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Zerumbone suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic
Ai Eguchi1, Yuki Kaneko, Akira Murakami
1Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Abstract:
Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs), such as lectin-like ox-LDL receptor-1 (LOX-1), is a key event in atherosclerosis. In the present study, we used differentiated Caco-2 cells as a model of the human small intestine to evaluate the suppressive effects of 16 traditional food items selected from Okinawa on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced LOX-1 mRNA expression in THP-1 human monocyte-like cells. Three Zingiberaceae plants, Curcuma aromatica Salisbury, Curcuma longa L., and Zingiber zerumbet Smith, markedly suppressed that expression. When added to the apical sides of Caco-2 monolayers, zerumbone, a sesquiterpene from Z. zerumbet Smith, was found to permeate into the basolateral medium as an intact structure in a time-dependent manner. alpha-Humulene, a structural analog of zerumbone lacking the alpha,beta-unsaturated carbonyl group, did not suppress LOX-1 mRNA expression, indicating that its electrophilic moiety might play pivotal roles in its activities. Further, zerumbone attenuated the expression of SR-A, SR-PSOX, and CD36, but not that of CD68 or CLA-1, leading to a blockade of DiI-acLDL uptake, while it also inhibited the transcriptional activities of activator protein-1 and nuclear factor-kappaB. Together, our results indicate that zerumbone is a potential phytochemical for regulating atherosclerosis with reasonable action mechanisms.
Insights
Zerumbone, a compound from Zingiber zerumbet, effectively suppresses oxidized LDL uptake by inhibiting key scavenger receptors and inflammatory pathways, offering potential for atherosclerosis regulation.
Area of Science:
- Biochemistry
- Pharmacology
- Nutritional Science
Background:
- Oxidized low-density lipoprotein (ox-LDL) uptake via macrophage scavenger receptors (SRs), like LOX-1, is crucial in atherosclerosis development.
- Traditional Okinawan foods were investigated for their potential to modulate these pathways.
Purpose of the Study:
- To evaluate the suppressive effects of 16 Okinawan traditional food items on LOX-1 mRNA expression.
- To identify specific compounds and elucidate their mechanisms in regulating atherosclerosis-related gene expression.
Main Methods:
- Differentiated Caco-2 cells and THP-1 cells were used to model intestinal absorption and macrophage responses.
- The impact of Zingiberaceae plant extracts and isolated compounds on LOX-1 mRNA expression, scavenger receptor levels, and transcription factor activity was assessed.
Main Results:
- Three Zingiberaceae plants (Curcuma aromatica, Curcuma longa, Zingiber zerumbet) significantly suppressed LOX-1 mRNA expression.
- Zerumbone, isolated from Z. zerumbet, permeated Caco-2 cells and inhibited LOX-1, SR-A, SR-PSOX, and CD36 expression, blocking ox-LDL uptake.
- Zerumbone's activity was linked to its electrophilic moiety and its ability to inhibit activator protein-1 and nuclear factor-kappaB.
Conclusions:
- Zerumbone demonstrates significant potential as a phytochemical for regulating atherosclerosis.
- Its mechanism involves downregulating scavenger receptor expression and key inflammatory signaling pathways.
