Dapagliflozin ameliorated retinal vascular permeability in diabetic retinopathy rats by suppressing inflammatory factors.

BACKGROUND: Diabetic retinopathy is a common microvascular complication of diabetes and one of the major causes of blindness in the working-age population. Emerging evidence has elucidated that inflammation drives the key mechanism of diabetes-mediated retinal disturbance. As a new therapeutic drug targeting diabetes, whether dapagliflozin could improve vascular permeability from the perspective of anti-inflammatory effect need to be further explored. METHODS: Type 2 diabetic retinopathy rat model was established and confirmed by fundus fluorescein angiography (FFA). ELISA detected level of plasma inflammatory factors and C-peptide. HE staining, immunohistochemistry and western blot detected histopathology changes of retina, expression of retinal inflammatory factors and tight junction proteins. RESULTS: Dapagliflozin exhibited hypoglycemic effect comparable to insulin, but did not affect body weight. By inhibiting expression of inflammatory factors (NLRP3, Caspase-1, IL-18, NF-κB) in diabetic retina and plasma, dapagliflozin reduced damage of retinal tight junction proteins and improved retinal vascular permeability. The anti-inflammatory effect of dapagliflozin was superior to insulin. CONCLUSIONS: Dapagliflozin improved retinal vascular permeability by reducing diabetic retinal and plasma inflammatory factors. The anti-inflammatory mechanism of dapagliflozin is independent of hypoglycemic effect and superior to insulin.

Effects of mulberry twig alkaloids(Sangzhi alkaloids) and metformin on blood glucose fluctuations in combination with premixed insulin-treated patients with type 2 diabetes.

Introduction: We aimed to evaluated the effect of premixed insulin (Ins), premixed insulin combined with metformin (Ins+Met) or mulberry twig alkaloids(Ins+SZ-A) on blood glucose fluctuations in patients with type 2 diabetes (T2DM) using continuous glucose monitors (CGM). Methods: Thirty patients with T2DM and poor blood glucose control using drugs were evaluated for eligibility during the screening period. Subsequently, their original hypoglycemic drugs were discontinued during the lead-in period, and after receiving Ins intensive treatment for 2 weeks, they were randomly assigned to receive either Ins, Ins+Met, or Ins+SZ-A treatment for the following 12 weeks. The main efficacy endpoint comprised changes in their CGM indicators changes (mean blood glucose level [MBG], standard deviation of blood glucose [SDBG], mean amplitude of glycemic excursions [MAGE], postprandial glucose excursions [PPGE], the largest amplitude of glycemic excursions [LAGE], mean of daily difference [MODD], time in range between 3.9-10.0 mmol/L [TIR] and area under the curve for each meal [AUCpp]) during the screening, lead-in, and after 12-week treatment period. Changes in glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 1-h postprandial blood glucose (1h-PBG), 2-h postprandial blood glucose (2h-PBG), fasting blood lipids and postprandial blood lipids were also measured at baseline and after 12 weeks of treatment. Results: The CGM indicators of the three groups during the lead-in period all showed significant improvements compared to the screening period (P<0.05). Compared with those in the lead-in period, all of the CGM indicators improved in the the Ins+Met and Ins+SZ-A groups after 12 weeks of treatment (P<0.05), except for MODD. After 12-week treatment, compared with the Ins group, Ins+Met and Ins+SZ-A groups showed improved MBG, SDBG, TIR, breakfast AUCpp,lunch AUCpp, HbA1c, FBG, 1h-PBG, fasting blood lipid and postprandial blood lipid indicators (P<0.05). Further, the LAGE, PPGE, MAGE, dinner AUCpp and 2h-PBG levels of the Ins+SZ-A group were significantly lower than those of the Ins+Met and Ins groups (P<0.05). Conclusion: Our findings highlight the efficacy of combination therapy (Ins+SZ-A or Ins+Met) in improving blood glucose fluctuations, as well as blood glucose and lipid levels. Ins+SZ-A reduces postprandial blood glucose fluctuations more than Ins+Met and Ins groups. Trial registration number: ISRCTN20835488.

Liraglutide intervention improves high-glucose-induced reactive gliosis of Müller cells and ECM dysregulation.

Reactive gliosis of Müller cells plays an important role in the pathogenesis of diabetic retinopathy (DR). Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve DR by inhibiting reactive gliosis. However, the mechanism of inhibition has yet to be elucidated. This study investigated the effects of liraglutide on Müller glia reactivity in the early stages of DR and the underlying mechanisms. Proteomics combined with bioinformatics analysis, HE staining, and immunofluorescence staining revealed ganglion cell loss, reactive gliosis of Müller cells, and extracellular matrix (ECM) imbalance in rats with early stages of DR. High glucose (HG) exposure up-regulated GFAP and TNF-α expression and down-regulated ITGB1 expression and FN1 content in extracellular fluid in rMC1 cells, thereby promoting reactive gliosis. GLP-1R knockdown and HG+DAPT inhibition experiments show that liraglutide balances ECM levels by inhibiting activation of the Notch1/Hes1 pathway and ameliorates high-glucose-induced Müller glia reactivity. Thus, the study provides new targets and ideas for improvement of DR in early stages.

ENCD: a manually curated database of experimentally supported endocrine system disease and lncRNA associations.

ENCD (http://www.bio-server.cn/ENCD/) is a manually curated database that provides comprehensive experimentally supported associations among endocrine system diseases (ESDs) and long non-coding ribonucleic acid (lncRNAs). The incidence of ESDs has increased in recent years, often accompanying other chronic diseases, and can lead to disability. A growing body of research suggests that lncRNA plays an important role in the progression and metastasis of ESDs. However, there are no resources focused on collecting and integrating the latest and experimentally supported lncRNA-ESD associations. Hence, we developed an ENCD database that consists of 1379 associations between 35 ESDs and 501 lncRNAs in 12 human tissues curated from literature. By using ENCD, users can explore the genetic data for diseases corresponding to the body parts of interest as well as study the lncRNA regulating mechanism for ESDs. ENCD also provides a flexible tool to visualize a disease- or gene-centric regulatory network. In addition, ENCD offers a submission page for researchers to submit their newly discovered endocrine disorders-genetic data entries online. Collectively, ENCD will provide comprehensive insights for investigating the ESDs associated with lncRNAs. Database URL http://www.bio-server.cn/ENCD.

Influence of different fibers on compressive toughness and damage of early age cemented tailings backfill.

For improving the utilization rate of tailings and the safety of cemented tailings backfill (CTB) as earthwork materials, the influence of three types of fibers (e.g., glass, polyacrylonitrile and mixture fibers of both) on compressive toughness and damage of early age CTB was studied. An equation for quantitative analysis of compressive toughness of fiber-reinforced CTB was established. An uniaxial compression test was carried out to monitor the damage acoustic emission (AE) activities of CTB during the loading process. Then, the microstructure of CTB after uniaxial compression test was observed by scanning electron microscope (SEM). The results indicated that mixed fiber has the most comprehensive reinforcement effect on compressive toughness and peak load of CTB. Three fibers inhibited the crack development rate of CTB, glass fiber mainly absorbed axial strain energy of CTB before peak load, while polyacrylonitrile fiber mainly absorbed fracture energy generated during the crack development of CTB after peak load, mixed fiber combined their advantages. The AE activities of three fiber-reinforced CTB samples are much stronger than those of non-reinforced CTB samples in the loading process, and these are no "quiet period" of AE activities. Three fibers all improved the durability of CTB in the damage process, and the damage process of mixed fiber-reinforced CTB is the most stable and showed an approximate linear growth trend. Polyacrylonitrile fiber has a strong resistance to crack after the peak load of CTB because of its ellipsoid part on the surface. As a result, this study can provide a theoretical reference for construction units to use fiber-reinforced CTB for engineering applications and filling work.

Bicyclol Regulates Hepatic Gluconeogenesis in Rats with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease by Inhibiting Inflammation.

Hepatic gluconeogenesis plays an important role in maintaining the body's glucose metabolism homeostasis. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases, when combined with type 2 diabetes mellitus (T2DM), it can cause severe glucose metabolism disorders. Studies have confirmed that chronic liver inflammatory lesions are the basis of T2DM combined with NAFLD (T2DM-NAFLD), inhibiting liver inflammation can improve glucose metabolism disorders. It is essential to explore safe and effective drugs to inhibit liver inflammation to improve the body's glucose metabolism disorders. Bicyclol is a biphenyl derivative that has anti-oxidative and anti-inflammatory properties. In the present study, the hepatoprotective effects and underlying mechanisms of bicyclol in T2DM-NAFLD were investigated, and T2DM-NAFLD with/without bicyclol treatment models were established. The results revealed that bicyclol alleviated fasting blood glucose, serum transaminase levels, insulin resistance, hepatic adipogenesis, lipid accumulation and markedly reduced T2DM-NAFLD rat histological alterations of livers. Not only that, bicyclol markedly attenuated T2DM-NAFLD induced production of inflammation factors (IL-1ß and TNF-α). Moreover, bicyclol suppressed the expression of insulin/gluconeogenesis signaling pathway (Akt, PGC-1α and PEPCK). These findings suggested that bicyclol might be a potentially effective drug for the treatment of T2DM-NAFLD and other metabolic disorders.