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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Type 2 diabetes (T2D) is a metabolic syndrome frequently associated with obesity and endoplasmic reticulum stress-mediated inflammation, which can trigger the unfolded protein response (UPR), impair insulin signaling, and promote apoptosis. To identify potential natural therapeutic candidates, this study investigated the mechanisms of action of 14 compounds from Uncaria tomentosa (UT), a medicinal plant from the Amazon rainforest, using in silico modeling. The study focused on the UPR, TRAF2\/JNK pro-inflammatory signaling pathway, and insulin signaling pathways, which play key roles in T2D. Some of the UT compounds were docked against several human proteins involved in these pathways, and molecular dynamics simulations confirmed stable interactions between the target proteins (PERK, TRAF2, JNK, TNF-\u03b1, IRS-1, PI3K, AKT, GSK3\u03b2, and PPAR\u03b3) and four of the UT compounds, 5-Carboxystrictosidine, Cinchonain, Epicatechin and Mitraphylline. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties analyses were conducted to predict the four compounds, revealing suitable pharmacokinetic properties. These findings suggest that specific UT compounds may be used in experimental tests to whether investigate their therapeutic potential in managing T2D by modulating signaling pathways related to the conditions UPR, inflammation, and insulin resistance.<\/jats:p>","DOI":"10.3390\/ijms27177724","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Insulin Signaling and TRAF2\/JNK Pathway: A Comprehensive In Silico Study of Uncaria tomentosa Compounds"],"prefix":"10.3390","volume":"27","author":[{"given":"Bruna Freitas","family":"Marchi","sequence":"first","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg (GU), 41390 G\u00f6teborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Shraddha","family":"Parate","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Chalmers University of Technology, 41296 G\u00f6teborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1168-7480","authenticated-orcid":false,"given":"Vibhu","family":"Jha","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"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, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5654-3109","authenticated-orcid":false,"given":"Leif A.","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg (GU), 41390 G\u00f6teborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"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, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2023). 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