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
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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 (IC
50 values ≤ 40.32 μM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (
9) possessed the highest inhibitory effect on
NO production with IC
50 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.
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