Translational research : the journal of laboratory and clinical medicine
-
Chronic kidney disease (CKD) is a strong risk factor for cardiovascular mortality and morbidity. We hypothesized that a senescent phenotype instigated by uremic toxins could account for early vascular aging (EVA) and vascular dysfunctions of microvasculature in end stage kidney disease (ESKD) patients which ultimately lead to increased cardiovascular complication. To test this hypothesis, we utilized both in vivo, and ex vivo approaches to study endothelial and smooth muscle function and structure, and characterized markers related to EVA in 82 ESKD patients (eGFR <15 ml/min) and 70 non-CKD controls. ⋯ Correspondingly, treating uremic vessel rings ex vivo with senolytic agents (Dasatinib + Quercetin) effectively reduced the senescence-associated secretory phenotype and changed the origin of extracellular vesicles. Notably, sex differences exist for certain abnormalities suggesting the importance of biological sex in the pathogenesis of vascular complications. In conclusion, the uremic microvasculature is characterized by a "senescence signature", which may contribute to EVA and cardiovascular complications in ESKD patients and could be alleviated by treatment with senolytic agents.
-
According to morphological features, tumor-infiltrating B cells (TIL-Bs) can be classified as lympho-myeloid aggregates (LMAs) and tertiary lymphoid structures (TLSs). As a disease with high incidence and mortality, research on esophageal squamous cell carcinoma (ESCC) TIL-Bs is still unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TIL-Bs in ESCC. ⋯ Subsequently, we demonstrate a close relationship between DN B cells and regulatory T cells (Tregs) using single cell RNA-seq data, bulk RNA-seq data and flow cytometry, and verified the spatial proximity of DN B cells and Tregs by mIF staining. Trajectory analysis and flow cytometry revealed that DN B cells highly expressed genes involved in the antigen processing and presentation pathway, such as HLA-DR. The abundance of DN B cells and LMAs in ESCC provides novel potential targets for optimal immunotherapy against ESCC.
-
Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. ⋯ Blockade of TREM2 by conventional/conditional knock-out or soluble TREM2 administration can attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found that Trem2 deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such as Ccl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.
-
Hepatocellular carcinoma (HCC) is a prevalent malignant tumor requiring effective treatments. Oncolytic viruses induce anti-tumor responses but have limited efficacy. Apolipoprotein A1 (ApoA1) inhibits inflammation, modulates immunity, and promotes anti-oxidation. ⋯ Notably, the cholesterol content in the CD8+ T cells studied was significantly correlated with the expression of PD-1 and LAG-3, with ApoA1 promoting cholesterol efflux and reducing cholesterol levels. Ad5-ApoA1 activates CD8+ T cells by promoting large-scale viral replication. High levels of ApoA1 protein expression promote cholesterol efflux, inhibit CD8+ T cell depletion, and reduce inflammatory factors, ultimately leading to superior therapeutic effects on hepatocellular carcinoma.