ion channels in the RBC's plasma membrane. MPO, an oxidant-producing enzyme, was shown to cause RBC deformability, leading to abnormalities in the blood microcirculation [69]. Dapsone is a well-known MPO inhibitor [9] that protects neurons from SARS-CoV-2 inflammasomes through RBC splitting and ameliorates SARS-CoV-2 ARDS [27].…”
Section: Investigation Of Sars-cov-2 Vaccination and Nanobody Drugsmentioning
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seems to be difficult to overcome. A pandemic of such a scale has not been seen since the 1918 influenza pandemic. Although the predominant clinical presentation is respiratory disease, neurological manifestations and sequelae are increasingly being recognized. We observed a case series of rapid recovery of ARDS within 24 h in the preliminary clinical features of COVID-19 ARDS-associated neurological disease. It was also noted that by 15 April, 2021, there was no SARS-CoV-2 ARDS on Sorok Island in South Korea, where lepers had been living together. We compared each of dapsone’s effects on humans and considered those of SARS-CoV-2. Dapsone showed different effects in the brain. The Sorokdo National Hospital reported a relationship between dapsone and the neuroinflammasome of Alzheimer’s disease (AD) in Sorok Island from January 2005 to June 2020. AD prevalence was low in the leprosy patient group who took dapsone regularly. The preliminary cross-sectional study of the trial group (22 subjects) and the control group (22 subjects) in the Hunt Regional Hospital reported the following results: The chi-square statistic is 5.1836. The p-value is 0.022801. The result is considered significant at p < 0.05. The results from the medical treatment from 21 December to 29 December 2020 were considered. The mortality rates at the ARDS onset stage were 0% with dapsone administered as a standard COVID-19 treatment and 40% without dapsone administered as a standard COVID-19 treatment, respectively. Based on the respiratory failure and sudden high death rate originating from the involvement of the brainstem, especially the pre-Bötzinger complex, dapsone can be used to significantly reduce the incidence of the cases of acute respiratory distress syndrome and other illnesses caused by SARS-CoV-2.
“…To test this method for platelets we recorded the kinetics of membrane potential of platelets activated by human myeloperoxidase (MPO), which was shown previously to modulate platelet aggregation, cytoskeleton reorganization, and store-operated calcium entry [44], as well as to activate neutrophils [45] and to bind to human red blood cells and change their properties [46,47]. Adding 100 nM of MPO to extracellular bath solution led to a slight hyperpolarization of the plasma membrane at the level of 10-12 mV (Fig.…”
Section: Measurement Of Membrane Potential In the Cellattached Modementioning
In this study, we have revisited the existing and suggested new approaches to the use of patch-clamp methodology for measuring the activity of single ion channels and membrane potential of human platelets in the cell-attached configuration. We recorded single-channel events of platelets in the cell-attached configuration after activation with potent agonists: thrombin and ionomycin. The feasibility of platelet membrane potential measurement in cell-attached mode was investigated both experimentally and with the help of simple electrical circuits, revealing that the single-channel events can alter the recorded potential by invoking oscillations. Here, the simple approach to obtain inside-out configuration was described and calcium-dependent single-channel ion currents were recorded. Taken together, this study introduces new approaches for further investigations of the role of ion channels and membrane potential in platelet physiological and pathophysiological response.
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