title: Z-guggulsterone negatively controls microglia-mediated neuroinflammation via blocking IκB-α-NF-κB signals.
abstract: Induction of pro-inflammatory factors is one of the characteristics of microglial activation and can be regulated by numerous active agents extracted from plants. Suppression of pro-inflammatory factors is beneficial to alleviate neuroinflammation. Z-guggulsterone, a compound extracted from the gum resin of the tree commiphora mukul, exhibits numerous anti-inflammatory effects. However, the role and mechanism of Z-guggulsterone in pro-inflammatory responses in microglia remains unclear. This study addressed this issue in in vitro murine microglia and in vivo neuroinflammation models. Results showed that Z-guggulsterone reduced inducible nitric oxide (iNOS) protein expression as well as nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production in LPS-stimulated BV-2 cells. Z-guggulsterone also reduced the mRNA level of iNOS, TNF-α, and IL-6. Mechanistic studies revealed that Z-guggulsterone attenuated the LPS-induced degradation of inhibitor κ B-α (IκB-α) as well as the LPS-induced nuclear translocation of nuclear factor-κB (NF-κB). Z-guggulsterone, however, failed to reduce the LPS-induced increase in NF-κB phosphorylation level. These major findings were ascertained in primary microglia where the LPS-induced increases in iNOS expression, NO content, and IκB-α degradation were diminished by Z-guggulsterone treatment. In a mouse model of neuroinflammation, Z-guggulsterone exhibited significant anti-inflammatory effects, which were exemplified by the attenuation of microglial activation and neuroinflammation-induced behavioral abnormalities in Z-guggulsterone-treated mice. Taken together, these studies demonstrate that Z-guggulsterone attenuates the LPS-mediated induction of pro-inflammatory factors in microglia via inhibition of IκB-α-NF-κB signals, providing evidence to uncover the potential role of Z-guggulsterone in neuroinflammation-associated disorder therapies.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Jili
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, Jiangsu Province 226001, China. Electronic address: charliechao888888@163.com.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China. Electronic address: asicampa@aliyun.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004790:Enzyme Induction; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011282:Pregnenediones / Q000494:pharmacology*; D021381:Protein Transport; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011282:Pregnenediones; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C023617:pregna-4,17-diene-3,16-dione; D052247:Nitric Oxide Synthase Type II
keywords: Inhibitor of κB-α; Lipopolysaccharide; Neuroinflammation; Nuclear factor-κB; Z-guggulsterone