MicroRNA-125a/VDR axis impaired autophagic flux and contributed to fibrosis in a CCL4-induced mouse model and patients with liver cirrhosis

He, Wei; Ni, Wei-Jie; Zhang, Lili; Wang, Xiang; Liu, Li; Fan, Zhining

doi:10.1016/j.lfs.2020.118666

Cited by 19 publications

(12 citation statements)

References 26 publications

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“…Furthermore, the latest studies have indicated that autophagy plays a key protective role in liver disease. For example, He et al indicated that the microRNA-125a/VDR axis reduced autophagic flux and subsequently led to fibrosis in a mouse model and in humans [ 45 ]. Importantly, a recent study revealed that autophagy is an efficient target in HSCs for attenuation of liver fibrosis [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect

Zhou

et al. 2021

Nutr Metab (Lond)

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Background This study investigated the mechanisms underlying the preventive effect of dihydromyricetin (DHM) against liver fibrosis involving hepatic stellate cells (HSCs) and hepatic natural killer (NK) cells. Methods A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 mice to study the antifibrotic effect of DHM based on serum biochemical parameters, histological and immunofluorescence stainings, and the expression of several fibrosis-related markers. Based on the immunoregulatory role of DHM, the effect of DHM on NK cell activation ex vivo was evaluated by flow cytometry. Then, we investigated whether DHM-induced autophagy was involved in HSCs inactivation using enzyme-linked immunosorbent assays, transmission electron microscopy, and western blot analysis. Thereafter, the role of DHM in NK cell-mediated killing was studied by in vitro coculture of NK cells and HSCs, with subsequent analysis by flow cytometry. Finally, the mechanism by which DHM regulates NK cells was studied by western blot analysis. Results DHM ameliorated liver fibrosis in C57BL/6 mice, as characterized by decreased serum alanine transaminase and aspartate transaminase levels, decreased expressions of collagen I alpha 1 (CoL-1α1), collagen I alpha 2 (CoL-1α2), tissue inhibitor of metalloproteinases 1 (TIMP-1), α-smooth muscle actin (α-SMA) and desmin, as well as increased expression of matrix metalloproteinase 1 (MMP1). Interestingly, HSCs activation was significantly inhibited by DHM in vivo and in vitro. As expected, DHM also upregulated autophagy-related indicators in liver from CCl4-treated mice. DHM also prevented TGF-β1-induced activation of HSCs in vitro by initiating autophagic flux. In contrast, the autophagy inhibitor 3-methyladenine markedly abolished the antifibrotic effect of DHM. Surprisingly, the frequency of activated intrahepatic NK cells was significantly elevated by DHM ex vivo. Furthermore, DHM enhanced NK cell-mediated killing of HSCs by increasing IFN-γ expression, which was abolished by an anti-IFN-γ neutralizing antibody. Mechanistically, DHM-induced IFN-γ expression was through AhR-NF-κB/STAT3 pathway in NK cells. Conclusion These results demonstrated that DHM can ameliorate the progression of liver fibrosis and inhibition of HSCs activation by inducing autophagy and enhancing NK cell-mediated killing through the AhR-NF-κB/STAT3-IFN-γ signaling pathway, providing new insights into the preventive role of DHM in liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect

Zhou

et al. 2021

Nutr Metab (Lond)

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“…In vivo , we established a classic HF animal model induced by CCl 4 to investigate the effect and mechanisms of AD-2 on HF. CCl 4 induces HF mainly by affecting enzymes and inflammatory factors in the body, thereby affecting the liver cell damage and re-repair processes . This model can well simulate the pathological features of human HF in stages S 0 –S 4 caused by hepatitis B virus infection and has become the best reagent for the widely used HF animal modeling method because of the advantages of economy, reliability, and high repeatability.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside AD-2 Ameliorating Lipopolysaccharide-Induced Activation in HSC-T6 Cells and Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice via Regulation of VD-VDR Axis

Chen

Lin

Yang

et al. 2023

J. Agric. Food Chem.

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Ginsenoside 25-hydroxy protopanaxadiol (AD-2) isolated from ginseng was proved to have anti-hepatic fibrosis (HF) effect in our previous study. But the mechanism is unknown. The present study investigated the anti-HF effects and mechanisms of AD-2 on the lipopolysaccharide (LPS)-induced activation in HSC-T6 cells and carbon tetrachloride (CCl4)-induced hepatic fibrosis (HF) in mice. Results showed that AD-2 significantly inhibited the LPS-induced activated HSC-T6 cells in vitro and markedly reduced the serum transaminase and hydroxyproline levels, pathological changes, and hepatic body ratio in CCl4-induced HF mice, indicating AD-2 ameliorated liver injury and reversed HF notably. Moreover, AD-2 decreased the expression of TGF-β1, α-SMA, and MMP2, and maintained TIMP1/MMP9 in balance with the level of vitamin D (VD) and the expression of VD nuclear receptor (VDR) and Sirt3 increased. In conclusion, the anti-HF mechanism of AD-2 is related to the inhibition of HSC activation, promotion of collagen degradation, and regulation of the VD/VDR axis.

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“…MiRNAs are expected to become new biomarkers for diagnosis, therapy prognosis prediction and treatment in breast cancer ( Bertoli et al, 2015 ). Studies have shown that miRNAs target VDR in breast carcinoma and liver fibrosis and then affect disease progression ( Liu X. et al, 2018 ; He et al, 2021 ), but whether these miRNAs are differentially expressed in TB is still unclear. It has been reported that miRNAs such as miR-92a-3p and miR-155 are highly expressed in TB and have an impact on the occurrence of the disease ( Wu et al, 2012 ; Wang et al, 2018 ), but much work still remains to be done to clarify the mechanisms underlying this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that miR-1204 is able to target VDR in breast cancer, leading to a poor prognosis ( Liu X. et al, 2018 ). MiR-125a can target VDR to promote the occurrence and progression of liver fibrosis ( He et al, 2021 ). Therefore, we wanted to explore whether any particular miRNAs are involved in TB regulation and are likely to depress TB by targeting VDR.…”

Section: Introductionmentioning

confidence: 99%

MiR-27a-3p and miR-30b-5p inhibited-vitamin D receptor involved in the progression of tuberculosis

Xiao

Yang²,

Zhou³

et al. 2022

Front. Microbiol.

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BackgroundMicroRNAs (miRNAs) play a vital role in tuberculosis (TB). Vitamin D receptor (VDR), an miRNA target gene, and its ligand, vitamin D3 (VitD3), have been reported to exert protective effects against TB. However, whether miRNAs can affect the progression of TB by targeting VDR has not been reported.Materials and methodsResearch subjects were selected according to defined inclusion criteria. A clinical database of 360 samples was established, including the subjects’ demographic information, miRNA expression profiles and cellular experimental results. Two candidate miRNAs, miR-27a-3p, and miR-30b-5p, were identified by a high-throughput sequencing screen and validated by qRT–PCR assays. Univariate and multivariate statistical analyses were performed. VDR and NF-kB p65 protein levels were detected by Western blot assays. Proinflammatory cytokine expression levels were detected by enzyme-linked immunosorbent assay (ELISA). Luciferase assays and fluorescence-activated cell sorting (FACS) were further applied to elucidate the detailed mechanisms.ResultsDifferential miRNA expression profiles were obtained, and miR-27a-3p and miR-30b-5p were highly expressed in patients with TB. These results showed that the two miRNAs were able to induce M1 macrophage differentiation and inhibit M2 macrophage differentiation. Further experiments showed that the two miRNAs decreased the VDR protein level and increased proinflammatory cytokine secretion by macrophages. Mechanistically, the miRNAs targeted the 3′ untranslated region (3′UTR) of the VDR mRNA and thereby downregulated VDR protein levels by post-transcriptional regulation. Then, due to the reduction in VDR protein levels, the NF-kB inflammatory cytokine signaling pathway was activated, thus promoting the progression of TB.ConclusionOur study not only identified differentially expressed miRNAs between the TB and control groups but also revealed that miR-27a-3p and miR-30b-5p regulate proinflammatory cytokine secretion and macrophage differentiation through VDR in macrophages. Thus, these two miRNAs influence the progression of TB.

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MicroRNA-125a/VDR axis impaired autophagic flux and contributed to fibrosis in a CCL4-induced mouse model and patients with liver cirrhosis

Cited by 19 publications

References 26 publications

Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect

Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect

Ginsenoside AD-2 Ameliorating Lipopolysaccharide-Induced Activation in HSC-T6 Cells and Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice via Regulation of VD-VDR Axis

MiR-27a-3p and miR-30b-5p inhibited-vitamin D receptor involved in the progression of tuberculosis

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