{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T01:01:13Z","timestamp":1767920473961,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Science, Technological Development and Innovation of the Republic of Serbia","award":["451-03-136\/2025-03\/200007"],"award-info":[{"award-number":["451-03-136\/2025-03\/200007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The lemon flavonoid extract Eriomin\u00ae (LE), which is rich in eriocitrin, has demonstrated antioxidant and anti-inflammatory properties in both animal and human studies. Given the established interplay among aging, oxidative stress, and inflammation, this study investigated the influences of LE on the pituitary\u2013adrenal (PA) axis in aged rats and its potential to mitigate age-related physiological changes in this system. The effects of LE (40 mg\/kg\/day suspended in sunflower oil) on the morphofunctional properties of the PA axis were studied in 24-month-old male Wistar rats following four weeks of oral treatment. Control groups included vehicle-treated (sunflower oil; CON) and untreated intact controls (ICON). Stereological and imaging analyses revealed no significant changes in pituitary ACTH cells; however, Pomc gene expression was significantly downregulated in the LE group compared to both controls (p \u2264 0.05). LE treatment resulted in a significant reduction in adrenal gland weight (p \u2264 0.05), adrenal gland volume (p \u2264 0.01), zona fasciculata (ZF) volume (p \u2264 0.01) and ZF cell volume (p \u2264 0.05). These changes were accompanied by a significant decrease in serum corticosterone levels (p \u2264 0.05). In conclusion, LE downregulated PA axis activity in aged rats. Considering the association between age-related increases in PA activity and adverse health outcomes, citrus flavonoid extracts such as LE may hold promise as anti-aging supplements aimed at mitigating age-related stress dysregulation.<\/jats:p>","DOI":"10.3390\/ijms26125818","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T11:53:14Z","timestamp":1750161194000},"page":"5818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Lemon Flavonoid Eriomin\u00ae Suppresses Pituitary\u2013Adrenal Axis Activity in Aged Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9141-5732","authenticated-orcid":false,"given":"Svetlana","family":"Trifunovi\u0107","sequence":"first","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6237-4021","authenticated-orcid":false,"given":"Ivona","family":"Gizdovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0994-1280","authenticated-orcid":false,"given":"Nata\u0161a","family":"Risti\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5352-763X","authenticated-orcid":false,"given":"Branko","family":"Filipovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6540-9603","authenticated-orcid":false,"given":"Vladimir","family":"Ajd\u017eanovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8366-3138","authenticated-orcid":false,"given":"Marko","family":"Miler","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7878-7075","authenticated-orcid":false,"given":"Thais","family":"Cesar","sequence":"additional","affiliation":[{"name":"Graduate Program in Food, Nutrition and Food Engineering, Sao Paulo State University (UNESP), Araraquara 14800-060, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-0619","authenticated-orcid":false,"given":"Branka","family":"\u0160o\u0161i\u0107-Jurjevi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"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","unstructured":"(2025, April 07). Ageing and Health. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/ageing-and-health."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S2213-8587(18)30026-3","article-title":"The Physiology of Endocrine Systems with Ageing","volume":"6","author":"Kaufman","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.maturitas.2022.10.006","article-title":"Adrenal Aging and Its Effects on the Stress Response and Immunosenescence","volume":"168","author":"Stamou","year":"2023","journal-title":"Maturitas"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.neubiorev.2016.05.036","article-title":"Aging and the HPA Axis: Stress and Resilience in Older Adults","volume":"68","author":"Gaffey","year":"2016","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Goncharova, N., Bowden, D., and Johnson, E. (2023). Editorial: The HPA Axis and Aging: Individual Features, Age-Related Pathology. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1222033"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3164\/jcbn.09-33","article-title":"Elevation by Oxidative Stress and Aging of Hypothalamic-Pituitary-Adrenal Activity in Rats and Its Prevention by Vitamin E","volume":"45","author":"Kobayashi","year":"2009","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Juszczyk, G., Mikulska, J., Kasperek, K., Pietrzak, D., Mrozek, W., and Herbet, M. (2021). Chronic Stress and Oxidative Stress as Common Factors of the Pathogenesis of Depression and Alzheimer\u2019s Disease: The Role of Antioxidants in Prevention and Treatment. Antioxidants, 10.","DOI":"10.3390\/antiox10091439"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Signorello, M.G., Ravera, S., and Leoncini, G. (2024). Oxidative Stress Induced by Cortisol in Human Platelets. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25073776"},{"key":"ref_10","first-page":"100","article-title":"Role Of Cortisol in The Synthesis of Glutamate During Oxidative Stress","volume":"2","author":"Godonu","year":"2025","journal-title":"Int. J. Sci. Res. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/ptr.6386","article-title":"Effectiveness of Eriomin\u00ae in Managing Hyperglycemia and Reversal of Prediabetes Condition: A Double-blind, Randomized, Controlled Study","volume":"33","author":"Ribeiro","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100714","DOI":"10.1016\/j.crfs.2024.100714","article-title":"Bridging the Gap in Antioxidant Activity of Flavonoids: Correlating the Oxidation of Human Plasma with Chemical and Cellular Assays","volume":"8","author":"Mohammadi","year":"2024","journal-title":"Curr. Res. Food Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yao, L., Liu, W., Bashir, M., Nisar, M.F., and Wan, C. (2022). (Craig) Eriocitrin: A Review of Pharmacological Effects. Biomed. Pharmacother., 154.","DOI":"10.1016\/j.biopha.2022.113563"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ji, M., Deng, Z., Rong, X., Li, R., You, Z., Guo, X., Cai, C., Zhao, Y., Gao, P., and Cao, G. (2022). Naringenin Prevents Oxidative Stress and Inflammation in LPS-Induced Liver Injury through the Regulation of LncRNA-mRNA in Male Mice. Molecules, 28.","DOI":"10.3390\/molecules28010198"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Madureira, M.B., Concato, V.M., Cruz, E.M.S., Bitencourt De Morais, J.M., Inoue, F.S.R., Concimo Santos, N., Gon\u00e7alves, M.D., Cremer De Souza, M., Basso Scandolara, T., and Fontana Mezoni, M. (2023). Naringenin and Hesperidin as Promising Alternatives for Prevention and Co-Adjuvant Therapy for Breast Cancer. Antioxidants, 12.","DOI":"10.3390\/antiox12030586"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.exger.2016.08.014","article-title":"Citrus Flavanones Naringenin and Hesperetin Improve Antioxidant Status and Membrane Lipid Compositions in the Liver of Old-Aged Wistar Rats","volume":"84","author":"Miler","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Miler, M., \u017divanovi\u0107, J., Kova\u010devi\u0107, S., Vidovi\u0107, N., Djordjevic, A., Filipovi\u0107, B., and Ajd\u017eanovi\u0107, V. (2024). Citrus Flavanone Effects on the Nrf2-Keap1\/GSK3\/NF-\u03baB\/NLRP3 Regulation and Corticotroph-Stress Hormone Loop in the Old Pituitary. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168918"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8242","DOI":"10.1021\/acs.jafc.0c03079","article-title":"Citrus Flavanones Upregulate Thyrotroph Sirt1 and Differently Affect Thyroid Nrf2 Expressions in Old-Aged Wistar Rats","volume":"68","author":"Miler","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"\u0160o\u0161i\u0107-Jurjevi\u0107, B., Borkovi\u0107-Miti\u0107, S., Pavlovi\u0107, S., Vlahovi\u0107, D., Miler, M., Cesar, T., Ajd\u017eanovi\u0107, V., Milenkovic, D., Stellaard, F., and Trifunovi\u0107, S. (2024). Lemon Flavonoid Extract Eriomin Improves Pro\/Antioxidant Status and Interferes with Cholesterol Metabolism without Affecting Serum Cholesterol Levels in Aged Rats. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105221"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1002\/biof.2038","article-title":"Lemon Extract Reduces the Hepatic Oxidative Stress and Persulfidation Levels by Upregulating the Nrf2 and Trx1 Expression in Old Rats","volume":"50","author":"Miler","year":"2024","journal-title":"BioFactors"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.neurobiolaging.2010.02.015","article-title":"Aging Increases Basal but Not Stress-Induced Levels of Corticosterone in the Brain of the Awake Rat","volume":"33","author":"Garrido","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tesic, V., Ciric, J., Jovanovic Macura, I., Zogovic, N., Milanovic, D., Kanazir, S., and Perovic, M. (2021). Corticosterone and Glucocorticoid Receptor in the Cortex of Rats during Aging\u2014The Effects of Long-Term Food Restriction. Nutrients, 13.","DOI":"10.3390\/nu13124526"},{"key":"ref_23","first-page":"627","article-title":"Genistein Stimulates the Hypothalamo-Pituitary-Adrenal Axis in Adult Rats: Morphological and Hormonal Study","volume":"27","year":"2012","journal-title":"Histol. Histopathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1248\/cpb.c14-00021","article-title":"Mechanism of Peroxisome Proliferator-Activated Receptor Gamma (PPAR\u03b3) Transactivation by Hesperetin Glucuronides Is Distinct from That by a Thiazolidine-2,4-Dione Agent","volume":"62","author":"Gamo","year":"2014","journal-title":"Chem. Pharm. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11373","DOI":"10.1080\/07391102.2022.2162127","article-title":"Citrus Nutraceutical Eriocitrin and Its Metabolites Are Partial Agonists of Peroxisome Proliferator-Activated Receptor Gamma (PPAR\u03b3): A Molecular Docking and Molecular Dynamics Study","volume":"45","author":"Gangadhariah","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_26","first-page":"107130","article-title":"Hyperglycemia Induces the Variations of 11 \u03b2 -Hydroxysteroid Dehydrogenase Type 1 and Peroxisome Proliferator-Activated Receptor- \u03b3 Expression in Hippocampus and Hypothalamus of Diabetic Rats","volume":"2012","author":"Qi","year":"2012","journal-title":"J. Diabetes Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1677\/joe.0.180r001","article-title":"Food Restriction Regulates Adipose-Specific Cytokines in Pituitary Gland but Not in Hypothalamus","volume":"180","author":"Wiesner","year":"2004","journal-title":"J. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1093\/jn\/136.4.932","article-title":"Dietary Lycopene Downregulates Carotenoid 15,15\u2032-Monooxygenase and PPAR-\u03b3 in Selected Rat Tissues","volume":"136","author":"Zaripheh","year":"2006","journal-title":"J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1159\/000314312","article-title":"Role of the PPAR-\u03b3 System in Normal and Tumoral Pituitary Corticotropic Cells and Adrenal Cells","volume":"92","author":"Mannelli","year":"2010","journal-title":"Neuroendocrinology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.bbrc.2008.12.071","article-title":"Rosiglitazone Reverses Memory Decline and Hippocampal Glucocorticoid Receptor Down-Regulation in an Alzheimer\u2019s Disease Mouse Model","volume":"379","author":"Escribano","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.yexmp.2016.10.002","article-title":"Activation of PPAR-\u03b3 Reduces HPA Axis Activity in Diabetic Rats by up-Regulating PI3K Expression","volume":"101","author":"Torres","year":"2016","journal-title":"Exp. Mol. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1152\/physrev.00024.2017","article-title":"POMC: The Physiological Power of Hormone Processing","volume":"98","author":"Harno","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E446","DOI":"10.1152\/ajpendo.00762.2007","article-title":"Failure of Adrenal Corticosterone Production in Pomc-Deficient Mice Results from Lack of Integrated Effects of Pomc Peptides on Multiple Factors","volume":"295","author":"Karpac","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/aja.1001640204","article-title":"Atrophy of the zona fasciculata in the adrenal cortex of thyroparathyroidectomized rats: A quantitative study","volume":"164","author":"Conran","year":"1982","journal-title":"Am. J. Anat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0960-0760(91)90205-J","article-title":"The Relationship Between Adrenal Vascular Events and Steroid Secretion: The Role of Mast Cells and Endothelin","volume":"40","author":"Hinson","year":"1991","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Baek, J.-Y., Kwak, J.-E., and Ahn, M.-R. (2024). Eriocitrin Inhibits Angiogenesis by Targeting VEGFR2-Mediated PI3K\/AKT\/mTOR Signaling Pathways. Nutrients, 16.","DOI":"10.3390\/nu16071091"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A Simple Practice Guide for Dose Conversion between Animals and Human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.exger.2015.09.010","article-title":"Testosterone and Estradiol Treatments Differently Affect Pituitary-Thyroid Axis and Liver Deiodinase 1 Activity in Orchidectomized Middle-Aged Rats","volume":"72","author":"Renko","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zivkovic, A., Trifunovic, S., Savic, D., Milosevic, K., and Lavrnja, I. (2024). Experimental Autoimmune Encephalomyelitis Influences GH-Axis in Female Rats. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115837"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.acthis.2016.07.007","article-title":"Functional Morphology of Pituitary -Thyroid and -Adrenocortical Axes in Middle-Aged Male Rats Treated with Vitex Agnus Castus Essential Oil","volume":"118","year":"2016","journal-title":"Acta Histochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1365-2818.1993.tb03321.x","article-title":"The Rotator","volume":"170","author":"Jensen","year":"1993","journal-title":"J. Microsc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:53:54Z","timestamp":1760032434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":41,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125818"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125818","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,17]]}}}