{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T08:29:47Z","timestamp":1765960187952,"version":"3.37.3"},"reference-count":35,"publisher":"Georg Thieme Verlag KG","issue":"08","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Planta Med"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lime flower (Tiliae flos) is traditionally used either for treatment of the common cold or to relieve symptoms of mental stress. Recently, the presence of a new class of piperidine and dihydro-pyrrole alkaloids from lime flower has been described. The present study aimed to investigate the pharmacological activity of hydroacetonic lime flower extracts, alkaloid-enriched lime flower fractions, and isolated alkaloids on the murine airway smooth muscle and the cholinergic system. While a hydroacetonic lime flower extract did not show any pharmacological activity, enriched Tilia alkaloid fractions potentiated acetylcholine-induced contractions of the trachea by ~\u200930%, showing characteristics comparable to galanthamine. Effects were abrogated by atropine, indicating an involvement of muscarinic receptors. The dihydro-pyrrole alkaloid tiliine A, the piperidine alkaloid tiliamine B, and the acetylated piperidine alkaloid tilacetine A were characterized as\n\t\t\t\t\tacetylcholinesterase inhibitors. The positive control galanthamine (IC50\u2009=\u20092.0\u2009\u00b5M, 95% CI 1.7 to 2.2\u2009\u00b5M) was approximately 100 times more potent compared to tiliine A (IC50\u2009=\u2009237\u2009\u00b5M, 95% CI 207 to 258\u2009\u00b5M) and tiliamine B (IC50\u2009=\u2009172\u2009\u00b5M, 95% CI 158 to 187\u2009\u00b5M). Neither DNA synthesis of HepG2 liver cells, HaCaT keratinocytes, and Caco-2 intestinal epithelial cells nor cell viability of primary human fibroblasts was reduced by the alkaloids. The indirect cholinergic activity of the alkaloids might explain some aspects of the traditional use of lime flowers and may extend the portfolio of compounds with regard to diseases involving parasympathetic malfunction or central cholinergic imbalance.<\/jats:p>","DOI":"10.1055\/a-1534-3766","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T12:19:38Z","timestamp":1630412378000},"page":"639-649","source":"Crossref","is-referenced-by-count":4,"title":["Alkaloids from Lime Flower (Tiliae flos) Exert Spasmodic Activity on Murine Airway Smooth Muscle Involving Acetylcholinesterase"],"prefix":"10.1055","volume":"88","author":[{"given":"Alexander","family":"Hake","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of M\u00fcnster, M\u00fcnster, Germany"},{"name":"Institute of Pharmaceutical Biology and Phytochemistry, University of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nico","family":"Symma","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry, University of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Esch","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry, University of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0886-8384","authenticated-orcid":false,"given":"Andreas","family":"Hensel","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry, University of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1572-9235","authenticated-orcid":false,"given":"Martina","family":"D\u00fcfer","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2021,7,16]]},"reference":[{"volume-title":"European Pharmacopoiea 10.0: Lime Flower \u2013 Tiliae flos","year":"2020","author":"Council of Europe \u2013 European Directorate for the Quality of Medicines","key":"ref2"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0378-8741(94)90098-1","article-title":"Isolation of pharmacologically active benzodiazepine receptor ligands from Tilia tomentosa (Tiliaceae)","volume":"44","author":"H Viola","year":"1994","journal-title":"J Ethnopharmacol"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/(SICI)1099-1573(199702)11:1<17::AID-PTR948>3.0.CO;2-6","article-title":"In vitro study of the interaction of Tilia europaea L. aqueous extract with GABAA receptors in rat brain","volume":"11","author":"C Cavadas","year":"1997","journal-title":"Phytother Res"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1055\/s-2007-981593","article-title":"Bioactivity-guided isolation of beta-sitosterol and some fatty acids as active compounds in the anxiolytic and sedative effects of Tilia americana var. mexicana","volume":"73","author":"E Aguirre-Hern\u00e1ndez","year":"2007","journal-title":"Planta Med"},{"key":"ref6","first-page":"23","article-title":"Pharmacological properties of Tilia europaea aqueous extract: Screening anxiolytic\/sedative activity in mice","volume":"31","author":"M D Cotrim","year":"1999","journal-title":"Arq Patol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1017\/S000711451000053X","article-title":"Oral bioavailability of quercetin from different quercetin glycosides in dogs","volume":"104","author":"M Reinboth","year":"2010","journal-title":"Br J Nutr"},{"key":"ref8","first-page":"287","article-title":"Effects of Tilia europae on guinea-pig ileum and aorta: abstract","volume":"114","author":"M D Cotrim","year":"1994","journal-title":"Br J Pharmacol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1080\/13880200701213195","article-title":"Studies on the direct effects of the alcohol extract of Tilia cordata on dispersed intestinal smooth muscle cells of guinea pig","volume":"45","author":"M K Al-Essa","year":"2007","journal-title":"Pharm Biol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1055\/s-2000-11118","article-title":"Evidence for bioadhesive effects of polysaccharides and polysaccharide-containing herbs in an ex vivo bioadhesion assay on buccal membranes","volume":"66","author":"J Schmidgall","year":"2000","journal-title":"Planta Med"},{"key":"ref11","first-page":"149","article-title":"Untersuchungen \u00fcber die Schleimpolysaccharide aus Lindenbl\u00fcten","volume":"49","author":"G Kram","year":"1983","journal-title":"[Analysis of linden flower mucilage ] Planta Med"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.jpba.2014.08.010","article-title":"HPLC-DAD and HPLC-ESI-MS analyses of Tiliae flos and its preparations","volume":"100","author":"A Karioti","year":"2014","journal-title":"J Pharm Biomed Anal"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1590\/S1516-05722013000200008","article-title":"Flavonol glycosides found in hydroethanolic extracts from Tilia cordata, a species utilized as anxiolytics","volume":"15","author":"G Negri","year":"2013","journal-title":"Rev Bras Pl Med"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1080\/10412905.1999.9701158","article-title":"The composition of essential oils from Tilia L. species growing in Turkey","volume":"11","author":"G Toker","year":"1999","journal-title":"J Essent Oil Res"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"8040","DOI":"10.1021\/acs.jafc.0c02826","article-title":"Multistep analysis of diol-LC-ESI-HRMS data reveals proanthocyanidin composition of complex plant extracts (PAComics)","volume":"68","author":"N Symma","year":"2020","journal-title":"J Agric Food Chem"},{"key":"ref16","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":"M E Czerwi\u0144ska","year":"2018","journal-title":"Fitoterapia"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1055\/a-1340-0099","article-title":"Novel piperidine and 3,4-dihydro-2H-pyrrole alkaloids from Tilia platyphyllos and Tilia cordata flowers","author":"N Symma","year":"2021","journal-title":"Planta Med"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1017\/S1041610203008688","article-title":"A clinical overview of cholinesterase inhibitors in Alzheimer\u02bcs disease","volume":"14","author":"M Farlow","year":"2002","journal-title":"Int Psychogeriatr"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0022-1759(85)90236-4","article-title":"Quantitation of 5-bromo-2-deoxyuridine incorporation into DNA: an enzyme immunoassay for the assessment of the lymphoid cell proliferative response","volume":"82","author":"T Porstmann","year":"1985","journal-title":"J Immunol Methods"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.fitote.2006.05.002","article-title":"Linarin, a selective acetylcholinesterase inhibitor from Mentha arvensis","volume":"77","author":"P P Oinonen","year":"2006","journal-title":"Fitoterapia"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.phytochem.2017.11.003","article-title":"Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle","volume":"145","author":"J Liu","year":"2018","journal-title":"Phytochemistry"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.intimp.2015.08.007","article-title":"Cholinergic activation of the murine trachealis muscle via non-vesicular acetylcholine release involving low-affinity choline transporters","volume":"29","author":"C Nassenstein","year":"2015","journal-title":"Int Immunopharmacol"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1002\/rcm.8172","article-title":"Mass spectrometry for characterization of homologous piperidine alkaloids and their activity as acetylcholinesterase inhibitors","volume":"32","author":"T R Freitas","year":"2018","journal-title":"Rapid Commun Mass Spectrom"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.bbrc.2005.05.068","article-title":"Juliflorine: A potent natural peripheral anionic-site-binding inhibitor of acetylcholinesterase with calcium-channel blocking potential, a leading candidate for Alzheimer\u02bcs disease therapy","volume":"332","author":"M I Choudhary","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.tiv.2014.02.001","article-title":"Tacrine induces apoptosis through lysosome- and mitochondria-dependent pathway in HepG2 cells","volume":"28","author":"C Gao","year":"2014","journal-title":"Toxicol In Vitro"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1152\/jappl.2001.90.3.757","article-title":"Effect of local acetylcholinesterase inhibition on sweat rate in humans","volume":"90","author":"M Shibasaki","year":"2001","journal-title":"J Appl Physiol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1345\/aph.1K139","article-title":"Evaluation of centrally acting cholinesterase inhibitor exposures in adults","volume":"41","author":"K R McCain","year":"2007","journal-title":"Ann Pharmacother"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.2147\/TCRM.S176281","article-title":"Effectiveness of intramuscular neostigmine to accelerate bladder emptying after spinal anesthesia","volume":"14","author":"T GA Senapathi","year":"2018","journal-title":"Ther Clin Risk Manag"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ncl.2018.01.011","article-title":"Treatment of myasthenia gravis","volume":"36","author":"C Farmakidis","year":"2018","journal-title":"Neurol Clin"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF00234938","article-title":"Phenylglucosides and the Na+\/glucose cotransporter (SGLT1): Analysis of interactions","volume":"142","author":"M P Lostao","year":"1994","journal-title":"J Membr Biol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1177\/1091581813507721","article-title":"Risk assessment of free hydroquinone derived from Arctostaphylos Uva-ursi folium herbal preparations","volume":"32","author":"S G de Arriba","year":"2013","journal-title":"Int J Toxicol"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"T Mosmann","year":"1983","journal-title":"J Immunol Methods"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colometric determination of acetylcholinesterase activity","volume":"7","author":"G L Ellman","year":"1961","journal-title":"Biochem Pharmacol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1039\/C6FO01778A","article-title":"Contribution of the phenolic composition to the antioxidant, anti-inflammatory and antitumor potential of Equisetum giganteum L. and Tilia platyphyllos SCOP","volume":"8","author":"I Jabeur","year":"2017","journal-title":"Food Funct"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"112084","DOI":"10.1016\/j.phytochem.2019.112084","article-title":"Comparative metabolomics of Tilia platyphyllos SCOP. bracts during phenological 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