The potential of mecciRNA in hepatic stellate cell to regulate progression of nonalcoholic hepatitis

Abstract

Background Nonalcoholic steatohepatitis (NASH) occupies a substantial proportion of chronic liver disease worldwide, of which pathogenesis needs further research. Recent studies have demonstrated the significant roles of circular RNAs (circRNAs) in NASH, while the function of a novel type of circRNAs, namely mitochondria-encoded circRNAs (mecciRNAs), remains elusive. Therefore, we aimed to investigate their potential to regulate the progression of NASH in this study. Methods GSE134146 was used to screen for differentially expressed mecciRNAs in NASH, while GSE46300 was used to identify NASH-related genes. To establish the mecciRNA-miRNA-mRNA networks, circMINE and miRNet databases were used for predicting downstream targets. Then, consensus clustering analysis was used to determine immune subtypes of NASH. Finally, we successfully validated our findings in vitro (LPS-treated hepatic stellate cells [HSCs]) and in vivo (MCD-diet mice) NASH models. Results We confirmed that circRNomics balance is disrupted in HSCs of NASH, while two mecciRNAs (hsa_circ_0089761 and hsa_circ_0089763) could function as competing for endogenous RNAs (ceRNAs) to regulate fibrosis-related signals. Furthermore, we constructed two ceRNA networks based on mecciRNAs for the first time. Cell and animal NASH models validated our findings that c-MYC and SMAD2/3 were upregulated in HSCs, while THBS1 and p-STAT3 were upregulated in hepatocytes. Moreover, we identified 21 core genes by overlapping the differentially expressed genes (NASH vs. Normal) with mecciRNA-targeted genes. According to their expression profiles, NASH patients could be divided in 2 different clusters, in which proinflammatory signals (TNF and IL-17 pathways) are significantly activated in Cluster 1. Conclusion We successfully established two novel mecciRNA-miRNA-mRNA networks in HSCs and hepatocytes, which were further confirmed by in vitro and in vivo models. Meanwhile, the novel immunotyping model revealed the heterogeneity of NASH, thereby might guiding treatment options. Altogether, our study brought a distinct perspective on the relationship between mecciRNAs and NASH.

Immunohistochemical Study of Stellate Cells in Patients with Chronic Viral Heptitis C Histopathological study

“…Our study found a significant relation between age of patient and stage of fibrosis with p value of 0.012. This finding coincides with Schuppan D., et al 9 , who found that the age of onset of infection has consistently been proven to be a primary factor impacting the pace of fibrosis advancement in hepatitis C, with the speed of fibrosis progression being directly connected with the age of onset of infection in fibrosis progression analyses. Immune factors, increased fibrogenesis, or decreased fibrolysis may be involved in the influence of age on fibrosis progression, although the precise mechanisms are unknown 10 Also Bhattacharya P. and Mukherjee S. 11stated that regular heavy alcohol consumption; age (>50-55 years); female gender; hispanic or white racial background; human leukocyte antigen DRB; HIV and other immune suppressive conditions; degree of steatosis; severity of inflammation; necrosis and injury; and a high iron load are all factors that enhance fibrosis and disease progression.…”

Differential Analysis of Key Proteins Related to Fibrosis and Inflammation in Soluble Egg Antigen of Schistosoma mansoni at Different Infection Times

“…Our data also showed that TGF-β secreted by PBMC with the SEA treatment causes activation of the LX-2 cells and leads to the upregulation of hepatic fibrotic markers α-SMA and collagen 1. A recent study reveals that the expression of C-myc and Smad2/3 are upregulated in LPS-treated hepatic stellate cells, while the expression of recombinant thrombospondin 1 and phosphorylation of STAT3 is upregulated in the hepatocytes of mice with liver fibrosis [ 77 ]. Based on the above results, the CUB domain-containing protein 1 (CDCP1) screened at the 12th infection week seems to be worthy of further investigation.…”

Identification and bioinformatic analysis of CircRNAs in the plasma of patients with very severe chronic obstructive pulmonary disease

“…In previous reports, overexpression of hsa_circ_0008882 inhibited the release of cytokines after copper exposure, thereby playing a role in the regulation of inflammatory responses related to chronic respiratory diseases [ 33 ]. Because of the characteristics of sequence lengths and partial cytoplasmic localization, hsa_circ_0089763 acts as a powerful miRNA sponge [ 34 ]. hsa_circ_0062683 is proposed for the first time in this study to be involved in COPD and may be associated with clinical indicators such as age.…”