Vernonia amygdalina, a widely consumed West African food herb, can be a boon in the discovery of safe anti-obesity agents given the extensive reports on its anti-obesity and antidiabetic potentials. The main aim of this study was to screen 78 Vernonia-Derived Phytocompounds (VDPs) against the active site regions of Human Pancreatic Lipase (HPL), Human Pancreatic Amylase and Human Glucosidase (HG) as drug targets associated with obesity in silico. Structure-based virtual screening helped to identify Luteolin 7-O-glucuronoside and Andrographidoid D2 as hit compounds with dual targeting tendency towards the HPL and HG. Analysis of the molecular dynamic simulation trajectory files of the ligand-receptor complexes as computed from the thermodynamic parameters plots showed not only increased flexibility and greater interaction potential of the active site residues of the receptor towards the VDPs as indicated by the root mean square fluctuation but also higher stability as indicated by the root mean square deviation, radius of gyration and number of hydrogen bonds. The cluster analysis further showed that the interactions with important residues were preserved in the dynamic environment. These observations were further verified from Molecular Mechanics Generalized Born Surface Area Analysis, which also showed that residual contributions to the binding free energies were mainly from catalytic residues at the active sites of the enzymes. The hit compounds also feature desirable physicochemical properties and drug-likeness. This study provides in silico evidence for the inhibitory potential of phytochemicals from Vernonia amygdalina against two target enzymes in obesity.

Photon production cross sections in 12C-12C and 40Ca-40Ca collisions at Elab=84 and 200 MeV/A are calculated in the framework of the quantum molecular dynamics approach using the medium-dependent NN cross section obtained from the G matrix. Photons are assumed to be produced by incoherent pn bremsstrahlung and a simple classical expression for the production cross section is used. The effects of the equation of state for nuclear matter on the photon production cross section are studied in detail. In the 12C-12C collision, the authors found little difference in the photon cross section due to differences in the equation of state both at 84 and 200 MeV/A. In the 40Ca-40Ca collision, slightly more high-energy photons are produced in the case of the soft equation of state and the difference is slightly larger at higher incident energies.

Despite high cure rates, about 20% of patients with advanced germ cell tumors (GCTs) fail cisplatin-based chemotherapy. High levels of DNA methylation have been identified in GCTs and linked to cisplatin resistance. Here, we examined the effects of DNA hypomethylating 5-azacitidine (5-aza) on two embryonal carcinoma cell lines (NCCIT, 2102Ep) and their cisplatin-resistant isogenic derivatives. Effects on cell viability and cisplatin sensitivity were assessed by the trypan blue exclusion method. Western blotting was used to examine induction of apoptosis 5-aza and results were validated by flow cytometry. Single agent treatment with 5-aza strongly impacted viability and induced apoptosis at low nanomolar concentrations, both in cisplatin-sensitive and -resistant cell lines. 5-aza exerted an immediate apoptotic response, followed by a prolonged inhibitory effect on cell viability and cell-cycle progression. Sequential treatment with 5-aza and cisplatin reduced cellular survival of the cisplatin-resistant sublines already at nanomolar concentrations, suggesting a partial restoration of cisplatin sensitivity by the compound. 5-aza demonstrated anti-tumor activity as a single agent at low nanomolar concentrations in GCT cells, irrespective of cisplatin-sensitivity. 5-aza may also have the potential at least to partially restore cisplatin-sensitivity in non-seminoma cells, supporting the hypothesis that combining DNA demethylating agents with cisplatin-based chemotherapy may be a valid therapeutic approach in patients with refractory GCTs.

Here we report that BCL2 blocks DNA double strand break (DSB) repair via nonhomologous end-joining (NHEJ), through sequestration of KU80 protein outside the nucleus. We find that this effect is associated with a repair switch to the error-prone PARP1-dependent end-joining (PARP1-EJ). We present in-vitro proof-of-concept for therapeutic targeting of this switch using PARP inhibitor to specifically enhance the radiosensitivity of BCL2-overexpressing cells. Given its erroneous behavior, PARP1-EJ might allow for the accumulation of genetic alterations and tumor progression. Consistently, we report an inverse correlation between BCL2 expression and biochemical recurrence-free survival of 10.259 prostate cancer (PCa) patients who underwent primary radical-prostatectomy for localized disease. Further, we evaluated retrospectively the impact of BCL2 expression on clinical outcome of 1.426 PCa patients, who had been given salvage radiotherapy at relapse after radical prostatectomy. In line with its role in blocking NHEJ, BCL2 over-expressers showed significantly better response to salvage radiotherapy compared to low-expressers. Collectively, our findings identify BCL2 status in PCa as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor olaparib as a radiosensitizing agent.