Elevated reactive oxygen species (ROS) in type 2 diabetes cause cellular damage in many organs. Recently, the new class of glucose-lowering agents, SGLT-2 inhibitors, have been shown to reduce the risk of developing diabetic complications; however, the mechanisms of such beneficial effect are largely unknown. Here we aimed to investigate the effects of dapagliflozin on cell proliferation and cell death under oxidative stress conditions and explore its underlying mechanisms. Human proximal tubular cells (HK-2) were used. Cell growth and death were monitored by cell counting, water-soluble tetrazolium-1 (WST-1) and lactate dehydrogenase (LDH) assays, and flow cytometry. The cytosolic and mitochondrial (ROS) production was measured using fluorescent probes (H2DCFDA and MitoSOX) under normal and oxidative stress conditions mimicked by addition of H2O2. Intracellular Ca2+ dynamics was monitored by FlexStation 3 using cell-permeable Ca2+ dye Fura-PE3/AM. Dapagliflozin (0.1-10 μM) had no effect on HK-2 cell proliferation under normal conditions, but an inhibitory effect was seen at an extreme high concentration (100 μM). However, dapagliflozin at 0.1 to 5 μM showed remarkable protective effects against H2O2-induced cell injury via increasing the viable cell number at phase G0/G1. The elevated cytosolic and mitochondrial ROS under oxidative stress was significantly decreased by dapagliflozin. Dapagliflozin increased the basal intracellular [Ca2+]i in proximal tubular cells, but did not affect calcium release from endoplasmic reticulum and store-operated Ca2+ entry. The H2O2-sensitive TRPM2 channel seemed to be involved in the Ca2+ dynamics regulated by dapagliflozin. However, dapagliflozin had no direct effects on ORAI1, ORAI3, TRPC4 and TRPC5 channels. Our results suggest that dapagliflozin shows anti-oxidative properties by reducing cytosolic and mitochondrial ROS production and altering Ca2+ dynamics, and thus exerts its protective effects against cell damage under oxidative stress environment.
  Vitamin D status is presently assessed by measuring total serum concentration of 25-hydroxyvitamin D [25(OH)D]. However, 25(OH)D concentration alone might not accurately reflect vitamin D status owing to its weak relationship with various clinical indices and inconsistency across races.  https://www.selleckchem.com/products/ml385.html  Recently, 24,25-dihydroxyvitamin D [24,25(OH)2D] and vitamin D metabolite ratio [VMR; ratio of 24,25(OH)2D to 25(OH)D] have emerged as vitamin D biomarkers. The present study aimed to determine the values of 24,25(OH)2D and VMR in healthy Koreans and compare them with other vitamin D biomarkers, including 25(OH)D and bioavailable 25(OH)D.
 
  Serum samples and medical information were collected from 200 individuals (100 females and 100 males) who underwent general health checks without self-reported symptoms. We measured 24,25(OH)2D concentration using liquid chromatography-tandem mass spectrometry, and concentrations of 25(OH)D and vitamin D binding protein using immunoassays. VMR and bioavailable 25(OH)D concentration were culation for the first time. Overall, our data reaffirm that 25(OH)D is the primary marker for determining vitamin D status in the general population.Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder of motor neurons which leads to complete loss of movement in patients. The only FDA approved drug Riluzole provides only symptomatic relief to patients. Early Diagnosis of the disease warrants the importance of diagnostic and prognostic models for predicting disease and disease progression respectively. In the present study we represent the predictive statistical model for ALS using plasma and CSF biomarkers. Forward stepwise (Binary likelihood) Logistic regression model is developed for prediction of ALS. The model has been shown to have excellent validity (94%) with good sensitivity (98%) and specificity (93%). The area under the ROC curve is 99.3%. Along with age and BMI, VEGF (Vascular Endothelial Growth Factor), VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) and TDP43 (TAR DNA Binding Protein 43) in CSF and VEGFR2 and OPTN (Optineurin) in plasma are good predictors of ALS.Evasive entrepreneurship (circumvention and exploitation of institutions by entrepreneurs) is a prevalent practice in many developing economies. Extant literature on the topic falls short of providing adequate theories to explain its triggers, mechanisms, and consequences. Leveraging extensive survey data from the World Bank, we used structural equation modeling to examine the relationship between evasive entrepreneurial behavior-tax evasion and bribery-and the relative payoff of such practices. Of the 2599 Nigerian entrepreneurs in our sample, the majority admitted to engaging in evasive entrepreneurship. The data suggest that institutional factors thought to constrain entrepreneurship in emerging markets are counter-intuitively perceived by founders as opportunities to earn large rents and improve firm performance. Our results emphasize the urgent need to eliminate institutional constraints that paradoxically enable the growth of evasive entrepreneurship in emerging economies. Our results also suggest that prevailing local conventions involving evasive behavior may motivate nascent entrepreneurs to imitate bribery and tax evasion, normalizing malfeasance as 'best practice.'When one learns that current struggles or transgressions of an individual or group are rooted in an unfortunate history, one experiences compassion and reduced blame. Prior research has demonstrated this by having participants receive (or not) a concrete historicist narrative regarding the particular individual or group under consideration. Here, we take a different approach. We explore the possibility that everyday people show meaningful variation in a broad lay theory that we call lay historicism. Lay historicists believe that-as a general fact-people's psychological characteristics and life outcomes are powerfully molded by their life histories. We present eight studies linking lay historicism to broad tendencies toward compassion and non-blaming. Collectively, Studies 1-5 suggest that lay historicism affects compassion and blame, respectively, via distinct mechanisms (1) Lay historicism is associated with compassion because it creates a sense that-as a general fact-past suffering lies behind present difficulties, and (2) lay historicism is associated with blame mitigation because historicists reject the idea that-as a general fact-people freely and autonomously create their moral character.