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Safrole‑induced expression of proinflammatory responses is associated with phosphorylation of mitogen‑activated protein kinase family and the nuclear factor‑κB/inhibitor of κB pathway in macrophages

Yung‑Lun Nia, Huan‑Ting Shena,b, Min‑Wei Leec, Kun‑Lin Yehd, Chen‑Yu Chiangd, Yu‑Hsiang Kuane,f*

aDepartment of Pulmonary Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Hospital, Taichung, Taiwan, bInstitute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan, cGraduate Institute of Microbiology and Public Health, National Chung Hsing University, Taichung, Taiwan, dDepartment of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan, eDepartment of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan, fDepartment of Pharmacology,
School of Medicine, Chung Shan Medical University, Taichung, Taiwan

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Open Access funded by Buddhist Compassion Relief Tzu Chi Foundation


Objective: Safrole, also called shikimol and Sassafras, is the carcinogenic and phenylpropanoid compound extracted from Sassafras tree and anise, betel, and camphor. Moreover, a high concentration of safrole can be occur in the saliva because of betel nut or areca quid chewing which a common habit observed in Southern and Southeastern Asia. Notably, macrophages are crucial phagocytic cells of the immune system. Nonetheless, to date, no evidence has been reported regarding safrole‑induced proinflammatory response and the corresponding mechanism in macrophages. Materials and Methods: In the present study, the cytokines expression, NO generation, protein phosphorylation, and expression were assessed by enzyme‑linked immunosorbent assay, Griess reagent, and Western blot assay, respectively. Results: In this study, we determined that safrole induces the generation of nitric oxide and proinflammatory cytokines, including tumor necrosis factor‑α, interleukin‑1β, and IL‑6 in RAW264.7 macrophages in a concentration‑dependent manner. Furthermore, inhibitor of κB (IκB) degradation was caused by safrole in a concentration‑dependent manner. In addition, the phosphorylation of nuclear factor (NF)‑κB and mitogen‑activated protein kinase (MAPK) family, including p38 MAPK, extracellular signal‑regulated kinase (ERK), and c‑Jun N‑terminal kinase, was induced by safrole began to increase at 10 μM and attained a plateau at 100 μM. Conclusion: These results indicated that safrole induces the expression of proinflammatory responses in macrophages through the NF‑κB/IκB pathway and its upstream factor, MAPK family phosphorylation.
Keywords: Macrophage, Mitogen‑activated protein kinase family, Nuclear factor‑κB


pathway, Proinflammatory cytokines, Safrole


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