Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong; Department of Oncology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao, China.
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
J Cancer Res Ther. 2023 Aug;19(4):1031-1039. doi: 10.4103/jcrt.jcrt_912_23.
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse reaction to chemotherapeutics, which seriously affects the outcome of chemotherapy and patients' quality of life. Although it is commonly seen, it lacks effective treatment. Our previous study found that ozone could alleviate neuropathic pain. Damage-associated molecular patterns (DAMPs) or Toll-like receptor 4 (TLR4) or tissue factor (TF)-mediated neuroinflammation and microcirculation disturbance is the main reason for CIPN. Suppressors of cytokine signaling (SOCS) 3 is an endogenous negative feedback regulator of inflammation via TLR4 inhibition.
Oxaliplatin (L-OHP) was used to establish mice's CIPN model. Nociceptive responses were assessed by observing the ICR mice's incidence of foot regression in mechanical indentation response experiments. Cell signaling assays were performed by Western blotting and immunohistochemistry. The mouse leukemia cells of monocyte-macrophage line RAW 264.7 were cultured to investigate the effects of ozone administration on macrophage.
Ozone decreased the expression of TF in the blood and sciatic nerve. It upregulated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-SOCS3 axis to relieve CIPN and inhibit TF expression in vivo. SOCS3 expression was induced by ozone to inhibit the p38/TF signaling in RAW 246.7 cells. Ozone also prevented L-OHP-induced sciatic nerve demyelination. Microglia activation was inhibited, and c-Fos and calcitonin gene-related peptide (CGRP) expression was decreased in the spinal dorsal horn via ozone.
In this study, we demonstrated that ozone could alleviate CIPN by upregulating the AMPK-SOCS3 axis to inhibit TF expression, which is a potential treatment for CIPN.
化疗引起的周围神经病变（CIPN）是化疗药物的严重不良反应，严重影响化疗效果和患者的生活质量。虽然它很常见，但缺乏有效的治疗方法。我们之前的研究发现臭氧可以缓解神经病理性疼痛。损伤相关分子模式（DAMPs）或 Toll 样受体 4（TLR4）或组织因子（TF）介导的神经炎症和微循环障碍是 CIPN 的主要原因。细胞因子信号转导抑制剂（SOCS）3 是通过 TLR4 抑制炎症的内源性负反馈调节剂。
奥沙利铂（L-OHP）用于建立小鼠的 CIPN 模型。通过观察 ICR 小鼠在机械压痕反应实验中足退缩的发生率来评估痛觉反应。通过 Western blot 和免疫组织化学检测细胞信号转导。培养单核-巨噬细胞系 RAW 264.7 的小鼠白血病细胞，研究臭氧给药对巨噬细胞的影响。
臭氧降低了血液和坐骨神经中 TF 的表达。它上调了腺苷 5'-单磷酸（AMP）-激活蛋白激酶（AMPK）-SOCS3 轴，以缓解体内 CIPN 并抑制 TF 的表达。臭氧诱导 SOCS3 表达，抑制 RAW 246.7 细胞中的 p38/TF 信号。臭氧还可防止 L-OHP 诱导的坐骨神经脱髓鞘。臭氧抑制小胶质细胞活化，降低脊髓背角中的 c-Fos 和降钙素基因相关肽（CGRP）表达。
在这项研究中，我们证明臭氧通过上调 AMPK-SOCS3 轴抑制 TF 表达来缓解 CIPN，这是治疗 CIPN 的一种潜在方法。
