The association of single nucleotide polymorphisms rs1053239 and rs2479 of cell death-inducing DFFA-like effector c with the risk of metabolic syndrome and its components, and with the efficacy and cost-effectiveness of antihypertensive drugs was investigated. Totally 1064 subjects with metabolic syndrome and 1099 controls of Chinese Han nationality were recruited. Clinical assessment was conducted with medication records collected at baseline and during 5-year follow-up. Carriers of rs2479 A allele were at higher risk to develop elevated fasting glucose than non-carriers (P = 0.004). A allele at rs2479 were associated with a 5-year aggravation of blood triglyceride (P < 0.001) and diastolic blood pressure (P = 0.003), and C allele at rs1053239 with the exacerbation of systolic (P < 0.001) and diastolic blood pressure (P = 0.001). Moreover, efficacy and cost-effectiveness of angiotensin II-targeted drugs were higher in subjects with rs2479 A allele or rs1053239 C allele. These findings suggest that carriers of rs2479 A allele are predisposed to the development of increased fasting glucose, and the progressive elevation of blood triglyceride. Individuals with A allele at rs2479 or C allele at rs1053239 are more susceptible to a rapid progression of blood pressure, and benefit more from angiotensin II-targeted therapy.

Hypertension is a highly prevalent disease and the leading cause of chronic kidney disease (CKD). Metabolic syndrome could also be the risk factor for CKD. We sought to study the association between metabolic syndrome components and the prevalence of CKD in patients with hypertension.

Cancer cachexia is a kind of whole-body metabolic disorder syndrome accompanied by severe wasting of muscle tissue in which cancer exosomes may be involved. Analysis of clinical samples showed that the serum exosome concentrations were correlated with the development of cancer cachexia. Exosomes secreted by C26 cells could decrease the diameter of C2C12 myotubes in vitro and decrease mouse muscle strength and tibialis anterior (TA) muscle weight in vivo. GW4869, an inhibitor of exosome excretion, ameliorated muscle wasting in C26 tumor-bearing mice. MicroRNA (miRNA) sequencing (miRNA-seq) analysis suggested that miR-195a-5p and miR-125b-1-3p were richer in C26 exosomes than in exosomes secreted from MC38 cells (non-cachexic). Both miR-195a-5p and miR-125b-1-3p mimics could induce atrophy of C2C12 myoblasts. Downregulation of Bcl-2 and activation of the apoptotic signaling pathway were observed in C2C12 myoblasts transfected with miR-195a-5p and miR-125b-1-3p mimics, in the gastrocnemius muscle of C26 tumor-bearing mice and in the TA muscle injected with C26 exosomes. Results of dual-luciferase assay confirmed the targeting of miR-195a-5p/miR-125b-1-3p to Bcl-2. Overexpression of Bcl-2 successfully reversed atrophy of C2C12 myoblasts induced by the two miRNA mimics. These results suggested that cancer exosome enriched miRNAs might induce muscle atrophy by targeting Bcl-2-mediated apoptosis.

CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction.