Danggui Buxue decoction alleviates cyclophosphamide-induced myelosuppression by regulating β-hydroxybutyric acid metabolism and suppressing oxidative stress

Abstract

AbstractContext Danggui Buxue Decoction (DBD) is an effective complementary medicine in alleviating myelosuppression after chemotherapy (MAC). However, its mechanism of action is elusive.Objective To illustrate that regulating β-hydroxybutyric acid (β-OHB) metabolism and suppressing oxidative stress could be a potential mechanism of action for DBD in alleviating MAC.Materials and methods After HPLC quantification and dose testing (3, 6 and 10 g/kg, gavage) of DBD, Sprague-Dawley rats were divided into control, cyclophosphamide (CTX) (30 mg/kg CTX for 5 days, intraperitoneal administration) and CTX + DBD groups (6 g/kg DBD for 14 days, gavage). Blood cell counts, thigh bone histological examination, β-OHB levels, oxidative stress indices and HDAC1 activity were tested. The biological function of β-OHB was verified in vitro (hBMSC cells were incubated in culture mediums that contained 40 μM CTX and β-OHB in 0, 1, 2.5, 5, 10 mM) and in vivo (MAC rat model, 3 g/kg β-OHB for 14 days, gavage).Results Rats in the CTX + DBD group showed upregulated blood cell counts (118–243%), β-OHB levels (495 nmol/mL in blood, 122 nmol/mg in marrow supernatant) and downregulated HDAC1 activity (59%), and oxidative stress indices (60–85%). In vitro, 5 mM β-OHB improved hBMSC cell migration (123%) and proliferation (131%). In vivo, rats treated with 3 g/kg β-OHB showed upregulated blood cell counts (121–182%) and downregulated HDAC1 activity (64%) and oxidative stress indices (65–83%).Discussion and conclusions DBD, a traditional Chinese medicine, alleviates MAC by intervening in β-OHB metabolism and oxidative stress.

Keywords

• Traditional Chinese medicine
• myelosuppression after chemotherapy
• endogenous metabolites
• histone 1 deacetylase
• hematopoietic microenvironment