Phloridzin reveals new treatment strategies for liver fibrosis
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ABSTRACT:
PROVIDER: PRJNA846301 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19546906_1.fastq.gz | Fastqsanger.gz | |||
| SRR19546906_2.fastq.gz | Fastqsanger.gz | |||
| SRR19546907_1.fastq.gz | Fastqsanger.gz | |||
| SRR19546907_2.fastq.gz | Fastqsanger.gz | |||
| SRR19546908_1.fastq.gz | Fastqsanger.gz |
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Project description:Liver fibrosis, is an urgent public health problem and is difficult to resolve. However, various drugs for the treatment of liver fibrosis in clinical practice have their own problems during use. In this study, we used phloridzin to treat hepatic fibrosis in the CCl4-induced C57/BL6N mouse model, which was extracted from lychee core, a traditional Chinese medicine. The therapeutic effect was evaluated by biochemical index detections and ultrasound detection. Furthermore, in order to determine the mechanism of phloridzin in the treatment of liver fibrosis, we performed high-throughput sequencing of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in different groups of liver tissues, and screened for differentially expressed genes, as well as performed gene co-expression analysis of the differential lncRNAs and mRNAs. The results showed that compared with the model group, the phloridzin treated groups showed a significant decrease in collagen deposition, and decreased levels of serum alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronic acid. GO and KEGG pathway enrichment analysis of the differential mRNAs was performed and revealed that phloridzin mainly affects cell ferroptosis. Gene co-expression analysis showed that the target genes of lncRNA were obvious in cell components such as focal adhesions, intercellular adhesion, and cell-substrate junctions, and in metabolic pathways such as carbon metabolism. These results showed that phloridizin can effectively treat liver fibrosis, and the mechanism may involve ferroptosis, carbon metabolism and related changes in biomechanics.
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Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
2021-07-13 | PXD025691 | Pride
Project description:To confirm the mechanism of miR-29a in liver fibrosis healing, we have employed whole genome microarray expression profiling as a discovery platform to identify genes. CCl4 and TAA liver fibrosis model mouse were used for this experiment. After five weeks liver fibrosis induction period, mouse have been observed for one week (1w) or two weeks (2w) and negative control nucleotide (N.C) or miR-29a were injected every 3 days on this period. We used CCl4 1w N.C (n = 1), 1w miR-29a (n = 1), 2w N.C (n = 1), 2w miR-29a (n = 1), and also used TAA model mouse (total n = 8) liver samples for microarray analysis. We can get only one gene (PDGF-c) as a target of miR-29a which relate to liver fibrosis and down-regulated more than 1.5 times in common miR-29a injected group than N.C group. CCl4 and TAA liver fibrosis model mouse were used for this experiment. After five weeks liver fibrosis induction period, mouse have been obserbed for one week (1w) or two weeks (2w) and negative control nucleotide (N.C) or miR-29a were injected every 3 days on this period. We used CCl4 1w N.C (n = 1), 1w miR-29a (n = 1), 2w N.C (n = 1), 2w miR-29a (n = 1), and also used TAA model mouse (total n = 8) liver samples for microarray analysis.
2015-03-31 | E-GEOD-67423 | biostudies-arrayexpress
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2019-07-01 | E-MTAB-7298 | biostudies-arrayexpress
Project description:The aim of this study is to compare mild and advanced liver fibrosis gene expression profiling and to identify novel markers of fibrosis progression. By transcriptome analysis with a cDNA array virtually covering every transcript in liver, we compared transcript levels in mild (F1 Metavir score) and advanced (F4 Metavir score) fibrosis. A stringent selection identified a list of 16 transcripts which completely separated the 2 groups of patients (8 F1 and 8 F4). We report that dysregulations at the transcriptional level do exist between mild fibrosis (F1) and advanced fibrosis (F4). Keywords: fibrosis stage-dependent analysis Fibrosis samples were analyzed for 16 patients : 8 mild fibrosis (F1-1 to F1-8) and 8 advanced fibrosis (F4-1 to F4-8). All data in the current study were obtained from 3 separate hybridizations per RNA sample.
2008-05-24 | E-GEOD-11536 | biostudies-arrayexpress
Project description:Our previous studies revealed that exogenous administration of TSG-6 can ameliorate liver fibrosis. We next analyzed liver transcriptome changes after TSG-6 treatment in order to explore possible therapeutic changes.
2021-10-23 | GSE121669 | GEO
Project description:We have developed a new model of radiation-induced liver fibrosis and aimed to understand the underlying mechanism using RNAseq.
2022-06-22 | GSE179782 | GEO
Project description:Background and aims: Oxidative stress triggers nonalcoholic steatohepatitis (NASH) and fibrosis. Previous animal studies demonstrated that the transcription factor NRF2, the master regulator of antioxidant response, protects against NASH and fibrosis. S217879, a new generation NRF2 activator has been recently shown to trigger NASH resolution and to reduce established fibrosis in rodents. Our aim was to evaluate the therapeutic potential of S217879 in human metabolic associated fatty liver disease (MAFLD) and its underlying mechanisms using the relevant experimental 3D model of patient-derived precision cut liver slices (PCLS). Methods: We treated PCLS from 12 patients with MAFLD with S217879 or Elafibranor (PPARα/δ agonist used as a referent molecule) for two days. Safety and efficacy profiles, steatosis, liver injury, inflammation and fibrosis were assessed as well as mechanisms involved in NASH pathophysiology, namely antioxidant response, autophagy and ER-stress. Results: Neither Elafibranor nor S217879 had toxic effects at the tested concentrations on human PCLS with MAFLD. PPARα/δ and NRF2 target genes (PDK4, FGF21 and NQO1, HMOX1, respectively) were strongly upregulated in PCLS in response to Elafibranor and S217879, respectively. Compared to untreated PCLS, Elafibranor and S217879-treated slices displayed lower triglycerides and reduced inflammation (IL-1β, IL-6, CCL2). Additional inflammatory markers (CCL5, STING, ICAM-1, VCAM-1) were downregulated by S217879. S217879 but not Elafibranor lowered DNA damages (p-H2A.X, RAD51, XRCC1) and apoptosis (cleaved Caspase-3), and inhibited fibrogenesis markers expression (α-SMA, COL1A1, COL1A2). Such effects were mediated through an improvement of lipid metabolism, activated antioxidant response and enhanced autophagic flux, without effect on ER-stress. Conclusion: This study highlights the therapeutic potential of a new NRF2 activator for NASH using patient-derived PCLS supporting the evaluation of NRF2 activating strategies in clinical trials.
2024-06-07 | GSE234415 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to a potential application of bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver fibrosis. I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
2018-11-27 | GSE114261 | GEO