Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Авг. 2, 2022

Abstract Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative and cancers, particularly CVD which accumulation lipids (mainly cholesteryl esters) within macrophage/foam cells underneath endothelial layer drives formation atherosclerotic lesions eventually. More more studies have shown that lowering level, especially low-density lipoprotein protects system prevents events effectively. Maintaining is determined by biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All processes should be precisely controlled regulatory pathways. Based on regulation homeostasis, many interventions been developed to lower inhibiting biosynthesis uptake or enhancing utilization Herein, we summarize historical review research events, current understandings molecular pathways playing key regulating cholesterol-lowering clinics preclinical well new targets their clinical advances. importantly, discuss benefits those for treatment including obesity, diabetes, nonalcoholic fatty liver disease, cancer, osteoporosis virus infection.

Язык: Английский

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Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Фев. 18, 2022

Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying protection against SARS-CoV-2 remains elusive. Here we reported for the first-time protective effects simvastatin treatment both in vitro and vivo . We found that significantly reduced viral replication lung damage , delaying SARS-CoV-2-associated physiopathology mortality K18-hACE2-transgenic mice model. Moreover, also downregulated inflammation triggered infection pulmonary tissue human neutrophils, peripheral blood monocytes, epithelial Calu-3 cells showing its potential modulate inflammatory response at site systemically. Additionally, observed affected course through displacing ACE2 on cell membrane lipid rafts. conclusion, our results show exhibits early inhibiting virus entry cytokine production, mechanisms least part dependent rafts disruption.

Язык: Английский

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Lipid Raft Integrity and Cellular Cholesterol Homeostasis Are Critical for SARS-CoV-2 Entry into Cells

Nutrients, Год журнала: 2022, Номер 14(16), С. 3417 - 3417

Опубликована: Авг. 19, 2022

Lipid rafts in cell plasma membranes play a critical role the life cycle of many viruses. However, involvement membrane cholesterol-rich lipid entry severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into target cells is not well known. In this study, we investigated whether presence microdomains required for SARS-CoV-2 host cells. Our results show that depletion cholesterol by methyl-beta-cyclodextrin (MβCD) treatment impaired expression surface receptor angiotensin-converting enzyme (ACE2), resulting significant increase The effects exerted MβCD could be substantially reversed exogenous replenishment. contrast, disturbance intracellular homeostasis statins or siRNA knockdown key genes involved biosynthesis and transport pathways reduced study also reveals SREBP2-mediated process These suggest cholesterol-enriched cellular are essential Pharmacological manipulation might provide new therapeutic strategies to alleviate

Язык: Английский

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Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 7, 2023

Abstract The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden our society. Most patients infected are asymptomatic or have mild symptoms. Although only small proportion of progressed severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, cardiovascular disorders, is accompanied mortality rates near 7 million deaths. Nowadays, effective therapeutic patterns for still lacking. It been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate avoid immunity, facilitate their own replication, initiate pathological response. Targeting interaction between holds promise developing strategies. In this review, we summarize discuss recent studies dedicated uncovering role life cycle aspects entry, assembly, pathogenesis an emphasis on glucose lipid metabolism. Microbiota long also discussed. Ultimately, recapitulate metabolism-modulating drugs repurposed statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, metformin.

Язык: Английский

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The role of lipid rafts in vesicle formation

Journal of Cell Science, Год журнала: 2023, Номер 136(9)

Опубликована: Май 1, 2023

ABSTRACT The formation of membrane vesicles is a common feature in all eukaryotes. Lipid rafts are the best-studied example domains for both eukaryotes and prokaryotes, their existence also suggested Archaea membranes. involved transport vesicles, endocytic exocytic synaptic extracellular as well enveloped viruses. Two mechanisms how vesicle have been proposed: first, that raft proteins and/or lipids located lipid associate with coat form budding vesicle, second, triggered by enzymatic generation cone-shaped ceramides inverted lyso-phospholipids. In cases, induction curvature facilitated relaxation tension domain. this Review, we discuss role raft-derived several intracellular trafficking pathways. We highlight different pathways endocytosis, intraluminal (ILVs) through inwards from multivesicular body (MVB) membrane, because inside MVB membranes likely to be loading RNA into ILVs. Finally, association glycoproteins via glycocalyx.

Язык: Английский

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

Life Science Alliance, Год журнала: 2024, Номер 7(5), С. e202302453 - e202302453

Опубликована: Фев. 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.

Язык: Английский

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SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Апрель 20, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells system are initial target of SARS-CoV-2, there is mounting evidence that COVID-19 a multi-organ disease. Still, direct affinity SARS-CoV-2 for other organs such as kidneys, often targeted severe COVID-19, remains poorly understood. We employed human induced pluripotent stem (iPS) cell-derived model to investigate kidney glomerular podocytes, and examined expression host factors binding processing virus. studied cellular uptake live virus well pseudotyped Infection podocytes with or spike-pseudotyped lentiviral particles revealed even at low multiplicity infection (MOI) 0.01. found iPS by can cause cell death podocyte foot process retraction, hallmark podocytopathies progressive diseases including collapsing glomerulopathy observed patients identified BSG/CD147 ACE2 receptors key mediators spike activity podocytes. These results show infect vitro via multiple interactions partners, may underlie high tissues. This potentially useful kidney-specific antiviral drug screening mechanistic studies organotropism.

Язык: Английский

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SARS-CoV-2 pseudovirus enters the host cells through spike protein-CD147 in an Arf6-dependent manner

Emerging Microbes & Infections, Год журнала: 2022, Номер 11(1), С. 1135 - 1144

Опубликована: Март 28, 2022

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants is threatening public health around the world. Endocytosis functions as an important way for viral infection, SARS-CoV-2 bears no exception. However, specific endocytic mechanism remains unknown. In this study, we used inhibitors to evaluate role different routes in pseudovirus infection found that was associated with caveolar/lipid raft- cytoskeleton-mediated endocytosis, but independent clathrin-mediated endocytosis macropinocytosis. Meanwhile, knockdown CD147 Rab5a Vero E6 Huh-7 cells inhibited co-localization spike protein, CD147, observed pseudovirus-infected cells, which weakened by silencing, illustrating entered host via CD147-mediated endocytosis. Additionally, Arf6 silencing markedly while little change knockout-Vero cells. This finding indicated Arf6-mediated trafficking plays a vital entry. Taken together, our findings provide new insights into CD147-Arf6 axis mediating entry further suggest blockade pathway seems be feasible approach prevent clinically.

Язык: Английский

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HDL cholesterol levels and susceptibility to COVID-19

EBioMedicine, Год журнала: 2022, Номер 82, С. 104166 - 104166

Опубликована: Июль 15, 2022

BackgroundHost cell-membrane cholesterol, an important player in viral infections, is constant interaction with serum high-density lipoprotein-cholesterol (HDL-C) and low-density (LDL-C). Low lipid levels during hospital admission are associated COVID-19 severity. However, the effect of antecedent on SARS-CoV-2 infection risk has not been explored.MethodsFrom our retrospective cohort from Arkansas Clinical Data-Repository, we used log-binomial regression to assess among trajectories 2 years testing, identified using group-based-trajectory modelling. We mixed-effects linear level trends followed up time of, 2-months following testing.FindingsAmong 11001 individuals a median age 59 (IQR 46-70), 1340 (12.2%) tested positive for COVID-19. The highest trajectory HDL-C was lowest (RR 0.63, 95%CI 0.46-0.86). Antecedent LDL-C, total cholesterol (TC), triglycerides (TG) were independently risk. In patients, (-7.7, -9.8 -5.5 mg/dL), LDL-C (-6.29, -12.2 -0.37 but TG levels, decreased transiently at testing.InterpretationHigher HDL-C, TC, or TG, lower Serum declined infection. Further studies needed determine potential role lipid-modulating therapies prevention management COVID-19.FundingResearch reported this publication supported by National Center Advancing Translational Sciences Institutes Health under Award Number UL1 TR003107.

Язык: Английский

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Computational Methods for the Interaction between Cyclodextrins and Natural Compounds: Technology, Benefits, Limitations, and Trends

Journal of Agricultural and Food Chemistry, Год журнала: 2022, Номер 70(8), С. 2466 - 2482

Опубликована: Фев. 16, 2022

Cyclodextrins (CDs) have a hollow structure with hydrophobic interior and hydrophilic exterior. Forming inclusion complexes CDs will maximize the bioavailability of natural compounds enable active components to be processed into functional foods, medicines, additives, so forth. However, experimental methods cannot explain CD–guest binding at atomic level. Different models been recently developed simulate interaction between guests study conformation analyze noncovalent forces. This review paper summarizes modeling CD-natural compound complexes. The include quantitative structure–activity relationships, molecular docking, dynamics simulations, quantum-chemical calculations. applications these enhance solubility bioactivities guest molecules, assist material transportation, promote extraction are also discussed. purpose this is explore mechanisms help expand new CDs.

Язык: Английский

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