Curcumin derivatives as photosensitizers in photodynamic therapy: photophysical properties and in vitro studies with prostate cancer cells.

Photodynamic therapy (PDT) is a minimally invasive approach to treat various forms of cancer, based on the ability of certain non-toxic molecules (photosensitizers) to generate reactive oxygen species (ROS) after excitation by light of a certain wavelength and eventually induce strong phototoxic reactions against malignant cells and other pathogens. Curcumin is one of the most extensively investigated phytochemicals with a wide range of therapeutic properties and has been shown to induce strong photocytotoxic effects in micromolar concentrations against a variety of cancer cell lines. Curcumin (1) is comparatively evaluated with the naturally occurring bisdemethoxy Curcumin (2), which lacks the two methoxy groups, as well as two newly synthesized curcuminoids, the cinnamaldehyde derivative (3) and the dimethylamino one (4), designed to increase the absorption maximum and hence the tissue penetration. The synthetic curcuminoids were successfully synthesized in sufficient amounts and their photophysical properties such as absorption, fluorescence, photobleaching and free radical generation were investigated. Compound 4 exhibited a significant increase in peak absorption (497 nm) and strong fluorescent emission signals were recorded for all curcuminoids. Photobleaching of 4 was comparable to 1 whereas 2 and 3 showed more extended photobleaching but much higher ROS production in very short irradiation times. Compounds 2 and 4 exhibited specific intracellular localization. After dark and light cytotoxicity experiments against LNCaP prostate cancer cell line for all curcuminoids, concentration of 3 µM and irradiance of 6 mW cm-2 were selected for the PDT application which resulted in remarkable results with very short LD50. Curcuminoids 2 and 4 exhibited a significant dose-dependent PDT effect. The biphasic dose-response photodynamic effect observed for 1 and 3 may provide a strategy against prolonged and sustained photosensitivity.

RAGE: a multi-ligand receptor unveiling novel insights in health and disease.

Receptor for advanced glycation end products (RAGE) is expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. It is a multi-ligand receptor and a member of the immunoglobulin superfamily of cell surface molecules. Its repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimer's disease, cancer and inflammation. Additionally, genetic polymorphisms in the RAGE gene may have impact on the functional activity of the receptor. It becomes obvious that RAGE pathway is a complicated one and the question of whether blockade of RAGE is a feasible and safe strategy for the prevention/treatment of chronic diseases is gradually gaining the attention of the pharmaceutical community. In this review the biology of RAGE and the triggered signaling cascades involved in health and disease will be presented. Additionally, its potential as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have been developed for RAGE blockade.

DIANA-microT web server: elucidating microRNA functions through target prediction.

Computational microRNA (miRNA) target prediction is one of the key means for deciphering the role of miRNAs in development and disease. Here, we present the DIANA-microT web server as the user interface to the DIANA-microT 3.0 miRNA target prediction algorithm. The web server provides extensive information for predicted miRNA:target gene interactions with a user-friendly interface, providing extensive connectivity to online biological resources. Target gene and miRNA functions may be elucidated through automated bibliographic searches and functional information is accessible through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The web server offers links to nomenclature, sequence and protein databases, and users are facilitated by being able to search for targeted genes using different nomenclatures or functional features, such as the genes possible involvement in biological pathways. The target prediction algorithm supports parameters calculated individually for each miRNA:target gene interaction and provides a signal-to-noise ratio and a precision score that helps in the evaluation of the significance of the predicted results. Using a set of miRNA targets recently identified through the pSILAC method, the performance of several computational target prediction programs was assessed. DIANA-microT 3.0 achieved there with 66% the highest ratio of correctly predicted targets over all predicted targets. The DIANA-microT web server is freely available at www.microrna.gr/microT.

DIANA-mirPath: Integrating human and mouse microRNAs in pathways.

SUMMARY: DIANA-mirPath is a web-based computational tool developed to identify molecular pathways potentially altered by the expression of single or multiple microRNAs. The software performs an enrichment analysis of multiple microRNA target genes comparing each set of microRNA targets to all known KEGG pathways. The combinatorial effect of co-expressed microRNAs in the modulation of a given pathway is taken into account by the simultaneous analysis of multiple microRNAs. The graphical output of the program provides an overview of the parts of the pathway modulated by microRNAs, facilitating the interpretation and presentation of the analysis results. AVAILABILITY: The software is available at http://microrna.gr/mirpath and is free for all users with no login or download requirement.

The aldose reductase inhibitory capacity of Sorbus domestica fruit extracts depends on their phenolic content and may be useful for the control of diabetic complications.

Aldose reductase (ALR2) is a rate-limiting enzyme in the polyol pathway associated with the conversion of glucose to sorbitol and whose activity is implicated in the development of the long-term diabetic complications. Upon previous years, several scientific efforts were focused towards the development of ALR2 inhibitors as effective secondary anti-diabetic drugs. To this regard and during our extensive phytochemical analysis of Sorbus domestica (fam. Rosaceae), twenty nine different extracts, fractions and residues of five different maturity stages of Sorbus domestica fruits were evaluated for their in vitro ALR2 inhibitory capacity. The data obtained thus far have indicated that the diethyl ether and ethyl acetate fractions possess high aldose reductase inhibitory activity. Furthermore, detailed phytochemical LC-DAD-MS (ESI+) analysis of such extracts has shown that this aldose reductase inhibitory activity could be attributed to the high content of flavonoids and hydroxycinnamoyl esters. These results suggest that Sorbus domestica fruit consumption may be a promising way for lowering the incidence of long-term complications of diabetes mellitus, especially at early stages, a possibility being discussed in this paper.

Pharmacokinetics of aztreonam administered i.p. in continuous ambulatory peritoneal dialysis (CAPD) patients.

The pharmacokinetics of Aztreonam (AZT) administered i.p. in six stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD) for end-stage renal disease (ESRD) were studied. One gram of AZT was added into a 2 L bag of dialysate (Medital-Bieffe) just prior to infusion into the peritoneal cavity. The dwell time was 8 h. The serum maximum concentration of AZT was 42.5 +/- 12.4 mg/L (mean +/- SD), achieved in 4.6 +/- 1.0 h. The elimination half-life was 2.4 +/- 0.8 h, almost equal to that found in normal subjects (1.7-2 h). The pharmacokinetic parameters of elimination, as elimination rate constant and clearance of AZT from peritoneal cavity were found 0.305 +/- 0.101 h-1 and 10.05 +/- 3.7 mL/min, respectively, while the bioavailability via the peritoneal membrane was 90.8 +/- 3.05% of administered dose. It is concluded that AZT is eliminated from dialysate at a high rate after i.p. administration and its dialysate and serum levels exceed the MIC for the majority of sensitive organisms including Pseudomonas species. Aztreonam appears to be a potentially useful antibiotic for CAPD peritonitis.