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DOI

https://doi.org/10.1016/j.jds.2025.10.022

First Page

457

Last Page

467

Abstract

Background/purpose Particulate matter (PM) exposure is associated with inflammation and extracellular matrix degradation in periodontal tissues. Cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and matrix metalloproteinase-1 (MMP-1) are key mediators in these processes. Nattokinase, a fibrinolytic enzyme derived from Bacillus subtilis fermentation, has recently gained attention for its potent anti-inflammatory and antioxidant effects. Materials and methods Human gingival fibroblasts (HGF-1 cells) were exposed to PM, and the protective effects of nattokinase pretreatment were systematically evaluated. COX-2, PGE2, and MMP-1 expression and release were analyzed using immunoblotting and enzyme-linked immunosorbent assay. The roles of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK) pathways were examined using pharmacological inhibitors. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis was validated by inhibitors and antioxidant response element (ARE)-luciferase assays. Results PM stimulation induced COX-2 expression, PGE2 release, and MMP-1 upregulation in HGF-1 cells through NADPH oxidase-mediated ROS generation, PI3K/Akt activation, and phosphorylation of p42/p44 MAPK and p38 MAPK. ROS and PI3K/Akt exhibited bidirectional regulation reinforcing COX-2 and MMP-1 induction. Nattokinase pretreatment markedly suppressed these pro-inflammatory and matrix-degrading responses. Mechanistically, nattokinase enhanced Nrf2 activation and HO-1 expression, thereby attenuating PM-induced signaling cascades and mediator release. Inhibition of Nrf2 or HO-1 abolished nattokinase's protective effects. Conclusion Nattokinase protects HGF-1 cells from PM-induced inflammation and matrix degradation by activating the Nrf2/HO-1 axis and suppressing NADPH oxidase-derived ROS, effectively interrupting the reciprocal regulation between ROS, PI3K/Akt, and MAPK pathways.

Publication Date

1-1-2026

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