Project description:Compared to whole serum miRNAs, miRNAs in serum small extracellular vesicles (sEVs) are well protected form RNA enzymes, thus provide a consistent source of miRNA for disease biomarker detection. Serum sEVs and their miRNA cargos released by injured liver cells could be promising biomarkers for diagnosis of liver diseases. We were very interested to find out the effects of liver injury on serum extracellular vesicles as well as the small RNA components they transported, if there is any difference between acute and chronic injury. Study in this regard will help us to identify new serum biomarkers for liver injury, and to find out if there are specific markers for acute or chronic liver injury. To identify potential biomarker for liver injury based on serum sEVs miRNAs, we established the carbon tetrachloride (CCL4) induced acute and chronic liver injury mice model, and examined the dynamic changes of small RNA components, especially miRNAs, in serum sEVs.
Project description:Acetaminophen is a widely used antipyretic and analgesic drug, and its overdose is the leading cause of drug-induced acute liver failure. This study aimed to investigate the effect and mechanism of Lacticaseibacillus casei Shirota (LcS), an extensively used and highly studied probiotic, on acetaminophen-induced acute liver injury. C57BL/6 mice were gavaged with LcS suspension or saline once daily for 7 days before the acute liver injury was induced via intraperitoneal injection of 300 mg/kg acetaminophen. The results showed that LcS significantly decreased acetaminophen-induced liver and ileum injury, as demonstrated by reductions in the increases in aspartate aminotransferase, total bile acids, total bilirubin, indirect bilirubin and hepatic cell necrosis. Moreover, LcS alleviated the acetaminophen-induced intestinal mucosal permeability, elevation in serum IL-1α and lipopolysaccharide, and decreased levels of serum eosinophil chemokine (eotaxin) and hepatic glutathione levels. Furthermore, analysis of the gut microbiota and metabolome showed that LcS reduced the acetaminophen-enriched levels of Cyanobacteria, Oxyphotobacteria, long-chain fatty acids, cholesterol and sugars in the gut. Additionally, the transcriptome and proteomics showed that LcS mitigated the downregulation of metabolism and immune pathways as well as glutathione formation during acetaminophen-induced acute liver injury. This is the first study showing that pretreatment with LcS alleviates acetaminophen-enriched acute liver injury, and it provides a reference for the application of LcS.
Project description:The aim of this study was to assess whether chronic treatment with RPV can modulate the progression of chronic liver disease, especially of non-alcoholic fatty liver disease (NAFLD), through a nutritional model in wild-type mice Mice were daily treated with RPV (p.o.) and fed with normal or high fat diet during 3 months to induce fatty liver disease
Project description:The key exosomal miRNAs in adaptive response to drug-induced liver (DILI) and liver regeneration were investigated and proved. This study aimed to decipher the mechanism of restorative events in the adaptive response to DILI by investigating circulating exosomal miRNAs. Using toosendanin-induced liver injury model, exosomal miR-106b-5p was identified as a robust driver in the adaptive response of TILI.
Project description:Background and aims: Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis. A common cause of ACLF is sepsis secondary to bacterial infection. Sepsis-associated ACLF involves a loss of differentiated liver function in the absence of direct liver injury, and its mechanism is unknown. We aimed to study the mechanism of sepsis associated ACLF using a novel mouse model. Approach and Results: Sepsis-associated ACLF was induced by cecal ligation and puncture procedure (CLP) in mice treated with thioacetamide (TAA). The combination of TAA and CLP resulted in a significant decrease in liver synthetic function and high mortality. These changes were associated with reduced metabolic gene expression and increased C/EBPβ transcriptional activity. We found that C/EBPβ binding to its target gene promoters was increased. In humans C/EBPβ chromatin binding was similarly increased in ACLF group compared to control cirrhosis. Hepatocyte specific Cebpb knockout mice had reduced mortality and increased gene expression of hepatocyte differentiation markers in TAA/CLP mice, suggesting that C/EBPβ promotes liver failure in these mice. C/EBPβ activation was associated with endothelial dysfunction, characterized by reduced Angiopoietin-1/Angiopoietin-2 ratio and increased endothelial production of HGF. Angiopoietin-1 supplementation or Hgf knockdown reduced hepatocyte C/EBPβ accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives acute-on-chronic liver failure via HGF-C/EBPβ pathway. Conclusion: The transcription factor C/EBPβ is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis.
Project description:Acute myeloid leukemia (AML) cells release abundant exosomal miR-7977 that transfer into bone marrow (BM) mesenchymal stromal cells (MSCs). We have shown that exosomal miR-7977 was highly released from AML cells and was transferred into BM MSCs. It has been well known that a microRNA has multiple targets. In fact, miRDB predicted 633 targets. Based on these findings, control and miR-7977mimic were transferred into BM MSCs. Subsequently, alteration of transcriptome was analyzed to gain insight into the role of miR-7977 in bone marrow micro environment.
Project description:To explore how tumor-derived exosomes activate fibroblasts and foster lung metastasis of liver cancer. MiRNAs encapsulated in exosomes are abundant and play an important role in cell-cell communication. Therefore, we hypothesized that tumor-derived exosomal miRNAs mediate fibroblasts activation. To identify the specific miRNAs involved, we conducted microarrays to generate miRNAs profiles of exosomes derived from the four liver cancer cell lines with different migration and invasion abilities. CSQT-2 and HCC-LM3 cells were high metastatic cancer cells, versus to HepG2 and MHCC-97L cells. We divided them into the following groups: CSQT-2 versus HepG2 (with different origins), HCC-LM3 versus MHCC-97L (with the same origin) and compared the up-regulated miRNAs in both two high-metastatic cancer cells-derived exosomes. Then, these up-regulated miRNAs were subjected to validation to define the most important exosomal miRNAs in regulating fibroblast activation and contributing to lung metastasis of liver cancer.