The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport.

The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co-bound in the inward-open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP-bound NBD2-induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with anticancer therapy.

PG545 alleviates diabetic retinopathy by promoting retinal Müller cell autophagy to inhibit the inflammatory response.

Diabetic retinopathy (DR), a major cause of blindness in working-age people, is attributed to the inflammatory response of retinal Müller cells (RMCs). The heparanase inhibitor PG545 plays proautophagic and anti-inflammatory roles. Intraperitoneal injection of PG545 at a dose of 20 mg/kg/d clearly reduced diabetes-induced body weight changes and fasting blood glucose levels in mice. PG545 also mitigated the reduction in retinal thickness and the formation of microaneurysms by promoting autophagy to inhibit the inflammatory response. In vitro, PG545 stimulated autophagy to downregulate the inflammatory response in high glucose-induced primary adult mouse RMCs. These data suggest that PG545 mitigates DR by promoting RMC autophagy to inhibit the inflammatory response.

Telemedicine for detecting diabetic retinopathy: a systematic review and meta-analysis.

OBJECTIVE: To determine the diagnostic accuracy of telemedicine in various clinical levels of diabetic retinopathy (DR) and diabetic macular oedema (DME). METHODS: PubMed, EMBASE and Cochrane databases were searched for telemedicine and DR. The methodological quality of included studies was evaluated using the Quality Assessment for Diagnostic Accuracy Studies (QUADAS-2). Measures of sensitivity, specificity and other variables were pooled using a random effects model. Summary receiver operating characteristic curves were used to estimate overall test performance. Meta-regression and subgroup analyses were used to identify sources of heterogeneity. Publication bias was evaluated using Stata V.12.0. RESULTS: Twenty articles involving 1960 participants were included. Pooled sensitivity of telemedicine exceeded 80% in detecting the absence of DR, low- or high-risk proliferative diabetic retinopathy (PDR), it exceeded 70% in detecting mild or moderate non-proliferative diabetic retinopathy (NPDR), DME and clinically significant macular oedema (CSME) and was 53% (95% CI 45% to 62%) in detecting severe NPDR. Pooled specificity of telemedicine exceeded 90%, except in the detection of mild NPDR which reached 89% (95% CI 88% to 91%). Diagnostic accuracy was higher with digital images obtained through mydriasis than through non-mydriasis, and was highest when a wide angle (100-200°) was used compared with a narrower angle (45-60°, 30° or 35°) in detecting the absence of DR and the presence of mild NPDR. No potential publication bias was detected. CONCLUSIONS: The diagnostic accuracy of telemedicine using digital imaging in DR is overall high. It can be used widely for DR screening. Telemedicine based on the digital imaging technique that combines mydriasis with a wide angle field (100-200°) is the best choice in detecting the absence of DR and the presence of mild NPDR.