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971.
972.
Guerrini G Ciciani G Bruni F Selleri S Martini C Daniele S Ghelardini C Di Cesare Mannelli L Costanzo A 《Bioorganic & medicinal chemistry》2011,19(24):7441-7452
The identification of compounds with selective anxiolytic-like effects, exerted through the benzodiazepine site on γ-aminobutyric acid type A (GABAA) receptors, and that show pronounced antihyperalgesia in several pain models, has oriented research towards the development of new agents for the relief of pain. Starting from our previously reported ligands at the benzodiazepine site on GABAA receptors showing selective anxiolytic-like effects, we have designed new compounds with the aim of identifying those devoid of the typical side effects of the classical benzodiazepines. Our preliminary results indicate that compounds 4, 10(±) and 11 have a very promising antihyperalgesic profile in different animal pain models (peripheral mono-neuropathy, STZ-induced hyperalgesia). In particular 11 exhibits high potency since it exerted its protective effect starting from the dose of 3 mg/kg po, after single injection. 相似文献
973.
Ferlin MG Conconi MT Urbani L Oselladore B Guidolin D Di Liddo R Parnigotto PP 《Bioorganic & medicinal chemistry》2011,19(1):448-457
This work investigated the in vitro and in vivo anti-angiogenic activity of some pyrroloazaflavones, exactly 2-phenyl-1H-pyrrolo[2,3-h]quinolin-4(7H)ones, with vinblastine as reference compound. Growth inhibitory activity, migration, and capillary-like structures formation were determined in human umbilical vein endothelial cell cultures, and Matrigel plug assay was carried out to evaluate in vivo effects on angiogenesis. Collectively, our results indicate that some pyrroloazaflavone derivatives, at non-cytotoxic concentrations and like vinblastine are able: (i) to exert in vitro anti-angiogenic activity and (ii) to counteract in vitro and in vivo the pro-angiogenic effects of fibroblast growth factor-2 (FGF-2). 相似文献
974.
Although statins, 3β-hydroxy-3β-methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsic toxicity or to the decrease of HMGR main isoprenoid end products, which are essential compounds for cell viability, is still debated. In addition to HMGR, the key and rate limiting step of cholesterol synthesis, many enzymes are involved in this multi-step pathway whose inhibition could be taken into account for a "nonstatin approach" in the management of hypercholesterolemia. In particular, due to their unique position downstream from HMGR, the inhibition of squalene synthase, farnesyl diphosphate farnesyltransferase (FDFT1), squalene epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase (OSC) should decrease plasma levels of cholesterol without affecting ubiquinone, dolichol, and isoprenoid metabolism. Thus, although FDFT1, SQLE and OSC are little studied, they should be considered as perspective targets for the development of novel drugs against hypercholesterolemia. Here, structure-function relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin-based therapy. 相似文献
975.
Cytochrome c (cytc) is pivotal in mitochondrial respiration and apoptosis. The heme-Fe-atom of native hexacoordinated horse heart cytc (hhcytc) displays a very low reactivity toward ligands and does not exhibit catalytic properties. However, on interaction with cardiolipin (CL), hhcytc changes its tertiary structure disrupting the heme-Fe-Met80 distal bond. The CL-hhcytc complex displays a very low midpoint potential, out of the range required for its physiological role, binds CO and NO with high affinity, facilitates peroxynitrite isomerization to NO??, and displays peroxidase activity. As a whole, the CL-hhcytc complex could play either proapoptotic effects, catalyzing lipid peroxidation and the subsequent hhcytc release into the cytoplasm, orantiapoptotic actions, such as scavenging peroxynitrite (i.e., protecting the mitochondrion from reactive nitrogen and oxygen species), and binding of CO and NO (i.e., inhibiting lipid peroxidation and hhcytc traslocation). Here, the CL-driven allosteric modulation of hhcytc properties is reviewed, highlighting proapoptotic and antiapoptotic actions 相似文献
976.
Cells respond to genotoxic insults by triggering a DNA damage checkpoint surveillance mechanism and by activating repair pathways. Recent findings indicate that the two processes are more related than originally thought. Here we discuss the mechanisms involved in responding to UV-induced lesions in different phases of the cell cycle and summarize the most recent data in a model where Nucleotide Excision Repair (NER) and exonucleolytic activities act in sequence leading to checkpoint activation in non replicating cells. The critical trigger is likely represented by problematic intermediates that cannot be completely or efficiently repaired by NER. In S phase cells, on the other hand, the replicative polymerases, blocked by bulky UV lesions, re-initiate DNA synthesis downstream of the lesions, leaving behind a ssDNA tract. If these gaps are not rapidly refilled, checkpoint kinases will be activated. 相似文献
977.
An open-source tool capable of converting SD files (and virtually any other format through OpenBabel) into MMFF-typed XYZ
coordinate files to be used with TINKER is described. SDF2XYZ2SDF allows including the power of TINKER molecular mechanics
computations in automated cheminformatics workflows, such as conformational searches and virtual screening protocols. 相似文献
978.
979.
Paolo De Franceschi Luca Pierantoni Luca Dondini Marco Grandi Silviero Sansavini Javier Sanzol 《Tree Genetics & Genomes》2011,7(4):663-683
The recent analysis of the S-locus region of apple and Japanese pear, two species of Pyrinae (Rosaceae), suggested multiple
and different F-box genes (called SFBBs) as candidates for the male determinant (pollen S) of RNase-based gametophytic self-incompatibility in these two species.
Here, we followed a phylogenetic approach to take advantage of the pattern of molecular evolution of the S-locus of Pyrinae
in characterizing SFBB homologs belonging to S-haplotypes of apple and three species of Pyrus (European, Japanese, and Chinese pears). Our results suggested that the S-locus region of Pyrinae contains no less than six
SFBB members and that its structure seems to be rather conserved between apple and pear species. In accordance with the prevailing
theory on S-haplotype evolution, the pollen S is expected to have coevolved with the S-RNase and to show some common features derived from the long-term evolution under frequency-dependent balancing selection, i.e.,
high sequence diversity, evidence of positive selection, and shared ancestral polymorphisms. Using this conceptual framework,
we present evidence that some SFBB genes may be better candidates for pollen S in Pyrinae than others. Overall, the SFBB genes analyzed exhibited much lower sequence diversity than their associated S-RNases; likewise, they showed little or no evidence of positive selection. However, evidence of coevolution with the S-RNase clearly emerged for two of them. Altogether our results suggested different evolutionary histories for different SFBBs putatively derived from their distinct involvement in self-incompatibility. 相似文献
980.
Ronsein GE de Oliveira MC Medeiros MH Miyamoto S Di Mascio P 《Free radical research》2011,45(3):266-275
Cholesterol (Ch) can be oxidized by reactive oxygen species, forming oxidized products such as Ch hydroperoxides (ChOOH). These hydroperoxides can disseminate the peroxidative stress to other cell compartments. In this work, the ability of ChOOH to induce strand breaks and/or base modifications in a plasmid DNA model was evaluated. In addition, HPLC/MS/MS analyses were performed to investigate the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) after the incubation of 2'-deoxyguanosine (dGuo) with ChOOH and Cu(2+). In the presence of copper ions, ChOOH induced DNA strand breaks in time and concentration-dependent manners. Purine and pyrimidine base modifications were also observed, as assessed respectively by the treatment with Fpg and Endo III repair enzymes. The detection of 8-oxodGuo by HPLC/MS/MS is in agreement with the dGuo oxidation in plasmid DNA. ChOOH-derived DNA damage adds further support to the role of lipid peroxidation in inducing DNA modifications and mutation. 相似文献