Activated glycine receptors may decrease endosomal NADPH oxidase activity by opposing ClC-3-mediated efflux of chloride from endosomes

McCarty, Mark F.; Assanga, Simon Bernard Iloki; Luján, Lidianys María Lewis; DiNicolantonio, James J.

doi:10.1016/j.mehy.2019.01.012

Cited by 9 publications

(5 citation statements)

References 88 publications

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“…However, these effects can be reversed by ClC-3 overexpression. 13,64,66,68 In addition, a previous study has demonstrated that VECs excrete ROS via ClC-3 channels, suggesting that ClC-3 may be involved in the extracellular transport of ROS. 13,69 Collectively, ClC-3 may play a significant role in dysregulated ROS production, leading to multiple pathological events of AS, including oxidative stress, LDL oxidative modification, and dysfunction of endothelial cells, macrophages, and VSMCs.…”

Section: Clc-3 and Oxidative Stressmentioning

confidence: 98%

“…ClC-3 inhibition can potentially slow endosomal NOX activity, and NOX1 is unable to generate ROS in VSMCs. 13,67 ClC-3-mediated phosphorylation and activation of the p38 MAPK signaling pathway are reportedly involved in NOX activation induced by LPS, IL, AngII, AT1, TNF-a, and TGF-b1. 64 ClC-3 silencing markedly inhibited the phosphorylation and activation of the p38 MAPK signaling pathway, as well as reduced NOX-derived ROS production.…”

Section: Clc-3 and Oxidative Stressmentioning

confidence: 99%

“…[9][10][11] Accumulating evidence suggests that overexpression of ClC-3 leads to increased plasma LDL, endothelial dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of VSMCs, and oxidative stress. 12,13 Furthermore, our previous studies have indicated that ox-LDL promotes foam cell formation, which is ClC-3 dependent. 14,15 Collectively, these findings suggest an important role for ClC-3 in AS development.…”

Section: Introductionmentioning

confidence: 99%

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ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

Niu

Xie

2021

J Cardiovasc Pharmacol Ther

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Chloride channel 3 (ClC-3), a Cl−/H+ antiporter, has been well established as a member of volume-regulated chloride channels (VRCCs). ClC-3 may be a crucial mediator for activating inflammation-associated signaling pathways by regulating protein phosphorylation. A growing number of studies have indicated that ClC-3 overexpression plays a crucial role in mediating increased plasma low-density lipoprotein levels, vascular endothelium dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of vascular smooth muscle cells (VSMCs), as well as oxidative stress and foam cell formation, which are the main factors responsible for atherosclerotic plaque formation in the arterial wall. In the present review, we summarize the molecular structures and classical functions of ClC-3. We further discuss its emerging role in the atherosclerotic process. In conclusion, we explore the potential role of ClC-3 as a therapeutic target for atherosclerosis.

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Section: Clc-3 and Oxidative Stressmentioning

confidence: 98%

Section: Clc-3 and Oxidative Stressmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

Niu

Xie

2021

J Cardiovasc Pharmacol Ther

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“…Activation of glycine receptors on immune and endothelial cells can inhibit inflammatory responses, likely through hyperpolarization of plasma and inhibition of endosomal nicotinamide adenine dinucleotide phosphate oxidase activity. 88,89 Of note, there are findings that show Ivermectin as an agonist for glycine receptors can highly increase the activation of such receptors [90][91][92][93] and whereby prevents LPS-mediated inflammation in macrophages. 86…”

Section: Ivermectin Inhibits the Inflammationassociated Phase Of Covi...mentioning

confidence: 99%

Potential therapeutic effects of Ivermectin in COVID-19

Nastaran

Motavallihaghi

Nikfar

et al. 2022

Exp Biol Med (Maywood)

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COVID-19 is a critical pandemic that affected communities around the world, and there is currently no specific drug treatment for it. The virus enters the human cells via spikes and induces cytokine production and finally arrests the cell cycle. Ivermectin shows therapeutic potential for treating COVID-19 infection based on in vitro studies. Docking studies have shown a strong affinity between Ivermectin and some virulence factors of COVID-19. Notably, clinical evidence has demonstrated that Ivermectin with usual doses is effective by both the prophylactic and therapeutic approaches in all phases of the disease. Ivermectin inhibits both the adhesion and replication of the virus. Local therapy of the lung with Ivermectin or combination therapy may get better results and decrease the dose of the drug.

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“…31 Theoretical considerations suggested that elevated plasma levels of the amino acid glycine-which is known to have intriguing anti-inflammatory properties-may suppress endosomal activation of NADPH oxidase in cells that express strychnine-inhibitable glycine receptors. 32 Indeed, endothelial cells express such receptors. 33 34 Hence, the impact of supplemental glycine-inexpensive, well-tolerated and pleasantly sweet-on TF expression in endothelial cells exposed to proinflammatory stimuli-including SARS-CoV-2-would be of interest to study.…”

mentioning

confidence: 99%

Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase

DiNicolantonio¹,

McCarty

2020

Open Heart

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The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.

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Activated glycine receptors may decrease endosomal NADPH oxidase activity by opposing ClC-3-mediated efflux of chloride from endosomes

Cited by 9 publications

References 88 publications

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

Potential therapeutic effects of Ivermectin in COVID-19

Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase

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