Ye Ming,1– 3,* Xinyi He,1– 3,* Zhenxing Zhao,1– 3,* Xuehuan Meng,1– 3 Ye Zhu,1– 3 Hao Tan,1– 3 Guoyin Yang,1– 3 Yun Hu,1– 3 Leilei Zheng1– 3 

1College of Stomatology, Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yun Hu; Leilei Zheng, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, People’s Republic of China, Tel/Fax +86 23 88860151 ; +86 23 88860161, Email 500188@hospital.cqmu.edu.cn; zhengleileicqmu@hospital.cqmu.edu.cn

Purpose: Oxidative stress and mitochondrial dysfunction are potential contributors to the compromised tissue regeneration capacity of alveolar bone in diabetic patients. Berberine, an active plant alkaloid, exhibits multiple pharmacological effects including antioxidation, blood glucose- and blood lipid-lowering properties. However, it remains uncertain whether berberine can improve impaired osteogenesis in type 2 diabetes mellitus (T2DM), and its poor solubility and oral bioavailability also constrain its applications in bone regeneration. Thus, our study aimed to probe the effects of berberine on bone marrow stem cells (BMSCs) in a diabetic microenvironment, with a greater emphasis on developing a suitable nano-delivery system for berberine and assessing its capability to repair diabetic alveolar bone defects.
Methods: Firstly, BMSCs were exposed to berberine within a high glucose and palmitate (HG+PA) environment. Reactive oxygen species levels, mitochondrial membrane potential, ATP generation, cell apoptosis, and osteogenic potential were subsequently assessed. Next, we explored the regulatory mechanism of autophagy flux in the positive effects of berberine. Furthermore, a nanocarrier based on emulsion electrospinning for sustained local delivery of berberine (Ber@SF/PCL) was established. We assessed its capacity to enhance bone healing in the alveolar bone defect of T2DM rats through micro-computed tomography and histology analysis.
Results: Berberine treatment could inhibit reactive oxygen species overproduction, mitochondrial dysfunction, apoptosis, and improve osteogenesis differentiation by restoring autophagy flux under HG+PA conditions. Notably, Ber@SF/PCL electrospun nanofibrous membrane with excellent physicochemical properties and good biological safety had the potential to promote alveolar bone remodeling in T2DM rats.
Conclusion: Our study shed new lights into the protective role of berberine on BMSCs under T2DM microenvironment. Furthermore, berberine-loaded composite electrospun membrane may serve as a promising approach for regenerating alveolar bone in diabetic patients.

Keywords: berberine, electrospun nanofibrous membrane, diabetes mellitus, alveolar bone remodeling, autophagy flux