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Naringenin alleviates bone cancer pain via NF-κB/uPA/PAR2 pathway in mice
Yaoyuan Li1, Guangda Zheng1, Yiting Tang2
1Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Naringenin alleviates bone cancer pain and damage in mice by inhibiting the TNF-α-mediated NF-κB/uPA/PAR2 pathway. This study reveals a new therapeutic approach for bone cancer pain.
Area of Science:
- Biomedical Science
- Pain Research
- Oncology
Background:
- Bone cancer pain (BCP) poses a significant clinical challenge.
- Existing treatments for BCP have limitations.
- Understanding the molecular mechanisms of BCP is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the protective effects of Naringenin (Nar) against bone cancer pain (BCP).
- To elucidate the role of the TNF-α-mediated NF-κB/uPA/PAR2 pathway in BCP.
- To explore Naringenin as a potential therapeutic agent for BCP.
Main Methods:
- Established a BCP mouse model by injecting LL2 cells into the femur.
- Assessed pain behaviors using paw withdrawal latency (PWL) and paw withdrawal threshold (PWT).
- Quantified molecular markers (TNF-α, uPA, PAR2, NF-κB pathway components, etc.) using ELISA, qPCR, Western blot, and immunohistochemistry.
- Evaluated bone structure using radiological analysis, micro-CT, and HE staining.
Main Results:
- Naringenin treatment significantly improved bone structure and reduced bone damage in BCP mice.
- Naringenin alleviated pain sensitization, indicated by increased PWL and PWT.
- Naringenin suppressed the TNF-α-mediated NF-κB/uPA/PAR2 pathway, reducing key molecular markers in bone tissue and serum.
Conclusions:
- Naringenin demonstrates significant protective effects against bone cancer pain and associated bone damage.
- The therapeutic mechanism involves the inhibition of the TNF-α-mediated NF-κB/uPA/PAR2 pathway.
- Naringenin represents a promising novel therapeutic strategy for managing bone cancer pain.
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