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Evaluation of proanthocyanidins in treating Type 2 diabetic osteoporosis via SIRT6/Nrf2/GPX4 pathways
Run-Xun Ma1,2, Bing-Hao Lin1,2, Si-Xiang Feng1,2
1Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract:
This study investigates the therapeutic potential of proanthocyanidins (PAC) in addressing Type 2 diabetic osteoporosis (T2DOP) by activating the SIRT6/Nrf2/GPX4 signaling pathways. T2DOP is characterized by compromised bone structure and heightened oxidative stress, where ferroptosis plays a pivotal role. Utilizing a T2DOP mouse model and MC3T3-E1 cells under high glucose conditions, we evaluated the impact of PAC on bone health and iron homeostasis. Our results, obtained through micro-CT, histological staining, Western blot, and immunofluorescence analyses, revealed reductions in bone density and decreased GPX4 expression in T2DOP conditions, indicating ferroptosis and oxidative stress. However, PAC treatment improved trabecular bone structure, reduced bone marrow adipocytes, decreased oxidative stress, and enhanced expression of key osteogenic proteins. These findings highlight PAC's potential in mitigating T2DOP through the SIRT6/Nrf2/GPX4 pathways, offering promising therapeutic insights for managing diabetic osteoporosis.
Insights
Proanthocyanidins (PAC) show therapeutic potential for Type 2 diabetic osteoporosis (T2DOP). PAC treatment improves bone structure and reduces oxidative stress by activating SIRT6/Nrf2/GPX4 pathways.
Area of Science:
- Biomedical Science
- Molecular Biology
- Cell Biology
Background:
- Type 2 diabetic osteoporosis (T2DOP) involves bone degradation and oxidative stress.
- Ferroptosis, a form of regulated cell death, is implicated in T2DOP pathogenesis.
- Impaired iron homeostasis contributes to the pathophysiology of T2DOP.
Purpose of the Study:
- To investigate the therapeutic effects of proanthocyanidins (PAC) on T2DOP.
- To elucidate the role of SIRT6/Nrf2/GPX4 signaling pathways in PAC's action.
- To assess PAC's impact on bone health and oxidative stress in a T2DOP model.
Main Methods:
- Established a T2DOP mouse model and used MC3T3-E1 cells under high glucose conditions.
- Administered PAC to T2DOP models and control groups.
- Analyzed bone structure using micro-CT and histological staining.
- Assessed protein expression via Western blot and immunofluorescence.
Main Results:
- T2DOP models exhibited reduced bone density and GPX4 expression, indicative of ferroptosis and oxidative stress.
- PAC treatment ameliorated trabecular bone structure and decreased bone marrow adiposity.
- PAC administration reduced oxidative stress markers and upregulated osteogenic proteins.
Conclusions:
- Proanthocyanidins (PAC) demonstrate significant potential in treating Type 2 diabetic osteoporosis.
- PAC exerts its therapeutic effects by modulating the SIRT6/Nrf2/GPX4 signaling cascade.
- PAC offers a promising therapeutic strategy for managing T2DOP by combating ferroptosis and oxidative damage.
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