Dataset Information

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.

ABSTRACT:

Background and aims

Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.

Methods

The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.

Results

Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl₄)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.

Conclusions

Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.

SUBMITTER: Chen L

PROVIDER: S-EPMC9647116 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.

Chen Li L Xia Siwei S Wang Shuqi S Zhou Yuanyuan Y Wang Feixia F Li Zhanghao Z Li Yang Y Kong Desong D Zhang Zili Z Shao Jiangjuan J Xu Xuefen X Zhang Feng F Zheng Shizhong S Zheng Shizhong S

Journal of clinical and translational hepatology 20220428 1

<h4>Background and aims</h4>Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.<h4>Methods</h4>The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver ...[more]

PMID: 36406329

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Project description:BackgroundThe Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer's disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood.MethodsThe activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6+/- mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6-/-: 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR.ResultsWe observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway.ConclusionThese findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD.

Dataset Information

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.

Background and aims

Methods

Results

Conclusions

Publications

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.

Similar Datasets

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