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Novel MST1 inhibitor accelerates murine liver regeneration following partial hepatectomy with improved survival in models of steatohepatitis

ABSTRACT: Novel MST1 inhibitor accelerates murine liver regeneration following partial hepatectomy with improved survival in models of steatohepatitis

PROVIDER: PRJNA964752 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24377464_1.fastq.gz	Fastqsanger.gz
	SRR24377464_2.fastq.gz	Fastqsanger.gz
	SRR24377465_1.fastq.gz	Fastqsanger.gz
	SRR24377465_2.fastq.gz	Fastqsanger.gz
	SRR24377466_1.fastq.gz	Fastqsanger.gz

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Novel MST1 inhibitor accelerates murine liver regeneration following partial hepatectomy with improved survival in models of steatohepatitis

Project description:Disrupted hepatocyte regeneration following surgical resection remains a clinical problem with few therapeutic options. The current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration may provide an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration in both normal and diseased murine preclinical models. mCLC846 demonstrated on target inhibition of MST1 and reduced EGFR inhibition which resulted in Yes-associated protein (YAP) activation. Oral delivery of mCLC846 perioperatively resulted in accelerated liver regeneration and improved survival in diet induced NASH models. Transcriptional analysis suggested that mCLC846 enhanced the normal regenerative pathways induced following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided survival benefit in models of diet induced non-alcoholic steatohepatitis.

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Partial hepatectomy accelerates colorectal metastasis by priming a prometastatic niche in the liver

Project description:Partial hepatectomy accelerates colorectal metastasis by priming a prometastatic niche in the liver

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Partial hepatectomy accelerates colorectal metastasis by priming a prometastatic niche in the liver

Project description:Despite being the standard of care for patients with Stage IV colorectal cancer (CRC), the effects of a resection of liver metastasis on the metastatic disease are poorly understood. To elucidate the influence of surgical metastasectomies on metastasized CRC, we investigated the cellular and molecular effects of partial hepatectomy in a mouse model of orthograde CRC liver metastasis.

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Comparison of hepatic gene change after partial hepatectomy

Project description:Partial hepatectomy, resection of a portion of liver mass, indues significant liver regenerative responses that consist of numerous genetic changes. To identify specific genetic changes, we compare the liver of mice underwent either hepatectomy or sham operation.

2010-11-01 | GSE22879 | GEO

Comparison of hepatic gene change after partial hepatectomy

2010-11-01 | E-GEOD-22879 | biostudies-arrayexpress

A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis.

Project description:Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

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Partial hepatectomy 1, 2, 4, 6h

Project description:Partial hepatectomy 1, 2, 4, 6h

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Partial hepatectomy 1, 2, 4, 6h

Project description:Adult male Sprague-Dawley rats (275-350 g) were anesthetized and subjected to two-thirds PHx. Liver sections removed by partial hepatectomy (PHx) were collected and used both as controls (time=0) and as individual reference material for each animal to reduce the error introduced by animal-to-animal variability. At 1, 2, 4, and 6 hours following PHx, rats were killed and liver samples were harvested. Keywords: Time series PHx (1, 2, 4, 6h)

2007-04-06 | GSE7415 | GEO

Expression data from rat hepatocyte during liver regeneration after partial hepatectomy

Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level.

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Effect of conditional deletion of S6 ribosomal protein following partial hepatectomy

Project description:Deletion of the RPS6 gene in mouse liver results in the inhibition of 40S ribosome biogenesis and the failure of hepatocytes to enter S-phase following partial hepatectomy. This microarray experiment was designed to assess the effects of RPS6 deletion on the expression of genes involved in liver regeneration following partial hepatectomy. Keywords: time course, liver

2009-05-01 | GSE13864 | GEO

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