<br>Poliumoside 通过激活 Nrf2/GPX4 通路抑制铁死亡，预防 2 型糖尿病相关骨质疏松症,Phytomedicine

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Poliumoside 通过激活 Nrf2/GPX4 通路抑制铁死亡，预防 2 型糖尿病相关骨质疏松症
Phytomedicine ( IF 6.7 ) Pub Date : 2024-01-07 , DOI: 10.1016/j.phymed.2024.155342
Chao-Yi Xu ₁ , Chun Xu ₂ , Yi-Ning Xu ₃ , Shi-Qi Du ₄ , Zi-Han Dai ₄ , Shu-Qing Jin ₄ , Gang Zheng ₅ , Cheng-Long Xie ₅ , Wen-Lai Fang ₅

Affiliation

背景

2 型糖尿病通常与骨质疏松症 (T2DOP) 有关，骨质疏松症会加速骨质退化并增加骨折风险。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。特别是从广东紫珠中提取的 Poliumoside (Pol)，已显示出良好的抗氧化和抗炎作用。然而，它对 T2DOP 的影响仍有待阐明。

目的

本研究的重点是阐明 Pol 对 HGHF 相关铁死亡的影响及其对 T2DOP 的影响。

学习规划

使用最小剂量的链脲佐菌素（STZ）腹腔注射并结合高脂肪和高糖饮食建立T2DOP小鼠模型。同时，为了在实验室环境中模拟糖尿病状况，将骨间充质干细胞（BMSC）维持在高葡萄糖和高脂肪（HGHF）环境中。

方法

使用 BODIPY-C11、FerroOrange 染色、线粒体功能评估和蛋白质印迹方法等方法，并结合免疫印迹和免疫荧光技术，确定了 HGHF 环境中 Pol 对 BMSC 的影响。为了了解 Pol 在小鼠 T2DOP 模型中的作用，采用了显微 CT、苏木精和伊红 (H&E) 染色、钙黄绿素-茜素红双标记和免疫组织化学等技术来进行详细的成像和组织学见解。

结果

我们的研究结果表明，Pol 可以对抗 HGHF 诱导的骨降解和铁死亡，谷胱甘肽 (GSH) 升高、丙二醛(MDA) 水平、脂质过氧化和线粒体活性氧 (ROS) 水平下降就证明了这一点。此外，Pol治疗导致股骨远端区域骨密度增加、GPX4 标记物增强、ROS 减少。在研究潜在的作用机制时，观察到 Pol 触发 Nrf2/GPX4 途径，而慢病毒-Nrf2 的引入抵消了 Pol 在 HGHF 处理的 BMSC 中的有益作用。

结论

Pol 通过激活 Nrf2/GPX4 信号通路抑制铁死亡，有效治疗 T2DOP。

"点击查看英文标题和摘要"

Poliumoside protects against type 2 diabetes-related osteoporosis by suppressing ferroptosis via activation of the Nrf2/GPX4 pathway

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.

Purpose

The focus of this study was to elucidate the influence of Pol in HGHF-associated ferroptosis and its implications in T2DOP.

Study Design

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.