Meng Jiang,Shanya Huang,Wang Duan,Qiaoshu Liu,Minxiang Lei
Diabetic vascular complications are the leading causes of death and disability in patients with diabetes. Alpha-mangostin has been reported to have anti-diabetic capacity in recent years. Here, we investigated the protective function of alpha-mangostin on endothelium in vitro and in vivo experiments. We also observed that alpha-mangostin improved impaired endothelium-dependent vasodilation (EDV) of diabetic animals while it limited the aSMase/ceramide pathway and up-regulated eNOS/NO pathway in aortas from diabetic mice. Meanwhile, alpha-mangostin inhibited elevated aSMase/ceramide pathway and reversed impaired EDV induced by high glucose in isolated mouse aortas. In addition, alpha-mangostin increased phosphorylation of eNOS and NO production in high glucose-treated aortas. Alpha-mangostin normalized high glucose-induced activation of aSMase/ceramide pathway and improved eNOS/NO pathway in endothelial cells with high glucose. In conclusion, alpha-mangostin regulates eNOS/NO pathway and improves EDV in aortas of diabetic mice through inhibiting aSMase activity and endogenous ceramide accumulation.
Alzheimer’s disease (AD), characterized by β -amyloid (A β ) aggregation and neuroinflammation, remains a formidable clinical challenge. Herein, we present an innovative nose-to-brain delivery platform utilizing lactoferrin (Lf)-functionalized lipid nanoparticles (LNPs) co-encapsulating α -mangostin ( α -M) and β -site APP cleaving enzyme 1 (BACE1) siRNA (siB). This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of α -M with the transcriptional silencing of BACE1 via siB, thereby simultaneously inhibiting A β production and enhancing its clearance. Fabricated via a microfluidic approach, the LNPs exhibited uniform particle size distribution, great encapsulation efficiency, and robust colloidal stability. Upon intranasal administration, Lf-functionalization enabled superior brain-targeting efficacy through receptor-mediated transcytosis. In vitro studies demonstrated that α -M reversed A β -induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of A β , while siB effectively suppressed BACE1 expression, abrogating A β synthesis. In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial A β plaque reduction, and alleviation of neuroinflammation and oxidative stress. This intricately designed LNP system, exploiting a non-invasive and efficient nose-to-brain delivery route, provides a biocompatible, synergistic, and transformative therapeutic strategy for the multifaceted management of AD.
Yi Wang,Ruge Lin,Laiming Zhang,Suqing Lan,Xingqian Ye,Haibo Pan,Shiguo Chen
Phenolic compounds are popular in screening novel hypoglycemic agents, but the impact of oxidative degradation on the determination of α-glucosidase inhibitory activity and bioavailability is unclear. Here we showed 12 phenolic compounds structure-dependently degraded during standard simulated digestion, while in physiological hypoxia their retention rates were all over 87.89 %. This enhancement of digestive stability resulted in the biggest drop of 31.72 % in IC 50 against α-glucosidase and a significant increase in bioavailability. Enzyme kinetic and multi-spectroscopic analysis confirmed oxygen weakened the affinity of compounds to α-glucosidase, but the mechanisms were not changed. Moreover, a two-chamber culture system was designed to meet conflicting demands for oxygen between epithelium and cavity, and better α-glucosidase inhibitory activities (51.61 % maximum reduction in glucose production) and absorption rates (up to 1.10 % from undetectable) were obtained than those of uncontrolled oxygen. Hence, the oxygen level should be monitored to assess the activities of phenolic compounds in vitro .
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