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MicroRNA (miR)-219a-5p has been implicated in the development of numerous progression of carcinoma and autoimmune diseases. However, whether miR-219a-5p is involved in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. In this study, we demonstrated that miR-219a-5p expression was significantly decreased in the inflamed intestinal mucosa and peripheral blood (PB)-CD4+ T cells from patients with IBD. Proinflammatory cytokines (e.g., IL-6, IL-12, IL-23 and TNF-α) inhibited miR-219a-5p expression in CD4+ T cells in vitro. Lentivirus-mediated miR-219a-5p downregulation facilitated Th1/Th17 cell differentiation, whereas miR-219a-5p overexpression exerted an opposite effect. Luciferase assays confirmed that ETS variant 5 (ETV5) was a functional target of miR-219a-5p and ETV5 expression was significantly increased in the inflamed intestinal mucosa and PB-CD4+ T cells from IBD patients. ETV5 overexpression enhanced Th1/Th17 immune response through upregulating the phosphorylation of STAT3 and STAT4. Importantly, supplementation of miR-219a-5p ameliorated TNBS-induced intestinal mucosal inflammation, characterized by decreased IFN-γ+ CD4+ T cells and IL-17A+ CD4+ T cells infiltration in the colonic lamina propria. Our data thus reveal a novel mechanism whereby miR-219a-5p suppresses intestinal inflammation through inhibiting Th1/Th17-mediated immune responses. miR-219a-5p might be a target for the treatment of IBD.

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Two bromide-bearing, fluorene-based, conjugated polymers with oligo(ethylene glycol)- and poly(ethylene glycol)-tethered spacers have been prepared by the Suzuki coupling polymerization of bromide-bearing, fluorene monomers. beta-Glucose and alpha-mannose residues have been covalently attached to the conjugated polymers by post-polymerization functionalization of the precursor polymers with thiol-functionalized carbohydrates under basic conditions through thioether linkage. A glucose-bearing glycopolymer with oligo(ethylene glycol)-tethered spacers (polymer A) displays poor water solubility. However, glycopolymers with poly(ethylene glycol)-tethered spacers (polymers B and C) are highly water-soluble due to their long, flexible, hydrophilic spacers. Incubation of the ORN178 strain of Escherichia coli (E. coli) with alpha-mannose-bearing glycopolymer (polymer C) results in the formation of fluorescent cell clusters, causing significant red shifts in UV/Vis absorption and fluorescent spectra of the polymer through multivalent cooperative interactions of the polymeric carbohydrates with the bacterial pili. In contrast, polymer C displays no interactions with a mutant ORN208 strain of E. coli.

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Poly(phenyleneethynylene)-based conjugated polyelectrolytes (PPE-SO(3)(-)) are a class of polyions with rigid backbones. This work uses fluorescence correlation spectroscopy to study how the diffusion of complexes, formed between a PPE-SO(3)(-) polyelectrolyte and octadecyltrimethylammonium bromide (OTAB) surfactant molecules, changes with OTAB concentration below its critical micelle concentration. The dependence of the hydrodynamic radius of the complexes on the OTAB concentration has three regimes. In the low concentration regime ( C(OTAB)/ C(monomer) < 6), the complex has a size comparable to that of the polymer in deionized water. In the intermediate concentration regime (6 < C(OTAB)/ C(monomer) < 400), the complexes have the largest size and substantial heterogeneity. In the high concentration regime (400 < C(OTAB)/ C(monomer) < 1800), the complexes have a size that is about three times larger than that in the low concentration regime. These results elucidate features of the self-assembly of a polyelectrolyte and an ionic surfactant and show that the C(OTAB)/ C(monomer) concentration ratio controls the composition of polyelectrolyte/surfactant complexes.

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This work shows that low charge density poly(p-phenylene-ethynylene)s (PPE-SO3Na-L and PPE-CO2Na-L), which feature sulfonate and carboxylate groups on every other phenyl ring, form aggregates in water, whereas high charge density poly(p-phenylene-ethynylene)s (PPE-SO3Na-H and PPE-CO2Na-H), which possess sulfonate or carboxylate groups on every phenyl ring, do not aggregate in water. The formation of aggregates of PPE-SO3Na-L and PPE-CO2Na-L is demonstrated by comparing the concentration and temperature dependence of their steady-state spectra in water to that in DMSO, in which the two polymers do not aggregate. For the weak polyelectrolytes PPE-CO2Na-H and PPE-CO2Na-L, the solution pH was changed to vary the charge density. In addition, the cationic surfactant, octadecyltrimethyl ammonium, is shown to dissociate the low charge density polymer aggregates and to form supramolecular complexes with each of the different polyelectrolytes. Fluorescence correlation spectroscopy was applied to provide insight into the sizes of aggregates under different solution conditions.

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Water-soluble regioregular head-to-tail zwitterionic fluorescent conjugated boronic acid-bearing polythiophene (polymer 2) was prepared through a postpolymerization quaternization of a pyridine group of 3-pyridineboronic acid with bromide groups of regioregular head-to-tail poly(3-bromohexylthiophene) (polymer 1). Titration of monosaccharides, lactose, ascorbic acid, or dopamine with 0.1 M phosphate buffer (pH 7.4), containing 4.0 microM of polymer 2, results in significant concentration-dependent quenching of the polymer fluorescence. The polymer displays an optimum response to the biological species at pH 7.0. The binding constants of polymer 2 with mannose, fructose, glucose, galactose, vitamin C, dopamine, and lactose are 3.33 x 10(4), 1.13 x 10(5), 1.23 x 10(5), 1.69 x 10(5), 3.17 x 10(5), 3.27 x 10(5), and 4.60 x 10(5), respectively.

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This study investigates the fluorescence quenching of a poly(p-phenyleneethynylene) (1) based polyelectrolyte by positively charged and neutral macromolecules. This work shows that the change in the fluorescence yield of 1 depends on a number of factors, including electrostatic, hydrophobic, and energy transfer interactions with the quencher and also changes in the solution conditions such as concentration and ionic strength. The fluorescence quenching is attributed to the formation of aggregates that form upon addition of different quenchers to a solution of 1 and/or the solution conditions. The extent of 1's aggregation is shown to depend on the type of interaction between the polymer and the quencher, the concentration of the polymer, and the ionic strength of the solution.

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The absorption and fluorescence properties of a polyphenylethynylene based conjugated polyelectrolyte with sulfonate solubilizing groups (PP2) are shown to change dramatically with solution conditions because of the equilibrium between unaggregated and aggregated forms of the polymer. The fluorescence of PP2 is strongly quenched on addition of counterions such as Na+, K+, Li+, and TBA+, an effect which arises from the creation of salt stabilized aggregates. The formation of aggregates has been further corroborated by concentration and temperature studies in water and comparisons to dimethylsulfoxide solvent, in which the polymer does not aggregate. In aqueous solutions, the addition of the cationic surfactant, octadecyltrimethyl ammonium, causes the polymer aggregates to dissociate and creates polymer/surfactant aggregates that have spectral properties like that of the unaggregated polymer.

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Two facile, convenient, and versatile synthetic approaches are used to covalently attach carbohydrate residues to conjugated poly(p-phenylene)s (PPPs) for highly water-soluble PPPs bearing alpha-mannopyranosyl and beta-glucopyranosyl pendants (polymers A and B), which highly fluoresce in phosphate buffer (pH 7.0). The post-polymerization functionalization approach is to treat bromo-bearing PPP (polymer 1) with 1-thiolethyl-alpha-D-mannose tetraacetate or 1-thiol-beta-D-glucose tetraacetate in THF solution in the presence of K(2)CO(3) at room temperature through formation of thioether bridges, affording polymer 2a or 2b. The prepolymerization functionalization approach is to polymerize a well-defined sugar-carrying monomer, affording polymer 2a. Polymers 2a and 2b were deacetylated under Zemplén conditions in methanol and methylene chloride containing sodium methoxide, affording polymers A and B, respectively. The multivalent display of carbohydrates on the fluorescent conjugated glycopolymer overcomes the characteristic low binding affinity of the individual carbohydrates to their receptor proteins. Titration of concanavalin A (Con A) to alpha-mannose-bearing polymer A resulted in significant fluorescent quenching of the polymer with Stern-Volmer quenching constant of 4.5 x 10(7). Incubation of polymer A with Escherichia coli (E. coli) lead to formation of fluorescently stained bacterial clusters. Beta-glucose-bearing polymer B displayed no response to Con A and E. coli.

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New ferrocene-coated poly(p-phenylene-ethynylenes) (PPEs) with end capping groups of protected thiol were prepared by a palladium-catalyzed Sonogashira coupling reaction. Ferrocene groups were covalently attached to polymers A and B through ethylene oxide tethers and to polymer C through methylene tethers. Polymers A and B are soluble in common solvents such as tetrahydrofuran (THF), chloroform, methylene chloride, acetone, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and polymer C is soluble in toluene, THF, chloroform, and methylene chloride. Polymers A-C display low quantum yield, caused by electron-transfer quenching of ferrocene groups as electron donors. The polymer thin films were prepared through incubation of gold electrodes in THF solutions containing the polymers for 2 days. Ferrocene in thin films of polymers A and B display significantly faster electron-transfer rate than that of polymer C. Hydrophilic ethylene oxide side chains of polymers A and B decrease formal potential of tethered ferrocene groups because of electron-donating effect from ethylene oxide side chains, which stabilizes the ferrocenium ion and leads to a cathodic shift of the redox wave.

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Functional, conjugated molecular structures have been fabricated on Au nanoparticles via the Sonogashira coupling reactions.

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This study investigates the fluorescence quenching of a polyphenyl based polyelectrolyte by positively charged macromolecules (proteins and dendrimers). This work shows that the fluorescence quenching of the dendrimer materials does not involve energy transfer or electron transfer but is correlated to the overall charge on the dendrimer and its size. The quenching is hypothesized to result from conformational changes that occur upon binding the polyelectrolyte to the protein or dendrimer. This mechanism is qualitatively different from that invoked for small-molecule analytes.

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The syntheses and metal-responsive properties of poly(p-phenyleenethynylene)s with grafted new pseudo-crown-ether groups are reported. These polymers exhibit high sensitivities to alkali ions because of their collective optical properties, which are very sensitive to ion-induced conformational changes. The quenching of polymer fluorescence caused by the conformational changes is proportional to the ion concentration. The selectivity of the sensing materials toward Li(+) ions is significantly enhanced by controlling the size of the binding site via manipulation of the polymer side-chain compositions. The polymers are very stable for their six-month solid-state storage at room temperature.

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Synthesis of adenine derivative of triphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 4 was accomplished by treatment of phosphonate 3 with 5-phosphoribosyl 1-pyrophosphate in the presence of 5-phosphoribosyl 1-pyrophosphate synthetase. It was found that triphosphonate 4 functions as an irreversible stoichiometric inactivator of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). Triphosphonate 4 exhibited potent inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. Paclitaxel ester derivatives of adenine-containing triphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 8-10 were also synthesized. Like triphosphonate 4, compound 8 exhibited inhibitory property toward RDPR. It also induced microtubule assembly similar to paclitaxel (5). The structure of the chlorodiester linker in 8 was found to account for this dual property. After treatment of MCF7 cells with compounds 4, 5, and 8, fluorescence microscope examination demonstrated the presence of nucleus shrinkage or segmentation. Bifunctional prodrug 8 exhibited higher lipophilicity than 4 and higher water-solubility than 5. Pro-dual-drug 8 exhibited more pronounced anticancer activity relative to that of the triphosphonate 4 and paclitaxel (5). In contrast, compound 9, resulting from the linkage of triphosphonate 4 and paclitaxel (5) through a diester unit, was only found to function as a highly water-soluble prodrug for paclitaxel (5). It induced microtubule assembly in vitro, but did not show inhibitory property toward RDPR. On the other hand, compound 10, an aggregate of triphosphonate 4 and paclitaxel (5), neither functioned as an inhibitor of RDPR nor exhibited microtubule assembly stimulating activity in vitro.

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A general and controlled bidirectional growth strategy enables a very rapid and efficient construction of OPV compounds possessing functional groups such as aldehyde and mercapto groups at both ends. The strategy employs only one reaction type with high yields and stereoselectivities to grow the conjugated chains, eliminating the need for protecting groups in the overall intermediates.

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By use of pro-dual-drug concept the synthesis of 6-beta-[(R)-2-(clavaminio-9-N-yl)-2-(4-hydroxyphenylacetamido)]penicillanic acid (10), 6-beta-[(R)-2-(amino)-2-(4-(clavulano-9-O-yl)phenylacetamido)]penicillanic acid (13), (Z)-4-[2-(amoxycillin-4-O-yl)ethylidene]-2-(clavulano-9-O-yl)-3-methoxy-Delta(alpha,beta)-butenolide (19), and 3-[(amoxicillin-4-O-yl)methyl]-7-(phenoxyacetamido)-(1-oxo)-3-cephem-4-carboxylic acid (23) was accomplished. Unlike penicillin G, ampicillin, or amoxicillin, these four heretofore undescribed compounds 10, 13, 19, and 23 showed notable activity against beta-lactamase (betaL) producing microorganisms, Staphylococcus aureus A9606, S. aureus A15091, S. aureus A20309, S. aureus 95, Escherichia coli A9675, E. coli A21223, E. coli 27C7, Pseudomonas aeruginosa 18S-H, and Klebsiella pneumoniae A20634 TEM. In comparison with amoxicillin (9), alpha-amino-substituted compound 10 and butenolide derivative 19 showed a broadened spectrum of antibacterial activity; yet they were found to be less active than 13 and 23. Like clavulanic acid (7) or cephalosporin-1-oxide (21), the newly synthesized compounds 10, 13, 15, 16, 19, or 23 functioned as potent inhibitors of various bacterial betaLs.

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