Structure based rational drug design of selective phosphodiesterase-4 ligands as anti-inflammatory molecules

Phosphodiesterase-4 enzyme (PDE4) has been gaining increasing attention for the last two decades as a pharmacotherapeutic target, as it is involved in the etiology of a variety of pathologies that comprise a majority of inflammation problems concerning respiratory pathway in major aspect. Intense efforts have been directed towards the development of effective and selective PDE4b inhibitors, but not much success has been reported till yet. This is because of the structural similarity between the two isoforms of PDE4, PDE4b (therapeutic effect) and PDE4d (side effect of emesis). Analogues of 1,2-dihydroxy-xanthen-9H-one were designed as selective ligands for PDE4b using the structure based drug design. The selectivity was determined by docking of xanthone analogues in PDE4b and PDE4d active sites respectively using GLIDE docking programme from Schrodinger Inc. ADME properties of the designed ligands were also predicted using QikProp from Schrodinger Inc. Interpretation of protein-ligand interactions and binding modes of xanthone analogues showed that these ligands are more selective for PDE4b than for PDE4d.info:eu-repo/semantics/publishedVersio

GENISTEIN ALLEVIATES HIGH GLUCOSE INDUCED TOXICITY AND ANGIOGENESIS IN CULTURED HUMAN RPE CELLS

Objective: Genistein, an iso flavonoid has been shown to possess many biological activities including anti-inflammatory, antioxidant and anti-angiogenic property. It has been shown to be protective in dampening diabetes induced retinal inflammation in vivo. Therefore, the purpose of the present study is to investigate the effect of genistein on glucose induced toxicity in cultured human RPE cells (ARPE-19).Methods: ARPE-19 cells were challenged with normal glucose (NG 5 mM) and high glucose (HG1 25 mM & HG2 50 mM) concentrations with or without genistein (20 µM) for 24 h. The mRNA expression of aldose reductase (ALR) and VEGF was measured by real-time PCR using SYBR green. Inhibitory effects upon ALR activity were performed. The VEGF levels of cell supernatant were estimated by sandwich ELISA. Cellular viability and mitochondrial function upon genistein treatment were assessed using dye exclusion method and MTT assay respectively.Results: Genistein at the studied concentration showed 93% of cell viability and no marked toxicity was observed on cell growth. ARPE-19 cells challenged with HG1 and HG2 showed (2.32) and (2.48) fold increase in ALR expression as compared to NG. Significant increase in VEGF165 expression was observed in ARPE-19 cells with HG1 and HG2 as compared to NG. The genistein treated cells significantly reduced the mRNA expression of both ALR and VEGF165. No significant increase in VEGF level was observed in ARPE-19 cell supernatant with HG1 and HG2 (220.68±5.24 and 228.96±7.19 pg/ml) as compared to NG (220.30±2.04 pg/ml), however, significant reduction was observed in response to treatment with genistein in HG1 and HG2 (155.51±9.33 and 122.85±4.76 pg/ml). Also ALR activity significantly reduced in genistein treated cells when compared with HG1 and HG2 concentrations.Conclusion: The results of the present study clearly demonstrate that genistein protects RPE cells from glucose toxicity. Genistein could be a prospective potent agent for treating complications linked with diabetes mellitus, such as diabetic retinopathy.Â

Developing and Applying a Single Strategy for Improved Intestinal Permeability of Diverse and Complex Phytomolecules: Nanoformulations of Rutin, Quercetin, Thymoquinone Provide Proof-of-Concept

Purpose: The clinical use and efficacy of phytomolecules are often hampered as their complex structure, poor aqueous solubility and low biological stability restricts their intestinal permeability which results in low oral bioavailability. Rutin (RT), quercetin (QU), thymoquinone (TQ) are few of such potent and therapeutically versatile phytomolecules that await maximal utilization. To address this lacuna, an attempt was made to develop a single strategy for enhanced intestinal permeation that can be applied to diverse phytomolecules. Method: A simple idea with easy-to-apply method was developed that involved preparing nanoparticles of the phytomolecules RT, QU, TQ using Eudragit matrix (RT-PNP, QU-PNP, TQ-PNP) and examined for particle characteristics, EE, in vitro release and kinetics. Phytomolecule loaded nanoparticle (PNPs) were encapsulated in HPMC grade capsule shell and evaluated for intestinal permeability by everted gut sac method. Result: The average particle sizes of RT-PNP, QU-PNP, TQ-PNP were 446±0.152, 39.6±0.006 and 186±0.513 nm, polydispersity indices were<0.5 with negative zeta potential. The % release of respective phytomolecule from RT-PNP, QU-PNP, TQ-PNP was significantly higher (P<0.05) at pH 6.8 than pH 1.2. PNPs followed Higuchi kinetics with non-Fickian diffusion mechanisms. The apparent intestinal permeability (Papp) of RT-PNP, QU-PNP, TQ-PNP were 14.45±4.85, 12.96±1.73 and 30.87±8.75 µg/cm2 , respectively, significantly (<0.5) greater vs RT, QU, TQ, respectively. CLSM confirmed significantly higher (P<0.05) intestinal permeation of RT-PNP, QU-PNP, TQ-PNP vs RT, QU, TQ, respectively. Conclusion: Developed PNPs appear to be a good approach to increase the permeability of hydrophobic phytomolecules

Computational Fluid Dynamics Applications to MAVs

Micro air Vehicles (MAVs) are unmanned autonomous flying machines with a linear dimension of about 15 cm gross take off weight approximately 100 g and expected loiter time of the order of about 60 minutes. The requirements of any MAV are its ability to loiter for a long duration and also to effectively maneuver in space overland, in buildings and other confined areas