Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

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

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Cyclic lipopeptides as membrane fusion inhibitors against SARS-CoV-2: New tricks for old dogs

Antiviral Research, Journal Year: 2023, Volume and Issue: 212, P. 105575 - 105575

Published: March 2, 2023

Language: Английский

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The Sentient Cell

Oxford University Press eBooks, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 5, 2023

Abstract This volume is the natural follow-up to Arthur Reber’s 2019 book, The First Minds: Caterpillars, ‘Karyotes, and Consciousness (TFM). In that earlier work, Cellular Basis of (CBC) theory was developed based on a number efforts published in variety journals between 1997 as well talks, colloquia, presentations at conferences. core proposition TFM life mind are co-terminous. All organisms, all species extant extinct, sentient. have an existentially secure consciousness—without which they would been evolutionary dead-ends, unable survive chaotic, dangerous environment first appeared. And, importantly, forms sentience, cognitive functioning right up including those expressed by humans, evolved from original expression consciousness birth prokaryotes. unicellular widely accepted, foundational principle biological social sciences. CBC simply applies same sentience.

Language: Английский

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Molecular docking as a tool for the discovery of novel insight about the role of acid sphingomyelinase inhibitors in SARS- CoV-2 infectivity

BMC Public Health, Journal Year: 2024, Volume and Issue: 24(1)

Published: Feb. 6, 2024

Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, > 6 million deaths. Symptoms included strain complications, leading to pneumonia. SARS-CoV-2 attaches the ACE-2 receptor of host cell membrane enter. Targeting entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes conversion sphingolipid (sphingomyelin) ceramide. Ceramide molecules aggregate/assemble on plasma form "platforms" facilitate viral intake into cell. Impairing ASMase activity will eventually disrupt In this review, we identified metabolism sphingolipids, sphingolipids' role in signal transduction cascades, infection mechanisms. Also, outlined structure underlying mechanisms inhibiting 40 with aid inhibitors acid (FIASMAs). silico molecular docking analyses FIASMAs revealed dilazep (S = - 12.58 kcal/mol), emetine 11.65 pimozide 11.29 carvedilol 11.28 mebeverine 11.14 cepharanthine 11.06 hydroxyzin 10.96 astemizole 10.81 sertindole 10.55 bepridil 10.47 kcal/mol) have higher inhibition than candidate drug amiodarone 10.43 making them better options for inhibition.

Language: Английский

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Lipid rafts disruption by statins negatively impacts the interaction between SARS-CoV-2 S1 subunit and ACE2 in intestinal epithelial cells

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

The causative agent of the COVID-19 pandemic, SARS-CoV-2, is a virus that targets mainly upper respiratory tract. However, it can affect other systems such as gastrointestinal (GI) Therapeutic strategies for this are still inconclusive and understanding its entry mechanism important finding effective treatments. Cholesterol an constituent in structure cellular membranes plays crucial role variety events. In addition, infectivity pathogenicity several viruses. ACE2, main receptor associated with lipid rafts which microdomains composed cholesterol sphingolipids. study, we investigate statins, lipid-lowering drugs, on trafficking ACE2 impact modulation interaction S1 Caco-2 cells. data show fluvastatin simvastatin reduce expression to variable extents, impair association sorting brush border membrane resulting substantial reduction subunit spike protein. By virtue effects statins demonstrated our these molecules, particularly fluvastatin, represent promising therapeutic intervention be used off-label treat SARS-CoV-2.

Language: Английский

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Treatment of COVID‐19‐Associated Ageusia and Xerostomia

Oral Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Language: Английский

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Caveolae: Metabolic Platforms at the Crossroads of Health and Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2918 - 2918

Published: March 24, 2025

Caveolae are small flask-shaped invaginations of the plasma membrane enriched in cholesterol and sphingolipids. They play a critical role various cellular processes, including signal transduction, endocytosis, mechanotransduction. Caveolin proteins, specifically Cav-1, Cav-2, Cav-3, addition to their as structural components caveolae, have been found regulate activity signaling molecules. A growing body research has highlighted pivotal caveolae caveolins maintaining metabolic homeostasis. Indeed, studies demonstrated that interact with key insulin signaling, glucose uptake, lipid metabolism, thereby influencing energy production storage. The dysfunction or altered expression associated disorders, obesity, type 2 diabetes, ocular diseases. Remarkably, mutations caveolin genes can disrupt balance, promote oxidative stress, exacerbate dysregulation. This review examines current on molecular mechanisms through which explores involvement pathogenesis discusses potential therapeutic strategies targeting function stabilization restore

Language: Английский

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Bromelain prevents Alzheimer's disease progression by suppressing oxidative stress and upregulating apolipoprotein A1 in 5x familial Alzheimer's disease transgenic mice

Journal of Agriculture and Food Research, Journal Year: 2025, Volume and Issue: unknown, P. 101927 - 101927

Published: April 1, 2025

Language: Английский

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Xuanfei Formula inhibited RSV infection by normalizing the SREBP2-mediated cholesterol synthesis process

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: May 2, 2024

Background and aims Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children elderly, often progressing to pneumonia severe sequelae. However, there are currently no feasible cost-effective interventions with proven efficacy for children, making medications anti-RSV activity urgently needed. Traditional Chinese medicine has shown promising therapeutic alleviating viral infection symptoms. Therefore, we aimed develop effective strategies RSV treatment based on traditional medicine. Methods results The status was assessed BALB/c mice or without Xuanfei Formula (XFF) over a one-week period using H&E staining, cytokine assays titer testing after challenge. Remarkably, first day XFF intervention, both pro-inflammation levels serum RSV-N gene copies lung were plummeted, compared RSV-infected group. This implied that might possess immune-independent capability. To elucidate underlying mechanism, employed transcriptome analysis followed by k-means analysis. reversal effects against primarily focused processes innate adaptive immunity. Additionally, found administration corrected disordered fatty acid cholesterol metabolism during infection. Lipidomics profiling indicated consistent abundance transcriptional changes but not acids. Cholesterol synthesis-related genes mRNA synthesis intermediates detection supported XFF’s repression upon biosynthesis. Aberrantly increased production been reported as necessary mimic that, observed lovastatin inhibited replication expression vitro . Transcription factor prediction differentially expressed (DEGs) involved implicated SREBP2. Through network pharmacology, stigmasterol β-sitosterol identified active ingredients within XFF, help further molecular docking mass spectrum detection. In experiments demonstrated reinforced bonding between SREBP cleavage-activation protein (SCAP) insulin-induced proteins (INSIGs) inhibit SREBP2 cleavage maturation consequent Conclusion exhibits excellent inhibiting SREBP2-mediated reduce ameliorate inflammation infected mice.

Language: Английский

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Discovery of a novel inhibitor of macropinocytosis with antiviral activity

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(9), P. 3012 - 3024

Published: July 2, 2024

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery a molecule with antiviral properties that named virapinib, which limits viral entry by macropinocytosis. The identification virapinib derives from chemical screen using high-throughput microscopy, where identified entities capable preventing infection pseudotype virus expressing spike (S) protein SARS-CoV-2. Subsequent experiments confirmed capacity inhibit SARS-CoV-2, as well additional viruses, such mpox and TBEV. Mechanistic analyses revealed compound inhibited macropinocytosis, limiting this route for viruses. Importantly, has no significant toxicity In summary, present inhibits thereby infectivity use SARS-CoV2.

Language: Английский

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