Li Mei, Wang Jing, Huo Bingjie, Wan Qianqian, Xing Liwei, Wang Yuming, Pei Huan, Wang Li, Xia Yafei, Cui Huantian
The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
Tianjin University, Tianjin, 300072, China.
Curr Drug Metab. 2024;25(9):695-705. doi: 10.2174/0113892002360132250122164637.
Chemotherapy-induced immunosuppression significantly impacts patient's quality of life. Umbelliferone (UMB) is known for its anti-inflammatory, antioxidant, and anti-apoptotic properties, but its effects on cyclophosphamide (CTX)-induced immunosuppression need further study.
We established a CTX-induced immunosuppressed mouse model and administered varying doses of UMB. Immune function was assessed by evaluating white blood cells, lymphocytes, thymus and spleen indices, and CD4/CD8 T cell ratios. Serum levels of IL-2, IFN-γ, IgA, IgM, and IgG, along with macrophage phagocytic activity, NK cytotoxicity, and lymphocyte proliferation, were measured. Untargeted metabolomics was used to identify key pathways regulated by UMB, and RT-qPCR and Western blotting were performed to analyze the expression of related enzymes and metabolites.
UMB intervention increased white blood cells, lymphocytes, thymus and spleen indices, and CD4+/CD8+ T cell ratios in CTX-immunosuppressed mice. It reversed reduced levels of serum IL-2, IFN-γ, IgA, IgM, and IgG and improved macrophage phagocytic activity, NK cytotoxicity, and lymphocyte proliferation. Key pathways identified by metabolomics included histidine and purine metabolism. UMB improved levels of histamine, L-glutamate, L-aspartate, xanthine, dAMP, deoxyinosine, xanthosine, and cGMP and upregulated HDC, ASPA, and PNP while downregulating XDH, PDE5, ROS, and MDA in spleen tissue. UMB enhanced SOD activity and GSH levels and reduced apoptosis, as indicated by lower TUNEL-positive expression.
UMB enhanced immune function in CTX-immunosuppressed mice through the regulation of histidine and purine metabolism, exhibiting antioxidant and anti-apoptotic effects. These findings highlight the potential of UMB in mitigating immunosuppression.
化疗引起的免疫抑制显著影响患者的生活质量。伞形花内酯（UMB）以其抗炎、抗氧化和抗凋亡特性而闻名，但其对环磷酰胺（CTX）诱导的免疫抑制的影响尚需进一步研究。
我们建立了CTX诱导的免疫抑制小鼠模型，并给予不同剂量的UMB。通过评估白细胞、淋巴细胞、胸腺和脾脏指数以及CD4/CD8 T细胞比率来评估免疫功能。测量血清白细胞介素-2（IL-2）、干扰素-γ（IFN-γ）、免疫球蛋白A（IgA）、免疫球蛋白M（IgM）和免疫球蛋白G（IgG）水平，以及巨噬细胞吞噬活性、自然杀伤细胞（NK）细胞毒性和淋巴细胞增殖。采用非靶向代谢组学来鉴定受UMB调节的关键通路，并进行逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法来分析相关酶和代谢物的表达。
UMB干预增加了CTX免疫抑制小鼠的白细胞、淋巴细胞、胸腺和脾脏指数以及CD4+/CD8+ T细胞比率。它逆转了血清IL-2、IFN-γ、IgA、IgM和IgG水平的降低，并改善了巨噬细胞吞噬活性、NK细胞毒性和淋巴细胞增殖。代谢组学鉴定的关键通路包括组氨酸和嘌呤代谢。UMB提高了脾脏组织中组胺、L-谷氨酸、L-天冬氨酸、黄嘌呤、脱氧腺苷一磷酸（dAMP）、脱氧肌苷、黄苷和环磷酸鸟苷（cGMP）的水平，并上调了组氨酸脱羧酶（HDC）、天冬氨酸酶（ASPA）和嘌呤核苷磷酸化酶（PNP），同时下调了黄嘌呤脱氢酶（XDH）、磷酸二酯酶5（PDE5）、活性氧（ROS）和丙二醛（MDA）。UMB增强了超氧化物歧化酶（SOD）活性和谷胱甘肽（GSH）水平，并减少了凋亡，这通过较低的TUNEL阳性表达得以体现。
UMB通过调节组氨酸和嘌呤代谢增强了CTX免疫抑制小鼠的免疫功能，表现出抗氧化和抗凋亡作用。这些发现突出了UMB在减轻免疫抑制方面的潜力。
