Glucocorticoids are the most common cause of secondary osteoporosis, which affects both women (pre- and postmenopausal) and men. In cases of prolonged treatment, glucocorticoids promote the loss and inactivation of the differentiational function of bone marrow mesenchymal stromal cells (BMSCs), risking the development of skeletal system diseases such as osteoporosis. This study reports for the first time the protective effect of the antimalarial artemisinin against glucocorticoid-induced insults on primary cultured rat BMSCs. At relatively low concentrations, artemisinin treatment improved BMSC survival by promoting a decline of reactive oxygen species (ROS) production that correlated with the decrease of caspase-3 activation, LDH release, mitochondrial membrane potential (Δψm) loss, and apoptosis induced by dexamethasone (DEXA). In addition, artemisinin improved the osteogenic differentiation of DEXA-damaged cells. DEXA inhibited extracellular-signal-regulated kinase 1/2 (ERK1/2) and cAMP response element binding protein (CREB) phosphorylation, and artemisinin treatment promoted their activation in a concentration-dependent manner. PD98059, the specific inhibitor of the ERK1/2 pathway, blocked ERK1/2 phosphorylation and artemisinin protection. Similarly, siCREB attenuated the protective effect of artemisinin, strongly suggesting the involvement of the ERK1/2-CREB pathway in the protective action of artemisinin against DEXA-induced damage in BMSCs. In addition, we found that the expression of antiapoptotic protein B-cell lymphoma 2 protein (BCL-2) was also upregulated by artemisinin. These studies demonstrate the therapeutic potential of artemisinin in the survival improvement of BMSCs exposed to glucocorticoid-induced apoptosis and suggest that artemisinin-mediated protection may occur via the activation of ERK1/2-CREB signaling pathway.

中文翻译：

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青蒿素通过调节 ERK1/2-CREB ​​信号通路逆转糖皮质激素诱导的骨髓间充质干细胞损伤

糖皮质激素是继发性骨质疏松症的最常见原因，它影响女性（绝经前和绝经后）和男性。在长期治疗的情况下，糖皮质激素会促进骨髓间充质基质细胞 (BMSCs) 分化功能的丧失和失活，从而有发生骨质疏松症等骨骼系统疾病的风险。本研究首次报道了抗疟青蒿素对糖皮质激素诱导的原代培养大鼠骨髓间充质干细胞损伤的保护作用。在相对较低的浓度下，青蒿素治疗通过促进活性氧 (ROS) 产生的下降来改善 BMSC 的存活率，而活性氧 (ROS) 的产生与 caspase-3 活化、LDH 释放、线粒体膜电位 ( Δψ ) 的下降相关。m) 地塞米松 (DEXA) 诱导的丢失和细胞凋亡。此外，青蒿素改善了 DEXA 损伤细胞的成骨分化。DEXA 抑制细胞外信号调节激酶 1/2 (ERK1/2) 和 cAMP 反应元件结合蛋白 (CREB) 磷酸化，青蒿素处理以浓度依赖性方式促进它们的活化。PD98059 是 ERK1/2 通路的特异性抑制剂，可阻断 ERK1/2 磷酸化和青蒿素保护。同样，siCREB ​​减弱了青蒿素的保护作用，强烈表明 ERK1/2-CREB ​​通路参与了青蒿素对 DEXA 诱导的 BMSCs 损伤的保护作用。此外，我们发现抗凋亡蛋白 B 细胞淋巴瘤 2 蛋白 (BCL-2) 的表达也被青蒿素上调。