{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:13:57Z","timestamp":1790079237848,"version":"4.0.1"},"reference-count":65,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["5\/13\/56\/2020\/NCD\u2010III"],"award-info":[{"award-number":["5\/13\/56\/2020\/NCD\u2010III"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Carcinogenesis is a dynamic, multistep process in which the initiation stage represents a critical and irreversible event that determines cellular fate. Although genetic alterations play a central role in tumor development, dysregulation of intracellular organelles such as the endoplasmic reticulum (ER) has emerged as an important contributor to cancer initiation. In the present study, we aimed to evaluate how modulation of ER stress affects the initiation phase of hepatocarcinogenesis. The initiation\u2010stage hepatocarcinogenic model was developed by administering a single dose of\n                    <jats:italic>N\u2010nitrosodiethylamine<\/jats:italic>\n                    (NDEA) (50\u2009mg\/kg b.w, i.p.) to male Wistar rats. To modulate ER activity, the endogenous chaperone inducer 1\u2010(3,4\u2010dihydroxyphenyl)\u20102\u2010thiocyanatoethanone (BIX) was administered intraperitoneally (0.1\u2009mg\/kg body weight) for 2 weeks prior to NDEA treatment. The effect of ER modulation on pro\u2010tumorigenic events was assessed in terms of oxidative DNA damage, expression of inflammatory cytokines, p53, and cellular proliferation. Modulation of UPR by BIX was evaluated based on expression levels of\n                    <jats:italic>PERK, ATF6, CHOP<\/jats:italic>\n                    , and p\u2010PERK\/PERK ratio. BIX treatment demonstrated marked attenuation of pro\u2010tumorigenic events as evidenced by significantly decreased levels of 8\u2010OHdG, TNF\u2010\u03b1, IL\u20106, PCNA, and p53, which were upregulated in the NDEA\u2010treated group. Histopathological analysis further confirmed the preservation of hepatic architecture in the BIX\u2010treated group as compared with the NDEA group. In addition, significantly decreased expression of UPR markers in the BIX\u2010treated group, as compared to the NDEA group, confirmed inhibition of UPR activation. Collectively, these findings demonstrated that BIX\u2010mediated ER\u2010stress modulation effectively inhibited the initiation of NDEA\u2010induced hepatocarcinogenesis.\n                  <\/jats:p>","DOI":"10.1002\/jbt.71000","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T17:12:32Z","timestamp":1782666752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regulation of Endoplasmic Reticulum Stress Suppresses Early Pro\u2010Tumorigenic Events During\n                    <i>N\u2010Nitrosodiethylamine<\/i>\n                    \u2010Induced Hepatocarcinogenesis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8548-4363","authenticated-orcid":false,"given":"Maya P.","family":"Shetty","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine Manipal College of Health Professions, Manipal Academy of Higher Education Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1543-3127","authenticated-orcid":false,"given":"Smita","family":"Hegde","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine Manipal College of Health Professions, Manipal Academy of Higher Education Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3697-2632","authenticated-orcid":false,"given":"Sanjay","family":"Bharati","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine Manipal College of Health Professions, Manipal Academy of Higher Education Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26073352"},{"issue":"8","key":"e_1_2_10_3_1","first-page":"3956","article-title":"DNA Damage in Cancer Development: 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