Dataset Information

Differential expression and bioinformatic analysis of circRNA in nonalcoholic steatohepatitis cirrhosis.

ABSTRACT: Aim: This study investigates the expression profile of circRNA in nonalcoholic steatohepatitis (NASH) cirrhosis and identifies the underlying pathogenesis of core genes of NASH cirrhosis.

Methods: The GEO 134146 dataset was obtained from GEO database. EdgeR software was used to analyze the differential expression of circRNA between NASH cirrhosis samples and normal samples, and Starbase and miRWalk databases were used to predict the targeted miRNA and mRNA. The protein-protein interaction network of these target genes was established by searching the string database of interacting genes, Cytoscape and Mcode analysis. In addition, David and Omicshare were used to analyze the functional enrichment and pathway enrichment of target genes.

Results: We evaluated 99 differentially expressed circRNAs, 27 of which were up-regulated, and 72 were down-regulated. A regulatory network consisting of 10 circRNAs, 30 miRNAs, and 1217 mRNAs was further constructed. The differential expression of circRNA is closely related to the functions of "target gene transcriptional regulation", "protein binding", "serine/threonine kinase", etc. The difference in circRNA is mainly related to the "MAPK" signaling pathway and the "FoxO" signaling pathway.

Conclusions: This study confirmed the abnormal regulation of circRNA in NASH cirrhosis. Bioinformatic analysis showed that abnormal expression of circRNA might be related to the occurrence and development of NASH cirrhosis.

SUBMITTER: Fan Y

PROVIDER: S-EPMC7716119 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Differential expression and bioinformatic analysis of circRNA in nonalcoholic steatohepatitis cirrhosis.

Fan Yuexin Y Zheng Yang Y Wang Jiahui J Zhao Tiejian T Liang Tianjian T

International journal of clinical and experimental pathology 20201101 11

<h4>Aim</h4>This study investigates the expression profile of circRNA in nonalcoholic steatohepatitis (NASH) cirrhosis and identifies the underlying pathogenesis of core genes of NASH cirrhosis.<h4>Methods</h4>The GEO 134146 dataset was obtained from GEO database. EdgeR software was used to analyze the differential expression of circRNA between NASH cirrhosis samples and normal samples, and Starbase and miRWalk databases were used to predict the targeted miRNA and mRNA. The protein-protein inter ...[more]

PMID: 33284878

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Project description:BackgroundCircRNAs are noncoding RNA molecules that have recently been described and shown to regulate miRNA functionality. While recent studies have suggested such circRNAs to be associated with pain related diseases in humans, no comprehensive migraine-related circRNA profiles have been generated, and there is currently no clear understanding of whether they can serve as regulators of migraine pathology.MethodsWe initially conducted a circRNA microarray analysis of the plasma of migraine patients and healthy controls. Based upon these data, we then selected 8 differentially expressed circRNAs and confirmed their expression in more migraine patient plasma samples via real-time PCR. We then performed functional and pathway enrichment analyses. Lastly, using a robust rank aggregation approach, we constructed a ceRNA network according to predicted circRNA-miRNA and miRNA-mRNA pairs in these migraine patient samples.ResultsWe were able to detect 2039 circRNAs in our patient samples, with 794 of 1245 these circRNAs being up- and downregulated in migraine patients relative to controls, respectively (fold change ≥ 1.5, p < 0.01). A qRT-PCR analysis confirmed that the expression of hsa_circRNA_100236, hsa_circRNA_102413, and hsa_circRNA_000367 was significantly enhanced in migraine patients, whereas the expression of hsa_circRNA_103809, hsa_circRNA_103670, and hsa_circRNA_101833 was significantly reduced in these individuals relative to healthy controls. We found these differentially regulated circRNAs to be associated with numerous predicted biological processes, with enrichment analyses suggesting that they may modulate the PI3K-Akt signaling so as to promote inflammation to drive migraine development. However, further research will be needed to formally test these mechanistic possibilities and to validate these circRNAs as potential biomarkers of migraine patients.ConclusionsOur results offer new potential insights into the mechanistic basis of this condition and suggest that hsa_circRNA_000367 and hsa_circRNA_102413 may offer value as regulators of migraine pathology.

Project description:ImportanceObesity is the most common risk factor for nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease that can lead to cirrhosis and hepatocellular carcinoma. Weight loss can be an effective treatment for obesity and may slow the progression of advanced liver disease.ObjectiveTo assess the cost-effectiveness of bariatric surgery in patients with NASH and compensated cirrhosis.Design, setting, and participantsThis economic evaluation study used a Markov-based state-transition model to simulate the benefits and risks of laparoscopic sleeve gastrectomy (SG), laparoscopic Roux-en-Y gastric bypass (GB), and intensive lifestyle intervention (ILI) compared with usual care in patients with NASH and compensated cirrhosis and varying baseline weight (overweight, mild obesity, moderate obesity, and severe obesity). Patients faced varied risks of perioperative mortality and complications depending on the type of surgery they underwent. Data were collected on March 22, 2017.Main outcomes and measuresLife-years, quality-adjusted life-years (QALYs), costs (in 2017 $US), and incremental cost-effectiveness ratios (ICERs) were calculated.ResultsDemographic characteristics of the patient population were based on a previously published prospective study (n = 161). Patients in the model were 41.0% female, and the base case age was 54 years. Compared with usual care, SG was associated with an increase in QALYs of 0.263 to 1.180 (bounds of ranges represent overweight to severe obesity); GB, 0.263 to 1.207; and ILI, 0.004 to 0.216. Sleeve gastrectomy was also associated with an increase in life-years of 0.693 to 1.930; GB, 0.694 to 1.947; and ILI, 0.012 to 0.114. With usual care, expected life-years in overweight, mild obesity, moderate obesity, and severe obesity were 12.939, 11.949, 10.976, and 10.095, respectively. With usual care, QALY in overweight was 6.418; mild obesity, 5.790; moderate obesity, 5.186; and severe obesity, 4.577. Sleeve gastrectomy was the most cost-effective option for patients across all weight classes assessed: ICER for SG in patients with overweight was $66 119 per QALY; mild obesity, $18 716 per QALY; moderate obesity, $10 274 per QALY; and severe obesity, $6563 per QALY. A threshold analysis on the procedure cost of GB found that for GB to be cost-effective, the cost of the surgery must be decreased from its baseline value of $28 734 by $4889 for mild obesity, by $3189 for moderate obesity, and by $2289 for severe obesity. In overweight patients, GB involved fewer QALYs than SG, and thus decreasing the cost of surgery would not result in cost-effectiveness.Conclusions and relevanceBariatric surgery could be highly cost-effective in patients with NASH compensated cirrhosis and obesity or overweight. The findings from this analysis suggest that it can inform clinical trials evaluating the effect of bariatric procedures in patients with NASH cirrhosis, including those with a lower body mass index.

Project description:BACKGROUND:The traditional Chinese medicine prescription, Qianggan formula have been confirmed to be effective on non-alcoholic steatohepatitis (NASH), however, the underlying molecular mechanisms remain obscure. METHODS:Thirty-six male C57BL/6 mice were randomly divided into three groups: normal chow diet group; methionine-and-choline-deficient diet (MCD) group, and Qianggan extract (QG) intervention group (0.4?g/kg daily) that fed with MCD. The efficacy of QG was biochemically and histologically evaluated. The expression profiles of messenger ribonucleic acids (mRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) were examined using microarray and verified by RT-qPCR. RESULTS:QG significantly improved the phenotypic characteristics of NASH, as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) levels and liver inflammatory cytokines were significantly decreased. By the cutoff of a 1.5-fold change and P?<?0.05, 6193 mRNAs, 5692 lncRNAs and 4843 circRNAs were identified as differentially expressed between the MCD and normal groups, and 514 mRNAs, 1182 lncRNAs and 443 circRNAs were identified as differentially expressed between the QG and MCD groups. The intersections (244 mRNAs, 259 lncRNAs and 98 circRNAs) among the three groups were chosen for analysis. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that most overlapping mRNAs were related to immune functions such as natural-killer-cell-mediated cytotoxicity, intestinal immune network for IgA production, and T cell receptor signaling pathway. Pathway interactions, protein-protein interactions and molecular complex detection (MCODE) analysis identified numerous immune-related hub genes e.g. natural cytotoxicity triggering receptor 1(Ncr1), C-X-C motif chemokine ligand 9 (Cxcl9), Klra1, and Cd28. Finally, two lncRNAs (Sngh1 and Slc36a3os) and four circRNAs (circ_0009029, circ_0004572, circ_0009212 and circ_0009453) in competing endogenous RNA (ceRNA) networks were constructed by Cytoscape, and immune-related mRNAs (e.g., Cd28, Cd8a, Il15, and Klrk1) were involved in the ceRNA networks. CONCLUSIONS:LncRNA and circRNA-associated immune ceRNA networks might be the targets of QG in alleviating NASH, and our work may provide valuable clues for exploring the mechanisms underlying the effect of QG.

Project description:Background and aimsSurrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis.Approach and resultsPatients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events.ConclusionsIn patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.

Dataset Information

Differential expression and bioinformatic analysis of circRNA in nonalcoholic steatohepatitis cirrhosis.

Publications

Differential expression and bioinformatic analysis of circRNA in nonalcoholic steatohepatitis cirrhosis.

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