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In previous studies, we found increased expression of Toll\u2010like receptors (TLRs), activated NF\u2010\u03baB p65 (RELA), and other proinflammatory signalling molecules. Proinflammatory NADPH oxidases generate reactive oxygen species, which are linked to neurodegeneration. We tested the hypothesis that AUD increased RELA activation increases NADPH oxidase\u2010oxidative stress and endoplasmic reticulum (ER) stress cell death cascades in association with neuronal cell death in the human orbitofrontal cortex (OFC). In the AUD OFC, we report mRNA induction of several NADPH oxidases, the dual oxidase <jats:italic>DUOX2<\/jats:italic>, and the oxidative stress lipid peroxidation marker 4\u2010HNE and the DNA oxidation marker 8\u2010OHdG that correlate with RELA, a marker of proinflammatory NF\u2010\u03baB activation. This was accompanied by increased expression of the ER stress\u2010associated regulator protein glucose\u2010regulated protein 78 (GRP78), transmembrane sensors activating transcription factor 6 (ATF6), protein kinase RNA\u2010like endoplasmic reticulum kinase (PERK), and inositol\u2010requiring kinase\/endonuclease 1 (pIRE1), and the pro\u2010apoptotic transcription factor C\/EBP homologous protein (CHOP). Expression of NADPH oxidase\u2010oxidative stress markers correlate with ER stress\u2010associated molecules. Induction of oxidative stress and ER stress signalling pathways correlate with expression of cell death\u2010associated caspases and neuronal cell loss. These data support the hypothesis that proinflammatory RELA\u2010mediated induction of NADPH oxidase\u2010oxidative stress and ER stress\u2010associated signalling cascades is associated with neuronal cell death in the post\u2010mortem human OFC of individuals with AUD.<\/jats:p>","DOI":"10.1111\/adb.13262","type":"journal-article","created":{"date-parts":[[2022,12,11]],"date-time":"2022-12-11T04:20:55Z","timestamp":1670732455000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder"],"prefix":"10.1111","volume":"28","author":[{"given":"Liya","family":"Qin","sequence":"first","affiliation":[{"name":"Bowles Center for Alcohol Studies, School of Medicine University of North Carolina at Chapel Hill  Chapel Hill North Carolina 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