Susana, Shalice R.Salvador-Reyes, Lilibeth A.2025-05-042022-03-22Susana, S. R., & Salvador-Reyes, L. A. (2022). Anti-inflammatory activity of monosubstituted xestoquinone analogues from the marine sponge Neopetrosia compacta. <i>Antioxidants</i>, <i>11</i>(4), Article 607.2076-392110.3390/antiox11040607https://hdl.handle.net/20.500.14697/391Samples were collected under gratuitous permit numbers GP-0084-15 and GP-0123-17, issued by the Department of Agriculture of the Philippines. We thank the municipalities of Bolinao, Pangasinan, and Puerto Galera, Oriental Mindoro for permission for sample collection. We acknowledge assistance from Z. L. Malto and DDHP chemical ecology group in obtaining the mass spectrometric data and sample collection, respectively.Chronic inflammation is recognized as a contributor to multiple chronic diseases, such as cancer, cardiovascular, and autoimmune disorders. Here, a natural products-initiated discovery of anti-inflammatory agents from marine sponges was undertaken. From the screening of 231 crude extracts, a total of 30 extracts showed anti-inflammatory activity with no direct cytotoxic effects at 50 μg/mL on RAW 264.7 (ATCC®TIB-71™) murine macrophage cells stimulated with 1 μg/mL lipopolysaccharide (LPS). Bioactivity-guided purification of the anti-inflammatory extract from the sponge <i>Neopetrosia compacta</i> led to the isolation of xestoquinone (1), adociaquinone B (2), adociaquinone A (3), 14-hydroxymethylxestoquinone (4), 15-hydroxymethylxestoquinone (5), and an inseparable 2:1 mixture of 14-methoxyxestoquinone and 15-methoxyxestoquinone (6). Compounds 1–6 caused a concentration-dependent reduction of nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells, with 4–6 having low micromolar IC50 and acceptable selectivity index. Gene expression analysis using qRT-PCR showed that 1, 5, and 6 downregulated <i>Il1b</i> and <i>Nos2</i> expression by 2.1- to 14.8-fold relative to the solvent control at 10 μM. Xestoquinone (1) and monosubstituted analogues (4–6), but not the disubstituted adociaquinones (2 and 3), caused Nrf2 activation in a luciferase reporter MCF7 stable cells. Compounds 5 and 6 caused a modest increase in <i>Nqo1</i> gene expression at 10 μM. The anti-inflammatory activity of xestoquinone (1) and monosubstituted analogues (4–6) may, in part, be mediated by Nrf2 activation, leading to attenuation of inflammatory mediators such as IL-1β and NOS2.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/PharmacologyBiotechnologyDrugsSpongesAnti-inflammatory agentsInflammationDiseasesNitric oxideTetrazoliumPharmacologyMarine natural productsMarine pharmacologyDrug developmentMarine biotechnologyArticleSDG 14 - Life below waterSDG 3 - Good health and well-beingspongesantiinflammatory agentsinflammationdiseasesnitric oxidebioactive compoundsdrugspharmacologybiotechnologyChallenge 2: Protect and restore ecosystems and biodiversityChallenge 4: Develop a sustainable and equitable ocean economyChallenge 10: Change humanity’s relationship with the ocean