{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T08:19:14Z","timestamp":1770279554674,"version":"3.49.0"},"reference-count":33,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Unigen"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Oxidative stress and chronic inflammation create a perpetual cycle in the elderly, where impaired immune function amplifies susceptibility to oxidative damage, and oxidative stress further weakens the immune response. This cycle is particularly detrimental to the respiratory system of the elderly, which is an easy target for constant exogenous harmful attacks during cold\/flu season or under heavy air pollution. Herbal medicines that protect respiratory function are seen as safer alternatives to conventional therapies; however, there is limited availability of scientifically validated, safe, and effective natural supplements for these conditions. In this study, we evaluated a standardized bioflavonoid composition, UP446, that contains bioactives from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu as a natural and nutritional supplement for its antioxidative and immunoregulatory effects in oxidative stress-accelerated aging and chemically induced immune suppression mouse models. Immunosenescence was induced through the repeated subcutaneous inoculation of D-galactose (D-Gal) at a dose of 500 mg\/kg\/day in CD-1 mice. UP446 was administered orally at doses of 100 mg\/kg and 200 mg\/kg starting in the fifth week of immunosenescence induction. This study lasted a total of ten weeks. All mice received a quadrivalent influenza vaccine 2 weeks before termination. Whole blood, serum, spleen homogenate, and thymus tissues were processed for analysis. Cyclophosphamide (Cy)-induced immunosuppression was triggered by three consecutive injections of cyclophosphamide at 80 mg\/kg\/day, followed by the oral administration of UP446 for 18 days at doses of 100 mg\/kg and 200 mg\/kg. Blood was collected from each animal at necropsy, and serum was isolated for IgA and IgG ELISA analysis. UP446 was found to improve immune response, as evidenced by the stimulation of innate (NK cells) and adaptive immune responses (T cells and cytotoxic T cells), an increase in antioxidant capacity (glutathione peroxidase), the preservation of vital immune organs (the thymus), and a reduction in NF\u03baB. UP446 also increased serum levels of IgA and IgG. The findings presented in this report demonstrate the antioxidative, anti-inflammatory, and immune-regulatory activities of UP446, suggesting its potential use in respiratory conditions involving immune stress due to aging, oxidative stress, and\/or pathogenic challenges.<\/jats:p>","DOI":"10.3390\/nu16183144","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T09:43:13Z","timestamp":1726652593000},"page":"3144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Botanical Bioflavonoid Composition from Scutellaria baicalensis- and Acacia catechu-Protected Mice against D-Galactose-Induced Immunosenescence, and Cyclophosphamide Induced Immune Suppression"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5009-1586","authenticated-orcid":false,"given":"Mesfin","family":"Yimam","sequence":"first","affiliation":[{"name":"Unigen Inc., 2121 South State Street, Suite #400, Tacoma, WA 98405, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Horm","sequence":"additional","affiliation":[{"name":"Department of Biology, Pacific Lutheran University, 12180 Park Ave. S, Tacoma, WA 98447, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandria","family":"O\u2019Neal","sequence":"additional","affiliation":[{"name":"Seagen Pfizer, 21717 30th Dr SE, Bothell, WA 98021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Chua","sequence":"additional","affiliation":[{"name":"Washington State Department of Health, 1610 NE 150th St, Shoreline, WA 98155, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Jiao","sequence":"additional","affiliation":[{"name":"Unigen Inc., 2121 South State Street, Suite #400, Tacoma, WA 98405, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Hong","sequence":"additional","affiliation":[{"name":"Unigen Inc., 2121 South State Street, Suite #400, Tacoma, WA 98405, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Jia","sequence":"additional","affiliation":[{"name":"Unigen Inc., 2121 South State Street, Suite #400, Tacoma, WA 98405, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114362","DOI":"10.1016\/j.fct.2023.114362","article-title":"Oxidative stress is the pivot for PM2.5-induced lung injury","volume":"184","author":"Hou","year":"2024","journal-title":"Food Chem. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.redox.2014.01.013","article-title":"Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury","volume":"2","author":"Entezari","year":"2014","journal-title":"Redox Biol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Patel, V., Dial, K., Wu, J., Gauthier, A.G., Wu, W., Lin, M., Espey, M.G., Thomas, D.D., Ashby, C.R., and Mantell, L.L. (2020). Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030977"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1089\/ars.2019.7818","article-title":"The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases","volume":"31","author":"Wang","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yimam, M., Horm, T., O\u2019Neal, A., Jiao, P., Hong, M., Brownell, L., Jia, Q., Lin, M., Gauthier, A., and Wu, J. (2023). A Standardized Botanical Composition Mitigated Acute Inflammatory Lung Injury and Reduced Mortality through Extracellular HMGB1 Reduction. Molecules, 28.","DOI":"10.20944\/preprints202308.0230.v1"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hajam, Y.A., Rani, R., Ganie, S.Y., Sheikh, T.A., Javaid, D., Qadri, S.S., Pramodh, S., Alsulimani, A., Alkhanani, M.F., and Harakeh, S. (2022). Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells, 11.","DOI":"10.3390\/cells11030552"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","unstructured":"Teissier, T., Boulanger, E., and Cox, L.S. (2022). Interconnections between Inflammageing and Immunosenescence during Ageing. Cells, 11.","DOI":"10.3390\/cells11030359"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100982","DOI":"10.1016\/j.arr.2019.100982","article-title":"Ageing, age-related diseases and oxidative stress: What to do next?","volume":"57","author":"Luo","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"670294","DOI":"10.1155\/2012\/670294","article-title":"Oxidative stress and immunosenescence: Therapeutic effects of melatonin","volume":"2012","author":"Espino","year":"2012","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S0304-4165(99)00152-X","article-title":"Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi","volume":"1472","author":"Gao","year":"1999","journal-title":"Biochim. Biophys. Acta (BBA) Gen. Subj."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Paudel, K.R., and Kim, D.W. (2020). Microparticles-Mediated Vascular Inflammation and its Amelioration by Antioxidant Activity of Baicalin. Antioxidants, 9.","DOI":"10.3390\/antiox9090890"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/08923973.2023.2165942","article-title":"Baicalin suppresses interleukin-1\u03b2-induced apoptosis, inflammatory response, oxidative stress, and extracellular matrix degradation in human nucleus pulposus cells","volume":"45","author":"Bai","year":"2023","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bernatoniene, J., and Kopustinskiene, D.M. (2018). The Role of Catechins in Cellular Responses to Oxidative Stress. Molecules, 23.","DOI":"10.3390\/molecules23040965"},{"key":"ref_15","unstructured":"Jia, Q. (2009). Formulation of a Mixture of Free-B-Ring Flavonoids and Flavans as a Therapeutic Agent. (US7514469B2), U.S. Patent."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.fct.2010.02.011","article-title":"90-day oral toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in rats","volume":"48","author":"Yimam","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Feng, H., Fan, J., Lin, L., Liu, Y., Chai, D., and Yang, J. (2019). Immunomodulatory Effects of Phosphorylated Radix Cyathulae officinalis Polysaccharides in Immunosuppressed Mice. Molecules, 24.","DOI":"10.3390\/molecules24224150"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1093\/gerona\/glq074","article-title":"Does accumulation of advanced glycation end products contribute to the aging phenotype?","volume":"65","author":"Semba","year":"2010","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1080\/13813455.2019.1673434","article-title":"The effect of resveratrol on advanced glycation end products in diabetes mellitus: A systematic review","volume":"128","author":"Maleki","year":"2022","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/bs.vh.2022.09.002","article-title":"The antioxidant glutathione","volume":"121","year":"2023","journal-title":"Vitam. Horm."},{"key":"ref_21","first-page":"1","article-title":"Antioxidative action of flavonoids, quercetin and catechin, mediated by the activation of glutathione peroxidase","volume":"24","author":"Nagata","year":"1999","journal-title":"Tokai J. Exp. Clin. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.2147\/DDDT.S319260","article-title":"Baicalin Alleviates Oxidative Stress and Inflammation in Diabetic Nephropathy via Nrf2 and MAPK Signaling Pathway","volume":"15","author":"Ma","year":"2021","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.2147\/DDDT.S163951","article-title":"Baicalin provides neuroprotection in traumatic brain injury mice model through Akt\/Nrf2 pathway","volume":"12","author":"Fang","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1006\/jmcc.1996.0045","article-title":"Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-kB transcription factor in mouse cardiac muscle","volume":"28","author":"Helenius","year":"1996","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Galli, F., Marcantonini, G., Giustarini, D., Albertini, M.C., Migni, A., Zatini, L., Gioiello, A., Rossi, R., and Bartolini, D. (2022). How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS-CoV-2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism. Antioxidants, 11.","DOI":"10.3390\/antiox11071366"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3109\/19390211.2010.493169","article-title":"A medicinal plant extract of Scutellaria Baicalensis and Acacia catechu reduced LPS-stimulated gene expression in immune cells: A comprehensive genomic study using QPCR, ELISA, and microarray","volume":"7","author":"Sung","year":"2010","journal-title":"J. Diet. Suppl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.thorsurg.2018.12.001","article-title":"The Role of the Thymus in the Immune Response","volume":"29","author":"Thapa","year":"2019","journal-title":"Thorac. Surg. Clin."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/1348-0421.12833","article-title":"Resveratrol ameliorates thymus senescence changes in D-galactose induced mice","volume":"64","author":"Wei","year":"2020","journal-title":"Microbiol. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1183\/09031936.01.00228801","article-title":"Lung mucosal immunity: Immunoglobulin-A revisited","volume":"18","author":"Pilette","year":"2001","journal-title":"Eur. Respir. J."},{"key":"ref_30","first-page":"678","article-title":"Role of Acacia catechu and Scutellaria baicalensis in Enhancing Immune Function Following Influenza Vaccination of Healthy Adults: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial","volume":"42","author":"Lewis","year":"2023","journal-title":"J. Am. Nutr. Assoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1177\/2156587216641831","article-title":"Prevention and Treatment of Influenza, Influenza-Like Illness, and Common Cold by Herbal, Complementary, and Natural Therapies","volume":"22","author":"Mousa","year":"2017","journal-title":"J. Evid. Based Complement. Altern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1007\/s00705-014-2192-2","article-title":"Antiviral activity of baicalin against influenza A (H1N1\/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase","volume":"159","author":"Ding","year":"2014","journal-title":"Arch. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1039\/c0np00005a","article-title":"Anti-influenza agents from Traditional Chinese Medicine","volume":"27","author":"Ge","year":"2010","journal-title":"Nat. Prod. Rep."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/18\/3144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:58:30Z","timestamp":1760111910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/18\/3144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,18]]},"references-count":33,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["nu16183144"],"URL":"https:\/\/doi.org\/10.3390\/nu16183144","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,18]]}}}