Conjugation of paclitaxel to C-6 hexanediamine-modified hyaluronic acid for targeted drug delivery to enhance antitumor efficacy.

Polymer-based paclitaxel (PTX) conjugates have demonstrated application potentials to improve the water solubility and enhance the efficiency of drug delivery. In this study, a novel HA-based drug conjugate, HA-6-PTX, was designed and successfully synthesized by chemically grafting PTX to the C-6 position of N-acetyl-d-glucosamine (GlcNAc) of hyaluronic acid (HA) using hexanediamine as the linker. Leaving the carboxylate of HA chain unaffected, the conjugate with drug loading as high as 21.8% showed an excellent water solubility of 168mg/mL and exhibited increased drug release in the presence of hyaluronidase. Compared to free PTX, HA-6-PTX demonstrated increased cytotoxicity and enhanced apoptosis-inducing effect against HepG2 and A549 cells due to the increased cellular uptake of drug via HA-receptor mediated endocytosis. It was concluded that the HA-6-PTX conjugate could be potentially utilized for further exploration as targeted drug delivery to enhance antitumor efficacy.

Synthesis and antibacterial activity of cinnamaldehyde acylhydrazone with a 1,4-benzodioxan fragment as a novel class of potent ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitor.

Fatty acid biosynthesis is essential for bacterial survival. ß-Ketoacyl-acyl carrier protein (ACP) synthase III (FabH), is a particularly attractive antibacterial target, since it is central to the initiation of fatty acid biosynthesis. Three series of 21 cinnamaldehyde acylhydrazone derivatives, A3-9, B3-9, and C3-9, were synthesized and evaluated for FabH-inhibitory activity. Compound B6 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis (minimum inhibitory concentrations (MICs) values: 1.56-3.13 µg/mL) and was comparable with the positive control. Docking simulation by positioning compound B6 in the FabH structure active site was performed to explore the possible binding model.

MicroRNAs regulate ocular neovascularization.

In this study, we used ischemia-induced retinal neovascularization (NV) as a model to investigate the possible role of microRNAs in a clinically important disease process. Microarray analysis demonstrated seven microRNAs (miR-106a, -146, -181, -199a, -214, -424, and -451) that were substantially increased and three microRNAs (miR-31, -150, and -184) that were substantially decreased in ischemic retina. Potential targets for the upregulated microRNAs were not identified, but bioinformatic analysis suggested target genes for the downregulated microRNAs, and these were confirmed using a luciferase reporter assay. Real-time reverse transcriptase PCR confirmed that the substantial levels of miR-31, -150, and -184 present in normal retina were significantly reduced in ischemic retina. Interestingly, constitutive levels of miR-31 and -184 are high in the cornea and lens, two avascular tissues. Intraocular injection of pre-miR-31, -150, or -184 significantly reduced ischemia-induced retinal NV, and injection of pre-miR-31 or -150 also significantly reduced choroidal NV. These data suggest that alteration of microRNA levels contributes to two types of ocular NV, and that injection or enhanced expression of microRNAs is a potential therapeutic strategy.

Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation.

Identification of tissue-specific gene regulatory networks can yield insights into the molecular basis of a tissue's development, function and pathology. Here, we present a computational approach designed to identify potential regulatory target genes of photoreceptor cell-specific transcription factors (TFs). The approach is based on the hypothesis that genes related to the retina in terms of expression, disease and/or function are more likely to be the targets of retina-specific TFs than other genes. A list of genes that are preferentially expressed in retina was obtained by integrating expressed sequence tag, SAGE and microarray datasets. The regulatory targets of retina-specific TFs are enriched in this set of retina-related genes. A Bayesian approach was employed to integrate information about binding site location relative to a gene's transcription start site. Our method was applied to three retina-specific TFs, CRX, NRL and NR2E3, and a number of potential targets were predicted. To experimentally assess the validity of the bioinformatic predictions, mobility shift, transient transfection and chromatin immunoprecipitation assays were performed with five predicted CRX targets, and the results were suggestive of CRX regulation in 5/5, 3/5 and 4/5 cases, respectively. Together, these experiments strongly suggest that RP1, GUCY2D, ABCA4 are novel targets of CRX.