{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:00:23Z","timestamp":1789567223753,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yonsei scholarship","award":["2024-11-1974"],"award-info":[{"award-number":["2024-11-1974"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Cancer cachexia involves progressive skeletal muscle and adipose tissue loss, which is further aggravated by cisplatin chemotherapy via increased systemic inflammation, tissue catabolism, and renal toxicity. The present study aimed to evaluate whether a combination of amaranth protein hydrolysate and Agastache rugosa extract (AKE) could attenuate cisplatin-associated cachexia and nephrotoxicity in CT26 tumor-bearing mice. Methods: Cancer cachexia was induced by subcutaneous CT26 cell inoculation in 6-week-old male BALB\/c mice, followed by a 7-day tumor establishment period. Cisplatin was then administered intraperitoneally, and AKE (125 or 250 mg\/kg\/day) was given daily by oral gavage for 14 days. Results: AKE administration significantly alleviated cisplatin-induced body weight loss and systemic inflammation, accompanied by preservation of skeletal muscle and adipose tissue mass, as well as increased myofiber cross-sectional area and adipocyte size. AKE markedly reduced serum inflammatory cytokines, blood urea nitrogen, and creatinine levels, indicating protection against cisplatin-induced renal injury. Mechanistically, AKE suppressed renal apoptosis through inhibition of mitogen-activated protein kinase signaling. In skeletal muscle, AKE attenuated muscle atrophy by modulating protein turnover pathways, including downregulation of muscle-specific ubiquitin ligases and restoration of Akt\/mTOR and FoxO3a signaling. Furthermore, AKE mitigated adipose tissue wasting by suppressing AMP-activated protein kinase-dependent browning and restoring adipogenic signaling involved in lipid storage and differentiation. Conclusions: These findings demonstrate that AKE confers comprehensive protection against cisplatin-induced cachexia and nephrotoxicity by coordinately preserving muscle and adipose tissue and attenuating renal injury, suggesting its potential as a functional nutritional strategy to alleviate chemotherapy-associated tissue wasting.<\/jats:p>","DOI":"10.3390\/nu18040665","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T07:50:30Z","timestamp":1771401030000},"page":"665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Combination of Amaranth Protein Hydrolysate and Korean Mint Extract Ameliorates Cisplatin-Induced Nephrotoxicity and Cachexia in CT26 Tumor-Bearing BALB\/c Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Junhee","family":"Lee","sequence":"first","affiliation":[{"name":"Graduate Program in Bioindustrial Engineering, Yonsei University, Seoul 03772, Republic of Korea"},{"name":"Health Research Division, DAESANG Wellife Co., Ltd., Seoul 03130, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3473-0404","authenticated-orcid":false,"given":"Yeeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate Program in Bioindustrial Engineering, Yonsei University, Seoul 03772, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2598-6066","authenticated-orcid":false,"given":"Mi-Bo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju Hyun","family":"Park","sequence":"additional","affiliation":[{"name":"Health Research Division, DAESANG Wellife Co., Ltd., Seoul 03130, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8972-6737","authenticated-orcid":false,"given":"Daedong","family":"Kim","sequence":"additional","affiliation":[{"name":"Health Research Division, DAESANG Wellife Co., Ltd., Seoul 03130, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Woo","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Program in Bioindustrial Engineering, Yonsei University, Seoul 03772, Republic of Korea"},{"name":"Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5550-6661","authenticated-orcid":false,"given":"Jae-Kwan","family":"Hwang","sequence":"additional","affiliation":[{"name":"Graduate Program in Bioindustrial Engineering, Yonsei University, Seoul 03772, Republic of Korea"},{"name":"Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.3390\/cancers3011351","article-title":"Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects","volume":"3","author":"Florea","year":"2011","journal-title":"Cancers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/sj.ki.5002786","article-title":"Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies","volume":"73","author":"Pabla","year":"2008","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12929-019-0518-9","article-title":"Molecular mechanisms of cisplatin-induced nephrotoxicity: A balance on the knife edge between renoprotection and tumor toxicity","volume":"26","author":"Volarevic","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1017\/S0029665118000186","article-title":"Barriers to cancer nutrition therapy: Excess catabolism of muscle and adipose tissues induced by tumour products and chemotherapy","volume":"77","author":"Schiessel","year":"2018","journal-title":"Proc. Nutr. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e13817","DOI":"10.1002\/jcsm.13817","article-title":"Cisplatin-Induced Muscle Wasting and Atrophy: Molecular Mechanism and Potential Therapeutic Interventions","volume":"16","author":"Huang","year":"2025","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Marceca, G.P., Nigita, G., Calore, F., and Croce, C.M. (2020). MicroRNAs in Skeletal Muscle and Hints on Their Potential Role in Muscle Wasting During Cancer Cachexia. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.607196"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biochi.2024.03.016","article-title":"The impact of chemotherapy on adipose tissue remodeling: The molecular players involved in this tissue wasting","volume":"223","author":"Barbosa","year":"2024","journal-title":"Biochimie"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sun, X., Feng, X., Wu, X., Lu, Y., Chen, K., and Ye, Y. (2020). Fat Wasting Is Damaging: Role of Adipose Tissue in Cancer-Associated Cachexia. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00033"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13045-023-01454-0","article-title":"Cancer cachexia: Molecular mechanisms and treatment strategies","volume":"16","author":"Setiawan","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1080\/10942912.2024.2304266","article-title":"An overview of the nutritional and therapeutic properties of amaranth","volume":"27","author":"Sattar","year":"2024","journal-title":"Int. J. Food Prop."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Toimbayeva, D., Saduakhasova, S., Kamanova, S., Kiykbay, A., Tazhina, S., Temirova, I., Muratkhan, M., Shaimenova, B., Murat, L., and Khamitova, D. (2025). Prospects for the Use of Amaranth Grain in the Production of Functional and Specialized Food Products. Foods, 14.","DOI":"10.3390\/foods14091603"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3746\/pnf.2024.29.2.154","article-title":"Korean Mint (Agastache rugosa) Extract and Its Bioactive Compound Tilianin Alleviate Muscle Atrophy via the PI3K\/Akt\/FoxO3 Pathway in C2C12 Myotubes","volume":"29","author":"Woo","year":"2024","journal-title":"Prev. Nutr. Food Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.36740\/WLek202312115","article-title":"The Potential Renoprotective Effect of Tilianin in Renal Ischemia Reperfusion Injury in Male Rat Model","volume":"76","author":"Altimimi","year":"2023","journal-title":"Wiad. Lek."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Perse, M. (2021). Cisplatin Mouse Models: Treatment, Toxicity and Translatability. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101406"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ferrara, M., Samaden, M., Ruggieri, E., and V\u00e9n\u00e9reau, E. (2022). Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.960341"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1097\/CM9.0000000000002846","article-title":"Cancer cachexia: Focus on cachexia factors and inter-organ communication","volume":"137","author":"Wang","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e191934","DOI":"10.1172\/JCI191934","article-title":"Cancer therapy and cachexia","volume":"135","author":"Thakir","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1016\/j.clnu.2021.02.005","article-title":"ESPEN practical guideline: Clinical Nutrition in cancer","volume":"40","author":"Muscaritoli","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ragni, M., Fornelli, C., Nisoli, E., and Penna, F. (2022). Amino acids in cancer and cachexia: An integrated view. Cancers, 14.","DOI":"10.3390\/cancers14225691"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dingemans, A.M., van Walree, N., Schramel, F., Soud, M.Y.E., Baltru\u0161kevi\u010dien\u0117, E., Lybaert, W., Veldhorst, M., van den Berg, C., and Kaasa, S. (2023). High protein oral nutritional supplements enable the majority of Cancer patients to meet protein intake recommendations during systemic Anti-cancer treatment: A randomised controlled parallel-group study. Nutrients, 15.","DOI":"10.3390\/nu15245030"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ayala-Ni\u00f1o, A., Rodr\u00edguez-Serrano, G.M., Gonz\u00e1lez-Olivares, L.G., Contreras-L\u00f3pez, E., Regal-L\u00f3pez, P., and Cepeda-Saez, A. (2019). Sequence identification of bioactive peptides from amaranth seed proteins (Amaranthus hypochondriacus spp.). Molecules, 24.","DOI":"10.3390\/molecules24173033"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100165","DOI":"10.1016\/j.fochx.2021.100165","article-title":"Identification and characterization of cholesterol esterase and lipase inhibitory peptides from amaranth protein hydrolysates","volume":"12","author":"Ajayi","year":"2021","journal-title":"Food Chem. X"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/sfp2.1002","article-title":"Structural, nutritional, and functional properties of amaranth protein and its application in the food industry: A review","volume":"1","author":"Zhang","year":"2023","journal-title":"Sustain. Food Proteins"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"112405","DOI":"10.1016\/j.foodres.2022.112405","article-title":"Amaranth proteins and peptides: Biological properties and food uses","volume":"164","author":"Zhu","year":"2023","journal-title":"Food Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liu, Z., Guan, C., Li, C., Zhang, N., Yang, C., Xu, L., Zhou, B., Zhao, L., Luan, H., and Man, X. (2022). Tilianin reduces apoptosis via the ERK\/EGR1\/BCL2L1 pathway in ischemia\/reperfusion-induced acute kidney injury mice. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.862584"},{"key":"ref_28","first-page":"170","article-title":"Markers of renal function tests","volume":"2","author":"Gowda","year":"2010","journal-title":"N. Am. J. Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"F264","DOI":"10.1152\/ajprenal.00045.2019","article-title":"Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model","volume":"317","author":"Tanimura","year":"2019","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17105","DOI":"10.1038\/nrdp.2017.105","article-title":"Cancer-associated cachexia","volume":"4","author":"Baracos","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1038\/s41401-021-00620-9","article-title":"Natural products: Potential treatments for cisplatin-induced nephrotoxicity","volume":"42","author":"Fang","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_32","first-page":"1","article-title":"Platinum-induced muscle wasting in cancer chemotherapy: Mechanisms and potential targets for therapeutic intervention","volume":"208","author":"Ferreira","year":"2018","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lfs.2016.11.033","article-title":"TNF-alpha and cancer cachexia: Molecular insights and clinical implications","volume":"170","author":"Patel","year":"2017","journal-title":"Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Conte, E., Bresciani, E., Rizzi, L., Cappellari, O., De Luca, A., Torsello, A., and Liantonio, A. (2020). Cisplatin-induced skeletal muscle dysfunction: Mechanisms and counteracting therapeutic strategies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041242"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Webster, J.M., Kempen, L., Hardy, R.S., and Langen, R.C.J. (2020). Inflammation and Skeletal Muscle Wasting During Cachexia. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.597675"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.freeradbiomed.2015.12.031","article-title":"The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass","volume":"98","author":"Rom","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1152\/physiol.00024.2006","article-title":"The mTOR pathway in the control of protein synthesis","volume":"21","author":"Wang","year":"2006","journal-title":"Physiology"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhang, H., Chi, M., Chen, L., Sun, X., Wan, L., Yang, Q., and Guo, C. (2020). Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1\/Akt\/FoxO Pathway. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.598166"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4363","DOI":"10.1002\/ptr.7132","article-title":"Daidzein alleviates cisplatin-induced muscle atrophy by regulating Glut4\/AMPK\/FoxO pathway","volume":"35","author":"Zhang","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/jcp.26811","article-title":"Adipose tissue dysfunction in cancer cachexia","volume":"234","author":"Daas","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jung, T.W., Park, T., Park, J., Kim, U., Je, H.D., Kim, H.D., Cho, S.W., Abd El-Aty, A.M., Song, J.H., and Kim, H.C. (2019). Phosphatidylcholine causes adipocyte-specific lipolysis and apoptosis in adipose and muscle tissues. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214760"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5280","DOI":"10.3390\/nu6115280","article-title":"Evidence and mechanisms of fat depletion in cancer","volume":"6","author":"Ebadi","year":"2014","journal-title":"Nutrients"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nrm2066","article-title":"Adipocyte differentiation from the inside out","volume":"7","author":"Rosen","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/4\/665\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T07:57:43Z","timestamp":1771401463000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/4\/665"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["nu18040665"],"URL":"https:\/\/doi.org\/10.3390\/nu18040665","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]}}}