Table 1.
Tangeretin pre-treatment improved liver function and inhibited cisplatin-induced aberrations in lipids profile.
Fig 1.
Tangeretin alleviates cisplatin-induced hepatic histopathologic injury in rats.
Representative photomicrographs of sections from of liver tissues stained by hematoxylin and eosin (× 400 magnification). (A) Control rats receiving saline vehicle showed normal histological structure of the hepatic lobule. (B) Rats which received silymarin (100 mg/kg p.o.) showed normal hepatic histology with few Kupffer cell activation (arrow). (C) Rats which received tangeretin (100 mg/kg p.o.) showed slight hydropic degeneration of hepatocytes (arrow). (D) Cisplatin-treated group showed dilatation and congestion of central vein and hepatic sinusoids (arrow). (E) Liver of rat from cisplatin-treated group group demonstrated congestion of central vein (short arrow), cytoplasmic vacuolization of hepatocytes (long arrow) and focal hepatic necrosis associated with inflammatory cell infiltration (arrow head) (F, G) Silymarin and tangeretin pre-treatment revealed attenuated morphological modifications with resolving Kupffer cell activation (arrow).
Table 2.
Liver microscopic damage.
Fig 2.
Tangeretin mitigates cisplatin-induced inflammatory response in liver tissues.
The effect of tangeretin pretreatment on cisplatin-induced inflammatory response in liver tissues as indicated by the modulation of TNF-α (A) and IL-10 (B). Columns, mean; bars, ± SEM (n = 8 independent values). Statistical analysis was carried out by using one way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparisons test. *Significant difference from normal control (vehicle) group at p < 0.05, #Significant difference from cisplatin group at p < 0.05. Tang 50; tangeretin (50 mg/kg), Tang 100; tangeretin (100 mg/kg).
Fig 3.
Tangeretin modulates cisplatin-induced protein expression of Bax and Bcl-2 in rat liver.
Representative images for the immunohistochemical detection of Bax (A -F) and Bcl-2 (G-L) expression in liver tissues (arrows) (magnification: × 400).
Fig 4.
Tangeretin counteracts cisplatin-induced apoptotic changes of Bax and Bcl-2 in protein expression in rat liver.
(A) Western blot analysis showed the expression levels of Bax and Bcl-2 in liver tissues after the indicated treatments. (B) Relative expression levels of Bax and Bcl-2. The amount of immunoblotted proteins was quantitated by densitometry and normalized to that of β-actin. Columns, mean; bars, ± SD (n = 3 independent experiments). (C) Relative caspase 3/7 activity in liver tissues after the indicated treatments. Columns, mean; bars, ± SD (n = 4 independent values). Statistical analysis was carried out by using one way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparisons test. Silymarin (100 mg/kg); Tangeretin (100 mg/kg); Cisplatin (7.5 mg/kg). *Significant difference from normal control (vehicle) group at p < 0.05, #Significant difference from cisplatin group at p < 0.05.
Fig 5.
Tangeretin limits cisplatin-induced oxidative stress in liver tissues.
The effect of tangeretin pretreatment on cisplatin-induced oxidative stress in liver tissues as indicated by the modulation of hepatic NO (A) and GSH content (B). Columns, mean; bars, ± SEM (n = 8 independent values). Statistical analysis was carried out by using one way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparisons test. *Significant difference from normal control (vehicle) group at p < 0.05, #Significant difference from cisplatin group at p < 0.05. Tang 50; tangeretin (50 mg/kg), Tang 100; tangeretin (100 mg/kg).
Fig 6.
Tangeretin boosts hepatic antioxidant defense in cisplatin-induced oxidative stress in liver tissues.
The effect of tangeretin pretreatment on cisplatin-induced oxidative stress in liver tissues as indicated by the modulation of GPx (A), MDA (B) and NRF-2 (C) content. Columns, mean; bars, ± SEM (n = 8 independent values). Statistical analysis was carried out by using one way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparisons test. *Significant difference from normal control (vehicle) group at p < 0.05, #Significant difference from cisplatin group at p < 0.05. Tang 50; tangeretin (50 mg/kg), Tang 100; tangeretin (100 mg/kg).
Fig 7.
Tangeretin downregulates MAPK pathway in cisplatin-induced acute hepatic injury.
Western blot analysis demonstrates that cisplatin increased the phosphorylation of p38 MAPK (upper panel), JNK (middle panel) and ErK1/2 (lower panel) without affecting the corresponding total protein levels, compared to the control group. Tangeretin and Silymarin pretreatments mitigated the phosphorylation of the three MAPKs. Tang 50; tangeretin (50 mg/kg), Tang 100; tangeretin (100 mg/kg).
Fig 8.
Diagram depicting the proposed protective mechanisms of tangeretin against cisplatin-induced hepatic injury.