{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T17:57:43Z","timestamp":1769623063505,"version":"3.49.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Enteric glial cells (EGCs) are key regulators of gut-brain axis immunity, and their excessive activation contributes to intestinal inflammation and neuroimmune disturbances implicated in early Parkinson\u2019s disease. Oridonin, a diterpenoid compound with known anti-inflammatory and autophagy-modulating properties, has not been extensively studied in peripheral glial models. Here, we investigated the effects of oridonin on TLR4-mediated inflammatory signaling and autophagy responses in LPS-stimulated EGCs, with molecular docking used as a supportive, hypothesis-generating approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rat-derived EGCs were exposed to LPS (10\u202f\u03bcg\/mL) to induce glial activation. Cells were treated with oridonin (1\u20135\u202f\u03bcM) with or without the selective TLR4 inhibitor TAK-242. mRNA levels of TLR4, S100B, LC3, and beclin-1 were quantified by RT-qPCR, while caspase-1 and IL-1\u03b2 protein levels were assessed by ELISA. Molecular docking was performed to explore potential interactions of oridonin and TAK-242 with the TLR4 receptor complex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LPS significantly increased TLR4 and S100B expression and upregulated the autophagy markers beclin-1 and LC3. Oridonin dose-dependently suppressed LPS-induced upregulation of TLR4 and S100B and attenuated the elevation of autophagy-related transcripts. Docking studies suggested that oridonin and TAK-242 may interact with regulatory regions of the TLR4 complex, including surface-exposed sites on the TLR4-MD-2 ectodomain and distinct sub-pockets within the intracellular TIR domain, with oridonin exhibiting a stronger predicted binding affinity. Although LPS increased TLR4 mRNA, it elicited only a modest increase in caspase-1 levels and no significant change in IL-1\u03b2 levels, consistent with incomplete inflammasome activation. Whereas TAK-242 alone did not fully suppress IL-1\u03b2, combined treatment with oridonin reduced cytokine levels more effectively, suggesting complementary downstream modulation rather than direct receptor-level synergy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Oridonin exerts powerful anti-inflammatory and autophagy-modulating effects in EGCs by inhibiting TLR4-driven signaling, normalizing excessive autophagic responses, and limiting IL-1\u03b2 output. Its dual capacity to suppress both upstream (TLR4\/S100B) and downstream (caspase-1\/IL-1\u03b2) components of the inflammatory cascade preserves EGC homeostasis under endotoxin stress. These findings highlight oridonin as a potential modulator of peripheral glial inflammation and support further investigation of its therapeutic potential in gut-brain axis disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncel.2026.1748505","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:22:57Z","timestamp":1769577777000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Oridonin attenuates TLR4-driven inflammation and autophagy in LPS-stimulated enteric glial cells: an in vitro and in silico analysis"],"prefix":"10.3389","volume":"20","author":[{"given":"Dilara","family":"Nemutlu Samur","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Alanya Alaaddin Keykubat University","place":["Antalya, T\u00fcrkiye"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayb\u00fcke","family":"Boyac\u0131","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Graduate School of Education, Alanya Alaaddin Keykubat University","place":["Antalya, T\u00fcrkiye"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erkan","family":"Maytalman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Alanya Alaaddin Keykubat University","place":["Antalya, T\u00fcrkiye"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"34984","DOI":"10.1038\/srep34984","article-title":"Structural insights into conformational stability of both wild-type and mutant EZH2 receptor","volume":"6","author":"Aier","year":"2016","journal-title":"Sci. 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