الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
 |  | from | 238 |  |  |
| | | from | 238 | | |
Abstract
The current study was conducted to investigate the potential antifibrotic effect of Deferasirox (DFX) and to elucidate the possible underlying molecular mechanisms in a rat model of liver fibrosis. To fulfill these goals, the study was divided into 2 parts;
Part 1: Screening of the hepatoprotective dose of DFX against con A-induced acute liver injury
Rats were randomly divided into five groups, as follows:
- group A: control rats who received vehicles only.
- group B: rats were intravenously injected with concanavalin A (con A) at a dose of 20 mg/kg only once to induce acute liver injury.
- Groups C, D, E: rats received 3 different doses of DFX (25, 50, 100 mg/kg respectively) orally only once, followed by an intravenous injection with 20 mg/kg con A two hours later.
This study revealed that 100 mg/kg DFX is the most hepatoprotective dose since it significantly decreased both ALT and AST levels, as compared to con A group and the other doses of DFX. This was confirmed by the histopathological examination where the 100 mg/kg DFX was able to restore the histological architecture and alleviate the damage induced by con A. So, this dose was used to investigate its antifibrotic effect.
Part 2: Studying the hepatoprotective mechanisms of DFX against con A-induced liver fibrosis
Rats were randomly divided into four groups, as follows;
- group A: control rats who received vehicles only.
- group B: rats were intravenously injected with con A (15 mg/kg) once per week for a total of 6 weeks to induce liver fibrosis.
- group C: rats received 100 mg/kg DFX orally 3 times/week, in addition to intravenous injection of con A (15 mg/kg) once/week for a total of 6 weeks.
- group D: rats received 100 mg/kg DFX orally 3 times/week for a total of 6 weeks.
The following parameters were assessed:
• Hepatotoxicity markers:
1. ALT serum activity.
2. AST serum activity.
3. Albumin level.
4. Calculation of liver index.
• Histopathological examination (H & E staining).
• Liver fibrosis markers:
1. Liver content of hydroxyproline.
2. α-SMA actin expression.
3. Masson trichrome stain.
• Oxidative stress markers:
1. Reduced glutathione (GSH).
2. Superoxide dismutase (SOD).
3. Catalase.
4. Lipid peroxides measured as malondialdehyde (MDA).
5. NOX-4 mRNA expression.
6. P22phox mRNA expression.
• Inflammatory markers:
1. Nuclear factor kappa b (NF-κB).
2. Inducible nitric oxide synthase (iNOS).
3. Tumor necrosis factor-alpha (TNF-α).
4. Interferon-gamma (IFN-γ).
• Iron homeostasis parameters:
1. Serum iron level.
2. Liver iron level.
3. Total iron binding capacity (TIBC).
4. Transferrin saturation.
5. CEBP- homologous protein (CHOP) mRNA expression.
6. Phosphorylated cyclic AMP responsive element binding protein (P-CREB).
7. Hepcidin expression.
The findings of this study revealed that DFX possess:
- Hepatoprotective effect as evidenced by the significant decrease in serum activities of ALT, and AST, albumin level and liver index as compared to con A-intoxicated group. Moreover, it provided significant protection against con A-induced histological damage.
- Antifibrotic effect as evidenced by the significant decrease in α-SMA expression, hepatic content of hydroxyproline, and minimal deposition of collagen shown in Masson trichrome stain as compared to con A-intoxicated group.
- Anti-oxidant properties as evidenced by the significant decrease in NOX-4 and p22phox mRNA expression, GSH levels, and activities of SOD, and CAT as compared to con A-intoxicated group.
- Anti-inflammatory properties as evidenced by the significant decrease in NF-κB, iNOS, TNF-α, and IFN-γ as compared to con A-intoxicated group.
- In addition, it maintained iron homeostasis through the significant decrease in serum & liver iron levels, transferrin saturation, CHOP mRNA expression, P-CREB expression, and the significant increase in both TIBC and hepcidin expression as compared to con A-intoxicated group. The significant decrease in hepatic iron deposition was confirmed histologically by the prussian blue stain where DFX was able to minimize iron deposition as compared to the significant iron deposition shown in con A-intoxicated group.
Based on the aforementioned results, our study confirmed the antifibrotic effect of DFX against con A-induced liver fibrosis through its antioxidant, anti-inflammatory, and iron-chelating properties.
In conclusion, this study sheds the light on the mechanistic clues to the potential antifibrotic effect of DFX. The present study proved that DFX maintained iron homeostasis through regulating P-CREB, CHOP, and hence, hepcidin. This contributed to its anti-oxidant effect where it lessened the expression of both NOX-4 and its catalytic subunit p22phox. Moreover, it had offset the increase in IFN-γ and TNF-α, thus preventing the immunological stimulation of the liver. Taken together, DFX could offer significant hepatoprotection and antifibrotic effect against iron overload-induced liver fibrosis (Fig. 4.1).