Evaluating natural bioactive chronobiotics in a C. elegans circadian disruption system induced by light-temperature entrainment

Apr 14, 2026Phytomedicine : international journal of phytotherapy and phytopharmacology

Testing natural time-regulating compounds in worm models with disrupted daily rhythms caused by light and temperature

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Abstract

The environmental perturbation in C. elegans successfully induced significant circadian rhythm disruption (CRD) with altered behavioral rhythms and core clock gene expression.

Key features of human CRD were replicated in C. elegans, indicating the model's relevance for studying circadian disruptions.
Significant disturbances in locomotor behavioral rhythms were observed alongside changes in the expression of core clock genes.
The model demonstrated good reproducibility and suitability for evaluating the effects of natural bioactive compounds (NBCs).
Several NBCs, including nobiletin and melatonin, were found to alleviate CRD-associated phenotypes to varying degrees.
The findings suggest potential therapeutic effects of plant-derived compounds on circadian regulation.

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BACKGROUND: The prevalence of circadian rhythm disruption (CRD) is increasing due to the worsening light pollution, rising societal stress, and globalized lifestyles. Long-term CRD can cause significant physiological changes and raise the risk of various health disorders. Natural bioactive compounds (NBC) are showing promise as novel circadian modulators because they can precisely target core clock networks, be administered flexibly, and have multi-target effects, requiring efficient screening models.

PURPOSE: The objective of this study was to establish and characterize a CRD model in C. elegans and to explore its applicability for evaluating the chronobiotic potential of NBCs.

METHODS: A synchronized light-temperature perturbation protocol was used to induce a stable CRD state in C. elegans. The model's validity was rigorously assessed by monitoring locomotor behavioral rhythms and quantifying transcriptional changes in core clock genes. Rhythm integrity and periodicity were analyzed using the Biodare2 platform. The restorative effects of administered nine NBCs were evaluated through this integrated behavioral, physiological, and molecular framework.

RESULTS: The environmental perturbation successfully recapitulated key features of human CRD, leading to markedly disturbed behavioral rhythms and altered expression of core clock genes. The model showed good reproducibility and proved suitable for compound evaluation. Several chronobiotic compounds, including nobiletin, serotonin, N-acetylserotonin, melatonin, catechin, and capsaicin, alleviated CRD-associated phenotypes to varying degrees, demonstrating the model's utility for investigating the circadian regulatory effects of NBCs.

CONCLUSION: Our multidimensional analysis in C. elegans reveals that natural bioactive compounds can modulate CRD, offering new perspectives on the therapeutic potential of plant-derived chronobiotics.

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Evaluating natural bioactive chronobiotics in a C. elegans circadian disruption system induced by light-temperature entrainment

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