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This leads to inflammation, activation of the unfolded protein response (UPR), insulin resistance, and cell death. Herbal medicines such as Uncaria tomentosa (UT) have shown potential as complementary treatments for T2D due to their protective effects. Purpose and study design: This study investigates the effect of UT aqueous extract on UPR and insulin resistance induced by PA in C2C12 myotubes. C2C12 myoblasts were grown in DMEM medium supplemented with 10% fetal bovine serum and differentiated into myotubes with 3.5% horse serum. The myotubes were incubated with 100 or 500 \u03bcM PA, 2\u2013100 \u00b5M thapsigargin (Tg) or tunicamycin (Tn), in the presence or absence of 250 \u03bcg\/mL UT extract or 100 \u00b5M TUDCA, for 2 or 6 h. The myotubes treated with UT extract for 6 h, after the incubation with 20 \u00b5M Tg, Tn or 500 \u00b5M PA, presented reduction in the expression of UPR-related genes ATF4 and CHOP by approximately 1.5-fold, and increased by 3-fold the expression of IRS-1, an insulin-signaling protein, when compared to myotubes incubated with only 20 \u00b5M Tg, Tn or 500 \u00b5M PA. These findings suggest that UT extract may serve as a modulator against skeletal muscle dyslipidemia by downregulating ATF4 and CHOP, reducing cell stress and death, while enhancing IRS-1 expression, which supports the use of the UT extract in managing insulin resistance and T2D.<\/jats:p>","DOI":"10.3390\/cimb48060624","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:27:21Z","timestamp":1781666841000},"page":"624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulatory Activity of Uncaria tomentosa Extract in the Expression of Proteins Involved in the Unfolded Protein Response and Insulin Resistance"],"prefix":"10.3390","volume":"48","author":[{"given":"Bruna Freitas","family":"Marchi","sequence":"first","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg (GU), 413 90 G\u00f6teborg, Sweden"},{"name":"Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), S\u00e3o Paulo 03828-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria de Lima","family":"Camandona","sequence":"additional","affiliation":[{"name":"Laboratory of Aging and Molecular Biology, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), S\u00e3o Paulo 03828-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athirson Moraes","family":"Chanavat","sequence":"additional","affiliation":[{"name":"Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), S\u00e3o Paulo 03828-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Roncoli","family":"Reigado","sequence":"additional","affiliation":[{"name":"Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), S\u00e3o Paulo 03828-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5824-8656","authenticated-orcid":false,"given":"Carla Roberta de Oliveira","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of S\u00e3o Paulo (ICB-USP), S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7567-0656","authenticated-orcid":false,"given":"Felipe Santiago","family":"Chambergo","sequence":"additional","affiliation":[{"name":"Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), S\u00e3o Paulo 03828-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-4392","authenticated-orcid":false,"given":"Viviane Abreu","family":"Nunes","sequence":"additional","affiliation":[{"name":"Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), S\u00e3o Paulo 03828-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1200\/JCO.2016.67.4044","article-title":"Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy","volume":"34","author":"Shlomai","year":"2016","journal-title":"J. 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