{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:49:10Z","timestamp":1778273350602,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Trade, Industry, and Energy of Korea","award":["P0024160"],"award-info":[{"award-number":["P0024160"]}]},{"name":"Korea Institute for the Advancement of Technology (KIAT)","award":["P0024160"],"award-info":[{"award-number":["P0024160"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Chalcones are recognized for their diverse pharmacological properties, including anti-inflammatory and anti-melanogenic effects. However, studies on 2\u2032-hydroxy-2-methoxychalcone derivatives remain limited. This study investigated the anti-inflammatory and melanin synthesis-inhibitory effects of three derivatives: 2\u2032-hydroxy-2,4-dimethoxychalcone (2,4-DMC), 2\u2032-hydroxy-2,5\u2032-dimethoxychalcone (2,5\u2032-DMC), and 2\u2032-hydroxy-2,6\u2032-dimethoxychalcone (2,6\u2032-DMC). In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, 2,6\u2032-DMC demonstrated a superior inhibition of nitric oxide (NO) production, pro-inflammatory cytokines, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) compared to the other derivatives. A mechanistic analysis revealed that 2,6\u2032-DMC modulates the NF-\u03baB and MAPK signaling pathways to attenuate inflammation. Additionally, 2,6\u2032-DMC exhibited a significant inhibition of \u03b1-melanocyte-stimulating hormone (\u03b1-MSH)-induced melanin synthesis in B16F10 melanoma cells by downregulating tyrosinase, TRP-1, TRP-2, and MITF expression. This regulation was achieved through the suppression of the Wnt\/\u03b2-catenin, PI3K\/AKT, MAPK, and PKA\/CREB pathways. Compared to 2,4-DMC and 2,5\u2032-DMC, 2,6\u2032-DMC\u2019s structural configuration, characterized by methoxy groups at the 2- and 6\u2032-positions, contributed to its enhanced molecular stability and binding affinity, amplifying its inhibitory effects. A primary skin irritation test confirmed that 2,6\u2032-DMC exhibited minimal irritation, demonstrating its safety for dermal applications. These findings suggest that 2,6\u2032-DMC holds promise as a dual-function agent for managing inflammatory conditions and hyperpigmentation-related disorders.<\/jats:p>","DOI":"10.3390\/cimb47020085","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T07:45:12Z","timestamp":1738136712000},"page":"85","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Insights on the Anti-Inflammatory and Anti-Melanogenic Effects of 2\u2032-Hydroxy-2,6\u2032-dimethoxychalcone in RAW 264.7 and B16F10 Cells"],"prefix":"10.3390","volume":"47","author":[{"given":"Sung-Min","family":"Bae","sequence":"first","affiliation":[{"name":"Department of Chemistry and Cosmetics, Jeju Inside Agency and Cosmetic Science Center, Jeju National University, Jeju 63243, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3000-7989","authenticated-orcid":false,"given":"Chang-Gu","family":"Hyun","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Cosmetics, Jeju Inside Agency and Cosmetic Science Center, Jeju National University, Jeju 63243, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"George, G., Koyiparambath, V.P., Sukumaran, S., Nair, A.S., Pappachan, L.K., Al-Sehemi, A.G., Kim, H., and Mathew, B. (2022). Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063121"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Quan, Y.S., Liu, J.Y., Wang, Y.L., Liu, Z., Quan, Z.S., Wang, S.H., and Yin, X.M. (2024). Application of Chalcone in the Structural Modification of Natural Products: An Overview. Chem. Biodivers., 19.","DOI":"10.1002\/cbdv.202401953"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dzi\u0105gwa-Becker, M., Oleszek, M., Zieli\u0144ska, S., and Oleszek, W. (2024). Chalcones-Features, Identification Techniques, Attributes, and Application in Agriculture. Molecules, 29.","DOI":"10.20944\/preprints202404.0112.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27769","DOI":"10.1021\/acsomega.2c01779","article-title":"Synthesis of Chalcones Derivatives and Their Biological Activities: A Review","volume":"7","author":"Elkanzi","year":"2022","journal-title":"ACS Omega"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10582","DOI":"10.1039\/D4FO03618B","article-title":"Biological effects and mechanisms of dietary chalcones: Latest research progress, future research strategies, and challenges","volume":"15","author":"Zhang","year":"2024","journal-title":"Food Funct."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Villa, S.M., Heckman, J., and Bandyopadhyay, D. (2024). Medicinally Privileged Natural Chalcones: Abundance, Mechanisms of Action, and Clinical Trials. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179623"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bhol, N.K., Bhanjadeo, M.M., Singh, A.K., Dash, U.C., Ojha, R.R., Majhi, S., Duttaroy, A.K., and Jena, A.B. (2024). The interplay between cytokines, inflammation, and antioxidants: Mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed. Pharmacother., 178.","DOI":"10.1016\/j.biopha.2024.117177"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1080\/17460441.2024.2436908","article-title":"Advances in chalcone-based anticancer therapy: Mechanisms, preclinical advances, and future perspectives","volume":"19","author":"Chowdhary","year":"2024","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1021\/acs.jmedchem.3c00012","article-title":"Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation","volume":"66","author":"Xue","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"22159","DOI":"10.1039\/D1RA03196A","article-title":"Natural and synthetic flavonoid derivatives as new potential tyrosinase inhibitors: A systematic review","volume":"11","author":"Obaid","year":"2021","journal-title":"RSC Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"oeab029","DOI":"10.1093\/ehjopen\/oeab029","article-title":"Inflammatory bowel disease and cardiovascular diseases: A concise review","volume":"2","author":"Wu","year":"2021","journal-title":"Eur. Heart J. Open"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.amjmed.2022.08.012","article-title":"Inflammatory Bowel Disease and Cardiovascular Diseases","volume":"135","author":"Chen","year":"2022","journal-title":"Am. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1016\/j.apsb.2022.01.002","article-title":"Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years","volume":"12","author":"Ju","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2147\/JIR.S278514","article-title":"Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation of PGE2?","volume":"14","author":"Mahesh","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Soliman, A.M., and Barreda, D.R. (2022). Acute Inflammation in Tissue Healing. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010641"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Raziyeva, K., Kim, Y., Zharkinbekov, Z., Kassymbek, K., Jimi, S., and Saparov, A. (2021). Immunology of Acute and Chronic Wound Healing. Biomolecules, 11.","DOI":"10.3390\/biom11050700"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Austermann, J., Roth, J., and Barczyk-Kahlert, K. (2022). The Good and the Bad: Monocytes\u2019 and Macrophages\u2019 Diverse Functions in Inflammation. Cells, 11.","DOI":"10.3390\/cells11121979"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119010","DOI":"10.1016\/j.lfs.2020.119010","article-title":"Monocytes and macrophages in COVID-19: Friends and foes","volume":"269","author":"Meidaninikjeh","year":"2021","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s00011-022-01584-0","article-title":"Inflammatory biomarkers on an LPS-induced RAW 264.7 cell model: A systematic review and meta-analysis","volume":"71","author":"Facchin","year":"2022","journal-title":"Inflamm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Han, H.J., and Hyun, C.G. (2023). Acenocoumarol Exerts Anti-Inflammatory Activity via the Suppression of NF-\u03baB and MAPK Pathways in RAW 264.7 Cells. Molecules, 28.","DOI":"10.3390\/molecules28052075"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/ics.12728","article-title":"Oxidative stress in the skin: Impact and related protection","volume":"43","author":"Chen","year":"2021","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7165","DOI":"10.1021\/acs.chemrev.3c00858","article-title":"Interactions of Melanin with Electromagnetic Radiation: From Fundamentals to Applications","volume":"124","author":"Xie","year":"2024","journal-title":"Chem. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Review Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Flieger, J., Raszewska-Famielec, M., Radzikowska-B\u00fcchner, E., and Flieger, W. (2024). Skin Protection by Carotenoid Pigments. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031431"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1111\/pcmr.12986","article-title":"Management of hyperpigmentation: Current treatments and emerging therapies","volume":"34","author":"Nautiyal","year":"2021","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7881717","DOI":"10.1155\/2022\/7881717","article-title":"Implications of Oxidative Stress in the Pathogenesis and Treatment of Hyperpigmentation Disorders","volume":"2022","author":"Xing","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Goenka, S., Johnson, F., and Simon, S.R. (2021). Novel Chemically Modified Curcumin (CMC) Derivatives Inhibit Tyrosinase Activity and Melanin Synthesis in B16F10 Mouse Melanoma Cells. Biomolecules, 11.","DOI":"10.3390\/biom11050674"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lee, Y., and Hyun, C.G. (2022). Mechanistic Insights into the Ameliorating Effect of Melanogenesis of Psoralen Derivatives in B16F10 Melanoma Cells. Molecules, 27.","DOI":"10.3390\/molecules27092613"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hossain, M.R., Ansary, T.M., Komine, M., and Ohtsuki, M. (2021). Diversified Stimuli-Induced Inflammatory Pathways Cause Skin Pigmentation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083970"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhong, C., Liang, G., Li, P., Shi, K., Li, F., Zhou, J., and Xu, D. (2023). Inflammatory response: The target for treating hyperpigmentation during the repair of a burn wound. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1009137"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.2147\/CCID.S385162","article-title":"Post-Inflammatory Hyperpigmentation in Dark Skin: Molecular Mechanism and Skincare Implications","volume":"15","author":"Markiewicz","year":"2022","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113598","DOI":"10.1016\/j.fct.2022.113598","article-title":"Non-steroidal anti-inflammatory drugs (NSAIDs): A current insight into its molecular mechanism eliciting organ toxicities","volume":"172","author":"Panchal","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105685","DOI":"10.1016\/j.jbspin.2023.105685","article-title":"NSAID: Current limits to prescription","volume":"91","author":"Wirth","year":"2024","journal-title":"Jt. Bone Spine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.freeradbiomed.2020.12.008","article-title":"The role of NO in COVID-19 and potential therapeutic strategies","volume":"163","author":"Fang","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41392-022-00955-7","article-title":"Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention","volume":"7","author":"Kong","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shah, K., and Kazi, J.U. (2022). Phosphorylation-Dependent Regulation of WNT\/Beta-Catenin Signaling. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.858782"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vainio, L., Taponen, S., Kinnunen, S.M., Halmetoja, E., Szabo, Z., Alakoski, T., Ulvila, J., Junttila, J., Lakkisto, P., and Magga, J. (2021). GSK3\u03b2 Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413586"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1111\/pcmr.12980","article-title":"The \u03b1-melanocyte-stimulating hormone\/melanocortin-1 receptor interaction: A driver of pleiotropic effects beyond pigmentation","volume":"34","author":"Herraiz","year":"2021","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/pcmr.12920","article-title":"Cyclic adenosine monophosphate (cAMP) signaling in melanocyte pigmentation and melanomagenesis","volume":"34","author":"Bang","year":"2021","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00894-016-2946-8","article-title":"The impact of position and number of methoxy group(s) to tune the nonlinear optical properties of chalcone derivatives: A dual substitution strategy","volume":"22","author":"Muhammad","year":"2016","journal-title":"J. Mol. Model."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1039\/D1EN01156A","article-title":"Effect of polycation nanostructures on cell membrane permeability and toxicity","volume":"9","author":"Knobloch","year":"2022","journal-title":"Environ. Sci. Nano"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/2\/85\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:38:18Z","timestamp":1759919898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/2\/85"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cimb47020085"],"URL":"https:\/\/doi.org\/10.3390\/cimb47020085","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,29]]}}}