Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy
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ABSTRACT: 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.
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.
Project description:Currently, the therapeutic prospects for cirrhosis patients are limited to liver transplantation and, therefore, there is an urgent need to develop new therapeutic strategies for improved treatments. Cirrhosis was induced in male Wistar rats with CCl4 treatment, and RNA from the complete livers was extracted and quantified through microarray experiments. Angiopoietins signalling is a key pathway in blood vessel normalization. Angiopoietin 1 (Ang1)-Tie2 signalling stabilizes blood vessels, Angiopoietin 2 (Ang2) on the other hand is a context-dependent antagonist of Ang1 and decreases its stabilizing effect giving rise to immature blood vessels. Cirrhotic conditions are characterized by higher expression and activity of Ang2 than healthy conditions, resulting in the loss of blood vessels stability. Previous work showed that inhibition of Ang2 via CVX-060 enhances Ang1-Tie2 signalling, and can stabilize the vascular system in cirrhotic livers. We therefore performed RNA extraction after treatment of cirrhotic rats with CVX-060 during 4 weeks. We observed changes in expression state (expressed/not expressed) in key transcription factors previously implicated in cirrhosis.
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)
Project description:Cirrhosis and cancers of the upper digestive tract, colorectal and ENT share common risk factors. Liver cirrhosis can change the elimination of cancer drugs.
Precise data on management and outcome of patients with liver cirrhosis undergoing chemotherapy are lacking. Most patients have been excluded from clinical trials evaluating conventional therapies.
The study of tolerance, side effects, and outcome in patients with cirrhosis could help improve chemotherapy management for better tolerance and efficacy.
The main objective is to estimate the frequency of liver cirrhosis among patients evaluated in CPR for ENT, upper digestive or colorectal cancer.
Secondary objective includes the evaluation ofthe impact of cirrhosis on the management of chemotherapy by comparing cirrhotic patients’ outcomes with a control group of matched non-cirrhotic patients.
Project description:In variceal bleeding liver function deterioration is a major cause of death. The effects of bleeding on intrahepatic microvascular dysfunction, which contributes to liver injury in cirrhosis, are largely unknown. The aims of this study were to evaluate the impact of hemorrhage/resuscitation (H/R) on cirrhotic microcirculation, and whether simvastatin, a drug that improves liver microcirculation, has hepatoprotective effects. The study was performed in three groups of rats: controls, rats with biliary cirrhosis (CBDL) and CBDL rats pre-treated with 3 doses (5 mg*Kg-1*day-1) of simvastatin. Rats were submitted to H/R or sham procedure. Subsequently, livers were isolated and perfused for functional assessment of liver microcirculation. Liver transcriptome was assessed with microarrays. H/R significantly impaired endothelial-dependent vasorelaxation in cirrhotic (p=0.035) but not control livers. H/R induced a similar increase in ALT in control and cirrhotic rats, whereas the increase in AST was 10 times higher in cirrhotic than in control rats (p=0.007). Simvastatin prevented the impairment in endothelial-dependent vasorelaxation induced by H/R, and reduced by half the increase in ALT and AST (p<0.05). Transcriptomics showed a marked upregulation of genes related to inflammatory response after H/R in cirrhotic livers, but not in controls, and this was blunted by simvastatin. In conclusion, H/R aggravates liver microvascular dysfunction in cirrhosis, and upregulates liver inflammatory pathways. This does not occur in control livers. Simvastatin prevented H/R-induced liver endothelial dysfunction, and attenuated liver injury and liver inflammatory response, suggesting that it might have potential for protecting the cirrhotic liver during bleeding complications.
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. Keywords: angiogenesis, cirrhosis, liver, Affymetrix, fibrosis
Project description:Gene profiling of hepatocytes in early and advanced cirrhotic Rats Two-condition experiment, Advanced cirrhosis vs Control liver, Advanced cirrhosis vs Early cirrhosis. Biological replicates: 5 Advanced cirrhosis, 5 Early cirrhosis, 5 control liver. Each hepatocyte was isolated independently. One replicate per array.
Project description:Background and aims: Patients with decompensated cirrhosis present serious infections of bacterial origin. During homeostasis, resident macrophages from the liver or Kupffer cells (KCS) play a key role in the phagocytosis of circulating bacteria. The objective of this study was to characterize the transcripomic and functional profile of KCs in liver cirrhosis and its relationship with the risk of infections. Methods: KCs were isolated from livers of patients with cirrhosis (n = 4) and controls (n = 5) and the profile was determined by RNA sequencing. The phenotype and altered molecular pathways of the isolated KCS were analyzed through GSEA . Results: The expression profile of KCs is specific and different depending on whether they reside in a cirrhotic or control liver. The GO analysis revealed that the pathways differentially expressed in KCs isolated from cirrhotic liver are implicated in the immune response. The GSEA showed that KCs isolated from patients with cirrhosis present a greater overexpression of M1 markers with respect to M2 (normalized enrichment score, NES: 1.68, p <0.01 vs. NES: 0.8, p <0.01). Conclusion: The KCS of patients with cirrhosis have a unique and distinct gene expression profile characterized by up-regulation of M1 markers.
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.
Project description:Study goal is to disclose features of gene expression profile of peripheral blood mononuclear cells obtained from type C cirrhotic patients with or without hepatocellular carcinomas. Keywords: gene expression profile, peripheral blood mononuclear cells, type C liver cirrhosis