Diosmin Alleviates Doxorubicin-Induced Liver Injury via Modulation of Oxidative Stress-Mediated Hepatic Inflammation and Apoptosis via NfkB and MAPK Pathway: A Preclinical Study

Figures

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  Figure 1. Effects of diosmin pretreatment on serum levels of ALT (A), AST (B), and ALP (C) in male Wistar rats exposed to DOX. DOX increased ALT, AST, and ALP, and diosmin attenuated these effects at both lower and higher dose. Error bars represent the mean ± SD (n = 5), where *** p < 0.001, ** p < 0.01, and NS p > 0.05. CON, control group; DOX, doxorubicin group; DOX + DSLD, group of doxorubicin and diosmin 100 mg/kg; DOX + DSHD, group of doxorubicin and diosmin 200 mg/kg.

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  Figure 2. Effects of diosmin pretreatment on oxidative stress markers, such as MDA (A), GSH (B), and CAT (C), in male Wistar rats exposed to DOX. Diosmin diminished the oxidative stress induced by DOX. DOX increased MDA and decreased GSH and CAT, and diosmin attenuated these effects at both lower and higher dose. Error bars represent the mean ± SD, where *** p < 0.001, ** p < 0.01, * p < 0.05, and NS p > 0.05. CON, control group; DOX, doxorubicin group; DOX + DSLD, group of doxorubicin and diosmin 100 mg/kg; DOX + DSHD, group of doxorubicin and diosmin 200 mg/kg.

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  Figure 3. (A–F) Effects of diosmin pretreatment on the gene expression of inflammatory and antioxidants genes. Data are presented as mean ± SD (n = 3), where ** p < 0.01, * p < 0.05 and NS p > 0.05. CON, control group; DOX, doxorubicin group; DOX + DSLD, group of doxorubicin and diosmin 100 mg/kg; DOX + DSHD, group of doxorubicin and diosmin 200 mg/kg.

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  Figure 4. Effects of diosmin pretreatment altered the level of protein expression of p65-NFkB and SOD. (A) Immunoblot representation of p65-NFkB and SOD; (B,C) graphical representation of p65-NFkB and SOD. Error bars represent the mean ± SD (n = 3). *** p < 0.001, ** p < 0.01, and NS p > 0.05. CON, control group; DOX, doxorubicin group; DOX + DSLD, group of doxorubicin and diosmin 100 mg/kg; DOX + DSHD, group of doxorubicin and diosmin 200 mg/kg.

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  Figure 5. Effects of diosmin pretreatment on altered the level of p38- and pAKT-mediated apoptosis cascade. (A) Immunoblot representation of p38 and pAKT; (B,C) graphical representation of p38 and pAKT. Error bars represent the mean ± SD (n = 3). *** p < 0.001 and * p < 0.05. CON, control group; DOX, doxorubicin group; DOX + DSLD, group of doxorubicin and diosmin 100 mg/kg; DOX + DSHD, group of doxorubicin and diosmin 200 mg/kg.

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  Figure 6. Effects of diosmin pretreatment on the expression of pro- and antiapoptotic protein and cleavage action of caspase in apoptosis cascade. (A) Immunoblot representation of Cleaved Caspase 3, BAX, and Bcl-2; (B–D) graphical representation of Cleaved Caspase 3, BAX, and Bcl-2. Error bars represent the mean ± SD (n = 3). *** p < 0.001 and ** p < 0.01. CON, control group; DOX, doxorubicin group; DOX + DSLD, group of doxorubicin and diosmin 100 mg/kg; DOX + DSHD, group of doxorubicin and diosmin 200 mg/kg.

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  Figure 7. Effects of diosmin pretreatment on light micrographs of the H & E stain liver tissues of 0.1 mm. (A) The normal tissue of the liver. (B) Irregular architecture of liver tissues caused by Dox administration appeared, as indicated by arrows. (C,D) Diosmin pre-treatment reduced harmful effects of Dox in cytoplasmic vacuoles, necrotic hepatocytes, and vascular congestion at both doses.

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  Figure 8. Schematic representation of hepatoprotective mechanism of diosmin against toxic effects of doxorubicin.