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Background/Aims: Hyperglycemia is an important risk factor for the most severe cardiovascular diseases in patients with diabetes. It has been demonstrated that cardiac stem cells (CSCs) play a pivotal role in the maintenance of cardiac homeostasis and regeneration. However, the mechanism underlying the influence of diabetes on CSCs remains unclear. This study demonstrated that hyperglycemia might promote adipogenesis in CSCs, which induces a decline in myocardial regeneration capability in diabetes. Methods: CSCs were isolated and cultured in high-glucose medium. The levels of β-catenin and TCF-4 in CSCs were determined by immunofluorescence staining and western blot analysis. Adipogenic transcriptional factors and CSCs markers were also examined by flow cytometry and western blot analysis after adipogenesis induction. In addition, Oil Red O staining was performed to investigate lipid droplet formation during adipogenesis induction with or without LiCl, a potent activator of TCF/β-catenin-dependent transcription. Results: High-glucose conditions inhibited nuclear translocation of β-catenin/TCF-4 and promoted adipogenesis in CSCs. After adipogenesis induction, expression of adipogenic transcriptional factors (PPARγ, ADD1, and C/EBPα) were increased (P < 0.01) and that of CSCs markers (c-Kit, Sca-1, MDR-1, and isl-1) were decreased (P< 0.01) in CSCs in the high-glucose group. Furthermore, lipid droplet formation was increased in CSCs cultured with high glucose, while LiCl attenuated lipid droplet formation in these CSCs (P < 0.01). Conclusion: These results demonstrated that hyperglycemia inhibited the β-catenin/TCF-4 pathway and promoted CSCs adipogenesis. Our findings suggest a new opportunity for future interventional strategie for abnormal myocardial regeneration and epicardial fat in patients with diabetes. [ABSTRACT FROM AUTHOR]

In article number 1802250 Qing Lin, Ling Zhang, and co‐workers report an artificial "closed‐loop" structure for intravenous glucose‐responsive insulin delivery. An acid‐sensitive matrix forms the "inner core" and RBCm‐derived coating the "outer shell". Under hyperglycemic condition, the glucose internalized by the anchored glucose transporters is enzymatically converted into gluconic acid and subsequently triggers acid degradation of the "inner core" to secrete insulin. [ABSTRACT FROM AUTHOR]

An artificial "closed‐loop" system that mimics the glucose‐responsive insulin secretion of pancreas β‐cells can potentially improve the treatment efficacy for diabetes. Herein, a lipid bilayer‐coated polymeric nanoparticle (NP) with "core–shell" structure is designed. As far as it is known, it is the first and only intravenous nanoplatform utilizing enzymatic‐oxidation scheme to achieve glucose‐responsive insulin delivery so far. Ethoxy acetal–derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as "inner core" loaded with insulin, and coloading glucose oxidase (GOx) and catalase (CAT) endow the "inner core" excellent glucose‐sensitive ability. Red blood cell membrane (RBCm)‐derived coating is adopted as "outer shell." It collectively provides a closed microenvironment for GOx‐based enzymatic‐oxidation scheme and camouflages it from elimination. Above all, the anchored glucose transporters (GLUTs) on the "outer shell" are able to sense blood glucose levels and facilitate the transport of outer blood glucose getting inside. Under a hyperglycemic condition, the internalized glucose is catalytically converted into gluconic acid with the aid of the GOx and subsequently triggers acid degradation of the "inner core" to secrete insulin. By governing the blood glucose levels on an automatic and continuous basis, the RBCm‐Ace‐DEX NPs can effectively respond to hyperglycemia and turn to resting conditions under normoglycemia. Ethoxy acetal derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as "inner core" and red blood cell membrane (RBCm)‐derived coating is adopted as "outer shell". This glucose‐responsive nanoplatform can steadily circulate in the blood at normalglycemia. While under hyperglycemic condition, the glucose internalized by the anchored GLUTs is catalytically converted into gluconic acid with the aid of GOx and CAT and subsequently triggers acid degradation of RBCm‐Ace‐DEX NPs to secrete insulin. [ABSTRACT FROM AUTHOR]