富马酸替诺福韦二吡呋酯通过下调 PI3K/Akt/mTOR 信号通路诱导

StephenW

富马酸替诺福韦二吡呋酯通过下调 PI3K/Akt/mTOR 信号通路诱导肝星状细胞凋亡直接改善肝纤维化
Sung Won Lee 1 2 , Sung Min Kim 1 , Wonhee Hur 1 , Byung-Yoon Kang 1 , Hae Lim Lee 1 2 , Heechul Nam 1 2 , Sun Hong Yoo 1 2 , Pil Soo Sung 1 2 , Jung Hyun Kwon 1 2 , Jeong Won Jang 1 2 , Seong-Jun Kim 3 , Seung Kew Yoon 1 2
隶属关系
隶属关系

    1
    生物医学与健康科学系，天主教大学肝脏研究中心，POSTECH-天主教生物医学工程研究所，韩国首尔韩国天主教大学。
    2
    大韩民国首尔天主教大学医学院内科系。
    3
    韩国大田韩国化学技术研究所。

    PMID：34879114 DOI：10.1371/journal.pone.0261067

抽象的

背景：迄今为止，尚未开发出用于治疗肝纤维化的抗纤维化药物。长期使用抗病毒药物富马酸替诺福韦二吡呋酯（TDF）和恩替卡韦（ETV）治疗慢性乙型肝炎患者导致肝纤维化消退，但其潜在机制尚未阐明。因此，我们旨在研究 TDF 和 ETV 对肝纤维化的直接影响。

方法：使用活化的肝星状细胞 (HSC) 细胞系评估 TDF 和 ETV 的作用。用每种抗病毒剂治疗后，检查细胞活力、形态、凋亡特征、自噬和抗纤维化信号通路。然后，在肝纤维化模型小鼠的肝组织中测量胶原沉积、纤维化标志物和活化的 HSC。

结果：TDF处理后，LX2和HSC-T6细胞活力降低，细胞呈现凋亡特征，但ETV没有诱导这些作用。 PARP 和 Caspase-3 的裂解以及抗凋亡基因 Bcl-xl 的抑制表明 TDF 处理后激活的 HSC 凋亡。 TDF 同时增加自噬，这也通过串扰调节细胞凋亡。 TDF 使 PI3K/Akt/mTOR 信号通路失活，这与细胞凋亡和自噬的激活有关。在肝纤维化小鼠模型中，TDF 减少了纤维化区域和激活的 HSC 标志物，但 ETV 处理没有减少。此外，TDF 处理后，凋亡细胞集中在门静脉周围纤维化区域，这表明 TDF 具有特异性的抗纤维化作用。

结论：TDF通过下调PI3K/Akt/mTOR信号通路直接改善肝纤维化，导致活化的HSC凋亡。 TDF 的抗纤维化作用表明它可能是治疗肝纤维化的治疗剂。

StephenW

Tenofovir disoproxil fumarate directly ameliorates liver fibrosis by inducing hepatic stellate cell apoptosis via downregulation of PI3K/Akt/mTOR signaling pathway
Sung Won Lee  1   2 , Sung Min Kim  1 , Wonhee Hur  1 , Byung-Yoon Kang  1 , Hae Lim Lee  1   2 , Heechul Nam  1   2 , Sun Hong Yoo  1   2 , Pil Soo Sung  1   2 , Jung Hyun Kwon  1   2 , Jeong Won Jang  1   2 , Seong-Jun Kim  3 , Seung Kew Yoon  1   2
Affiliations
Affiliations

    1
    Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea.
    2
    Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
    3
    Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.

    PMID: 34879114 DOI: 10.1371/journal.pone.0261067

Abstract

Background: Antifibrotic agent for the treatment of liver fibrosis has not been developed so far. Long term treatment of chronic hepatitis B patients with antiviral drugs tenofovir disoproxil fumarate (TDF) and entecavir (ETV) results in the regression of liver fibrosis, but the underlying mechanism has not been clarified. Therefore, we aimed to investigate the direct impact of TDF and ETV on liver fibrosis.

Methods: Activated hepatic stellate cell (HSC) cell lines were used to evaluate the effects of TDF and ETV. After treatment with each antiviral agent, cell viability, morphology, apoptotic features, autophagy and antifibrosis signalling pathways were examined. Then, collagen deposition, fibrosis markers and activated HSCs were measured in liver tissues of the liver fibrosis model mice.

Results: After TDF treatment, the viabilities of LX2 and HSC-T6 cells were decreased, and the cells exhibited apoptotic features, but ETV did not induce these effects. Cleavage of PARP and Caspase-3 and the inhibition of the antiapoptotic gene Bcl-xl indicated activated HSC apoptosis following TDF treatment. TDF simultaneously increased autophagy, which also regulated apoptosis through crosstalk. TDF inactivated the PI3K/Akt/mTOR signalling pathway, which was associated with the activation of both apoptosis and autophagy. In the liver fibrosis mouse model, the fibrotic area and activated HSC markers were decreased by TDF but not ETV treatment. Additionally, apoptotic cells were concentrated in the periportal fibrotic area after TDF treatment, which indicated the specific antifibrotic effect of TDF.

Conclusions: TDF directly ameliorates liver fibrosis by downregulating the PI3K/Akt/mTOR signalling pathway, which results in the apoptosis of activated HSCs. The antifibrotic effects of TDF indicate that it may be a therapeutic agent for the treatment of liver fibrosis.

StephenW

https://journals.plos.org/ploson ... &type=printable

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ETV/TDF治疗慢乙肝的8年累积HBsAg清除率为1%左右