Overexpression of HSP27 accelerates stress-induced gastric ulcer healing via the CXCL12/CXCR4 axis.

Chronic stress often triggers gastrointestinal complications, including gastric injury and ulcers. Understanding the role of heat shock protein 27 (HSP27) in stress-induced gastric ulcers could unveil novel therapeutic targets. Here, we established a stress-induced gastric ulcer rat model using water immersion restraint stress and administered adenovirus-packaged HSP27 overexpression vector. Gastric ulcer severity was scored, and mucosal changes were assessed. Gastric epithelial and endothelial cells were treated with lipopolysaccharide and transfected with HSP27 overexpression vectors to evaluate cell viability, migration and angiogenesis. Expression levels of HSP27, C-X-C motif chemokine ligand 12 (CXCL12) and C-X-C motif chemokine receptor 4 (CXCR4) were measured in tissues and cells. HSP27 expression was initially low during stress-induced gastric ulceration but increased during ulcer healing. HSP27 overexpression accelerated ulcer healing in rats, promoting gastric epithelial cell proliferation and migration and gastric endothelial cell angiogenesis through the CXCL12/CXCR4 axis. Inhibitor IT1t reversed the effects of HSP27 overexpression on cell proliferation, migration and angiogenesis. In summary, HSP27 overexpression facilitated ulcer healing, which was partially mediated by the CXCL12/CXCR4 axis.

3D Printing of Tricalcium Phosphate/Poly Lactic-co-glycolic Acid Scaffolds Loaded with Carfilzomib for Treating Critical-sized Rabbit Radial Bone Defects.

The rapid development of scaffold-based bone tissue engineering strongly relies on the fabrication of advanced scaffolds and the use of newly discovered functional drugs. As the creation of new drugs and their clinical approval often cost a long time and billions of U.S. dollars, producing scaffolds loaded with repositioned conventional drugs whose biosafety has been verified clinically to treat critical-sized bone defect has gained increasing attention. Carfilzomib (CFZ), an approved clinical proteasome inhibitor with a much fewer side effects, is used to replace bortezomib to treat multiple myeloma. It is also reported that CFZ could enhance the activity of alkaline phosphatase and increase the expression of osteogenic transcription factors. With the above consideration, in this study, a porous CFZ/ß-tricalcium phosphate/poly lactic-co-glycolic acid scaffold (designated as "cytidine triphosphate [CTP]") was produced through cryogenic three-dimensional (3D) printing. The hierarchically porous CTP scaffolds were mechanically similar to human cancellous bone and can provide a sustained CFZ release. The implantation of CTP scaffolds into critical-sized rabbit radius bone defects improved the growth of new blood vessels and significantly promoted new bone formation. To the best of our knowledge, this is the first work that shows that CFZ-loaded scaffolds could treat nonunion of bone defect by promoting osteogenesis and angiogenesis while inhibiting osteoclastogenesis, through the activation of the Wnt/ß-catenin signaling. Our results suggest that the loading of repositioned drugs with effective osteogenesis capability in advanced bone tissue engineering scaffold is a promising way to treat critical-sized defects of a long bone.