title: Therapeutic effects of R8, a semi-synthetic analogue of Vasicine, on murine model of allergic airway inflammation via STAT6 inhibition.
abstract: This is a follow-up study of our previous work in which we screened a series of Vasicine analogues for their anti-inflammatory activity in a preventive OVA induced murine model of asthma. The study demonstrated that R8, one of the analogues, significantly suppressed the Th2 cytokine production and eosinophil recruitment to the airways. In the present study, we have been using two standard experimental murine models of asthma, where the mice were treated with R8 either during (preventive use) or after (therapeutic use) the development of asthma features. In the preventive model, R8 reduced inflammatory cell infiltration to the airways, OVA specific IgE and Th2 cytokine production. Also, the R8 treatment in the therapeutic model decreased methacholine induced AHR, Th2 cytokine release, serum IgE levels, infiltration of inflammatory cells into the airways, phosphorylation of STAT6 and expression of GATA3. Moreover, R8 not only reduced goblet cell metaplasia in asthmatic mice but also reduced IL-4 induced Muc5AC gene expression in human alveolar basal epithelial cells. Further, R8 attenuated IL-4 induced differentiation of murine splenocytes into Th2 cells in vitro. So, we may deduce that R8 treatment profoundly reduced asthma features by attenuating the differentiation of T cells into Th2 cells by interfering with the binding of IL-4 to its receptor in turn decreasing the phosphorylation of STAT6 and expression of GATA3 in murine model of asthma. These preclinical findings suggest a possible therapeutic role of R8 in allergic asthma.
authors: PK-PD Toxicology Division, Indian Institute of Integrative Medicine-CSIR, Jammu, India; School of Biotechnology, Shri Mata Vaishno Devi University, Katra Jammu, India.
authors: Sheikh
authors: S
authors: Rayees
authors: Molecular Immunogenetics Laboratory, Institute of genomics and Integrative Biology-CSIR, Delhi, India.
authors: Ulaganathan
authors: U
authors: Mabalirajan
authors: Biotransformation Group-Industrail Biotechnology, Scion Research, New Zealand.
authors: Wajid Waheed
authors: WW
authors: Bhat
authors: School of Biotechnology, Shri Mata Vaishno Devi University, Katra Jammu, India.
authors: Shafaq
authors: S
authors: Rasool
authors: PK-PD Toxicology Division, Indian Institute of Integrative Medicine-CSIR, Jammu, India.
authors: Rafiq Ahmad
authors: RA
authors: Rather
authors: Molecular Immunogenetics Laboratory, Institute of genomics and Integrative Biology-CSIR, Delhi, India.
authors: Lipsa
authors: L
authors: Panda
authors: Chemistry Division, Indian Institute of Integrative Medicine-CSIR, Jammu, India.
authors: Naresh Kumar
authors: NK
authors: Satti
authors: Plant Biotechnology Division, Indian Institute of Integrative Medicine-CSIR, Jammu, India.
authors: Surrinder Kumar
authors: SK
authors: Lattoo
authors: Molecular Immunogenetics Laboratory, Institute of genomics and Integrative Biology-CSIR, Delhi, India.
authors: Balaram
authors: B
authors: Ghosh
authors: PK-PD Toxicology Division, Indian Institute of Integrative Medicine-CSIR, Jammu, India. Electronic address: singh_gd@iiim.ac.in.
authors: Gurdarshan
authors: G
authors: Singh
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D016207:Cytokines / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011799:Quinazolines / Q000737:chemistry*; D052999:Quinazolinones / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors*; D018675:Toxicity Tests
chemical_list: C000604932:5-benzoyl-5a,6,7,8,9,10-hexahydroazepino(2,1-b)quinazoline-12(5H)-one; D000470:Alkaloids; D018927:Anti-Asthmatic Agents; D001381:Azepines; D016207:Cytokines; D011799:Quinazolines; D052999:Quinazolinones; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D007073:Immunoglobulin E; C019592:vasicine; D010047:Ovalbumin
keywords: GATA3; Preventive; STAT6; Th2 cytokine; Therapeutic; Vasicine