The association of sleep quality with dry eye disease: the Osaka study

Motoko Kawashima,1 Miki Uchino,1,2 Norihiko Yokoi,3 Yuichi Uchino,1,2 Murat Dogru,1 Aoi Komuro,3 Yukiko Sonomura,3 Hiroaki Kato,3 Shigeru Kinoshita,3 Kazuo Tsubota1 1Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, 2Ryogoku Eye Clinic, Sumida-ku, Tokyo, 3Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan Purpose: To investigate the association of dry eye disease with sleep quality. Methods: In 2011, a cross-sectional survey was conducted among all the employees, mainly young and middle-aged Japanese office workers, who used visual display technology, at a company in Osaka, Japan (N=672; age range =26–64 years). The participants were classified according to the Japanese dry eye diagnosis criteria by dry eye examination results including the Schirmer test, fluorescein and lissamine green staining, tear film break-up time, and symptom questionnaire into three groups as follows: definite dry eye disease, probable dry eye disease, and no dry eye disease. To determine sleep quality, Japanese version of the Pittsburgh Sleep Quality Index (global score) was implemented. The global score (range =0–21) was calculated by summing seven sleep variable scores (scale, 0–3); scores ≥5.5 indicated poor sleep. Results: The total mean global score was 5.1±2.3 (completed N=383); 45% of the dry eye disease participants reported having poor sleep quality, while 34% of the no dry eye disease participants did so, with a significant difference found in the global score (P=0.002). Furthermore, a statistically significant association was observed between the global score and dry eye disease (P=0.005). Conclusion: Poor sleep quality is associated with dry eye disease, especially with dry eye symptoms. Keywords: dry eye, sleep quality, symptom, questionnaire, Pittsburgh Sleep Quality Index, tear film break-up time, visual display terminal

The natural metabolite 4-cresol improves glucose homeostasis and enhances beta-cell function

Exposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration of non-toxic doses of 4-cresol in complementary preclinical models of CMD reduces adiposity, glucose intolerance, and liver triglycerides, enhances insulin secretion in vivo, stimulates islet density and size, and pancreatic β-cell proliferation, and increases vascularization, suggesting activated islet enlargement. In vivo insulin sensitivity is not affected by 4-cresol. The incubation of mouse isolated islets with 4-cresol results in enhanced insulin secretion, insulin content, and β-cell proliferation of a magnitude similar to that induced by GLP-1. In both CMD models and isolated islets, 4-cresol is associated with the downregulated expression of the kinase DYRK1A, which may mediate its biological effects. Our findings identify 4-cresol as an effective regulator of β-cell function, which opens up perspectives for therapeutic applications in syndromes of insulin deficiency

Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity

Klotho is a circulating protein, and Klotho deficiency disturbs endothelial integrity, but the molecular mechanism is not fully clarified. We report that vascular endothelium in Klotho-deficient mice showed hyperpermeability with increased apoptosis and down-regulation of vascular endothelial (VE)-cadherin because of an increase in VEGF-mediated internal calcium concentration ([Ca2+]i) influx and hyperactivation of Ca2+-dependent proteases. Immunohistochemical analysis, the pull-down assay using Klotho-fixed agarose, and FRET confocal imaging confirmed that Klotho protein binds directly to VEGF receptor 2 (VEGFR-2) and endothelial, transient-receptor potential canonical Ca2+ channel 1 (TRPC-1) and strengthens the association to promote their cointernalization. An in vitro mutagenesis study revealed that the second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of VEGFR-2 and the third extracellular loop of TRPC-1. In Klotho-deficient endothelial cells, VEGF-mediated internalization of the VEGFR-2/TRPC-1 complex was impaired, and surface TRPC-1 expression increased 2.2-fold; these effects were reversed by supplementation of Klotho protein. VEGF-mediated elevation of [Ca2+]i was sustained at higher levels in an extracellular Ca2+-dependent manner, and normalization of TRCP-1 expression restored the abnormal [Ca2+]i handling. These findings provide evidence that Klotho protein is associated with VEGFR-2/TRPC-1 in causing cointernalization, thus regulating TRPC-1–mediated Ca2+ entry to maintain endothelial integrity