PDF(Pubmed)
Abstract：
UNASSIGNED: It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research.
UNASSIGNED: First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo.
UNASSIGNED: CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent.
UNASSIGNED: Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.
UNASSIGNED: First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo.
UNASSIGNED: CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent.
UNASSIGNED: Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.
摘要：
■众所周知,破骨细胞活性受到细胞内pH波动的显著影响。因此,pH敏感的门控纳米药物递送系统代表了减轻破骨细胞过度活性的有希望的治疗方法。我们之前的研究表明，柚皮苷，一种天然类黄酮,有效减轻破骨细胞活性。然而,柚皮苷的口服利用率低，半衰期短，阻碍了其临床应用。我们开发了一种药物递送系统，其中壳聚糖，作为看门人，包覆载有柚皮苷(CS@MSNs-柚皮苷)的介孔二氧化硅纳米颗粒。然而,CS@MSNs-柚皮苷对破骨细胞的抑制作用和潜在机制尚不清楚，保证进一步的研究。
■首先，我们合成了CS@MSNs-柚皮苷，并进行了全面表征。我们还测量了pH梯度溶液中的药物释放速率并验证了其生物安全性。随后，我们研究了CS@MSNs-柚皮苷对骨髓源性巨噬细胞诱导的破骨细胞的影响，在探索潜在机制的同时，重点关注分化和骨吸收活性。最后,我们建立了大鼠双侧临界大小的颅骨缺损模型,其中CS@MSNs-柚皮苷分散在GelMA水凝胶中以实现原位药物递送。我们观察到CS@MSNs-柚皮苷在体内促进骨再生和抑制破骨细胞活性的能力。
■CS@MSNs-柚皮苷表现出高的均匀性和分散性，低细胞毒性（浓度≤120μg/mL），和显著的pH敏感性。体外，与Naringin和MSNs-Naringin相比，CS@MSNs-柚皮苷更有效地抑制破骨细胞的形成和骨吸收活性。这种作用伴随着NF-κB和MAPK信号通路中关键因子的磷酸化减少，细胞凋亡水平增加，以及随后的破骨细胞特异性基因和蛋白质的产生减少。在体内,CS@MSNs-Naringin的表现优于Naringin和MSNs-Naringin，促进新骨形成，同时更大程度地抑制破骨细胞活性。
■我们的研究表明，CS@MSNs-Naringin在体外和体内表现出惊人的抗破骨细胞能力，而且促进颅骨缺损的骨再生。
■首先，我们合成了CS@MSNs-柚皮苷，并进行了全面表征。我们还测量了pH梯度溶液中的药物释放速率并验证了其生物安全性。随后，我们研究了CS@MSNs-柚皮苷对骨髓源性巨噬细胞诱导的破骨细胞的影响，在探索潜在机制的同时，重点关注分化和骨吸收活性。最后,我们建立了大鼠双侧临界大小的颅骨缺损模型,其中CS@MSNs-柚皮苷分散在GelMA水凝胶中以实现原位药物递送。我们观察到CS@MSNs-柚皮苷在体内促进骨再生和抑制破骨细胞活性的能力。
■CS@MSNs-柚皮苷表现出高的均匀性和分散性，低细胞毒性（浓度≤120μg/mL），和显著的pH敏感性。体外，与Naringin和MSNs-Naringin相比，CS@MSNs-柚皮苷更有效地抑制破骨细胞的形成和骨吸收活性。这种作用伴随着NF-κB和MAPK信号通路中关键因子的磷酸化减少，细胞凋亡水平增加，以及随后的破骨细胞特异性基因和蛋白质的产生减少。在体内,CS@MSNs-Naringin的表现优于Naringin和MSNs-Naringin，促进新骨形成，同时更大程度地抑制破骨细胞活性。
■我们的研究表明，CS@MSNs-Naringin在体外和体内表现出惊人的抗破骨细胞能力，而且促进颅骨缺损的骨再生。
