Abstract
Three new compounds, 4-geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone (1), hypericumone A (2) and hypericumone B (3), were obtained from the aerial parts of Hypericum sampsonii, along with six known compounds (4–9). The structures of these compounds were determined through spectroscopic and MS analyses. Hypericumone A (2), sampsonione J (8) and otogirinin A (9) exhibited potent inhibition (IC50 values ≤ 40.32 μM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (9) possessed the highest inhibitory effect on NO production with IC50 value of 32.87 ± 1.60 μM. The well-known proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α) was also inhibited by otogirinin A (9). Western blot results demonstrated that otogirinin A (9) downregulated the high expression of inducible nitric oxide synthase (iNOS). Further investigations on the mechanism showed that otogirinin A (9) blocked the phosphorylation of MAPK/JNK and IκBα, whereas it showed no effect on the phosphorylation of MAPKs/ERK and p38. In addition, otogirinin A (9) stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that otogirinin A (9) could be considered as potential compound for further development of NO production-targeted anti-inflammatory agent.
Highlights
The n-hexane fraction of the MeOH extract of H. sampsonii showed the most potent inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) accumulation in RAW264.7 macrophages, while H2 O fraction had no effect on NO generation (Figure 1)
We carried out the chromatographic purification of the hexane-soluble fraction of MeOH extracts of aerial parts of H. sampsonii on a silica gel column and preparative thin-layer chromatography (TLC) afforded three undescribed (1–3) and six known compounds (4–9) (Figure 2)
To investigate the Mitogen-activated protein kinases (MAPKs) pathway, we examined whether otogirinin A (9) effected on LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38 MAPKs by Western blot analysis
Summary
Hypericum sampsonii Hance (Hypericaceae) has been used as a traditional medicine herb for reducing blood stasis, relieving swelling and detoxification in Taiwan [1,2]. There was no biologic activity report for 8 and 9, except that 8 showed no significant cytotoxicity against P338 cell line [18]. Their analogous benzoylphloroglucinol derivatives, garcimultiflorone G [19] and sampsonione B [20] was reported to exhibit anti-inflammatory activity. This report depicts the structural elucidation of three new Compounds 1–3, the inhibitory activities of all isolated compounds against LPS-induced NO generation and the anti-inflammatory mechanism of otogirinin A (9)
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