title: A novel synthetic derivative of squamosamide FLZ inhibits the high mobility group box 1 protein-mediated neuroinflammatory responses in murine BV2 microglial cells.
abstract: High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson's disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses. The effects of FLZ on HMGB1 release from microglial cells induced by lipopolysaccharide were first explored by Western blot assay and ELISA. Then, co-immunoprecipition was used to study FLZ's effect on the interaction between HMGB1 and its receptor TLR4. Finally, we employed HMGB1 to simulate pro-inflammatory responses and then studied the inhibitory effects of FLZ on its bioactivity. FLZ has a significant inhibitory effect on HMGB1 release while it exerts no inhibitory effect on the binding between HMGB1 and TLR4. After the recognition of HMGB1 by TLR4, NF-κB signaling pathway is activated. FLZ could efficaciously alleviate HMGB1-induced inflammatory responses via the suppression of TLR4/MyD88/NF-κB signaling pathway. FLZ could inhibit HMGB1 release as well as HMGB1-induced inflammatory responses, HMGB1 might be one of the FLZ anti-inflammatory targets, and interfering at this inflammatory mediator may have benefit effects on neurodegenerative disorders, such as Parkinson's disease.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
authors.forename: De-Chuan
authors.initials: DC
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.|Beijing Institute for Brain Disorders, 10 Xitoutiao, Youanmen Wai, Beijing, 100054, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China. danzhang@imm.ac.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism*; D047468:Immunoprecipitation; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D044482:Benzeneacetamides; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010636:Phenols; D051197:Toll-Like Receptor 4; C084439:squamosamide
keywords: FLZ; High mobility group box 1; Microglia; Neuroinflammation; Parkinson’s disease