Natural product inhibitors of ocular angiogenesis

Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly. Despite the presence of effective therapy in many cases, these diseases are still a significant health burden. Anti-VEGF biologics are the standard of care, but may cause ocular or systemic side effects after intraocular administration and patients may be refractory. Many anti-angiogenic compounds inhibit tumor growth and metastasis alone or in combination therapy, but a more select subset of them has been tested in the context of ocular neovascular diseases. Here, we review the promise of natural products as anti-angiogenic agents, with a specific focus on retinal and choroidal neovascularization. The multifunctional curcumin and the chalcone isoliquiritigenin have demonstrated promising anti-angiogenic effects in mouse models of DR and choroidal neovascularization (CNV) respectively. The homoisoflavanone cremastranone and the flavonoid deguelin have been shown to inhibit ocular neovascularization in more than one disease model. The isoflavone genistein and the flavone apigenin on the other hand are showing potential in the prevention of retinal and choroidal angiogenesis with long-term administration. Many other products with anti-angiogenic potential in vitro such as the lactone withaferin A, the flavonol quercetin, and the stilbenoid combretastatin A4 are awaiting investigation in different ocular disease-relevant animal models. These natural products may serve as lead compounds for the design of more specific, efficacious, and affordable drugs with minimal side effects

Performance Evaluation of Common Rail Direct Injection (CRDI) Engine Fuelled with Uppage Oil Methyl Ester (UOME)

For economic and social development of any country energy is one of the most essential requirements. Continuously increasing price of crude petroleum fuels in the present days coupled with alarming emissions and stringent emission regulations has led to growing attention towards use of alternative fuels like vegetable oils, alcoholic and gaseous fuels for diesel engine applications. Use of such fuels can ease the burden on the economy by curtailing the fuel imports. Diesel engines are highly efficient and the main problems associated with them is their high smoke and NOx emissions. Hence there is an urgent need to promote the use of alternative fuels in place of high speed diesel (HSD) as substitute. India has a large agriculture base that can be used as a feed stock to obtain newer fuel which is renewable and sustainable. Accordingly Uppage oil methyl ester (UOME) biodiesel was selected as an alternative fuel. Use of biodiesels in diesel engines fitted with mechanical fuel injection systems has limitation on the injector opening pressure (300 bar). CRDI system can overcome this drawback by injecting fuel at very high pressures (1500-2500 bar) and is most suitable for biodiesel fuels which are high viscous. This paper presents the performance and emission characteristics of a CRDI diesel engine fuelled with UOME biodiesel at different injection timings and injection pressures. From the experimental evidence it was revealed that UOME biodiesel yielded overall better performance with reduced emissions at retarded injection timing of -10° BTDC in CRDI mode of engine operation

The First Synthesis of the Antiangiogenic Homoisoflavanone, Cremastranone

An antiangiogenic homoisoflavanone, cremastranone, was synthesized for the first time. This scalable synthesis, which includes selective demethylation, could be used to develop lead molecules to treat angiogenesis-induced eye diseases. Synthetic cremastranone inhibited the proliferation, migration and tube formation ability of human retinal microvascular endothelial cells, important steps in pathological angiogenesis

Studies on wear resistance of PTFE filled with glass and bronze particles based on Taguchi technique

An attempt has been made to study the influence of wear parameters like applied load, sliding speed, sliding distance on the dry sliding wear of polytetrafluroethylene (PTFE), PTFE + 25% glass and PTFE + 40% bronze composites. Experiments, based on the techniques of Taguchi, were performed to acquire data in a controlled way. An orthogonal array and the analysis of variance were employed to investigate the influence of process parameters on the wear of composites. The worn surfaces were examined using scanning electron microscope (SEM). The experimental results show that sliding distance and applied load were found to be the more significant factors among the other control factors on wear. The objective is to establish a correlation between dry sliding wear of composites and wear parameters. These correlations were obtained by multiple regressions. A good agreement between the predicted and actual wear resistance was seen

Doctor of Philosophy

dissertationFroth flotation is a highly complex, multiphase, and multiscale process that is usually performed in large tanks called mechanical flotation cells. The aim of this research is to investigate the single and multiphase flow hydrodynamics in lab scale flotation cells by decoupling the hydrodynamics from physicochemical effects. Both experimental and numerical approaches are used to study the behavior of flows in lab and pilot scale flotation cells. Nonintrusive experimental techniques such as particle image velocity (PIV) and electrical resistance tomography (ERT) techniques are used to measure flow velocities, solids holdup, mixing efficiency, and to interpret flow pattern. Eulerian-Eulerian computational fluid dynamics (CFD) models are developed and tested for solid-liquid (slurry) and gas-liquid flows in stirred tanks and flotation cells. Using single phase CFD simulations, the effect of flotation specific impeller blade shape and impeller size on mean flow and pumping behavior is tested in lab scale flotation cells for the first time. In the absence of a stator, the mean flow is found to transition from radial to axial type flow when the off-bottom clearance is below the critical value. This prediction is experimentally verified using time averaged PIV data. Based on the analysis of pumping and power number data, the rectangular shaped blade design is found to be the most efficient. The impeller blade shape is found to critically affect the flow in the vicinity of the impeller and a design with the largest surface area is needed to create an intense turbulence zone, needed for mixing and dispersion of incoming air. Eulerian-Eulerian CFD model is used to study the solid phase suspension and mixing characteristics for monosized silica particles. Experimental comparison with the results from the literature for stirred tanks and in-house ERT measurements suggest that the model performs reasonably well. Population balance equation model (PBM) is coupled with CFD to study gas dispersion, mixing, and local bubble size distribution in the stirred tank and flotation cell using quadrature method of moments (QMOM) approach in ANSYS Fluent solver. The default QMOM model in Fluent is found to be inaccurate due to independent solution of moment transport equations and therefore is supplied with a moment correction algorithm from the literature to successfully identify and correct the invalid moment sequence during the CFD simulation. The new model is found to be superior to the current models in its ability to satisfactorily predict the overall gas holdup and local bubble size distribution for stirred tanks under moderate aeration and agitation rates. This model is extended to study the development of flow regimes based on the gas dispersion pattern in a generic flotation cell. Though highly useful, the coupled CFD-PBM approach is computationally intensive and requires considerable effort to achieve an accurate solution. This motivated us to develop a PBM based on the high-order moment conserving method of classes (HMMC) approach for a pilot scale XCELL flotation cell for frother concentration over critical coalescence concentration, thus, only considering breakage of bubbles. Nonlinear optimization solvers in Matlab are used to calculate the point estimates of adjustable parameters in breakage models. The 95% bootstrap calculated using empirical bootstrap indicates very high confidence in estimated parameters. The HMMC model provides an accurate description of steady state bubble size distribution and the mean number diameters only using overall gas holdup and specific energy as inputs

Surface dissolution and degradation of dental resin-based materials with special emphasis by the effects of solvent ethanol, dimethacrylate monomer resin and catalyst solution of ethylene glycol

In today’s modern dentistry, various synthetic materials are used for the replacement or restoration of the missing teeth or parts of teeth structures. These are primarily either polymers or composite materials. The evolution of the synthetic polymers dates back to the use of natural rubbers to poly(methylmethacrylate), (PMMA) to the present-day use of cross-linked copolymers and interpenetrating polymer network (IPN). One commonly used polymer is the group of denture base polymers where polymer beads of poly(methylmethacrylate) and the monomer of methylmethacrylate (MMA) form multiphase polymer system. During the phase of polymerization, some residual MMA monomers are left unconverted and heat-cured however, auto polymerized denture base polymers differ in this respect. In crosslinked dental resins, monomers are typically bis-phenol A-glycidyl methacrylate (bis-GMA) and triethylene glycol dimethacrylate (TEGDMA) or epoxies and they on combination with PMMA form IPN polymer. This study aimed to investigate surface crazing and surface dissolving of dental polymer with solvent and disinfectant ethanol by chemical reaction of transesterification. Scanning electron microscopy, infrared spectroscopy, and Nanoindentation were used as the research methods. The outcomes of the study on various dental polymers suggested that ethanol had a significant influence on affecting the surface roughness, and nanomechanical properties with surface topographical changes of denture base polymers. The effect of ethanol was dependent on time and concentration. Transesterification of the crosslinked bis-GMA based substrate was seen on contrary to the epoxy resin, which did not show signs of transesterification. This was explained by the lack of the ester group in the mainly studied epoxy polymer

IMPROVED INFECTIOUS LARYNGOTRACHEITIS VIRUS VACCINES USING NEWCASTLE DISEASE VIRUS VECTOR

Infectious laryngotracheitis (ILT) is a highly contagious acute respiratory disease of chickens for which safe and efficacious vaccines are not available currently. In the present study, we have generated three recombinant Newcastle disease viruses (rNDV's) expressing three major envelope glycoproteins gB, gC and gD of ILTV individually. A single oculonasal inoculation of chickens with rNDV's elicited detectable level of systemic antibodies specific to ILTV. Following challenge with virulent strain of ILTV, chickens immunized with the rNDV's displayed partial protection with reduced clinical signs and shorter duration of disease compared to the control group. Our data suggested that NDV vectored ILTV vaccines are useful against ILTV infection, but might require augmentation by a second dose or require modification of ILTV glycoproteins which allow them to incorporate into the mature rNDV virions for better induction of humoral and cell mediated immune responses

Design, synthesis and biological evaluation of photoaffinity probes of antiangiogenic homoisoflavonoids

A naturally occurring homoisoflavonoid, cremastranone (1) inhibited angiogenesis in vitro and in vivo. We developed an analogue SH-11037 (2) which is more potent than cremastranone in human retinal microvascular endothelial cells (HRECs) and blocks neovascularization in animal models. Despite their efficacy, the mechanism of these compounds is not yet fully known. In the course of building on a strong foundation of SAR and creating a novel chemical tool for target identification of homoisoflavonoid-binding proteins, various types of photoaffinity probes were designed and synthesized in which benzophenone and biotin were attached to homoisoflavanonoids using PEG linkers on either the C-3′ or C-7 position. Notably, the photoaffinity probes linking on the phenol group of the C-3′ position retain excellent activity of inhibiting retinal endothelial cell proliferation with up to 72 nM of GI50