PMID- 34385920 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210814 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - Antiatherogenic Effects of Quercetin in the THP-1 Macrophage Model In Vitro, With Insights Into Its Signaling Mechanisms Using In Silico Analysis. PG - 698138 LID - 10.3389/fphar.2021.698138 [doi] LID - 698138 AB - 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 muM 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 muM for 24 h either in the absence or presence of interferon (IFN-gamma) 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 microM 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-gamma, 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-alpha 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. CI - Copyright (c) 2021 Huwait, Saddeek, Al-Massabi, Almowallad, Pushparaj and Kalamegam. FAU - Huwait, Etimad A AU - Huwait EA AD - Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Cell Culture Unit and Experimental Biochemistry Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia. FAU - Saddeek, Salma Y AU - Saddeek SY AD - Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Cell Culture Unit and Experimental Biochemistry Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Chemistry Department, Faculty of Sciences, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia. FAU - Al-Massabi, Rehab F AU - Al-Massabi RF AD - Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Cell Culture Unit and Experimental Biochemistry Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Biochemistry Department, Faculty of Sciences, University of Tabuk, Tabuk, Saudi Arabia. FAU - Almowallad, Sanaa J AU - Almowallad SJ AD - Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Cell Culture Unit and Experimental Biochemistry Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Biochemistry Department, Faculty of Sciences, University of Tabuk, Tabuk, Saudi Arabia. FAU - Pushparaj, Peter Natesan AU - Pushparaj PN AD - Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. FAU - Kalamegam, Gauthaman AU - Kalamegam G AD - Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. AD - Pharmaceutical Division, Nibblen Life Sciences Private Limited, Chennai, India. LA - eng PT - Journal Article DEP - 20210727 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC8353397 OTO - NOTNLM OT - SwissTargetPrediction OT - THP-1 macrophages OT - atherosclerosis OT - brain destruction OT - cell migration OT - inflammmation OT - ingenuity pathway analysis OT - stroke COIS- GK is employed (honorary) by the company Nibblen Life Sciences Private Limited, Chennai, as the Research Director and Technical Advisor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MA declared a past co-authorship with one of the authors PP. EDAT- 2021/08/14 06:00 MHDA- 2021/08/14 06:01 PMCR- 2021/07/27 CRDT- 2021/08/13 07:06 PHST- 2021/04/21 00:00 [received] PHST- 2021/06/25 00:00 [accepted] PHST- 2021/08/13 07:06 [entrez] PHST- 2021/08/14 06:00 [pubmed] PHST- 2021/08/14 06:01 [medline] PHST- 2021/07/27 00:00 [pmc-release] AID - 698138 [pii] AID - 10.3389/fphar.2021.698138 [doi] PST - epublish SO - Front Pharmacol. 2021 Jul 27;12:698138. doi: 10.3389/fphar.2021.698138. eCollection 2021.