Spinal Nrf2 translocation may inhibit neuronal NF-κB activation and alleviate allodynia in a rat model of bone cancer pain.
Spinal Nrf2 translocation may inhibit neuronal NF-κB activation and alleviate allodynia in a rat model of bone cancer pain.
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脊髓Nrf 2转位可能抑制神经元NF-κB活化并减轻骨癌痛大鼠模型的异常性疼痛。
DOI：
10.1111/jnc.15468
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发表时间：
2021-09
影响因子：
4.7
通讯作者：
Yao, Ming
中科院分区：
文献类型：
--
作者：
Fu, Jie;Ni, Chaobo;Ni, Hua-Dong;Xu, Long-Sheng;He, Qiu-Li;Pan, Huan;Huang, Dong-Dong;Sun, Yan-Bao;Luo, Ge;Liu, Ming-Juan;Yao, Ming
骨癌性疼痛（Bone cancer pain， BCP）是临床亟待解决的病理问题，但目前对其机制的研究成果有限。核因子红系2 （NFE2）相关因子2 （Nrf2）已被证实与疼痛有关，但其在BCP中的作用及其具体机制尚不清楚。本研究旨在验证BCP诱导Nrf2从细胞质向细胞核转移，并进一步促进核转录激活血红素加氧酶- 1 (HO - 1)，抑制核因子κB （NF - κB）信号的激活，最终调节神经炎症反应的假设。采用Von‐Frey法对BCP大鼠进行行为分析，采用western blotting、实时定量PCR （RT‐PCR）和酶联免疫吸附试验（ELISA）检测分子表达变化，采用免疫荧光法检测细胞定位。结果表明，BCP诱导脊髓Nrf2核蛋白表达增加，胞质蛋白表达减少。Nrf2核蛋白表达的进一步升高可以缓解痛觉过敏，激活HO - 1抑制NF - κB核蛋白和炎症因子的表达。引人注目的是，鞘内注射相应的siRNA逆转了上述效果。此外，双免疫标记结果显示，Nrf2和NF‐κB在BCP大鼠脊髓神经元中共表达。综上所述，这些发现表明Nrf2进入细胞核可促进HO‐1的表达，抑制NF‐κB信号通路的激活，减少神经炎症并最终发挥抗伤害性作用。我们提出Nrf2（核因子红系2 （NFE2）相关因子2）调节NF - κB（核因子κB）激活以减轻神经炎症和骨癌疼痛（BCP）：骨癌诱导的氧化应激驱动Nrf2与Keap - 1 （kelch样ECH相关蛋白1）解离并转录到脊髓神经元的细胞核，从而启动机体的防御反应。进一步促进Nrf2进入细胞核可增加HO‐1（血红素加氧酶‐1）表达，抑制NF‐κB活化和脊髓神经元下游炎症因子释放，最终减轻疼痛。我们相信这些发现有助于为BCP的治疗提供新的治疗策略。
Bone cancer pain (BCP) is a clinical pathology that urgently needs to be solved, but research on the mechanism of BCP has so far achieved limited success. Nuclear factor erythroid 2 (NFE2)‐related factor 2 (Nrf2) has been shown to be involved in pain, but its involvement in BCP and the specific mechanism have yet to be examined. This study aimed to test the hypothesis that BCP induces the transfer of Nrf2 from the cytoplasm to the nucleus and further promotes nuclear transcription to activate heme oxygenase‐1 (HO‐1) and inhibit the activation of nuclear factor‐kappa B (NF‐κB) signalling, ultimately regulating the neuroinflammatory response. Von‐Frey was used for behavioural analysis in rats with BCP, whereas western blotting, real‐time quantitative PCR (RT‐PCR) and enzyme‐linked immunosorbent assay (ELISA) were used to detect molecular expression changes, and immunofluorescence was used to detect cellular localization. We demonstrated that BCP induced increased Nrf2 nuclear protein expression with decreased cytoplasmic protein expression in the spinal cord. Further increases in Nrf2 nuclear protein expression can alleviate hyperalgesia and activate HO‐1 to inhibit the expression of NF‐κB nuclear protein and inflammatory factors. Strikingly, intrathecal administration of the corresponding siRNA reversed the above effects. In addition, the results of double immune labelling revealed that Nrf2 and NF‐κB were coexpressed in spinal cord neurons of rats with BCP. In summary, these findings suggest that the entry of Nrf2 into the nucleus promotes the expression of HO‐1, inhibiting activation of the NF‐κB signalling pathway, reducing neuroinflammation and ultimately exerting an anti‐nociceptive effect. We propose that Nrf2 (Nuclear factor erythroid 2 (NFE2)‐related factor 2) regulates NF‐κB (Nuclear factor‐kappa B) activation to attenuate neuroinflammation and bone cancer pain (BCP): Bone cancer–induced oxidative stress drives the dissociation of Nrf2 with Keap‐1 (kelch‐like ECH‐related protein 1) and transcription to the nucleus in spinal cord neurons, thereby initiating the body's defence response. Further promoting Nrf2 entry into the nucleus could increase HO‐1 (heme oxygenase‐1) expression to inhibit NF‐κB activation and downstream inflammatory factor release in spinal cord neurons and finally reduce pain. We believe that these findings can help provide new therapeutic strategies for the treatment of BCP.
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DOI：
10.1016/j.bbi.2014.06.199
发表时间：
2014-11
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Allette YM;Due MR;Wilson SM;Feldman P;Ripsch MS;Khanna R;White FA
通讯作者：
White FA
影响因子：
5.8
作者：
Lewis, Kate M.;Harford-Wright, Elizabeth;Ghabriel, Mounir N.
通讯作者：
Ghabriel, Mounir N.
H(2) 治疗通过 HO-1/CO 途径减轻神经性疼痛大鼠模型的疼痛行为和细胞因子释放
影响因子：
5.1
作者：
Chen, Yajun;Chen, Hongguang;Wang, Guolin
通讯作者：
Wang, Guolin
影响因子：
5.6
作者：
Bellezza, Ilaria;Tucci, Arianna;Minelli, Alba
通讯作者：
Minelli, Alba
DOI：
10.1007/s00018-016-2223-0
发表时间：
2016-09
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Loboda A;Damulewicz M;Pyza E;Jozkowicz A;Dulak J
通讯作者：
Dulak J