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Short hairpin RNA attenuates liver fibrosis by regulating the PPAR?? and NF??B pathways in HBV?induced liver fibrosis in mice.

ABSTRACT: 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)?? administration could persistently inhibit HBV replication and concomitantly prevent liver fibrosis. However, the differentially expressed proteins and critical regulatory networks of AAV?shRNA treatment remain unclear. Accordingly, in the present study, we aimed to analyze differentially expressed proteins in the liver of AAV?shRNA?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. In total 2,743 proteins were recognized by iTRAQ?based quantitative proteomics analysis. Gene Ontology analysis revealed that the differentially expressed proteins 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 Genomes pathway analysis indicated that oxidative stress and the peroxisome proliferator?activated receptor (PPAR) signaling pathway were activated after treatment. Verification studies revealed that AAV?shRNAs inhibited hepatic stellate cell activation and inflammation by suppressing nuclear factor??B p65 phosphorylation and ??smooth muscle actin expression via upregulation of PPAR??. Hepatocytes steatosis was also decreased by activating the PPAR signaling pathway and improving lipid metabolism. The expression level of TGF?? was decreased due to upregulation of PPAR?? expression and direct inhibition using AAV?shRNA targeting TGF??. TGF???induced oxidative stress was suppressed by increasing glutathione S?transferase Pi 1 and reducing peroxiredoxin 1. Collectively, the present results indicated that AAV?shRNAs were effective in modulating liver fibrosis by reducing oxidative stress, inflammation and activating the PPAR signaling pathway.

SUBMITTER: Ye L

PROVIDER: S-EPMC7549542 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Short hairpin RNA attenuates liver fibrosis by regulating the PPAR‑γ and NF‑κB pathways in HBV‑induced liver fibrosis in mice.

Ye Lei L Chen Ting T Cao Jiaqi J Sun Liying L Li Wuping W Zhang Chenghai C

International journal of oncology 20200922 5

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 ...[more]

PMID: 33491741

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Project description:BackgroundAfter traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood-brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway.MethodsC57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated.ResultsHCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ.ConclusionsHCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.

Dataset Information

Short hairpin RNA attenuates liver fibrosis by regulating the PPAR?? and NF??B pathways in HBV?induced liver fibrosis in mice.

Publications

Short hairpin RNA attenuates liver fibrosis by regulating the PPAR‑γ and NF‑κB pathways in HBV‑induced liver fibrosis in mice.

Similar Datasets

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