The Evaluation of Drugs as Potential Modulators of the Trafficking and Maturation of ACE2, the SARS-CoV-2 Receptor DOI Creative Commons

Nesreen F. Alkhofash,

Bassam R. Ali

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 764 - 764

Published: June 27, 2024

ACE2, part of the angiotensin-converting enzyme family and renin–angiotensin–aldosterone system (RAAS), plays vital roles in cardiovascular renal functions. It is also primary receptor for SARS-CoV-2, enabling its entry into cells. This project aimed to study ACE2’s cellular trafficking maturation cell surface assess impact various drugs compounds on these processes. We used biochemical analyses evaluate as potential leads COVID-19 therapeutics. Our screening assay focused ACE2 levels subcellular localization with without drug treatments. Results showed that generally fast robust, certain having a mild impact. Out twenty-three tested compounds, eight significantly reduced levels, three caused approximately 20% decreases. Screening inhibitors revealed significant effects from most molecular modulators protein trafficking, proposed drugs, no statins. noted manipulating could be beneficial or harmful, depending context. Thus, using this approach uncover therapeutics requires thorough understanding biogenesis biology.

Language: Английский

Host genetic diversity and genetic variations of SARS-CoV-2 in COVID-19 pathogenesis and the effectiveness of vaccination DOI

Mahda Delshad,

Mohammad‐Javad Sanaei, Atieh Pourbagheri‐Sigaroodi

et al.

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 111, P. 109128 - 109128

Published: Aug. 8, 2022

Language: Английский

Citations

13
HDL-Related Parameters and COVID-19 Mortality: The Importance of HDL Function DOI Creative Commons
Julia T. Stadler, Hansjörg Habisch, Florian Prüller

et al.

Antioxidants, Journal Year: 2023, Volume and Issue: 12(11), P. 2009 - 2009

Published: Nov. 16, 2023

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting significant public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with severity of beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare metabolic profiles COVID-19-infected patients non-COVID-19 pneumonia. We compared control group COVID-19 using inflammatory markers ensure differences were due infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, HDL-related parameters key discriminators between COVID-19-positive pneumonia patients. More specifically, HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, cholesterol, phospholipids, significantly different. These findings underscore potential impact factors COVID-19. Significantly, among metrics, efflux capacity (CEC) displayed strongest negative association mortality. CEC is measure how well removes from cells, which may affect way enters cells. In summary, this study validates previously established infection further highlights significance functionality context

Language: Английский

Citations

8
Mechanical activation of TWIK-related potassium channel by nanoscopic movement and rapid second messenger signaling DOI Creative Commons
Erling N. Petersen, Mahmud Arif Pavel,

Samuel S. Hansen

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: July 27, 2023

Rapid conversion of force into a biological signal enables living cells to respond mechanical forces in their environment. The is believed initially affect the plasma membrane and then alter behavior proteins. Phospholipase D2 (PLD2) mechanosensitive enzyme that regulated by structured membrane-lipid site comprised cholesterol saturated ganglioside (GM1). Here we show stretch activation TWIK-related K + channel (TREK-1) mechanically evoked PLD2 spatial patterning involving ordered GM1 4,5-bisphosphate (PIP 2 ) clusters mammalian cells. First, deforms lipids, which disrupts interaction with lipids allows complex TREK-1 associate PIP clusters. association activates enzyme, produces second messenger phosphatidic acid (PA) gates channel. Co-expression catalytically inactive inhibits currents membrane. Cellular uptake culture depletion from astrocytes releases mouse brain. Depletion ortholog flies results hypersensitivity force. We conclude mechanosensitivity combines ion permeability elicit response.

Language: Английский

Citations

7
Super-resolution imaging of potassium channels with genetically encoded EGFP DOI Creative Commons

Isabelle M. Call,

Julian L. Bois,

Scott B. Hansen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 14, 2023

The plasma membrane is a well-organized structure of lipids and proteins, segmented into lipid compartments under 200 nm in size. This specific spatial patterning crucial for the function proteins necessitates super-resolution imaging its elucidation. Here, we establish that genetically encoded enhanced green fluorescent protein (EGFP), when combined with direct optical reconstruction microscopy (dSTORM), tracks shear- cholesterol-induced nanoscopic potassium channels overexpressed HEK293T cells. Leveraging EGFP dSTORM (EGFP-STORM), our findings indicate cholesterol directs C-terminus TWIK-related channel (TREK-1) to ceramide-enriched ganglioside (GM1) clusters. In absence C-terminus, associates phosphatidylinositol 4,5-bisphosphate (PIP

Language: Английский

Citations

7
Comparison of structural effects of cholesterol, lanosterol, and oxysterol on phospholipid (POPC) bilayers DOI Creative Commons

Ayumi Okayama,

Tatsuya Hoshino,

Kohei Wada

et al.

Chemistry and Physics of Lipids, Journal Year: 2024, Volume and Issue: 259, P. 105376 - 105376

Published: Feb. 6, 2024

Language: Английский

Citations

2
GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons DOI
Zixuan Yuan, Mahmud Arif Pavel, Scott B. Hansen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 29, 2024

The γ-aminobutyric acid (GABA) type A receptor (GABA

Language: Английский

Citations

2
Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol DOI Creative Commons
Fei Chen,

Aiko Matsuda,

G. R. Scott Budinger

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 12, 2023

Patients with chronic lung disease, obesity, and other co-morbid conditions are at increased risk of severe illness death when infected acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hypercapnia, the elevation CO in blood tissue, commonly occurs patients including those pulmonary infections, is also associated high mortality risk. We previously reported that hypercapnia increases viral replication influenza A virus infection mice. have shown culture elevated upregulates expression cholesterol synthesis genes primary human bronchial epithelial cells. Interestingly, factors increase content lipid rafts droplets, platforms for entry assembly, enhance SARS-CoV-2 infection. In current study, we investigated effects on ACE2 pseudovirus (p-SARS-CoV-2) into airway found p-SARS-CoV-2 uptake by epithelium mice, cultured VERO Hypercapnia total cellular raft-associated Moreover, reducing inhibitors sterol regulatory element binding protein (SREBP2) or statins, depletion cholesterol, each blocked hypercapnia-induced Cigarette smoke extract (CSE) expression, accumulation cells, an effect not additive to hypercapnia, but inhibited statins. These findings reveal a mechanism may account, part, poor clinical outcomes advanced disease who cigarettes. Further, our results suggest possibility cholesterol-lowering therapies be particular benefit exposed SARS-CoV-2.

Language: Английский

Citations

5
Mechanical activation of TWIK-related potassium channel by nanoscopic movement and rapid second messenger signaling DOI Open Access
Erling N. Petersen, Mahmud Arif Pavel,

Samuel S. Hansen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2019, Volume and Issue: unknown

Published: Sept. 5, 2019

Abstract Rapid conversion of force into a biological signal enables living cells to respond mechanical forces in their environment. The is believed initially affect the plasma membrane and then alter behavior proteins. Phospholipase D2 (PLD2) mechanosensitive enzyme that regulated by structured membrane-lipid site comprised cholesterol saturated ganglioside (GM1). Here we show stretch activation TWIK-related K + channel (TREK-1) mechanically evoked PLD2 spatial patterning involving ordered GM1 4,5- bisphosphate (PIP 2 ) clusters. First, deforms lipids, which lowers cholesterol, disrupts interaction with allows complex TREK-1 associate PIP association activates enzyme, produces second messenger phosphatidic acid (PA) gates channel. Co-expression catalytically inactive inhibits currents membrane. Cellular uptake culture depletion from astrocytes releases lipids mouse brain. Depletion ortholog flies results hypersensitivity force. We conclude mechanosensitivity combines ion permeability elicit response. Summary Shear thinning through messenger.

Language: Английский

Citations

13
SARS-CoV-2 mediated neurological disorders in COVID-19: Measuring the pathophysiology and immune response DOI

Hsu Pi-ching,

Md. Shahed-Al-Mahmud

Life Sciences, Journal Year: 2022, Volume and Issue: 308, P. 120981 - 120981

Published: Sept. 21, 2022

Language: Английский

Citations

6
Effect of Comorbidities on the Infection Rate and Severity of COVID-19: Nationwide Cohort Study With Propensity Score Matching DOI Creative Commons
Jiyong Kim, Seong Hun Park, Jong‐Moon Kim

et al.

JMIR Public Health and Surveillance, Journal Year: 2022, Volume and Issue: 8(11), P. e35025 - e35025

Published: Oct. 13, 2022

A vaccine against COVID-19 has been developed; however, transmission continues. Although there have many studies of comorbidities that important roles in COVID-19, some reported contradictory results.This study was conducted using real-world data from patients South Korea and aimed to investigate the impact patient demographics on infection rate severity COVID-19.Data were derived a nationwide Korean cohort with propensity score (PS) matching. We included infected individuals who COVID-19-positive between January 1, 2020, May 30, PS-matched uninfected controls. PS matching performed balance baseline characteristics each comorbidity adjust for potential confounders, such as age, sex, Charlson Comorbidity Index, medication, other comorbidities, matched binary variables. The outcomes confirmed affecting COVID-19. endpoints positivity severe clinical (such tracheostomy, continuous renal replacement therapy, intensive care unit admission, ventilator use, cardiopulmonary resuscitation, death).The 8070 positive test results proportions group higher 60 years or older (severe those older, 16.52%; ages, 2.12%), insured Medicaid (Medicaid, 10.81%; insurance, 5.61%), disabilities (with disabilities, 18.26%; without 5.07%). high pulmonary disease (odds ratio [OR] 1.88; 95% CI 1.70-2.03), dementia (OR 1.75; 1.40-2.20), gastrointestinal 1.74; 1.62-1.88), stroke 1.67; 1.23-2.27), hepatobiliary 1.31; 1.19-1.44), diabetes mellitus 1.28; 1.16-1.43), cardiovascular 1.20; 1.07-1.35). In contrast, it lower hyperlipidemia 0.73; 0.67-0.80), autoimmune 0.60-0.89), cancer 0.62-0.86). kidney 5.59; 2.48-12.63), hypertension 2.92; 1.91-4.47), 1.84; 1.15-2.94), 1.72; 1.35-2.19), 1.54; 1.17-2.04), 1.43; 1.09-1.87), psychotic disorders 1.29; 1.01-6.52). However, low 0.78; 0.60-1.00).Upon considering use statins, concluded people could rates

Language: Английский

Citations

6