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FNF-12, a novel benzylidene-chromanone derivative, attenuates inflammatory response in in vitro and in vivo asthma models mediated by M2-related Th2 cytokines via MAPK and NF-kB signaling

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Abstract

Background and aim

This study evaluates a novel benzylidene-chromanone derivative, FNF-12, for efficacy in in vitro and in vivo asthma models.

Methods

Rat basophilic leukemia (RBL-2H3) and acute monocytic leukemia (THP-1)-derived M2 macrophages were used. Human whole blood-derived neutrophils and basophils were employed. Flow cytometry was used for studying key signalling proteins. Platelet activation factor (PAF)-induced asthma model in guinea pigs was used for in vivo studies.

Results

The chemical structure of FNF-12 was confirmed with proton-nuclear mass resonance (NMR) and mass spectroscopy. FNF-12 controlled degranulation in RBL-2H3 cells with an IC50 value of 123.7 nM and inhibited TNF-α release from these cells in a dose-responsive way. The compound effectively controlled the migration and elastase release in activated neutrophils. IC50 value in the FcεRI-basophil activation assay was found to be 205 nM. FNF-12 controlled the release of lipopolysaccharide (LPS)-induced interleukin-10, I-309/CCL1 and MDC/CCL22 in THP-1 derived M2 macrophages. The compound suppressed LPS-induced mitogen activated protein kinase (MAPK)-p-p38 and nuclear factor kappa B(NF-kB)-p-p65 expression in these cells. A dose-dependent decrease in the accumulation of total leucocytes, eosinophils, neutrophils and macrophages was observed in PAF-induced animal models.

Conclusion

FNF-12 was able to control the inflammatory responses in in vitro and in vivo asthma models, which may be driven by controlling M2-related Th2 cytokines via MAPK and NF-kB signaling.

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Abbreviations

ACD solution:

Citrate–dextrose solution

Avidin–HRP:

Avidin–horseradish peroxidase

BAL:

Bronchoalveolar lavage

DMSO:

Dimethylsulphoxide

DNP–BSA:

2,4-Dinitrophenol–bovine serum albumin

ELISA:

Enzyme-linked immunosorbent assay

EMEM:

Eagle's minimum essential medium

fMLP:

N-Formyl-methionyl-leucyl-phenylalanine

HBSS:

Hank’s balanced salt solution

HWB:

Human whole blood

IgE:

Immunoglobulin E

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MPO:

Myeloperoxidase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide

NF-kB:

Nuclear factor kappa B

NMR:

Nuclear mass resonance

PAF:

Platelet activation factor

PBS:

Phosphate-buffered saline

PE:

Phycoerythrin

PIPES:

Ethanesulphonic acid

RBL-2H3:

Rat basophilic leukemia

THP-1:

Acute monocytic leukaemia

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

The authors express their gratitude to SMARTBIO LABS, Chennai, Tamil Nadu, India, for the help rendered in this study.

Funding

The authors extend their thanks to the Deanship of Scientific Research at King Khalid University, Abha, Saudi Arabia, for funding this work through Grant number RGP. 1/265/42.

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Authors and Affiliations

  1. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia

    Mohammad Abohassan, Mesfer Al Shahrani, Mohammad Y. Alshahrani, Naseem Begum & Prasanna Rajagopalan

  2. Central Research Laboratory, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia

    Prasanna Rajagopalan

  3. Post Graduate and Research Department of Chemistry, Presidency College, Chennai, Tamil Nadu, India

    Suresh Radhakrishnan

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  1. Mohammad Abohassan
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  2. Mesfer Al Shahrani
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Contributions

MA—funding, experimental, data curing. MAS—data analysis, statistical analysis, experimental. MYA—experimental, manuscript preparation. NB—data analysis, revision of manuscript. SR—experimental, data analysis, reference management. PR—conceptional design, data analysis, manuscript finalization, supervision.

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Correspondence to Prasanna Rajagopalan.

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Abohassan, M., Al Shahrani, M., Alshahrani, M.Y. et al. FNF-12, a novel benzylidene-chromanone derivative, attenuates inflammatory response in in vitro and in vivo asthma models mediated by M2-related Th2 cytokines via MAPK and NF-kB signaling. Pharmacol. Rep 74, 96–110 (2022). https://doi.org/10.1007/s43440-021-00325-0

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