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Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

ABSTRACT: While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE200459 | GEO | 2022/04/10

REPOSITORIES: GEO

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Project description:Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that gene mutations that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons enhance survival during hypertonic stress. Enhanced survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, loss of ASH neuron function reduces protein damage in non-neuronal cells. Improved proteostasis capacity is due in part to upregulation of genes that play important roles in managing protein damage. We propose that inhibitory signaling from ASH neurons normally suppresses expression of genes required for non-neuronal cell proteostasis. Because all cells have the capacity to sense and respond to stressors, inhibitory neuronal signaling may be important for minimizing activation of cellular stress resistance and proteostasis pathways during short duration and less extreme stressors or stressors that can be avoided by behavioral changes. Neuronal regulation of systemic proteostasis allows the nervous system to monitor environmental variables and more effectively partition finite energy resources between different organismal processes. Our studies add to a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. mRNA expression profiling of synchronized L4 stage wild-type N2 Bristol and VC1262 osm-9(ok1677) C. elegans strains under control (51mM NaCl) and hypertonic stress (200mM NaCl).

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Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

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