QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure-activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents

DISTO: a large acceptance multiparticle spectrometer for 1–3 GeV proton beams

Abstract A magnetic spectrometer system has been constructed for the study of reactions with multiple charged particles in the final state, induced by polarized proton beams of few GeV energy. The system is based on a large-gap dipole magnet, with a liquid hydrogen target and scintillating fiber tracking detectors embedded inside the magnet. Multiwire proportional chambers, plastic scintillator hodoscopes, and threshold Cherenkov detectors placed outside the magnet provide additional tracking, triggering and particle identification capabilities. The system has been applied to study exclusive hyperon as well as pseudoscalar and vector meson production reactions at bombarding energies below 3 GeV. Additionally, it has been used to monitor the proton beam polarization at Laboratoire National Saturne. The components and performance of the system are reported

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.

Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization

Additional file 1 of Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

Supplementary Material

Hypoglycaemic activity of Bauhinia holophylla through GSK3-β inhibition and glycogenesis activation

Context: Bauhinia L. species, including Bauhinia holophylla (Bong.) Steud. (Fabaceae), have traditionally been used to treat diabetes. Bauhinia is a complex botanical genus, and the indiscriminate use of the diverse Bauhinia species is reflected in the experimental divergence of their medicinal potential. Objective: The hypoglycaemic and hypolipidaemic effects, molecular mechanism of action and phytochemical properties of an authentic extract of B. holophylla leaves were evaluated. Materials and methods: A phytochemical study of a 70% EtOH extract was performed using FIA-ESI-IT-MS/MSn and HPLC-PAD-ESI-IT-MS. The extract (200 or 400 mg/kg b.w.) was administered for 14 days to streptozotocin-induced diabetic Swiss mice. Glucose tolerance and insulin sensitivity, blood parameters, gene and protein expression, and the in vivo and in vitro inhibition of intestinal glucosidases were assessed. Results: HPLC-PAD-ESI-IT-MS analysis identified flavonoid derivatives of quercetin, myricetin, luteolin and kaempferol. Treatment with 400 mg/kg of the extract reduced blood glucose (269.0 ± 32.4 mg/dL vs. 468.0 ± 32.2 mg/dL for diabetic animals), improved glucose tolerance, decreased cholesterol and triglyceride levels, and increased the mRNA expression of proteins involved in glucogenesis in the liver and muscle, such as PI3-K/Akt, GS, GSK3-β (ser-9), AMPK and Glut4. The activity of intestinal maltase was inhibited in vitro (IC50: 43.0 µg/mL for the extract compared to 516.4 µg/mL for acarbose) and in vivo. Discussion and conclusions: Treatment with B. holophylla was associated with a marked hypoglycaemic effect through the stimulation of glycogenesis and inhibition of gluconeogenesis and intestinal glucose absorption, without increasing basal insulinaemia