Myelosuppression is one of the serious side effects of anticancer chemotherapeutic drugs that deteriorate the bodily functions of patients, thereby affecting the quality of life considerably. Prevention of myelosuppression in anticancer chemotherapy is an important research topic. A stabilized chemotherapy-induced myelosuppression animal model is necessary in experimental research. This study aimed to establish an optimized animal model of chemotherapy-induced bone marrow suppression. After C57BL/6 mice were treated with intermediate- and high-dose (25/50 mg/kg) cyclophosphamide (CTX) for 10 days, the body-weight, changes in thymus and spleen, number of white blood cells (WBCs), red blood cells (RBCs), and platelets (PLTs) and changes in bone marrow in the mice were systematically evaluated at the next 2, 7 and 14 days. Our results demonstrated that CTX treatments could significantly decrease the body-weight of mice, as well as the ratios of the weights of thymus and spleen to body-weight. The physiological structures of thymus and spleen were destroyed by CTX treatments. The number of WBCs and RBCs significantly declined after CTX treatments; however, the number of PLTs increased. Moreover, the expression of Sca1 in bone marrow cells decreased on Day 2 but increased on Day 14. The expression of CD34 decreased in bone marrow cells after CTX treatments. In conclusion, mice models, with high-dose CTX treatments for 10 days, can be an optimized animal model for chemotherapy-induced bone marrow suppression.

The Aconitum species, which mainly contain bioactive Aconitum alkaloids, are frequently administered concomitantly with other herbal medicines or chemical drugs in clinics. The potential risk of drug–drug interactions (DDIs) arising from co-administration of Aconitum alkaloids and other drugs against specific targets such as P-glycoprotein (P-gp) must be evaluated. This study focused on the effects of three representative Aconitum alkaloids: aconitine (AC), benzoylaconine (BAC), and aconine, on the expression and activity of P-gp. We observed that Aconitum alkaloids increased P-gp expression in LS174T and Caco-2 cells in the order AC > BAC > aconine. Nuclear receptors were involved in the induction of P-gp. AC and BAC increased the P-gp transport activity. Strikingly, intracellular ATP levels and mitochondrial mass also increased. Furthermore, exposure to AC decreased the toxicity of vincristine and doxorubicin towards the cells. In vivo, AC significantly up-regulated the P-gp protein levels in the jejunum, ileum, and colon of FVB mice, and protected them against acute AC toxicity. Taken together, the findings of our in vitro and in vivo experiments indicate that AC can induce P-gp expression, and that co-administration of AC with P-gp substrate drugs may cause DDIs. Our findings have important implications for Aconitum therapy in clinics.

Jian-pi-bu-xue-formula (JPBXF), a TCM formula composed of twelve Chinese medicinal herbs, has been used in clinic to ease patients' state of weakness and fatigue especially after receiving anti-tumor chemotherapy in China. The lack of the phytochemical characterization, detail therapeutic evaluation and mechanism of JPBXF remains the main limitation for its spreading. In this study, we systematically evaluated the effectiveness and underline mechanism of JPBXF on cyclophosphamide (CTX)-induced myelosuppression and identified the main constituents of JPBXF aqueous extract. JPBXF treatments reversed CTX-induced myelosuppression through increasing the number of haematopoietic stem cells (HSCs) and expression of C-kit in bone marrow cells. Simultaneously, JPBXF treatments alleviated CTX-induced blood cells reduction by increasing numbers of RBCs and WBCs and levels of GM-CSF, TPO and EPO in plasma. JPBXF treatments reduced CTX-induced immunosuppression by increasing expressions of CD3, CD4, and CD8a in PBMCs, and recovering structure damages of thymus and spleen. Moreover, JPBXF notably increased the expression of NRF2 compared with CTX group, and subsequently up-regulated HO1 and NQO1 both in mRNA and protein levels. In addition, eighteen compounds were recognized from JPBXF aqueous extract and the potential targets of the identified compounds were predicted. Overall, JPBXF can greatly reverse CTX-induced myelosuppression in C57BL/6 mice, especially in improving the blood and immune function through activating NRF2/HO1/ NQO1 signaling pathway, which provides a reliable reference for JPBXF application in clinical. By recognizing eighteen compounds in JPBXF aqueous extract and predicting the underline mechanisms of the identified compounds, our study would provide theoretical guidance for further research of JPBXF.