Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
J Orthop Surg (Hong Kong). 2024 May-Aug;32(2):10225536241266671. doi: 10.1177/10225536241266671.
This investigation aims to explore the protective role of Naringenin (Nar) in bone cancer pain (BCP) via TNF-α-mediated NF-κB/uPA/PAR2 pathway.
BCP model was manipulated by the injection of LL2 cells into femur of mice. The levels of TNF-α and uPA in bone tissue and serum were studied by ELISA. The expressions of PAR2, PKC-γ, PKA and TRPV1 were determined by qPCR and western blot. Levels of p-IKKβ, IKKβ, p-p65, p65 were determined by western blot. Levels of p-p65 and uPA in bone tissue were studied by immunohistochemistry. Behavior tests in this investigation included paw withdrawal latency (PWL) and the paw withdrawal threshold (PWT). Radiological analysis and micro-CT were used to study bone structure. The lesions of bone tissue were determined by HE staining. The Dorsal root ganglia (DRG) isolated from mice were used to determine the level of PAR2 pathway.
Naringenin improved the BCP-induced bone damage based on the increases of BV/TV, Conn. D, BMD and BMC and the decrease of bone destruction score. Naringenin repressed the reductions of PWT and PWL in BCP mice. Naringenin decreased the levels of PAR2, PKC-γ, PKA and TRPV1 of DRG and reduced the levels of p-IKKβ, p-p65, and uPA in serum and bone tissue in BCP. Importantly, naringenin suppressed the enhancement of TNF-α in serum and bone tissue in BCP mice.
Naringenin alleviated pain sensitization and bone damage of mice with BCP via TNF-α-mediated NF-κB/uPA/PAR2 pathway. We demonstrated a novel pathway for anti-BCP treatment with naringenin.
本研究旨在通过 TNF-α 介导的 NF-κB/uPA/PAR2 通路探讨柚皮素（Nar）在骨癌痛（BCP）中的保护作用。
通过将 LL2 细胞注入小鼠股骨来建立 BCP 模型。通过 ELISA 研究骨组织和血清中 TNF-α 和 uPA 的水平。通过 qPCR 和 Western blot 测定 PAR2、PKC-γ、PKA 和 TRPV1 的表达。通过 Western blot 测定 p-IKKβ、IKKβ、p-p65 和 p65 的水平。通过免疫组化研究骨组织中 p-p65 和 uPA 的水平。本研究中的行为测试包括足底退缩潜伏期（PWL）和足底退缩阈值（PWT）。放射学分析和 micro-CT 用于研究骨结构。通过 HE 染色确定骨组织病变。从小鼠分离背根神经节（DRG）用于确定 PAR2 通路的水平。
柚皮素通过增加 BV/TV、Conn.D、BMD 和 BMC 以及降低骨破坏评分，改善了 BCP 引起的骨损伤。柚皮素抑制了 BCP 小鼠 PWT 和 PWL 的降低。柚皮素降低了 DRG 中 PAR2、PKC-γ、PKA 和 TRPV1 的水平，并降低了 BCP 小鼠血清和骨组织中 p-IKKβ、p-p65 和 uPA 的水平。重要的是，柚皮素抑制了 BCP 小鼠血清和骨组织中 TNF-α 的增强。
柚皮素通过 TNF-α 介导的 NF-κB/uPA/PAR2 通路缓解了 BCP 小鼠的痛觉敏化和骨损伤。我们证明了柚皮素抗 BCP 的新途径。
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