Gene Expression of brain cortex microvessels in two rat models of acute liver failure (ALF)
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE79906 | GEO | 2016/04/05
SECONDARY ACCESSION(S): PRJNA317351
REPOSITORIES: GEO
Similar Datasets
Project description:Evaluation of early transcriptional changes in blood brain barrier genes involved in the patogenesis of brain edema associated with ALF. Two different well stablished rat models were analyzed: Portacaval anastomosis plus hepatic artery ligation and portacaval anastomosis plus total hepatectomy. ALF was induced by portocaval anastomosis (PCA) and 24 hours after the surgery animals underwent hepatic artery ligation (HAL) or total hepatectomy (HEP). Sham rats were subjected to a fictitious two-step surgery. Between 8 and 12 hours after the last surgery rats were euthanized by decapitation, to avoid anesthetic effects, and cortical microvessels isolated.
2016-04-05 | E-GEOD-79906 | biostudies-arrayexpress
Project description:Superbugs such as drug-resistant Mycobacterium tuberculosis (DR-M.tb) poses a serious global health threat. Upon infection, M.tb reaches the alveolar space and comes in close contact with soluble components of the human alveolar lining fluid (ALF) for an uncertain period of time prior to and following its encounter with alveolar compartment cells. Homeostatic ALF hydrolases, which main function is maintaining lung health, modify the M.tb cell envelope, driving M.tb-host cell interactions. Still, the contribution of human ALF to M.tb adaptation to the host during infection is poorly understood. Here, we exposed 4 M.tb strains (H37Rv, HN878, CDC1551, W-7642) with different levels of virulence, transmissibility, and drug resistance to human ALF for shorter (15 min) and longer (12 h) periods of time. RNA sequencing was performed to determine the strains’ transcriptional profiles in response to ALF exposure. Gene expression analysis showed a clear temporal and strain-specific adaptation to human ALF. When comparing ALF-exposed vs. unexposed bacteria for each M.tb strain, differential expression (DE) analysis revealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE was detected at 12 h post-ALF exposure, with DR-M.tb strain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated early in all strains post-ALF exposure. These results indicate that M.tb-ALF contact (15 min to 12 h prior to M.tb recognition by host cells in the alveolar space) drives global metabolic and physiologic changes in M.tb during the initial stages of the infection, with potential implications in infection outcome.
2024-02-20 | GSE228998 | GEO
Project description:Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available singlenuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as Cxcl14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, Cxcl14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or Cxcl14 with a neutralizing antibody. We found that targeting Cxcl14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting the senescent hepatocyte had no effect. This data supports that the sustained induction of p21 in hepatocytes with persistent Cxcl14 secretion are critical mechanistic events leading to ALF in mice and human patients.
2024-04-15 | GSE255777 | GEO
Project description:Acute liver failure (ALF) has an extremely high mortality rate and lacks effective treatment. Previous studies have shown that targeting macrophage pyruvate kinase isoenzyme type M2 (PKM2) may be a new approach for ALF treatment, but the exact mechanism remains to be elucidated. In this project, based on Single-cell RNA-sequencing (scRNA-seq), Pkm myeloid selective knockout (PL) mice and wild-type (WT) mice were used to establish ALF model, analyze the single-cell transcriptomic features of liver tissues of WT mice during ALF pathology, and screen for the differentially expressed genes in liver tissues of PL mice. Potential molecular pathways of PKM2 regulation of ALF in macrophages were explored by bioinformatics analysis and validated by molecular biology methods. Result shows that, up-regulated genes in macrophages and neutrophils in mouse liver tissues during ALF were mainly enriched in multiple programmed death, such as pyroptosis, apoptosis and necroptosis, and immune-inflammation pathways. The down-regulated genes in PL mouse liver macrophages and neutrophils were mostly enriched in the above pathways. Among them, Pkm knockdown significantly down-regulated the expression of key genes of NOD-like signaling pathway, such as NLRP3, IL-1β and IL-18, inhibited hepatic macrophage pyroptosis and attenuated ALF. This study will help to elucidate the molecular mechanism of PKM2 regulating macrophage inflammatory response involved in ALF, suggesting that PKM2 may be a potential therapeutic target for ALF, and providing a theoretical basis for further research on new methods of targeting PKM2 in the treatment of ALF.
2024-10-28 | GSE254497 | GEO
Project description:Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae that leads to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from hematogenous source into the brain across the blood-brain barrier (BBB); the mechanisms however are still poorly understood. Current treatment strategies include adjuvant dexamethasone therapy for cerebral edema, the prime reason for neurological complications and mortality, which is followed up by antibiotics. The success of corticosteroids is however inconclusive, necessitating the development of new therapies for controlling cerebral edema. We have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we therefore hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is critically involved in the transmigration of pathogens across the BBB. In human and murine meningitis brain samples, HIF-1 activation was observed by immunohistochemistry. HIF-1α/VEGF expression and permeability was therefore analyzed in vitro in infected brain endothelial cells (ECs). Localization of S. pneumoniae in brain ECs from mouse/human sources was visualized in vitro and in vivo by confocal, super-resolution, and electron microscopy. S. pneumoniae infection in brain ECs resulted in upregulation of HIF-1α/VEGF by Western blotting and qRT-PCR that was associated with increased paracellular permeability, which was supported by bacterial localization at cell-cell junctions. RNA sequencing of brain microvessels from hematogenously infected mice with increased permeability and S. pneumoniae deposition in the brain showed upregulation of genes in HIF-1α/VEGF pathway. Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells and by using primary brain ECs from HIF-1α KO mice revealed a reduced endothelial permeability and transmigration of S. pneumoniae. We thus demonstrate a critical role for HIF-1α/VEGF in transmigration of S. pneumoniae across the BBB and propose targeting this pathway to prevent BBB dysfunction in infections.
2022-09-13 | GSE122952 | GEO
Project description:Candidatus Nasuia deltocephalinicola str. NAS-ALF Genome sequencing
| PRJNA206993 | ENA
Project description:Candidatus Karelsulcia muelleri str. Sulcia-ALF Genome sequencing
| PRJNA206992 | ENA
Project description:M.tb adaptation to human alveolar lining fluid (ALF)
| PRJNA952527 | ENA
Project description:Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome due to a sudden loss of hepatic cells leading to multiorgan failure. The mechanisms whereby HBV induces ALF are unknown. We used gene expression profiling to establish a molecular definition of hepatitis B virus (HBV)-associated ALF. Two patients who underwent liver transplantation for HBV-associated ALF were studied. Gene expression profiling was performed on 8 liver specimens obtained from the two patients with ALF (4 samples per liver) and individual liver specimens from 8 liver donors and normal livers from 11 patients who underwent resection for angioma. Statistical analyses were used to identify the signature genes of HBV-associated ALF. Multivariate permutation analysis identified 1,368 transcripts that were differentially expressed in ALF; 709 were up-regulated and 659 down-regulated. The most represented up-regulated transcripts were those involved in the immune response, whereas the most abundant down-regulated transcripts were those involved in metabolism and hepatic synthesis. ALF was characterized by overriding B-cell signature comprising genes related to mature B cells and plasma cells with abundant polyclonal expression of immunoglobulin genes. By contrast, there was a limited T-cell signature and up-regulation of several inhibitors of T-cell activation. Immunohistochemical analysis confirmed the prominent B-cell signature showing diffuse liver infiltration by plasma blasts and plasma cells with strong cytoplasmic staining for IgM and IgG, associated with a significant deposition of complement factors. Using phage display technology, we demonstrated that the molecular target of the massive intrahepatic antibody response is the hepatitis B core antigen (HBcAg). These data suggest that the humoral immunity may exert a primary role in the pathogenesis of HBV-associated ALF. Liver samples were obtained from explanted livers of two patients with HBV-associated ALF (4 samples per liver), 8 normal liver donors and 11 patients who underwent resection for angioma. Gene expression profiling was used to establish a molecular definition of ALF. Patient data derived from associated publication Table S2. This dataset is part of the TransQST collection.
2010-04-26 | E-GEOD-14668 | biostudies-arrayexpress