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  • br Concluding remarks ROP is a major cause of


    Concluding remarks ROP is a major cause of childhood blindness in the world. Current pharmacological therapy focus on anti-VEGF strategy, but this strategy is associated with the unintended effects on delayed eye growth and retinal vasculature development of preterm infants. Preclinical studies using OIR demonstrate that elevated A2AR and A2BR signaling promotes pathological angiogenesis while A1R signaling apparently confers protection OIR. We recently identified a pathway that affects pathologic, but not developmental, angiogenesis of the eye, and involves the A2AR: genetic inactivation of the A2AR attenuated OIR without affecting normal postnatal retinal vascularization (Liu et al., 2010). This raises the exciting possibility that A2AR activity in the retina may be selectively targeted for treatment of ROP. This notion is further substantiated by clinical evidence that caffeine treatment of GDC0199 of prematurity is associated with reduced ROP (Schmidt et al., 2007). Further understanding of the A2AR, A2BR and A1R signaling interacting with other molecular and cellular pathways leading to distinct physiological development and pathological angiogenesis may lead to new strategy to achieve maximal therapeutic effects of adenosine receptor-based treatment with minimal unwanted side effects. Identification of the effective therapeutic window and cellular (endothelium and neuronal and glial) mechanisms of adenosine receptor strategies for the prevention and treatment of pathological retinal neovascularization will provide the required preclinical evidence to translate adenosine receptor-based treatment for ROP. The caffeine- and A2AR-based therapeutic strategies have high translational potential since caffeine is widely used in neonate care and KW6002 shows noted safety profile in phase III clinical trials.
    Introduction Many olfactory cues pervade aquatic environment of fish and elicit various behavioral and endocrine responses that are essential for survival and reproduction. Fishes efficiently use the sense of smell for locating food sources, detecting and escaping from dangerous environment, communicating social information, and memorizing beneficial and detrimental contexts. The fish olfactory system is highly elaborated to receive, discriminate, and perceive various kinds of water-soluble chemicals such as amino acids, bile acids, amines, steroids, prostaglandins, and nucleotides [1]. Nucleotides are essential for all living organisms as genetic materials, energy source, and intracellular and intercellular signaling molecules. In addition, it has been reported that various fishes and amphibians can sense nucleotides in environmental water as potential feeding stimulants or odorants [2]. For example, electrophysiological and anatomical studies revealed that ATP and other nucleotides induce excitatory responses of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) and neurons in the posterior olfactory bulb (OB) in channel catfish [3, 4, 5, 6]. A neural activity imaging experiment with voltage-sensitive dye showed that nucleotides activate a latero-posterior portion of the OB in zebrafish [7]. A Ca2+ imaging analysis revealed that ATP activates both OSNs and supporting cells in the OE of Xenopus lavies [8]. However, it is largely unknown which olfactory receptor is activated by nucleotides, how the odor information of nucleotides is transferred to the OB and further to higher olfactory centers, and what behavioral responses fish actually show upon nucleotide stimulation. In the present study, we aim to elucidate the functional olfactory receptor and neural correlates that receive and transmit the information of nucleotides from the periphery to the central brain, evoking behavioral output responses in zebrafish.
    Discussion To our knowledge, this is the first report demonstrating that the adenosine receptor plays a crucial role as an olfactory receptor. Based on the amino acid sequence homology and syntenic conservation (Figure S4), we identified A2c gene orthologs in all the fish species (both freshwater and seawater fishes) and amphibian species whose genome sequences are available (Figure 5A; Table S2). This finding suggests that the A2c receptor is commonly used in aquatic lower vertebrates for detection of food source. In addition, the presence of A2c genes in sea lamprey and spotted gar indicates that the appearance of the first A2c gene occurred extremely early during the evolution of the vertebrate olfactory system. In contrast, the A2c gene is not present in reptiles, birds, or mammals, suggesting the loss of the A2c gene with the aquatic-to-terrestrial transition of vertebrate organisms during evolution.