ABSTRACT
Stabilization of G-quadruplex (G4) structures in mitochondria leads to the damage of mitochondrial DNA (mtDNA), making mtDNA G4s a promising target in the field of cancer therapy in recent years. Damaged mtDNA released into the cytosol can stimulate cytosolic DNA-sensing pathways, and cGAS-STING pathway is a typical one with potent immunostimulatory effects. A few small molecule ligands of mtDNA G4s are identified with antitumor efficacy, but little is known about their results and mechanisms on immunomodulation. In this study, we engineered a series of triphenylamine-based analogues targeting mtDNA G4s, and A6 was determined as the most promising compound. Cellular studies indicated that A6 caused severe mtDNA damage. Then, damaged mtDNA stimulated cGAS-STING pathway, resulting in the following cytokine production of tumor cells and the maturation of DCs. In vivo experiments certified that A6 exerted suppressive influences on tumor growth and metastasis in 4T1 cell-bearing mice by the regulation of TME, including the remodeling of macrophages and the activation of T cells. To our knowledge, it is the first time to report a ligand targeting mtDNA G4s to activate the cGAS-STING immunomodulatory pathway, providing a novel strategy for the future development of mtDNA G4-based antitumor agents.
Subject(s)
G-Quadruplexes , Animals , Mice , Ligands , Mitochondria , DNA, Mitochondrial , Amines , Immunomodulation , NucleotidyltransferasesABSTRACT
Barranca yajiagengensis, a novel filamentous microalga, can accumulate lutein under high-light and low-nitrogen conditions. It is well known that lutein has antioxidant, anti-inflammatory and immune-modulating properties. The purpose of this study is to evaluate the effects of including lutein-rich B. yajiagengensis powder in the diet of Trachinotus ovatus on the growth performance, antioxidant capacity, immunity, liver, and intestinal morphology. For this aim, three experimental diets containing 0% (BY0), 1% (BY1), and 5% (BY5) B. yajiagengensis powder were formulated for six-week feeding trials. The results indicated that growth performance, feed utilization, and intestinal morphology were not affected by different diet treatments. Fish fed with the BY5 diet promoted antioxidant ability by activating the Nrf2-ARE signal pathway and enhancing antioxidant enzymes activities. Furthermore, the BY5 diet improved non-specific immunity and antibacterial ability by activating lysozymes and the complement system and increasing the nitric oxide (NO) content and total nitric oxide synthase activity. Dietary B. yajiagengensis supplementation improved the liver morphology and exerted hepatoprotective effects. Therefore, as a natural source of lutein, B. yajiagengensis has the potential as a safe and non-toxic immunostimulant for T. ovatus. A diet supplemented with 5% B. yajiagengensis is recommended to improve the growth, antioxidant capacity, immune response, and liver health of T. ovatus.
ABSTRACT
BACKGROUND: The aim of this study was to systematically assess the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) for patients with heart failure (HF) and diabetes mellitus (DM). METHODS: We conducted a comprehensive search for controlled studies that evaluated the efficacy and safety of MRAs in patients with DM and HF. Medline, Embase and Cochrane databases were searched. Two reviewers independently identified citations, extracted data and evaluated quality. Risk estimations were abstracted and pooled where appropriate. RESULTS: Four observational studies were included. MRAs use was associated with reduced mortality compared with controls (RR = 0.78; 95% CI: 0.69-0.88; I(2) = 0%; P < 0.001). Increased risk of developing hyperkalaemia was observed in those patients taking MRAs (RR = 1.74; 95% CI: 1.27-2.38; I(2) = 0%; P = 0.0005). CONCLUSIONS: The current cumulative evidence suggests that MRAs can improve clinical outcomes but increase the risk of hyperkalaemia in patients with DM and HF. TRIAL REGISTRATION: PROSPERO CRD42015025690 .
