College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Oct 12;52(5):544-557. doi: 10.3724/zdxbyxb-2023-0261.
To investigate the effect of borneol on cutaneous toxicity of gilteritinib and to explore possible compounds that can intervene with the cutaneous toxicity.
C57BL/6J male mice were given gilteritinib by continuous gavage for 28 d and the damage to keratinocytes in the skin tissues was observed with hematoxylin and eosin (HE) staining, TUNEL assay and immunohistochemistry. Human keratinocytes HaCaT were treated with gilteritinib, and cell death and morphological changes were examined by SRB staining and microscopy; apoptosis of HaCaT cells was examined by Western blotting, flow cytometry with propidium iodide/AnnexinⅤ double staining and immunofluorescence; the accumulation of cellular reactive oxygen species (ROS) was examined by flow cytometry with DCFH-DA. Compounds that can effectively intervene the cutaneous toxicity of gilteritinib were screened from a natural compound library using SRB method, and the intervention effect of borneol on gilteritinib cutaneous toxicity was further investigated in HaCaT cells and C57BL/6J male mice.
studies showed pathological changes in the skin with apoptosis of keratinocytes in the stratum spinosum and stratum granulosum in the modeling group. studies showed apoptosis of HaCaT cells, significant up-regulation of cleaved poly (ADP-ribose) polymerase (c-PARP) and gamma-H2A histone family member X (γ-H2AX) levels, and increased accumulation of ROS in gilteritinib-modeled skin keratinocytes compared with controls. Screening of the natural compound library revealed that borneol showed excellent intervention effects on the death of HaCaT cells. , cell apoptosis was significantly reduced in the borneol+gilteritinib group compared to the gilteritinib control group. The levels of c-PARP, γ-H2AX and ROS in cells were significantly decreased. , borneol alleviated gilteritinib-induced skin pathological changes and skin cell apoptosis in mice.
Gilteritinib induces keratinocytes apoptosis by causing intracellular ROS accumulation, resulting in cutaneous toxicity. Borneol can ameliorate the cutaneous toxicity of gilteritinib by reducing the accumulation of ROS and apoptosis of keratinocytes in the skin tissue.
研究龙脑对吉特替尼皮肤毒性的影响，并探讨可能干预皮肤毒性的化合物。
连续灌胃给予 C57BL/6J 雄性小鼠吉特替尼 28 天，观察皮肤组织角质细胞损伤情况，苏木精-伊红（HE）染色、TUNEL 检测和免疫组织化学检测。用吉特替尼处理人角质细胞 HaCaT，SRB 染色和显微镜观察细胞死亡和形态变化；用 Western blot、碘化丙啶/Annexin V 双染色和免疫荧光检测 HaCaT 细胞凋亡；用 DCFH-DA 流式细胞术检测细胞内活性氧（ROS）积累。用 SRB 法从天然化合物库中筛选能有效干预吉特替尼皮肤毒性的化合物，并进一步研究龙脑对 HaCaT 细胞和 C57BL/6J 雄性小鼠吉特替尼皮肤毒性的干预作用。
研究表明，建模组皮肤出现角质细胞凋亡、棘层和颗粒层病理改变。研究表明，与对照组相比，吉特替尼模型皮肤角质细胞 HaCaT 细胞凋亡，c-PARP 和 γ-H2AX 水平明显上调，ROS 积累增加。天然化合物库筛选发现龙脑对 HaCaT 细胞死亡具有良好的干预作用。与吉特替尼对照组相比，龙脑+吉特替尼组细胞凋亡明显减少。细胞中 c-PARP、γ-H2AX 和 ROS 水平明显降低。与吉特替尼组相比，龙脑减轻了小鼠吉特替尼诱导的皮肤病理改变和皮肤细胞凋亡。
吉特替尼通过引起细胞内 ROS 积累诱导角质细胞凋亡，导致皮肤毒性。龙脑通过减少皮肤组织角质细胞中 ROS 的积累和凋亡，可改善吉特替尼的皮肤毒性。
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