{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T14:37:13Z","timestamp":1782830233136,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,30]],"date-time":"2024-11-30T00:00:00Z","timestamp":1732924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Technology Development Program","award":["S3052953"],"award-info":[{"award-number":["S3052953"]}]},{"name":"Ministry of SMEs and Startups","award":["S3052953"],"award-info":[{"award-number":["S3052953"]}]},{"name":"R&amp;D+ Program funded by the Jeonbuk Technopark","award":["S3052953"],"award-info":[{"award-number":["S3052953"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives. Men experience Leydig cell and mitochondrial dysfunction due to the accumulation of reactive oxygen species during aging, leading to hormonal imbalances in the body. This results in symptoms of testosterone deficiency syndrome (TDS) as testosterone levels decline. Consequently, there is a growing need for alternative therapies, such as phytotherapy, to regulate testosterone secretion. Methods. In this study, we evaluated the potential of elderberry extract powder (KSB191) as a functional ingredient for improving TDS by analyzing its mechanism in regulating testosterone imbalance. The major compounds of KSB191 were rutin and fructose\u2013leucine, and the efficacy of KSB191 was confirmed by observing increases in total testosterone, free testosterone, and sperm motility in an aged rat model with decreased testosterone levels. Additionally, we assessed safety by analyzing levels of prostate-specific antigen, alanine aminotransferase, aspartate aminotransferase, and creatinine. Results. To confirm the effectiveness of KSB191 in increasing testosterone synthesis and inhibiting its breakdown, we analyzed the expression levels of genes related to testosterone synthesis and degradation in the testis tissue. KSB191 not only increases the expression levels of enzymes (3\u03b2-HSD, CYP17A1, and 17\u03b2-HSD) that catalyze testosterone synthesis in Leydig cells, but also reduces the expression of enzymes (5\u03b1-reductase and CYP19A1) that degrade testosterone, thereby enhancing testosterone production in the body. Conclusions. KSB191 is predicted to be a novel functional ingredient that acts on Leydig cells and increases testosterone synthesis (particularly, the increase in free testosterone), ultimately alleviating the symptoms of TDS.<\/jats:p>","DOI":"10.3390\/nu16234169","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T04:04:04Z","timestamp":1733198644000},"page":"4169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effect of Elderberry (Sambucus nigra L.) Extract Intake on Normalizing Testosterone Concentration in Testosterone Deficiency Syndrome Rat Model Through Regulation of 17\u03b2-HSD, 5\u03b1-Reductase, and CYP19A1 Expression"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-0798","authenticated-orcid":false,"given":"Jiyeon","family":"Kim","sequence":"first","affiliation":[{"name":"KOSABIO Inc., Namyangju-si 12106, Republic of Korea"},{"name":"College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinho","family":"An","sequence":"additional","affiliation":[{"name":"KOSABIO Inc., Namyangju-si 12106, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngcheon","family":"Song","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mincheol","family":"Jang","sequence":"additional","affiliation":[{"name":"Hurum Co., Ltd., Geumcheon-gu, Seoul 08505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4880-6340","authenticated-orcid":false,"given":"Hyunseok","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Sahmyook University, Seoul 01795, Republic of Korea"},{"name":"PADAM Natural Material Research Institute, Sahmyook University, Seoul 01795, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangbum","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41392-022-01251-0","article-title":"Aging and aging-related diseases: From molecular mechanisms to interventions and treatments","volume":"7","author":"Guo","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111230","DOI":"10.1016\/j.mad.2020.111230","article-title":"Aging fits the disease criteria of the international classification of diseases","volume":"189","author":"Khaltourina","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Song, J., Xiao, L., Zhang, Z., Wang, Y., Kouis, P., Rasmussen, L.J., and Dai, F. (2024). Effects of reactive oxygen species and mitochondrial dysfunction on reproductive aging. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1347286"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1196\/annals.1336.014","article-title":"Mitochondrial function in Leydig cell steroidogenesis","volume":"1061","author":"Hales","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1080\/21505594.2016.1259053","article-title":"Aging and sex hormones in males","volume":"8","author":"Decaroli","year":"2017","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/gerona\/glq183","article-title":"Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: The HORMA trial","volume":"66","author":"Sattler","year":"2011","journal-title":"J. Gerontol. Ser. A: Biomed. Sci. Med. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/ncpuro1167","article-title":"Testosterone deficiency: A common, unrecognized syndrome","volume":"5","author":"Tostain","year":"2008","journal-title":"Nat. Clin. Pract. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/and.12214","article-title":"Phytoandrogenic properties of E urycoma longifolia as natural alternative to testosterone replacement therapy","volume":"46","author":"George","year":"2014","journal-title":"Andrologia"},{"key":"ref_9","first-page":"294","article-title":"Testosterone deficiency syndrome: Diagnosis and treatment","volume":"44","author":"Alcaraz","year":"2020","journal-title":"Actas Urol\u00f3gicas Espa\u00f1olas"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"686","DOI":"10.5534\/wjmh.200174","article-title":"Compliance with testosterone replacement therapy in patients with testosterone deficiency syndrome: A 10-year observational study in Korea","volume":"40","author":"Kang","year":"2022","journal-title":"World J. Men\u2019s Health"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Montano, L.M., Sommer, B., Solis-Chagoyan, H., Romero-Martinez, B.S., Aquino-Galvez, A., Gomez-Verjan, J.C., Calixto, E., Gonzalez-Avila, G., and Flores-Soto, E. (2022). Could lower testosterone in older men explain higher COVID-19 morbidity and mortalities?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020935"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4103\/0970-1591.124197","article-title":"Risks of testosterone replacement therapy in men","volume":"30","author":"Osterberg","year":"2014","journal-title":"Indian J. Urol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"230","DOI":"10.5534\/wjmh.170004","article-title":"Efficacy and safety of a mixed extract of Trigonella foenum-graecum seed and Lespedeza cuneata in the treatment of testosterone deficiency syndrome: A randomized, double-blind, placebo-controlled clinical trial","volume":"36","author":"Park","year":"2018","journal-title":"World J. Men\u2019s Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-food-072023-034423","article-title":"Elderberry, An Ancient Remedy: A Comprehensive Study of the Bioactive Compounds in Three Sambucus nigra L. Subspecies","volume":"15","author":"Uhl","year":"2024","journal-title":"Annu. Rev. Food Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1080\/87559129.2020.1788578","article-title":"Sambucus nigra L. fruits and flowers: Chemical composition and related bioactivities","volume":"38","author":"Ferreira","year":"2022","journal-title":"Food Rev. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3390\/nutraceuticals3010007","article-title":"European Black elderberry fruit extract inhibits replication of SARS-CoV-2 in vitro","volume":"3","author":"Setz","year":"2023","journal-title":"Nutraceuticals"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dom\u00ednguez, R., Pateiro, M., Munekata, P.E., Santos L\u00f3pez, E.M., Rodr\u00edguez, J.A., Barros, L., and Lorenzo, J.M. (2021). Potential use of elderberry (Sambucus nigra L.) as natural colorant and antioxidant in the food industry. A review. Foods, 10.","DOI":"10.3390\/foods10112713"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/13685538.2018.1498079","article-title":"Lycium chinense Mill improves hypogonadism via anti-oxidative stress and anti-apoptotic effect in old aged rat model","volume":"23","author":"Jeong","year":"2020","journal-title":"Aging Male"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chinnappan, S.M., George, A., Pandey, P., Narke, G., and Choudhary, Y.K. (2021). Effect of Eurycoma longifolia standardised aqueous root extract\u2013Physta\u00ae on testosterone levels and quality of life in ageing male subjects: A randomised, double-blind, placebo-controlled multicentre study. Food Nutr. Res., 65.","DOI":"10.29219\/fnr.v65.5647"},{"key":"ref_20","first-page":"9","article-title":"Chemical profiles and antioxidant activity of black elder (Sambucus nigra L.)-A Review","volume":"74","author":"Muste","year":"2017","journal-title":"Bull. UASVM Food Sci. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.lfs.2015.01.037","article-title":"Inhibition of microglial activation by elderberry extracts and its phenolic components","volume":"128","author":"Simonyi","year":"2015","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lee, S., Kim, J., Kong, H., and Kim, Y.-S. (2024). Ameliorative effects of elderberry (Sambucus nigra L.) extract and extract-derived monosaccharide-amino acid on H2O2-induced decrease in testosterone-deficiency syndrome in a TM3 Leydig cell. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0302403"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jep.2014.09.007","article-title":"Treatment of benign prostatic hyperplasia with Croton membranaceus in an experimental animal model","volume":"157","author":"Afriyie","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"172","DOI":"10.4162\/nrp.2013.7.3.172","article-title":"Effect of Phellius linteus water extract on benign prostatic hyperplasia","volume":"7","author":"Kim","year":"2013","journal-title":"Nutr. Res. Pract."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ajur.2017.11.005","article-title":"The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia","volume":"5","author":"Kim","year":"2018","journal-title":"Asian J. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.bbabio.2010.01.004","article-title":"Mitochondrial energy metabolism and ageing","volume":"1797","author":"Bratic","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/biolre\/ioy059","article-title":"Leydig cells: Formation, function, and regulation","volume":"99","author":"Zirkin","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.beem.2012.05.002","article-title":"Role of mitochondria in steroidogenesis","volume":"26","author":"Papadopoulos","year":"2012","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1210\/er.2003-0030","article-title":"Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones","volume":"25","author":"Payne","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1210\/er.2010-0013","article-title":"The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders","volume":"32","author":"Miller","year":"2011","journal-title":"Endocr. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101152","DOI":"10.1016\/j.xcrm.2023.101152","article-title":"CYP19A1 mediates severe SARS-CoV-2 disease outcome in males","volume":"4","author":"Beck","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Shigehara, K., Kato, Y., Izumi, K., and Mizokami, A. (2022). Relationship between testosterone and sarcopenia in older-adult men: A narrative review. J. Clin. Med., 11.","DOI":"10.3390\/jcm11206202"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/B978-0-12-800094-6.00002-9","article-title":"Free testosterone: Clinical utility and important analytical aspects of measurement","volume":"63","author":"Shea","year":"2014","journal-title":"Adv. Clin. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"126","DOI":"10.5534\/wjmh.2013.31.2.126","article-title":"The relationship between testosterone deficiency and men\u2019s health","volume":"31","author":"Tsujimura","year":"2013","journal-title":"World J. Men\u2019s Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1016\/j.eururo.2007.05.021","article-title":"Relationship between the Saint Louis University ADAM questionnaire and sexual hormonal levels in a male outpatient population over 50 years of age","volume":"52","year":"2007","journal-title":"Eur. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.urology.2005.03.060","article-title":"Relationship between serum sex steroids and Aging Male Symptoms score and International Index of Erectile Function","volume":"66","author":"Basar","year":"2005","journal-title":"Urology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.maturitas.2005.07.004","article-title":"Comparison of screening questionnaires for the diagnosis of hypogonadism","volume":"53","author":"Morley","year":"2006","journal-title":"Maturitas"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1053\/meta.2002.31975","article-title":"Evaluation of assays available to measure free testosterone","volume":"51","author":"Morley","year":"2002","journal-title":"Metab.-Clin. Exp."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biocel.2015.07.001","article-title":"Testosterone deficiency induced by progressive stages of diabetes mellitus impairs glucose metabolism and favors glycogenesis in mature rat Sertoli cells","volume":"66","author":"Rato","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_40","unstructured":"Nassar, G.N., and Leslie, S.W. (2023). Physiology, Testosterone, StatPearls Publishing."},{"key":"ref_41","unstructured":"O\u2019Donnell, L., Stanton, P., and de Kretser, D.M. (2017). Endocrinology of the Male Reproductive System and Spermatogenesis, MDText.com, Inc."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, L., Lin, W., Wang, Z., Huang, R., Xia, H., Li, Z., Deng, J., Ye, T., Huang, Y., and Yang, Y. (2024). Hormone Regulation in Testicular Development and Function. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115805"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"125","DOI":"10.5534\/wjmh.2015.33.3.125","article-title":"Testosterone replacement therapy and prostate cancer incidence","volume":"33","author":"Eisenberg","year":"2015","journal-title":"World J. Men\u2019s Health"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.sxmr.2017.09.004","article-title":"Alternatives to testosterone therapy: A review","volume":"6","author":"Lo","year":"2018","journal-title":"Sex. Med. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"bvaa141","DOI":"10.1210\/jendso\/bvaa141","article-title":"Prostate-specific antigen concentrations in response to testosterone treatment of severely hypogonadal men","volume":"4","author":"Sachdev","year":"2020","journal-title":"J. Endocr. Soc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1097\/MOU.0000000000000128","article-title":"Serum markers in prostate cancer detection","volume":"25","author":"Bratt","year":"2015","journal-title":"Curr. Opin. Urol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.2174\/0929867311320240006","article-title":"Drug-induced liver injury: Mechanisms, types and biomarkers","volume":"20","author":"Vinken","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/obr.12282","article-title":"Testosterone and obesity","volume":"16","author":"Kelly","year":"2015","journal-title":"Obes. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.medcli.2015.06.020","article-title":"Testosterone deficiency, metabolic syndrome and diabetes mellitus","volume":"146","year":"2016","journal-title":"Med. 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