title: A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model.
abstract: Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6-8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model.
authors.affiliation: Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: J C-W
authors.initials: JC
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors.forename: F-Y
authors.initials: FY
authors.lastname: Goh
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: S-R
authors.initials: SR
authors.lastname: Sagineedu
authors.affiliation: Faculty of Pharmacy, Segi University, Jalan Teknologi, 47810 Petaling Jaya, Malaysia.
authors.forename: A C-H
authors.initials: AC
authors.lastname: Yong
authors.affiliation: Histopathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: S M
authors.initials: SM
authors.lastname: Sidik
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: N H
authors.initials: NH
authors.lastname: Lajis
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore; Immunology Program, Life Science Institute, National University of Singapore, Singapore. Electronic address: fred_wong@nuhs.edu.sg.
authors.forename: W S F
authors.initials: WS
authors.lastname: Wong
authors.affiliation: Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia; Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia. Electronic address: rcxjs@upm.edu.my.
authors.forename: J
authors.initials: J
authors.lastname: Stanslas
mesh_terms: D000072283:A549 Cells; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin; D015398:Signal Transduction
chemical_list: D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004224:Diterpenes; D007074:Immunoglobulin G; D007783:Lactones; D016328:NF-kappa B; C000619531:SRS27 compound; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: A549 cell line; Airway hyperresponsiveness; Andrographolide analogues; Mouse asthma model; NF-κB; Ovalbumin; Oxidative stress