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Discovery of Fungus-Derived Nornidulin as a Novel TMEM16A Inhibitor: A Potential Therapy to Inhibit Mucus Secretion in Asthma. | LitMetric

AI Article Synopsis

  • The study investigates the potential of a compound called nornidulin, derived from fungi, as an inhibitor of TMEM16A chloride channels, aiming to reduce mucus secretion in asthma.
  • Using Calu-3 cells and a mouse model of asthma, researchers demonstrated that nornidulin significantly blocks TMEM16A activity without compromising cell viability or barrier function.
  • The findings suggest that nornidulin effectively reduces calcium-dependent mucus release in airway cells and mucus secretion in asthma-affected mice, highlighting its promise as an anti-asthmatic treatment.

Article Abstract

Introduction: Inhibition of Ca-activated transmembrane protein 16A (TMEM16A) Cl channels has been proposed to alleviate mucus secretion in asthma. In this study, we identified a novel class of TMEM16A inhibitors from natural sources in airway epithelial Calu-3 cells and determine anti-asthmatic efficacy of the most potent candidate in a mouse model of asthma.

Methods: For electrophysiological analyses, IL-4-primed Calu-3 cell monolayers were mounted in Ussing chamber and treated with various fungus-derived depsidones prior to the addition of UTP, ionomycin, thapsigargin, or E to stimulate TMEM16A Cl current. Ca-induced mucus secretion in Calu-3 cell monolayers was assessed by determining MUC5AC protein remaining in the cells using immunofluorescence staining. OVA-induced female BALB/c mice was used as an animal model of asthma. After the course of induction, cellular and mucus components in bronchoalveolar lavage were analyzed. Lungs were fixed and undergone with H&E and PAS staining for the evaluation of airway inflammation and mucus production, respectively.

Results: The screening of fungus-derived depsidones revealed that nornidulin completely abolished the UTP-activated TMEM16A current in Calu-3 cell monolayers with the IC and a maximal effect being at ~0.8 µM and 10 µM, respectively. Neither cell viability nor barrier function was affected by nornidulin. Mechanistically, nornidulin (10 µM) suppressed Cl currents induced by ionomycin (a Ca-specific ionophore), thapsigargin (an inhibitor of the endoplasmic reticulum Ca ATPase), and E (a putative TMEM16A activator) without interfering with intracellular Ca ([Ca]) levels. These results suggest that nornidulin exerts its effect without changing [Ca], possibly through direct effect on TMEM16A. Interestingly, nornidulin (at 10 µM) reduced Ca-dependent mucus release in the Calu-3 cell monolayers. In addition, nornidulin (20 mg/kg) inhibited bronchoalveolar mucus secretion without impeding airway inflammation in ovalbumin-induced asthmatic mice.

Discussion And Conclusion: Our study revealed that nornidulin is a novel TMEM16A inhibitor that suppresses mucus secretion without compromising immunologic activity. Further development of nornidulin may provide a new remedy for asthma or other diseases associated with allergic mucus hypersecretion without causing opportunistic infections.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657771PMC
http://dx.doi.org/10.2147/JEP.S427594DOI Listing

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