{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T20:08:35Z","timestamp":1782763715160,"version":"3.54.5"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,11]],"date-time":"2016-04-11T00:00:00Z","timestamp":1460332800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,11]],"date-time":"2016-04-11T00:00:00Z","timestamp":1460332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. <jats:italic>Citrus unshiu<\/jats:italic> peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB\/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an <jats:italic>in vitro<\/jats:italic> experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss.<\/jats:p>","DOI":"10.1038\/srep24214","type":"journal-article","created":{"date-parts":[[2016,4,11]],"date-time":"2016-04-11T09:50:02Z","timestamp":1460368202000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Citrus unshiu peel extract alleviates cancer-induced weight loss in mice bearing CT-26 adenocarcinoma"],"prefix":"10.1038","volume":"6","author":[{"given":"Aeyung","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minju","family":"Im","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Jung","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Yeul","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,11]]},"reference":[{"key":"BFsrep24214_CR1","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.clnu.2008.06.013","volume":"27","author":"WJ Evans","year":"2008","unstructured":"Evans, W. J. et al. Cachexia: a new definition. Clin Nutr 27, 793\u2013799 (2008).","journal-title":"Clin Nutr"},{"key":"BFsrep24214_CR2","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1152\/physrev.00016.2008","volume":"89","author":"MJ Tisdale","year":"2009","unstructured":"Tisdale, M. J. Mechanisms of cancer cachexia. Physiol Rev 89, 381\u2013410 (2009).","journal-title":"Physiol Rev"},{"key":"BFsrep24214_CR3","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1093\/ajcn\/83.6.1345","volume":"83","author":"KC Fearon","year":"2006","unstructured":"Fearon, K. C., Voss, A. C., Hustead, D. S. & Cancer Cachexia Study, G. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr 83, 1345\u20131350 (2006).","journal-title":"Am J Clin Nutr"},{"key":"BFsrep24214_CR4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.4251\/wjgo.v7.i4.17","volume":"7","author":"T Aoyagi","year":"2015","unstructured":"Aoyagi, T., Terracina, K. P., Raza, A., Matsubara, H. & Takabe, K. Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol 7, 17\u201329 (2015).","journal-title":"World J Gastrointest Oncol"},{"key":"BFsrep24214_CR5","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.pan.2014.11.006","volume":"15","author":"I Ozola Zalite","year":"2015","unstructured":"Ozola Zalite, I. et al. Influence of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma: a systematic review. Pancreatology 15, 19\u201324 (2015).","journal-title":"Pancreatology"},{"key":"BFsrep24214_CR6","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","volume":"16","author":"KC Fearon","year":"2012","unstructured":"Fearon, K. C., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16, 153\u2013166 (2012).","journal-title":"Cell Metab"},{"key":"BFsrep24214_CR7","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1172\/JCI200420174","volume":"114","author":"S Acharyya","year":"2004","unstructured":"Acharyya, S. et al. Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest 114, 370\u2013378 (2004).","journal-title":"J Clin Invest"},{"key":"BFsrep24214_CR8","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1242\/dmm.010389","volume":"6","author":"P Bonaldo","year":"2013","unstructured":"Bonaldo, P. & Sandri, M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6, 25\u201339 (2013).","journal-title":"Dis Model Mech"},{"key":"BFsrep24214_CR9","doi-asserted-by":"publisher","first-page":"e13262","DOI":"10.1371\/journal.pone.0013262","volume":"5","author":"S Bhatnagar","year":"2010","unstructured":"Bhatnagar, S. et al. Tumor necrosis factor-alpha regulates distinct molecular pathways and gene networks in cultured skeletal muscle cells. Plos One 5, e13262 (2010).","journal-title":"Plos One"},{"key":"BFsrep24214_CR10","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.phrs.2015.05.010","volume":"99","author":"V Dutt","year":"2015","unstructured":"Dutt, V., Gupta, S., Dabur, R., Injeti, E. & Mittal, A. Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action. Pharmacol Res 99, 86\u2013100 (2015).","journal-title":"Pharmacol Res"},{"key":"BFsrep24214_CR11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s13539-011-0049-z","volume":"3","author":"S Busquets","year":"2012","unstructured":"Busquets, S. et al. Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. J Cachexia Sarcopenia Muscle 3, 37\u201343 (2012).","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"BFsrep24214_CR12","doi-asserted-by":"publisher","first-page":"e102436","DOI":"10.1371\/journal.pone.0102436","volume":"9","author":"K Ando","year":"2014","unstructured":"Ando, K. et al. Tocilizumab, a proposed therapy for the cachexia of Interleukin6-expressing lung cancer. Plos One 9, e102436 (2014).","journal-title":"Plos One"},{"key":"BFsrep24214_CR13","doi-asserted-by":"publisher","first-page":"E410","DOI":"10.1152\/ajpendo.00039.2012","volume":"303","author":"A Bonetto","year":"2012","unstructured":"Bonetto, A. et al. JAK\/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab 303, E410\u2013421 (2012).","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFsrep24214_CR14","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1517\/14656560902960162","volume":"10","author":"C Madeddu","year":"2009","unstructured":"Madeddu, C., Maccio, A., Panzone, F., Tanca, F. M. & Mantovani, G. Medroxyprogesterone acetate in the management of cancer cachexia. Expert Opin Pharmacother 10, 1359\u20131366 (2009).","journal-title":"Expert Opin Pharmacother"},{"key":"BFsrep24214_CR15","doi-asserted-by":"publisher","first-page":"72","DOI":"10.3322\/canjclin.52.2.72","volume":"52","author":"A Inui","year":"2002","unstructured":"Inui, A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin 52, 72\u201391 (2002).","journal-title":"CA Cancer J Clin"},{"key":"BFsrep24214_CR16","doi-asserted-by":"publisher","first-page":"129","DOI":"10.4103\/0973-1075.73644","volume":"16","author":"E Tazi","year":"2010","unstructured":"Tazi, E. & Errihani, H. Treatment of cachexia in oncology. Indian J Palliat Care 16, 129\u2013137 (2010).","journal-title":"Indian J Palliat Care"},{"key":"BFsrep24214_CR17","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1007\/s00535-013-0787-0","volume":"48","author":"H Suzuki","year":"2013","unstructured":"Suzuki, H., Asakawa, A., Amitani, H., Nakamura, N. & Inui, A. Cancer cachexia\u2013pathophysiology and management. J Gastroenterol 48, 574\u2013594 (2013).","journal-title":"J Gastroenterol"},{"key":"BFsrep24214_CR18","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1016\/j.ejca.2011.06.048","volume":"48","author":"H Wang","year":"2012","unstructured":"Wang, H., Chan, Y. L., Li, T. L. & Wu, C. J. Improving cachectic symptoms and immune strength of tumour-bearing mice in chemotherapy by a combination of Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang. Eur J Cancer 48, 1074\u20131084 (2012).","journal-title":"Eur J Cancer"},{"key":"BFsrep24214_CR19","doi-asserted-by":"publisher","first-page":"976926","DOI":"10.1155\/2012\/976926","volume":"2012","author":"S Yae","year":"2012","unstructured":"Yae, S. et al. Hochuekkito (TJ-41), a Kampo Formula, Ameliorates Cachexia Induced by Colon 26 Adenocarcinoma in Mice. Evid Based Complement Alternat Med 2012, 976926 (2012).","journal-title":"Evid Based Complement Alternat Med"},{"key":"BFsrep24214_CR20","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.3168\/jds.2013-7390","volume":"97","author":"KY Min","year":"2014","unstructured":"Min, K. Y., Kim, H. J., Lee, K. A., Kim, K. T. & Paik, H. D. Antimicrobial activity of acid-hydrolyzed Citrus unshiu peel extract in milk. J Dairy Sci 97, 1955\u20131960 (2014).","journal-title":"J Dairy Sci"},{"key":"BFsrep24214_CR21","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1142\/S0192415X12500462","volume":"40","author":"YC Oh","year":"2012","unstructured":"Oh, Y. C. et al. Anti-inflammatory effect of Citrus Unshiu peel in LPS-stimulated RAW 264.7 macrophage cells. Am J Chin Med 40, 611\u2013629 (2012).","journal-title":"Am J Chin Med"},{"key":"BFsrep24214_CR22","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.jnutbio.2011.12.009","volume":"24","author":"HJ Park","year":"2013","unstructured":"Park, H. J. et al. Citrus unshiu peel extract ameliorates hyperglycemia and hepatic steatosis by altering inflammation and hepatic glucose- and lipid-regulating enzymes in db\/db mice. J Nutr Biochem 24, 419\u2013427 (2013).","journal-title":"J Nutr Biochem"},{"key":"BFsrep24214_CR23","doi-asserted-by":"publisher","first-page":"E469","DOI":"10.1152\/ajpendo.00204.2014","volume":"307","author":"SC Bodine","year":"2014","unstructured":"Bodine, S. C. & Baehr, L. M. Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx\/atrogin-1. Am J Physiol Endocrinol Metab 307, E469\u2013484 (2014).","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFsrep24214_CR24","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1042\/BJ20112024","volume":"446","author":"S Lokireddy","year":"2012","unstructured":"Lokireddy, S. et al. Myostatin is a novel tumoral factor that induces cancer cachexia. Biochem J 446, 23\u201336 (2012).","journal-title":"Biochem J"},{"key":"BFsrep24214_CR25","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s13539-011-0035-5","volume":"2","author":"Y Elkina","year":"2011","unstructured":"Elkina, Y., von Haehling, S., Anker, S. D. & Springer, J. The role of myostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle 2, 143\u2013151 (2011).","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"BFsrep24214_CR26","doi-asserted-by":"publisher","first-page":"7087","DOI":"10.1074\/jbc.M610378200","volume":"282","author":"HL Eley","year":"2007","unstructured":"Eley, H. L. & Tisdale, M. J. Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation. J Biol Chem 282, 7087\u20137097 (2007).","journal-title":"J Biol Chem"},{"key":"BFsrep24214_CR27","doi-asserted-by":"publisher","first-page":"227S","DOI":"10.1093\/jn\/129.1.227S","volume":"129","author":"SH Lecker","year":"1999","unstructured":"Lecker, S. H., Solomon, V., Mitch, W. E. & Goldberg, A. L. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr 129, 227S\u2013237S (1999).","journal-title":"J Nutr"},{"key":"BFsrep24214_CR28","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1142\/S0192415X05002680","volume":"33","author":"M Suzuki","year":"2005","unstructured":"Suzuki, M. et al. Anti-hepatitis C virus effect of citrus unshiu peel and its active ingredient nobiletin. Am J Chin Med 33, 87\u201394 (2005).","journal-title":"Am J Chin Med"},{"key":"BFsrep24214_CR29","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1080\/14756360600988989","volume":"22","author":"C Zhang","year":"2007","unstructured":"Zhang, C. et al. Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts. J Enzyme Inhib Med Chem 22, 91\u201398 (2007).","journal-title":"J Enzyme Inhib Med Chem"},{"key":"BFsrep24214_CR30","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.jep.2010.07.018","volume":"133","author":"S Lee","year":"2011","unstructured":"Lee, S. et al. Extracts from Citrus unshiu promote immune-mediated inhibition of tumor growth in a murine renal cell carcinoma model. J Ethnopharmacol 133, 973\u2013979 (2011).","journal-title":"J Ethnopharmacol"},{"key":"BFsrep24214_CR31","doi-asserted-by":"publisher","first-page":"783","DOI":"10.3390\/molecules19010783","volume":"19","author":"DW Lim","year":"2014","unstructured":"Lim, D. W., Lee, Y. & Kim, Y. T. Preventive effects of Citrus unshiu peel extracts on bone and lipid metabolism in OVX rats. Molecules 19, 783\u2013794 (2014).","journal-title":"Molecules"},{"key":"BFsrep24214_CR32","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.1016\/j.fct.2012.07.007","volume":"50","author":"SK Ha","year":"2012","unstructured":"Ha, S. K., Park, H. Y., Eom, H., Kim, Y. & Choi, I. Narirutin fraction from citrus peels attenuates LPS-stimnulated inflammtory response through inhibition of NF-\u03baB and MAPKs activation. Food Chem Toxicol 50, 3498\u20133504 (2012).","journal-title":"Food Chem Toxicol"},{"key":"BFsrep24214_CR33","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.fct.2014.06.014","volume":"71","author":"SC Ho","year":"2014","unstructured":"Ho, S. C. & Kuo, C. T. Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti-neuroinflammatory capacity of tangerine peel (Citri reticulatae pericarpium). Food Chem Toxicol 71, 176\u2013182 (2014).","journal-title":"Food Chem Toxicol"},{"key":"BFsrep24214_CR34","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s11010-007-9539-x","volume":"305","author":"IY Choi","year":"2007","unstructured":"Choi, I. Y. et al. Hesperidin inhibits expression of hypoxia inducible factor alpha and inflammatory cytokine production from mast cells. Mol Cell Biochem 305, 153\u2013161 (2007).","journal-title":"Mol Cell Biochem"},{"key":"BFsrep24214_CR35","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1111\/j.1476-5381.2011.01243.x","volume":"163","author":"H Jeong","year":"2011","unstructured":"Jeong, H. et al. Hesperidin promotes MyoD-induced myogenic differentiation in vitro and in vivo . Br J Pharmacol 163, 598\u2013608 (2011).","journal-title":"Br J Pharmacol"},{"key":"BFsrep24214_CR36","doi-asserted-by":"crossref","first-page":"7758","DOI":"10.18632\/oncotarget.3483","volume":"6","author":"H Wang","year":"2015","unstructured":"Wang, H. et al. Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium. Oncotarget 6, 7758\u20137773 (2015).","journal-title":"Oncotarget"},{"key":"BFsrep24214_CR37","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1016\/j.intimp.2008.08.008","volume":"8","author":"Y Zhang","year":"2008","unstructured":"Zhang, Y. et al. Sophocarpine and matrine inhibit the production of TNF-alpha and IL-6 in murine macrophages and prevent cachexia-related symptoms induced by colon 26 adenocarcinoma in mice. Int Immunopharmacol 8, 1767\u20131772 (2008).","journal-title":"Int Immunopharmacol"},{"key":"BFsrep24214_CR38","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/ijc.10338","volume":"99","author":"N Iizuka","year":"2002","unstructured":"Iizuka, N. et al. Anticachectic effects of the natural herb Coptidis rhizoma and berberine on mice bearing colon 26\/clone 20 adenocarcinoma. Int J Cancer 99, 286\u2013291 (2002).","journal-title":"Int J Cancer"},{"key":"BFsrep24214_CR39","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.3892\/or.2015.4527","volume":"35","author":"A Kim","year":"2016","unstructured":"Kim, A., Im, M. & Ma, J. Y. Sosiho-tang ameliorates cachexia-related symptoms in mice bearing colon 26 adenocarcinoma by reducing systemic inflammation and muscle loss. Oncol Rep 35, 1841\u20131850 (2016).","journal-title":"Oncol Rep"},{"key":"BFsrep24214_CR40","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1142\/S0192415X1550055X","volume":"43","author":"YC Oh","year":"2015","unstructured":"Oh, Y. C. et al. Inhibitory effects of Epimedium Herb on the inflammatory response in vitro and in vivo . Am J Chin Med 43, 953\u2013968 (2015).","journal-title":"Am J Chin Med"},{"key":"BFsrep24214_CR41","doi-asserted-by":"publisher","first-page":"e98703","DOI":"10.1371\/journal.pone.0098703","volume":"9","author":"A Kim","year":"2014","unstructured":"Kim, A., Im, M., Yim, N. H., Kim, T. & Ma, J. Y. A novel herbal medicine, KIOM-C, induces autophagic and apoptotic cell death mediated by activation of JNK and reactive oxygen species in HT1080 human fibrosarcoma cells. Plos One 9, e98703 (2014).","journal-title":"Plos One"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep24214.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24214","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24214.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T03:45:28Z","timestamp":1672890328000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep24214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,11]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,26]]}},"alternative-id":["BFsrep24214"],"URL":"https:\/\/doi.org\/10.1038\/srep24214","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,11]]},"assertion":[{"value":"18 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24214"}}