title: LFG-500, a newly synthesized flavonoid, attenuates lipopolysaccharide-induced acute lung injury and inflammation in mice.
abstract: Acute lung injury (ALI) often causes significant morbidity and mortality worldwide. Improved treatment and effective strategies are still required for ALI patients. Our previous studies demonstrated that LFG-500, a novel synthesized flavonoid, has potent anti-cancer activities, while its anti-inflammatory effect has not been revealed. In the present study, the in vivo protective effect of LFG-500 on the amelioration of lipopolysaccharide (LPS)-induced ALI and inflammation was detected. LFG-500 attenuated LPS-induced histological alterations, suppressed the infiltration of inflammatory cells in lung tissues and bronchoalveolar lavage fluid, as well as inhibited the secretion of several inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in lung tissues after LPS challenge. In addition, the in vitro effects and mechanisms were studied in LPS stimulated RAW 264.7 cells and THP-1 cells. LFG-500 significantly decreased the secretion and expression of TNF-α, IL-1β, and IL-6 through inhibiting the transcriptional activation of NF-κB. Moreover, overexpression of NF-κB p65 reversed the inhibitory effect of LFG-500 on LPS-induced NF-κB activation and inflammatory cytokine secretion. Further elucidation of the mechanism revealed that p38 and JNK MAPK pathways were involved in the anti-inflammation effect of LFG-500, through which LFG-500 inhibited the classical IKK-dependent pathway and led to inactivation of NF-κB. More importantly, LFG-500 suppressed the expression and nuclear localization of NF-κB in LPS-induced ALI mice. Taken together, these results demonstrated that LFG-500 could attenuate LPS-induced ALI and inflammation by suppressing NF-κB activation, which provides new evidence for the anti-inflammation activity of LFG-500.
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Du
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China. Electronic address: anticancer_drug@163.com.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, People's Republic of China. Electronic address: yinxx@xzmc.edu.cn.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Yin
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D015394:Molecular Structure
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005419:Flavonoids; C000598105:LFG-500; D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4
keywords: Acute lung injury; DAPI (PubChem CID: 2954); DMSO (PubChem CID: 679); LFG-500; LPS (PubChem CID: 53481793); Lipopolysaccharide; NF-κB; Solutol HS15 (PubChem CID: 124898); Trypan blue (PubChem CID: 101417452)