Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050004, China.
Department of Thoracic Surgery, Hebei Provincial Chest Hospital, Shijiazhuang, 050047, China.
Inflammation. 2022 Dec;45(6):2406-2418. doi: 10.1007/s10753-022-01701-5. Epub 2022 Jun 15.
The side effects of doxorubicin (Dox) may influence the long-term survival of patients with malignancies. Therefore, it is necessary to clarify the mechanisms generating these side effects induced by Dox and identify effective therapeutic strategies. Here, we found that interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels were significantly increased in vascular tissues of Dox-treated mice and Dox-treated vascular smooth muscle cells (VSMCs). Furthermore, we revealed that Dox downregulated the phosphatase and tension homology deleted on chromosome 10 (PTEN) level while upregulated p-AKT and p65 level in VSMCs in vitro. Overexpression of PTEN in VSMCs partly reversed Dox-induced inflammation. Importantly, we demonstrated that Morin could inhibit Dox-induced inflammation by facilitating an increase of PTEN, thus inhibiting the activation of protein kinase B (AKT)/nuclear factor kappa B (NF-κB)/pathway. Additionally, we showed that Morin could reduce the miR-188-5p level, which was increased in Dox-treated VSMCs. Inhibition of miR-188-5p suppressed Dox-induced vascular inflammation in vitro. In conclusion, Morin reduced the Dox-induced vascular inflammatory by moderating the miR-188-5p/PTEN/AKT/NF-κB pathway, indicating that Morin might be a therapeutic agent for overcoming the Dox-induced vascular inflammation.
多柔比星 (Dox) 的副作用可能会影响恶性肿瘤患者的长期生存。因此，有必要阐明产生 Dox 诱导的这些副作用的机制，并确定有效的治疗策略。在这里，我们发现多柔比星处理的小鼠和多柔比星处理的血管平滑肌细胞 (VSMCs) 血管组织中白细胞介素 6 (IL-6)、白细胞介素 1β (IL-1β) 和肿瘤坏死因子-α (TNF-α) 水平显著升高。此外，我们揭示了 Dox 在体外下调 VSMCs 中的磷酸酶和张力同源缺失物 10 (PTEN) 水平，同时上调 p-AKT 和 p65 水平。在 VSMCs 中转染 PTEN 过表达部分逆转了 Dox 诱导的炎症。重要的是，我们证明了莫林通过促进 PTEN 的增加来抑制 Dox 诱导的炎症，从而抑制蛋白激酶 B (AKT)/核因子 kappa B (NF-κB)/途径的激活。此外，我们还表明，莫林可以降低 miR-188-5p 的水平，该水平在 Dox 处理的 VSMCs 中增加。抑制 miR-188-5p 可抑制体外 Dox 诱导的血管炎症。总之，莫林通过调节 miR-188-5p/PTEN/AKT/NF-κB 通路减少 Dox 诱导的血管炎症，表明莫林可能是克服 Dox 诱导的血管炎症的治疗剂。
