Identification of key immune-related genes associated with LPS/D-GalN-induced acute liver failure in mice based on transcriptome sequencing
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE217659 | GEO | 2023/04/03
REPOSITORIES: GEO
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Project description:BackgroundThe aim of this study was to identify key immune-related genes in acute liver failure (ALF) by constructing an ALF mouse model for transcriptome sequencing.MethodsThe C57BL/6 mouse with ALF model was induced by lipopolysaccharide (LPS)/ D-galactosamine (D-GalN). After successful modelling, the liver tissues of all mice were obtained for transcriptome sequencing. The key immune-related genes in mice with ALF were identified by differential expression analysis, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), enrichment analysis, and protein-protein interaction (PPI) analysis.ResultsAn LPS/D-GalN-induced ALF mouse model was successfully constructed, and transcriptome sequencing was performed. Significant differences in the proportions of monocytes, macrophages M0, macrophages M1 and neutrophils were shown by immune infiltration analysis, and 5255 genes highly associated with these four immune cells were identified by WGCNA. These immune genes were found to be significantly enriched in the TNF signalling pathway by enrichment analysis. Finally, PPI analysis was performed on genes enriched in this pathway and three key genes (CXCL1, CXCL10 and IL1B) were screened out and revealed to be significantly upregulated in ALF.ConclusionsKey immune-related genes in ALF were identified in this study, which may provide not only potential therapeutic targets for treating ALF and improving its prognosis, but also a reliable scientific basis for the immunotherapy of the disease.
| S-EPMC10166078 | biostudies-literature
Project description:Identification of key immune-related genes associated with LPS/D-GalN-induced acute liver failure in mice based on transcriptome sequencing
| PRJNA899894 | ENA
Project description:Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n=28) and non-survivors (n=30) of acetaminophen (APAP)-induced ALF from the NIH-sponsored Acute Liver Failure Study Group, and from control volunteers (n=10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom ALT was lower on day 1 than day 3, indicating a time point before the peak of injury (n=10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1,682 quantifiable proteins, 79 were elevated ≥4-fold in ALF patients vs. controls and 23 of those were further elevated ≥4-fold in non-survivors vs. survivors, indicating potential to predict death. Interestingly, the biomarker with best performance was LDH. To confirm the prognostic potential of LDH, we measured activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the non-survivors vs. survivors on both days. In addition, receiver operating characteristic (ROC) curve analyses revealed that LDH alone performed similarly to the model for end-stage liver disease (MELD), while a combination of MELD and LDH outperformed either alone. Finally, Upstream Analysis of our proteomics data indicated activation of LKB1-AMPK signaling in liver regeneration after APAP overdose and we confirmed that in mice. Overall, we conclude LDH can predict death in APAP-induced ALF and that LKB1-AMPK signaling may be a promising therapeutic target to improve survival.
2022-08-12 | PXD029576 | Pride
Project description:Background & Aims: The Rho GTPase RAC1 regulates key drivers of acute liver failure (ALF) such as oxidative stress and inflammation. The goal of this study was to determine the therapeutic potential of RAC1 pharmacological inhibition in ALF. Methods: The involvement of RAC1 in human ALF was explored by analyzing public transcriptome datasets. Murine models of ALF were induced by administration of either Concanavalin A, acetaminophen or D-Galactosamine/Lipopolysaccharide. In vitro assays were conducted on hepatocytes and macrophages primary cultures and cell lines. 1D-142 was used to explore the effect of RAC1 pharmacological inhibition. RNA-Seq analysis was performed and correlated with ALF human datasets to explore the therapeutic potential of RAC1 inhibition. Liver explants from patients with liver failure were treated in vitro with 1D-142. Results: RAC1-related pathways are upregulated in human ALF samples and correlate with immune activation and oxidative stress. Administration of 1D-142 ameliorated liver damage across all ALF murine models. 1D-142 treatment diminishes reactive oxygen species formation and reduces inflammatory cells migration and suppresses cytokine production both in vivo and in vitro. Transcriptome analysis of treated livers indicates that RAC1 pharmacological inhibition modulates dysregulated biological processes observed in ALF patients. Liver explants from ALF patients treated with 1D-142 exhibited reduced necrosis and reduced expression of pro-inflammatory genes. Conclusions: RAC1 plays a critical role in driving inflammation and oxidative stress in ALF. Targeted inhibition of RAC1 with 1D-142 protects against ALF in murine models; thus, RAC1 inhibition could be a potential therapeutic option for ALF.
2025-08-20 | GSE297179 | GEO
Project description:Acute hepatic injury caused by inflammatory liver disease is associated with high mortality. This study examined the role of caveolin-1 (Cav-1) in lipopolysaccharide (LPS) and D-galactosamine (GalN)-induced fulminant hepatic injury in wild type and Cav-1-null (Cav-1-/- ) mice. Hepatic Cav-1 expression was induced post-LPS/GalN treatment in wild-type mice. LPS/GalN-treated Cav-1-/- mice showed reduced lethality and markedly attenuated liver damage, neutrophil infiltration and hepatocyte apoptosis as compared to wild-type mice. Cav-1 deletion significantly reduced LPS/GalN-induced caspase-3, caspase-8 and caspase-9 activation and pro-inflammatory cytokine and chemokine expression. Additionally, Cav-1-/- mice showed suppressed expression of Toll-like receptor 4 (TLR4) and CD14 in Kupffer cells and reduced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 in liver cells. Cav-1 deletion impeded LPS/GalN-induced inducible nitric oxide synthase expression and nitric oxide production and hindered nuclear factor-κB (NF-κB) activation. Taken together, Cav-1 regulated the expression of mediators that govern LPS-induced inflammatory signalling in mouse liver. Thus, deletion of Cav-1 suppressed the inflammatory response mediated by the LPS-CD14-TLR4-NF-κb pathway and alleviated acute liver injury in mice.
| S-EPMC6201225 | biostudies-literature
Project description:Swertia cincta Burkill is widely distributed along the southwestern region of China. It is known as "Dida" in Tibetan and "Qingyedan" in Chinese medicine. It was used in folk medicine to treat hepatitis and other liver diseases. To understand how Swertia cincta Burkill extract (ESC) protects against acute liver failure (ALF), firstly, the active ingredients of ESC were identified using liquid chromatography-mass spectrometry (LC-MS), and further screening. Next, network pharmacology analyses were performed to identify the core targets of ESC against ALF and further determine the potential mechanisms. Finally, in vivo experiments as well as in vitro experiments were conducted for further validation. The results revealed that 72 potential targets of ESC were identified using target prediction. The core targets were ALB, ERBB2, AKT1, MMP9, EGFR, PTPRC, MTOR, ESR1, VEGFA, and HIF1A. Next, KEGG pathway analysis showed that EGFR and PI3K-AKT signaling pathways could have been involved in ESC against ALF. ESC exhibits hepatic protective functions via anti-inflammatory, antioxidant, and anti-apoptotic effects. Therefore, the EGFR-ERK, PI3K-AKT, and NRF2/HO-1 signaling pathways could participate in the therapeutic effects of ESC on ALF.
| S-EPMC10333062 | biostudies-literature
Project description:IntroductionAcute liver failure (ALF) is a clinical condition with many causes, fast progression, and a poor prognosis. Previous research has indicated that microbial factors have a role in ALF, but a clear picture has yet to emerge.MethodsTo investigate the specific involvement of microbial metabolites in ALF development, we pretreated D-GalN/LPS-induced ALF mice with indole derivatives, an influential class of gut microbial metabolites.ResultsContrary to their typical role as anti-inflammatory agents in the host, indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indolepropionic acid (IPA) gavage sensitize mice to D-GalN/LPS-induced-ALF with a rapid rise in serum transaminases and histologic lesion. For a clearer picture, we performed comprehensive analysis for the IAA therapy. IAA markedly amplified inflammatory response and cellular damage. The transcriptome analysis indicated the participation of the TNF-α/NF-κB signaling pathway. The structure of gut microbiota in ileum and the expression of Toll-like receptor 2 (Tlr2) in the liver were also significantly changed.DiscussionIn conclusion, IAA pretreatment can exacerbate D-GalN/LPS-induced ALF via probable Tlr2/NF-κB pathway involvement and ileac dysbiosis characterized by enriched gram-positive genus with potential pathogenesis. Microbial metabolites IAA may aggravate individual susceptibility to D-GalN/LPS-induced ALF. Further investigation of the underlying mechanism is needed, and intervention with indole derivatives and related commensal species should be undertaken with caution.
| S-EPMC9852867 | biostudies-literature
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
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:The liver has inherent regenerative capacity via mitotic division of mature hepatocytes. However, if the hepatic loss is massive or mature hepatocyte proliferation is impaired by chronic liver injury, HSPC are activated to support liver regeneration. Access to liver tissue from 4 patients who underwent liver transplantation for hepatitis B virus (HBV)- associated acute liver failure (ALF) provided us with the opportunity to investigate the molecular mechanisms of liver regeneration in humans by means of gene expression profiling and immunohistochemistry (IHC). Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual liver specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two-well defined clusters that segregated according to the histopathological severity, i.e. massive hepatic necrosis (MHN; 2 patients) and submassive hepatic necrosis (SHN; 2 patients). We found that ALF is characterized by a strong hepatic stem/progenitor cell (HSPC) gene signature, as also confirmed by IHC, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of cancer stem cell genes (EpCAM, CK19 and CK7), whereas the most upregulated genes in SHN were related to cellular growth and proliferation (AKR1B10, NQO1, RRM2, SFN, TOP2A, CCNB1, CDC20, ANLN and KI67). The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound healing process. Conclusion: Our data provide evidence of marked HSPC cell activation and fibrogenesis in HBV-associated ALF, which positively correlate with the extent of liver necrosis. Moreover, we detected a strong tumorigenesis gene signature in ALF, which underlines the relationship between liver regeneration and liver cancer. Liver samples were obtained from explanted liver of four patients with HBV-associated acute liver failure (4-5 samples per liver) and 10 individual normal liver donors and gene expression profiling was used to establish a molecular definition of this disease. This dataset is part of the TransQST collection.
2012-12-01 | E-GEOD-38941 | biostudies-arrayexpress