{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T22:44:45Z","timestamp":1784069085750,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,18]],"date-time":"2019-05-18T00:00:00Z","timestamp":1558137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2016R1A6A1A03007648, NRF-2017R1A6A3A11033480, NRF-2018R1A2B6001733, and NRF-2016R1D1A1B03930222"],"award-info":[{"award-number":["NRF-2016R1A6A1A03007648, NRF-2017R1A6A3A11033480, NRF-2018R1A2B6001733, and NRF-2016R1D1A1B03930222"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Atherosclerosis is the key factor responsible for cardiovascular events, which is a major cause of morbidities and mortalities worldwide. It is well known that high-density lipoprotein (HDL) oxidation and glycation increases the risk for atherosclerosis. Epimedium koreanum has been used as a traditional oriental medicine for treating erectile dysfunction, kidney diseases, osteoporosis, and breast cancer. However, no reports on the effects of E. koreanum on HDL modification exist. In this study, we investigated the inhibitory effects of E. koreanum extract and its eight flavonoids, which are: (1) anhydroicaritin 3-O-rhamnoside, (2) \u03b2-anhydroicaritin, (3\u20135) epimedins A-C, (6) epimedoside A, (7) icariin, and (8) des-O-methyl-\u03b2-anhydroicaritin, against HDL modification. HDLs obtained from pooled human plasma samples were incubated in vitro with E. koreanum extract or each compound in the presence of copper sulfate or fructose. The HDL modifications were evaluated by measuring generation of conjugated dienes, production of thiobarbituric acid reactive substances, change in electrophoretic mobility of apoA-I, advanced glycation end products formation, and apoA-I aggregation. Consequently, E. koreanum extract and compound 8 suppressed HDL modification through inhibition of lipid peroxidation, apoA-I aggregation, negative charge increase, and AGEs formation. In particular, compound 8 showed more potent inhibitory effect on HDL modification than the extracts, suggesting its protective role against atherosclerosis via inhibition of HDL oxidation and glycation.<\/jats:p>","DOI":"10.3390\/nu11051110","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T11:05:07Z","timestamp":1558350307000},"page":"1110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Epimedium koreanum Extract and Its Flavonoids Reduced Atherosclerotic Risk via Suppressing Modification of Human HDL"],"prefix":"10.3390","volume":"11","author":[{"given":"Jae-Yong","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Duksung Women\u2019s University, Seoul 01369, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Hee","family":"Shim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Duksung Women\u2019s University, Seoul 01369, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,18]]},"reference":[{"key":"ref_1","first-page":"e29","article-title":"Heart disease and stroke statistics\u20142015 update: A report from the American Heart Association","volume":"131","author":"Mozaffarian","year":"2015","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"714653","DOI":"10.1155\/2013\/714653","article-title":"The role of oxidized low-density lipoproteins in atherosclerosis: The myths and the facts","volume":"2013","author":"Maiolino","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1097\/MOL.0b013e328348a43f","article-title":"Susceptibility of LDL and its subfractions to glycation","volume":"22","author":"Soran","year":"2011","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1001\/jama.2009.1619","article-title":"Major lipids, apolipoproteins, and risk of vascular disease","volume":"302","author":"Sarwar","year":"2009","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1194\/jlr.R039297","article-title":"Cardioprotective functions of HDLs","volume":"55","author":"Rye","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1161\/01.ATV.8.6.737","article-title":"High density lipoprotein cholesterol and mortality. The Framingham Heart Study","volume":"8","author":"Wilson","year":"1988","journal-title":"Arteriosclerosis"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1016\/S0022-2275(20)37453-8","article-title":"Apolipoprotein-mediated removal of cellular cholesterol and phospholipids","volume":"37","author":"Oram","year":"1996","journal-title":"J. Lipid Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/S0022-2275(20)33462-3","article-title":"Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: Steps 2 and 3","volume":"41","author":"Navab","year":"2000","journal-title":"J. Lipid Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1161\/01.RES.0000146094.59640.13","article-title":"Anti-inflammatory properties of HDL","volume":"95","author":"Barter","year":"2004","journal-title":"Circ. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/biof.1205","article-title":"The dual nature of HDL: Anti-inflammatory and pro-inflammatory","volume":"41","author":"Gao","year":"2015","journal-title":"Biofactors"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/MED.0b013e32832922fc","article-title":"Dysfunctional high-density lipoprotein","volume":"16","author":"Feng","year":"2009","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0021-9150(96)05840-6","article-title":"In vitro oxidised HDL exerts a cytotoxic effect on macrophages","volume":"125","author":"Hurtado","year":"1996","journal-title":"Atherosclerosis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S0939-4753(04)80026-7","article-title":"Effect of non-enzymatic glycation on aluminium-induced lipid peroxidation of human high density lipoproteins (HDL)","volume":"14","author":"Ferretti","year":"2004","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kim, J.Y., Lee, E.Y., Park, J.K., Song, Y.W., Kim, J.R., and Cho, K.H. (2016). Patients with rheumatoid arthritis show altered lipoprotein profiles with dysfunctional high-density lipoproteins that can exacerbate inflammatory and atherogenic process. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0164564"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.clinbiochem.2013.10.026","article-title":"Relation of atrial fibrillation (AF) and change of lipoproteins: Male patients with AF exhibited severe pro-inflammatory and pro-atherogenic properties in lipoproteins","volume":"47","author":"Kim","year":"2014","journal-title":"Clin. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3858\/emm.2009.41.2.009","article-title":"Myocardial infarction patients show altered lipoprotein properties and functions when compared with stable angina pectoris patients","volume":"41","author":"Cho","year":"2009","journal-title":"Exp. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jep.2011.01.001","article-title":"The genus Epimedium: An ethnopharmacological and phytochemical review","volume":"134","author":"Ma","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","first-page":"81","article-title":"Analysis of active ingredients of traditional Chinese herbal drug. Assay of icariin in Epidemium","volume":"4","author":"Liu","year":"1984","journal-title":"Chin. J. Pharm. Anal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jep.2015.11.007","article-title":"Anti-osteoporosis effect of Epimedium via an estrogen-like mechanism based on a system-level approach","volume":"177","author":"Xu","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.carbpol.2015.07.044","article-title":"The activation of Epimedium polysaccharide-propolis flavone liposome on Kupffer cells","volume":"133","author":"Fan","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.lfs.2005.04.057","article-title":"Inhibitory effect of Epimedium extract on S-adenosyl-L-homocysteine hydrolase and biomethylation","volume":"78","author":"Zhang","year":"2005","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.indcrop.2013.08.017","article-title":"Microwave assisted extraction of flavonoids from cultivated Epimedium sagittatum: Extraction yield and mechanism, antioxidant activity and chemical composition","volume":"50","author":"Zhang","year":"2013","journal-title":"Ind. Crops Prod."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ejphar.2011.02.005","article-title":"An anticancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase (ERK) pathway and inhibits growth of breast cancer cells","volume":"658","author":"Guo","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"352","DOI":"10.3390\/v7010352","article-title":"Epimedium koreanum Nakai displays broad spectrum of antiviral activity in vitro and in vivo by inducing cellular antiviral state","volume":"7","author":"Cho","year":"2015","journal-title":"Viruses"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.3892\/mmr.2016.4813","article-title":"Icariin inhibits oxidized low-density lipoprotein-induced proliferation of vascular smooth muscle cells by suppressing activation of extracellular signal-regulated kinase 1\/2 and expression of proliferating cell nuclear antigen","volume":"13","author":"Hu","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1139\/cjpp-2016-0367","article-title":"Icariin improves eNOS\/NO pathway to prohibit the atherogenesis of apolipoprotein E-null mice","volume":"95","author":"Xiao","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1172\/JCI103182","article-title":"The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum","volume":"34","author":"Havel","year":"1955","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/0003-2697(78)90586-9","article-title":"A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples","volume":"87","author":"Markwell","year":"1978","journal-title":"Anal. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3109\/10715768909073429","article-title":"Continuous monitoring of in vitro oxidation of human low density lipoprotein","volume":"6","author":"Esterbauer","year":"1989","journal-title":"Free Radic. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0891-5849(91)90192-6","article-title":"Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes","volume":"11","author":"Esterbauer","year":"1991","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40199-015-0126-5","article-title":"Protection by beta-hydroxybutyric acid against insulin glycation, lipid peroxidation and microglial cell apoptosis","volume":"23","author":"Sabokdast","year":"2015","journal-title":"Daru"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0022-2275(20)41889-9","article-title":"Quantitative measurement of lipoprotein surface charge by agarose gel electrophoresis","volume":"33","author":"Sparks","year":"1992","journal-title":"J. Lipid Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cameron, S.J., Morrell, C.N., Bao, C., Swaim, A.F., Rodriguez, A., and Lowenstein, C.J. (2015). A novel anti-Inflammatory effect for high density lipoprotein. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144372"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/jn\/133.10.3047","article-title":"Vitamin C inhibits lipid oxidation in human HDL","volume":"133","author":"Hillstrom","year":"2013","journal-title":"J. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1016\/S0022-2275(20)31582-0","article-title":"A cell-free assay for detecting HDL that is dysfunctional in preventing the formation of or inactivating oxidized phospholipid","volume":"42","author":"Navab","year":"2001","journal-title":"J. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.jfda.2017.05.011","article-title":"Effect of drying processes on prenylflavonoid content and antioxidant activity of Epimedium koreanum Nakai","volume":"26","author":"Zhao","year":"2018","journal-title":"J. Food Drug Anal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6457","DOI":"10.1073\/pnas.88.15.6457","article-title":"High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification","volume":"88","author":"Nagano","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4196\/kjpp.2014.18.1.1","article-title":"Advanced glycation end products and diabetic complications","volume":"18","author":"Singh","year":"2014","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1007\/s001250050049","article-title":"Glycation impairs high-density lipoprotein function","volume":"43","author":"Hedrick","year":"2000","journal-title":"Diabetologia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0306-3623(98)00028-7","article-title":"Human serum paraoxonase","volume":"31","author":"Mackness","year":"1998","journal-title":"Gen. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1172\/JCI1649","article-title":"Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase","volume":"101","author":"Aviram","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1177\/2042018818788802","article-title":"Glycated LDL-C and glycated HDL-C in association with adiposity, blood and atherogenicity indices in metabolic syndrome patients with and without prediabetes","volume":"9","author":"Kasabri","year":"2018","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_43","first-page":"1","article-title":"Effect of consumption of dark chocolate on lipoproteins and serum lipids","volume":"12","author":"Nanetti","year":"2008","journal-title":"Mediterr. J. Nutr. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.atherosclerosis.2009.05.017","article-title":"A new insight into resveratrol as an atheroprotective compound: Inhibition of lipid peroxidation and enhancement of cholesterol efflux","volume":"207","author":"Berrougui","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1021\/jf2046009","article-title":"Glabridin protects paraoxonase 1 from linoleic acid hydroperoxide inhibition via specific interaction: A fluorescence-quenching study","volume":"60","author":"Atrahimovich","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1111\/j.1582-4934.2012.01542.x","article-title":"Genistein as a potential inducer of the anti-atherogenic enzyme paraoxonase-1: Studies in cultured hepatocytes in vitro and in rat liver in vivo","volume":"16","author":"Schrader","year":"2012","journal-title":"J. Cell Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1210\/jc.2013-2845","article-title":"Anthocyanin supplementation improves HDL-associated paraoxonase 1 activity and enhances cholesterol efflux capacity in subjects with hypercholesterolemia","volume":"99","author":"Zhu","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jfda.2017.03.007","article-title":"The inhibition of advanced glycation end-products by five fractions and three main flavonoids from Camellia nitidissima Chi flowers","volume":"26","author":"Yang","year":"2018","journal-title":"J. Food Drug Anal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1080\/14786419.2017.1356835","article-title":"Flavonoid profile, antioxidant and antiglycation properties of Retama sphaerocarpa fruits extracts","volume":"32","author":"Boussahel","year":"2018","journal-title":"Nat. Prod. Res."},{"key":"ref_50","first-page":"1874","article-title":"Dietary flavonoid aglycones and their glycosides: Which show better biological significance?","volume":"57","author":"Xiao","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.1021\/jf9001445","article-title":"Low-density-lipoprotein (LDL)-bound flavonoids increase the resistance of LDL to oxidation and glycation under pathophysiological concentrations of glucose in vitro","volume":"57","author":"Wu","year":"2009","journal-title":"J. Agric. Food Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/5\/1110\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:53:25Z","timestamp":1760187205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/5\/1110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,18]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["nu11051110"],"URL":"https:\/\/doi.org\/10.3390\/nu11051110","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,18]]}}}