4-CMTB Ameliorates Ovalbumin-Induced Allergic Asthma through FFA2 Activation in Mice

Lee, Ju‐Hyun; Im, Dong‐Soon

doi:10.4062/biomolther.2020.176

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…GRI977143 or H2L5186303 was administered via intraperitoneal injection 30 min before OVA sensitization or challenge. BALF was collected from the lung tissues on D32 followed by staining for cell population analysis [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

Lee

2022

IJMS

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Lysophosphatidic acid (LPA), an intercellular lipid mediator, is increased in the bronchoalveolar fluids of patients with asthma after allergen exposure. LPA administration exaggerates allergic responses, and the type 2 LPA receptor (LPA2) has been reported as a therapeutic target for asthma. However, results with LPA2 agonist and antagonist along with LPA2 gene deficient mice have been controversial and contradictory. We compared the effects of LPA2 antagonist (H2L5186303) and agonist (GRI977143) in a single experimental protocol of ovalbumin (OVA)-induced allergic asthma by treating drugs before antigen sensitization or challenge. H2L5186303 showed strong suppressive efficacy when administered before OVA sensitization and challenge, such as suppression of airway hyper responsiveness, inflammatory cytokine levels, mucin production, and eosinophil numbers. However, GRI977143 showed significant suppression when administered before an OVA challenge. Increases in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid, Th2 cytokine levels, inflammatory scores, and mucin production were differentially ameliorated by the two drugs. The results demonstrate the multiple roles of LPA2 in asthmatic responses. We suggest that the development of LPA2 antagonists would achieve better therapeutic efficacy against asthma than agonists.

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Section: Methodsmentioning

confidence: 99%

Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

Lee

2022

IJMS

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“…NJK14047 was administered via intraperitoneal injection 30 min before OVA sensitization (D0 and D14) or 30 min before OVA challenge (D28, D29, and D30). Bronchoalveolar lavage fluid (BALF) was collected from the lung on D32, and the cell population of BALF cells was analyzed after staining ( Lee and Im, 2021a ).…”

Section: Methodsmentioning

confidence: 99%

NJK14047 Suppression of the p38 MAPK Ameliorates OVA-Induced Allergic Asthma during Sensitization and Challenge Periods

Lee

Son

Kim

et al. 2022

Biomol Ther (Seoul)

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p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.

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“…Step 2: In a vial, tert-butyl ester of 14 (15 mg, 33 μmol) dissolved in dry DCM (200 μL) was added TFA (64 μL, 0.83 mmol) and the reaction was stirred under argon at rt for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (× 3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was filtered through a plug of Celite (EtOAc/PE, 1 : 2, 5 mL, and then EtOAc, 10 mL), concentrated in vacuo, and freeze dried (water, 2 mL) to give 14 as a sticky solid (10 mg, 74 % yield); 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.18 (br s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 7…”

Section: -((3-chlorobenzyl)amino)-4-oxo-3-(4-(trifluoromethyl)benzyl) Butanoic Acid (14) Step 1: Tert-butyl 4-((3-chlorobenzyl)amino)-4oxmentioning

confidence: 99%

“…The free fatty acid receptor 2 (FFA2) and the closely related FFA3 are G protein-coupled receptors that sense short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate, [1] and that have been implicated in mediation of the physiological effects of SCFA-producing gut microbiota. [2] FFA2 is relatively broadly expressed in immune cells, intestine, adipose tissue and pancreas, [3] and has been suggested as a target for treatment of metabolic disorders, such as type 2 diabetes [4] and chronic kidney disease, [5] inflammatory disorders, including inflammatory bowel disease [6] and allergic asthma, [7] as well as infectious diseases. [8] Antagonists were suggested for treatment of type 2 diabetes based on results from FFA2 and FFA3 knockout mice.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

et al. 2021

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Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB (1). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.

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4-CMTB Ameliorates Ovalbumin-Induced Allergic Asthma through FFA2 Activation in Mice

Cited by 10 publications

References 37 publications

Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

NJK14047 Suppression of the p38 MAPK Ameliorates OVA-Induced Allergic Asthma during Sensitization and Challenge Periods

Structure‐Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

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