PMID- 34048809 OWN - NLM STAT- MEDLINE DCOM- 20210628 LR - 20210628 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 278 DP - 2021 Aug 1 TI - In vitro evaluation of the involvement of Nrf2 in maslinic acid-mediated anti-inflammatory effects in atheroma pathogenesis. PG - 119658 LID - S0024-3205(21)00644-5 [pii] LID - 10.1016/j.lfs.2021.119658 [doi] AB - AIMS: Maslinic acid (MA) is a naturally occurring pentacyclic triterpene known to exert cardioprotective effects. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) for MA-mediated anti-inflammatory effects in atheroma pathogenesis in vitro, including evaluation of tumor necrosis factor-alpha (TNF-alpha)-induced monocyte recruitment, oxidized low-density lipoprotein (oxLDL)-induced scavenger receptors expression, and nuclear factor-kappa B (NF-kB) activity in human umbilical vein endothelial cells (HUVECS) and human acute monocytic leukemia cell line (THP-1) macrophages. MATERIALS AND METHODS: An in vitro monocyte recruitment model utilizing THP-1 and HUVECs was developed to evaluate TNF-alpha-induced monocyte adhesion and trans-endothelial migration. To study the role of Nrf2 for MA-mediated anti-inflammatory effects, Nrf2 inhibitor ML385 was used as the pharmacological inhibitor. The expression of Nrf2, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 36 (CD36), and scavenger receptor type A (SR-A) in HUVECs and THP-1 macrophages were investigated using RT-qPCR and Western blotting. The NF-kappaB activity was determined using NF-kappaB (p65) Transcription Factor Assay Kit. KEY FINDINGS: The results showed opposing effects of MA on Nrf2 expression in HUVECs and THP-1 macrophages. MA suppressed TNF-alpha-induced Nrf2 expression in HUVECs, but enhanced its expression in THP-1 macrophages. Combined effects of MA and ML385 suppressed MCP-1, VCAM-1, and SR-A expressions. Intriguingly, at the protein level, ML385 selectively inhibited SR-A but enhanced CD36 expression. Meanwhile, ML385 further enhanced MA-mediated inhibition of NF-kappaB activity in HUVECs. This effect, however, was not observed in THP-1 macrophages. SIGNIFICANCE: MA attenuated foam cell formation by suppressing VCAM-1, MCP-1, and SR-A expression, as well as NF-kappaB activity, possibly through Nrf2 inhibition. The involvement of Nrf2 for MA-mediated anti-inflammatory effects however differs between HUVECs and macrophages. Future investigations are warranted for a detailed evaluation of the contributing roles of Nrf2 in foam cells formation. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Ooi, Bee Kee AU - Ooi BK AD - School of Biosciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan 47500, Malaysia. FAU - Phang, Su Wen AU - Phang SW AD - School of Biosciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan 47500, Malaysia. FAU - Yong, Phelim Voon Chen AU - Yong PVC AD - School of Biosciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan 47500, Malaysia. FAU - Chellappan, Dinesh Kumar AU - Chellappan DK AD - Department of Life Sciences, School of Pharmacy, International Medical University (IMU), Bukit Jalil, 57000, Kuala Lumpur, Malaysia. FAU - Dua, Kamal AU - Dua K AD - Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia. FAU - Khaw, Kooi-Yeong AU - Khaw KY AD - Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia. FAU - Goh, Bey Hing AU - Goh BH AD - Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: goh.bey.hing@monash.edu. FAU - Pusparajah, Priyia AU - Pusparajah P AD - Medical Health and Translational Research Group, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia. Electronic address: priyia.pusparajah@monash.edu. FAU - Yap, Wei Hsum AU - Yap WH AD - School of Biosciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan 47500, Malaysia; Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences (FHMS), Taylor's University, Subang Jaya 47500, Malaysia. Electronic address: weihsum.yap@taylors.edu.my. LA - eng PT - Journal Article DEP - 20210525 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - 0 (Anti-Inflammatory Agents) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Triterpenes) RN - 0 (Tumor Necrosis Factor-alpha) RN - E233J88OHQ (maslinic acid) SB - IM MH - Anti-Inflammatory Agents/*pharmacology MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Macrophages/drug effects/metabolism/pathology MH - Monocytes/drug effects/metabolism/pathology MH - NF-E2-Related Factor 2/analysis/*metabolism MH - Plaque, Atherosclerotic/drug therapy/*metabolism/pathology MH - THP-1 Cells MH - Triterpenes/*pharmacology MH - Tumor Necrosis Factor-alpha/analysis/*metabolism OTO - NOTNLM OT - Maslinic acid OT - Monocytes recruitment OT - NF-kappaB OT - Nrf2 OT - Scavenger receptors OT - Transendothelial migration EDAT- 2021/05/29 06:00 MHDA- 2021/06/29 06:00 CRDT- 2021/05/28 20:12 PHST- 2021/02/07 00:00 [received] PHST- 2021/05/10 00:00 [revised] PHST- 2021/05/21 00:00 [accepted] PHST- 2021/05/29 06:00 [pubmed] PHST- 2021/06/29 06:00 [medline] PHST- 2021/05/28 20:12 [entrez] AID - S0024-3205(21)00644-5 [pii] AID - 10.1016/j.lfs.2021.119658 [doi] PST - ppublish SO - Life Sci. 2021 Aug 1;278:119658. doi: 10.1016/j.lfs.2021.119658. Epub 2021 May 25.