{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:44:51Z","timestamp":1780393491146,"version":"3.54.1"},"reference-count":34,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Science and Technology Agency","award":["JPMJPF2017"],"award-info":[{"award-number":["JPMJPF2017"]}]},{"name":"Japan Science and Technology Agency","award":["JPMJSA1506"],"award-info":[{"award-number":["JPMJSA1506"]}]},{"name":"Science and Technology Research Partnership for Sustainable Development","award":["JPMJPF2017"],"award-info":[{"award-number":["JPMJPF2017"]}]},{"name":"Science and Technology Research Partnership for Sustainable Development","award":["JPMJSA1506"],"award-info":[{"award-number":["JPMJSA1506"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Natural resources have recently received considerable attention as complementary or alternative hematinic agents. In this regard, olive leaf extract, which is rich in bioactive phenolic compounds, has been reported to induce erythroid differentiation in human hematopoietic stem cells. Therefore, in the present study, we aimed to explore the potential hematinic properties of aqueous olive leaf extract (WOL) in vivo. After 24 days of administering WOL to healthy mice orally, red blood cell (RBC), hematocrit, reticulocyte, and reticulocyte hemoglobin content (CHr) showed a significant increase. Additionally, WOL promoted plasma iron levels and the expression of splenic ferroportin (Fpn), an iron transporter. Additionally, a single-arm pilot study involving a limited number of healthy volunteers was conducted to assess WOL\u2019s feasibility, compliance, and potential benefits. Following an 8-week intervention with WOL, RBC count and hemoglobin level were significantly increased. Notably, there were no significant changes in the safety measures related to liver and kidney functions. Furthermore, we identified oleuropein and oleuroside as the active components in WOL to induce erythroid differentiation in the K562 cell line. Altogether, our study presents evidence of the hematinic potential of WOL in the in vivo studies, opening up exciting possibilities for future applications in preventing or treating anemia.<\/jats:p>","DOI":"10.3390\/nu15194095","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T03:44:42Z","timestamp":1695354282000},"page":"4095","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hematinic Potential of Olive Leaf Extract: Evidence from an In Vivo Study in Mice and a Pilot Study in Healthy Human Volunteers"],"prefix":"10.3390","volume":"15","author":[{"given":"Shinji","family":"Kondo","sequence":"first","affiliation":[{"name":"Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2816-9118","authenticated-orcid":false,"given":"Farhana","family":"Ferdousi","sequence":"additional","affiliation":[{"name":"Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan"},{"name":"Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinchang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Graduate School of Life and Environmental Science, University of Tsukuba, Tsukuba 305-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofya","family":"Suidasari","sequence":"additional","affiliation":[{"name":"Nutrition Act Co., Ltd., Ginza, Tokyo 104-0061, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Yokozawa","sequence":"additional","affiliation":[{"name":"Nutrition Act Co., Ltd., Ginza, Tokyo 104-0061, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Nutrition Act Co., Ltd., Ginza, Tokyo 104-0061, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Tominaga","sequence":"additional","affiliation":[{"name":"Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1399-9541","authenticated-orcid":false,"given":"Hiroko","family":"Isoda","sequence":"additional","affiliation":[{"name":"Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-8572, Japan"},{"name":"Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e627","DOI":"10.1016\/S2214-109X(22)00084-5","article-title":"National, regional, and global estimates of anaemia by severity in women and children for 2000\u201319: A pooled analysis of population-representative data","volume":"10","author":"Stevens","year":"2022","journal-title":"Lancet Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1056\/NEJMra1401038","article-title":"Iron-Deficiency Anemia","volume":"372","author":"Camaschella","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/j.1365-2141.2006.06279.x","article-title":"A detailed study of time-dependent changes in human red blood cells: From reticulocyte maturation to erythrocyte senescence","volume":"135","author":"Gifford","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/MOH.0b013e32832990a4","article-title":"Ineffective erythropoiesis and thalassemias","volume":"16","author":"Rivella","year":"2009","journal-title":"Curr. Opin. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"200","DOI":"10.2215\/CJN.03840907","article-title":"Novel erythropoiesis-stimulating agents: A new era in anemia management","volume":"3","author":"Macdougall","year":"2008","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1378\/chest.127.1.295","article-title":"Anemia, allogenic blood transfusion, and immunomodulation in the critically ill","volume":"127","author":"Raghavan","year":"2005","journal-title":"Chest"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18016","DOI":"10.1038\/nrdp.2018.16","article-title":"Haemochromatosis","volume":"4","author":"Brissot","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_8","unstructured":"Visithra, J. (2016). A Study to Access and Compare the Effectiveness of Fenugreek Leaves with Elemental Iron and Elemental Iron Alone on Anemia among Women Residing in Selected Community at Choolai, College of Nursing, Madras Medical College."},{"key":"ref_9","first-page":"185","article-title":"Biochemical and histological studies on the Ameliorative role of fenugreek products in tannic acid-induced iron deficiency anemia in Albino rats","volume":"7","author":"Ibrahim","year":"2011","journal-title":"Egypt. J. Exp. Biol."},{"key":"ref_10","unstructured":"Chunaeni, S., Lusiana, A., and Martanti, L. (2020). Journal of Physics: Conference Series, IOP Publishing."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"176","DOI":"10.31344\/ijhhs.v7i2.549","article-title":"The Effectiveness of Giving Crystal Guava Juice (Psidium guajava L.\u201cCrystal\u201d) on Haemoglobin Levels in Female Adolescents with Anaemia","volume":"7","author":"Mayasari","year":"2023","journal-title":"Int. J. Hum. Health Sci."},{"key":"ref_12","first-page":"332","article-title":"Preliminary phytochemical analysis of leaf powder extracts of Psidium guajava L.","volume":"6","author":"Gayathri","year":"2014","journal-title":"Int. J. Pharmacogn. Phytochem. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.freeradbiomed.2021.03.019","article-title":"Black pepper prevents anemia of inflammation by inhibiting hepcidin over-expression through BMP6-SMAD1\/ IL6-STAT3 signaling pathway","volume":"168","author":"Banerjee","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103740","DOI":"10.1016\/j.jff.2019.103740","article-title":"Dietary luteolin protects against renal anemia in mice","volume":"65","author":"Li","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Boss, A., Bishop, K., Marlow, G., Barnett, M., and Ferguson, L. (2016). Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions. Nutrients, 8.","DOI":"10.3390\/nu8080513"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1089\/jmf.2011.0243","article-title":"Olive Leaf Extract as a Hypoglycemic Agent in Both Human Diabetic Subjects and in Rats","volume":"15","author":"Wainstein","year":"2012","journal-title":"J. Med. Food"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.phymed.2010.06.007","article-title":"The neuroprotective effect of olive leaf extract is related to improved blood\u2013brain barrier permeability and brain edema in rat with experimental focal cerebral ischemia","volume":"18","author":"Mohagheghi","year":"2011","journal-title":"Phytomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1016\/j.clnu.2018.11.009","article-title":"Olive leaf tea may have hematological health benefit over green tea","volume":"38","author":"Ferdousi","year":"2019","journal-title":"Clin. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"927619","DOI":"10.1155\/2014\/927619","article-title":"Olive (Olea europaea) Leaf Extract Induces Apoptosis and Monocyte\/Macrophage Differentiation in Human Chronic Myelogenous Leukemia K562 Cells: Insight into the Underlying Mechanism","volume":"2014","author":"Samet","year":"2014","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.1002\/mnfr.201000650","article-title":"Apigetrin induces erythroid differentiation of human leukemia cells K562: Proteomics approach","volume":"55","author":"Tsolmon","year":"2011","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.diff.2015.07.001","article-title":"Olive leaf components apigenin 7-glucoside and luteolin 7-glucoside direct human hematopoietic stem cell differentiation towards erythroid lineage","volume":"89","author":"Samet","year":"2015","journal-title":"Differentiation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7229","DOI":"10.1111\/jcmm.16752","article-title":"Comprehensive transcriptome analysis of erythroid differentiation potential of olive leaf in haematopoietic stem cells","volume":"25","author":"Kondo","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1182\/blood.V45.3.321.321","article-title":"Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome","volume":"45","author":"Lozzio","year":"1975","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, Z., Li, Z., Li, X., Xiao, J., and Li, C. (2023). Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1161541"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jphs.2020.01.007","article-title":"Ellagic acid attenuates liver toxicity induced by valproic acid in rats","volume":"143","author":"Abdelkader","year":"2020","journal-title":"J. Pharmacol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Abuzinadah, M.F., and Ahmad, A. (2020). Pharmacological studies on the efficacy of a thymoquinone-containing novel polyherbal formulation against cisplatin-induced hepatorenal toxicity in rats. J. Food Biochem., 44.","DOI":"10.1111\/jfbc.13131"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"789","DOI":"10.14202\/vetworld.2022.789-796","article-title":"Acute and sub-chronic oral toxicity study of purple sweet potato (Ipomoea batatas [L.] Lam) yogurt in mice (Mus musculus)","volume":"15","author":"Khairani","year":"2022","journal-title":"Vet. World"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, X., Ren, M., Zhang, X., and Wang, L. (2022). Insoluble dietary fiber (non-starch polysaccharides) from rice bran attenuates cadmium-induced toxicity in mice by modulating the gut microbiota and alleviating liver and kidney injury. Food Biosci., 48.","DOI":"10.1016\/j.fbio.2022.101807"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"704635","DOI":"10.3389\/fped.2021.704635","article-title":"Splenomegaly in Children and Adolescents","volume":"9","author":"Suttorp","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.bbamcr.2012.01.014","article-title":"Hepcidin and iron homeostasis","volume":"1823","author":"Ganz","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.cmet.2005.02.005","article-title":"Cellular iron: Ferroportin is the only way out","volume":"1","author":"Ganz","year":"2005","journal-title":"Cell Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1182\/blood.V89.4.1430","article-title":"Negative Regulation of the Erythropoietin Gene Expression by the GATA Transcription Factors","volume":"89","author":"Imagawa","year":"1997","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1182\/blood-2005-02-0561","article-title":"Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin","volume":"106","author":"Drakesmith","year":"2005","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1093\/emboj\/cdg392","article-title":"HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1 in normoxia","volume":"22","author":"Berra","year":"2003","journal-title":"EMBO J."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/19\/4095\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:55:30Z","timestamp":1760129730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/19\/4095"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,22]]},"references-count":34,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["nu15194095"],"URL":"https:\/\/doi.org\/10.3390\/nu15194095","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,22]]}}}