BackgroundMetabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect.MethodsA 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures.ResultsDAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q–R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K+-channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca2+-homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na+-currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart.ConclusionsOverall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion–fission proteins, out of its glucose-lowering effect.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0790-0) contains supplementary material, which is available to authorized users.
Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.
The pleiotropic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the heart have been recognised in obese or diabetic patients. However, little is known regarding the molecular mechanisms of these agonists in cardioprotective actions under metabolic disturbances. We evaluated the effects of GLP-1R agonist liraglutide treatment on left ventricular cardiomyocytes from high-carbohydrate induced metabolic syndrome rats (MetS rats), characterised with insulin resistance and cardiac dysfunction with a long-QT. Liraglutide (0.3 mg/kg for 4 weeks) treatment of MetS rats significantly reversed long-QT, through a shortening the prolonged action potential duration and recovering inhibited K + -currents. We also determined a significant recovery in the leaky sarcoplasmic reticulum (SR) and high cytosolic Ca 2+ -level, which are confirmed with a full recovery in activated Na + /Ca 2+ -exchanger currents (I NCX ). Moreover, the liraglutide treatment significantly reversed the depolarised mitochondrial membrane potential (MMP), increased production of oxidant markers, and cellular acidification together with the depressed ATP production. Our light microscopy analysis of isolated cardiomyocytes showed marked recoveries in the liraglutide-treated MetS group such as marked reverses in highly dilated T-tubules and SR-mitochondria junctions.Moreover, we determined a significant increase in depressed GLUT4 protein level in liraglutide-treated MetS group, possibly associated with recovery in casein kinase 2α. Overall, the study demonstrated a molecular mechanism of liraglutide-induced cardioprotection in MetS rats, at most, via its pleiotropic effects, such as alleviation in the electrical abnormalities, Ca 2+ -homeostasis, and mitochondrial dysfunction in ventricular cardiomyocytes.
The study aims to evaluate the vismodegib treatment in local advanced (laBCC) and metastatic (mBCC) basal cell carcinoma. The data of 29 patients were retrospectively reviewed. The clinical and histopathological features of the patients and adverse events of vismodegib were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier analysis. The median follow-up period was 17 months (range: 1.6-57.3), and the median age at diagnosis 73 years (range: 39-88). The most common disease location was head and neck (86.2%), and the most common non-skin sites of disease were lymph nodes (13.8%), bone (13.8%), lung (6.9%), and brain (6.9%). Three (10.3%) patients had Gorlin's syndrome. The number of metastatic patients was 5 (17.2%). With vismodegib treatment, the complete response rate was 27.6%, partial response 55.2%, and stable response 10.3%. Treatment responses were most frequently seen within 2 months from the beginning of vismodegib. The median OS was 43.3 ± 9.0 months (25.6-61.1) for all patients. The median PFS in the laBCC was 15.7 ± 1.8 months (12.2-19.3), and 12.1 ± 4.6 months (2.9-21.2) in the mBCC. In the univariable analysis for the OS, only the treatment after the vismodegib was statistically significant, showing chemotherapy was better comparing to no treatment or surgery. The most common adverse events were fatigue-58.6%, muscle spasms-48.3%, alopecia-13.8%, and weight loss-13.8%. This real-life data study shows that vismodegib treatment in locally advanced and metastatic BCC was well tolerated and effective.
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