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

Lipid Rafts in Signalling, Diseases, and Infections: What Can Be Learned from Fluorescence Techniques? DOI Creative Commons
Sara Anselmo,

Elisa Bonaccorso,

Chiara M. A. Gangemi

et al.

Membranes, Journal Year: 2025, Volume and Issue: 15(1), P. 6 - 6

Published: Jan. 1, 2025

Lipid rafts are dynamic microdomains in the membrane, rich cholesterol and sphingolipids, that critical for biological processes like cell signalling, membrane trafficking, protein organization. Their essential role is claimed both physiological pathological conditions, including cancer, neurodegenerative diseases, viral infections, making them a key area of research. Fluorescence-based approaches, super-resolution fluorescence microscopy techniques, enable precise analysis organization, dynamics, interactions these microdomains, thanks also to innovative design appropriate fluorescent probes. Moreover, non-invasive approaches allow study live cells, facilitating collection quantitative data under physiologically relevant conditions. This review synthesizes latest insights into lipid underscores how techniques have advanced our understanding microdomains. The findings emphasize pivotal health disease, providing foundation future research potential therapeutic interventions.

Language: Английский

Citations

4
Links between COVID-19 and Alzheimer’s Disease—What Do We Already Know? DOI Open Access
Ewa Rudnicka-Drożak, Paulina Drożak, Grzegorz Mizerski

et al.

International Journal of Environmental Research and Public Health, Journal Year: 2023, Volume and Issue: 20(3), P. 2146 - 2146

Published: Jan. 25, 2023

Alzheimer’s disease (AD) is a life-changing condition whose etiology explained by several hypotheses. Recently, new virus contributed to the evidence of viral involvement in AD: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease. AD was found be one most common comorbidities, and it increase mortality from this as well. Moreover, patients were observed present with distinct clinical features COVID-19, delirium being prevalent group. The SARS-CoV-2 enters host cells through angiotensin-converting enzyme (ACE2) receptor. ACE2 overexpressed brains AD, thus increases invasion. Furthermore, inhibition receptor may also decrease brain-derived neurotrophic factor (BDNF), contributing neurodegeneration. ApoE ε4 allele, risk facilitate entry into cells. neuroinflammation oxidative stress existing enhance inflammatory response associated COVID-19. pandemic social distancing measures negatively affected mental health, cognitive function, neuro-psychiatric symptoms patients. This review comprehensively covers links between disease, including presentation, molecular mechanisms, effects distancing.

Language: Английский

Citations

34
The shared role of cholesterol in neuronal and peripheral inflammation DOI Creative Commons
Scott B. Hansen, Hao Wang

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 249, P. 108486 - 108486

Published: June 29, 2023

Language: Английский

Citations

28
Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry DOI Creative Commons
Thomas Grewal,

Mai Khanh Linh Nguyen,

Christa Buechler

et al.

Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(5), P. e202302453 - e202302453

Published: Feb. 22, 2024

The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical reduce the severity COVID-19. However, continuous emergence new SARS-CoV-2 subtypes highlights need develop additional approaches that oppose viral infections. Targeting host factors support virus entry, replication, and propagation provide opportunities lower infection rates improve COVID-19 outcome. This includes cellular cholesterol, which is for spike proteins capture machinery cell entry. Once endocytosed, exit from late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, ezetimibe have revealed potential protect against pharmacological inhibition cholesterol exiting endosomes/lysosomes identified drug candidates, including antifungals, block infection. review describes multiple roles at surface endolysosomes entry drugs targeting homeostasis infectivity disease severity.

Language: Английский

Citations

9
HDL-based therapeutics: A promising frontier in combating viral and bacterial infections DOI Creative Commons
Alankrita Rani,

Julia T. Stadler,

Gunther Marsche

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 260, P. 108684 - 108684

Published: July 2, 2024

Language: Английский

Citations

6
Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework DOI Open Access
Laure‐Alix Clerbaux, Maria Cristina Albertini, Núria Amigó

et al.

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(15), P. 4464 - 4464

Published: July 31, 2022

Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the and understanding how they mechanistically influence COVID-19. Here, we describe eleven selected (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution exposure to chemicals) by applying Adverse Outcome Pathway (AOP), which well-established in regulatory toxicology. framework aims model sequence of events leading an adverse health outcome. Several linear AOPs depicting pathways from binding virus ACE2 up observed have been developed integrated into a network offering unique overview mechanisms underlying disease. As SARS-CoV-2 infectibility activity major starting points inflammatory response central development COVID-19, evaluated those intrinsic extrinsic modulate processes impacting outcomes. Applying this AOP-aligned approach enables identification current knowledge gaps orientating for further research allows propose biomarkers identify high-risk also facilitates expertise synergy different disciplines address public issues.

Language: Английский

Citations

23
COVID‐19 and the impact on Alzheimer's disease pathology DOI Open Access
Susana Furman, Kim N. Green, Thomas E. Lane

et al.

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 18, 2023

Abstract Coronavirus disease 2019 (COVID‐19) has rapidly escalated into a global pandemic that primarily affects older and immunocompromised individuals due to underlying clinical conditions suppressed immune responses. Furthermore, COVID‐19 patients exhibit spectrum of neurological symptoms, indicating can affect the brain in variety manners. Many studies, past recent, suggest connection between viral infections an increased risk neurodegeneration, raising concerns about effects possibility it may contribute Alzheimer's (AD) onset or worsen already existing AD pathology through inflammatory processes given both share pathological features factors. This leads us question whether is factor for how these two might influence each other. Considering extensive reach devastating impact ongoing pandemic, their combined could have significant public health consequences worldwide. image

Language: Английский

Citations

11
GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons DOI Creative Commons
Zixuan Yuan, Mahmud Arif Pavel, Scott B. Hansen

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: April 22, 2025

The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. lipid environment is critical for GABAAR function. How lipids regulate channel cell membrane not fully understood. Here we employed super resolution imaging of to demonstrate that agonist induces rapid and reversible translocation phosphatidylinositol 4,5-bisphosphate (PIP2) clusters mouse primary cortical neurons. This relies on nanoscopic separation PIP2 rafts (cholesterol-dependent ganglioside clusters). In resting state, associates with this colocalization enhanced by uptake astrocytic secretions. These secretions delay desensitization enhance maximum current. an Alzheimer's Disease (AD) model high brain cholesterol, shifts into rafts. Our findings suggest cholesterol signaling molecule astrocytes regulates GABAARs neurons secreting cholesterol. have implications treating mood disorders AD associated altered lipids.

Language: Английский

Citations

0
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: 2024, Volume and Issue: 12

Published: Feb. 26, 2024

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

3
The Influence of SARS-CoV-2 Infection on the Development of Selected Neurological Diseases DOI Open Access

Klaudia Kryńska,

Katarzyna Kuliś,

Wiktoria Mazurek

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8715 - 8715

Published: Aug. 9, 2024

In 2024, over 775 million cases of COVID-19 were recorded, including approximately 7 deaths, indicating its widespread and dangerous nature. The disease is caused by the SARS-CoV-2 virus, which can manifest a wide spectrum symptoms, from mild infection to respiratory failure even death. Neurological such as headaches, confusion, impaired consciousness, have also been reported in some patients. These observations suggest potential invade central nervous system induce neuroinflammation during infection. This review specifically explores relationship between selected neurological diseases multiple sclerosis (MS), ischemic stroke (IS), Alzheimer's (AD). It has observed that virus increases production cytokines whose action cause destruction myelin sheaths nerve cells. Subsequently, body may synthesize autoantibodies attack cells, resulting damage brain's anatomical elements, potentially contributing onset sclerosis. Additionally, exacerbates inflammation, worsening clinical condition individuals already suffering MS. Moreover, secretion pro-inflammatory lead an escalation blood clot formation, result thrombosis, obstructing flow brain precipitating stroke. AD characterized intense inflammation heightened oxidative stress, both are exacerbated demonstrates enhanced cell entry presence ACE2 receptor, elevated ApoE ε4 allele. Consequently, worsens progresses more rapidly, increasing mortality rate among above information underscores numerous connections diseases.

Language: Английский

Citations

3