Abstract
Celastrus orbiculatus Thunb has been known as an ethnopharmacological medicinal plant for antitumor, anti-inflammatory, and analgesic effects. Although various pharmacological studies of C. orbiculatus extract has been reported, an anti-inflammatory mechanism study of their phytochemical constituents has not been fully elucidated. In this study, compounds 1–17, including undescribed podocarpane-type trinorditerpenoid (3), were purified from C. orbiculatus and their chemical structure were determined by high-resolution electrospray ionization mass (HRESIMS) and nuclear magnetic resonance (NMR) spectroscopic data. To investigate the anti-inflammatory activity of compounds 1–17, nitric oxide (NO) secretion was evaluated in LPS-treated murine macrophages, RAW264.7 cells. Among compounds 1–17, deoxynimbidiol (1) and new trinorditerpenoid (3) showed the most potent inhibitory effects (IC50: 4.9 and 12.6 μM, respectively) on lipopolysaccharide- (LPS-) stimulated NO releases as well as proinflammatory mediators, such as inducible nitric oxide (iNOS), cyclooxygenase- (COX-) 2, interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α. Its inhibitory activity of proinflammatory mediators is contributed by suppressing the activation of nuclear transcription factor- (NF-) κB and mitogen-activated protein kinase (MAPK) signaling cascades including p65, inhibition of NF-κB (IκB), extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38. Therefore, these results demonstrated that diterpenoids 1 and 3 obtained from C. orbiculatus may be considered a potential candidate for the treatment of inflammatory diseases.
Highlights
Celastrus orbiculatus Thunb. (Oriental bittersweet) is a perennial woody vine belonging to the family Celastraceae, which is native to East Asia including China, Japan, and Korea [1, 2]
Medium-pressure liquid chromatography (MPLC) was performed using a Combiflash RF (Teledyne Isco, Lincoln, NE, USA), and semipreparative HPLC was performed on a Shimadzu LC-6 AD (Shimadzu Co., Tokyo, Japan) instrument equipped with a SPD-20A detector using Phenomenex Luna C18 (250 × 21:2 mm, 5 μm, Phenomenex, Torrance, CA, USA), Phenomenex Kinetex C18 (150 × 21:2 mm, 5 μm), Phenomenex Luna C8 (150 × 21:2 mm, 5 μm), and YMC C18 J’sphere ODS H80 (250 × 20 mm, 4 μm, YMC Co., Kyoto, Japan) columns. 1H, 13C, and 2D nuclear magnetic resonance (NMR) spectroscopic data were measured on a JEOL JNM-ECA600 or JEOL JNM-EX400 instrument (JEOL, Tokyo, Japan) using TMS as a reference
C. orbiculatus is regarded as a medicinal plant including several terpenoids in East Asia and is treated with clinical prescription for health management [11, 36, 37], the biological activity and its composition against the inflammatory action of C. orbiculatus have hardly been found
Summary
Celastrus orbiculatus Thunb. (Oriental bittersweet) is a perennial woody vine belonging to the family Celastraceae, which is native to East Asia including China, Japan, and Korea [1, 2]. Macrophage activated by antigen, pathogens, and endogenous inflammatory stimuli is associated with functional and physiological changes in the cells and generates proinflammatory and cytotoxic mediators such as nitric oxide (NO), tumor necrosis factor α (TNF-α), interleukin-1β (IL1β), IL-6, reactive oxygen mediators, and hydrolytic enzymes [25, 26]. Excessive NO and inflammatory cytokines released from macrophages are implicated in cytotoxicity by initiating both apoptosis and necrosis of normal tissues as well as destruction of tumor cells and exogenous pathogens [27, 28]. Blocking these inflammatory mediators is considered to be effective for prevention of inflammation diseases
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