Abstract
Diospyros kaki Thunb. is widely distributed in East Asian countries, its leaves being mainly used for making tea. In this study, coussaric acid (CA) and betulinic acid (BA), both triterpenoid compounds, were obtained from D. kaki leaf extracts through bioassay-guided isolation. CA and BA showed anti-inflammatory effects via inhibition of the nuclear factor-κB (NF-κB) pathway, providing important information on their anti-inflammatory mechanism. Furthermore, they markedly inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages, and suppressed tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) levels. Furthermore, they decreased protein expression of inducible nitric oxide synthase and cyclooxygenase-2. Pre-treatment with CA and BA inhibited LPS-induced NF-κB. We further examined the effects of CA and BA on heme oxygenase (HO)-1 expression in RAW 264.7 macrophages: BA induced HO-1 protein expression in a dose-dependent manner, while CA had no effect. We also investigated whether BA treatment induced nuclear translocation of Nrf2. BA inhibited LPS-induced NF-κB-binding activity, as well as pro-inflammatory mediator and cytokine production (e.g., NO, PGE2, TNF-α, IL-1β, IL-6), by partial reversal of this effect by SnPP, an inhibitor of HO-1. These findings further elucidate the anti-inflammatory mechanism of CA and BA isolated from D. kaki.
Highlights
Inflammation is an important part of the protective immune response against harmful stimuli.uncontrolled inflammation can lead to the development of diseases, such as inflammatory bowel disease, rheumatoid arthritis, neurodegenerative disorders, and sepsis [1]
By using the nitric oxide (NO) assay, we tested to isolate the compounds with anti-inflammatory properties from fractions 4 and 5, and obtained coussaric acid (CA) and betulinic acid (BA) (Figure 1)
The structures of CA and BA were identified by proton nuclear magnetic resonance (1 H-NMR), 13 C-NMR, and distortionless enhancement by polarization transfer (DEPT), and confirmed by comparing the NMR spectral data with those previously reported [24,25,26,27,28]
Summary
Inflammation is an important part of the protective immune response against harmful stimuli. Uncontrolled inflammation can lead to the development of diseases, such as inflammatory bowel disease, rheumatoid arthritis, neurodegenerative disorders, and sepsis [1]. Lipopolysaccharide (LPS), an exogenous bacterial endotoxin, activates macrophages such that they produce various pro-inflammatory cytokines and mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β. Nuclear factor-κB (NF-κB) is a key transcriptional factor involved in immune and inflammatory responses [4]. Heme oxygenase-1 (HO-1) has been recognized as an important molecule in the regulation of inflammation because it inhibits the production of pro-inflammatory cytokines and mediators in activated macrophages [5,6,7]. Nuclear transcription factor-E2-related factor 2 (Nrf2) has been reported to be crucial for HO-1 induction [8]
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