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Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

ABSTRACT: Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

PROVIDER: PRJNA1010729 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25793677_1.fastq.gz	Fastqsanger.gz
	SRR25793677_2.fastq.gz	Fastqsanger.gz
	SRR25793678_1.fastq.gz	Fastqsanger.gz
	SRR25793678_2.fastq.gz	Fastqsanger.gz
	SRR25793679_1.fastq.gz	Fastqsanger.gz

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Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

Project description:Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs at the expense of neural lineages. We next show that the clinically-approved drug, Rapamycin, inhibits AP1-mediated senescence and restores aberrant NCC differentiation trajectory in human organoids exposed to VPA. Notably, in vivo validation in developing zebrafish highlighted the therapeutic promise of this approach. Collectively our data identifies a novel mechanism for VPA-associated neurodevelopmental teratogenicity and a potential pharmacological preventative strategy. The results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery and safety testing.

2023-09-05 | GSE241903 | GEO

Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder

Project description:The aim of the study was to investigate the involvement of the mTOR pathway in the autism spectrum disorder. Adolescent male rats, prenatally exposed to valproic acid (500 mg/kg ip on gestational day 12.5), were treated with the mTOR inhibitor rapamycin (10 mg/kg, ip, two consecutive days starting at postnatal day 35). Transcriptomic analysis was performed on the ventral portion of coronal sections, containing the striatum. Behavioral experiments, the electrophysiology on striatal slices, a morphological analysis by confocal microscopy and the determination synaptic proteins expression in the nucleus accumbens were also performed.

2022-09-06 | E-MTAB-12056 | biostudies-arrayexpress

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Project description:Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

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Transcription profiling of human embryonic stem cells in response to valproic acid and valproic acid analogs

Project description:Transcriptional profiling of valproic acid and valproic acid analogs in human embryonic stem cells.

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Project description:The goal of this study is to define genes that are differentially expressed in Down syndrome leukemic blasts after treatment with valproic acid (VPA) Here we report the identification gene sets that are downregulated in Down syndrome leukemic cell lines after exposure to valproic acid (VPA)

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Responder and non-responder proteomic and phosphoproteomic profiles to ATRA/Valproic acid before treatment

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Preoperative Valproic Acid and Radiation Therapy for Rectal Cancer

Project description:The purpose of this study is to first determine the maximum tolerated dose of capecitabine given alone or in combination with valproic acid during preoperative short-course radiotherapy (Phase 1). The next part of the study (Phase 2)will explore whether the addition of valproic acid or the addition of capecitabine to short-course radiotherapy, before optimal radical surgery might increase the pathologic complete tumor regression rate in patients with low-moderate risk rectal cancer.

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Genome-wide expression profiling after Valproic acid treatment in Saccharomyces cerevisiae

Project description:Valproic acid (VA) is a small-chain branched fatty acid, widely used as anticonvulsant, and mood stabilizer to treat psychiatric illness. Valproic acid is also known to inhibit the histone deacetylases (HDACs), which makes it as a potent antitumor agent in alone or in combination with other cytotoxic drugs. Beside its conventional activities, valproic acid reported to have much broader, complicated effects and affect many complex physiological processes. However the molecular mechanisms of valproic acid are unclear. So, we used budding yeast transcriptome analysis to better understand the molecular mechanism of action of valproic acid. The clusters of differentially expressed genes in microarray after VA (6mM) treatment and their functional enrichment analysis revealed its overall effects on various biological processes such as cell cycle, signal transduction, metabolism, transcription, ubiquitination, transporter activities and many more. The microarray data were validated by quantitative real-time PCR.

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