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Targeting of REST with rationally-designed small-molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

ABSTRACT: Targeting of REST with rationally-designed small-molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

PROVIDER: PRJNA983731 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24915409.fastq.gz	Fastqsanger.gz
	SRR24915410.fastq.gz	Fastqsanger.gz
	SRR24915411.fastq.gz	Fastqsanger.gz
	SRR24915412.fastq.gz	Fastqsanger.gz
	SRR24915413.fastq.gz	Fastqsanger.gz

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Targeting of REST with rationally-designed small-molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

Project description:To validate role of REST (RE-1 silencing transcription factor) in glioblastoma (GBM) growth, we used CRISPR/Cas9 gene editing to generate REST-null single-cell clonal lines from GBM cell line (T98G) and non-neural HEK293 cells. We then performed gene expression profiling using data obtained from Tag-Seq of 8 cell lines: T98G CRISRP Control and 4 T98G REST-KO clones (C10, F7, G2, D4); HEK293 CRISPR Control and 2 HEK293 REST-KO clones (D10, E6).

2024-03-27 | GSE234912 | GEO

Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells.

Project description:BackgroundGlioblastoma (GBM) is an aggressive brain cancer associated with poor prognosis, intrinsic heterogeneity, plasticity, and therapy resistance. In some GBMs, cell proliferation is fueled by a transcriptional regulator, repressor element-1 silencing transcription factor (REST).ResultsUsing CRISPR/Cas9, we identified GBM cell lines dependent on REST activity. We developed new small molecule inhibitory compounds targeting small C-terminal domain phosphatase 1 (SCP1) to reduce REST protein level and transcriptional activity in glioblastoma cells. Top leads of the series like GR-28 exhibit potent cytotoxicity, reduce REST protein level, and suppress its transcriptional activity. Upon the loss of REST protein, GBM cells can potentially compensate by rewiring fatty acid metabolism, enabling continued proliferation. Combining REST inhibition with the blockade of this compensatory adaptation using long-chain acyl-CoA synthetase inhibitor Triacsin C demonstrated substantial synergetic potential without inducing hepatotoxicity.ConclusionsOur results highlight the efficacy and selectivity of targeting REST alone or in combination as a therapeutic strategy to combat high-REST GBM.

| S-EPMC11015551 | biostudies-literature

A rationally designed JAZ subtype-selective agonist of jasmonate perception

Project description:A rationally designed JAZ subtype-selective agonist of jasmonate perception

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Rationally designed, self-assembly, multifunctional hydrogel depot repairs severe spinal cord injury

Project description:Rationally designed, self-assembly, multifunctional hydrogel depot repairs severe spinal cord injury

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Multiplexed characterization of rationally designed promoter architectures deconstructs combinatorial logic for IPTG-inducible systems

Project description:Multiplexed characterization of rationally designed promoter architectures deconstructs combinatorial logic for IPTG-inducible systems

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Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable

Project description:Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable

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A rationally designed JAZ subtype-selective agonist of jasmonate perception

Project description:Gene expression profiles of WT, jaz9 and jaz10 mutant treated with mock or with 3, 6, or 8 was performed using the custom microarray Agilent-034592 The experiments were designed to explore the effect of antagonist of jasmonate perception in WT and two mutants

2018-08-05 | GSE110858 | GEO

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria.

Project description:A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by approximately 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.

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Human (21d bed rest) Muscle LC-MSMS

Project description:Muscle atrophy is one of the main deleterious consequences of physical inactivity. Bed rest represents a unique model of physical inactivity and results in main changes in muscle metabolic function. However, our knowledge on the detrimental effects of bed rest still needs clarification. The aim of this study was to decipher the mechanisms involved in disuse muscle atrophy and the effects of different countermeasures in healthy men. A cross-over trial was designed, with each trial consisting in a 7-day ambulatory control period for baseline data collection, followed by 21 days head-down tilt bed rest with or without resistive vibration exercise only or combined with nutritional (protein) supplement as countermeasures. The changes in the Vastus lateralis muscle proteome collected in the eight volunteers were characterized using mass spectrometry-based label-free quantitative proteomics.

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Polycomb Repressor Complex2 and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype

Project description:These experiments were designed to test the hypothesis that REST and Polycomb Repressor Complex 2 function cooperatively in undifferentiated ESCs. Our results show that H3K27me3-enriched genes show no de-repression in REST-/- ESCs, while REST target genes show significant de-repression.

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