Liposomal Resveratrol and/or Carvedilol Attenuate Doxorubicin-Induced Cardiotoxicity by Modulating Inflammation, Oxidative Stress and S100A1 in Rats

Figure 1. Carvedilol (CAR) and/or resveratrol (RES) and LIPO-RES ameliorate serum CK-MB (A), troponin-I (B) and LDH (C) in DOX-intoxicated rats. Data are expressed as mean ± SEM, (n = 6). *** p < 0.001 versus Control. # p < 0.05, ## p < 0.01 and ### p < 0.001 versus DOX.

Figure 2. Photomicrographs of sections in the left ventricles (LV) of (A) control rats showing normal histology of cardiomyocyte cytoplasm (star) and nuclei (arrows) and normal distribution of endomysium (bold arrow). (B) DOX-intoxicated rats showing foci of degenerated cardiomyocytes and collection of inflammatory cells in the endomysium (bold arrow). (C) CAR-treated rats showing mild improvement of myocardium with less degeneration (arrow) and inflammatory cells (bold arrow). (D) RES-treated rats showing foci of degenerated cardiomyocytes (arrow) and few inflammatory cells (bold arrow). (E) CAR/RES- and (F) LIPO-RES-treated rats showing moderate decrease in degeneration (arrow) and inflammatory cells (bold arrow); and (G) CAR/LIPO-RES-treated rats with no degeneration or inflammatory cells and the cardiomyocytes appear normal. (× 400; H&E; scale bar: 50 µm).

Figure 3. Photomicrographs of anti-TLR-4-stained LV sections in: (A) Control rats showing the absence of immune reaction in cardiomyocytes cytoplasm and nuclei (arrow); (B) DOX-intoxicated rats showing very strong immune positivity; (C) CAR-treated rats showing mild immune positive reaction; (D) RES-treated rats showing strong positive immune reaction; (E) CAR/RES-treated rats showing very mild immunostaining; (F) LIPO-RES-treated rats showing moderate immune reaction and (G) CAR/LIPO-RES-treated rats showing marked decrease in TLR-4 immune reactivity. (H) Mean ± SEM of TLR-4 immunostaining in LV sections of different groups, (n = 6). *** p < 0.001 versus Control and ### p < 0.001 versus DOX.

Figure 4. Photomicrographs of anti-iNOS-stained LV sections in: (A) Control rats showing the absence of immune reaction in cardiomyocytes cytoplasm and nuclei (arrow); (B) DOX-intoxicated rats showing multiple scattered foci of strong immune positivity; (C) CAR- (D) RES- (E) CAR/RES- and (F) LIPO-RES-treated rats showing moderate decrease in iNOS expression, and; (G) CAR/LIPO-RES-treated rats showing marked decrease in iNOS immune reactivity. (H) Mean ± SEM of iNOS immunostaining in LV sections of different groups, (n = 6). *** p < 0.001 versus Control and ### p < 0.001 versus DOX.

Figure 5. CAR and/or RES and LIPO-RES decrease cardiac TNF-α (A) and IL-6 (B) in DOX-intoxicated rats. Data are expressed as mean ± SEM, (n = 6). *** p < 0.001 versus Control. # p < 0.05, ## p < 0.01 and ### p < 0.001 versus DOX.

Figure 6. CAR and/or RES and LIPO-RES decrease cardiac MDA (A) and increase GSH (B) and SOD (C) in DOX-intoxicated rats. Data are expressed as mean ± SEM, (n = 6). *** p < 0.001 versus Control. # p < 0.05, ## p < 0.01 and ### p < 0.001 versus DOX.

Figure 7. Effect of CAR and/or RES and LIPO-RES on cardiac S100A1. (A) Representative Western blotting of S100A1 and GAPDH. (B) CAR and/or RES and LIPO-RES up-regulated cardiac S100A1 in DOX-intoxicated rats. Data are expressed as mean ± SEM, (n = 6). *** p < 0.001 versus Control. ### p < 0.001 versus DOX.

Figure 8. CAR and/or RES and LIPO-RES increase cardiac SERCA2a in DOX-intoxicated rats. Data are expressed as mean ± SEM, (n = 6). *** p < 0.001 versus Control. ### p < 0.001 versus DOX.