Synthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators

Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARγ ligand binding domain is described.     

DPP4 Gene DNA Methylation in the Omentum is Associated With Its Gene Expression and Plasma Lipid Profile in Severe Obesity

Severely obese subjects with the metabolic syndrome (MS) have higher dipeptidyl peptidase‐4 (DPP4) expression in their visceral adipose tissue (VAT) compared to obese individuals without MS. We tested the hypothesis that methylation level of CpG sites in the DPP4 promoter CpG island in VAT was genotype‐dependent and associated with DPP4 mRNA abundance and MS‐related phenotypes. The VAT DNA was extracted in 92 severely obese premenopausal women undergoing biliopancreatic derivation for the treatment of obesity. Women were nondiabetic and none of them used medication to treat MS features. Cytosine methylation rates (%) of 102 CpG sites in the DPP4 CpG island were assessed by pyrosequencing of sodium bisulfite‐treated DNA. Methylation rates were >10% for CpG sites 94–102. Their mean methylation rate (%Meth_94–102) was different between genotypes for DPP4 polymorphisms rs13015258 (P = 0.001), rs17848915 (P = 0.0004), and c.1926 G>A (P = 0.001). The %Meth_94–102 correlated negatively with DPP4 mRNA abundance (r = ?0.25, P < 0.05) and positively with plasma high‐density lipoprotein (HDL) cholesterol concentrations (r = 0.22, P < 0.05), whereas DPP4 mRNA abundance correlated positively with plasma total‐/HDL‐cholesterol ratio (r = 0.25; P < 0.05). In the VAT of nondiabetic severely obese women, genotype‐dependent methylation levels of specific CpG sites in the DPP4 promoter CpG island were associated with DPP4 gene expression and variability in the plasma lipid profile. Higher DPP4 gene expression in VAT and its relationship with the plasma lipid profile may be explained by actually unknown DPP4 biological effect or, to another extent, may also be a marker of VAT inflammation known to be associated with metabolic disturbances.     

Antimicrobial activity of silymarin mediated zinc oxide and hydroxy apatite nanoparticles against oral pathogens

The nanoparticles such as hydroxyapatite, zinc oxide, titanium dioxide and zirconium nanoparticles have application in dentistry. Therefore, it is of interest to document the antimicrobial activity of silymarin mediated zinc oxide and hydroxy apatite nanoparticles against oral pathogens. Hence, we synthesized hydroxyapatie and zinc oxide nanoparticles with silymarin and characterized by UV-visible spectrophotometer. Data shows that silymarin mediated HAP and ZnO nanoparticles have antimicrobial activity against oral pathogens such as Pseudomonas sp, Staphylococcus aureus, Streptococcus mutans, Enterococcus faecalis and Candida albicans.     

How proprioceptive impairments affect quiet standing in patients with multiple sclerosis

To assess if multiple sclerosis patients with proprioceptive impairment are specifically affected during quiet standing with eyes open and how they can develop motor compensatory processes, 56 patients, classified from sensory clinical tests as ataxo-spastic (MS-AS) or only having spasticity (MS-S), were compared to 23 healthy adults matched for age. The postural strategies were assessed from the centre-of-pressure trajectories (CP), measured from a force platform in the eyes open standing condition for a single trial lasting 51.2?s. The vertical projection of the centre of gravity (CG_v) and its vertical difference from the CP (CP-CG_v) were then estimated through a biomechanical relationship. These two movements permit the characterization of the postural performance and the horizontal acceleration communicated to the CG and from that, the global energy expenditure, respectively. Both MS-AS and MS-S groups demonstrate larger CG_v and CP-CG_v movements than healthy individuals of the same age. Whilst similar CG_v values are noticed in both MS subgroups, suggesting similar postural performances, statistically significant differences are observed for the CP-CG_v component. Biomechanically, this feature expresses the necessity for the MS-AS group to develop augmented neuro-muscular means to control their body movements, as compared to the MS-S group. By demonstrating for both groups of patients similar postural performance accompanied by a varying degree of energy expenditure to maintain undisturbed upright stance, this study reveals that MS-AS patients which are affected by proprioceptive loss can compensate for this deficit with more efficient control strategies, when standing still with their eyes open.     

The Diversity of Flower Flies (Diptera: Syrphidae) in Colombia and Their Neotropical Distribution

In Colombia, like most Neotropical countries, faunistic studies on flower flies have been occasional and most of them have been primarily focused on taxonomy. Colombia is the second-most species-rich country in flower fly diversity in the Neotropics after Brazil, and has one of the highest numbers of species per unit area (2.49 per 10,000?km²), based on a review of literature and national collections. Including new data presented here, a total of 47 genera and 300 species are recorded in Colombia. The genera Scaeva Fabricius and Lycastrirhyncha Bigot, as well as 101 species are recorded here for the first time. The altitudinal range and the distribution of the flower fly genera in Colombia are presented. A preliminary comparison of the fauna of Colombia with that of other Neotropical countries is given. A historical perspective is also provided in order to illustrate how Colombian Syrphidae knowledge has progressed over the last 168?years. Information presented here will be useful for ongoing and future biodiversity research as well as conservation projects on Syrphidae in the Neotropical region.     

Cloning and expression of an anti-LDL(-) single-chain variable fragment,and its inhibitory effect on experimental atherosclerosis

The in vivo modified forms of low-density lipoprotein (LDL) are important for the formation of foam cells and as mediators of the immuno-inflammatory process involved in the progression of atherosclerosis. Electronegative LDL, LDL(-), is a LDL subfraction with pro-inflammatory properties that is present in human blood. To investigate possible atheroprotective effects, an anti-LDL(-) single-chain variable fragment (scFv) was expressed in the methylotrophic yeast Pichia pastoris and its activity was evaluated in vitro against macrophages and in experimental atherosclerosis in Ldlr^-/- mice. The recombinant 2C7 scFv was produced in a yield of 9.5 mg of protein/L. The specificity and affinity of purified 2C7 scFv against LDL(-) was confirmed by ELISA. To assess the activity of 2C7 scFv on foam cell formation, RAW 264.7 macrophages were exposed to LDL(-) in the presence or absence of 2C7 scFv. The 2C7 scFv inhibited the uptake of LDL(-) by macrophages in a dose-dependent manner, and internalization of LDL(-) by these cells was found to be mediated by the CD36 and CD14 receptor. In addition, compared with untreated cells, lipid accumulation in macrophages was decreased, and the expression of Cd36, Tlr-4 and Cox-2 was downregulated in macrophages treated with 2C7 scFv. Importantly, compared with untreated mice, the treatment of Ldlr^-/- mice with 2C7 scFv decreased the atherosclerotic lesion area at the aortic sinus. In conclusion, our data show that 2C7 scFv inhibits foam cell formation and atherosclerotic plaque development by modulating the expression of genes relevant to atherogenesis. These results encourage further use of this antibody fragment in the development of new therapeutic strategies that neutralize the pro-atherogenic effects of LDL(-).     

Impact of transgenic Bt-cotton on the diversity of pink-pigmented facultative methylotrophs

Pink-pigmented facultative methylotrophs (PPFMs) are one of the beneficial proteobacteria commonly found in phyllosphere, rhizosphere and as endophytes in cotton. To assess the impact of transgenic Bt-cotton on changes in the diversity and community profile of PPFMs by comparing with its non-transgenic cotton, a polyphasic approach including differential carbon-substrate utilization profiling and DNA fingerprinting techniques like ARDRA, RISA, BOX-PCR and ERIC-PCR were studied. PPFMs from phyllosphere, rhizoplane and internal tissues of the stem of both Bt-cotton and non-Bt-cotton were isolated and analysed in this study. All the results suggested that the diversity richness of PPFMs present in the phyllosphere, rhizoplane and internal tissues did not differ between Bt- and non-Bt-cotton. In this study, there was no evidence to indicate any adverse effects of Bt-cotton on the diversity of plant-associated methylobacteria.     

The discovery of equipotent PPARalpha/gamma dual activators

We report the design and synthesis of equipotent PPARalpha/gamma dual agonists starting from selective PPAR alpha agonist 1. In vivo data for 7 in the Zucker fa/fa rat are presented.