Academic Journal
Kushenol E alleviates sepsis-associated cognitive dysfunction via microglial indoleamine 2,3-dioxygenase 1 inhibition.
| Τίτλος: | Kushenol E alleviates sepsis-associated cognitive dysfunction via microglial indoleamine 2,3-dioxygenase 1 inhibition. |
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| Συγγραφείς: | Yang Y; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China., Lin W; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China., Zhuo Y; Department of Anesthesiology, Xiamen Haicang Hospital, Xiamen 361026, China., Yang J; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China., Wei Y; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China., Pan W; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China., Liao Y; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China. Electronic address: liaoyanlingfjsl@126.com., Yao Y; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China. Electronic address: fjslyys@fjmu.edu.cn. |
| Πηγή: | Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2026 Jul 25; Vol. 157, pp. 158338. Date of Electronic Publication: 2026 May 25. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Urban & Fischer Verlag Country of Publication: Germany NLM ID: 9438794 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1618-095X (Electronic) Linking ISSN: 09447113 NLM ISO Abbreviation: Phytomedicine Subsets: MEDLINE |
| Imprint Name(s): | Publication: Stuttgart : Urban & Fischer Verlag Original Publication: Stuttgart ; New York : G. Fischer, c1994- |
| Ιατρικοί όροι (MeSH): | Indoleamine-Pyrrole 2,3,-Dioxygenase*/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase*/metabolism , Microglia*/drug effects , Microglia*/enzymology , Cognitive Dysfunction*/drug therapy , Cognitive Dysfunction*/etiology , Sepsis*/complications , Sepsis-Associated Encephalopathy*/drug therapy , Flavonoids*/pharmacology, Oxidative Stress/drug effects ; Kynurenine/metabolism ; Animals ; Male ; Mice, Inbred C57BL ; Mice |
| Περίληψη: | Background: Sepsis-associated encephalopathy (SAE) affects up to 70% of septic patients, but lacks specific therapeutic interventions. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes tryptophan degradation via the kynurenine pathway, producing neurotoxic metabolites that drive neuroinflammation. Purpose: This study investigates whether kushenol E, a prenylated flavonoid from Sophora flavescens, mitigates SAE by inhibiting microglial IDO1. Methods: Sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6J mice. Cognitive function was assessed by the novel object recognition test and the Morris water maze. Neuronal injury, neuroinflammation, and oxidative stress were evaluated by histology and biochemical assays. IDO1 expression was quantified by quantitative PCR and Western blot, and kynurenine pathway metabolites were profiled by LC-MS/MS. Kushenol E inhibition of murine IDO1 was verified in IFN-γ-stimulated BV-2 microglia. AAV9-mediated F4/80⁺ myeloid-cell-targeted IDO1 overexpression was used as an in vivo rescue strategy. Results: CLP induced cognitive impairment, neuronal loss, neuroinflammation, and oxidative stress, accompanied by marked microglial IDO1 upregulation. Kushenol E preserved cognitive function, hippocampal integrity, and synaptic architecture; suppressed neuroinflammation; and limited neurotoxic kynurenine accumulation. Mechanistically, kushenol E inhibited IDO1 catalytic activity without altering its transcript or protein levels. In IFN-γ-stimulated BV-2 microglia, kushenol E suppressed kynurenine production in a concentration-dependent manner (IC Conclusion: Kushenol E mitigates SAE primarily by inhibiting microglial IDO1 catalytic activity, thereby limiting neurotoxic kynurenine production. These findings nominate microglial IDO1 as a therapeutic target for SAE and support kushenol E as a lead compound for the management of cognitive sequelae in sepsis survivors. (Copyright © 2026 Elsevier GmbH. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Cognitive dysfunction; Indoleamine 2,3-dioxygenase 1; Kushenol E; Kynurenine pathway; Microglia; Sepsis-associated encephalopathy |
| Substance Nomenclature: | 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) 0 (IDO1 protein, mouse) 343-65-7 (Kynurenine) 0 (Flavonoids) |
| Entry Date(s): | Date Created: 20260530 Date Completed: 20260612 Latest Revision: 20260612 |
| Update Code: | 20260613 |
| DOI: | 10.1016/j.phymed.2026.158338 |
| PMID: | 42217344 |
| Βάση Δεδομένων: | MEDLINE |
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