{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T22:47:06Z","timestamp":1765234026558,"version":"build-2065373602"},"reference-count":83,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002911","name":"Universidad Complutense de Madrid","doi-asserted-by":"publisher","award":["PR12\/24-31551"],"award-info":[{"award-number":["PR12\/24-31551"]}],"id":[{"id":"10.13039\/501100002911","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The colonic epithelium renews rapidly and must balance proliferation with apoptosis to preserve barrier integrity. We investigated whether grape antioxidant dietary fiber (GADF), a grape pomace-derived dietary fiber matrix naturally rich in high molecular weight non-extractable polyphenols, modulates barrier integrity, through proliferation\/cell cycle and apoptosis. To gain mechanistic insight, we examined the role of heat-shock proteins (Hsps), and AMP-activated protein kinase (AMPK)\u2013mTOR\u2013lipid-metabolism signaling in healthy proximal colon. Male Wistar rats received either a cellulose-based control diet or an isoenergetic diet where cellulose was replaced with 5% GADF for four weeks. Morphometric analysis, immunohistochemistry, Western blotting, TUNEL, and caspase activity assays quantified cell cycle, apoptotic, Hsps, and metabolic pathways. GADF strengthened the epithelial barrier, increasing goblet cells, occludin, and ZO-1, while reducing crypt depth. Proliferation was suppressed, as indicated by reduced PCNA, cyclins E and D1, and higher p-p53Ser392, p21Cip1\/Waf1, and p27Kip1 levels, consistent with G1 arrest. Apoptosis was attenuated, with increased mitochondrial Bcl-2\/Bax and Bcl-xL\/Bax ratios, lower cytosolic cytochrome c and apoptosis-inducing factor (AIF), and reduced caspase-9 and caspase-3 activities. Hsp27, but not Hsp70, was selectively induced. GADF activated AMPK and p-Raptor, enhanced ACC1 phosphorylation and CPT1, and supported a shift toward fatty acid \u03b2-oxidation. Correlation analysis revealed a strong association between Hsp27 and p-p53Ser392, suggesting potential links between barrier proteins and metabolic pathways. In conclusion, GADF preserves barrier integrity and redirects metabolism via AMPK\u2013Hsp27 signaling, thereby promoting colonic homeostasis. These findings highlight grape pomace as a sustainable source of functional ingredients for nutritional strategies to reinforce epithelial defenses and reduce disease risk.<\/jats:p>","DOI":"10.3390\/ijms262110564","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"10564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sustainable Grape Antioxidant Dietary Fiber Preserves Proximal Colonic Homeostasis via Hsp27 and AMPK Signaling"],"prefix":"10.3390","volume":"26","author":[{"given":"Paula","family":"Ortega-Men\u00e9ndez","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Hern\u00e1ndez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"},{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Hospital Cl\u00ednico San Carlos, IdISSC, c\/Prof. Mart\u00edn Lagos Street, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9103-5991","authenticated-orcid":false,"given":"Silvina Rosa","family":"Drago","sequence":"additional","affiliation":[{"name":"Institute of Food Technology, National Scientific and Technical Research Council (CONICET), Faculty of Chemical Engineering, National University of the Littoral (FIQ-UNL), 1\u00ba de Mayo 3250, Santa Fe 3000, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9370-6314","authenticated-orcid":false,"given":"Carlos","family":"Guill\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Complutense University of Madrid, IdISSC, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-4558","authenticated-orcid":false,"given":"Jara","family":"P\u00e9rez-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jos\u00e9 Antonio Nov\u00e1is 10, 28040 Madrid, Spain"},{"name":"CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ISCIII), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5056-6489","authenticated-orcid":false,"given":"Dulcenombre","family":"G\u00f3mez-Garre","sequence":"additional","affiliation":[{"name":"Microbiota and Vascular Biology Laboratory, IdISSC, c\/Prof. Mart\u00edn Lagos Street, 28040 Madrid, Spain"},{"name":"Biomedical Research Networking Center in Cardiovascular Diseases (CIBERCV), Monforte de Lemos Avenue 3\u20135, 28029 Madrid, Spain"},{"name":"Department of Physiology, Faculty of Medicine, Complutense University of Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0187-707X","authenticated-orcid":false,"given":"Luis","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2160-5175","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Azcutia","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"},{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Hospital Cl\u00ednico San Carlos, IdISSC, c\/Prof. Mart\u00edn Lagos Street, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-9149","authenticated-orcid":false,"given":"Mar\u00eda Elvira","family":"L\u00f3pez-Oliva","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"},{"name":"Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, Hospital Cl\u00ednico San Carlos, IdISSC, c\/Prof. Mart\u00edn Lagos Street, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1177\/0300985814559404","article-title":"Epithelial Cell Shedding and Barrier Function: A Matter of Life and Death at the Small Intestinal Villus Tip","volume":"52","author":"Williams","year":"2015","journal-title":"Vet. 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