ICAM-1 overexpression and subsequent adhesion of leukocytes to endothelial cells play critical roles in the early stage of atherosclerosis. Danshenol A (DA) is an abietane-type diterpenoid isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. The mechanisms under its regulation of adhesion of molecular expression are explored. Here, the effect of DA on TNF-α-induced ICAM-1 expression was investigated in endothelial cells. TNF-α-induced ICAM-1 expression and subsequent adhesion of monocytes, as well as elevated reactive oxygen species (ROS) generation and NOX4 expression were all significantly reversed by DA, siNOX4 and NOX4 inhibitor GKT137831. Furthermore, TNF-α-induced ICAM-1 expression, which was increased via IKKβ/IκBα-mediated activation of NF-κB p65, was also inhibited by DA. Interestingly, NOX4 overexpression suppressed the ICAM-1 expression, and this finding may be ascribed to the activation of Nrf-2. Additionally, NF-κB inhibitor PDTC, siNOX4, or DA can decrease the TNF-α-induced ICAM-1 expression and suppress the adhesion of monocytes. In all, DA inhibited TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion to endothelial cells through the NOX4-dependent IKKβ/NF-κB pathway. Besides, NOX4 played dual role in regulating ICAM-1 expression via diverse signal pathway. This novel bioactivity will make DA a good candidate to be further explored for therapeutic or preventive application for atherosclerosis.
Yuting Chen,Jie Min,Xiali Yu,Haixiang Ni,Yamei Jin
IntroductionAn increase in the intraorbital adipose tissue is the main pathological feature of thyroid-associated ophthalmopathy (TAO). IGF-1R activates PI3K/AKT signaling and accelerates adipogenesis. Pingmu decoction has been demonstrated to promote orbital adipocyte apoptosis; however, less is reported regarding the action mechanism of Danshenol A (DA), a single active ingredient of Salvia miltiorrhiza (Danshen). Accordingly, this study aimed to investigate the role and association of DA and IGF-1R in the proliferation and lipid accumulation of orbital adipocytes.MethodsPrimary human orbital preadipocytes were chosen and authenticated using immunofluorescence. Cells were treated with the IGF-1R agonist ginsenoside Rg5, IGF-1R overexpression plasmid, dexamethasone (Dex), and/or DA, after which cell proliferation and differentiation were assessed by cell counting kit-8 (CCK-8), oil red O staining, real-time quantitative polymerase chain reaction, and Western blot assays.ResultsOrbital preadipocytes showed positive expression of Pref-1. Treatment with IGF-1R agonist, as well as Dex, promoted orbital adipocyte viability and lipid accumulation, and increased the expression of adiponectin and leptin. It was observed that the overexpression of IGF-1R boosted PI3K/AKT activation and elevated PPARγ and C/EBPα expressions. Importantly, DA reversed the effects of IGF-1R on cell viability, lipid accumulation, and the PI3K/AKT signaling pathway.DiscussionThis study, for the first time, revealed the molecular mechanism by which DA regulates orbital fat metabolism through targeted inhibition of the IGF-1R/PI3K/AKT signaling axis. Notably, IGF-1R overexpression partially counteracted the inhibitory effect of DA, suggesting that this component has multi-target regulatory characteristics.ConclusionThis study not only reveals a new mechanism by which DA treats TAO but also provides theoretical support for the treatment of adipose metabolism.
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