Suppression of APAP-induced hepatotoxicity using Slit2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1236219 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32696336_1.fastq.gz | Fastqsanger.gz | |||
| SRR32696336_2.fastq.gz | Fastqsanger.gz | |||
| SRR32696337_1.fastq.gz | Fastqsanger.gz | |||
| SRR32696337_2.fastq.gz | Fastqsanger.gz | |||
| SRR32696338_1.fastq.gz | Fastqsanger.gz |
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Project description:APAP-induced hepatotoxicity can be suppressed by treating Slit2
2025-03-19 | GSE291946 | GEO
Project description:Purpose: This study investigated the protective effect and further elucidated the mechanisms of action of O. elatus on acetaminophen (APAP)-induced liver injury (AILI). Methods: O. elatus chlorogenic-enriched fraction (OEB) was administrated orally daily for seven consecutive days, followed by a single intraperitoneal injection of an overdose of APAP after the final OEB administration. Results: OEB decreased alanine aminotransferase, aspartate aminotransferase, total cholesterol, total triglycerides contents, regulated superoxide dismutase, catalase, glutathione, malondialdehyde levels, and affected the metabolism of APAP. Furthermore, OEB treatment regulated lipid metabolism, activated the peroxisome proliferator-activated receptors signaling pathway in mice with AILI, affected immune cells, and decreased neutrophil infiltration. Conclusions: This study indicated that OEB is a potential drug candidate for the prevention of APAP-induced hepatotoxicity and elucidated a potential protective mechanism by OEB.
2021-08-20 | GSE182399 | GEO
Project description:The relative quantification of sex-specific proteomic responses led to the detection of potential biomarkers for hepatotoxicity and as well as the identification of the underlying molecular perturbation needed to unravel the impact of APAP-induced liver injury on physiological system.
2019-11-18 | PXD013357 | Pride
Project description:Acetaminophen (APAP) is a commonly used analgesic responsible for more than half of acute liver failure cases. Identification of previously unknown genetic risk factors would provide mechanistic insights and novel therapeutic targets for APAP-induced liver injury. This study used a genome-wide CRISPR-Cas9 screen to evaluate genes that are protective against, or cause susceptibility to, APAP-induced liver injury. HuH7 human hepatocellular carcinoma cells containing CRISPR-Cas9 gene knockouts were treated with 15mM APAP for 30 minutes to 4 days. A gene expression profile was developed based on the 1) top screening hits, 2) overlap of expression data from APAP overdose studies, and 3) predicted affected biological pathways. We further demonstrated the implementation of intermediate time points for the identification of early and late response genes. This study illustrated the power of a genome-wide CRISPR-Cas9 screen to systematically identify novel genes involved in APAP-induced hepatotoxicity and to provide potential targets to develop novel therapeutic modalities.
2019-02-04 | GSE112463 | GEO
Project description:RNAseq on APAP, APAP+MSC, APAP+HDF at 24h
| PRJNA814326 | ENA
Project description:RNAseq of liver homogenate 24h after APAP (300mg/kg) exposure followed by either MSC or HDF at 90 min. MSCs, not HDFs, ameliorate APAP-induced liver injury.
2022-09-16 | GSE198277 | GEO
Project description:Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury (DILI) and acute liver failure (ALF), and patients with advanced APAP toxicity rarely benefit from N-acetylcysteine (NAC), which is the first-line agent used in the clinic. Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have shown promising effects in the treatment of DILI by decreasing neutrophil infiltration. However, the specific mechanism underlying the therapeutic effects of MSCs or MSC-EVs still needs to be elucidated. In this study, by using RNA-seq, we found that CXCL1, which is a chemoattractant for neutrophils, is a key molecule in MSC-mediated amelioration of DILI, and by luciferase reporter assay, we verified that MSC-EV-derived miR-186-5p binds to the 3’-UTR of CXCL1 to inhibit its expression in hepatocytes. Neutralizing CXCL1 reduces APAP-induced liver damage in vivo, and the agomir miR-186-5p shows excellent potential in the treatment of DILI. Overall, these findings suggest that the use of MSC-EVs may be a promising novel strategy for preventing DILI and that targeting the miR-186-5P/CXCL1 axis is a feasible approach for improving the efficacy of MSCs in the treatment of DILI.
2024-11-13 | GSE252192 | GEO
Project description:Background The axon guidance cue Slit2 recently has been found to regulate calcium homeostasis and molecular signaling in various stress events in different organs. However, whether Slit2 plays a role in cardiac ischemia-reperfusion (IR) injury has not been reported. Here, we aimed to investigate the role of Slit2 and the underlying mechanisms in cardiac IR injury. Methods Langendorff-perfused isolated hearts from Slit2-overexpressing (Slit2-Tg) mice and their background strain C57BL/6J mice were subjected to 20 min of global ischemia followed by 40 min of reperfusion. Left ventricular function of isolated hearts was monitored. Infarct size of post-IR hearts was determined by staining with 2,3,5-triphenyltetrazolium chloride (TTC) and histological changes of cardiac tissues and cells were determined with hematoxylin-eosin (HE) staining and transmission electron microscopy. Transcriptomic analysis was used to predict the biological processes and signaling pathways affected by Slit2 overexpression in the post-IR myocardium. Pro-Q staining and Western blotting was used to assess the phosphorylation levels of cardiac myofilaments and expression levels of myofilament-associated protein kinase and phosphatases. Results Slit2 overexpression increased post-IR left ventricular developed pressure (LVDP) by 35% and reduced infarct size by 53%, along with decreased myofibrillar disruption, mitochondrial swelling, and mitochondrial cristae dissolution. Slit2 overexpression significantly changed post-IR gene expression profiles. Functional products of these genes include regulation of cation transmembrane transport, cation homeostasis, collagen fibril organization, and regulation of heart rate. And post-IR myocardial KEGG pathways upregulated by Slit2 overexpression include ECM-receptor interaction, PI3K-Akt signaling pathway, and adrenergic signaling. Slit2 overexpression impacted myofilament phosphorylation together with myofilament-associated protein kinase C (PKC) isoforms and protein phosphatases (PPs). IR in C57BL/6J hearts upregulated phosphorylation of cardiac troponin-I (cTnI), which was suppressed by Slit2 overexpression. Myofilament‐associated PKCε, PKCδ, and PP2A were significantly increased post‐IR in C57BL/6J hearts, but in Slit2‐Tg hearts, myofilament‐associated PKCε and PP2A were increased and PKCδ was suppressed. Conclusions Our results demonstrate that Slit2 overexpression protects cardiac function and reduces IR injury, which is associated with Slit2‐induced gene profile shifts. The suppression of MyBP‐C and troponin‐I phosphorylation, and myofilament‐associated PKCδ levels induced by Slit2 overexpression could contribute to the cardioprotection of Slit2 in post-IR myocardium.
2019-07-04 | GSE133796 | GEO
Project description:EV-derived miR-186-5p alleviates APAP-induced liver injury by the suppression of CXCL1
| PRJNA1058487 | ENA
Project description:Rationale: Slit2 is a possible modulator of vascular endothelial growth factor (VEGF) - induced angiogenesis, but its effects have not been tested in large animal models. Objective: We studied the effect of Slit2 on therapeutic angiogenesis induced by VEGF receptor 2 (VEGFR2) ligands Vammin and VEGF-DΔNΔC in vivo in rabbit skeletal muscles. The Slit2 target genes were also studied by RNA sequencing (RNA-Seq) in endothelial cells. Methods and Results: Adenoviral intramuscular gene transfers were performed into rabbit hindlimbs. Confocal and multiphoton microscopy were used for blood vessel imaging. Signaling experiments and gene expression analyses were performed to study mechanisms of Slit2 action. Slit2 decreased VEGFR2-mediated vascular permeability. It also reduced VEGFR2-mediated increase in blood perfusion and capillary enlargement, whereas sprouting of the capillaries was increased. Slit2 gene transfer alone did not have any effects on vascular functions or morphology. VEGFR2 activation was not affected by Slit2, but eNOS phosphorylation was diminished. The transcriptome profiling showed Slit2 downregulating angiogenesis-related genes such as nuclear receptor subfamily 4 group A member 1 (NR4A1) and Stanniocalcin-1 (STC-1) as well as genes related to endothelial cell migration and vascular permeability. Conclusions: Combining Slit2 with VEGFs adjusts VEGFR2-mediated angiogenic effects into a more physiological direction. This possibly allows the use of higher VEGF vector doses to achieve a more widespread vector and VEGF distribution in the target tissues leading to a better therapeutic outcome while reducing excess vascular permeability. HUVEC mRNA profiles after adenoviral vector gene transfers in duplicate.
2015-05-26 | E-GEOD-63283 | biostudies-arrayexpress