Selective inhibitors of Jumonji domain-containing protein (JMJD) histone demethylases are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs. On the basis of the crystal structure of JMJD2A and a homology model of JMJD2C, we designed and prepared a series of hydroxamate analogues bearing a tertiary amine. Enzyme assays using JMJD2C, JMJD2A, and prolyl hydroxylases revealed that hydroxamate analogue 8 is a potent and selective JMJD2 inhibitor, showing 500-fold greater JMJD2C-inhibitory activity and more than 9100-fold greater JMJD2C-selectivity compared with the lead compound N-oxalylglycine 2. Compounds 17 and 18, prodrugs of compound 8, each showed synergistic growth inhibition of cancer cells in combination with an inhibitor of lysine-specific demethylase 1 (LSD1). These findings suggest that combination treatment with JMJD2 inhibitors and LSD1 inhibitors may represent a novel strategy for anticancer chemotherapy.
Purpose: To evaluate the usefulness of indocyanine green angiography (ICGA) to detect leaking spots and the effectiveness of ICGA-guided focal laser photocoagulation in eyes with diabetic macular edema (DME). Methods: Ten eyes (8 patients) with diffuse DME diagnosed using fluorescein angiography (FA) and refractory to a sub-Tenon injection of triamcinolone acetonide (STTA), grid laser photocoagulation, or both were enrolled. FA and ICGA were performed using the Heidelberg Retina Angiograph 2. Hyperfluorescent spots on early-phase FA and on early- and late-phase ICGA were superimposed onto the macular thickness map measured by optical coherence tomography (OCT) and counted to calculate the spot density in the area with or without macular edema (ME). ICGA-guided focal laser photocoagulation was carried out. In 7 eyes, STTA was simultaneously performed. The central macular thickness (CRT) and macular volume (MV) were measured by OCT. Results: On early-phase FA, 4.8 ± 2.3 and 2.3 ± 1.5 hyperfluorescent spots/disk area were observed inside and outside the ME, respectively. In contrast, the spot density was significantly decreased to 1.8 ± 0.9 inside the ME and was only 0.3 ± 0.4 outside the ME on late-phase ICGA (p < 0.01). The mean follow-up period after ICGA-guided photocoagulation was 19.0 months. The mean best-corrected visual acuity improved significantly from 0.77 ± 0.34 logarithm of the minimum angle of resolution at baseline to 0.52 ± 0.37 at the last visit (p < 0.01). Both CRT and MV significantly decreased (p < 0.01). Recurrence of DME was observed in 4 eyes: 3 eyes were treatable only with STTA and 1 required additional ICGA-guided laser photocoagulation. Conclusions: ICGA may be useful to detect leaking spots responsible for DME, enabling less invasive focal laser photocoagulation even in some of the eyes with diffuse DME.
To date, biochemical approaches to membrane receptors have been limited to the following methods: knockout or overexpression of membrane receptors by gene introduction and genome engineering or extraction of membrane receptor-surfactant complexes from innate cells and their introduction into model biomembranes. Here, we describe the development of a third method involving gene expression using cell-free in situ protein synthesis inside model biomembrane capsules. We verified this method by synthesizing olfactory receptors from the silkmoth Bombyx mori inside giant vesicles and found that they were excited in the presence of their ligand the Bombyx mori sex pheromone.
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