Carvedilol attenuates liver fibrosis by suppressing autophagy and promoting apoptosis in hepatic stellate cells

Meng, Dongxiao; Li, Zhen; Wang, Guangchuan; Ling, Liping; Wu, Ying; Zhang, Chunqing

doi:10.1016/j.biopha.2018.10.005

Cited by 98 publications

(59 citation statements)

References 37 publications

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“…Both pSMAD3, a transcriptional activator of TGF-β, and p-PI3K have crucial functions in the early activation of HSC [26,27]. Meanwhile, elevated LC3B Ⅱ expression is an important autophagosomal marker [28]. Using western blot analyses, our study revealed that the miR29-MCD group exhibited a significant decrease in p-SMAD3, p-PI3K, and LC3B II protein levels compared with the WT-MCD group ( p < 0.001, Figure 4D; p < 0.001, Figure 4E; p = 0.005, Figure 4F, respectively).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice

Yang

Kuo

Wang

et al. 2019

IJMS

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MicroRNA-29 (miR-29) has been found to reduce liver inflammation and fibrosis following a liver injury. Meanwhile, DNA methyltransferase has been reported to participate in the development of non-alcoholic steatohepatitis (NASH). The aim of this study is to investigate the miR-29a regulation of methyltransferase signaling and epigenetic program in NASH progression. Methods: miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates were subjected to the methionine-choline-deficient (MCD) diet-induced animal model of NASH. Primary hepatic stellate cells were transfected with a miR-29a mimic and antisense inhibitor. We then analyzed gene expressions with qRT-PCR, immunohistochemical stain, Western blot, and luciferase reporter assay. The results demonstrated that increased miR-29a alleviated the MCD diet-induced body weight loss and steatosis and decreased aspartate aminotransferase (AST) levels in mice. Furthermore, hepatic tissue in miR-29aTg mice displayed a weak fibrotic matrix, as shown with Sirius Red staining concomitant with low fibrotic α-SMA expression within affected tissues compared to the wild-type mice fed the MCD diet. Forced miR-29a expression reduced the MCD diet exaggeration of reactive oxygen species (ROS) production by immunohistochemically staining 8-OHdG. Increased miR-29a signaling also resulted in the downregulation of DNMT3b, TGF-β, IL-6, heme oxygenase-1 (HO-1), p-SMAD3, PI3K, and L3BII expression within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced DNMT3b expression in primary HSCs. Our data provide new insights that miR-29a improves MCD diet-induced liver inflammation, steatosis and fibrosis, and highlight the potential of miR-29a targeted therapy for treating NASH.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice

Yang

Kuo

Wang

et al. 2019

IJMS

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“…We found that there was a close relationship between apoptosis and autophagy. Carvedilol inhibited autophagy and promoted apoptosis in hepatic stellate cells, and the late inhibition of autophagy preceded the induction of apoptosis [ 45 ], and one research indicated that inhibited apoptosis protease caspase-8 caused cell death and autophagy enhancement, and inhibition of autophagy-related genes saved cell death [ 46 ]. Under starvation or other stress conditions, Bcl-2 and Bcl-xL must replace Beclin-1 to initiate autophagy [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Jiang

Liu

Wangwang

et al. 2020

BioMed Research International

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Purpose. Arctigenin (ARG) is a natural lignan compound extracted from Arctium lappa and has displayed anticancer function and therapeutic effect in a variety of cancers. Arctigenin is mainly from Arctium lappa extract. It has been shown to induce autophagy in various cancers. However, as for whether arctigenin induces autophagy in gliomas or not, the specific mechanism is still worth exploring. Methods. Using CCK8, the monoclonal experiment was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. PI/RNase and FITC-conjugated anti-annexin V were used to detect the cell cycle and apoptosis. Western blotting was used to determine the specified protein level, and constructed LC3B-GFP plasmid was used for analysis of autophagy.Results. Our research showed that ARG inhibited the growth and proliferation and invasion and migration of glioma cells in a dose-dependent manner (U87MG and T98G) and arrested the cell cycle and induced apoptosis. Interestingly, ARG induced autophagy in a dose-dependent manner. We applied Western blotting to measure the increase in the key autophagy protein LC3B, as well as some other autophagy-related proteins (increase in Beclin-1 and decrease in P62). In order to further explore the mechanism that ARG passed initiating autophagy to inhibit cell growth, we further found by Western blotting that AKT and mTOR phosphorylation proteins (P-AKT, P-mTOR) were reduced after ARG treatment, and we used AKT agonists to rescue, and the phosphorylated proteins of AKT and mTOR increased, and we found that the autophagy-related proteins were also reversed. And interestingly, the protein of apoptosis was also reversed along with autophagy. Conclusions. We thought ARG inhibited the proliferation of glioma cells by inducing autophagy and apoptosis through the AKT/mTOR pathway.

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“…3c and d, the number of autophagosomes in the ROP17-overexpressing cells was greater than that in control cells. In addition, the number of GFP-LC3B puncta is a good indicator of autophagosome presence and is closely related to the number of autophagosomes [23]. ROP17-overexpressing HEK 293T cells and parental cells transfected with GFP-LC3 were subjected to serum starvation.…”

Section: The Overexpression Of Rop17 Promotes the Autophagy Induced Bmentioning

confidence: 99%

Toxoplasma Gondii ROP17 Promotes Autophagy via the Bcl-2–Beclin 1 Pathway

Guo

Jia

Wang

et al. 2020

Preprint

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Abstract Background Toxoplasmosis caused by Toxoplasma gondii (T. gondii) has been and continues to be a major threat to public health worldwide. Proteins with serine/threonine (S/T) kinase activity, such as rhoptry organelle protein (ROP)16 and ROP18, are secreted by T. gondii rhoptries organelles that play important roles in modulating the survival and proliferation of Toxoplasma. ROP17 is another important effector kinase protein. Nevertheless, little is known about its function in regulating the interplay between T. gondii and host cells during infection. In this study, we investigated the function and the underlying mechanisms of ROP17 in vitro and in vivo. Methods The autophagy of cells in the small intestines of mice infected with T. gondii tachyzoite (RH strain) was detected by assessing the LC3B, Beclin 1 and p62 levels using immunohistochemical staining. ROP17 overexpression augmented starvation-induced autophagy in HEK 293T cells as measured by MDC staining, transmission electron microscopy (TEM), fluorescence microscopy and Western blot analysis. The interaction of ROP17 and Bcl-2 was confirmed using co-immunoprecipitation (co-IP) analysis. Moreover, the levels of phosphorylation of Bcl-2 and total Bcl-2 in the small intestines of mice infected with T. gondii tachyzoite were detected using immunohistochemical staining. In the end, Pearson coefficient was used to analyse correlations between the expression of ROP17 with the expression of autophagy markers LC3B, beclin 1 and p62, and with phosphorylation of Bcl-2 and Bcl-2. Results Infection with T. gondii resulted in autophagy of mouse small intestine cells accompanied by increased levels of LC3B and Beclin 1 and decreased levels of p62, which were measured by immunohistochemistry. Meantime, the elevated levels of Phosphorylated Bcl-2 and declined Bcl-2 in T. gondii-infected mouse small intestine tissue and in ROP17 overexpressing HEK 293T cells were detected by immunohistochemistry and Western blotting. ROP17 overexpression promoted serum starvation-induced cellular autophagy in the HEK293T cells, reflecting the augmentation of autophagosomes and GFP-LC3B puncta accompanied by increased levels of LC3B and Beclin 1 and decreased levels of p62. Moreover, we found that ROP17 interacted with Bcl-2 and phosphorylated and degraded it to liberate Beclin 1, thus promoting autophagy. Pearson coefficient analysis showed that there exsited strong positive correlations between the expression of ROP17 with the expression of LC3B, Beclin 1 and phosphorylation of Bcl-2, while strong negative correlations between the expression of ROP17 and the expression of p62 and Bcl-2. Conclusions Our findings indicate that ROP17 plays a pivotal role in maintaining Toxoplasma survival and proliferation in host cells by promoting cellular autophagy, which depends on the Beclin 1-Bcl-2 pathway.

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Carvedilol attenuates liver fibrosis by suppressing autophagy and promoting apoptosis in hepatic stellate cells

Cited by 98 publications

References 37 publications

MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice

MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Toxoplasma Gondii ROP17 Promotes Autophagy via the Bcl-2–Beclin 1 Pathway

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