Platycodin D inhibits diabetic retinopathy via suppressing TLR4/MyD88/NF-κB signaling pathway and activating Nrf2/HO-1 signaling pathway.

Diabetic retinopathy (DR) is one of the most frequently occurring diabetic complications associated with inflammation and oxidative stress. Platycodin D (PLD) is a bio-active saponin that has been reported to exhibit anti-inflammation, anti-oxidative, and antidiabetic activities. Therefore, we speculated the protective effects of PLD on DR in the present study. Our results demonstrated that PLD attenuated high glucose (HG)-induced inflammation, as evidenced by decreased production of TNF-α, IL-1ß, IL-6. The HG-induced oxidative stress was prevented by PLD with decreased ROS production and malondialdehyde (MDA) level, as well as increased activities of superoxide dismutase and glutathione (GSH). In addition, treatment of PLD significantly decreased the apoptotic rate in HG-induced ARPE-19 cells. The HG-caused increases in expression of bax and cleaved capsase-3, as well a decrease in bcl-2 expression were attenuated by PLD. Furthermore, PLD suppressed the activation of TLR4/MyD88/NF-κB and enhanced the activation of Nrf2/HO-1 pathway in HG-induced ARPE-19 cells. Additionally, overexpression of TLR4 attenuated the anti-inflammatory, while knockdown of Nrf2 reversed the anti-oxidative and anti-apoptotic activities of PLD in HG-stimulated ARPE-19 cells. Furthermore, PLD attenuates retinal damage in DR rats. Finally, we demonstrated that PLD weakened the TLR4/MyD88/NF-κB p65 pathway and promoted the Nrf2/HO-1 pathway in vivo. Taken together, these findings indicated that PLD exerted protective effects against DR, which were attributed to the regulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways.

Sustained Delivery of Timolol Using Nanostructured Lipid Carriers-Laden Soft Contact Lenses.

The contact lens prepared by the conventional soaking method using timolol-soaking solution showed poor drug uptake and high burst release with altered critical lens properties. In this study, timolol-loaded nanostructured lipid carriers (NLCs) were prepared and evaluated for enhanced timolol uptake and sustained release for the effective management of glaucoma. The characterization studies indicated that timolol-loaded NLCs were spherical in shape with an average size of 130-138 nm and a zeta potential of -46.6 to 51.3 mV. Critical lens properties such as swelling, optical transmittance, and protein adherence were improved with NLC-laden lenses compared to the conventional soaked lenses (SM-TB). Moreover, SM-TB lens showed low timolol uptake, high burst release, and short release duration up to 24 h compared to timolol-NLC-laden lens that showed high timolol uptake, and the cumulative release was sustained up to 96 h. The ability to sustain timolol release improved proportionally with an increase in the amount of Capmul MCMC8 (liquid lipid) in NLCs. In addition, NLC-laden lens was found to be safe according to the results of ocular irritation and histopathological studies. In the rabbit tear fluid model, NLC-30%-Cap-CL batch showed high timolol concentration at all time points up to 60 h. Further, pharmacodynamic study showed sustained reduction in IOP by NLC-30%-Cap-CL batch for 96 h compared to 48 h and 6 h with SM-TB lens and eye drop solution, respectively. In conclusion, NLCs enhanced timolol uptake in the contact lens from the soaking solution using soaking method with improved in vitro and in vivo results for better clinical outcomes in the patients with glaucoma.

Clinical characteristics, rates of blindness, and geographic features of PACD in China.

OBJECTIVE: To analyze the rates of blindness with the demographics and clinical characteristics of patients with primary angle-closure disease (PACD) to provide a comprehensive epidemiologic reference in China. METHODS: A retrospective analysis was conducted in the Chinese Glaucoma Study Consortium database, which is a national multicenter glaucoma research alliance of 111 hospitals participating between December 21, 2015 and September 9, 2018. The diagnosis of PACD was made by qualified physicians through examination. Comparison of sex, age, family history, subtypes of PACD, and blindness were analyzed. RESULTS: A total of 5762 glaucoma patients were included, of which 4588 (79.6%) had PACD. Of PACD patients, 72.1% were female with the sex ratio (F/M) of 2.6, and the average age of patients was 63.8±9.3 years with the majority between 60 and 70 years. Additionally, 30% of these patients had low vision in one eye, 8.8% had low vision in both eyes, 1.7% had blindness in one eye, and 0.3% had blindness in both eyes. There were statistical differences with regards to age between male and female patients with PACD, with male patients being older on average. Primary angle-closure glaucoma was more commonly diagnosed in males (60%) compared to females (35.9%), whereas acute primary angle closure (APAC) was more commonly diagnosed in females (54.3%) compared to males (37.7%). The visual acuity in APAC patients was lower and the rate of low vision and blindness was higher than other subtypes. CONCLUSION: PACD was the major type of glaucoma in Chinese hospitals. There were more female patients with PACD, mostly between 60 and 70 years old, with higher rates of APAC in women. APAC resulted in the worst visual outcomes of all PACD subtypes.

Association between islet autoantibodies and the prevalence of autoimmune uveitis.

AIM: To evaluate the predictive value of islet autoantibodies for the diagnosis of autoimmune uveitis (AU), as well as to characterize the association bet ween islet autoantibodies and AU. METHODS: Totally 97 patients with AU and 100 healthy persons without any autoimmune diseases as the control group were recruited. Multiple serum islet autoantibodies were measured using commercial enzyme-linked immunosorbent assay kits (ELISA). A supplementary questionnaire was used to complement the subject's demographics and clinical features. The level of glucose concentrations and white blood cells were measured. Conditional logistic regression was performed to estimate odds ratios (ORs), and 95% confidence intervals (CIs) of AU according to islet autoantibodies and to evaluate the predictive value of islet autoantibodies for AU diagnosis. Autoantibodies subgroups and other variables were included into analysis. RESULTS: In AU patients, the prevalence of detecting at least one of the autoantibodies was 31.9% (31/97). The most frequent autoantibody was ZnT8A (30.9%), followed by GADA (11.3%), IA-2A (4.1%), ICA (2.1%) and IAA (2.1%). Islet autoantibodies were found to be correlated positively with AU diagnosis [OR (95%CI): 13.86 (3.28, 58.50), P<0.001]. Moreover, Zn-T8A was remarkably correlated with AU diagnosis [OR (95%CI): 6.13 (1.96, 19.17), P<0.001], In contrast, neither GADA nor other islet antibodies (IA-2A, ICA and IAA) showed any association with AU risk under an additive model. CONCLUSION: The prevalence of islet antibodies, especially ZnT8A, in patients with AU is higher. Islet antibodies as well as novel biomarkers should be included in routine evaluation at AU and is a valuable biological marker to classify newly-diagnosed uveitis.

Upregulation of heme oxygenase-1 by Brahma-related gene 1 through Nrf2 signaling confers protective effect against high glucose-induced oxidative damage of retinal ganglion cells.

High glucose (HG)-induced oxidative damage of retinal ganglion cells (RGCs) contributes to the pathogenesis of diabetic retinopathy, a severe complication of diabetes mellitus. Brahma-related gene 1 (Brg1) has currently emerged as a cytoprotective protein that alleviates oxidative damage induced by various stress. However, whether Brg1 is involved in the regulation of HG-induced oxidative damage of RGCs remains unknown. In this study, we aimed to investigate the potential role and underlying mechanism of Brg1 in regulating HG-induced damage of RGCs. We found that Brg1 expression was significantly downregulated in RGCs in response to HG treatment. Functional experiments showed that Brg1 knockdown enhanced HG-induced apoptosis and production of reactive oxygen species, while Brg1 overexpression suppressed HG-induced apoptosis and reactive oxygen species production, showing a protective effect. Moreover, Brg1 overexpression resulted in an increase in nuclear expression of nuclear factor-erythroid-2-related factor-2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in RGCs. Notably, inhibition of Nrf2 or HO-1 significantly blocked Brg1-mediated protection against HG-induced damage. Overall, these findings demonstrate that Brg1 protects RGCs from HG-induced oxidative damage through promotion of Nrf2/HO-1 signaling, indicating a potential role of Brg1 in the pathogenesis of diabetic retinopathy.

SIRT6 protects retinal ganglion cells against hydrogen peroxide-induced apoptosis and oxidative stress by promoting Nrf2/ARE signaling via inhibition of Bach1.

Oxidative stress-induced damage of retinal ganglion cells (RGCs) is a major contributor to retinal degenerative diseases, such as glaucoma. Sirtuin 6 (SIRT6) has emerged as a cytoprotective protein against various insults. However, whether SIRT6 exerts a protective effect against oxidative stress-damaged RGCs remains unknown. In this study, we aimed to investigate the potential role and regulatory mechanism of SIRT6 in hydrogen peroxide (H2O2)-induced oxidative damage of RGCs in vitro. We found that SIRT6 expression was significantly downregulated in RGCs with H2O2 treatment. Functional experiments showed that overexpression of SIRT6 improved survival and reduced apoptosis and the production of reactive oxygen species (ROS) in H2O2-treated RGCs. In contrast, SIRT6 knockdown had the opposite effect. Moreover, we found that SIRT6 overexpression promoted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the activity of antioxidant response element (ARE). In addition, we found that the promotional effect of SIRT6 on Nrf2/ARE signaling was associated with inhibition of BTB and CNC homology 1 (Bach1), an inhibitor of Nrf2. However, overexpression of Bach1 or inhibition of Nrf2/ARE signaling partially reversed the SIRT6-mediated protective effect. Taken together, these results demonstrate that SIRT6 protects RGCs from oxidative stress-induced damage by promoting the activation of Nrf2/ARE signaling via inhibition of Bach1, suggesting a potential role of SIRT6 in retinal degenerative diseases.

Eriodictyol inhibits high glucose-induced oxidative stress and inflammation in retinal ganglial cells.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus and is considered as a leading cause of blindness. Oxidative stress and inflammation are significant drivers for the development of DR. Eriodictyol, a flavonoid compound, was proved to possess anti-inflammatory, antioxidative, and antidiabetic activities. However, the role of eriodictyol in DR has not been unveiled. In the current study, we explored the protective effects of eriodictyol on high glucose (HG)-induced rat retinal ganglial cells (RGCs). The results suggested that eriodictyol improved cell viability of HG-induced rat RGC-5 cells in a dose-dependent manner. Eriodictyol reduced the reactive oxygen species production and increased the activities of superoxide dismutase, glutathione peroxidase and catalase in rat RGC-5 cells in response to HG stimulation. The production of proinflammatory cytokines including tumor necrosis factor alpha and interleukin-8 was diminished after eriodictyol treatment. Eriodictyol also suppressed cell apoptosis induced HG in rat RGC-5 cells. Furthermore, eriodictyol enhanced the nuclear translocation of nuclear factor erythroid-2 (E2)-related factor 2 (Nrf2) and elevated the expression of antioxidant enzyme heme-oxygenase-1 (HO-1). These findings suggested that eriodictyol protects the RGC-5 cells from HG-induced oxidative stress, inflammation, and cell apoptosis through regulating the activation of Nrf2/HO-1 pathway.