Condensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), casein kinase II (CKII), and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern of NCT binding at the core centromere, the region of maximal condensin enrichment, tracks the abundance of acetylated histone H4, as regulated by the Hat1-Mis16 acetyltransferase complex and recognized by the first Nrc1 bromodomain. Strikingly, mutants in NCT or Hat1-Mis16 restore the formation of segregation-competent chromosomes in cells containing defective condensin. These results are consistent with a model where NCT targets CKII to chromatin in a cell-cycle-directed manner in order to modulate the activity of condensin during chromosome condensation and decondensation.
The mammalian hyaluronidase degrades hyaluronic acid by the cleavage of the β-1,4-glycosidic bond furnishing a tetrasaccharide molecule as the main product which is a highly angiogenic and potent inducer of inflammatory cytokines. Ursolic acid 1, isolated from Prismatomeris tetrandra, was identified as having the potential to develop inhibitors of hyaluronidase. A series of ursolic acid analogues were either synthesized via structure modification of ursolic acid 1 or commercially obtained. The evaluation of the inhibitory activity of these compounds on the hyaluronidase enzyme was conducted. Several structural, topological and quantum chemical descriptors for these compounds were calculated using semi empirical quantum chemical methods. A quantitative structure activity relationship study (QSAR) was performed to correlate these descriptors with the hyaluronidase inhibitory activity. The statistical characteristics provided by the best multi linear model (BML) (R² = 0.9717, R²cv = 0.9506) indicated satisfactory stability and predictive ability of the developed model. The in silico molecular docking study which was used to determine the binding interactions revealed that the ursolic acid analog 22 had a strong affinity towards human hyaluronidase.
This study examined the effects of melatonin on leptin-induced changes in sperm parameters in adult rats. Five groups of Sprague-Dawley rats were treated with either leptin or leptin and melatonin or melatonin for 6 weeks. Leptin was given daily via the intraperitoneal route (60 μg kg-1 body weight) and melatonin was given in drinking water (10 mg kg-1 or 20 mg kg-1 body weight per day). Upon completion, sperm count, sperm morphology, 8-hydroxy-2-deoxyguanosine, Comet assay, TUNEL assay, gene expression profiles of antioxidant enzymes, respiratory chain reaction enzymes, DNA damage, and apoptosis genes were estimated. Data were analyzed using ANOVA. Sperm count was significantly lower whereas the fraction of sperm with abnormal morphology, the level of 8-hydroxy-2-deoxyguanosine, and sperm DNA fragmentation were significantly higher in rats treated with leptin only. Microarray analysis revealed significant upregulation of apoptosis-inducing factor, histone acetyl transferase, respiratory chain reaction enzyme, cell necrosis and DNA repair genes, and downregulation of antioxidant enzyme genes in leptin-treated rats. Real-time polymerase chain reaction showed significant decreases in glutathione peroxidase 1 expression with increases in the expression of apoptosis-inducing factor and histone acetyl transferase in leptin-treated rats. There was no change in the gene expression of caspase-3 (CASP-3). In conclusion, the adverse effects of leptin on sperm can be prevented by concurrent melatonin administration.