{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:26:23Z","timestamp":1790313983509,"version":"4.1.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T00:00:00Z","timestamp":1716163200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013420","name":"Tsumura and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013420","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013420","name":"Tsumura and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013420","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Fatigue can lead to several health issues and is particularly prevalent among elderly individuals with chronic inflammatory conditions. Ninjin\u2019yoeito, a traditional Japanese herbal medicine, is used to address fatigue and malaise, anorexia, and anemia. This study aimed to examine whether relieving inflammation in the brain and skeletal muscle of senescence-accelerated mice prone 8 (SAMP8) could reduce fatigue-like conditions associated with aging. First, SAMP8 mice were divided into two groups, with and without ninjin\u2019yoeito treatment. The ninjin\u2019yoeito-treated group received a diet containing 3% ninjin\u2019yoeito for a period of 4 months starting at 3 months of age. At 7 months of age, all mice underwent motor function, treadmill fatigue, and behavioral tests. They were then euthanized and the skeletal muscle weight, muscle cross-sectional area, and concentration of interleukin (IL)-1\u03b2 and IL-1 receptor antagonist (IL-1RA) in both the brain and skeletal muscle were measured. The results showed that the ninjin\u2019yoeito-treated group had higher motor function and spontaneous locomotor activity than the untreated group did and ran for significantly longer in the treadmill fatigue test. Moreover, larger muscle cross-sectional area, lower IL-1\u03b2 concentrations, and higher IL-1RA concentrations were observed in both the brain and skeletal muscle tissues of the ninjin\u2019yoeito-treated group than in the untreated group. The results suggest that ninjin\u2019yoeito improves age-related inflammatory conditions in both the central and peripheral tissues and reduces fatigue.<\/jats:p>","DOI":"10.1371\/journal.pone.0303833","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T17:38:41Z","timestamp":1716226721000},"page":"e0303833","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Ninjin\u2019yoeito reduces fatigue-like conditions by alleviating inflammation of the brain and skeletal muscles in aging mice"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3563-2473","authenticated-orcid":true,"given":"Shotaro","family":"Otsuka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoma","family":"Matsuzaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Kakimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Tachibe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Kawatani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiya","family":"Takada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Tani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruki","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Inadome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Nojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harutoshi","family":"Sakakima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Mizuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Matsubara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuro","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"pone.0303833.ref001","doi-asserted-by":"crossref","first-page":"S57","DOI":"10.1016\/j.critrevonc.2003.07.003","article-title":"Fatigeue and aging.","volume":"48","author":"P Tralongo","year":"2003","journal-title":"Crit Rev Oncol Hematol"},{"key":"pone.0303833.ref002","article-title":"Fatigue and the prediction of negative health outcomes: A systematic review with meta-analysis.","author":"V Knoop","year":"2021","journal-title":"Ageing Research Reviews. Elsevier Ireland Ltd"},{"key":"pone.0303833.ref003","doi-asserted-by":"crossref","first-page":"114767","DOI":"10.1016\/j.jep.2021.114767","article-title":"Anti-fatigue effect of hypericin in a chronic forced exercise mouse model","volume":"284","author":"Y Sun","year":"2022","journal-title":"J Ethnopharmacol"},{"key":"pone.0303833.ref004","article-title":"Establishment and identification of an animal model of long-term exercise-induced fatigue","author":"K Yan","year":"2022","journal-title":"Frontiers in Endocrinology. Frontiers Media S.A."},{"key":"pone.0303833.ref005","first-page":"10","article-title":"An adrenalectomy mouse model reflecting clinical features for chronic fatigue syndrome.","author":"JS Lee","year":"2020","journal-title":"Biomolecules"},{"key":"pone.0303833.ref006","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.biopha.2019.01.042","article-title":"ShenQi FuZheng Injection ameliorates fatigue-like behavior in mouse models of cancer-related fatigue.","volume":"111","author":"G Zhu","year":"2019","journal-title":"Biomedicine & Pharmacotherapy."},{"key":"pone.0303833.ref007","article-title":"Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit","author":"M. Yamashita","year":"2020","journal-title":"International Journal of Tryptophan Research. SAGE Publications Ltd"},{"key":"pone.0303833.ref008","first-page":"1975","article-title":"Study on the Correlation Between NF-\u03baB and Central Fatigue.","volume-title":"Journal of Molecular Neuroscience","author":"X Yang","year":"2021"},{"key":"pone.0303833.ref009","article-title":"Molecular mechanisms of muscle fatigue","author":"D Constantin-Teodosiu","year":"2021","journal-title":"International Journal of Molecular Sciences. MDPI"},{"key":"pone.0303833.ref010","first-page":"9","article-title":"Brain interleukin-1\u03b2 and the intrinsic receptor antagonist control peripheral toll-like receptor 3-mediated suppression of spontaneous activity in rats.","author":"M Yamato","year":"2014","journal-title":"PLoS One."},{"key":"pone.0303833.ref011","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neuroscience.2017.06.048","article-title":"NLRP3 inflammasome activation mediates fatigue-like behaviors in mice via neuroinflammation","volume":"358","author":"Z Zhang","year":"2017","journal-title":"Neuroscience"},{"key":"pone.0303833.ref012","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1111\/ejn.12668","article-title":"Induction of interleukin-1\u03b2 byactivated microglia is a prerequisite for immunologically induced fatigue","volume":"40","author":"M Ifuku","year":"2014","journal-title":"European Journal of Neuroscience"},{"key":"pone.0303833.ref013","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.bbi.2009.02.015","article-title":"IL-1\/IL-1ra balance in the brain revisited\u2013Evidence from transgenic mouse models","volume":"23","author":"S Spulber","year":"2009","journal-title":"Brain Behav Immun"},{"key":"pone.0303833.ref014","first-page":"291","article-title":"Role of brain IL-1\u03b2 on fatigue after exercise-induced muscle damage","author":"MD Carmichael","year":"2006","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"pone.0303833.ref015","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00296-004-0463-z","article-title":"The effect of interleukin-1 blockade on fatigue in rheumatoid arthritis\u2014A pilot study.","volume":"25","author":"R Omdal","year":"2005","journal-title":"Rheumatol Int"},{"key":"pone.0303833.ref016","doi-asserted-by":"crossref","first-page":"113590","DOI":"10.1016\/j.expneurol.2020.113590","article-title":"Effect of low-intensity motor balance and coordination exercise on cognitive functions, hippocampal A\u03b2 deposition, neuronal loss, neuroinflammation, and oxidative stress in a mouse model of Alzheimer\u2019s disease","volume":"337","author":"K Nakanishi","year":"2021","journal-title":"Exp Neurol"},{"key":"pone.0303833.ref017","first-page":"25","article-title":"Effects of low-intensity exercise on spontaneously developed knee osteoarthritis in male senescence-accelerated mouse prone 8.","author":"K Norimatsu","year":"2023","journal-title":"Arthritis Res Ther."},{"key":"pone.0303833.ref018","first-page":"23","article-title":"Analysis of the Effects of Ninjin\u2019yoeito on Physical Frailty in Mice.","author":"S Otsuka","year":"2022","journal-title":"Int J Mol Sci."},{"key":"pone.0303833.ref019","article-title":"Anti-inflammatory diets and fatigue.","author":"U Ha\u00df","year":"2019","journal-title":"Nutrients. MDPI AG"},{"key":"pone.0303833.ref020","article-title":"Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine","author":"Q He","year":"2020","journal-title":"Biol Pharm Bull"},{"key":"pone.0303833.ref021","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.2174\/0929867324666170414164607","article-title":"Anti-fatigue Effects of Active Ingredients from Traditional Chinese Medicine: A Review","volume":"26","author":"S-S Zhou","year":"2017","journal-title":"Curr Med Chem"},{"key":"pone.0303833.ref022","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3233\/ADR-170026","article-title":"A Possibility of Simultaneous Treatment with the Multicomponent Drug, Ninjin\u2019yoeito, for Anorexia, Apathy, and Cognitive Dysfunction in Frail Alzheimer\u2019s Disease Patients: An Open-Label Pilot Study.","volume":"1","author":"M Ohsawa","year":"2017","journal-title":"J Alzheimers Dis Rep"},{"key":"pone.0303833.ref023","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1089\/acm.2014.0211","article-title":"Ren shen yangrong tang for fatigue in cancer survivors: A Phase I\/II open-label study","volume":"21","author":"Y Xu","year":"2015","journal-title":"Journal of Alternative and Complementary Medicine"},{"key":"pone.0303833.ref024","first-page":"5","article-title":"Combined Use of Ninjin\u2019yoeito Improves Subjective Fatigue Caused by Lenalidomide in Patients With Multiple Myeloma: A Retrospective Study.","author":"T Ito","year":"2018","journal-title":"Front Nutr."},{"key":"pone.0303833.ref025","article-title":"Multifunctional Actions of Ninjinyoeito, a Japanese Kampo Medicine: Accumulated Scientific Evidence Based on Experiments With Cells and Animal Models, and Clinical Studies.","author":"K Miyano","year":"2018","journal-title":"Frontiers in Nutrition. Frontiers Media S.A"},{"key":"pone.0303833.ref026","article-title":"Herbal Medicine Ninjin\u2019yoeito in the Treatment of Sarcopenia and Frailty.","author":"NS Uto","year":"2018","journal-title":"Frontiers in Nutrition. Frontiers Media S.A."},{"key":"pone.0303833.ref027","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1093\/bbb\/zbab049","article-title":"Orange peel extract reduces the inflammatory state of skeletal muscle after downhill running via an increase in IL-1RA","volume":"85","author":"T Suzuki","year":"2021","journal-title":"Biosci Biotechnol Biochem"},{"key":"pone.0303833.ref028","doi-asserted-by":"crossref","first-page":"113317","DOI":"10.1016\/j.jep.2020.113317","article-title":"Radix Polygalae extract exerts antidepressant effects in behavioral despair mice and chronic restraint stress-induced rats probably by promoting autophagy and inhibiting neuroinflammation","volume":"265","author":"Y Zhou","year":"2021","journal-title":"J Ethnopharmacol"},{"key":"pone.0303833.ref029","doi-asserted-by":"crossref","first-page":"114332","DOI":"10.1016\/j.jep.2021.114332","article-title":"Pharmacokinetic study of Ninjin\u2019yoeito: Absorption and brain distribution of Ninjin\u2019yoeito ingredients in mice.","volume":"279","author":"T Matsumoto","year":"2021","journal-title":"J Ethnopharmacol"},{"key":"pone.0303833.ref030","first-page":"2016","article-title":"The treadmill fatigue test: A simple, high-throughput assay of fatigue-like behavior for the mouse","author":"JP Dougherty","year":"2016","journal-title":"Journal of Visualized Experiments"},{"key":"pone.0303833.ref031","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1249\/MSS.0000000000000980","article-title":"Neutrophil Depletion Attenuates Muscle Injury after Exhaustive Exercise.","volume":"48","author":"N Kawanishi","year":"2016","journal-title":"Med Sci Sports Exerc."},{"key":"pone.0303833.ref032","first-page":"13","article-title":"Korean red ginseng ameliorates fatigue via modulation of 5-ht and corticosterone in a sleep-deprived mouse model.","author":"JY Kang","year":"2021","journal-title":"Nutrients"},{"key":"pone.0303833.ref033","first-page":"45","article-title":"Anti-fatigue effect of quercetin on enhancing muscle function and antioxidant capacity","author":"X Chen","year":"2021","journal-title":"J Food Biochem"},{"key":"pone.0303833.ref034","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.bbi.2012.06.006","article-title":"Biomarkers for chronic fatigue","volume":"26","author":"NG Klimas","year":"2012","journal-title":"Brain Behav Immun"},{"key":"pone.0303833.ref035","article-title":"Interleukin-1 as a mediator of fatigue in disease: A narrative review","author":"ME Roerink","year":"2017","journal-title":"Journal of Neuroinflammation. BioMed Central Ltd."},{"key":"pone.0303833.ref036","first-page":"3175","article-title":"Correction: Ligustilide improves aging-induced memory deficit by regulating mitochondrial related inflammation in SAMP8 mice [Aging.,","volume":"12","author":"WL Zhu","year":"2019"},{"key":"pone.0303833.ref037","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.biopha.2018.06.106","article-title":"Neuroprotective effect of 1-Deoxynojirimycin on cognitive impairment, \u03b2-amyloid deposition, and neuroinflammation in the SAMP8 mice.","volume":"106","author":"W Chen","year":"2018","journal-title":"Biomedicine & Pharmacotherapy."},{"key":"pone.0303833.ref038","first-page":"7","article-title":"Protective effects of ginseng on neurological disorders.","author":"WY Ong","year":"2015","journal-title":"Front Aging Neurosci."},{"key":"pone.0303833.ref039","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.neuropharm.2016.08.013","article-title":"Trans-cinnamaldehyde improves memory impairment by blocking microglial activation through the destabilization of iNOS mRNA in mice challenged with lipopolysaccharide","volume":"110","author":"L Zhang","year":"2016","journal-title":"Neuropharmacology"},{"key":"pone.0303833.ref040","first-page":"14","article-title":"Tenuigenin protects dopaminergic neurons from inflammation via suppressing NLRP3 inflammasome activation in microglia.","author":"Z Fan","year":"2017","journal-title":"J Neuroinflammation."},{"key":"pone.0303833.ref041","article-title":"Pro-resolving effect of ginsenosides as an anti-inflammatory mechanism of Panax ginseng.","author":"DS Im","year":"2020","journal-title":"Biomolecules. MDPI AG"},{"key":"pone.0303833.ref042","article-title":"Age and age-related diseases: Role of inflammation triggers and cytokines.","author":"IM Rea","year":"2018","journal-title":"Frontiers in Immunology. Frontiers Media S.A."},{"key":"pone.0303833.ref043","first-page":"13","article-title":"Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice","author":"L Piao","year":"2022","journal-title":"Stem Cell Res Ther"},{"key":"pone.0303833.ref044","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1249\/MSS.0b013e3181a645a6","article-title":"In vivo alterations in skeletal muscle form and function after disuse atrophy","volume":"41","author":"BC Clark","year":"2009","journal-title":"Med Sci Sports Exerc"},{"key":"pone.0303833.ref045","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.meatsci.2015.05.009","article-title":"The muscle protein synthetic response to food ingestion.","volume":"109","author":"SHM Gorissen","year":"2015","journal-title":"Meat Sci"},{"key":"pone.0303833.ref046","first-page":"7","article-title":"Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors.","author":"K Miyano","year":"2020","journal-title":"Front Nutr."},{"key":"pone.0303833.ref047","first-page":"8","article-title":"Lactobacillus plantarum TWK10 supplementation improves exercise performance and increases muscle mass in mice.","author":"YM Chen","year":"2016","journal-title":"Nutrients"},{"key":"pone.0303833.ref048","doi-asserted-by":"crossref","first-page":"115927","DOI":"10.1016\/j.jep.2022.115927","article-title":"Stimulation of functional recovery via neurorepair mechanisms by the traditional Japanese Kampo medicine, Ninjin\u2019yoeito, and physical exercise in a rat ischemic stroke model","volume":"302","author":"A Tani","year":"2023","journal-title":"J Ethnopharmacol"},{"key":"pone.0303833.ref049","first-page":"538","article-title":"Mouse models of sarcopenia: classification and evaluation.","volume-title":"Journal of Cachexia, Sarcopenia and Muscle","author":"Xie W qing","year":"2021"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0303833","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T17:39:14Z","timestamp":1716226754000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0303833"}},"subtitle":[],"editor":[{"given":"Andre","family":"van Wijnen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,5,20]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0303833","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,20]]}}}