Liberation of energy stores from adipocytes is critical to support survival in times of energy deficit, however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency, disrupts metabolic homeostasis 1,2 . Coupled to lipolysis is the release of a recently identified hormone, fatty acid-binding protein 4 (FABP4) 3 . While circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans [4][5][6][7] , no mechanism of action has yet been described [8][9][10] . Here, we show that hormonal FABP4 forms a novel functional hormone complex with Adenosine Kinase (ADK) and Nucleoside Diphosphate Kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial impact of this hormone on beta-cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves Reprints and permissions information is available at www.nature.com/reprints.
In this study, we aimed to investigate ocular manifestations in patients with vitiligo. Sixty-one patients with vitiligo were included in the study. From the patients who referred for examination to the dermatology and ophthalmology clinic, 57 patients without any systemic disease were taken as the control group. In both groups, otorefractometry, keratometry, visual acuity test, intraocular pressure measurement, anterior segment, and fundus examinations of the eye with slit lamp, Schirmer test, and perimetry were carried out. The mean age was 24.54 ± 11.90 years and 23.03 ± 8.72 years in the patients and control group, respectively. The mean Schirmer test results were as follows: 16.74 ± 9.11 mm and 17.64 ± 9.41 mm for the right and left eyes of the patients, and 21.96 ± 12.51 mm and 23.42 ± 12.51 mm for the right and left eyes of controls, respectively. Of the patients, 36 eyes showed lenticular findings. However, only 12 eyes of the controls have some lenticular findings. Twenty-nine eyes in the vitiligo group and four in the controls showed some fundus findings. When the two groups were compared with each other, there was a statistically significant difference between them in terms of Schirmer test results, lens, and fundus findings (P < 0.05 for all). However, there was no significant difference in terms of age, gender, visual acuity, refraction, keratometry, intraocular pressure, perimetry, and corneal findings (P > 0.05 for all). Patients with vitiligo may have more lenticular and retinal findings than normal. They can be more prone to dry eye syndrome as well.
BackgroundThe aim of this study was to investigate the thickness of the retinal nerve fiber layer (RNFL), the ganglion cell layer (GCL), and choroid thickness (CT) in patients who have migraines, with and without aura, using spectral optical coherence tomography (OCT).MethodsForty-five patients who had migraines without aura (Group 1), 45 patients who had migraines with aura (Group 2), and 30 healthy participants (control group) were included in the study. Spectral OCT was used to measure the RNFL, GCL and CT values for all patients.ResultsThe mean age of Group 1, Group 2, and the control group was 34.6 ± 4.3, 32.8 ± 4.9, and 31.8 ± 4.6 years, respectively. The mean attack frequency was 3.6/month in Group 1 and 3.7/month in Group 2. The mean age among the groups (p = 0.27) and number of attacks in migraine patients (p = 0.73) were not significantly different. There was significant thinning in the RNFL and GCL in Group 2 (p < 0.05, p < 0.001 respectively), while there were no significant differences in RNFL and GCL measurements between Group 1 and the control group (p > 0.05). All groups were significantly different from one another with respect to CT, with the most thinning observed in Group 2 (p < 0.001). When all migraine patients (without grouping) were compared with the control group, there were significant differences on all parameters: RNFL thickness, GCC thickness and CT (p < 0.05).ConclusionsRNFL and GCL were significantly thinner in the migraine patients with aura as compared with both the migraine patients without aura and the control subjects. In migraine, both with aura and without aura, patients’ choroid thinning should be considered when evaluating ophthalmological findings.
A cell-based high-throughput screen (HTS) was developed to detect phosphodiesterase 8 (PDE8) and PDE4/8 combination inhibitors. By replacing the Schizosaccharomyces pombe PDE gene with the murine PDE8A1 gene in strains lacking adenylyl cyclase, we generated strains whose protein kinase A (PKA)-stimulated growth in 5-fluoro orotic acid (5FOA) medium reflects PDE8 activity. From our previously-identified PDE4 and PDE7 inhibitors, we identified a PDE4/8 inhibitor that allowed us to optimize screening conditions. Of 222,711 compounds screened, ∼0.2% displayed composite Z scores of >20. Additional yeast-based assays using the most effective 367 compounds identified 30 candidates for further characterization. Among these, compound BC8-15 displayed the lowest IC50 value for both PDE4 and PDE8 inhibition in in vitro enzyme assays. This compound also displays significant activity against PDE10A and PDE11A. BC8-15 elevates steroidogenesis in mouse Leydig cells as a single pharmacological agent. Assays using BC8-15 and two structural derivatives support a model in which PDE8 is a primary regulator of testosterone production by Leydig cells, with an additional role for PDE4 in this process. BC8-15, BC8-15A, and BC8-15C, which are commercially available compounds, display distinct patterns of activity against PDE4, PDE8, PDE10A, and PDE11A, representing a chemical toolkit that could be used to examine the biological roles of these enzymes in cell culture systems.
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