New perspectives of quercetin and vitamin C effects on fibronectin-binding integrins and chemokine receptors in prostate cancer cell lines.

OBJECTIVES: The aim of this study is to investigate the effect of two abundant dietary supplements, quercetin and vitamin C on some factors involved in metastasis and proliferation of prostate cancer, which are resistant to conventional chemotherapies in late stages. BACKGROUND: Bone and brain are two common sites of metastases in prostate cancer, nevertheless the factors involved in their metastatic pathways are not well understood. METHODS: The effect of quercetin (75µM) and vitamin C (100 µM) on CXCR4, CXCR7 chemokine receptors, α4, α5 and ß1 integrins, ki-67 proliferation marker and Vascular endothelial growth factor, VEGF was evaluated using Quantitative Reverse Transcription PCR (RT-qPCR). RESULTS: The effect of quercetin and vitamin C alone was different on PC3 and DU145 prostate cancer cell lines, but sequential combination reduced significantly the expression of CXCR and CXCR7 chemokine receptors, α4, α5 and ß1 integrin subunits, VEGF and Ki-67 proliferation markers in PC3 and DU145 cell lines. CONCLUSION: Our results indicated the beneficial effect of quercetin and vitamin C on prostate cancer cells with different metastatic sites and their differential response to the treatment which in turn may lead us to reach suitable therapeutic outcomes to combat cancer (Fig. 3, Ref. 36).

Molecular dynamics simulation and experimental study of the surface-display of SPA protein via Lpp-OmpA system for screening of IgG.

Staphylococcal protein A (SpA) is a major virulence factor of Staphylococcus aureus. S. aureus is able to escape detection by the immune system by the surface display of protein A. The SpA protein is broadly used to purify immunoglobulin G (IgG) antibodies. This study investigates the fusion ability of Lpp'-OmpA (46-159) to anchor and display five replicate domains of protein A with 295 residues length (SpA295) of S. aureus on the surface of Escherichia coli to develop a novel bioadsorbent. First, the binding between Lpp'-OmpA-SPA295 and IgGFc and the three-dimensional structure was investigated using molecular dynamics simulation. Then high IgG recovery from human serum by the surface-displayed system of Lpp'-OmpA-SPA295 performed experimentally. In silico analysis was demonstrated the binding potential of SPA295 to IgG after expression on LPP-OmpA surface. Surface-engineered E. coli displaying SpA protein and IgG-binding assay with SDS-PAGE analysis exhibited high potential of the expressed complex on the E. coli surface for IgG capture from human serum which is applicable to conventional immune precipitation.

Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation.

Trametinib was endorsed by the FDA in 2013 as a single agent for adult melanoma patients. Trametinib inhibits cell growth and proliferation in multiple tumor xenografts by preventing RAF phosphorylation of MEK and thus restricting accumulation of activated MEK. In this study, the focus of investigation was the mechanism of the interaction between trametinib and MEK1/2 via computational simulation. To specify the best interaction site of inhibitor with MEK1/2 based on the interaction energy ranking, first we performed a docking and then we studied the interactions of the ATP-bound MEK with trametinib, with RAF and the complex of the ATP-bound MEK-trametinib with RAF via molecular dynamic simulations. The results showed that trametinib inactivates the enzyme by bonding to a group of amino acids including Lys97/101, SER218/216, Asp208/212, and Met143/147 in MEK1/2. By bonding to the essential amino acids, trametinib inhibits the activity of the enzyme. All in all, the acquired results can be of great use in designing new inhibitors.

Lens parameters as predictors of intraocular pressure changes after phacoemulsification.

PURPOSE: To evaluate intraocular pressure (IOP) change after cataract surgery in non-glaucomatous eyes with narrow and open angles (OAs) and its relation to novel lens parameters measured by anterior segment optical coherence tomography (AS-OCT). SETTING: University affiliated hospital, Farabi Eye Hospital, Tehran, Iran. DESIGN: Prospective interventional case series. METHODS: In this prospective study, 85 non-glaucomatous eyes underwent phacoemulsification and lens implantation. Thirty-nine eyes had OAs and 46 eyes had narrow angles (NAs). IOP and biometric parameters were measured by AS-OCT preoperatively and 3 months after surgery. Change in IOP and its relation to biometric parameters, including lens vault (LV), anterior vault (AV), defined as the sum of the LV and the ACD, and relative LV (rLV), defined as the ratio of the LV to the AV, were evaluated. The main outcome measure was degree of IOP change after phacoemulsification. RESULTS: Of the 85 patients included in the analysis, 35 were male and 50 were female with an overall mean age of 62.2 ± 8.9 years. The average IOP reduction was -4.95 ± 2.26 mm Hg, from a preoperative mean of 17.12 ± 2.47 mm Hg, at 3 months after cataract surgery. The amount of IOP reduction was significantly greater in the NA compared with the OA group. In multivariate linear regression analysis, preoperative IOP and AV were significantly associated with IOP decrease (all ≤ 0.03). CONCLUSION: Cataract surgery results in IOP reduction in both OA and NA eyes. The amount of IOP reduction is related to AV.

Hepatitis B virus surface protein mutations clustered mainly in CTL immune epitopes in chronic carriers: results of an Iranian nationwide study.

Mutations within the coding region of hepatitis B surface antigen (HBsAg) have been found naturally in chronic carriers. To characterize the mutations of HBsAg from Iranian chronic carriers who were vaccine and/or medication naive. The surface genes from 360 patients were amplified and directly sequenced. The distribution of amino acid substitutions was classified according to different immune epitopes of the surface protein. All isolates belonged to genotype D. 222 (61.6%) of 360 patients contained at least one amino acid substitution. 404 (74.5%) of 542 amino acid changes occurred in different immune epitopes of HBsAg, of which 112 (27.7%) in 32 residues of B-cell epitopes (62 in the 'a' determinant); 111 (27.4%) in 32 residues of T helper; and 197 (48.7%) in 32 residues inside cytotoxic T lymphocyte (CTL) epitopes. One Th (186-197) and two CTL (28-51 and 206-215) epitopes were found to be hotspot motifs for the occurrence of 213 (52.7%) substitutions. 20 stop codons were identified in different epitopes. There was a significant association between amino acid substitutions and anti-HBe seropositivity; however, the correlation between such changes with viral load and ALT levels was not significant. In chronic hepatitis B virus(HBV) carriers, positive selection in particular outside the 'a' determinant appeared to exert influence on the surface proteins. These changes could be immune escape mutations naturally occurring due to the host immune surveillance especially at the T-cell level.

Determining the distance to monotonicity of a biological network: a graph-theoretical approach.

The authors use ideas from graph theory in order to determine how distant is a given biological network from being monotone. On the signed graph representing the system, the minimal number of sign inconsistencies (i.e. the distance to monotonicity) is shown to be equal to the minimal number of fundamental cycles having a negative sign. Suitable operations aiming at computing such a number are also proposed and shown to outperform all algorithms that are so far existing for this task. [Includes supplementary material].

Preparation and characterization of poly lactide-co-glycolide nanoparticles of SN-38.

SN-38 (7-ethyl-10-hydroxycamptothecin) is the active metabolite of irinotecan (CPT-11), which is 100-1000-fold more cytotoxic than irinotecan. Nonetheless, the extreme hydrophobicity of SN-38 has prevented its clinical use. SN-38 is poorly soluble in aqueous solutions, and it is practically insoluble in most physiologically compatible and pharmaceutically acceptable solvents. One way of improving the solubility and stability of SN-38 is to formulate the drug into nanoparticles. Incorporation of cytotoxic agents into nanoparticles has also shown increased toxicity. In this study, poly lactide-co-glycolide was used for the preparation of nanoparticles of SN-38. The nanoparticles were fabricated by an emulsification/solvent evaporation method. The effect of several variables on nanoparticle characteristics was evaluated, including the ratio of drug-polymer, the amount of the poly vinyl alcohol as surfactant, and the internal phase volume/composition. The SN-38 encapsulation efficiency and the particle size distribution were optimized by varying these parameters. Nanoparticles were spherical with a relatively mono-dispersed size distribution. As the ratio of acetone to dichloromethane increased, a considerable decrease in the particle size of nanoparticles was achieved. The encapsulation efficiency of all samples was more than 80%. Changing the poly vinyl alcohol concentration in the external phase had some effects on size and morphology and encapsulation efficiency. It was shown that SN-38 nanoparticles are considerably stable in a long-term stability study.