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C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

ABSTRACT: C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

PROVIDER: PRJNA1115223 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29149966_1.fastq.gz	Fastqsanger.gz
	SRR29149966_2.fastq.gz	Fastqsanger.gz
	SRR29149967_1.fastq.gz	Fastqsanger.gz
	SRR29149967_2.fastq.gz	Fastqsanger.gz
	SRR29149968_1.fastq.gz	Fastqsanger.gz

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C286 an orally available retinoic acid receptor Beta agonist drug regulates multiple pathways to achieve SCI repair

Project description:Retinoic acid receptor beta (RARbeta) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal mode of action. We have developed a first in class RARbeta agonist drug, C286, with demonstrated safety in a Phase 1 trial and proven efficacy in a sensory root avulsion rat model. Using genome-wide and pathway enrichment analysis in spinal cords of avulsed rats we show that C286 modulates regenerative pathways amongst which extracellular matrix (ECM) and adhesion molecules were of note. Protein expression analysis showed that C286 upregulates tenascin-C, integrin alpha9 and osteopontin in the injured cord. We further demonstrate the drug's efficacy in a rodent model of spinal cord contusion where it remodulates ECM molecules, hampers inflammation and prevents tissue loss. Treatment with the agonist induced upregulation of RARbeta in dorsal root and spinal neurons. In the single ascending dose (SAD) cohorts in white blood cells from healthy human participants RARbeta2 expression increases with dose and at the highest dose administered the pharmacokinetics are similar to doses used in rat proof of concept (POC) studies. We also show plasma S100B in nerve injured rats as a correlative measure of axonal regeneration. Finally, comparison with other clinically available retinoids which are non RARbeta selective showed these were ineffective in aiding regain of function in avulsed rats. Taken together our data suggests that further clinical testing of C286 in POC trials is justifiable for a broad spectrum of SCIs

2024-08-08 | GSE268237 | GEO

Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

Project description:Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.

2020-07-28 | GSE151588 | GEO

Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

Project description:Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

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Differential gene expression following SCI in trkB.T1 null

Project description:We asked what genes are significantly differentially regulated in the spinal cord of SCI trkB.T1 WT and trkB.T1 KO mice. TrkB.T1 is upregulated shortly after SCI although the precise mechanisms underyling this upregulation are poorly understood. In the trkB.T1 null, we show less mechanical allodynia and better locomotor recovery following SCI. The microarray studies helped us to elucidate a signaling pathway that is differently regulated in the WT versus KO mice at 1 day after SCI. In this study, we did not examine gene changes within a genotype after SCI. Rather, we examined DGE by genotype at each time point. Spinal cord tissue from WT and KO mice in a sham condition (intact spinal cord) versus 1D, 3D and 7D following SCI was harvested for microarray analyses.

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Differential gene expression following SCI in trkB.T1 null

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