{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:11:25Z","timestamp":1784826685937,"version":"3.55.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"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>Background<\/jats:title>\n                    <jats:p>\n                      Acute hypoxic exposure combined with exhaustive exercise can impair exercise performance and induce metabolic, inflammatory, oxidative, and tissue stress. Cycloastragenol, a bioactive constituent of\n                      <jats:italic>Astragalus membranaceus<\/jats:italic>\n                      , has shown antioxidant and tissue-protective potential, but its role in acute hypoxic exercise stress remains unclear. This study investigated whether cycloastragenol pretreatment attenuates fatigue- and injury-related responses in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A combined exploratory network pharmacology and animal experimental approach was used. Eighty-four male C57BL\/6\u202fJ mice were randomly assigned to seven groups: blank control, model control (MC), normoxic exercise,\n                      <jats:italic>Rhodiola rosea<\/jats:italic>\n                      positive control (300\u202fmg\/kg\/day), and low-, medium-, and high-dose cycloastragenol groups (25, 50, and 100\u202fmg\/kg\/day). Pretreatments were administered by oral gavage once daily for 40\u202fdays. The MC, positive-control, and cycloastragenol groups then underwent continuous 24-h simulated hypobaric hypoxia equivalent to 5,000\u202fm, followed by treadmill running to exhaustion. Outcomes included exhaustion time, serum biochemical and inflammatory markers, gastrocnemius ATPase activities, representative histopathology, and selected protein-expression endpoints. Data were analyzed using one-way ANOVA with Dunnett\u2019s test, eta squared, and Cohen\u2019s\n                      <jats:italic>d<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network pharmacology identified 116 overlapping targets and suggested HIF-1, PI3K-Akt, FoxO, and IL-17 signaling as hypothesis-generating pathways. Compared with MC, high-dose cycloastragenol prolonged exhaustion time (133.67\u202f\u00b1\u202f7.45 vs. 96.92\u202f\u00b1\u202f9.42\u202fmin;\n                      <jats:italic>d<\/jats:italic>\n                      \u202f=\u202f+4.33;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), reduced BUN (16.14\u202f\u00b1\u202f1.21 vs. 23.38\u202f\u00b1\u202f1.61\u202fmmol\/L;\n                      <jats:italic>d<\/jats:italic>\n                      \u202f=\u202f\u22125.09;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), lactate (7.72\u202f\u00b1\u202f1.77 vs. 16.27\u202f\u00b1\u202f2.62\u202fmmol\/L;\n                      <jats:italic>d<\/jats:italic>\n                      \u202f=\u202f\u22123.82;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), MDA (1.08\u202f\u00b1\u202f0.07 vs. 1.20\u202f\u00b1\u202f0.10\u202fnmol\/mg;\n                      <jats:italic>d<\/jats:italic>\n                      \u202f=\u202f\u22121.41;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.01), IL-6 (14.92\u202f\u00b1\u202f1.00 vs. 28.69\u202f\u00b1\u202f1.41\u202fpg.\/mL;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), and TNF-\u03b1 (51.31\u202f\u00b1\u202f2.18 vs. 114.93\u202f\u00b1\u202f1.84\u202fng\/mL;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001), while increasing T-SOD activity and Na\u202f+\u202f-K\u202f+\u202f-ATPase activity. Representative HE images and Western blot results suggested qualitative tissue protection and modulation of HIF-1alpha, FoxO1, Nrf2, and HO-1 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Cycloastragenol pretreatment was associated with improved tolerance to acute hypoxic exhaustive exercise and attenuation of metabolic, inflammatory, oxidative, and tissue-related responses in mice. Direct hepatic glycogen, muscle glycogen, and blood glucose endpoints were not measured; further mechanistic and translational studies are needed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1856961","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:42:58Z","timestamp":1784824978000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cycloastragenol improves tolerance to acute hypoxic exhaustive exercise stress in mice: integrated network pharmacology and experimental evidence"],"prefix":"10.3389","volume":"13","author":[{"given":"Dan","family":"Liu","sequence":"first","affiliation":[{"name":"Southwest Jiaotong University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Henan University","place":["Kaifeng, 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