Decorin and TGF-β(1 )polymorphisms and development of COPD in a general population

BACKGROUND: Decorin, an extracellular matrix (ECM) proteoglycan, and TGF-β(1 )are both involved in lung ECM turnover. Decorin and TGF-β(1 )expression are decreased respectively increased in COPD lung tissue. Interestingly, they act as each other's feedback regulator. We investigated whether single nucleotide polymorphisms (SNPs) in decorin and TGF-β(1 )underlie accelerated decline in FEV(1 )and development of COPD in the general population. METHODS: We genotyped 1390 subjects from the Vlagtwedde/Vlaardingen cohort. Lung function was measured every 3 years for a period of 25 years. We tested whether five SNPs in decorin (3'UTR and four intron SNPs) and three SNPs in TGF-β(1 )(3'UTR rs6957, C-509T rs1800469 and Leu10Pro rs1982073), and their haplotypes, were associated with COPD (last survey GOLD stage = II). Linear mixed effects models were used to analyze genotype associations with FEV(1 )decline. RESULTS: We found a significantly higher prevalence of carriers of the minor allele of the TGF-β(1 )rs6957 SNP (p = 0.001) in subjects with COPD. Additionally, we found a significantly lower prevalence of the haplotype with the major allele of rs6957 and minor alleles for rs1800469 and rs1982073 SNPs in TGF-β(1 )in subjects with COPD (p = 0.030), indicating that this association is due to the rs6957 SNP. TGF-β(1 )SNPs were not associated with FEV(1 )decline. SNPs in decorin, and haplotypes constructed of both TGF-β(1 )and decorin SNPs were not associated with development of COPD or with FEV(1 )decline. CONCLUSION: Our study shows for the first time that SNPs in decorin on its own or in interaction with SNPs in TGF-β(1 )do not underlie the disturbed balance in expression between these genes in COPD. TGF-β(1 )SNPs are associated with COPD, yet not with accelerated FEV(1 )decline in the general population

Photocytotoxicity of mTHPC (Temoporfin) Loaded Polymeric Micelles Mediated by Lipase Catalyzed Degradation

Purpose. To study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation. Methods. Micelles of mPEG750-b-oligo(ɛ-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg ®). Results. Micelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30 % (w/w), likely due to π–π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored. Conclusion. The high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo. KEY WORDS: drug release; enzymatic degradation; meta-tetra(hydroxyphenyl)chlorin (mTHPC); photodynamic therapy (PDT); polymeric micelles

Dependence of Intramyocardial Pressure and Coronary Flow on Ventricular Loading and Contractility: A Model Study

The phasic coronary arterial inflow during the normal cardiac cycle has been explained with simple (waterfall, intramyocardial pump) models, emphasizing the role of ventricular pressure. To explain changes in isovolumic and low afterload beats, these models were extended with the effect of three-dimensional wall stress, nonlinear characteristics of the coronary bed, and extravascular fluid exchange. With the associated increase in the number of model parameters, a detailed parameter sensitivity analysis has become difficult. Therefore we investigated the primary relations between ventricular pressure and volume, wall stress, intramyocardial pressure and coronary blood flow, with a mathematical model with a limited number of parameters. The model replicates several experimental observations: the phasic character of coronary inflow is virtually independent of maximum ventricular pressure, the amplitude of the coronary flow signal varies about proportionally with cardiac contractility, and intramyocardial pressure in the ventricular wall may exceed ventricular pressure. A parameter sensitivity analysis shows that the normalized amplitude of coronary inflow is mainly determined by contractility, reflected in ventricular pressure and, at low ventricular volumes, radial wall stress. Normalized flow amplitude is less sensitive to myocardial coronary compliance and resistance, and to the relation between active fiber stress, time, and sarcomere shortening velocity

Self-assembled nanogel made of mannan : synthesis and characterization

Amphiphilic mannan (mannan-C16) was synthesized by the Michael addition of hydrophobic 1-hexadecanethiol (C16) to hydroxyethyl methacrylated mannan (mannan-HEMA). Mannan-C16 formed nanosized aggregates in water by selfassembly via the hydrophobic interaction among C16molecules as confirmed by hydrogen nuclearmagnetic resonance (1H NMR), fluorescence spectroscopy, cryo-field emission scanning electron microscopy (cryo-FESEM), and dynamic light scattering (DLS). The mannan-C16 critical aggregation concentration (cac), calculated by fluorescence spectroscopy with Nile red and pyrene, ranged between 0.04 and 0.02mg/mL depending on the polymer degree of substitution ofC16 relative to methacrylated groups. Cryo-FESEM micrographs revealed that mannan-C16 formed irregular spherical macromolecular micelles, in this work designated as nanogels, with diameters ranging between 100 and 500 nm. The influence of the polymer degree of substitution, DSHEMA andDSC16, on the nanogel size and zeta potential was studied byDLS at different pH values and ionic strength and as a function of mannan-C16 and urea concentrations. Under all tested conditions, the nanogel was negatively charged with a zeta potential close to zero. Mannan-C16 with higher DSHEMA and DSC16 values formed larger nanogels andwere also less stable over a 6month storage period and at concentrations close to the cac.When exposed to solutions of different pH and aggressive conditions of ionic strength and urea concentration, the size of mannan-C16 varied to some extent but was always in the nanoscale range.International Iberian Nanotechnology Laboratory (INL)Fundação para a Ciência e a Tecnologia (FCT

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward