Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model

Kan, Fangming; Ye, Lei; Yan, Tao; Cao, Jiaqi; Zheng, Jianhua; Li, Wuping

doi:10.1186/s12864-017-3984-z

Cited by 22 publications

(24 citation statements)

References 40 publications

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“…In this regard, in relation to the implication of antioxidants activity against viral replication, it has been also described that antioxidants can suppress virus-induced oxidative stress and reduce RNA virus production 91 . GSTP1, NKEF and TRX are known antioxidant enzymes with implication and up-regulation in RNA-virus infections 92 and rhabdovirus infections 24 , 93 . However, whether these enzymes may contribute to halting or reducing viral replication remains to be studied.…”

Section: Discussionmentioning

confidence: 99%

Identification of diverse defense mechanisms in rainbow trout red blood cells in response to halted replication of VHS virus

et al. 2018

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Background: It has been described that fish nucleated red blood cells (RBCs) generate a wide variety of immune-related gene transcripts when viruses highly replicate inside them and are their main target cell. The immune response and mechanisms of fish RBCs against viruses targeting other cells or tissues has not yet been explored and is the objective of our study. Methods: Rainbow trout RBCs were obtained from peripheral blood, ficoll purified and exposed to Viral Haemorrhagic Septicaemia virus (VHSV). Immune response was evaluated by means of RT-qPCR, flow cytometry, immunofluorescence and isobaric tag for relative and absolute quantification (iTRAQ) protein profiling. Results: VHSV N gene transcripts incremented early postexposure and were drastically decreased after 6 hours postexposure (hpe). The expression of type I interferon ( ifn1) gene was significantly downregulated at early postexposure (3 hpe), together with a gradual downregulation of interferon-inducible mx and pkr genes until 72 hpe. Type I IFN protein was downregulated and interferon-inducible Mx protein was maintained at basal levels. Co-culture assays of RBCs, previously exposed to UV-inactivated VHSV, and TSS (stromal cell line from spleen) revealed IFN crosstalk between both cell types. On the other hand, anti-microbial peptide β-defensin 1 and neutrophil chemotactic factor interleukin 8 were slightly upregulated in VHSV-exposed RBCs. iTRAQ profiling revealed that VHSV exposure can induce a global protein downregulation in rainbow trout RBCs, mainly related to RNA stability and proteasome pathways. Antioxidant/antiviral response is also suggested to be involved in the response of rainbow trout RBCs to VHSV. Conclusions: A variety of mechanisms are proposed to be implicated in the antiviral response of rainbow trout RBCs against VHSV halted infection. Ongoing research is focused on understanding the mechanisms in detail.

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Section: Discussionmentioning

confidence: 99%

Identification of diverse defense mechanisms in rainbow trout red blood cells in response to halted replication of VHS virus

et al. 2018

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“…These cytokines include TGF-β, platelet-derived growth factor (PDGF), TNF-α, interferons (IFNα/β), and interleukins (IL-1/6/17) [41,42]. Of all the different cytokine mediated pathways, upregulated TGF-B signaling is thought to be the principal fibrogenic pathway that activates HSCs to synthesize fibrogenic materials like collagen and alpha smooth muscle actin (α-SMA) [106][107][108][109]. In HBV-infected patients, the HBx protein has been identified as an activator of cytokine signaling [110], notwithstanding the synergistic effect induced by chronic inflammation, oxidative stress, and hepatocyte loss that triggers the activation of quiescent HSCs into myofibroblasts, which are the main source of ECM production (e.g., collagen 1/111, α-SMA) in the liver [106,107].…”

Section: Mirna Regulating Hbv-induced Fibrosis/cirrhosismentioning

confidence: 99%

The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis

Sartorius

Makarova

Sartorius

et al. 2019

Cells

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The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.An estimated 841,080 new liver cancers (LCs) were diagnosed worldwide in 2018, with hepatocellular carcinoma (HCC), the most common histological subtype, accounting for 75% to 90% of LCs [1]. A 12.4% increase of LC was recorded between 2008 (696,000) to 2012 (782,000) [2] and [3] 7.6% between 2012 and 2018 (841,080) [1]. HCC is listed globally as a leading cancer in men and women [4], with a recent report indicating that 83% of new cases diagnosed occurred in less well

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“…In order to identify the therapeutic mechanisms of liver fibrosis by AAVshRNA treatment, we next focused on differentially expressed proteins related to oxidative stress, the PPAR signaling pathway, lipid metabolism, and inflammation, which are involved in hepatic fibrosis.Indeed, in our previous study, oxidative stress was found to play an important role in liver fibrosis [45].…”

Section: Verification Of Proteins Associated With Oxidative Stress Anmentioning

confidence: 89%

“…Removal of the causative agent (HBV) by RNA interference (RNAi) is an effective strategy for treating HBV-induced liver fibrosis, whereas inhibition of the TGF-β pathway alone is not effective. Our study showed the advantages of the combinatorial use of shRNAs against both HBV and TGF-β in alleviating liver fibrosis [44,45]. The mechanisms through which RNAi protects against HBV are unclear, and the inhibiting or activating responses of host factors remains elusive.…”

Section: Introductionmentioning

confidence: 85%

Short hairpin RNA attenuates liver fibrosis by regulating the peroxisome proliferator-activated receptor-γ and nuclear factor-κB pathways in hepatitis B virus-induced liver fibrosis in mice

Cao

Sun

et al. 2019

Preprint

Self Cite

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Background: Progressive liver fibrosis, caused by chronic viral infection and metabolic disorders, results in the development of cirrhosis and hepatocellular carcinoma. However, no antifibrotic therapies have been approved to date. In our previous study, adeno-associated virus (AAV) short hairpin RNAs (shRNAs) targeting hepatitis B virus (HBV) and transforming growth factor (TGF)-β administration could persistently inhibit HBV replication and concomitantly prevent liver fibrosis. However, the differentially expressed proteins and critical regulatory networks of AAVshRNA treatment remain unclear. Accordingly, in this study, our major goal was we aimed to analyze differentially expressed proteins in the liver of AAV-shRNAs-treated mice with HBV infection and liver fibrosis using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics and to elucidate the underlying antifibrotic mechanisms. Results: In total 2743 proteins were recognized by iTRAQ-based quantitative proteomics analysis. Gene ontology analysis suggested that the differentially expressed proteins were mostly participated in peptide metabolism in the biological process category, cytosolic ribosomes in the cell component category, and structural constituents of ribosomes in the molecular function category. Kyoto Encyclopedia of Genes and Genomespathway analysis indicated that oxidative stress and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were actived after treatment. Verification studies showed that AAVshRNAs inhibited hepatic stellate cell activation and inflammation by suppressing nuclear factor-κB p65 phosphorylation and α-smooth muscle actin expression via upregulation of PPAR-γ. Hepatocytes steatosis was also decreased by activating PPAR signaling pathway and improving lipid metabolism. TGF-β level was decreased owning to increase PPAR-γ expression and directly inhibition using AAVshRNAs targeting TGF-β. TGF-β-induced oxidative stress was suppressed by increasing glutathione S-transferase Pi 1 and reducing peroxiredoxin 1. Conclusions: Our results indicated that AAV-shRNAs were effective for modulating liver fibrosis by reducing oxidative stress, inflammation and activating PPAR signaling pathway.

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Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model

Cited by 22 publications

References 40 publications

Identification of diverse defense mechanisms in rainbow trout red blood cells in response to halted replication of VHS virus

Identification of diverse defense mechanisms in rainbow trout red blood cells in response to halted replication of VHS virus

The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis

Short hairpin RNA attenuates liver fibrosis by regulating the peroxisome proliferator-activated receptor-γ and nuclear factor-κB pathways in hepatitis B virus-induced liver fibrosis in mice

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