背景:2型糖尿病通常与骨质疏松症(T2DOP)有关,一种加速骨骼退化并增加骨折风险的疾病。与传统的更年期骨质疏松症不同,糖尿病环境加剧了骨折和骨坏死的可能性。特别是脊髓灰质炎(Pol),源自广云春花,已显示出有希望的抗氧化和抗炎作用。然而,其对T2DOP的影响尚待阐明。
目的:本研究的重点是阐明Pol在HGHF相关铁性凋亡中的影响及其在T2DOP中的意义。
方法:通过腹膜内输注最小剂量的链脲佐菌素(STZ)结合高脂高糖饮食建立T2DOP小鼠模型。同时,在实验室环境中模拟糖尿病,骨髓间充质干细胞(BMSCs)维持在高糖高脂(HGHF)环境中.
方法:使用方法确定Pol对HGHF环境中BMSCs的影响,如BODIPY-C11,铁橙染色,线粒体功能评估,和西方印迹方法,再加上免疫印迹和免疫荧光技术。为了了解Pol在小鼠T2DOP模型中的作用,包括显微CT在内的技术,苏木精和伊红(H&E)染色,双重标记与钙黄绿素-茜素红,和免疫组织化学用于详细的成像和组织学见解。
结果:我们的研究结果表明,Pol对抗HGHF诱导的骨降解和铁性凋亡,谷胱甘肽(GSH)水平升高和丙二醛(MDA)水平下降证明,脂质过氧化,和线粒体活性氧(ROS)。此外,Pol治疗导致骨密度增加,增强的GPX4标记,股骨远端区域的ROS减少。在研究潜在的作用机制时,观察到Pol触发了Nrf2/GPX4通路,慢病毒-Nrf2的引入否定了Pol在HGHF处理的BMSCs中的有益作用。
结论:Pol通过激活Nrf2/GPX4信号通路抑制铁凋亡,有效治疗T2DOP。
BACKGROUND: Type 2 diabetes is often linked with osteoporosis (T2DOP), a condition that accelerates bone degeneration and increases the risk of fractures. Unlike conventional menopausal osteoporosis, the diabetic milieu exacerbates the likelihood of fractures and osteonecrosis. In particular poliumoside (Pol), derived from Callicarpa kwangtungensis Chun, has shown promising anti-oxidant and anti-inflammatory effects. Yet, its influence on T2DOP remains to be elucidated.
OBJECTIVE: The focus of this study was to elucidate the influence of Pol in HGHF-associated ferroptosis and its implications in T2DOP.
METHODS: A murine model of T2DOP was established using a minimal dosage of streptozotocin (STZ) through intraperitoneal infusion combined with a diet high in fat and sugar. Concurrently, to mimic the diabetic condition in a lab environment, bone mesenchymal stem cells (BMSCs) were maintained in a high-glucose and high-fat (HGHF) setting.
METHODS: The impact of Pol on BMSCs in an HGHF setting was determined using methods, such as BODIPY-C11, FerroOrange staining, mitochondrial functionality evaluations, and Western blot methodologies, coupled with immunoblotting and immunofluorescence techniques. To understand the role of Pol in a murine T2DOP model, techniques including micro-CT, hematoxylin and eosin (H&E) staining, dual-labeling with calcein-alizarin red, and immunohistochemistry were employed for detailed imaging and histological insights.
RESULTS: Our findings suggest that Pol acts against HGHF-induced bone degradation and ferroptosis, as evidenced by an elevation in glutathione (GSH) and a decline in malondialdehyde (MDA) levels, lipid peroxidation, and mitochondrial reactive oxygen species (ROS). Furthermore, Pol treatment led to increased bone density, enhanced GPX4 markers, and reduced ROS in the distal femur region. On investigating the underlying mechanism of action, it was observed that Pol triggers the Nrf2/GPX4 pathway, and the introduction of lentivirus-Nrf2 negates the beneficial effects of Pol in HGHF-treated BMSCs.
CONCLUSIONS: Pol is effective in treating T2DOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.