Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. The mechanism by which medium- and long-chain triglyceride (MCT/LCT) propofol plays a role in promoting NAFLD remains unclear. In this study, we investigated the effect of MCT/LCT propofol on NAFLD progression and its mechanism of action. In Huh-7 and HepG3 cells induced by free fatty acids (FFA), propofol downregulated the expression levels of TG and lipid metabolism-related proteins by promoting the activation of the PI3K/AKT pathway and suppressing FFA-induced lipid metabolic disorders. In a high-fat diet (HFD) -induced NAFLD mouse model, we demonstrated that propofol significantly inhibited liver steatosis, inflammatory cell infiltration, and fibrosis. In conclusion, our results suggest that MCT/LCT propofol reduces liver lipid accumulation by activating the PI3K/AKT pathway and further suppressing the NAFLD process.

Chimeric antigen receptor (CAR) T-cell therapy is mostly limited to hematological malignancies and has a poor effect on solid tumors. CAR T cells as a kind of immune cell may be affected by some immunomodulatory drugs such as pomalidomide, so the use of pomalidomide may improve the effect of CART cells on solid tumors. In this study, CD133-or HER2-specific CART cells were chosen to investigate whether pomalidomide can regulate the function of CAR T cells in vitro. We found that pomalidomide can significantly enhance the ability of CD133-CAR T cells and HER2-CAR T cells to kill tumor cells and increase the cytokine secretion of CD133-CAR T cells and HER2-CAR T cells. Also, pomalidomide was shown to induce down-regulation of protein levels of IL-2 transcriptional repressors Aiolos and Ikaros in CART cells. This study suggests that the combination of pomalidomide and CAR T cells may be a new strategy for the treatment of solid tumors.

Chimeric antigen receptor (CAR) T cell therapy still faces the challenge of immunosuppression when treating solid tumors. TGF-β is one of the critical factors in the tumor microenvironment to help tumors escape surveillance by the immune system. Here we tried using the combination of a small molecule inhibitor of TGF-β receptor I, Galunisertib, and CAR T cells to explore whether Galunisertib could enhance CAR T cell function against solid tumor cells. In vitro experiments showed Galunisertib could significantly enhance the specific cytotoxicity of both CD133- and HER2-specific CAR T cells. However, Galunisertib had no direct killing effect on target cells. Galunisertib significantly increased the cytokine secretion of CAR T cells and T cells that do not express CAR (Nontransfected T cells). Galunisertib did not affect the proliferation of T cells, the antigen expression on target cells and CD69 on CAR T cells. We found that TGF-β was secreted by T cells themselves upon activation, and Galunisertib could reduce TGF-β signaling in CAR T cells. Our findings can provide the basis for further preclinical and clinical studies of the combination of Galunisertib and CAR T cells in the treatment of solid tumors.

利用中链聚羟基脂肪酸酯(mcl-PHA)的黏着性作为后整理剂基质,构筑含有pomalidomide经皮给药的后整理剂,并用其整理纺织品.通过后整理剂缓释pomalidomide及透皮吸收改善CAR T细胞治疗实体瘤的效果.使用mcl-PHA作为基质构筑经皮给药系统,检测药物透皮量;并使用CD133-CAR T细胞作为效应细胞,U251 CD133-OE luc(转入萤火虫荧光素酶基因且过表达CD133的人胶质瘤细胞)作为靶细胞,探究pomalidomide是否可以在体外调节CAR T细胞的功能.结果 表明:mcl-PHA构筑的具有经皮给药功能的后整理剂具有缓释、促进药物透皮吸收功能,且药物量能达到体外实验的需求;pomalidomide可显著增强CD133-CART细胞杀伤肿瘤细胞的能力,并提高CD133-CAR T细胞的细胞因子分泌水平.mcl-PHA作为后整理基质构筑的含有pomalidomide药物系统的医用纺织品联合CAR T细胞治疗可能成为实体瘤治疗的一种新策略.

Chimeric antigen receptor (CAR) T-cell immunotherapy still faces many challenges in the treatment of solid tumors, one of which is T-cell dysfunction or exhaustion. Immunomodulator lenalidomide may improve CAR T-cell function. In this study, the effects of lenalidomide on CAR T-cell functions (cytotoxicity, cytokine secretion, and cell proliferation) were investigated. Two different CAR T cells (CD133-specific CAR and HER2-specific CAR) were prepared, and the corresponding target cells including human glioma cell line U251 CD133-OE that overexpress CD133 and human breast cancer cell line MDA-MB-453 were used for functional assay. We found that lenalidomide promoted the killing of U251 CD133-OE by CD133-CAR T cells, the cytokine secretion, and the proliferation of CD133-CAR T cells. Lenalidomide also enhanced the cytotoxicity against MDA-MB-453 and the cytokine secretion of HER2-CAR T cells but did not affect their proliferation significantly. Furthermore, lenalidomide may regulate the function of CAR T cells by inducing the degradation of transcription factors Ikaros and Aiolos.