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MZM, extracted from machilus zuihoensis var. mushaensis, a natural FPR1

agonist, expressed a biased effect on human neutrophil

#,1
4
1,2
Hsiang-Ruei Liao,* ,1,2,3 Chen-Lung Chen, Hsun-Shuo Chang, Pei-Wen Hsieh, Y u -
3
1
Yao Kao, Fu-Chao Liu, Ju-Hsin Cheng, Ching-Ping Tseng
4
2

1 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of
Medicine, Chang-Gung University, Kweishan, Taoyuan, Taiwan, Republic of China
2 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University,
Kweishan, Taoyuan, Taiwan, Republic of China
3 Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan,
Republic of China
4 School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung,
Taiwan, Republic of China
* E-mail: liaoch@mail.cgu.edu.tw

Abstract
The formyl peptide receptor 1 (FPR1), highly expressed in neutrophils, is a crucial regulator
of neutrophil recruitment, superoxide anion production, and the resolution of inflammation. The
dual functionality of FPR1 makes them appealing targets for developing FPR-based
therapeutics as new anti-inflammatory treatments. This study demonstrates that MZM extracted
from machilus zuihoensis var. mushaensis targets and acts as an agonist of FPR1, exhibiting a
biased effect. MZM-mediated superoxide anion production, cathepsin G release, and
intracellular signal were assessed with FPR1 antagonist or inhibitor in human neutrophils.
Molecular docking was conducted to analyze the binding mode of MZM to FPR1, and cell
migration experiments were performed to evaluate the effect of MZM. MZM stimulated
superoxide anion production and cathepsin G release in neutrophils in a concentration-
dependent manner. These effects and the intracellular signaling associated with the superoxide
anion production, such as protein phosphorylation and variations in calcium levels, were
inhibited by the FPR1-specific inhibitor, cyclosporin H. In contrast, a FPR2 inhibitor, WRW4,
had no inhibitory effect on MZM. Gq-protein inhibitor, YM-254890, did not inhibit MZM-
induced superoxide anion and calcium mobilization. Computer docking analysis revealed that
MZM and FPR1 possess multiple binding sites. Cyclosporin H reversibly competes with MZM
binding to FPR1. Additionally, MZM does not trigger chemotaxis in neutrophils. Conclusions:
MZM binds to FPR1, activating the Gi-protein and promoting superoxide anion production
without inducing chemotaxis in neutrophils, demonstrating the biased effect of MZM. MZM is
a valuable tool for conducting mechanistic studies of FPR1 in relation to inflammation.

Keywords: MZM; FPR1; Neutrophil; Biased effect