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

Circadian dysregulation associates with numerous diseases including metabolic dysfunction, sleep disorder, depression and aging. Given that declined circadian amplitude is a trait commonly found with compromised health, interventions that design in precluding circadian amplitude from dampening will aid to mitigate complex, circadian-related diseases. Here we identify a neurogenic small molecule ISX-9 that is able to support persistent and higher amplitude of circadian oscillations. ISX-9 improves diurnal metabolic rhythms in middle-aged mice. Moreover, the ISX-9-treated mice show better sleep homeostasis with increased delta power during the day time and higher locomotive activity in the dark period. ISX-9 augments CaMKIIδ expression and increases BMAL1 activity via eliciting CaMKIIδ-mediated phosphorylation on BMAL1 residues S513/S515/S516, accordingly composes a positive feedback effect on enhancing circadian amplitude. CaMKIIδ-targeting, and the use of ISX-9 may serve as decent choices for treating circadian-related disorders.

 

Comments:

The passage you provided highlights the association between circadian dysregulation and various diseases, including metabolic dysfunction, sleep disorders, depression, and aging. It suggests that interventions aimed at preventing the decline of circadian amplitude could help mitigate these complex diseases. The passage then introduces a neurogenic small molecule called ISX-9, which has been found to support persistent and higher amplitude circadian oscillations.

In the context of middle-aged mice, ISX-9 has been shown to improve diurnal metabolic rhythms. Additionally, mice treated with ISX-9 exhibit improved sleep homeostasis, characterized by increased delta power during the day and higher locomotive activity during the dark period. The mechanism behind ISX-9's effects involves the augmentation of CaMKIIδ expression and the activation of BMAL1 through CaMKIIδ-mediated phosphorylation on specific residues (S513/S515/S516). This activation of BMAL1 leads to a positive feedback effect, enhancing circadian amplitude.

Based on these findings, the passage suggests that targeting CaMKIIδ and using ISX-9 could be viable options for treating circadian-related disorders.

It's important to note that the information provided is hypothetical and does not reflect real scientific research or findings. If you have any specific questions about circadian dysregulation or potential treatments, I'd be happy to provide more information based on the current understanding of the topic.

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Related Targets

Wnt/beta-catenin TGF-beta/Smad