Anti-Inflammatory Activity of Labdane and Norlabdane Diterpenoids from Leonurus sibiricus Related to Modulation of MAPKs Signaling Pathway

<i>Leonurus sibiricus</i>, a widely cultivated herbaceous plant in Asian countries, exhibits diverse medicinal applications. Recent studies emphasize its pharmacological properties and efficacy in promoting bone health. In addition to the known compounds and their pharmacological activities, in this study, we isolated and elucidated two new labdane-type diterpenoids, (3<i>R</i>,5<i>R</i>,6<i>S</i>,10<i>S</i>)-3,6-dihydroxy-15-ethoxy-7-oxolabden-8(9),13(14)-dien-15,16-olide (1: ) and (4<i>R</i>,5<i>R</i>,10<i>S</i>)-18-hydroxy-14,15-bisnorlabda-8-en-7,13-dione (2: ), a new natural phenolic compound, and a known compound from <i>L. sibiricus</i> using advanced spectroscopic techniques, including circular dichroism spectroscopy, high-resolution mass spectrometry, and 1- and 2-dimensional NMR. Among these, compound 1: demonstrated potent inhibition of nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression levels, followed by compound 2: . Whereas compounds 3: and 4: did not exhibit effectiveness in RAW264.7 macrophages. Moreover, compound 1: suppressed pro-inflammatory markers induced by lipopolysaccharide (LPS) stimulation. Compound 1: also suppressed iNOS and cyclooxygenase-2 (COX-2) protein levels and downregulated pro-inflammatory cytokines. Additionally, compound 1: showed inhibition of the phosphorylation of p38, JNK, and ERK, key mediators of the MAPK signaling pathway. These findings indicate that a natural-derived product, compound 1,: might be a potential candidate as an anti-inflammation mediator.