Discovery of novel,orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.     

Interaction of Zinc, Ascorbic Acid, and Folic Acid in Glycation with Albumin as Protein Model

Using albumin as model, we conducted series of in vitro glycation experiments to examine role of zinc in glycation using glucose at 4–100 mg/ml, incubations at 37°C or 60°C, duration of 2 or 4 weeks and in presence of zinc or ascorbic acid (AA) or folic acid (FA). Modifications of bovine serum albumin (BSA) were examined by using fluorescence of advanced glycation end products (AGEs) and dityrosine, UV, and Fourier transformed infrared spectroscopy. Adding zinc (0 to 768.5 μmol/l) resulted in significant inhibition of albumin glycation by glucose with a linear fit, $ y = - 0.0{895}x + {23}0.{99}\left( {{R^2} = 0.{7676},p = 0.0{13}} \right) $ . The glycation by fructose was greater than that of glucose with stronger inhibitory effect by zinc in fructose–glycation (t?=??5.8, p?=?0.002). Addition of zinc significantly decreased fluorescence as seen in Zn?+?FA or Zn?+?AA sets as compared to sets of FA alone (p?=?0.00056) or AA alone (p?=?0.037). The fluorescence for dityrosine and AGE had a correlation of 0.897 (p?<?0.01). The data from fluorescence, UV, and FTIR spectra collectively suggested inhibitory effect of zinc in BSA glycation alone or in presence of FA and AA, showing new dimension for the protective action of zinc in hyperglycemic conditions.     

Decolorization and partial degradation of monoazo dyes in sequential fixed-film anaerobic batch reactor (SFABR)

Decolorization of two monoazo dyes, acid orange 6 (AO6) and acid orange 7 (AO7), were studied in sequential fixed-film anaerobic batch reactor (SFABR) with varying dye concentrations and 500 mg/L glucose as the co-substrate. More than 90% dye decolorization could be achieved, even at 300 mg/L, with both AO6 and AO7 and dye decolorization rates were 168 mg/L/d and 176 mg/L/d, respectively. COD removals with these two monoazo dyes were significantly different, as 75% and 35% decrease were observed with AO6 and AO7, respectively. UV-visible spectral as well as HPLC analysis of SFABR treated effluent showed the accumulation of 4-aminobenzenesulfonate (4-ABS) from AO6 and AO7. Aminoresorcinol (AR) formed from AO6 decolorization could not be detected at the end of SFABR cycle. This along with high COD removal indicated its further degradation. Formation of pink coloration on exposure to air indicated the presence of 1-amino-2-naphthol (AN) in AO7 fed reactor effluent. Thus both 4-ABS and AN were resistant to further degradation under anaerobic conditions. Presence of nitrate did not decrease the observed decolorization at the end of 24h SFABR cycle, although initial rate was decreased. This indicates the suitability of SFABR configuration for the treatment of azo-dye containing wastewaters in the presence of nitrate.     

Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells

Ectopic expression of the Mycobacterium tuberculosis PE-family gene Rv1818c, triggers apoptosis in the mammalian Jurkat T cells, which is blocked by anti-apoptotic protein Bcl-2. Although complete overlap is not observed, a considerable proportion of cellular pools of ectopically expressed Rv1818c localizes to mitochondria. However, recombinant Rv1818c does not trigger release of cytochrome c from isolated mitochondria even though Rv1818c protein induced apoptosis of Jurkat T cells. Apoptosis induced by Rv1818c is blocked by the broad-spectrum caspase inhibitory peptide zVAD-FMK. Unexpectedly, Rv1818c-induced apoptosis is not blocked in a Jurkat sub-clone deficient for caspase-8 (JI 9.2) or in cells where caspase-9 function is inhibited or expression of caspase-9 reduced by siRNA, arguing against a central role for these caspases in Rv1818c-induced apoptotic signaling. Depleting cellular pools of the mitochondrial protein Smac/DIABLO substantially reduces apoptosis consistent with mitochondrial involvement in this death pathway. We present evidence that Rv1818c-induced apoptosis is blocked by the co-transfection of an endogenous inhibitor of caspase activation, XIAP in T cells. Additionally, Rv1818c is released into extracellular environment via exosomes secreted by M. tuberculosis infected BM-DC's and macrophages. Furthermore, the extracellular Rv1818c protein can be detected in T cells co-cultured with infected BM-DC's. Taken together, these data suggest that Rv1818c-induced apoptotic signaling is likely regulated in part by the Smac-dependent activation of caspases in T cells.     

Generation of mice deficient for Lbx2, a gene expressed in the urogenital system, nervous system, and Pax3 dependent tissues

Lbx2 is a member of the ladybird family of homeobox genes. The first murine ortholog identified, Lbx1, is required for hypaxial musculature and dorsal spinal cord neuron development. The second murine ortholog, Lbx2, is expressed in the developing urogenital and nervous systems. To elucidate the function of Lbx2, we generated a gene-targeted allele of Lbx2 in mice. Lbx2 deficiency did not impair mouse development, and Lbx2 null mice appeared healthy and fertile. Replacement of Lbx2 by the lacZ gene provides a valuable histological marker for Lbx2-expressing cells. Given the important role of Pax3 in neural crest, we intercrossed our Lbx2 deficient mice with Splotch Pax3 mutant mice to determine if Pax3 affects Lbx2 expression. There was reduced Lbx2 expression in dorsal root ganglia and cranial nerve ganglia with Pax3 deficiency, but not in the genital tubercle. This suggested that Pax3 is required for Lbx2 expression in affected neural crest-derived tissues.     

Global DNA methylation profile at LINE-1 repeats and promoter methylation of genes involved in DNA damage response and repair pathways in human peripheral blood mononuclear cells in response to γ-radiation

Molecular and Cellular Biochemistry - DNA methylation is an epigenetic mechanism, which plays an important role in gene regulation. The present study evaluated DNA methylation profile of LINE1...