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40. SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1β pathway

Author

Fan Minghao, Chen Zhenmei, Shao Weiqing, Chen Yiran, Lin Zhifei, Yi Chenhe, Li Yitong, Lu Lu, Zhou Yu, and Lin Jing

Subjects
hepatocellular carcinoma, SREBP2, lenvatinib, betulin, cholesterol, interleukin-1β, Biochemistry, QD415-436, Genetics, QH426-470
Abstract

Lenvatinib has become the first-line therapy in advanced hepatocellular carcinoma (HCC), but its efficacy is still limited because of the inevitable development of resistance. It has been reported that cellular cholesterol levels are associated with tyrosine kinase inhibitor (TKI) efficacy. Here, we show that betulin, a sterol regulatory element-binding protein 2 (SREBP2) inhibitor, markedly enhances the anti-tumor effect of lenvatinib in HCC both in vitro and in vivo. Our results also show that the combination treatment of lenvatinib and betulin synergistically inhibits the proliferation and clonogenicity of HCC cells. The mRNA and protein expressions of IL-1β are markedly decreased in HCC cells treated with betulin, while the sensitivity of HCC cells to lenvatinib is enhanced. Moreover, we find that the knockdown of IL-1β also enhances the efficacy of lenvatinib, and recombinant IL-1β protein rescues cell viability, which is reduced by lenvatinib in HCC cells. Further mechanistic studies indicate that betulin decreases the level of IL-1β in HCC cells by inhibiting the mTOR signaling pathway. Finally, the growth of the tumors in xenograft mouse models subjected to combination treatment is significantly suppressed. In summary, our study reveals that the SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1β pathway, which may be a promising therapeutic strategy for patients with HCC.

Published
2023
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48. Modeling and control of power electronic converters in power systems

Author

Li, Yitong, Junyent-Ferre, Adria, Green, Timothy, and Gu, Yunjie

Subjects
621.31
Abstract

Power grids are undergoing a dominant transformation due to the increasing number of power electronic devices installed in generation, transmission, distribution, and demand, etc. Compared with traditional power systems dominated by synchronous generators, the growth of power electronics induces new behaviour of power network dynamics, physical constraints, running costs, etc, which urgently calls for a new framework of modeling, control, and stability analysis. This thesis first focuses on the impedance method for modeling ac-dc power converters in power systems, designing the controllers, and analyzing the stability. A tool called Impedance circuit model is proposed to intuitively derive the impedance model of a grid-connected power converter. Compared with the conventional all-in-one impedance model, the proposed tool maps the control parameters explicitly to discrete virtual impedances in an impedance circuit and meanwhile captures the multi-control-loop interaction and coupling of a converter. Another tool named frame-dynamics-embedding impedance model is also proposed to systematically embed the frame dynamics (grid synchronization) of a power converter into its impedance model. This tool also enables the impedance model of power networks by making the reference frames of different devices consistent. The frame-transformation impedance model is finally proposed to reveal the relationship of impedance models in synchronous dq and stationary alpha/beta frames. These proposed tools make up an impedance modeling framework, which are applied to the most fundamental and widely-used converters in power systems [i.e., the voltage-source inverters (VSIs)] as examples in this thesis. Both simulation and experiment tests are conducted to validate the corresponding theoretical analysis. VSIs are the widely-used ac-dc converters which integrate sources or loads to the utility ac grids. But with the increasing use of dc in the ac-dominated power systems, an ac-dc converter is also required to perform as an interlinking converter, which links dc networks and the utility ac grids. It forms hybrid ac-dc grids and brings more integration and control problems. Hence, in addition to conventional VSIs, this thesis also explores novel topologies and control algorithms of ac-dc converters with advanced features to connect dc networks to ac grids. They are able to improve the grid integration and enhance the grid reliability (e.g., bidirectional voltage stiffness transfer, bipolar-dc-imbalance handling, dc-side fault blocking, high-frequency galvanic isolation, etc). Down-scaled prototypes for them are built and tested to validate the corresponding theoretical analysis and the proposed control algorithms. It is expected that the work in this thesis can inspire not only the fundamental framework of modeling and control analysis, but also the advanced development of converter topologies and control methods of power converters in power system applications.

Published
2021
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