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Upon unresolved ER stress, this organelle activates the unfolded protein response (UPR). Sustained UPR activates is known to occur in inflammatory processes, deeming the ER a potential molecular target for the treatment of inflammation. This work characterizes the inflammatory\/UPR-related molecular machinery modulated by an in-house library of natural products, aiming to pave the way for the development of new selective drugs that act upon the ER to counter inflammation-related chronic diseases. Starting from a library of 134 compounds of natural occurrence, mostly occurring in medicinal plants, nontoxic molecules were screened for their inhibitory capacity against LPS-induced nuclear factor kappa B (NF-\u03baB) activation in a luciferase-based reporter gene assay. Since several natural products inhibited NF-\u03baB expression in THP-1 macrophages, their effect on reactive oxygen species (ROS) production and inflammasome activation was assessed, as well as their transcriptional outcome regarding ER stress. The bioactivities of several natural products are described herein for the first time. We report the anti-inflammatory potential of guaiazulene and describe 5-deoxykaempferol as a novel inhibitor of inflammasome activation. Furthermore, we describe the dual potential of 5-deoxykaempferol, berberine, guaiazulene, luteolin-4\u2019-<jats:italic>O<\/jats:italic>-glucoside, myricetin, quercetagetin and sennoside B to modulate inflammatory signaling ER stress. Our results show that natural products are promising molecules for the discovery and pharmaceutical development of chemical entities able to modulate the inflammatory response, as well as proteostasis and the UPR.<\/jats:p>","DOI":"10.1007\/s13105-024-01014-1","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T06:51:21Z","timestamp":1710831081000},"page":"421-437","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Naturally occurring small molecules with dual effect upon inflammatory signaling pathways and endoplasmic reticulum stress response"],"prefix":"10.1007","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9139-2884","authenticated-orcid":false,"given":"Daniela","family":"Correia da Silva","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0740-4396","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Valent\u00e3o","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-7592","authenticated-orcid":false,"given":"David M.","family":"Pereira","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"1014_CR1","doi-asserted-by":"publisher","first-page":"7683","DOI":"10.1093\/nar\/gkt563","volume":"41","author":"W B\u2019chir","year":"2013","unstructured":"B\u2019chir W, Maurin A-C, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P, Bruhat A (2013) The eIF2\u03b1\/ATF4 pathway is essential for stress-induced autophagy gene expression. 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