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61.
62.
Szulc ZM Bielawski J Gracz H Gustilo M Mayroo N Hannun YA Obeid LM Bielawska A 《Bioorganic & medicinal chemistry》2006,14(21):7083-7104
In the course of our studies on compartment-specific lipid-mediated cell regulation, we identified an intimate connection between ceramides (Cers) and the mitochondria-dependent death-signaling pathways. Here, we report on a new class of cationic Cer mimics, dubbed ceramidoids, designed to act as organelle-targeted sphingolipids (SPLs), based on conjugates of Cer and dihydroceramide (dhCer) with pyridinium salts (CCPS and dhCCPS, respectively). Ceramidoids having the pyridinium salt unit (PSU) placed internally (alpha and gamma- CCPS) or as a tether (omega-CCPS) in the N-acyl moiety were prepared by N-acylation of sphingoid bases with different omega-bromo acids or pyridine carboxylic acid chlorides following capping with respective pyridines or alkyl bromides. Consistent with their design, these analogs, showed a significantly improved solubility in water, well-resolved NMR spectra in D(2)O, broadly modified hydrophobicity, fast cellular uptake, and higher anticancer activities in cells in comparison to uncharged counterparts. Structure-activity relationship (SAR) studies in MCF-7 breast carcinoma cells revealed that the location of the PSU and its overall chain length affected markedly the cytotoxic effects of these ceramidoids. All omega-CCPSs were more potent (IC(50/48 h): 0.6-8.0 microM) than their alpha/gamma-CCPS (IC(50/48 h): 8-20 microM) or D-erythro-C6-Cer (IC(50/48 h): 15 microM) analogs. omega-DhCCPSs were also moderately potent (IC(50/48 h): 2.5-12.5 microM). Long-chain omega-dhCCPSs were rapidly and efficiently oxidized in cells to the corresponding omega-CCPSs, as established by LC-MS analysis. CCPS analogs also induced acute changes in the levels and composition of endogenous Cers (upregulation of C16-, C14-, and C18-Cers, and downregulation of C24:0- and C24:1-Cers). These novel ceramidoids illustrate the feasibility of compartment-targeted lipids, and they should be useful in cell-based studies as well as potential novel therapeutics. 相似文献
63.
Shuvy M Abedat S Beeri R Valitsky M Daher S Kott-Gutkowski M Gal-Moscovici A Sosna J Rajamannan NM Lotan C 《American journal of physiology. Heart and circulatory physiology》2011,300(5):H1829-H1840
Renal failure is associated with aortic valve calcification. Using our rat model of uremia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n = 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n = 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosis-related genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. 相似文献
64.
65.
Julian Baur Jeannine Roy Martin A. Schfer Nalini Puniamoorthy Wolf U. Blanckenhorn Patrick T. Rohner 《Journal of evolutionary biology》2020,33(3):297-308
Sexual selection is generally held responsible for the exceptional diversity in secondary sexual traits in animals. Mating system evolution is therefore expected to profoundly affect the covariation between secondary sexual traits and mating success. Whereas there is such evidence at the interspecific level, data within species remain scarce. We here investigate sexual selection acting on the exaggerated male fore femur and the male wing in the common and widespread dung flies Sepsis punctum and S. neocynipsea (Diptera: Sepsidae). Both species exhibit intraspecific differences in mating systems and variation in sexual size dimorphism (SSD) across continents that correlates with the extent of male–male competition. We predicted that populations subject to increased male–male competition will experience stronger directional selection on the sexually dimorphic male foreleg. Our results suggest that fore femur size, width and shape were indeed positively associated with mating success in populations with male‐biased SSD in both species, which was not evident in conspecific populations with female‐biased SSD. However, this was also the case for wing size and shape, a trait often assumed to be primarily under natural selection. After correcting for selection on overall body size by accounting for allometric scaling, we found little evidence for independent selection on any of these size or shape traits in legs or wings, irrespective of the mating system. Sexual dimorphism and (foreleg) trait exaggeration is therefore unlikely to be driven by direct precopulatory sexual selection, but more so by selection on overall size or possibly selection on allometric scaling. 相似文献
66.
InRita rita the upper lip is associated with the rostral cap and the lower lip with a skin fold. The epithelia of the lips, which are
modified with respect to the peculiar feeding behaviour of the fish, are mucogenic. The superficial layer of epithelial cells,
in addition to the mucous cells, are involved in active secretion of mucopolysaccharides. Mucus, apart from its diverse functions,
as in fish epidermis, lubricates the epithelia giving protection against possible mechanical injury during the searching and
catching of prey from bottom debris. Furthermore, the epithelia are thick, an adaptation to their mucogenic nature, so as
to provide additional protection. The contents of the club cells are proteinaceous, which correlates with the helical filaments
reported in similar cells in fish epidermis. Characteristic ridges on the surface of the lips are considered to be an adaptation
to assist in manipulation during the procuring of food. Mucus secreted in the grooves between them reduces friction and prevents
the deposition of foreign matter. The skin fold facilitates an increase in gape. The taste buds and ampullary organs, which
on the lips and the rostral cap are associated with the localization of prey and triggering of a pick-up reflex, are not located
on the skin fold, as the latter often remains concealed between the lower lip and the ventral head skin. The importance of
histochemical analysis as a supplement to histological studies is emphasised. 相似文献
67.
68.
Babasaheb P. Bandgar Shrikant S. Gawande Ragini G. Bodade Nalini M. Gawande Chandrahasya N. Khobragade 《Bioorganic & medicinal chemistry》2009,17(24):8168-8173
A novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-propenone (3) have been prepared by the Claisen–Schmidt condensation of 1-(2,4-dimethoxy-phenyl)-ethanone (1) and substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2). Substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2) were prepared by Vilsmeir–Haack reaction on acetophenonephenylhydrazones to offer the target compounds. The structures of the compounds were established by IR, 1H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (TNF-α and IL-6 inhibitory assays), antioxidant (DPPH free radical scavenging assay) and antimicrobial activities (agar diffusion method) against some pathogenic bacteria and fungi. Of 10 compounds screened, compounds 3a, 3c and 3g exhibited promising IL-6 inhibitory (35–70% inhibition, 10 μM), free radical scavenging (25–35% DPPH activity) and antimicrobial activities (MIC 100 μg/mL and 250 μg/mL) at varied concentrations. The structure–activity relationship (SAR) and in silico drug relevant properties (HBD, HBA, PSA, c Log P, molecular weight, EHOMO and ELUMO) further confirmed that the compounds are potential lead compounds for future drug discovery study. Toxicity of the compounds was evaluated theoretically and experimentally and revealed to be nontoxic except 3d and 3j. 相似文献
69.
Summary A patient with partial trisomy 22 (PT22) is presented. Inheritance is presumed to be due to secondary nondisjunction in her mother, who has a balanced translocation t(11;22)(q25;q13). The problem of the phenotypic heterogeneity observed with this chromosome change is discussed. 相似文献
70.
Weixing Shen Faiyaz Ahmad Steven Hockman John Ma Hitoshi Omi Nalini Raghavachari Vincent Manganiello 《Cell cycle (Georgetown, Tex.)》2010,9(23):4720-4734
Mechanisms of cAMP/PKA-induced meiotic arrest in oocytes are not completely identified. In cultured, G2/M-arrested PDE3A-/- murine oocytes, elevated PKA activity was associated with inactivation of Cdc2 and Plk1, and inhibition of phosphorylation of histone H3 (S10) and of dephosphorylation of Cdc25B (S323) and Cdc2 (Thr14/Tyr15). In cultured WT oocytes, PKA activity was transiently reduced and then increased to that observed in PDE3A-/- oocytes; Cdc2 and Plk1 were activated, phosphorylation of histone H3 (S10) and dephosphorylation of Cdc25B (S323) and Cdc2 (Thr14/Tyr15) were observed. In WT oocytes, PKAc were rapidly translocated into nucleus, and then to the spindle apparatus, but in PDE3A-/- oocytes, PKAc remained in the cytosol. Plk1 was reactivated by incubation of PDE3A-/- oocytes with PKA inhibitor, Rp-cAMPS. PDE3A was co-localized with Plk1 in WT oocytes, and co-immunoprecipitated with Plk1 in WT ovary and Hela cells. PKAc phosphorylated rPlk1 and Hela cell Plk1 and inhibited Plk1 activity in vitro. Our results suggest that PKA-induced inhibition of Plk1 may be critical in oocyte meiotic arrest and female infertility in PDE3A-/- mice.Key words: mice oocytes, PDE3A, cAMP, PKA, polo-like kinase 1, centrosome, prophase arrested 相似文献