Antiatherogenic Effects of Quercetin in the THP-1 Macrophage Model In Vitro, With Insights Into Its Signaling Mechanisms Using In Silico Analysis

Abstract

Background: Atherosclerosis (AS), a major risk factor for stroke and brain tissue destruction, is an inflammatory disease of the blood vessels, and the underlying pathology is inflammation mediated by various chemokines and cytokines. Quercetin, a natural flavonol, is reported to have both anti-inflammatory and antioxidant properties. As such, in the present study, we evaluated the antiatherogenic effects of quercetin in a human THP-1 cell line in vitro and also the signaling mechanisms using in silico analysis.Materials and Methods: THP-1 macrophages exposed to different concentrations of quercetin (5–100 μM for 24 h) were tested for cytotoxicity. Real-time gene expression assay for intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) was carried out following treatment with quercetin at 15 and 30 μM for 24 h either in the absence or presence of interferon (IFN-γ) for 3 h to induce inflammation. Monocyte migration and cholesterol efflux were also assessed.Results: Quercetin did not exert any cytotoxic effects on THP-1 cells at the various concentrations tested. The gene expression assay showed a significant decrease in ICAM-1 (by 3.05 and 2.70) and MCP-1 (by 22.71 and 27.03), respectively. Quercetin at 15 µM decreased THP-1 monocyte migration by 33% compared to the MCP-1-treated cells. It also increased cholesterol efflux significantly by1.64-fold and 1.60-fold either alone or in combination with IFN-γ, respectively. Ingenuity Pathway Analysis of the molecular interactions of quercetin identified canonical pathways directly related to lipid uptake and cholesterol efflux. Furthermore, CD36, SR-A, and LXR-α also demonstrated significant increases by 72.16-, 149.10-, and 29.68-fold, respectively.Conclusion: Our results from both in vitro and in silico studies identified that quercetin inhibited the THP-1 monocyte migration, MCP-1, and ICAM-1 and increased cholesterol efflux probably mediated via the LXR/RXR signaling pathway. Therefore, quercetin will help prevent cell infiltration in atherosclerotic plaques and reduce the risk of stroke or brain destruction.

Berberine modulates cardiovascular diseases as a multitarget-mediated alkaloid with insights into its downstream signals using in silico prospective screening approaches

“…These antioxidant modulators improve vascular endothelial cells dysfunction, foam cells and atherosclerotic lesions formation, pathogenesis of CVDs, and apoptosis through upregulating the cellular cholesterol uptake receptors and its efflux transporters signaling and alleviating the levels of vascular oxidative stress and pro-inflammatory modulators such as LPO, IL6, IL1β, TNFα, IFNγ, iNOS, and MCP-1 ( Ooi et al, 2018 , Wu et al, 2022 ). As proatherogenic factors, TNFα, IL6, MCP-1/CCL2, and MMP9 potentially accelerate monocytes migration and adhesion, induce endothelial cells dysfunction, accelerate foam cells formation, disturb macrophages cholesterol efflux signaling, and develop pathogenesis features of CVDs ( Huwait et al, 2021 , Wang et al, 2023 ).…”

“…Furthermore, Atherosclerosis greatly develops to chestpain, myocardial infarction, ischemia, fibrosis, and several cardiac problems ( Ma et al, 2021 ). Oxidative stress generation and inflammatory responses are greatly associated with the pathogenesis of CVDs through attenuating antioxidant defenses and accelerating LDLs oxidation (ox-LDLs), macrophage foam cells formation, monocytes adherence and migration, endothelial cells dysfunction, atherosclerotic plaques/lesions formation, plaques rupture, vascular remodeling, and atherothrombosis as well as infiltration of vascular smooth muscle cells to arterial intima ( Ooi et al, 2018 , Cao et al, 2021 , Huwait et al, 2021 , Ghatani et al, 2022 ). Targeting oxidative stress is an effective response to attenuate several cardiac diseases.…”

Exploration of potential molecular mechanisms and genotoxicity of anti-cancer drugs using next generation knowledge discovery methods

“…They were then submitted to core analysis utilizing IPA to interpret both biological and toxicological functions differentially regulated by these drugs, using Fisher’s exact test and Benjamini Hochberg Multiple Testing Correction (P < 0.05). 7 - 9 …”

“… 7 , 9 , 10 On the basis of the similarity between the query molecule and the curated collection utilizing 2D and 3D similarity measures inside the wider bioactivity data of ChEMBL version 23, ligand-based target prediction was done. 9 A score greater than 0.5 suggests that the compounds have the same protein target. 9 In reverse screening, the total score is used to determine the likelihood of targeting a certain protein.…”

“… 9 A score greater than 0.5 suggests that the compounds have the same protein target. 9 In reverse screening, the total score is used to determine the likelihood of targeting a certain protein. Dual-based reverse screening has proven effective for predicting macromolecular targets.…”