Intracellular bacteria are considered one of the mechanisms that result in the failed therapy of bacterial infection and increase of antibiotic resistance. Nanotechnology-based drug delivery carriers have been receiving increasing attention for improving the intracellular antibacterial activity of antibiotics, but are accompanied by disadvantages such as complex preparation procedures, lack of active targeting, and monotherapy, which need to be further designed. Herein, the bacteria-infected macrophage targeted nanoparticle is fabricated to eliminate intracellular bacterial infections by antibiotic release, intracellular reactive oxygen species (ROS) level and proinflammatory response up-regulation. These nanoparticles were formed through the reaction of the amino group on selenocystamine dihydrochloride and the aldehyde group on oxidized dextran (ox-Dex), that encapsulate vancomycin (Van) through hydrophobic interaction. These nanoparticles could targeted uptake by macrophages via endocytosis, and response to the bacteria infected intracellular microenvironment (ROS and glutathione (GSH)) to controlled release antibiotic. Furthermore, the nanoparticles could consume intracellular GSH and promote a significant rise in level of ROS in macrophage, subsequently up-regulating proinflammatory response to reinforce antibacterial activity. These nanoparticles could accelerate bacteria-infected wound healing. This work fabricated a nanoparticle with bacteria-infected macrophage targeted and microenvironment-responsive antibiotic delivery, cellular ROS generation, and proinflammatory up-regulation activity to eliminate intracellular bacteria, which open up a new possibility for developing multifunctional drug delivery against intracellular infection.
Gang Yu,Jianxin He,Zhongshan Gao,Linglin Fu,Qiaozhi Zhang
Advanced glycation end-products (AGEs) are complex and heterogeneous compounds widely present in processed foods. Previous studies evidenced the adverse effects of AGEs on gut homeostasis, but the precise pathological mechanisms and molecular pathways responsible for the disruption of intestinal barrier integrity by AGEs remain incompletely elucidated. In this study, protein-bound AGEs (BSA-MGO), the most common type of dietary AGEs, were prepared by methylglyoxal-mediated glycation, and an in vitro human epithelial colorectal adenocarcinoma (Caco-2) cell model was employed to evaluate the impact of protein-bound AGEs on gut epithelial function. Results showed that exposure to BSA-MGO significantly increased the permeability of Caco-2 cell monolayers as evidenced by the decreased transepithelial electrical resistance value, increased paracellular transport of FITC-dextran, and down-regulated tight-junction proteins. Parallelly, BSA-MGO induced pro-inflammatory responses and oxidative stress in the monolayers. Transcriptomic profiling further revealed that BSA-MGO disrupted the retinol metabolism, thereby contributing to the barrier integrity damage in epithelial cells. Overall, these results provide valuable insights into the disrupting effects of dietary AGEs on intestinal barrier function, and the perturbed pathways present potential targets for further exploration of the molecular mechanisms underlying the detrimental effect of processed foods on gut health.
The potential for mitigating intestinal inflammation through the gut-bone axis in the treatment of osteoporosis is significant. While various gut-derived postbiotics or bacterial metabolites have been created as dietary supplements to prevent or reverse bone loss, their efficacy and safety still need improvement. Herein, a colon-targeted drug delivery system is developed using surface engineering of polyvinyl butyrate nanoparticles by shellac resin to achieve sustained release of postbiotics butyric acid at the colorectal site. These engineered postbiotics nanoparticles can effectively suppress macrophage inflammatory activation, modulate the redox balance, and regulate the composition of the gut microbiota, thereby restoring epithelial barriers, inhibiting bacterial invasion, and down-regulating pro-inflammatory responses. As a result, the remission of systemic inflammation is accompanied by a rebalancing of osteoblast and osteoclast activity, alleviating inflammatory bowel disease-related and post-menopausal bone loss. Specifically, the treatment of engineered postbiotics nanoparticles can also improve the quality and quantity of bone with restoration of deteriorative mechanical properties, which indicating a therapeutic potential on fracture prevention. This study provides valuable insights into the gut-bone axis and establishes a promising and safe therapeutic strategy for osteoporosis.
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