Abstract:
:Cyclophosphamide (CPA) is a chemotherapeutic drug widely used in the treatment of breast cancer or leukemia in clinic. However, CPA was reported to have hepatotoxicity. This study aims to observe the engaged mechanism of CPA-induced liver injury in mice and the protection of liquiritin (LQ) and liquiritigenin (LG). Liver sinusoidal endothelial injury induced by CPA (20, 40 mg/kg) in mice was evidenced by the elevated hepatic metalloproteinase-9 (MMP-9) expression, and the results from liver histological evaluation and scanning electron microscope observation. CPA increased hepatic infiltration of neutrophils, liver myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6) content, hepatic IL-6 mRNA expression, toll-like receptor-4 (TLR4) expression and nuclear factor κB (NFκB) activation in mice. Elevated serum contents of damage associated molecular patterns (DAMPs) including high mobility group box 1 (HMGB1), heat shock protein 60 (HSP60) and glucose-regulated protein 94 (Grp94) were found in mice treated with CPA. Liver sinusoidal endothelial injury and inflammation induced by CPA were diminished in TLR4 knock-out mice. LG and LQ (40, 80 mg/kg) both ameliorated liver sinusoidal endothelial injury, and reduced the increased hepatic infiltration of neutrophils, MPO activity, hepatic IL-6 mRNA expression and NFκB activation induced by CPA. In summary, these results indicate that TLR4-NFκB-mediated inflammatory injury initiated by DAMPs was critically involved in CPA-induced hepatotoxicity. LG and LQ alleviated CPA-induced liver sinusoidal endothelial injury and inflammatory injury in mice.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Chen M,Zhang C,Zhang J,Kai G,Lu B,Huang Z,Ji Ldoi
10.1016/j.ejphar.2019.172421subject
Has Abstractpub_date
2019-08-05 00:00:00pages
172421eissn
0014-2999issn
1879-0712pii
S0014-2999(19)30372-3journal_volume
856pub_type
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