A randomised controlled study on the effects of different surface treatments and adhesive self-etch functional monomers on the immediate repair bond strength and integrity of the repaired resin composite interface

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The antioxidant capacity of sea buckthorn (Hippophae rhamnoides L.) berries depends on the genotype and harvest time

Berries of sea buckthorn (Hippophae rhamnoides L.) are characterized by increasing popularity due to their presumable health-effects. The aim of this study was to compare the antioxidant capacity and total polyphenolic content in the berries of six Hungarian grown sea buckthorn genotypes and characterize the genetic variability in this trait. The harvest time of sea buckthorn berries affects the antioxidant capacity and total phenolic contents in berries of three popular cultivars of German origin. Berries harvested in October had higher antioxidant capacity compared with those harvested one month later. The extent of the difference was genotype-specific. Our analysis revealed a nearly 3-fold difference between the lowest and highest antioxidant capacities of the 6 tested genotypes with ‘Leikora’ showing the highest ferric reducing antioxidant power and total phenolic content. The TEAC values ranged between 1.76 and 3.13 mmol Trolox/100g fresh weight with Pető 1 and ‘Frugana’ having the highest values. The results presented in this study demonstrated that Hippophae rhamnoides berries possess in vitro antioxidant activity strongly determined by genotype but also influenced by harvest time

Potential application of network descriptions for understanding conformational changes and protonation states of ABC transporters.

The ABC (ATP Binding Cassette) transporter protein superfamily comprises a large number of ubiquitous and functionally versatile proteins conserved from archaea to humans. ABC transporters have a key role in many human diseases and also in the development of multidrug resistance in cancer and in parasites. Although a dramatic progress has been achieved in ABC protein studies in the last decades, we are still far from a detailed understanding of their molecular functions. Several aspects of pharmacological ABC transporter targeting also remain unclear. Here we summarize the conformational and protonation changes of ABC transporters and the potential use of this information in pharmacological design. Network related methods, which recently became useful tools to describe protein structure and dynamics, have not been applied to study allosteric coupling in ABC proteins as yet. A detailed description of the strengths and limitations of these methods is given, and their potential use in describing ABC transporter dynamics is outlined. Finally, we highlight possible future aspects of pharmacological utilization of network methods and outline the future trends of this exciting field

Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.

Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma

Identification of PPARgamma ligands with One-dimensional Drug Profile Matching.

INTRODUCTION: Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. The PPARgamma action of the selected generics was also investigated by in vitro and in vivo experiments. MATERIALS AND METHODS: The in silico oDPM method was used to determine the binding potency of 1,255 generics to 149 proteins collected. In vitro PPARgamma activation was determined by measuring fatty acid-binding protein 4/adipocyte protein gene expression in a Mono Mac 6 cell line. The in vivo insulin sensitizing effect of the selected compound (nitazoxanide; 50-200 mg/kg/day over 8 days; n = 8) was established in type 2 diabetic rats by hyperinsulinemic euglycemic glucose clamping. RESULTS: After examining the closest neighbors of each of the reference set's members and counting their most abundant neighbors, ten generic drugs were selected with oDPM. Among them, four enhanced fatty acid-binding protein/adipocyte protein gene expression in the Mono Mac 6 cell line, but only bromfenac and nitazoxanide showed dose-dependent actions. Induction by nitazoxanide was higher than by bromfenac. Nitazoxanide lowered fasting blood glucose levels and improved insulin sensitivity in type 2 diabetic rats. CONCLUSION: We demonstrated that the oDPM method can predict previously unknown therapeutic effects of generic drugs. Nitazoxanide can be the prototype chemical structure of the new generation of insulin sensitizers

The antioxidant capacity of sea buckthorn (Hippophae rhamnoides L.) berries depends on the genotype and harvest time

Berries of sea buckthorn (Hippophae rhamnoides L.) are characterized by increasing popularity due to their presumable healtheffects. The aim of this study was to compare the antioxidant capacity and total polyphenolic content in the berries of six Hungarian grown sea buckthorn genotypes and characterize the genetic variability in this trait. The harvest time of sea buckthorn berries affects the antioxidant capacity and total phenolic contents in berries of three popular cultivars of German origin. Berries harvested in October had higher antioxidant capacity compared with those harvested one month later. The extent of the difference was genotype-specific. Our analysis revealed a nearly 3-fold difference between the lowest and highest antioxidant capacities of the 6 tested genotypes with ‘Leikora’ showing the highest ferric reducing antioxidant power and total phenolic content. The TEAC values ranged between 1.76 and 3.13 mmol Trolox/100g fresh weight with Pető 1 and ‘Frugana’ having the highest values. The results presented in this study demonstrated that Hippophae rhamnoides berries possess in vitro antioxidant activity strongly determined by genotype but also influenced by harvest time