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971.
972.
973.
Viel T Boisgard R Kuhnast B Jego B Siquier-Pernet K Hinnen F Dollé F Tavitian B 《Oligonucleotides》2008,18(3):201-212
Molecular imaging was used to study the biodistribution, pharmacokinetics, and activity of naked small interfering RNAs (siRNAs). siRNAs with riboses chemically modified in the 2' position were compared with unmodified siRNA. In vitro, replacement of the 2'-hydroxyl (2'OH) group of certain nucleotides in an siRNA sequence by a fluorine atom (2'F) on both antisense (AS) and sense (S) strands [2'F(AS/S)], or by a methoxy group (2'OMe) on the S strand [2'OH(AS)/2'OMe(S)], was compatible with RNA interference. Different siRNAs [2'F(AS/S), 2'OH(AS)/2'OMe(S), and 2'OH(AS/S)] were labeled with fluorine-18 (conjugation with [(18)F]FPyBrA), and comparative dynamic and quantitative imaging was performed with positron emission tomography. After intravenous injections of [(18)F]siRNAs in rodents, total radioactivity was rapidly eliminated by the kidneys and the liver. Tissue distribution of the different siRNAs were similar, and their bioavailability (as judged from blood persistence and stability) increased in the order 2'OH(AS/S) = 2'OH(AS)/2'OMe(S) < 2'F(AS/S). However, in our in vivo model, the 2'F(AS/S) siRNA, despite its higher bioavailability, was not able to induce a higher interference effect with respect to the 2'OH(AS/S) siRNA. Molecular imaging approaches, applied in the present work to both natural and chemically modified siRNAs, can contribute to the development of these macromolecules as therapeutic agents. 相似文献
974.
In malaria endemic areas, regardless of immunity acquired during lifelong exposure to malaria, pregnant women become susceptible to Plasmodium falciparum infections. Malaria during pregnancy is associated with a massive sequestration of infected erythrocytes in the placenta and the emergence of a unique parasite-derived adhesive molecule (encoded by var2CSA) that binds to chondroitin sulfate A (CSA). How P. falciparum achieves the timely expression of the CSA ligand in pregnant women remains puzzling. We investigated whether host serum-specific factors present only during pregnancy may induce var2CSA expression. Our panel of experiments did not reveal significant changes in var2CSA levels and CSA-binding capacity. 相似文献
975.
Aurélien Lorin Laurence Lins Vincent Stroobant Robert Brasseur Benoit Charloteaux 《Journal of peptide science》2008,14(4):423-428
We had previously predicted successfully the minimal fusion peptides (FPs) of the human immunodeficiency virus 1 (HIV-1) gp41 and the bovine leukemia virus (BLV) gp30 using an original approach based on the obliquity/fusogenicity relationship of tilted peptides. In this paper, we have used the same method to predict the shortest FP capable of inducing optimal fusion in vitro of the simian immunodeficiency virus (SIV) mac isolate and of other SIVs and human immunodeficiency virus (HIV-2) isolates. In each case, the 11-residue-long peptide was predicted as the minimal FP. For the SIV mac isolate, liposome lipid-mixing and leakage assays confirmed that this peptide is the shortest peptide inducing optimal fusion in vitro, being therefore the minimal FP. These results are another piece of evidence that the tilted properties of FPs are important for the fusion process and that our method can be used to predict the minimal FPs of other viruses. 相似文献
976.
977.
Feruloyl esterases are part of the enzymatic spectrum employed by fungi and other microorganisms to degrade plant polysaccharides.
They release ferulic acid and other aromatic acids from these polymeric structures and have received an increasing interest
in industrial applications such as in the food, pulp and paper and bio-fuel industries. This review provides an overview of
the current knowledge on fungal feruloyl esterases focussing in particular on the differences in substrate specificity, regulation
of their production, prevalence of these enzymes in fungal genomes and industrial applications. 相似文献
978.
The inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) can be divided in three functionally distinct regions: a ligand-binding domain, a modulatory domain and a channel domain. Numerous regulatory mechanisms including inter- and intra-molecular protein-protein interactions and phosphorylation events act via these domains to regulate the function of the IP(3)R. Regulation at the level of the ligand-binding domain primarily affects the affinity for IP(3). The extent of IP(3)-induced Ca(2+) release (IICR) is, however, not only determined by the affinity for IP(3) but also by the effectiveness of the coupling between ligand binding and channel opening. As a result, regulation as well as malfunction of IICR may be affected by both steps in the activation mechanism. The 3D structures of the two subdomains of the ligand-binding domain have recently been determined by X-ray diffraction analysis. This allows a more detailed molecular explanation of the regulatory events situated at the ligand-binding domain of the IP(3)R. In this review, we will focus on recent structural and functional data on the ligand-binding domain that have extended and clarified the view on the molecular mechanisms of IP(3)R regulation. 相似文献
979.
980.
Issa Abu-Dayyeh Marina Tiemi Shio Shintaro Sato Shizuo Akira Benoit Cousineau Martin Olivier 《PLoS neglected tropical diseases》2008,2(12)
Parasites of the Leishmania genus can rapidly alter several macrophage (MØ) signalling pathways in order to tame down the innate immune response and inflammation, therefore favouring their survival and propagation within their mammalian host. Having recently reported that Leishmania and bacterial LPS generate a significantly stronger inflammatory response in animals and phagocytes functionally deficient for the Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), we hypothesized that Leishmania could exploit SHP-1 to inactivate key kinases involved in Toll-like receptor (TLR) signalling and innate immunity such as IL-1 receptor-associated kinase 1 (IRAK-1). Here we show that upon infection, SHP-1 rapidly binds to IRAK-1, completely inactivating its intrinsic kinase activity and any further LPS-mediated activation as well as MØ functions. We also demonstrate that the SHP-1/IRAK-1 interaction occurs via an evolutionarily conserved ITIM-like motif found in the kinase domain of IRAK-1, which we named KTIM (Kinase Tyrosyl-based Inhibitory Motif). This regulatory motif appeared in early vertebrates and is not found in any other IRAK family member. Our study additionally reveals that several other kinases (e.g. Erk1/2, IKKα/β) involved in downstream TLR signalling also bear KTIMs in their kinase domains and interact with SHP-1. We thus provide the first demonstration that a pathogen can exploit a host protein tyrosine phosphatase, namely SHP-1, to directly inactivate IRAK-1 through a generally conserved KTIM motif. 相似文献