Engineered DBCO+PD-1 Nanovesicles Carrying 1-MT for Cancer-Targeted Immunotherapy.

Liver cancer cells evade immune surveillance and anticancer response through various pathways, including the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immune checkpoint axis that exhausts CD8+ T cells. Inhibitors or antibodies of the PD-L1/PD-1 signaling axis are considered promising drugs for cancer immunotherapy and exhibit favorable clinical responses. However, adverse effects, immune tolerance, and delivery barriers of most patients limit the clinical application of PD-L1/PD-1 antibodies. Thus, it is critical to develop a novel delivery strategy to enhance anticancer immunotherapy. In this study, we bioengineered cell membrane-derived nanovesicles (NVs) presenting PD-1 proteins and dibenzocyclooctyne (DBCO) to encapsulate 1-methyltryptophan (1-MT) (DBCO+PD-1@1-MT NVs). DBCO can specifically interact with N-azidoacetylmannosamine-tetraacetylate (Ac4ManN3) labeled onto metabolic cells for targeted killing of cancers. We next explored the effects of DBCO+PD-1@1-MT NVs on anticancer Hepa1-6 cells in vitro and in vivo. Results showed that PD-1@1-MT NVs dramatically inhibited Hepa1-6 proliferation, promoted peripheral blood mononuclear cell (PBMC) expansion, and strengthened anticancer therapy via blockading the PD-1/PD-L1 immune checkpoint axis, owing to the 1-methyltryptophan (1-MT) enhancement of anticancer immunotherapy efficacy through suppressing the activity of indoleamine 2,3-dioxygenase (IDO). Thus, 1-MT was encapsulated into PD-1 NVs to synergistically enhance cancer immunotherapy. Results have shown that PD-1@1-MT NVs obviously attenuated tumor growth, promoting IFN-γ production, increasing the T cells infiltration in tumors and spleens, and improving the survival period of tumor-bearing mice compared to monotherapy. Therefore, we propose a promising delivery strategy of the combination of DBCO+PD-1 NVs and 1-MT for specific and effective cancer-targeted immunotherapy.

Identification and verification of CCNB1 as a potential prognostic biomarker by comprehensive analysis.

As one of the most common types of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) is highly invasive and lethal. This study aims to develop biomarkers and targets for the diagnosis and treatment of PDAC. Differentially expressed genes (DEGs) were screened via GEO2R, protein network was constructed through STRING and Cytoscape. Functional enrichment analysis was performed, followed by survival analysis and expression validation. A total of 115 DEGs were identified, including 108 upregulated and 7 downregulated genes. After enrichment, survival analysis, one potential gene, Cyclin B1 (CCNB1), was selected for further expression verification at the mRNA and protein level. Taker together, CCNB1 may act as a potential biomarker which provided new idea for elucidation of the pathogenesis of PDAC.

LncRNA MEG3 up-regulates SIRT6 by ubiquitinating EZH2 and alleviates nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a global health threat. Here, we presented the significant role of a novel signaling axis comprising long non-coding RNA maternally expressed gene 3 (MEG3), enhancer of zeste homolog 2 (EZH2), and sirtuin 6 (SIRT6) in controlling lipid accumulation, inflammation, and the progression of NAFLD. Mice fed with high-fat diet (HFD) were established as in vitro and in vivo NAFLD models, respectively. Lipid accumulation was measured by oil red O staining and assays for triglycerides or cholesterol. Inflammation was examined by ELISA for pro-inflammatory cytokines. Gene expressions were examined by RT-qPCR or Western blot. Interactions between key signaling molecules were examined by combining expressional analysis, RNA immunoprecipitation, cycloheximide stability assay, co-immunoprecipitation, and chromatin immunoprecipitation. MEG3 level was reduced in FFA-challenged hepatocytes or liver from HFD-fed mice, and the reduction paralleled the severity of NAFLD in clinic. Overexpressing MEG3 suppressed FFA-induced lipid accumulation or inflammation in hepatocytes. By promoting the ubiquitination and degradation of EZH2, MEG3 upregulated SIRT6, an EZH2 target. SIRT6 essentially mediated the protective effects of MEG3 in hepatocytes. Consistently, overexpressing MEG3 alleviated HFD-induced NAFLD in vivo. By controlling the expressions of genes involved in lipid metabolism and inflammation, the MEG3/EZH2/SIRT6 axis significantly suppressed lipid accumulation and inflammation in vitro, and NAFLD development in vivo. Therefore, boosting MEG3 level may benefit the treatment of NAFLD.