Shizukaol A exerts anti-inflammatory effect by regulating HMGB1/Nrf2/HO-1 pathway |
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| Affiliation: | 1. Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China;2. Shanghai Institute of Pharmaceutical Industry, Shanghai 200433, PR China;3. State Key Laboratory of Innovative Natural Medicine and TCM Injections, PR China;1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China;2. Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;3. Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China;4. Research Institute of Resource Insects, Chinese Academy of Forestry, Kunming 650224, China;5. Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China |
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| Abstract: | BackgroundSarcandra glabra (Thunb.) Makino (Chloranthaceae) has a long history of being used in Traditional Chinese medicines (TCMs) to treat painful joints, fractures, arthritis, and other diseases caused by inflammation. It has been reported that lindenane-type sesquiterpenoid dimers are main anti-inflammatory ingredient of S. glabra. Meanwhile, shizukaol A, the precursor of these sesquiterpene dimers, possesses a good inhibitory effect on nitric oxide (NO) in our previous study. But its anti-inflammatory mechanism is still unclear.PurposeThis study aimed to explore the possible anti-inflammatory mechanism and potential targets of shizukaol A in lipopolysaccharide (LPS)-induced RAW 264.7 cells.MethodsThe release of NO and inflammatory cytokines in LPS-stimulated RAW 264.7 cells were measured by Griess reagent and ELISA, respectively. The relevant proteins including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) p65, High mobility group box 1 (HMGB1) were detected by western blot. Nuclear translocation of p65, HMGB1 and nuclear factor E2-related factor 2 (Nrf2) were examined by immunofluorescence. The level of reactive oxygen species (ROS) was tested by flow cytometry. The target of shizukaol A was investigated by molecular docking and Drug Affinity Responsive Target Stability (DARTS).ResultsShizukaol A had a good inhibitory effect on NO with half maximal inhibitory concentration (IC50) of 13.79 ± 1.11 μM. Shizukaol A could down-regulate the expression of iNOS and COX-2. Further studies demonstrated that shizukaol A can significantly inhibit phosphorylation and nuclear translocation of NF-κB. Meanwhile, shizukaol A decreased the level of ROS and enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Furthermore, shizukaol A up-regulated the expression of Nrf2 and its nuclear translocation. More importantly, shizukaol A could inhibit activation of HMGB1 by targeting HMGB1.ConclusionShizukaol A inhibited inflammation by targeting HMGB1 to regulate the Nrf2/HO-1 signaling pathway. Thus, shizukaol A may be an attractive therapeutic candidate for inflammatory diseases. |
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