ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude

Li, Huilin; Ou, Jiali; Li, Yaqun; Xu, Niannian; Li, Qing; Wu, Ping; Peng, Chao; Tang, Yun‐Chi; Chang, Hung-Chun

doi:10.1038/s42003-022-03725-x

Cited by 4 publications

(1 citation statement)

References 66 publications

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“…In ethanol‐dependent male rats, ISX9 was found to decrease enhanced fear responses and retrieval (Staples et al, 2021). Recently, Li et al demonstrated that ISX9 could promote circadian amplitude via potentiation of CaMKIIδ‐mediated brain and muscle ARNT‐Like 1 (BMAL1; aryl hydrocarbon receptor nuclear translocator‐like protein 1/ARNTL) activation (Li et al, 2022). However, the molecular mechanism of ISX9 action remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Isoxazole 9 (ISX9), a small molecule targeting Axin, activates Wnt/β‐catenin signalling and promotes hair regrowth

Sayed

Song

Muluh

et al. 2023

British J Pharmacology

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Background and Purpose Isoxazole 9 (ISX9) is a neurogenesis‐promoting small molecule compound that can up‐regulate the expression of NeuroD1 and induce differentiation of neuronal, cardiac and islet endocrine progenitors. So far, the molecular mechanisms underlying the action of ISX9 still remain elusive. Experimental Approach To identify a novel agonist of the Wnt/β‐catenin, a cell‐based SuperTOPFlash reporter system was used to screen known‐compound libraries. An activation effect of ISX9 on the Wnt/β‐catenin pathway was analysed with the SuperTOPFlash or SuperFOPFlash reporter system. Effects of ISX9 on Axin1/LRP6 interaction were examined using a mammalian two‐hybrid system, co‐immunoprecipitation, microscale thermophoresis, emission spectra and mass spectrometry assays. The expression of Wnt target and stemmness marker genes were evaluated with real‐time PCR and immunoblotting. In vivo hair regeneration abilities of ISX9 were analysed by immunohistochemical staining, real‐time PCR and immunoblotting in hair regrowth model using C57BL/6J mice. Key Results In this study, ISX9 was identified as a novel agonist of the Wnt/β‐catenin pathway. ISX9 targeted Axin1 by covalently binding to its N‐terminal region and potentiated the LRP6‐Axin1 interaction, thereby resulting in the stabilization of β‐catenin and up‐regulation of Wnt target genes and stemmness marker genes. Moreover, the topical application of ISX9 markedly promoted hair regrowth in C57BL/6J mice and induced hair follicle transition from telogen to anagen via enhancing Wnt/β‐catenin pathway. Conclusions and Implications Taken together, our study unravelled that ISX9 could activate Wnt/β‐catenin signalling by potentiating the association between LRP6 and Axin1, and may be a promising therapeutic agent for alopecia treatment.

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Section: Introductionmentioning

confidence: 99%