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1.
Free Radic Biol Med ; 211: 47-62, 2024 02 01.
Article in English | MEDLINE | ID: mdl-38043870

ABSTRACT

The suppression of tumor proliferation via cellular senescence has emerged as a promising approach for anti-tumor therapy. Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adaptor protein involved in the NF-κB signaling pathway and reactive oxygen species (ROS) production, has been implicated in hepatocellular carcinoma (HCC) proliferation. However, little is currently known about whether TRAF2 promotes HCC development by inhibiting cellular senescence. Replicative senescence model and IR-induced mouse model demonstrated that TRAF2 expression was decrease in senescence cells or liver tissues. Depletion of TRAF2 could inhibit proliferation and arrest the cell cycle via activating p53/p21WAF1 and p16INK4a/pRb signaling pathways in HCC cells and eventually lead to cellular senescence. Mechanistically, TRAF2 deficiency increased the expression of mitochondrial protein reactive oxygen species modulator 1 (ROMO1) and subsequently activated the NAD+/SIRT3/SOD2 pathway to promote the production of ROS and cause mitochondrial dysfunction, which eventually contributed to DNA damage response (DDR). Our findings demonstrate that TRAF2 deficiency inhibits the proliferation of HCC by promoting senescence. Therefore, targeting TRAF2 through various approaches holds therapeutic potential for treating HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Sirtuin 3 , Animals , Mice , Carcinoma, Hepatocellular/pathology , Cellular Senescence/genetics , Liver Neoplasms/pathology , NAD/metabolism , Reactive Oxygen Species/metabolism , Sirtuin 3/genetics , Sirtuin 3/metabolism , TNF Receptor-Associated Factor 2/genetics
2.
MedComm (2020) ; 4(5): e354, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37638336

ABSTRACT

Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.

3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(6): 589-593, 2021 Nov.
Article in Chinese | MEDLINE | ID: mdl-34821089

ABSTRACT

Objective: To investigate the protective effects of L-carnitine (LC) on lipopolysaccharide (LPS) - injured mouse pulmonary microvascular endothelial cells (PMVECs) and its effects on autophagy and apoptosis. Methods: Cultured mouse PMVECs were divided into three groups: ① Control group, ② LPS group (10 µg/ml, 3, 6, 12, 24 h), ③ LPS (10 µg/ml, 24 h)+LC (2.5, 5.0, 10 µg/ml) (LPS+LC) group. PMVECs apoptosis was examined by Annexin V-FITC/PI double labeling method. Autophagosome was detected by immunofluorescence staining. Levels of autophagy-related protein LC3 and apoptosis-related protein caspase-3 were detected by Western blot. PMVECs viability was measured by CCK-8. Results: ① Compared with the control group, LPS treatment inhibited the PMVECs viability significantly, whereas the apoptosis rate and the expression of autophagy protein LC3 II were markedly increased after LPS treatment for 6 h, 12 h and 24 h. ② Compared with LPS group (10 µg/ml, 24 h), the PMVECs viability, levels of autophagy protein LC3 II and caspase-3 protein expression as well as apoptosis rate in LPS+LC group were increased significantly. Conclusion: LC can increase the activity of PMVECs injuried by LPS, promote autophagy and inhibit apoptosis of PMVECs.


Subject(s)
Apoptosis/drug effects , Autophagy/drug effects , Carnitine/pharmacology , Endothelial Cells , Animals , Cells, Cultured , Lipopolysaccharides , Mice
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