The downregulation of miR-22 and miR-372 may contribute to gestational diabetes mellitus through regulating glucose metabolism via the PI3K/AKT/GLUT4 pathway.

BACKGROUND: Identifying effective regulatory mechanisms will be significant for Gestational diabetes mellitus (GDM) diagnosis and treatment. METHODS: The expressions of miR-22 and miR-372 in placenta tissues from 75 pregnant women with GDM and 75 matched healthy controls and HRT8/SVneo cells (a model of insulin resistance) were analyzed by qPCR. The expressions of PI3K, AKT, IRS, and GLUT4 in high glucose-treated HRT8/SVneo cells transfected with miR-22 or miR-372 mimics or inhibitors was assessed by Western blot. A luciferase gene reporter assay was employed to verify miRNAs' target genes. RESULTS: The expressions of miR-22 and miR-372 in placental tissues from GDM patients and HRT8/SVneo cells were significantly decreased compared with the respective controls. The GLUT4 expression was significantly decreased in the placenta tissues of GDM and HRT8/SVneo cells with high glucose transfected with miR-22 and miR-372 inhibitors. We confirmed that SLC2A4, the gene encoding GLUT4, was a direct target of miR-22 and miR-372. In this study, we report that the lower expressions of miR-22 and miR-372 in placental tissue from GDM patients. CONCLUSION: Our results further suggested that the downregulations of miR-22 and miR-372 may contribute to GDM through regulating the PI3K/GLUT4 pathway.

Complete rejection of large established breast cancer by local immunochemotherapy with T cell activation against neoantigens.

Cancer immunotherapies, including immune checkpoint blockage and adoptive transfer of CAR-T cells, have achieved historical successes for many kinds of malignancy. However, a minority of patients survive long term over 5 years without relapse, perhaps owing to tumor heterogeneity and potent immunosuppression in the tumor microenvironment. Here, using an established mouse tumor model of triple-negative 4T1 breast cancer, we show that local immunochemotherapy triggers powerful local and systemic antitumor immunity. Paraneoplastic injection of CpG, α-OX40, and anthracycline completely eliminated both local and distant large established 4T1 breast cancer without obvious relapse. Analysis of the immune cells at tumor tissues, draining lymph nodes, and spleens revealed that the local treatment increased the infiltration of CD4+ and CD8+ T cells in all three tissues and inhibited the accumulation of myeloid-derived suppressor cells in the spleen in a delayed response. Most importantly, this treatment triggered systemic T cell response against 4T1 tumors and some of their neoantigen epitopes as detected by IFN-γ ELISpot and intracellular cytokine assays in splenocytes. Furthermore, T cells showed specific cytotoxic activity against 4T1 tumor cells in vitro. In general, this local immunochemotherapy provides a new approach to target highly diverse neoantigens in various types of cancers without complicated and expensive antigen identification via next-generation sequencing.

A Local and Low-Dose Chemotherapy/Autophagy-Enhancing Regimen Treatment Markedly Inhibited the Growth of Established Solid Tumors Through a Systemic Antitumor Immune Response.

Chemotherapy is one of the main options for the treatment of a variety of malignant tumors. However, the severe side effects resulting from the killing of normal proliferating cells limit the application of cancer-targeting chemotherapeutic drugs. To improve the efficacy of classic systemic chemotherapy, the local delivery of high-dose chemotherapeutic drugs was developed as a method to enhance local drug concentrations and minimize systemic toxicity. Studies have demonstrated that chemotherapy is often accompanied by cancer-associated immunogenic cell death (ICD) and that autophagy is involved in the induction of ICD. To improve the efficacy of local cancer chemotherapy, we hypothesized that the local delivery of chemotherapeutic plus autophagy-enhancing agents would enhance the promotive effects of ICD on the antitumor immune response. Here, we report that a low-dose chemotherapy/autophagy enhancing regimen (CAER) not only resulted in the increased death of B16F10 and 4T1 tumor cells, but also induced higher levels of autophagy in vitro. Importantly, the local delivery of the CARE drugs significantly inhibited tumor growth in B16F10 and 4T1 tumor-bearing mice. Systemic antitumor T-cell immunity was observed in vivo, including neoantigen-specific T-cell responses. Furthermore, bioinformatic analysis of human breast cancer and melanoma tissues showed that autophagy-associated gene expression was upregulated in tumor samples. Increased autophagy and immune cell infiltration in tumor tissues were positively correlated with good prognosis of tumor patients. This work highlights a new approach to improve the effects of local chemotherapy and enhance systemic antitumor immunity.

Interferon-gamma Facilitates Neurogenesis by Activating Wnt/ß-catenin Cell Signaling Pathway via Promotion of STAT1 Regulation of the ß-Catenin Promoter.

Interferon-gamma (IFN-γ) is critical for central nervous system (CNS) functions and it may be a promising treatment to stimulate CNS regeneration. However, previous studies reported inconsistent results, and the molecular mechanisms remain controversial. Here we show that IFN-γ-treated mice via intraperitoneal injection have elevated IFN-γ level in central hippocampus and superior cognitive behaviors IFN-γ could activates the level of protein expression of Wnt7a, ß-catenin, and CyclinD1 in Wnt/ß-catenin signaling pathway of mice hippocampus. Functional and mechanism analysis in vitro revealed that IFN-γ promoted the proliferation and differentiation in primary cultured neural stem cells (NSCs). STAT1 was accountable for IFN-γ-induced activation of the ß-catenin promoter, and IFN-γ increased the binding affinity of STAT1 to ß-catenin promoter based on luciferase activity and chromatin immunoprecipitation. Our results suggest that IFN-γ exerts many effects ranging from cognitive function in vivo to NSC proliferation, self-renewal, and differentiation in vitro. It does so by recruiting STAT1 to the ß-catenin promoter, enhancing cis-regulation by STAT1, and ultimately activating Wnt/ß-catenin signaling. In this study, we first found that STAT1 was recruited into the promoter of ß-catenin to activate ß-catenin expression, and this effect was regulated by IFN-γ. It is also discovered firstly that Wnt/ß-catenin and JAK/STAT pathways form cross-links through STAT1. Promoting neurogenesis through immune stimulation might be a promising strategy for repairing the diseased/injured CNS. This study provides a scientific basis for immunomodulation to promote nerve regeneration and offer a new therapeutic direction for central nervous system regeneration.