{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:46:59Z","timestamp":1789138019860,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,9]],"date-time":"2019-04-09T00:00:00Z","timestamp":1554768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004442","name":"Narodowym Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2015\/19\/N\/NZ7\/00959"],"award-info":[{"award-number":["UMO-2015\/19\/N\/NZ7\/00959"]}],"id":[{"id":"10.13039\/501100004442","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Salicylate-rich plants are an attractive alternative to synthetic anti-inflammatory drugs due to a better safety profile and the advantage of complementary anti-inflammatory and antioxidant effects of the co-occurring non-salicylate phytochemicals. Here, the phytochemical value and biological effects in vitro and ex vivo of the stems of one of such plants, Gaultheria procumbens L., were evaluated. The best extrahent for effective recovery of the active stem molecules was established in comparative studies of five extracts. The UHPLC-PDA-ESI-MS3, HPLC-PDA, and UV-photometric assays revealed that the selected acetone extract (AE) accumulates a rich polyphenolic fraction (35 identified constituents; total content 427.2 mg\/g dw), mainly flavanols (catechins and proanthocyanidins; 201.3 mg\/g dw) and methyl salicylate glycosides (199.9 mg\/g dw). The extract and its model components were effective cyclooxygenase-2, lipoxygenase, and hyaluronidase inhibitors; exhibited strong antioxidant capacity in six non-cellular in vitro models (AE and procyanidins); and also significantly and dose-dependently reduced the levels of reactive oxygen species (ROS), and the release of cytokines (IL-1\u03b2, IL-8, TNF-\u03b1) and proteinases (elastase-2, metalloproteinase-9) in human neutrophils stimulated ex vivo by lipopolysaccharide (LPS) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). The cellular safety of AE was demonstrated by flow cytometry. The results support the application of the plant in traditional medicine and encourage the use of AE for development of new therapeutic agents.<\/jats:p>","DOI":"10.3390\/ijms20071753","type":"journal-article","created":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T03:47:36Z","timestamp":1554868056000},"page":"1753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Salicylate and Procyanidin-Rich Stem Extracts of Gaultheria procumbens L. Inhibit Pro-Inflammatory Enzymes and Suppress Pro-Inflammatory and Pro-Oxidant Functions of Human Neutrophils Ex Vivo"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-2339","authenticated-orcid":false,"given":"Piotr","family":"Michel","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1 St., 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-1321","authenticated-orcid":false,"given":"Sebastian","family":"Granica","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Warsaw Medical University, 1 Banacha St., 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2437-3242","authenticated-orcid":false,"given":"Anna","family":"Magiera","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1 St., 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Rosi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1 St., 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Jurek","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1 St., 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0141ukasz","family":"Poraj","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1 St., 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8468-1365","authenticated-orcid":false,"given":"Monika Anna","family":"Olszewska","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1 St., 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12071","DOI":"10.3390\/molecules181012071","article-title":"Gaultheria: Phytochemical and pharmacological characteristics","volume":"18","author":"Liu","year":"2013","journal-title":"Molecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.2174\/092986711796391552","article-title":"Antioxidant properties and associated mechanisms of salicylates","volume":"18","author":"Baltazar","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ejphar.2005.11.030","article-title":"Gaultherin, a natural salicylate derivative from Gaultheria yunnanensis: Towards a better non-steroidal anti-inflammatory drug","volume":"530","author":"Zhang","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2174\/1389557513666131211110004","article-title":"Naturally occurring methyl salicylate glycosides","volume":"14","author":"Meng","year":"2014","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5168","DOI":"10.2174\/0929867324666171003122502","article-title":"Gaultheria ethnobotany and bioactivity: Blueberry relatives with anti-inflammatory, antioxidant, and anticancer constituents","volume":"25","author":"Luo","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3875","DOI":"10.3390\/molecules16053875","article-title":"Anti-inflammatory activity of methyl salicylate glycosides isolated from Gaultheria yunnanensis (Franch.) Rehder","volume":"16","author":"Zhang","year":"2011","journal-title":"Molecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1021\/mp2003779","article-title":"A novel naturally occurring salicylic acid analogue acts as an anti-inflammatory agent by inhibiting nuclear factor-kappaB activity in RAW264.7 macrophages","volume":"9","author":"Zhang","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1248\/bpb.30.465","article-title":"Analgesic and anti-inflammatory activities of a fraction rich in gaultherin isolated from Gaultheria yunnanensis (Franch.) Rehder","volume":"30","author":"Zhang","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yahfoufi, N., Alsadi, N., Jambi, M., and Matar, C. (2018). The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients, 10.","DOI":"10.3390\/nu10111618"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20498","DOI":"10.3390\/molecules191220498","article-title":"Polyphenolic profile, antioxidant and anti-inflammatory activity of eastern teaberry (Gaultheria procumbens L.) leaf extracts","volume":"19","author":"Michel","year":"2014","journal-title":"Molecules"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/pca.1203","article-title":"A RP-HPLC-DAD-APCI\/MSD method for the characterisation of medicinal Ericaceae used by the Eeyou Istchee Cree First Nations","volume":"21","author":"Saleem","year":"2010","journal-title":"Phytochem. Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1300\/J133v04n01_05","article-title":"The determination of salicylates in Gaultheria procumbens for use as a natural aspirin alternative","volume":"4","author":"Ribnicky","year":"2003","journal-title":"J. Nutraceuticals Funct. Med. Foods"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.fitote.2018.02.018","article-title":"The influence of procyanidins isolated from small-leaved lime flowers (Tilia cordata Mill.) on human neutrophils","volume":"127","author":"Dudek","year":"2018","journal-title":"Fitoterapia"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ho, G.T.T., Wangensteen, H., and Barsett, H. (2017). Elderberry and elderflower extracts, phenolic compounds, and metabolites and their effect on complement, RAW 264.7 macrophages and dendritic cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030584"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.smim.2016.03.007","article-title":"The role of neutrophils in inflammation resolution","volume":"28","author":"Jones","year":"2016","journal-title":"Semin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.yexcr.2010.12.021","article-title":"Chemokines as targets for therapy","volume":"317","author":"Garin","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.phymed.2015.10.004","article-title":"Ellagitannins modulate the inflammatory response of human neutrophils ex vivo","volume":"22","author":"Granica","year":"2015","journal-title":"Phytomedicine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s11418-014-0873-5","article-title":"Contribution of C-glucosidic ellagitannins to Lythrum salicaria L. influence on pro-inflammatory functions of human neutrophils","volume":"69","author":"Piwowarski","year":"2015","journal-title":"J. Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Michel, P., Owczarek, A., Matczak, M., Kosno, M., Szyma\u0144ski, P., Mikiciuk-Olasik, E., Kilanowicz, A., Weso\u0142owski, W., and Olszewska, M.A. (2017). Metabolite profiling of eastern teaberry (Gaultheria procumbens L.) lipophilic leaf extracts with hyaluronidase and lipoxygenase inhibitory activity. Molecules, 22.","DOI":"10.3390\/molecules22030412"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3724\/SP.J.1009.2012.00115","article-title":"Chemical constituents from the water-soluble fraction of wild Sargentodoxa cuneata","volume":"10","author":"Tang","year":"2012","journal-title":"Chin. J. Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1080\/14786419.2014.1003932","article-title":"Dhasingreoside: New flavonoid from the stems and leaves of Gaultheria fragrantissima","volume":"29","author":"Cong","year":"2015","journal-title":"Nat. Prod. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1080\/10286020.2014.898634","article-title":"Two novel lignans from Gaultheria yunnanensis","volume":"16","author":"Gao","year":"2014","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.lfs.2008.03.009","article-title":"Cinnamtannin B-1 as an antioxidant and platelet aggregation inhibitor","volume":"82","author":"Salido","year":"2008","journal-title":"Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.freeradbiomed.2015.03.023","article-title":"Identification of phenolics in litchi and evaluation of anticancer cell proliferation activity and intracellular antioxidant activity","volume":"84","author":"Wen","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhan, J., Wang, K., Chang, X., Xu, G., Zhang, C., Zhang, Y., Li, Y., Zhou, Q., Yao, Y., and Zhang, C. (2016). GSPE inhibits HMGB1 release, attenuating renal IR-induced acute renal injury and chronic renal fibrosis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101647"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1155\/2016\/5698931","article-title":"Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox?","volume":"2016","author":"Biswas","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/ptr.1604","article-title":"Lipoxygenase inhibitors from natural plant sources. Part 2: Medicinal plants with inhibitory activity on arachidonate 12-lipoxygenase, 15-lipoxygenase and leukotriene receptor antagonists","volume":"19","author":"Schneider","year":"2005","journal-title":"Phyther. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37S","DOI":"10.1016\/S0002-9343(99)00115-1","article-title":"Role and regulation of cyclooxygenase-2 during inflammation","volume":"106","author":"Simon","year":"1999","journal-title":"Am. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.2174\/092986709788453078","article-title":"Hyaluronidase inhibitors: A biological and therapeutic perspective","volume":"16","author":"Girish","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_31","first-page":"51","article-title":"A one-stage procedure for isolation of granulocytes and lymphocytes from human blood. General sedimentation properties of white blood cells in a 1g gravity field","volume":"97","year":"1968","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.it.2010.05.006","article-title":"Neutrophil kinetics in health and disease","volume":"31","author":"Summers","year":"2010","journal-title":"Trends Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, S., Xu, M., Niu, Q., Xu, S., Ding, Y., Yan, Y., Guo, S., and Li, F. (2015). Efficacy of procyanidins against in vivo cellular oxidative damage: A systematic review and meta-analysis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139455"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1515\/cclm-2011-0817","article-title":"Lipid peroxidation markers in Crohn\u2019s disease: The associations and diagnostic value","volume":"50","author":"Boehm","year":"2012","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1182\/blood-2010-07-273417","article-title":"Interleukin-1 in the pathogenesis and treatment of inflammatory diseases","volume":"117","author":"Dinarello","year":"2011","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.intimp.2012.11.014","article-title":"Evaluation of the new anti-inflammatory compound ethyl salicylate 2-O-\u03b2-D-glucoside and its possible mechanism of action","volume":"15","author":"Xin","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/S0024-3205(00)00449-5","article-title":"The effect of cocoa procyanidins on the transcription and secretion of interleukin 1\u03b2 in peripheral blood mononuclear cells","volume":"66","author":"Mao","year":"2000","journal-title":"Life Sci."},{"key":"ref_38","first-page":"160","article-title":"Neutrophil elastase as an inflammatory mediator","volume":"27","year":"2002","journal-title":"Cent. J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/emm.2000.25","article-title":"Molecular characteristics of the inhibition of human neutrophil elastase by nonsteroidal antiinflammatory drugs","volume":"32","author":"Kang","year":"2000","journal-title":"Exp. Mol. Med."},{"key":"ref_40","first-page":"821","article-title":"In vitro and in vivo studies on the cardioprotective action of oligomeric procyanidins in a Crataegus extract of leaves and blooms","volume":"47","author":"Chatterjee","year":"1997","journal-title":"Arzneim. Forsch."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.3390\/molecules17033093","article-title":"Profiling of phenolic compounds and antioxidant activity of dry extracts from the selected Sorbus species","volume":"17","author":"Olszewska","year":"2012","journal-title":"Molecules"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jff.2017.10.046","article-title":"Sorbus domestica L. leaf extracts as functional products: Phytochemical profiling, cellular safety, pro-inflammatory enzymes inhibition and protective effects against oxidative stress in vitro","volume":"40","author":"Matczak","year":"2018","journal-title":"J. Funct. Foods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.indcrop.2014.04.031","article-title":"Determination of phenolic contents and antioxidant activities of extracts of Jatropha curcas L. seed shell, a by-product, a new source of natural antioxidant","volume":"58","author":"Fu","year":"2014","journal-title":"Ind. Crops Prod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.mex.2015.05.001","article-title":"Optimized enzymatic colorimetric assay for determination of hydrogen peroxide (H2O2) scavenging activity of plant extracts","volume":"2","author":"Fernando","year":"2015","journal-title":"MethodsX"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1753\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:44:04Z","timestamp":1760186644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,9]]},"references-count":44,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071753"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071753","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,9]]}}}