Renin Angiotensin System Inhibition as treatment for Covid-19?

Williams, Bryan

doi:10.1016/j.eclinm.2021.101023

Cited by 9 publications

(10 citation statements)

References 10 publications

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“… 24 – 27 The impact of inhibition of the renal angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors or by angiotensin receptor blockers (ARBs) has been considered in relation to treatment and outcome of COVID-19 infection, and studies are ongoing. 28 – 30 The experiments presented in this report support a sequence of activation of cellular transcriptional events which proceed from direct effects of the interaction between the spike protein receptor binding domain (SPRBD) and the ACE2 receptor in human airway epithelial cells (AEC). Recognition of the takeover of normal signaling mechanisms by the SARS-CoV-2 spike protein-ACE2 interaction suggests the potential benefit of some targeted pharmacological interventions based on these pathways.…”

Section: Introductionsupporting

confidence: 55%

SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK

Bhattacharyya,

Tobacman

2024

Sig Transduct Target Ther

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Immunostaining in lungs of patients who died with COVID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in N-acetylgalactostamine-4-sulfatase (Arylsulfatase B; ARSB). To explain these findings, human small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain (SPRBD) and transcriptional mechanisms were investigated. Phospho-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD, and their inhibition suppressed the promoter activation of the carbohydrate sulfotransferases CHST15 and CHST11, which contributed to chondroitin sulfate biosynthesis. Decline in ARSB was mediated by phospho-38 MAPK-induced N-terminal Rb phosphorylation and an associated increase in Rb-E2F1 binding and decline in E2F1 binding to the ARSB promoter. The increases in chondroitin sulfotransferases were inhibited when treated with phospho-p38-MAPK inhibitors, SMAD3 (SIS3) inhibitors, as well as antihistamine desloratadine and antibiotic monensin. In the mouse model of carrageenan-induced systemic inflammation, increases in phospho-p38 MAPK and expression of CHST15 and CHST11 and declines in DNA-E2F binding and ARSB expression occurred in the lung, similar to the observed effects in this SPRBD model of COVID-19 infection. Since accumulation of chondroitin sulfates is associated with fibrotic lung conditions and diffuse alveolar damage, increased attention to p38-MAPK inhibition may be beneficial in ameliorating Covid-19 infections.

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Section: Introductionsupporting

confidence: 55%

SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK

Bhattacharyya,

Tobacman

2024

Sig Transduct Target Ther

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“…As we previously published, a multiweapon approach is needed to successfully combat SARS-CoV-2 and COVID-19 disease ( Labarrere and Kassab, 2021 ), involving vaccines ( Jin et al, 2022 ) especially vaccines that selectively and efficiently induce antibodies that target the SARS-CoV-2 receptor binding domain ( Robbiani et al, 2020 ), pattern recognition proteins such as surfactant proteins A and D ( Arroyo et al, 2021 ; Ghati et al, 2021 ; Wang et al, 2021a ; DePietro and Salzberg, 2022 ; Labarrere and Kassab, 2022 ), modulators of mannose binding lectin, C1q, C-reactive protein ( Tang et al, 2011 ; Torzewski et al, 2020 ; Labarrere and Kassab, 2021 ; Ringel et al, 2021 ), and IgM natural antibodies, TLR inhibitors, modulators of cellular components (neutrophils, basophils, eosinophils, mast cells, monocytes, macrophages, dendritic cells, regulatory T cells, natural killer cells) of innate immunity, cellular components of both innate and adaptive immune systems (γδ T cells, natural killer T cells), soluble constituents of adaptive immunity (polyreactive IgM antibodies to the viral disease, among others), and cellular components of adaptive immunity (T cell subsets like Th1 CD4+ T cells, cytotoxic CD8+ T cells, Th2 cells, Th17 cells, Th9 cells), viral replication inhibitors, renin-angiotensin system inhibitors ( Williams, 2021 ) and human recombinant soluble ACE2 ( Abd El-Aziz et al, 2020 ), as well as heparin and glycosaminoglycan antithrombotics ( Magnani, 2021 ), among others. Sadly, there are no effective antivirals and vaccines to definitively treat or prevent COVID-19.…”

Section: Sars-cov-2 New Therapeutic Approachesmentioning

confidence: 99%

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

Labarrere

Kassab²

2022

Front. Microbiol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 19 (COVID-19) has numerous risk factors leading to severe disease with high mortality rate. Oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels seems to be a common pathway associated with the high COVID-19 mortality. GSH is a unique small but powerful molecule paramount for life. It sustains adequate redox cell signaling since a physiologic level of oxidative stress is fundamental for controlling life processes via redox signaling, but excessive oxidation causes cell and tissue damage. The water-soluble GSH tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) is present in the cytoplasm of all cells. GSH is at 1–10 mM concentrations in all mammalian tissues (highest concentration in liver) as the most abundant non-protein thiol that protects against excessive oxidative stress. Oxidative stress also activates the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 to regulate the expression of genes that control antioxidant, inflammatory and immune system responses, facilitating GSH activity. GSH exists in the thiol-reduced and disulfide-oxidized (GSSG) forms. Reduced GSH is the prevailing form accounting for >98% of total GSH. The concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell and its alteration is related to various human pathological processes including COVID-19. Oxidative stress plays a prominent role in SARS-CoV-2 infection following recognition of the viral S-protein by angiotensin converting enzyme-2 receptor and pattern recognition receptors like toll-like receptors 2 and 4, and activation of transcription factors like nuclear factor kappa B, that subsequently activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) expression succeeded by ROS production. GSH depletion may have a fundamental role in COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of COVID-19 disease and increasing GSH levels may prevent and subdue the disease. The life value of GSH makes for a paramount research field in biology and medicine and may be key against SARS-CoV-2 infection and COVID-19 disease.

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“…Both of these genes are involved in RAS 2 . The inhibition of this system may be a therapeutic option and an important pathway for COVID‐19 treatment 1,91 …”

Section: Discussionmentioning

confidence: 99%

Haplotypic variants of COVID‐19 related genes are associated with blood pressure and metabolites levels

Gholami

Zoughi

Hasanzad

et al. 2022

Journal of Medical Virology

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The genetic association of coronavirus disease 2019 (COVID‐19) with its complications has not been fully understood. This study aimed to identify variants and haplotypes of candidate genes implicated in COVID‐19 related traits by combining the literature review and pathway analysis. To explore such genes, the protein‐protein interactions and relevant pathways of COVID‐19‐associated genes were assessed. A number of variants on candidate genes were identified from Genome‐wide association studies (GWASs) which were associated with COVID‐19 related traits (p ˂ 10‐6). Haplotypic blocks were assessed using haplotypic structures among the 1000 Genomes Project (r2 ≥ 0.8, D′ ≥ 0.8). Further functional analyses were performed on the selected variants. The results demonstrated that a group of variants in ACE and AGT genes were significantly correlated with COVID‐19 related traits. Three haplotypes were identified to be involved in the blood metabolites levels and the development of blood pressure. Functional analyses revealed that most GWAS index variants were expression quantitative trait loci and had transcription factor binding sites, exonic splicing enhancers or silencer activities. Furthermore, the proxy haplotype variants, rs4316, rs4353, rs4359, and three variants, namely rs2493133, rs2478543, and rs5051, were associated with blood metabolite and systolic blood pressure, respectively. These variants exerted more regulatory effects compared with other GWAS variants. The present study indicates that the genetic variants and candidate haplotypes of COVID‐19 related genes are associated with blood pressure and blood metabolites. However, further observational studies are warranted to confirm these results.

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Renin Angiotensin System Inhibition as treatment for Covid-19?

Cited by 9 publications

References 10 publications

SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK

SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

Haplotypic variants of COVID‐19 related genes are associated with blood pressure and metabolites levels

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