MEOX2 Participates in Hepatic Stellate Cells-Induced Liver Fibrosis by Regulating the PI3K/AKT Signaling Pathway.

BACKGROUND: Hepatic stellate cells (HSCs) serve as the crucial accelerating factor in the progression of liver fibrosis (LF). In contrast to HSCs, adult-derived human liver stem/progenitor cells (ADHLSCs) exhibit greater potency in terms of differentiation and proliferation, rendering them highly applicable in LF treatment. The objective of this study is to identify new therapeutic targets for LF by comparing differentially expressed genes (DEGs) between ADHLSCs and HSCs. METHODS: We investigated DEGs between ADHLSCs and HSCs using the GSE49995 dataset obtained from the Gene Expression Omnibus (GEO) database, aiming to identify new therapeutic targets for LF. Subsequently, we activated HSCs to delve deeper into the mesenchyme homeobox 2 (MEOX2), PH domain Leucine-rich repeat protein phosphatase (PHLPP), and Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in LF progression, employing platelet-derived growth factor (PDGF), and conducted infection with Overexpression (OE)-MEOX2 and shRNA-MEOX2 (sh-MEOX2) lentiviruses. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay, while cell proliferation was evaluated through 5-ethynyl-2'-deoxyuridine (EdU) staining and flow cytometry. Relative mRNA expression levels were determined via qPCR. Western blot analysis was performed to measure protein expression levels, and the regulatory role of MEOX2 was investigated using dual luciferase reporter assays. RESULTS: We identified 332 DEGs that were down-regulated and 201 DEGs that were up-regulated between ADHLSCs and HSCs. Notably, MEOX2 expression in ADHLSCs was significantly reduced. These DEGs primarily participated in the collagen-containing extracellular matrix and the PI3K/AKT signaling pathway. MEOX2 could inhibit cancer cell proliferation via the PI3K/AKT signaling pathway. Additionally, the JASRPAR2022 database predicted the target gene PHLPP of MEOX2. Our results indicated that OE-MEOX2 significantly inhibited HSCs' cell vitality and proliferation. Further analysis revealed that MEOX2 binds to PHLPP promoters, thereby up-regulating its transcription. This action led to the inhibition of p-AKT expression, consequently reducing HSC proliferation and slowing the progression of LF. CONCLUSIONS: MEOX2 up-regulates PHLPP expression and inhibits AKT phosphorylation, thereby reducing the cell activity and proliferation ability of HSCs and inhibiting the progression of LF.

Therapeutic outcome of dapagliflozin in patients with type 2 diabetes and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

Introduction: The efficacy of dapagliflozin remains controversial for patients with type 2 diabetes and non-alcoholic fatty liver disease. We conduct this meta-analysis to explore the influence of dapagliflozin versus placebo on the treatment efficacy of type 2 diabetes complicated with non-alcoholic fatty liver disease. Methods: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through November 2021 for randomized controlled trials (RCTs) assessing the efficacy of dapagliflozin versus placebo for type 2 diabetes complicated with non-alcoholic fatty liver disease. This meta-analysis is performed using the random-effect model. Results: Four RCTs are included in the meta-analysis. Overall, compared with patients with type 2 diabetes and non-alcoholic fatty liver disease, dapagliflozin treatment is associated with significantly reduced alanine aminotransferase (ALT, standard mean difference [SMD]=-1.27; 95% confidence interval [CI]span style="font-family: 'Times New Roman'">=-1.60 to -0.95; P<0.00001), aspartate-aminotransferase (AST, SMD=-1.37; 95% CI=-2.08 to -0.65; P=0.0002), fasting glucose (SMD=-0.78; 95% CI=-1.28 to -0.27; P=0.003) and HbA1c (SMD=-0.77; 95% CI=-1.21 to -0.34; P=0.0005), but demonstrated no obvious influence on homeostatic Model Assessment of Insulin Resistance (HOMA-IR, SMD=-0.36; 95% CI=-0.86 to 0.14; P=0.16). Conclusions: Dapagliflozin benefits to improve hepatic function and glucose control in patients with type 2 diabetes and non-alcoholic fatty liver disease, as evidenced by the reduction in ALT, AST, fasting glucose and HbA1c.

False positive anti-hepatitis A virus immunoglobulin M in autoimmune hepatitis/primary biliary cholangitis overlap syndrome: A case report.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated liver disease affecting all age groups. Associations between hepatitis A virus (HAV) and AIH have been described for many years. Herein, we report a case of an AIH/primary biliary cholangitis (PBC) overlap syndrome with anti-HAV immunoglobulin M (IgM) false positivity. CASE SUMMARY: A 55-year-old man was admitted with manifestations of anorexia and jaundice along with weakness. He had marked transaminitis and hyperbilirubinemia. Viral serology was positive for HAV IgM and negative for others. Autoantibody screening was positive for anti-mitochondria antibody but negative for others. Abdominal ultrasound imaging was normal. He was diagnosed with acute hepatitis A. After symptomatic treatment, liver function tests gradually recovered. Several months later, his anti-HAV IgM positivity persisted and transaminase and bilirubin levels were also more than 10 times above of the upper limit of normal. Liver histology was prominent, and HAV RNA was negative. Therefore, AIH/primary biliary cholangitis (PBC) overlap syndrome diagnosis was made based on the "Paris Criteria". The patient was successfully treated by immunosuppression. CONCLUSION: This case highlights that autoimmune diseases or chronic or acute infections, may cause a false-positive anti-HAV IgM result because of cross-reacting antibodies. Therefore, the detection of IgM should not be the only method for the diagnosis of acute HAV infection. HAV nucleic acid amplification tests should be employed to confirm the diagnosis.

H2S mitigates severe acute pancreatitis through the PI3K/AKT-NF-κB pathway in vivo.

AIM: To study the effect of hydrogen sulfide (H2S) on severe acute pancreatitis (SAP) in a rat model. METHODS: Sprague-Dawley (SD) rats were administered an intraperitoneal injection of saline containing 20% L-Arg (250 mg/100 g) hourly for over 2 h to induce SAP. The rats were treated with DL-propargylglycine (PAG, 50 mg/kg) or different dosages of NaHS (5 mg/kg, 10 mg/kg, 20 mg/kg or 100 mg/kg). PAG or NaHS was administered 1 h before induction of pancreatitis. Rats were sacrificed 24 h after the last L-Arg injection. Blood and pancreas tissues were collected. RESULTS: The H2S and cystathionine-γ-lyase mRNA levels in SAP rats were significantly lower than those in the control group, and treatment with PAG further reduced the H2S level. Nevertheless, H2S was significantly increased after NaHS administration compared with the SAP group, and the degree of upregulation was associated with the NaHS dosage. NaHS reduced the levels of plasma amylase, interleukin-6 and myeloperoxidase in pancreatic tissue. NaHS suppressed the degradation of IκBα and the activity of nuclear factor-κB, as well as the phosphorylation of PI3K/AKT. CONCLUSION: H2S plays an anti-inflammatory role in SAP in vivo.