Drug and Alcohol Rehabilitation: Ergosterol Biosynthesis in Aspergillus Fumigatus: Its Relevance as an Antifungal Target and Role in Antifungal Drug Resistance.

Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance.

Filed under: Drug and Alcohol Rehabilitation

Front Microbiol. 2012; 3: 439
Alcazar-Fuoli L, Mellado E

Ergosterol, the major sterol of fungal membranes, is essential for developmental growth and the main target of antifungals that are currently used to treat fatal fungal infections. Emergence of resistance to existing antifungals is a current problem and several secondary resistance mechanisms have been described in Aspergillus fumigatus clinical isolates. A full understanding of ergosterol biosynthetic control therefore appears to be essential for improvement of antifungal efficacy and to prevent antifungal resistance. An ergosterol biosynthesis pathway in A. fumigatus has been proposed with 14 sterol intermediates resulting in ergosterol and another secondary final compound C-24 ethyl sterol. Transcriptomic analysis of the A. fumigatus response to host-imposed stresses or antifungal agents is expanding our understanding of both sterol biosynthesis and the modes of action of antifungal drugs. Ultimately, the identification of new targets for novel drug design, or the study of combinatorial effects of targeting sterol biosynthesis together with other metabolic pathways, is warranted.
HubMed – drug

 

Human lung on a chip: innovative approach for understanding disease processes and effective drug testing.

Filed under: Drug and Alcohol Rehabilitation

Front Pharmacol. 2012; 3: 205
Fukumoto J, Kolliputi N

HubMed – drug

 

Choroidal neovascularization reduced by targeted drug delivery with cationic liposome-encapsulated paclitaxel or targeted photodynamic therapy with verteporfin encapsulated in cationic liposomes.

Filed under: Drug and Alcohol Rehabilitation

Mol Vis. 2013; 19: 54-61
Gross N, Ranjbar M, Evers C, Hua J, Martin G, Schulze B, Michaelis U, Hansen LL, Agostini HT

PURPOSE: Intravitreal antivascular endothelial growth factor (anti-VEGF) application has revolutionized the treatment of choroidal neovascularization (CNV), a hallmark of wet age-related macular degeneration. However, additional treatment options are desirable as not all CNV lesions respond to anti-VEGF injections. Here, we assessed the feasibility of targeted delivery of cationic liposome-encapsulated paclitaxel (EndoTAG-1) in treating CNV. Furthermore, we investigated whether a new formulation of verteporfin encapsulated in cationic liposomes (CL-VTP) enhances the effect of photodynamic therapy (PDT). METHODS: EndoTAG-1, LipoSPA, and CL-VTP were produced by encapsulating paclitaxel, succinyl-paclitaxel, or verteporfin in cationic liposomes (CL). Mice underwent argon laser coagulations at day 0 (D0) to induce CNV. EndoTAG-1 and LipoSPA were injected into the tail vein at D1, D3, D5, D7, and D9. Taxol, CL, or trehalose buffer alone was injected in control animals. At D10, all animals were perfused with fluorescein isothiocyanate (FITC)-dextran. Flatmounts comprising the retinal pigment epithelium, choroid, and sclera were prepared for quantifying the CNV by measuring the area of lesions perfused with FITC-dextran. For PDT, mice received an injection with CL-VTP or Visudyne at D10. One eye was treated with PDT while the other served as a control. Evaluation of RPE-choroid-scleral and retinal flatmounts was performed at D12, D14, or D17. Perfusion with FITC-dextran and tetramethylrhodamine-5-(and 6)-isothiocyanate-lectin staining was used to distinguish between perfused and non-perfused choroidal vessels. RESULTS: EndoTAG-1 or LipoSPA significantly reduced CNV size to 15% compared to trehalose controls. The mean CNV area of mice treated with CL was reduced (though not significantly) to about one-half of the value of the trehalose control group. The same was observed for paclitaxel. Thus, the reduction in the CNV size between treatment with CL and treatment with EndoTAG-1 or LipoSPA was 40%, which was not significant. PDT using either CL-VTP or Visudyne reduced CNV size to 65% (D17) of trehalose control size. CNV size was further diminished to 56% with Visudyne and 53% with CL-VTP when PDT was repeated twice. Most importantly, PDT-associated retinal damage was less pronounced using CL-VTP compared to Visudyne. CONCLUSIONS: Systemic intravenous injection of paclitaxel (EndoTAG-1)- or succinyl-paclitaxel (LipoSPA)-loaded CL had a significant antiangiogenic effect in a CNV mouse model. PDT with CL-VTP was as effective as Visudyne in neovascular obliteration but induced less tissue damage. Our data suggest that systemic application of cationic liposome formulations may serve to treat ocular neovascular diseases. This approach may reduce the need for intraocular injections and may benefit patients with neovascular lesions irresponsive to anti-VEGF treatment.
HubMed – drug

 

Quinotrierixin inhibits proliferation of human retinal pigment epithelial cells.

Filed under: Drug and Alcohol Rehabilitation

Mol Vis. 2013; 19: 39-46
Chen C, Wang JJ, Li J, Yu Q, Zhang SX

PURPOSE: To investigate the effect of quinotrierixin, a previously reported inhibitor of X-box binding protein 1 (XBP1), on cell proliferation and viability in human retinal pigment epithelium (RPE) cells. METHODS: Subconfluent human RPE cells (ARPE-19) were exposed to quinotrierixin for 16-24 h. Cell proliferation was determined with 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, hemocytometer counts, and CyQUANT NF Cell Proliferation Assay. Apoptosis was detected with terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling assay. XBP1 mRNA splicing and expression of endoplasmic reticulum stress response genes were determined in cells exposed to thapsigargin in the presence or absence of quinotrierixin. Overexpression of spliced XBP1 was achieved with adenovirus. RESULTS: Quinotrierixin reduced RPE cell proliferation in a dose-dependent manner without inducing apoptosis. In cells exposed to thapsigargin, quinotrierixin inhibited XBP1 mRNA splicing and PKR-like endoplasmic reticulum kinase activation, and reduced cellular and nuclear levels of spliced XBP1 and C/EBP homologous protein. Paradoxically, quinotrierixin exacerbated endoplasmic reticulum stress-induced phosphorylation of eIF2?, which in turn led to decreased protein translation. Overexpressing spliced XBP1 partially reversed the inhibition of cell proliferation by quinotrierixin. These results suggest that inhibiting XBP1 splicing contributes to quinotrierixin’s negative effect on RPE cell proliferation, but other mechanisms such as reduction of protein translation are also involved. CONCLUSIONS: Quinotrierixin inhibits RPE cell proliferation and may be used as a novel antiproliferative drug for treating proliferative vitreoretinopathy. Future studies are needed to investigate the in vivo effect of quinotrierixin on RPE proliferation in animal models of proliferative vitreoretinopathy.
HubMed – drug

 

Optimal Halbach Permanent Magnet Designs for Maximally Pulling and Pushing Nanoparticles.

Filed under: Drug and Alcohol Rehabilitation

J Magn Magn Mater. 2012 Mar 1; 324(5): 742-754
Sarwar A, Nemirovski A, Shapiro B

Optimization methods are presented to design Halbach arrays to maximize the forces applied on magnetic nanoparticles at deep tissue locations. In magnetic drug targeting, where magnets are used to focus therapeutic nanoparticles to disease locations, the sharp fall off of magnetic fields and forces with distances from magnets has limited the depth of targeting. Creating stronger forces at depth by optimally designed Halbach arrays would allow treatment of a wider class of patients, e.g. patients with deeper tumors. The presented optimization methods are based on semi-definite quadratic programming, yield provably globally optimal Halbach designs in 2 and 3-dimensions, for maximal pull or push magnetic forces (stronger pull forces can collect nano-particles against blood forces in deeper vessels; push forces can be used to inject particles into precise locations, e.g. into the inner ear). These Halbach designs, here tested in simulations of Maxwell’s equations, significantly outperform benchmark magnets of the same size and strength. For example, a 3-dimensional 36 element 2000 cm(3) volume optimal Halbach design yields a ×5 greater force at a 10 cm depth compared to a uniformly magnetized magnet of the same size and strength. The designed arrays should be feasible to construct, as they have a similar strength (? 1 Tesla), size (? 2000 cm(3)), and number of elements (? 36) as previously demonstrated arrays, and retain good performance for reasonable manufacturing errors (element magnetization direction errors ? 5°), thus yielding practical designs to improve magnetic drug targeting treatment depths.
HubMed – drug

 

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