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241.
Griebenow N Buchmueller A Kolkhof P Schamberger J Bischoff H 《Bioorganic & medicinal chemistry letters》2011,21(12):3648-3653
Novel squalene synthase inhibitors are disclosed. The design, synthesis, SAR and pharmacological profile of the compounds are discussed. 相似文献
242.
Lampa A Ehrenberg AE Vema A Åkerblom E Lindeberg G Danielson UH Karlén A Sandström A 《Bioorganic & medicinal chemistry》2011,19(16):4917-4927
Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers. 相似文献
243.
244.
Kuemmerle-Deschner JB Lohse P Koetter I Dannecker GE Reess F Ummenhofer K Koch S Tzaribachev N Bialkowski A Benseler SM 《Arthritis research & therapy》2011,13(6):R196
Introduction
Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. 相似文献245.
Humphry M Reinstädler A Ivanov S Bisseling T Panstruga R 《Molecular Plant Pathology》2011,12(9):866-878
Loss-of-function alleles of plant-specific MLO (Mildew Resistance Locus O) genes confer broad-spectrum powdery mildew resistance in monocot (barley) and dicot (Arabidopsis thaliana, tomato) plants. Recessively inherited powdery mildew resistance in pea (Pisum sativum) er1 plants is, in many aspects, reminiscent of mlo-conditioned powdery mildew immunity, yet the underlying gene has remained elusive to date. We used a polymerase chain reaction (PCR)-based approach to amplify a candidate MLO cDNA from wild-type (Er1) pea. Sequence analysis of the PsMLO1 candidate gene in two natural er1 accessions from Asia and two er1-containing pea cultivars with a New World origin revealed, in each case, detrimental nucleotide polymorphisms in PsMLO1, suggesting that PsMLO1 is Er1. We corroborated this hypothesis by restoration of susceptibility on transient expression of PsMLO1 in the leaves of two resistant er1 accessions. Orthologous legume MLO genes from Medicago truncatula and Lotus japonicus likewise complemented the er1 phenotype. All tested er1 genotypes showed unaltered colonization with the arbuscular mycorrhizal fungus, Glomus intraradices, and with nitrogen-fixing rhizobial bacteria. Our data demonstrate that PsMLO1 is Er1 and that the loss of PsMLO1 function conditions durable broad-spectrum powdery mildew resistance in pea. 相似文献
246.
Rose AJ Díaz MB Reimann A Klement J Walcher T Krones-Herzig A Strobel O Werner J Peters A Kleyman A Tuckermann JP Vegiopoulos A Herzig S 《Cell metabolism》2011,14(1):123-130
Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling. 相似文献
247.
We have examined the use of RNA interference as a means of downregulating gene expression and provide the first comparison
of shRNA and artificial miRNA constructs for transgenic livestock. Several in vitro assays were performed to identify the
most effective RNAi constructs. shRNA and miRNA constructs achieved significant downregulation of two porcine target genes:
the milk whey protein beta-lactoglobulin and the tumour suppressor p53. Results of different assays were, however, sometimes
at variance, indicating that no one assay can be relied upon to predict the effectiveness of an RNAi construct. Our findings
are that screening of RNAi constructs is most informative if carried out in primary cells that express the target gene and
are competent for somatic cell nuclear transfer. Importantly, the use of miRNA constructs makes tissue specific gene knockdown
in large animals a realistic possibility. 相似文献
248.
Reinhold D Bank U Entz D Goihl A Stoye D Wrenger S Brocke S Thielitz A Stefin S Nordhoff K Heimburg A Täger M Ansorge S 《Biological chemistry》2011,392(3):233-237
Cellular dipeptidyl peptidase IV (DP IV, CD26) and amino-peptidase N (APN, CD13) play regulatory roles in T cell activation and represent potential targets for treatment of inflammatory disorders. We have developed a novel therapeutic strategy, 'peptidase-targeted Immunoregulation' (PETIR?), which simultaneously targets both cellular DP IV and APN via selective binding sites different from the active sites with a single inhibitor. To prove the therapeutic concept of PETIR? in autoimmunity of the central nervous system (CNS), we evaluated the effect of a single substance, PETIR-001, in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) in SJL/J mice. Administration of PETIR-001 significantly delayed and decreased clinical signs of active EAE, when given in a therapeutic manner intraperitoneally from day 15 to day 24 after induction of EAE. Both the acute phase and the first relapse of EAE were markedly inhibited. Importantly, a similar therapeutic benefit was obtained after oral administration of PETIR-001 from day 12 to day 21 after disease induction. Our results demonstrate that PETIR-001 exhibits a therapeutic effect on EAE in SJL/J mice. Thus, PETIR? represents a novel and efficient therapeutic approach for immunotherapy of CNS inflammation. 相似文献
249.
Röseler S Sandrock K Bartsch I Busse A Omran H Loges NT Zieger B 《Biological chemistry》2011,392(8-9):779-781
Septins are cytoskeletal GTP-binding proteins involved in processes characterized by active membrane movement, such as cytokinesis, vesicle trafficking and exocytosis. Most septins are expressed ubiquitously, however, some septins accumulate in particular tissues. The ubiquitous SEPT11 also shows high expression levels in the central nervous system and in platelets. Here, SEPT11 is involved in vesicle trafficking and may play a role in synaptic connectivity. Interestingly, mice that harbor a homozygous Sept11 null mutation, die in utero. From day 11.5 post coitum onwards, development of homozygous embryos seems to be retarded and the embryos from day 13.5 onwards were dead. 相似文献
250.