Integrated Approaches to Drug Discovery for Oxidative Stress-Related Retinal Diseases

Excessive oxidative stress induces dysregulation of functional networks in the retina, resulting in retinal diseases such as glaucoma, age-related macular degeneration, and diabetic retinopathy. Although various therapies have been developed to reduce oxidative stress in retinal diseases, most have failed to show efficacy in clinical trials. This may be due to oversimplification of target selection for such a complex network as oxidative stress. Recent advances in high-throughput technologies have facilitated the collection of multilevel omics data, which has driven growth in public databases and in the development of bioinformatics tools. Integration of the knowledge gained from omics databases can be used to generate disease-related biological networks and to identify potential therapeutic targets within the networks. Here, we provide an overview of integrative approaches in the drug discovery process and provide simple examples of how the approaches can be exploited to identify oxidative stress-related targets for retinal diseases

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

The primary cilium is a single immotile microtubule-based organelle that protrudes into the extracellular space. Malformations and dysfunctions of the cilia have been associated with various forms of syndromic and non-syndromic diseases, termed ciliopathies. The primary cilium is therefore gaining attention due to its potential as a therapeutic target. In this review, we examine ciliary receptors, ciliogenesis, and ciliary trafficking as possible therapeutic targets. We first discuss the mechanisms of selective distribution, signal transduction, and physiological roles of ciliary receptors. Next, pathways that regulate ciliogenesis, specifically the Aurora A kinase, mammalian target of rapamycin, and ubiquitin-proteasome pathways are examined as therapeutic targets to regulate ciliogenesis. Then, in the photoreceptors, the mechanism of ciliary trafficking which takes place at the transition zone involving the ciliary membrane proteins is reviewed. Finally, some of the current therapeutic advancements highlighting the role of large animal models of photoreceptor ciliopathy are discussed

Diet-induced obesity in zebrafish shares common pathophysiological pathways with mammalian obesity

<p>Abstract</p> <p>Background</p> <p>Obesity is a multifactorial disorder influenced by genetic and environmental factors. Animal models of obesity are required to help us understand the signaling pathways underlying this condition. Zebrafish possess many structural and functional similarities with humans and have been used to model various human diseases, including a genetic model of obesity. The purpose of this study was to establish a zebrafish model of diet-induced obesity (DIO).</p> <p>Results</p> <p>Zebrafish were assigned into two dietary groups. One group of zebrafish was overfed with <it>Artemia </it>(60 mg dry weight/day/fish), a living prey consisting of a relatively high amount of fat. The other group of zebrafish was fed with <it>Artemia </it>sufficient to meet their energy requirements (5 mg dry weight/day/fish). Zebrafish were fed under these dietary protocols for 8 weeks. The zebrafish overfed with <it>Artemia </it>exhibited increased body mass index, which was calculated by dividing the body weight by the square of the body length, hypertriglyceridemia and hepatosteatosis, unlike the control zebrafish. Calorie restriction for 2 weeks was applied to zebrafish after the 8-week overfeeding period. The increased body weight and plasma triglyceride level were improved by calorie restriction. We also performed comparative transcriptome analysis of visceral adipose tissue from DIO zebrafish, DIO rats, DIO mice and obese humans. This analysis revealed that obese zebrafish and mammals share common pathophysiological pathways related to the coagulation cascade and lipid metabolism. Furthermore, several regulators were identified in zebrafish and mammals, including APOH, IL-6 and IL-1β in the coagulation cascade, and SREBF1, PPARα/γ, NR1H3 and LEP in lipid metabolism.</p> <p>Conclusion</p> <p>We established a zebrafish model of DIO that shared common pathophysiological pathways with mammalian obesity. The DIO zebrafish can be used to identify putative pharmacological targets and to test novel drugs for the treatment of human obesity.</p

Tandem Dye-Sensitized Solar Cells Based on TCO-less Back Contact Bottom Electrodes

Mechanically stacked and series connected tandem dye sensitized solar cells (T-DSSCs) are fabricated in novel architectures. The architecture consist of TCO tandem DSSCs stacked with TCO-less back contact DSSCs as bottom electrodes (TCO-less tandem DSSCs). Resulting TCO-less tandem DSSCs architecture finds its usefulness in efficient photon harvesting due to improved light transmission and enhanced photons reaching to the bottom electrodes. The fabricated tandem performance was verified with visible light harvesting model dyes D131 and N719 as a proof of concept and provided the photoconversion efficiency (PCE) of 6.06% under simulated condition. Introduction of panchromatic photon harvesting by utilizing near infrared light absorbing Si-phthalocyanine dye in combination with the modified tandem DSSC architecture led to enhancement in the PCE up to 7.19%.India-Japan Expert Group Meeting on Biomolecular Electronics & Organic Nanotechnology for Environment Preservation (IJEGMBE 2015), December 23-26, 2015, Fukuoka, Japa

Prostaglandin F 2 ␣, but Not Latanoprost, Increases the Ca 2؉ Sensitivity of the Pig Iris Sphincter Muscle

PURPOSE. To determine the mechanisms underlying prostaglandin (PG) F 2 ␣-, carbachol (CCh)-, or latanoprost (a PGF 2 ␣ analogue)-induced contraction of the pig iris sphincter muscle. METHODS. Effects of these agents on myofilament Ca 2ϩ sensitivity were evaluated and compared with the use of receptorcoupled permeabilized preparations by ␣-toxin. The effects of PGF 2 ␣ and CCh on the phosphorylation of myosin light chain (MLC) were also analyzed. RESULTS. In the intact strips, all three of these agents induced contractions. CONCLUSIONS. PGF 2 ␣, but not latanoprost, induced Ca 2ϩ sensitization of the pig iris sphincter muscle in an MLC phosphorylation-dependent manner through the rho-rho kinase pathway. The effect of latanoprost on the Ca 2ϩ sensitization mechanism was different from that of PGF 2 ␣ and was thought to play a beneficial role in glaucoma treatment. (Invest Ophthalmol Vis Sci

In vivo imaging of zebrafish retinal cells using fluorescent coumarin derivatives

<p>Abstract</p> <p>Background</p> <p>The zebrafish visual system is a good research model because the zebrafish retina is very similar to that of humans in terms of the morphologies and functions. Studies of the retina have been facilitated by improvements in imaging techniques. <it>In vitro </it>techniques such as immunohistochemistry and <it>in vivo </it>imaging using transgenic zebrafish have been proven useful for visualizing specific subtypes of retinal cells. In contrast, <it>in vivo </it>imaging using organic fluorescent molecules such as fluorescent sphingolipids allows non-invasive staining and visualization of retinal cells <it>en masse</it>. However, these fluorescent molecules also localize to the interstitial fluid and stain whole larvae.</p> <p>Results</p> <p>We screened fluorescent coumarin derivatives that might preferentially stain neuronal cells including retinal cells. We identified four coumarin derivatives that could be used for <it>in vivo </it>imaging of zebrafish retinal cells. The retinas of living zebrafish could be stained by simply immersing larvae in water containing 1 μg/ml of a coumarin derivative for 30 min. By using confocal laser scanning microscopy, the lamination of the zebrafish retina was clearly visualized. Using these coumarin derivatives, we were able to assess the development of the zebrafish retina and the morphological abnormalities induced by genetic or chemical interventions. The coumarin derivatives were also suitable for counter-staining of transgenic zebrafish expressing fluorescent proteins in specific subtypes of retinal cells.</p> <p>Conclusions</p> <p>The coumarin derivatives identified in this study can stain zebrafish retinal cells in a relatively short time and at low concentrations, making them suitable for <it>in vivo </it>imaging of the zebrafish retina. Therefore, they will be useful tools in genetic and chemical screenings using zebrafish to identify genes and chemicals that may have crucial functions in the retina.</p