{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T07:02:31Z","timestamp":1767769351400,"version":"3.48.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Periplaneta americana<\/jats:italic>\n                      L\n                      <jats:italic>.<\/jats:italic>\n                      is one of the most famous traditional Chinese medicines (TCMs)\n                      <jats:italic>,<\/jats:italic>\n                      and CII-3 is the major bioactive extract of\n                      <jats:italic>Periplaneta americana<\/jats:italic>\n                      L. In recent years, CII-3 has gradually attracted the attention of researchers for its powerful capacity for treating immunocompromised diseases. However, systematical chemical composition investigation and mechanisms on immunomodulation of CII-3 have not been thoroughly scrutinized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The chemical ingredients of CII-3 were determined by ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF\/MS), and immune-enhancing mechanisms and active constituents were investigated by integration of metabolomics with network pharmacology and molecular docking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 25 components were identified in the aqueous extract of CII-3, among which 10 were unambiguously confirmed by comparison with reference standards. In immunosuppressed rats, oral administration of CII-3 normalized biochemical profiles by promoting the secretion of immune-related cytokines (IL-2, IL-6) and immunoglobulins (IgG, IgM), significantly improving immune organ indices, and alleviating pathological lesions in the thymus and spleen. Furthermore, CII-3 stimulation attenuated CTX-induced upregulation of IL-6 mRNA levels and concurrently enhanced IL-2 mRNA expression in these two immune organs. Based on metabolomics analysis, 27 differential metabolites along with 7 crucial metabolic pathways including starch and sucrose metabolism, arginine biosynthesis, porphyrin and chlorophyll metabolism, nicotinate and nicotinamide metabolism, steroid biosynthesis, pyrimidine metabolism and tryptophan metabolism were regulated after CII-3 treatment, suggesting that CII-3 has the potential to target these metabolites and key pathways to improve immunosuppression. Nitric oxide synthase 1 (NOS1), nitric oxide synthase 3 (NOS3), acetylcholinesterase (ACHE), cluster of differentiation 38 (CD38) and poly (ADP-ribose) polymerase 1 (PARP1) were considered as the pivotal targets, and ginsenine, cyclo (Tyr-Asp), guanosine, tryptophan and inosine were deemed potential active components of CII-3 in alleviating immunosuppression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The proposed approach provides a valuable evidence for demonstrating the material basis of CII-3. The results obtained in the present study elucidated that the potential immunomodulatory activity of CII-3 might be closely associated with these crucial targets, which can modulate the levels of major metabolites through multiple metabolic pathways, thus ameliorating immunosuppression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2025.1718560","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:59:18Z","timestamp":1767769158000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the immunomodulatory mechanisms of Periplaneta americana L. extract CII-3: insight from integrated metabolomics and network pharmacology"],"prefix":"10.3389","volume":"13","author":[{"given":"Yilin","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingxiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianqian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiali","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2743","DOI":"10.1016\/j.celrep.2017.05.093","article-title":"Lanosterol modulates TLR4-mediated innate immune responses in macrophages","volume":"19","author":"Araldi","year":"2017","journal-title":"Cell Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.plaphy.2010.12.008","article-title":"Nicotinamide metabolism in ferns: formation of nicotinic acid glucoside","volume":"49","author":"Ashihara","year":"2011","journal-title":"Plant Physiol. 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