RNA-seq analysis of brain tissue treated by VEGFC in BDL-induced cirrhotic rat with hepatic encephalopathy
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PROVIDER: PRJNA627703 | ENA |
REPOSITORIES: ENA
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Project description:Aims: Hepatic encephalopathy (HE) is a serious neurological complication in patients with liver cirrhosis. Nothing is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. Methods: A 4-week bile duct ligation (BDL) model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated using archived GSE41919. Motor function of rats was assessed by the rotarod test. AAV8-VEGF-C was injected into the cisterna magna of BDL rats one day after surgery to induce meningeal lymphangiogenesis. Results: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (p<0.001) as well as increased neuroinflammation as indicated by significant increases in IL-1, INF, TNF and Iba1 expression in at least one of the three regions of the cortex. Motor function was also impaired in rats with HE (p<0.05). Human brains of cirrhotic patients with HE also exhibited upregulation of pro-inflammatory genes (NF-κβ, Iba1, TNFα and IL-1β) (n=6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (p=0.035) and tracer dye uptake in the anterior and middle regions of the cortex (p=0.006 & 0.003, respectively), their corresponding meninges (p=0.086 & 0.006, respectively) and the draining lymph nodes (p=0.02). Further, AAV8-VEGF-C decreased microglia activation (p<0.001) and neuroinflammation, and ameliorated motor dysfunction (p=0.024). Conclusion: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.
2023-04-23 | GSE149227 | GEO
Project description:Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE.
2021-01-27 | GSE149741 | GEO
Project description:Hepatic Encephalopathy is the brain disorder caused by liver damage, characterized by cognitive and motor impairments. Glutamate a predominant excitatory neurotransmitter over activate post-synaptic neuron via NMDAR receptors leads to neuronal derangement. NMDAR as a therapeutic target is not viable option due to its crucial role in brain physiology. In order to discover new non-NMDAR therapeutic targets high resolution mass spectrometry (HRMS) technique was used for proteomic profiling of the hippocampal proteins in Moderate hepatic encephalopathy (MoHE) rat model.
2024-05-27 | PXD036723 | Pride
Project description:Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies.
2023-05-30 | GSE230287 | GEO
Project description:Identify differentially expressed genes related to the neurodegenerative process in a new animal model of hepatic encephalopathy (HE). The animal model consists on the simulation of several bouts of HE in PCA rats, being the precipitant factors of the episodes ammonia (NH3) and/or lipopolisaccharide (LPS) or saline.
2015-07-29 | GSE71425 | GEO
Project description:Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is seen as the clinical manifestation of a low grade cerebral edema associated with oxidative-nitrosative stress, however, comprehensive data on HE-associated molecular derangements in human brain are lacking. In the present study we used a whole human genome micro-array approach for gene expression profiling in post mortem brain samples from cirrhotic patients with or without HE and non-cirrhotic controls. Altered expression levels were found for a total of 1012 genes in liver cirrhotic patients without and with HE and HE-characteristic gene expression changes were identified. Genes with altered expression pattern in HE were related oxidative stress, microglia activation, inflammatory signalling pathways, cellular proliferation and apoptosis. Despite an up-regulation of genes associated with microglia activation, pro-inflammatory cytokine mRNA profiles remained unchanged in the brain of patients with liver cirrhosis and HE as compared to controls. Interestingly, many genes counteracting pro-inflammatory signalling and inflammatory cytokine expression were up-regulated in the cerebral cortex of patients with liver cirrhosis and HE. It is concluded that pathogenetic mechanisms of HE deduced from cell culture and animal experiments, such as oxidative stress, altered Zn2+-homeostasis and microglia activation also apply to human brain from cirrhotic patients with HE. The study also revealed a not yet recognized increased expression of genes antagonizing pro-inflammatory signalling and inflammatory cytokine expression. The dataset comprises 19 samples divided into three sample groups each representing a certain liver disease condition of humans.
2013-05-01 | E-GEOD-41919 | biostudies-arrayexpress
Project description:Background and aims: There are considerable evidences demonstrating that angiogenesis and chronic inflammation are mutually dependent. However, although cirrhosis progression is characterized with a chronic hepatic inflammatory process, this connection is not sufficiently explored as a therapeutic strategy. Therefore, this study was aimed to assess the potential benefits of targeting angiogenesis in cirrhotic livers to modulate inflammation and fibrosis. For this purpose, we evaluate the therapeutic utility of angiogenesis inhibitors. Methods: The in vivo effects of angiogenesis inhibitors were monitored in liver of cirrhotic rats by measuring angiogenesis, inflammatory infiltrate, fibrosis, a-smooth muscle actin (a-SMA) accumulation, differential gene expression (by microarrays), and portal pressure. Results: Cirrhosis progression was associated with a significant enhancement of vascular density and expression of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1, angiopoietin-2 and placental growth factor (PlGF) in cirrhotic livers. The newly formed hepatic vasculature expressed vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Interestingly, the expression of these adhesion molecules correlated well with local inflammatory infiltrate. Livers of cirrhotic rats treated with angiogenesis inhibitors presented a significant decrease in hepatic vascular density, inflammatory infiltrate, a-SMA abundance, collagen expression and portal pressure. Conclusion: Angiogenesis inhibitors may offer a potential novel therapy for cirrhosis due to its multiple mechanisms of action against angiogenesis, inflammation and fibrosis in cirrhotic livers. Experiment Overall Design: RNA from liver of 4 non-treated cirrhotic rats or 4 rats treated with angiogenesis inhibitors was hybridized to 8 high-density oligonucleotide microarray (Rat2302, Affymetrix, Santa Clara, CA)
2008-06-15 | E-GEOD-6929 | biostudies-arrayexpress
Project description:Identify differentially expressed genes related to the neurodegenerative process in a new animal model of hepatic encephalopathy (HE). The animal model consists on the simulation of several bouts of HE in PCA rats, being the precipitant factors of the episodes ammonia (NH3) and/or lipopolisaccharide (LPS) or saline. Regular administration (one every two weeks up to 10 infussion) of NH3 (20 μl/min along 3h) and/or LPS (5mg/kg) or in PCA rats. Sham rats were used as a surgery control.
2015-07-29 | E-GEOD-71425 | biostudies-arrayexpress
Project description:Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients
| PRJNA629828 | ENA
Project description:Gene expression profiling was performed in each of hepatocyte fraction and non-parenchymal cell fraction enriched with activated hepatic stellate cells/myofibroblasts from cirrhotic rat livers induced by repeated, low-dose diethylnitrosamine (DEN) treatment.
2016-12-16 | GSE63726 | GEO