{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T15:39:00Z","timestamp":1781624340180,"version":"3.54.5"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Immunocompetence reflects the immune system\u2019s capacity to mount effective responses against antigens. Cyclophosphamide (CYP), a chemotherapeutic and experimental immunosuppressive agent, disrupts T-helper (Th)1\/Th2 balance and compromises immune organ integrity. Bioactive peptides derived from the sea cucumber\n                      <jats:italic>Apostichopus japonicus<\/jats:italic>\n                      , which is rich in type I collagen, have shown emerging immunomodulatory potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A collagenase-derived sea cucumber protein hydrolysate (SCPH) was prepared using Clostridium collagenase-I and characterized for amino acid composition and peptide profiles. BALB\/c mice were administered CYP (80 mg\/kg, i.p.) to induce immunosuppression, followed by oral SCPH treatment. Body weight, spleen and thymus indices, leukocyte counts, Th1\/Th2-associated gene expression (IFNG, TBX21, IL4, GATA3), serum cytokines and immunoglobulins, and splenic histology and immunohistochemistry were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CYP treatment induced body weight loss, reduced immune organ indices, altered leukocyte profiles, and disrupted Th1\/Th2-associated markers. SCPH administration partially reversed these changes by restoring spleen and thymus indices, normalizing circulating immune cell levels, upregulating Th1-associated genes (IFNG, TBX21), and downregulating Th2-associated genes (IL4, GATA3). SCPH also increased serum Th1 mediators (IFNG, IgG, IgM) while reducing Th2-associated markers (IL-4, IL-10, IgA, sIgA). Histological and immunohistochemical analyses confirmed improved splenic architecture with elevated T-bet and reduced GATA3 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion\/conclusion<\/jats:title>\n                    <jats:p>These findings indicate that SCPH promotes Th1-biased immune rebalancing in CYP-induced immunosuppressed mice, suggesting its potential as a marine-derived immunonutritional agent. Further mechanistic studies are warranted to explore its therapeutic and translational applications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1758733","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:26:03Z","timestamp":1769491563000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Sea cucumber protein hydrolysate restores the Th1\/Th2 paradigm in cyclophosphamide-induced immunosuppressed mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Nabeel Ahmed","family":"Farooqui","sequence":"first","affiliation":[{"name":"Department of Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ata Ur","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Duke University Medical 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Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleed","family":"Yousuf","sequence":"additional","affiliation":[{"name":"Institute of Cancer Stem Cell, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamina","family":"Alioui","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aamna","family":"Atta","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Abusidu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal","family":"Saleh","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Lab, Bahria University of Health Sciences","place":["Karachi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eslam","family":"Ghaleb","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Clinical Care Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Basic Medical Science, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimra Zafar","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Institute of Cancer Stem Cell, Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Wang","sequence":"additional","affiliation":[{"name":"Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital at Dalian Medical University","place":["Dalian, 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adaptive immune systems in physiological and pathological pregnancy","volume":"12","author":"Weng","year":"2023","journal-title":"Biology"},{"key":"ref5","first-page":"1373186","article-title":"In vitro immunity: an overview of immunocompetent organ-on-chip models","volume-title":"Front Immunol","author":"Morrison","year":"2024"},{"key":"ref6","first-page":"1285052","article-title":"Potential of dietary hemp and cannabinoids to modulate immune response to enhance health and performance in animals: opportunities and challenges","volume-title":"Front Immunol","author":"Hassan","year":"2023"},{"key":"ref7","first-page":"223","article-title":"Th1\/Th2 balance: the hypothesis, its limitations, and implications for health and disease","volume":"8","author":"Kidd","year":"2003","journal-title":"Altern Med Rev"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1086\/317537","article-title":"Type 1\/type 2 immunity in infectious diseases","volume":"32","author":"Spellberg","year":"2001","journal-title":"Clin Infect Dis"},{"key":"ref9","first-page":"17876","article-title":"The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes","volume-title":"Proc Natl Acad Sci","author":"Jenner","year":"2009"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"4557","DOI":"10.1093\/nar\/gkac258","article-title":"The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes","volume":"50","author":"Hertweck","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s40779-025-00660-w","article-title":"Emerging strategies for monkeypox: antigen and antibody applications in diagnostics, vaccines, and treatments","volume":"12","author":"Wang","year":"2025","journal-title":"Mil Med 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sectors","volume":"15","author":"Bhati","year":"2025","journal-title":"Appl Sci"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.3390\/md13074006","article-title":"Marine peptides: bioactivities and applications","volume":"13","author":"Cheung","year":"2015","journal-title":"Mar Drugs"},{"key":"ref21","first-page":"110963","article-title":"Marine collagen and its derivatives: versatile and sustainable bio-resources for healthcare","volume-title":"Mater Sci Eng C","author":"Salvatore","year":"2020"},{"key":"ref22","volume-title":"Innovative thermal and non-thermal processing, bioaccessibility and bioavailability of nutrients and bioactive compounds","author":"Barba","year":"2019"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"11236","DOI":"10.3390\/ijms241411236","article-title":"Glycine: the smallest anti-inflammatory micronutrient","volume":"24","author":"Aguayo-Cer\u00f3n","year":"2023","journal-title":"Int J Mol 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In international conference on future of medicine and biological information engineering (MBIE 2024)","author":"Xie","year":"2024"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"101080","DOI":"10.1016\/j.blre.2023.101080","article-title":"Combining post-transplant cyclophosphamide with antithymocyte globulin for graft-versus-host disease prophylaxis in hematological malignancies","volume":"62","author":"Dul\u00e9ry","year":"2023","journal-title":"Blood Rev"},{"key":"ref39","first-page":"1293","article-title":"Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb\/c mice","volume-title":"Int Immunopharmacol","author":"Huyan","year":"2011"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/BF00205439","article-title":"Effect of low-dose cyclophosphamide therapy on specific and nonspecific T cell-dependent immune responses of spleen cells from mice bearing large MOPC-315 plasmacytomas","volume":"27","author":"Wise","year":"1988","journal-title":"Cancer Immunol Immunother"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1046\/j.1365-2249.1998.00589.x","article-title":"IL-10 and IL-4 co-operate to normalize in vitro IgA production in IgA-deficient (IgAD) patients","volume":"112","author":"Marconi","year":"1998","journal-title":"Clinical Experimental Immunol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"120","DOI":"10.4049\/jimmunol.1302734","article-title":"IL-1\u03b2 promotes the differentiation of polyfunctional human CCR6+ CXCR3+ Th1\/17 cells that are specific for pathogenic and commensal microbes","volume":"193","author":"Duhen","year":"2014","journal-title":"J Immunol"},{"key":"ref43","first-page":"182","article-title":"IL-1 and T helper immune responses","volume-title":"Front Immunol","author":"Santarlasci","year":"2013"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"9","DOI":"10.4049\/jimmunol.1601775","article-title":"Inducing mucosal IgA: a challenge for vaccine adjuvants and delivery systems","volume":"199","author":"Boyaka","year":"2017","journal-title":"J Immunol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1080\/01926230600867743","article-title":"Normal structure, function, and histology of the spleen","volume":"34","author":"Cesta","year":"2006","journal-title":"Toxicol Pathol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1080\/01926230600865523","article-title":"Enhanced histopathology of the spleen","volume":"34","author":"Elmore","year":"2006","journal-title":"Toxicol Pathol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2800","DOI":"10.3390\/ijms26062800","article-title":"Polydatin alleviates cyclophosphamide-induced mouse immunosuppression by promoting splenic lymphocyte proliferation and Thymic T cell development and differentiation","volume":"26","author":"Sun","year":"2025","journal-title":"Int J Mol Sci"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1354794","DOI":"10.3389\/fphar.2024.1354794","article-title":"Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum venetum flowers via enhancing immune response, reducing oxidative stress, and regulating gut microbiota in mice","volume":"15","author":"Zhao","year":"2024","journal-title":"Front Pharmacol"},{"key":"ref49","first-page":"920","article-title":"Severe leptospirosis features in the spleen indicate cellular immunosuppression similar to that found in septic shock","volume-title":"Front Immunol","author":"Duarte-Neto","year":"2019"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1080\/01926230600867750","article-title":"Histopathology of the spleen","volume":"34","author":"Suttie","year":"2006","journal-title":"Toxicol Pathol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1177\/0192623311431467","article-title":"Differentiation of rodent immune and hematopoietic system reactive lesions from neoplasias","volume":"40","author":"Ward","year":"2012","journal-title":"Toxicol Pathol"},{"key":"ref52","first-page":"4067","article-title":"Initial TCR signal strength imprints GATA3 and Tbet expression driving T-helper cell fate decisions","volume-title":"bioRxiv","author":"Al-Aghbar","year":"2024"},{"key":"ref53","first-page":"928018","article-title":"Dissecting the dynamic transcriptional landscape of early T helper cell differentiation into Th1, Th2, and Th1\/2 hybrid cells","volume-title":"Front Immunol","author":"Burt","year":"2022"}],"container-title":["Frontiers in 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