Branched-Chain Amino Acids Catabolism Pathway Regulation Plays a Critical Role in the Improvement of Leukopenia Induced by Cyclophosphamide in 4T1 Tumor-Bearing Mice Treated With Lvjiaobuxue Granule

Abstract

Background: Cyclophosphamide is a common tumor chemotherapy drug used to treat various cancers. However, the resulting immunosuppression leads to leukopenia, which is a serious limiting factor in clinical application. Therefore, the introduction of immunomodulators as adjuvant therapy may help to reduce the hematological side effects of cyclophosphamide. Lvjiaobuxue granule has been widely used in the clinical treatment of gynecological diseases such as anemia and irregular menstruation. Recently, it has been found to increase the function of white blood cells, but its mechanism of action is still unclear. We aimed to reveal the mechanisms of Lvjiaobuxue granule against acute leukopenia by an integrated strategy combining metabolomics with network pharmacology.Methods: Subcutaneously inoculated 4T1 breast cancer cells to prepare tumor-bearing mice, intraperitoneal injection of cyclophosphamide to establish a 4T1 tumor-bearing mice leukopenia animal model, using pharmacodynamic indicators, metabolomics, network pharmacology and molecular biology and other technical methods. To comprehensively and systematically elucidate the effect and mechanism of Lvjiaobuxue granule in improving cyclophosphamide-induced leukopenia in 4T1 tumor-bearing mice.Results: Lvjiaobuxue granule can improve the blood routine parameters and organ index levels of the leukopenia model of 4T1 tumor-bearing mice. Metabolomics studies revealed that 15 endogenous metabolites in the spleen of mice were considered as potential biomarkers of Lvjiaobuxue granule for their protective effect. Metabonomics and network pharmacology integrated analysis indicated that Lvjiaobuxue granule exerted the leukocyte elevation activity by inhibiting the branched-chain amino acids (BCAAs) degradation pathway and increasing the levels of valine, leucine and isoleucine. The results of molecular biology also showed that Lvjiaobuxue granule can significantly regulate the key enzymes in the catabolism of BCAAs, which further illustrates the importance of BCAAs in improving leukopenia.Conclusion: Lvjiaobuxue granule exerts obvious pharmacological effects on the leukopenia model of 4T1 tumor-bearing mice induced by cyclophosphamide, which could be mediated by regulating the branched-chain amino acid degradation pathway and the levels of valine, leucine and isoleucine.

Ranferon-12 tonic mitigates haematological abnormalities in cyclophosphamide-treated rats

“…haematopoietic stem cells and haematopoietic progenitor cells) from producing peripheral blood cells (Liu et al, 2014). Hence, measuring these peripheral blood cells count, directly mirrors the haematopoietic function (Tian et al, 2021). In line with previous studies (El-Naggar et al, 2015;Iqubal et al, 2020;Kameo et al, 2021), CPA administration at 200 mg/kg i.p.…”

Prevention effect of total ginsenosides and ginseng extract from Panax ginseng on cyclophosphamide‐induced immunosuppression in mice

“…Wang et al reported that ginseng protein enhanced the immunoregulation of macrophages (Wang et al, 2018), which improved Alzheimer's disease by activating the BDNF/TrkB signaling pathway and regulating the intestinal microbial diversity (Li et al, 2022). Tian et al reported that Lvjiaobuxue granule could improve the leukopenia induced by CP in 4T1 tumor-bearing mice by regulating the branched-chain amino acid degradation pathway and the levels of Val, Leu, and Ile (Tian et al, 2021). Such proteins or peptides of GE also participate in immune regulation in immunosuppressed mice.…”

Effects of Soy–Whey Protein Nutritional Supplementation on Hematopoiesis and Immune Reconstitution in an Allogeneic Transplanted Mice

“…Wilkinson et al reported that reduced BCAA levels inhibited hematopoietic stem cell proliferation and survival in vitro and rendered these cells incapable of sustaining normal physiological activity in vivo [ 54 ]. Likewise, dietary BCAA depletion could lead to a significant decrease in WBC and RBC counts in normal mice [ 55 ]. Because soy and whey protein extracts contain abundant BCAAs [ 56 , 57 ], post-BMT DP supplementation was likely to reverse BCAA-deficits and promote survival and the proliferation of HSC and WBC populations [ 58 , 59 ].…”