TRIM40 ameliorates diabetic retinopathy through suppressing inflammation via Reelin/DAB1 signaling disruption: A mechanism by proteasomal degradation of DAB1.

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Reelin, an extracellular matrix protein, and its effector protein Disabled1 (DAB1) have been linked to cellular events and retinal development. However, whether and how Reelin/DAB1 signaling causes DR remains to be investigated. In our study, significantly increased expression of Reelin, very low density lipoprotein receptor (VLDLR), ApoE receptor 2 (ApoER2) and phosphorylated DAB1 in retinas of streptozotocin (STZ)-induced DR mouse model was observed, along with enhanced expression of proinflammatory factors. Similar results are confirmed in high glucose (HG)-treated human retinal pigment epithelium cell line ARPE-19. Surprisingly, dysregulated tripartite motif-containing 40 (TRIM40), an E3 ubiquitin ligase, is found to be involved in DR progression by bioinformatic analysis. We observe a negative correlation between TRIM40 and p-DAB1 protein expression levels under HG conditions. Importantly, we find that TRIM40 over-expression markedly ameliorates HG-induced p-DAB1, PI3K, p-protein B kinase (AKT) and inflammatory response in HG-treated cells, but dose not affect Reelin expression. Of note, Co-IP and double immunofluorescence identify an interaction between TRIM40 and DAB1. Furthermore, we show that TRIM40 enhances K48-linked polyubiquitination of DAB1, thereby promoting DAB1 degradation. Finally, promoting TRIM40 expression by intravenous injection of the constructed adeno-associated virus (AAV-TRIM40) markedly ameliorates DR phenotypes in STZ-treated mice, as indicated by the decreased blood glucose and glycosylated hemoglobin (HbAlc) levels, and increased hemoglobin contents. Additionally, diabetes-related elevation of acellular capillaries was also meliorated in mice over-expressing TRIM40. The electroretinogram (ERG) deficits were strongly rescued in mice receiving AAV-TRIM40 injection. Moreover, AAV-TRIM40 attenuates the inflammation and p-DAB1 expression in retinal tissues of STZ-treated mice. Collectively, our findings disclose a mechanism through which TRIM40 limits DAB1 stability under physiological conditions and reveals TRIM40 as a potential therapeutic target for the intervention of Reelin/DAB1 signaling, contributing to DR treatment.

Berberine inhibits human retinal vascular endothelial cell apoptosis induced by high glucose / 中华眼底病杂志

Objective:To observe the inhibitory effect of berberine (BBR) on the apoptosis of human retinal vascular endothelial cells (hREC) under high glucose environment.Methods:hREC was divided into blank control group (NC group), high glucose group (HG group), BBR treatment group (BN group), and BBR+high glucose treatment group (BH group). The cells of each group were cultured in Dulbecco's modified eagle medium; 5.5 and 30.0 mmol/L glucose were added to the medium of the NC group and HG group, respectively; 5.0 mmol/L glucose and 5.0 mmol/L BBR was added to the BN group; 30.0 mmol/L glucose and 5.0 mmol/L BBR was added to the medium of the BH group. Flow cytometry was used to observe the apoptosis rate of each group. Western blotting was used to detect the relative expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), and Cytochrome C (Cyt-C) and cysteine aspastic acid-specific protease 3 (Caspase-3) proteins in each group of cells. The difference between the two groups was tested by t test, and the difference among multiple groups was analyzed by one-way analysis of variance. Results:The results of flow cytometry showed that compared with the NC group, the apoptosis rate of the HG group significantly increased, and the difference was statistically significant ( P<0.01); compared with the HG group, the apoptosis rate of the BH group significantly reduced, the difference was statistical significance ( P<0.05). Western blot test results showed that, compared with the NC group, the relative expression of Bax and Caspase-3 protein in the HG group increased, and the relative expression of Bcl-2 protein decreased. The difference was statistically significant ( P<0.01). Compared with the HG group, the relative expression of Bax, Cyt-C, and Caspase-3 protein in BH group cells decreased, and the relative expression of Bcl-2 protein increased, and the difference was statistically significant ( P<0.01). Conclusion:BBR can inhibit hREC apoptosis by affecting the expression of apoptotic protein under high glucose environment.

Preoperative and intraoperative adjunctive intravitreal conbercept in 23G vitrectomy for proliferative diabetic retinopathy / 眼科新进展

Objective To discuss the effects and influence of preoperative and postoperative adjunctive intravitreal conbercept in 23G vitrectomy for proliferative diabetic retinopathy (PDR).Methods A retrospective research was performed on 42 PDR eyes from January 2015 to February 2016 in the Second Affiliated Hospital of Nanchang University,who received either intravitreal 0.05 mL conbercept injection 7 days before 23G vitrectomy (group A,n =22) or intravitreal 0.05 mL conbercept injection at the end of 23 G vitrectomy (group B,n =20).The operative time,postoperative vitreous hemorrhage (VH),intraoperative and postoperative other differences of clinical indicators and postoperative best-corrected visual acuity (BCVA) between the two groups were compared.Results The average operation time,intraoperative electric coagulation hemostasis rate,iatrogenic hiatal incidence and intraoperative hemorrhage rate of group A were lower than those of group B (all P ＜ 0.05).BCVA at 6 months after surgery did not differ significantly between two groups (P ＞ 0.05),but the difference was statistically significant between pre-operation and post-operation (P ＜ 0.05).The incidences of early (≤ 1 month) postoperative VH were 18.2％ (4 eyes) and 15.0％ (3 eyes) in group A and B,respectively (P ＞ 0.05).The incidences of later (＞ 1 month) postoperative VH were 27.3％ (6 eyes) and 0 in group A and B,respectively,the difference was statistically significant (P ＜0.05).The percentages of reoperation were 13.6％ (3eyes with postoperative VH) and 10.0％ (2 eyes with traction retinal detachment) respectively in group A and B.The average times of supplementary laser photocoagulation were (2.3 ± 1.0) times and (1.4 ±0.6) times in group A and B,respectively in follow-up period (P ＜ 0.05).Conclusion The adjunctive use of intraoperative intravitreal injection of conbercept can prevent effectively postoperative VH and decrease conveniently the time of supplementary laser photocoagulation in 23G vitrectomy for PDR,as well as the preoperative adjunctive use can decrease the operation time,intraoperative complications and incidences of early postoperative VH.

STUDY ON THE HEMODYNAMICS OF SUPERIOR MESENTERIC ARTERY IN PATIENTS WITH CIRRHOSIS / 中国现代普通外科进展

Objective: To study superior mesenteric artery hemodynamics in patients with hepatic cirrhosis and to investigate the mechanism of hepatic cirrhosis ascites. Methods: superior mesenteric artery hymodynamics were measured py duplex Doppler ultrasound in 80 patients with hepatic cirrhosis,50 control supjects. Results: Both SMA-Pl and SMA-Rl in patients with hepatic cirrhosis compensation or decompensation were decreased. SMA-Pl was lower in those with ascites without ascites. and tends to worsen in relation to severity of varicosity in esophagus. Conclusion: SMA-Pl decrease occurs in cirrhosis since the early stage of the disease. Hyperdynamics of SMA relates to ascites formation and esophageal varicecosity.