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Michelle P. Clark Thao Huynh Shringar Rao Liana Mackiewicz Hugh Mason Shahla Romal Michael D. Stutz Sang H. Ahn Linda Earnest Vitina Sozzi Margaret Littlejohn Bang M. Tran Norbert Wiedemann Elizabeth Vincan Joseph Torresi Hans J. Netter Tokameh Mahmoudi Peter Revill Marc Pellegrini Gregor Ebert 《Cell death & disease》2021,12(7)
A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.Subject terms: Target validation, Hepatitis B, Preclinical research, Translational research 相似文献
233.
Dextranmethylcarboxylate benzylamide sulfate (DMCBSu), a functionalized dextran, exhibits anticoagulant properties. Its synthesis involves three steps: a carboxymethylation with monochloroacetic acid in alkaline water-iso-propanol, a benzylamidification of some of the methylcarboxylate groups with benzylamine in the presence of a water soluble carbodiimide and a partial sulfation of the remaining hydroxyl groups with SO3-pyridine in dimethylformamide. This procedure yields reproducibly DMCBSu with degrees of substitution in methylcarboxylate (MC), benzylamide (B) and sulfate (Su) groups, respectively, up to 1.61, 0.35 and 1.5, each obtained in one step. For a degree of substitution of methylcarboxylate ca. 1, the presence of sulfate groups is absolutely necessary to confer anticoagulant activities to the samples. In addition, the anticoagulant ability is higher for derivatives bearing benzylamide groups. The anticoagulant ability of DMCBSu increases with the degree of sulfation, reaching 20% of heparin activity for a degree of substitution of Su groups about 1.3. 相似文献
234.
Shailubhai K Khai Huynh Q Boddupalli H Yu HH Jacob GS 《Biochemical and biophysical research communications》1999,256(1):170-176
A microsomal galactose-6-O-sulfotransferase (Gal-6-O-Stase) from porcine lymph nodes, able to transfer the sulfate group from adenosine 3'-phosphate 5'-phosphosulphate (PAPS) onto 2'-fucosyllactose (2'-FL) and other sialyl LewisX (sLex)-related sugars, has been purified and characterized. The enzyme was purified to about 35,000-fold by a combination of conventional and affinity chromatographic steps. The purified enzyme preparation exhibited two protein bands at around 80-90 and 170 kDa on 7.5% SDS-PAGE under reducing conditions. Both of these protein bands always comigrated in the gel when peak fractions containing Gal-6-O-Stase activity from the 3',5'-ADP-agarose column were subjected to 6% SDS-PAGE under reducing conditions. These protein bands also showed similar binding patterns to WGA (wheat germ agglutinin), Con A (concanvalin A), and EBA (elderberry agglutinin). Similarly, when the enzyme preparation after the hydroxylapatite step was photolabeled with 8-azido-[32P]-PAPS, both 80-90 and 170 kDa protein bands were labeled in a specific manner. These results suggest a possible association of these two protein bands with the enzyme activity. The carbohydrate substrate specificity of this enzyme suggests that it is well suited to catalyze the sulphonation at the C-6 position of the galactose residues of oligosaccharides that are structurally similar to sLex. Furthermore, a survey of several porcine organs revealed that this enzyme was selectively expressed in lymphoid tissues such as lymph nodes (peripheral and mesenteric) and spleen. These findings suggest that this enzyme may be involved in the assembly of 3'-sialyl-6'-sulfo Lewisx, the major capping group of HEV-ligands for L-selectin. 相似文献
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We report the chemical synthesis of Fuc(12)Gal-O(CH2)7CH3 (1) an analog of the natural blood group (O)H disaccharide Fuc(12)Gal-OR. Compound 1 was a good substrate for recombinant blood group B glycosyltransferase (GTB) and was used as a precursor for the enzymatic synthesis of the blood group B analog Gal(3)[Fuc(12)]Gal-O(CH2)7CH3 (2). To probe the mechanism of the GTB reaction, kinetic evaluations were carried out employing compound 1 or the natural acceptor disaccharide Fuc(12)Gal-O(CH2)7CH3 (3) with UDP-Gal and UDP-GalNAc donors. Comparisons of the kinetic constants for alternative donor and acceptor pairs suggest that the GTB mechanism is Theorell-Chance where donor binding precedes acceptor binding. GTB operates with retention of configuration at the anomeric center of the donor. Retaining reactions are thought to occur via a double-displacement mechanism with formation of a glycosyl-enzyme intermediate consistent with the proposed Theorell-Chance mechanism. 相似文献
237.
Sexually dimorphic behaviors are likely to involve neural pathways that express the androgen receptor (AR). We have genetically modified the AR locus to visualize dimorphisms in neuronal populations that express AR. Analysis of AR-positive neurons reveals both known dimorphisms in the preoptic area of the hypothalamus and the bed nucleus of the stria terminalis as well as novel dimorphic islands in the basal forebrain with a clarity unencumbered by the vast population of AR-negative neurons. This genetic approach allows the visualization of dimorphic subpopulations of AR-positive neurons along with their projections and may ultimately permit an association between neural circuits and specific dimorphic behaviors. 相似文献
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Fructification and yield of the edible mushrooms Pleurotus pulmonarius and Stropharia rugosoannulata are clearly enhanced when wheat straw is supplemented with 30% Lolium perenne grass chaff. The bioactive compound in the methanol extract of grass chaff was identified as beta-adenosine. In vitro biological activity tests showed that 0.012 mg of beta-adenosine per ml of medium stimulated earlier fructification of Pleurotus pulmonarius. Mushroom fruiting trials showed that when 12 mg beta-adenosine was added to 1 kg wet wheat straw, primordia of Pleurotus pulmonarius appeared two days earlier and primordia of Stropharia rugosoannulata appeared 18 days earlier when compared to pure wheat straw substrate. This concentration of beta-adenosine had no impact on the mushroom yield of Pleurotus, but resulted in a 2.2 fold increase in yield for Stropharia. beta-Adenosine at 25 mg per kg wet wheat straw increased the yield of Pleurotus with 52% and the yield of Stropharia with 258%, but this concentration delayed primordial formation in Pleurotus. 相似文献