Endogenous FGF1 Deficiency Aggravates Doxorubicin-Induced Hepatotoxicity.
Chunjie GuZijuan LiuYingjian LiMei YiSimeng WangXia FanSun DaChi ZhangXiaoqing YanGuicheng WuPublished in: Toxics (2023)
Doxorubicin (DOX) is a broad-spectrum antineoplastic agent that widely used in clinic. However, its application is largely limited by its toxicity in multiple organs. Fibroblast growth factor 1 (FGF1) showed protective potential in various liver diseases, but the role of endogenous FGF1 in DOX-induced liver damage is currently unknown. Both wild-type (WT) and FGF1 knockout (FGF1-KO) mice were treated with DOX. DOX induced loss of body weight and liver weight and elevation of ALT and AST in WT mice, which were aggravated by FGF1 deletion. FGF1 deletion exacerbated hepatic oxidative stress mirrored by further elevated 3-nitrosative modification of multiple proteins and malondialdehyde content. These were accompanied by blunted compensatively antioxidative responses indicated by impaired upregulation of nuclear factor erythroid 2-related factor 2 and its downstream antioxidant gene expression. The aggravated oxidative stress was coincided with exacerbated cell apoptosis in DOX-treated FGF1-KO mice reflected by further increased TUNEL positive cell staining and BCL-2-associated X expression and caspase 3 cleavage. These detrimental changes in DOX-treated FGF1-KO mice were associated with worsened intestinal fibrosis and increased upregulation fibrotic marker connective tissue growth factor and α-smooth muscle actin expression. However, DOX-induced hepatic inflammatory responses were not further affected by FGF1 deletion. These results demonstrate that endogenous FGF1 deficiency aggravates DOX-induced liver damage and FGF1 is a potential therapeutic target for treatment of DOX-associated hepatoxicity.
Keyphrases
- oxidative stress
- diabetic rats
- high glucose
- wild type
- gene expression
- poor prognosis
- growth factor
- drug induced
- body weight
- nuclear factor
- primary care
- smooth muscle
- body mass index
- dna damage
- toll like receptor
- cell proliferation
- dna methylation
- type diabetes
- physical activity
- induced apoptosis
- immune response
- systemic sclerosis
- idiopathic pulmonary fibrosis
- binding protein
- cell death
- climate change
- mesenchymal stem cells
- weight loss
- endoplasmic reticulum stress
- weight gain
- insulin resistance
- stress induced
- heat shock
- oxide nanoparticles
- flow cytometry