Nanocarrier-Assisted Delivery of Berberine Promotes Diabetic Alveolar Bone Regeneration by Scavenging ROS and Improving Mitochondrial Dysfunction

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2024 Oct 14

PMID 39399826

Authors

Ye Ming

Xinyi He

Zhenxing Zhao

Xuehuan Meng

Ye Zhu

Hao Tan

Guoyin Yang

Yun Hu

Leilei Zheng

Affiliations

Soon will be listed here.

Abstract

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.

References

Zhang Y, Wang T, Li J, Cui X, Jiang M, Zhang M . Bilayer Membrane Composed of Mineralized Collagen and Chitosan Cast Film Coated With Berberine-Loaded PCL/PVP Electrospun Nanofiber Promotes Bone Regeneration. Front Bioeng Biotechnol. 2021; 9:684335. PMC: 8327095. DOI: 10.3389/fbioe.2021.684335. View

Willems P, Rossignol R, Dieteren C, Murphy M, Koopman W . Redox Homeostasis and Mitochondrial Dynamics. Cell Metab. 2015; 22(2):207-18. DOI: 10.1016/j.cmet.2015.06.006. View

Wang H, Chang X, Ma Q, Sun B, Li H, Zhou J . Bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration. Bioact Mater. 2022; 21:324-339. PMC: 9483739. DOI: 10.1016/j.bioactmat.2022.08.029. View

Prentki M, Corkey B . Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM?. Diabetes. 1996; 45(3):273-83. DOI: 10.2337/diab.45.3.273. View

Liu J, Zhao X, Pei D, Sun G, Li Y, Zhu C . The promotion function of Berberine for osteogenic differentiation of human periodontal ligament stem cells via ERK-FOS pathway mediated by EGFR. Sci Rep. 2018; 8(1):2848. PMC: 5809428. DOI: 10.1038/s41598-018-21116-3. View

Puppi D, Piras A, Detta N, Dinucci D, Chiellini F . Poly(lactic-co-glycolic acid) electrospun fibrous meshes for the controlled release of retinoic acid. Acta Biomater. 2009; 6(4):1258-68. DOI: 10.1016/j.actbio.2009.08.015. View

Gao J, Feng Z, Wang X, Zeng M, Liu J, Han S . SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. Cell Death Differ. 2017; 25(2):229-240. PMC: 5762839. DOI: 10.1038/cdd.2017.144. View

Jiao H, Xiao E, Graves D . Diabetes and Its Effect on Bone and Fracture Healing. Curr Osteoporos Rep. 2015; 13(5):327-35. PMC: 4692363. DOI: 10.1007/s11914-015-0286-8. View

Kassebaum N, Bernabe E, Dahiya M, Bhandari B, Murray C, Marcenes W . Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J Dent Res. 2014; 93(11):1045-53. PMC: 4293771. DOI: 10.1177/0022034514552491. View

10.

Gao X, Al-Baadani M, Wu M, Tong N, Shen X, Ding X . Study on the Local Anti-Osteoporosis Effect of Polaprezinc-Loaded Antioxidant Electrospun Membrane. Int J Nanomedicine. 2022; 17:17-29. PMC: 8743381. DOI: 10.2147/IJN.S341216. View

11.

Zeimaran E, Pourshahrestani S, Fathi A, Razak N, Kadri N, Sheikhi A . Advances in bioactive glass-containing injectable hydrogel biomaterials for tissue regeneration. Acta Biomater. 2021; 136:1-36. DOI: 10.1016/j.actbio.2021.09.034. View

12.

Hu Z, Ma C, Rong X, Zou S, Liu X . Immunomodulatory ECM-like Microspheres for Accelerated Bone Regeneration in Diabetes Mellitus. ACS Appl Mater Interfaces. 2017; 10(3):2377-2390. PMC: 6437671. DOI: 10.1021/acsami.7b18458. View

13.

Ye K, Kuang H, You Z, Morsi Y, Mo X . Electrospun Nanofibers for Tissue Engineering with Drug Loading and Release. Pharmaceutics. 2019; 11(4). PMC: 6523318. DOI: 10.3390/pharmaceutics11040182. View

14.

Chen B, Zhang J . Bcl-xL is required for the protective effects of low-dose berberine against doxorubicin-induced cardiotoxicity through blocking apoptosis and activating mitophagy-mediated ROS elimination. Phytomedicine. 2022; 101:154130. DOI: 10.1016/j.phymed.2022.154130. View

15.

Wang J, Liu S, Li J, Zhao S, Yi Z . Roles for miRNAs in osteogenic differentiation of bone marrow mesenchymal stem cells. Stem Cell Res Ther. 2019; 10(1):197. PMC: 6599379. DOI: 10.1186/s13287-019-1309-7. View

16.

Graves D, Ding Z, Yang Y . The impact of diabetes on periodontal diseases. Periodontol 2000. 2019; 82(1):214-224. DOI: 10.1111/prd.12318. View

17.

Xu X, Wang X, Yang Y, Ares I, Martinez M, Lopez-Torres B . Neonicotinoids: mechanisms of systemic toxicity based on oxidative stress-mitochondrial damage. Arch Toxicol. 2022; 96(6):1493-1520. DOI: 10.1007/s00204-022-03267-5. View

18.

Huang D, Zuo Y, Zou Q, Zhang L, Li J, Cheng L . Antibacterial chitosan coating on nano-hydroxyapatite/polyamide66 porous bone scaffold for drug delivery. J Biomater Sci Polym Ed. 2010; 22(7):931-44. DOI: 10.1163/092050610X496576. View

19.

Li S, Jiang Y, Xing X, Lin R, Li Q, Zhou W . Protective Mechanism of Berberine on Human Retinal Pigment Epithelial Cells against Apoptosis Induced by Hydrogen Peroxide via the Stimulation of Autophagy. Oxid Med Cell Longev. 2021; 2021:7654143. PMC: 8378965. DOI: 10.1155/2021/7654143. View

20.

Wu C, Yuan Y, Liu H, Li S, Zhang B, Chen W . Epidemiologic relationship between periodontitis and type 2 diabetes mellitus. BMC Oral Health. 2020; 20(1):204. PMC: 7353775. DOI: 10.1186/s12903-020-01180-w. View