{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T22:24:42Z","timestamp":1780611882606,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T00:00:00Z","timestamp":1634256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["031B0349A, 031B0349B, 031B0349C"],"award-info":[{"award-number":["031B0349A, 031B0349B, 031B0349C"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Salix cortex-containing medicine is used against pain conditions, fever, headaches, and inflammation, which are partly mediated via arachidonic acid-derived prostaglandins (PGs). We used an activity-guided fractionation strategy, followed by structure elucidation experiments using LC-MS\/MS, CD-spectroscopy, and 1D\/2D NMR techniques, to identify the compounds relevant for the inhibition of PGE2 release from activated human peripheral blood mononuclear cells. Subsequent compound purification by means of preparative and semipreparative HPLC revealed 2\u2032-O-acetylsalicortin (1), 3\u2032-O-acetylsalicortin (2), 2\u2032-O-acetylsalicin (3), 2\u2032,6\u2032-O-diacetylsalicortin (4), lasiandrin (5), tremulacin (6), and cinnamrutinose A (7). In contrast to 3 and 7, compounds 1, 2, 4, 5, and 6 showed inhibitory activity against PGE2 release with different potencies. Polyphenols were not relevant for the bioactivity of the Salix extract but salicylates, which degrade to, e.g., catechol, salicylic acid, salicin, and\/or 1-hydroxy-6-oxo-2-cycohexenecarboxylate. Inflammation presents an important therapeutic target for pharmacological interventions; thus, the identification of relevant key drugs in Salix could provide new prospects for the improvement and standardization of existing clinical medicine.<\/jats:p>","DOI":"10.3390\/ijms222011138","type":"journal-article","created":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T13:45:17Z","timestamp":1634564717000},"page":"11138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Identification of Salicylates in Willow Bark (Salix Cortex) for Targeting Peripheral Inflammation"],"prefix":"10.3390","volume":"22","author":[{"given":"Kyriaki","family":"Antoniadou","sequence":"first","affiliation":[{"name":"Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Herz","sequence":"additional","affiliation":[{"name":"Molecular Preventive Medicine, University Medical Center and Faculty of Medicine, University of Freiburg, 79108 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8332-0496","authenticated-orcid":false,"given":"Nguyen Phan Khoi","family":"Le","sequence":"additional","affiliation":[{"name":"Molecular Preventive Medicine, University Medical Center and Faculty of Medicine, University of Freiburg, 79108 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena Karolin","family":"Mittermeier-Kle\u00dfinger","sequence":"additional","affiliation":[{"name":"Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"F\u00f6rster","sequence":"additional","affiliation":[{"name":"Urban Plant Ecophysiology, Humboldt University of Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Zander","sequence":"additional","affiliation":[{"name":"Urban Plant Ecophysiology, Humboldt University of Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ulrichs","sequence":"additional","affiliation":[{"name":"Urban Plant Ecophysiology, Humboldt University of Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-4410","authenticated-orcid":false,"given":"Inga","family":"Mewis","sequence":"additional","affiliation":[{"name":"Urban Plant Ecophysiology, Humboldt University of Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4057-7165","authenticated-orcid":false,"given":"Thomas","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5342-2600","authenticated-orcid":false,"given":"Corinna","family":"Dawid","sequence":"additional","affiliation":[{"name":"Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5620-1595","authenticated-orcid":false,"given":"Evelyn","family":"Lamy","sequence":"additional","affiliation":[{"name":"Molecular Preventive Medicine, University Medical Center and Faculty of Medicine, University of Freiburg, 79108 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.phrs.2018.11.001","article-title":"Molecular pharmacology of inflammation: Medicinal plants as anti-inflammatory agents","volume":"139","author":"Tasneem","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_2","unstructured":"EMA (2017). Assessment Report on Salix [Various Species Including S. purpurea, S. daphnoides Vill., S. fragilis L.], Cortex."},{"key":"ref_3","first-page":"99","article-title":"Influence of the season on the salicylate and phenolic glycoside contents in the bark of Salix daphnoides, Salix pentandra, and Salix purpurea","volume":"82","author":"Ulrichs","year":"2008","journal-title":"J. Appl. Bot. Food Qual. Angew. Bot."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1007\/s10886-006-9059-2","article-title":"Age-related shifts in leaf chemistry of clonal aspen (Populus tremuloides)","volume":"32","author":"Donaldson","year":"2006","journal-title":"J. Chem. Ecol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1104\/pp.122.3.895","article-title":"Salicylates of intact Salix myrsinifolia plantlets do not undergo rapid metabolic turnover","volume":"122","author":"Ruuhola","year":"2000","journal-title":"Plant Physiol."},{"key":"ref_6","first-page":"710","article-title":"Die Biotransformation der Phenolglycoside Leiocarposid und Salicin\u2015Beispiele f\u00fcr Besonderheiten von Absorption und Metabolismus glycosidischer Verbindungen","volume":"44","author":"Pfeifer","year":"1989","journal-title":"Pharmazie"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1592\/phco.30.2.115","article-title":"An Aspirin a Day: Are We Barking Up the Wrong Willow Tree?","volume":"30","author":"Krantz","year":"2010","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.phymed.2010.03.022","article-title":"Anti-inflammatory effects of the willow bark extract STW 33-I (Proaktiv\u00ae) in LPS-activated human monocytes and differentiated macrophages","volume":"17","author":"Bonaterra","year":"2010","journal-title":"Phytomedicine"},{"key":"ref_9","first-page":"677","article-title":"Mechanisms Involved in the Anti-inflammatory Effect of a Standardized Willow Bark Extract","volume":"55","author":"Khayyal","year":"2005","journal-title":"Arzneimittelforschung"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s002280100325","article-title":"Pharmacokinetics of salicin after oral administration of a standardised willow bark extract","volume":"57","author":"Schmid","year":"2001","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"SL49","DOI":"10.1055\/s-0033-1351875","article-title":"Catechol is a bioactive metabolite of Willow bark","volume":"79","author":"Knuth","year":"2013","journal-title":"Planta Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1055\/s-0030-1270722","article-title":"Catechol, a bioactive degradation product of salicortin, reduces TNF-\u03b1 induced ICAM-1 expression in human endothelial cells","volume":"77","author":"Knuth","year":"2011","journal-title":"Planta Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1074\/jbc.M106685200","article-title":"Chemoprotection by phenolic antioxidants. Inhibition of tumor necrosis factor alpha induction in macrophages","volume":"277","author":"Ma","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ejphar.2008.04.035","article-title":"Anti-inflammatory effects of catechols in lipopolysaccharide-stimulated microglia cells: Inhibition of microglial neurotoxicity","volume":"588","author":"Zheng","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8205","DOI":"10.1021\/jf100887v","article-title":"Factors influencing the variability of antioxidative phenolic glycosides in Salix species","volume":"58","author":"Ulrichs","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","first-page":"782763","article-title":"Bioaccessibility In Vitro of Nutraceuticals from Bark of Selected Salix Species","volume":"2014","author":"Sugier","year":"2014","journal-title":"Sci. World J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gligori\u0107, E., Igi\u0107, R., Suvajd\u017ei\u0107, L., and Gruji\u0107-Leti\u0107, N. (2019). Species of the Genus Salix L.: Biochemical Screening and Molecular Docking Approach to Potential Acetylcholinesterase Inhibitors. Appl. Sci., 9.","DOI":"10.3390\/app9091842"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1023\/A:1024266612585","article-title":"Trade-Off Between Synthesis of Salicylates and Growth of Micropropagated Salix pentandra","volume":"29","author":"Ruuhola","year":"2003","journal-title":"J. Chem. Ecol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1023\/A:1023821304656","article-title":"In vitro degradation of willow salicylates","volume":"29","author":"Ruuhola","year":"2003","journal-title":"J. Chem. Ecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1055\/s-2006-962172","article-title":"Isolation of phenolic compounds from the bark of Salix pentandra","volume":"55","author":"Shao","year":"1989","journal-title":"Planta Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jff.2016.02.034","article-title":"Benzyl isothiocyanate but not benzyl nitrile from Brassicales plants dually blocks the COX and LOX pathway in primary human immune cells","volume":"23","author":"Herz","year":"2016","journal-title":"J. Funct. Foods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.phymed.2016.02.025","article-title":"Nasturtium (Indian cress, Tropaeolum majus nanum) dually blocks the COX and LOX pathway in primary human immune cells","volume":"23","author":"Tran","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12974-020-1703-1","article-title":"Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception","volume":"17","author":"Jang","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1248\/bpb.34.1170","article-title":"Prostaglandin E2 and Pain\u2014An Update","volume":"34","author":"Kawabata","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S0049-0172(97)80046-7","article-title":"Mechanism of action of aspirin-like drugs","volume":"26","author":"Vane","year":"1997","journal-title":"Semin. Arthritis Rheum"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1021\/jm0613166","article-title":"Structural and functional basis of cyclooxygenase inhibition","volume":"50","author":"Blobaum","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2147\/JPR.S75160","article-title":"Patrignani, New insights into the use of currently available non-steroidal anti-inflammatory drugs","volume":"8","author":"Brune","year":"2015","journal-title":"J. Pain Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Le, N.P.K., Herz, C., Gomes, J.V.D., F\u00f6rster, N., Antoniadou, K., Mittermeier-Kle\u00dfinger, V.K., Mewis, I., Dawid, C., Ulrichs, C., and Lamy, E. (2021). Comparative Anti-Inflammatory Effects of Salix Cortex Extracts and Acetylsalicylic Acid in SARS-CoV-2 Peptide and LPS-Activated Human In Vitro Systems. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136766"},{"key":"ref_29","first-page":"229","article-title":"A chemotaxonomic survey of phenolic compounds in Swiss willow species","volume":"98","author":"Meier","year":"1992","journal-title":"Proc. R. Soc. Edinburgh. Sect. B. Boil. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1021\/np50085a022","article-title":"Phenolic glycosides from Salix lasiandra","volume":"55","author":"Reichardt","year":"1992","journal-title":"J. Nat. Prod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.fitote.2015.08.013","article-title":"Salicin derivatives from Salix glandulosa and their biological activities","volume":"106","author":"Kim","year":"2015","journal-title":"Fitoterapia"},{"key":"ref_32","first-page":"78","article-title":"Neuroprotective compounds from Salix pseudo-lasiogyne twigs and their anti-amnesic effects on scopolamine-induced memory deficit in mice","volume":"79","author":"Yang","year":"2013","journal-title":"Planta Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1021\/acs.jnatprod.8b00022","article-title":"Saponins from European Licorice Roots (Glycyrrhiza glabra )","volume":"81","author":"Schmid","year":"2018","journal-title":"J. Nat. Prod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S0031-9422(00)94801-5","article-title":"Cinnamrutinoses A and B, glycosides of Populus tremula","volume":"35","author":"Jossang","year":"1994","journal-title":"Phytochemistry"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Noleto-Dias, C., Wu, Y., Bellisai, A., Macalpine, W., Beale, M.H., and Ward, J.L. (2019). Phenylalkanoid Glycosides (Non-Salicinoids) from Wood Chips of Salix triandra \u00d7 dasyclados Hybrid Willow. Molecules, 24.","DOI":"10.3390\/molecules24061152"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1080\/10286020.2015.1028920","article-title":"New salicin derivatives from the leaves ofPopulus euphratica","volume":"17","author":"Wei","year":"2015","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5566","DOI":"10.3390\/molecules20045566","article-title":"The absolute configuration of salicortin, HCH-salicortin and tremulacin from Populus trichocarpa\u00d7 deltoides Beaupr\u00e9","volume":"20","author":"Feistel","year":"2015","journal-title":"Molecules"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.bbapap.2005.06.005","article-title":"How to study proteins by circular dichroism","volume":"1751","author":"Kelly","year":"2005","journal-title":"Biochim. Biophys. Acta (BBA) Proteins Proteom."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s10886-010-9757-7","article-title":"Biosynthesis of Phenolic Glycosides from Phenylpropanoid and Benzenoid Precursors in Populus","volume":"36","author":"Babst","year":"2010","journal-title":"J. Chem. Ecol."},{"key":"ref_40","unstructured":"ESCOP, Salicis cortex\u2014Willow Bark (2017). ESCOP Monographs. The Scientific Foundation for Herbal Medicinal Products, European Scientific Cooperative on Phytotherapy (ESCOP)."},{"key":"ref_41","unstructured":"Knuth, S. (2013). Pharmakologische und pharmakokinetische Untersuchungen zu Salicylalkoholderivaten aus Salicis Cortex. [Ph.D. Thesis, University of Regensburg]."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.phymed.2011.08.065","article-title":"Contribution of flavonoids and catechol to the reduction of ICAM-1 expression in endothelial cells by a standardised Willow bark extract","volume":"19","author":"Freischmidt","year":"2012","journal-title":"Phytomedicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1007\/s10354-007-0437-3","article-title":"Willow bark extract: The contribution of polyphenols to the overall effect","volume":"157","author":"Nahrstedt","year":"2007","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_44","first-page":"511","article-title":"Chemoprofiling as Breeding Tool for Pharmaceutical Use of Salix","volume":"12","author":"Antoniadou","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1021\/jf405529b","article-title":"Accurate Determination of Reference Materials and Natural Isolates by Means of Quantitative 1H NMR Spectroscopy","volume":"62","author":"Frank","year":"2014","journal-title":"J. Agric. Food Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11138\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:15:37Z","timestamp":1760166937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,15]]},"references-count":45,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011138"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011138","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,15]]}}}