Graduate Institute of Natural Products, College of Medicine, Chang-Gung University, Tao Yuan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, 333, Taiwan, Republic of China; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan, Republic of China.
Graduate Institute of Natural Products, College of Medicine, Chang-Gung University, Tao Yuan, Taiwan, Republic of China.
Chem Biol Interact. 2021 Aug 25;345:109490. doi: 10.1016/j.cbi.2021.109490. Epub 2021 Jun 16.
The uncontrol respiratory burst in neutrophils can lead to inflammation and tissue damage. This study investigates the effect and the underlying mechanism of ε-viniferin, a lignan from the root of Vitis thunbergii var. thunbergii, inhibits N-formyl-L-methionyl-L-leucyl-l-phenylalanine (fMLP) induced respiratory burst by antagonizing formyl peptide receptor 1 in human neutrophils. Briefly, ε-viniferin specifically inhibited fMLP (0.1 μM: formyl peptide receptor 1 agonist or 1 μM: formyl peptide receptor 1, 2 agonist)-induced superoxide anion production in a concentration-dependent manner (IC = 2.30 ± 0.96 or 9.80 ± 0.21 μM, respectively) without affecting this induced by formyl peptide receptor 2 agonist (WKYMVM). ε-viniferin inhibited fMLP (0.1 μM)-induced phosphorylation of ERK, Akt, Src or intracellular calcium mobilization without affecting these caused by WKYMVM. The synergistic suppression of fMLP (1 μM)-induced superoxide anion production was observed only in the combination of ε-viniferin and formyl peptide receptor 2 antagonist (WRW4) but not in combination of ε-viniferin and formyl peptide receptor 1 antagonist (cyclosporine H). ε-viniferin inhibited FITC-fMLP binding to formyl peptide receptors. Moreover, the synergistic suppression of FITC-fMLP binding was observation only in the combination of ε-viniferin and WRW4 but not in other combinations. ATPγS induced superoxide anion production through formyl peptide receptor 1 in fMLP desensitized neutrophils and this effect was inhibited by ε-viniferin. The concentration-response curve of fMLP-induced superoxide anion was not parallel shifted by ε-viniferin. Furthermore, the inhibiting effect of ε-viniferin on fMLP-induced superoxide anion production was reversible. These results suggest that ε-viniferin is an antagonist of formyl peptide receptor 1 in a reversible and non-competitive manner.
中性粒细胞中不受控制的呼吸爆发会导致炎症和组织损伤。本研究探讨了来自葡萄根的木脂素ε-viniferin 通过拮抗人中性粒细胞中的甲酰肽受体 1 抑制 N-甲酰-L-甲硫氨酸-L-亮氨酸-L-苯丙氨酸 (fMLP) 诱导的呼吸爆发的作用及其潜在机制。简要地说，ε-viniferin 特异性抑制 fMLP（0.1μM：甲酰肽受体 1 激动剂或 1μM：甲酰肽受体 1、2 激动剂）诱导的超氧阴离子产生，呈浓度依赖性（IC = 2.30 ± 0.96 或 9.80 ± 0.21μM，分别），而不影响由甲酰肽受体 2 激动剂（WKYMVM）引起的超氧阴离子产生。ε-viniferin 抑制 fMLP（0.1μM）诱导的 ERK、Akt、Src 磷酸化或细胞内钙动员，而不影响 WKYMVM 引起的磷酸化。仅在 ε-viniferin 和甲酰肽受体 2 拮抗剂（WRW4）的组合中观察到 fMLP（1μM）诱导的超氧阴离子产生的协同抑制，但在 ε-viniferin 和甲酰肽受体 1 拮抗剂（环孢菌素 H）的组合中没有观察到。ε-viniferin 抑制 FITC-fMLP 与甲酰肽受体的结合。此外，仅在 ε-viniferin 和 WRW4 的组合中观察到 FITC-fMLP 结合的协同抑制，而在其他组合中没有观察到。ATPγS 通过 fMLP 脱敏的中性粒细胞中的甲酰肽受体 1 诱导超氧阴离子产生，该效应被 ε-viniferin 抑制。fMLP 诱导的超氧阴离子的浓度-反应曲线没有被 ε-viniferin 平行移位。此外，ε-viniferin 对 fMLP 诱导的超氧阴离子产生的抑制作用是可逆的。这些结果表明，ε-viniferin 以可逆和非竞争性方式作为甲酰肽受体 1 的拮抗剂。
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