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. 2023 Nov 20;11(11):3098.
doi: 10.3390/biomedicines11113098.

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice

Dhafer Y Alhareth  1 , Abdulrazaq Alanazi  1 , Wael A Alanazi  1 , Mushtaq A Ansari  1 , Mahmoud N Nagi  1 , Sheikh F Ahmad  1 , Mohamed S M Attia  1 , Ahmed Nadeem  1 , Saleh A Bakheet  1 , Sabry M Attia  1
Affiliations

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice

Dhafer Y Alhareth et al. Biomedicines. .

Abstract

Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

Keywords: animal model; carfilzomib; hepatotoxicity; inflammation; oxidative and nitrosative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Serum levels of alanine aminotransferase (ALT, (A)) and aspartate aminotransferase (AST, (B)) in treated and untreated mice (mean ± SD, N = 6). Group 1, control animals; Group 2, CFZ (2 mg/kg); Group 3, LPS/GalN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg); Group 4, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/0.5 mg/kg); Group 5, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/1 mg/kg); Group 6, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/2 mg/kg). ** p < 0.01 vs. control group and a p < 0.05, b p < 0.01 vs. LPS/GalN/DMSO group (ANOVA test followed by Tukey–Kramer multiple comparisons test).
Figure 2
Figure 2
Levels of serum tumor necrosis factor alpha (TNF-α, (A)), hepatic nuclear factor kappa beta (NF-кB, (B)), and hepatic caspase 3 activation (C) in treated and untreated mice (mean ± SD, N = 6). Group 1, control animals; Group 2, CFZ (2 mg/kg); Group 3, LPS/GalN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg); Group 4, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/2 mg/kg). ** p < 0.01 vs. control group and b p < 0.01 vs. LPS/GalN/DMSO group (ANOVA test followed by Tukey–Kramer multiple comparisons test).
Figure 3
Figure 3
Levels of hepatic cyclooxygenase-II (COX-II, (A)) expression and hepatic myeloperoxidase activity (MPO, (B)) in treated and untreated mice (mean ± SD, N = 6). Group 1, control animals; Group 2, CFZ (2 mg/kg); Group 3, LPS/GalN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg); Group 4, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/2 mg/kg). ** p < 0.01 vs. control group and b p < 0.01 vs. LPS/GalN/DMSO group (ANOVA test followed by Tukey–Kramer multiple comparisons test).
Figure 4
Figure 4
Levels of hepatic inducible nitric oxide synthase (iNOS, (A)) and nitric oxide (NO, (B)) in treated and untreated mice (mean ± SD, N = 6). Group 1, control animals; Group 2, CFZ (2 mg/kg); Group 3, LPS/GalN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg); Group 4, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/2 mg/kg). ** p < 0.01 vs. control group and b p < 0.01 vs. LPS/GalN/DMSO group (ANOVA test followed by Tukey–Kramer multiple comparisons test).
Figure 5
Figure 5
Levels of hepatic malondialdehyde (MDA, (A)) and glutathione (GSH, (B)) in treated and untreated mice (mean ± SD, N = 6). Group 1, control animals; Group 2, CFZ (2 mg/kg); Group 3, LPS/GalN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg); Group 4, LPS/GalN/DMSO/CFZ (10 µg/kg/400 mg/kg/200 µL/kg/2 mg/kg). ** p < 0.01 vs. control group and b p < 0.01 vs. LPS/GalN/DMSO group (ANOVA test followed by Tukey–Kramer multiple comparisons test).
Figure 6
Figure 6
Histopathological investigation of hematoxylin/eosin-stained hepatic sections of treated and untreated mice at a scale bar of 50 µm. (A): Liver tissue from control mice showing a normal central vein (CV, white arrow), from which radiate the hepatic cords separated by hepatic sinusoids (S). (B): Liver tissue from mice injected with CFZ (2 mg/kg) showing a normal central vein (CV, white arrow) with surrounding intact hepatocytes (Hc). (C): Liver tissue from mice injected with LPS/GALN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg) showing infiltration of leukocytes in liver tissue, congestion/dilation in the central vein (DCV) (green arrow) with loss of hepatic architecture, blood sinusoids (red arrow) in some areas, fatty changes (yellow arrow), and foci of hepatic cell necrosis with Councilman body formation (black arrow). (D): Liver tissue from mice injected with LPS/GALN/DMSO (10 µg/kg/400 mg/kg/200 µL/kg) and CFZ (2 mg/kg) showing normal central vein (CV, white arrow) and preservation of cellular architecture and integrity of hepatocytes (Hc). The histopathological scoring of the observed pathological changes is shown by the bar graph ((E), mean ± SD). ** p < 0.01 vs. control group and b p < 0.01 vs. LPS/GalN/DMSO group (Kruskal–Wallis test followed by Dunn’s multiple comparisons test).
Figure 7
Figure 7
A schematic illustration of the possible mechanism(s) implicated in LPS/GalN/DMSO-caused hepatic cell death and its proposed points of interference with CFZ. ↑ = increase and ↓ = decrease.
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