Amiodarone (AM) is the most effective antiarrhythmic agent currently available. However, clinical application of AM is limited by its serious toxic adverse effects including optic neuropathy. The purpose of this study was to explore the effects of AM and to assess if insulin-like growth factor-1 (IGF-1) could protect retinal neuronal cells from AM-induced apoptosis, and to determine the molecular mechanisms underlying the effects. Accordingly, the phosphorylation/activation of Akt and FoxO3a were analyzed by Western blot while the possible pathways involved in the protection of IGF-1 were investigated by application of various pathway inhibitors. The full electroretinogram (FERG) was used to evaluate in vivo effect of AM and IGF-1 on rat retinal physiological functions. Our results showed that AM concentration dependently caused an apoptosis of RGC-5 cells, while IGF-1 protected RGC-5 cells against this effect by AM. The protective effect of IGF-1 was reversed by PI3K inhibitors LY294002 and wortmannin as well as the Akt inhibitor VIII. AM decreased p-Akt and p-FoxO3a while increased the nuclear localization of FoxO3a in the RGC-5 cells. IGF-1 reversed the effect of AM on the p-Akt and p-FoxO3a and the nuclear translocation of FoxO3a. Similar results were obtained in primary cultured retinal ganglia cells. Furthermore, FERG in vivo recording in rats showed that AM decreased a-wave and b-wave of FERG while IGF-1 reversed the effects of AM. These data show that AM induced apoptosis of retinal neuronal cells via inhibiting the PI3K/Akt/FoxO3a pathway while IGF-1 protected RGC-5 cells against AM-induced cell apoptosis by stimulating this pathway.

Amiodarone is one of the most effective anti-arrhythmic drugs available, but its clinical applications are limited by toxic side effects including optic toxicity. The purpose of this study was to investigate the toxic effect of amiodarone on D407 cells (a human retinal pigmented epithelial (RPE) cell line) and the mechanisms of the protective effect of insulin-like growth factor-1 (IGF-1). EXPERIMENTAL APPROACHThe involvement of the kinases, Akt and ERK, was analysed by Western blot. Intracellular accumulation of ROS was measured using fluorophotometric quantification. A pharmacological approach with inhibitors was used to investigate the pathways involved in the protective action of IGF-1. KEY RESULTSAmiodarone concentration-dependently augmented the production of ROS, lipid peroxidation and apoptosis in D407 cells. IGF-1 time-and concentration-dependently reversed these effects of amiodarone and protected D407 cells from amiodarone-mediated toxicity. Amiodarone inhibited the pAkt but not pErk, and IGF-1 reversed this inhibitory effect of amiodarone. However, IGF-1 failed to suppress amiodarone-induced cytotoxicity in the presence of PI3K/Akt inhibitor LY294002 suggesting the direct involvement of the PI3K/Akt pathway. Furthermore, in vivo rat flash electroretinogram (FERG) recordings showed that IGF-1 reverses the amiodarone-induced decrease in a-and b-waves. The immunocytochemistry findings confirmed that vitreous IGF-1 injections promote the survival of RPE cells in rat retina treated with amiodarone. CONCLUSION AND IMPLICATIONSIGF-1 can protect RPE cells from amiodarone-mediated injury via the PI3K/Akt pathway in vivo and in vitro. IGF-1 has potential as a protective drug for the prevention and treatment of amiodarone-induced optic toxicity.Abbreviations FERG, flash electroretinogram; IGF-1, insulin-like growth factor-1; INL, inner nuclear layer; IPL, inner plexiform layer; RGCs, retinal ganglionic cells; RPE, retinal pigmented epithelium

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Objective: We aimed to determine the clinical prognostic factors of chronic rhinosinusitis after endoscopic sinus surgery (ESS) in order to better guide the management of patients. Methods: A total of 254 patients with chronic rhinosinusitis after ESS with a follow-up of 24 months were evaluated retrospectively. Clinical grouping, hyperplasia of the ethmoid bone, anatomic variations, allergy, polyps, previous sinonasal surgery and recurrent polyps were analyzed. Results: The success rates were 64.4 and 91.9% with and without hyperplasia of the ethmoid bone, 87.6 and 86.4% with and without anatomic variations, 67.9 and 92.0% with and without allergy, 81.0 and 94.0% with and without polyps, 72.8 and 93.6% with and without history of surgery and 52.3 and 94.3% with and without recurrent polyps. In logistic multiple regression analysis, allergy (p = 0.0002; estimate, –4.2094), nasal polyps (p = 0.0007; estimate, –3.6393) and history of surgery (p < 0.0001; estimate, –5.0938) were found to reach a statistically significant level. Conclusions: We propose that allergy, polyps and history of surgery might be significant indicators of poor prognosis after ESS.

We explored has_circ_0071106 as a diagnostic marker for type 2 diabetes (T2DM) in south China, and predicted the functional mechanism of the target circRNA. A total of 107 T2DM patients and 107 healthy reference persons were included as the research objects. In the first stage, the circRNA microarray was used to detect the peripheral blood of 4 T2DM and 4 control groups to screen the differential expression profile of circRNA. In the second stage, four circRNAs were screened from the differential expression profiles of circRNA, and real-time polymerase chain reaction (Q-PCR) technology was used to verify the blood samples of 103 T2DM and 103 controls. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis in bioinformatics were used to predict the functional mechanism of target circRNA. Lastly,we found that has_circ_0071106 increase the risk of T2DM (OR=2.819 (95% CI: 1.415~5.616)). Thearea under the ROCcurve has_circ_0071106 was 0.690, the sensitivity was 62.1%, and the specificity was 69.9%. The function prediction results showed that has_circ_0071106 was involved in biological processes such as protein binding, gene transcription, and may be involved in the pathway of hsa-miR-29a-5p regulating diabetes, has_circ_0071106 may be used as a diagnostic marker for T2DM.