| Summary: | Qin Pi (<i>Fraxinus chinensis</i> Roxb.) is commercially used in healthcare products for the improvement of intestinal function and gouty arthritis in many countries. Three new secoiridoid glucosides, (8<i>E</i>)-4′′-<i>O</i>-methylligstroside (<b>1</b>), (8<i>E</i>)-4′′-<i>O</i>-methyldemethylligstroside (<b>2</b>), and 3′′,4′′-di-<i>O</i>-methyl-demethyloleuropein (<b>3</b>), have been isolated from the stem bark of <i>Fraxinus chinensis</i>, together with 23 known compounds (<b>4</b>–<b>26</b>). The structures of the new compounds were established by spectroscopic analyses (1D, 2D NMR, IR, UV, and HRESIMS). Among the isolated compounds, (8<i>E</i>)-4′′-<i>O</i>-methylligstroside (<b>1</b>), (8<i>E</i>)-4′′-<i>O</i>-methyldemethylligstroside (<b>2</b>), 3′′,4′′-di-<i>O</i>-methyldemethyloleuropein (<b>3</b>), oleuropein (<b>6</b>), aesculetin (<b>9</b>), isoscopoletin (<b>11</b>), aesculetin dimethyl ester (<b>12</b>), fraxetin (<b>14</b>), tyrosol (<b>21</b>), 4-hydroxyphenethyl acetate (<b>22</b>), and (+)-pinoresinol (<b>24</b>) exhibited inhibition (IC<sub>50</sub> ≤ 7.65 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leuckyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds <b>1</b>, <b>9</b>, <b>11</b>, <b>14</b>, <b>21</b>, and <b>22</b> inhibited fMLP/CB-induced elastase release with IC<sub>50</sub> ≤ 3.23 μg/mL. In addition, compounds <b>2</b>, <b>9</b>, <b>11</b>, <b>14</b>, and <b>21</b> showed potent inhibition with IC<sub>50</sub> values ≤ 27.11 μM, against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. The well-known proinflammatory cytokines<i>,</i> tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), were also inhibited by compounds <b>1</b>, <b>9</b>, and <b>14</b>. Compounds <b>1</b>, <b>9</b>, and <b>14</b> displayed an anti-inflammatory effect against NO, TNF-α, and IL-6 through the inhibition of activation of MAPKs and IκBα in LPS-activated macrophages. In addition, compounds <b>1</b>, <b>9</b>, and <b>14</b> stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that compounds <b>1</b>, <b>9</b>, and <b>14</b> could be considered as potential compounds for further development of NO production-targeted anti-inflammatory agents.
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