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R406-Inhibition of Syk-Cn-NFAT Signaling Axis Promotes Chemical Reprogramming via Metabolic Rewiring and H2S Production

ABSTRACT: Small molecules not only are convenient and useful for controlling cell fates, but also can provide better understanding of the molecular mechanisms of cell-fate transitions. Here, we identified that spleen tyrosine kinase (Syk) inhibitor R406 could significantly promote the early stage of mouse chemical reprogramming. Furthermore, R406 alleviated the Syk-calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling cascade-mediated suppression of glycine, serine and threonine metabolic genes transcriptionally, which is previously unrecognized. In turn, R406 upregulated metabolites of glycine, serine and threonine metabolism and downstream transsulfuration cysteine biosynthesis pathway and cysteine metabolism. Subsequently, increased cellular hydrogen sulfide (H2S) after R406 treatment downregulated oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS), modulated redox homeostasis, and significantly enhanced chemical reprogramming. In sum, our studies have not only improved the chemical reprogramming technique, but also identified interesting molecular mechanisms of chemical-induced pluripotent reprogramming, which hold great potentials in regenerative medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE154687 | GEO | 2021/03/14

REPOSITORIES: GEO

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Project description:Curcumin is a polyphenolic compound extracted from the turmeric plant (Curcuma longa) and has been extensively studied for its anti-inflammatory and anti-proliferative properties. The safety and effectiveness of curcumin have been thoroughly proven. However, the mechanisms underlying the treatment of osteoarthritis remain unclear. This study aimed to reveal the potential mechanism of curcumin in the treatment of osteoarthritis through metabolomics and transcriptomics. First, we verified the effect of curcumin on inflammatory factors in human articular chondrocytes. Secondly, we used cellular metabolomics to explore the cellular metabolic mechanism of curcumin against osteoarthritis. Third, we evaluated differences in gene expression in human articular chondrocytes by transcriptomics. Finally, to evaluate essential targets and elucidate the underlying mechanisms of curcumin in the treatment of osteoarthritis, we performed a screen for proteins in pathways shared by metabolomics and transcriptomics. Our results showed that curcumin significantly reduced the levels of inflammatory markers, such as IL-β, IL-6, and TNF-α, in human articular chondrocytes. Cellular metabolomics identified 106 differential metabolites, including beta-aminopropionitrile, 3-amino-2-piperidone, pyrrole-2-carboxaldehyde, and various other components. Transcriptome analysis yielded 1050 differential mRNAs. Enrichment analysis showed that differential metabolites and mRNA were significantly enriched in 7 pathways including glycine, serine, and threonine metabolism; interconversion of pentose and glucuronic acid; glycerolipid metabolism; histidine metabolism; mucin type O-glycan biosynthesis; phosphoinositide metabolism; and cysteine and methionine metabolism. A total of 23 key targets were identified to be involved in these pathways. We speculate that curcumin may alleviate osteoarthritis by targeting key proteins involved in glycine, serine, and threonine metabolism, inhibiting pyruvate production, and regulating glycolysis.

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R406-Inhibition of Syk-Cn-NFAT Signaling Axis Promotes Chemical Reprogramming via Metabolic Rewiring and H2S Production

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