الفهرس 
I-Introduction & Aim of the workOnly 14 pages are availabe for public view
 |  | from | 191 |  |  |
| | | from | 191 | | |
Abstract
Oxidative stress is one of the aggravating factors that caused damage to the pathogenesis of many diseases. In our study, MTX is a folic acid antagonist widely used for treatment and prophylaxis of several disorders, comprising autoimmune diseases, malignant tumours, and inflammatory disorders. However, its deleterious effects due to oxidative and inflammatory pathways initiation have been reported as the most serious problem that faces the physician.
In order to overcome and an early protecting against these deleterious effects antioxidant and anti-inflammatory drug, PHLwas chosen using NAC as a standard agent.
In our study, sixty-six male Swiss albino rats were divided into six groups; 11 rats in each group, rats were randomly divided into a normal control group, a respective group (PHL 40 mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20 mg/kg, i.p., once), and three treated groups received NAC (150 mg/kg/day; a reference standard), PHL (40 mg/kg/day) and PHL (80 mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX.
At the end of the experiment, rats were anaesthetized, blood samples drawn and, the liver and kidneys of each rat were dissected out for assessment of biochemical, molecular and histopathological parameters as follows:
Assessment of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum creatinine and urea as kidney function biomarkers, serum cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α), as inflammatory biomarkers, hepatic and renal total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2-), catalase (CAT), glutathione-S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic and renal caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings.
These results obtained as follows:
1. A single administration of MTX was shown to cause deterioration in liver and kidney function biomarkers evidenced by a significant increase in serum levels of ALT, AST and LDH, urea and creatinine, as compared to control group. Additionally, MTX caused significant elevations in inflammatory mediators COX-2 and TNF-α as compared to control group, which confirmed a link between MTX injury and inflammation. Moreover, MTX was demonstrated to initiate oxidative and nitrosative biomarkers evidenced by a significant reduction in hepatic and renal TAC, a significant reduction in hepatic and renal GSH content, significantly reduced hepatic and renal antioxidant enzymes CAT, GST and SOD activities, and significantly elevated hepatic and renal TBARS and NO2- contents. Additionally, MTX was shown to increase cell apoptosis, which manifested by a significant upregulation of hepatic mRNA caspase-3 expression. Furthermore, a reduction in survival rate, which manifested by acute hepatic and renal failure caused by MTX. Finally, a progression of histopathological changes with inflammatory cell infiltration in the hepatic and renal tissues compared to control group, which strongly coherent with biochemical findings.
2. Phloridzin administration depends mainly on its metabolite form Phloretin, pre-treatment with PHL showed corrections in liver and kidney function biomarkers, which manifested by significantly reduced serum levels of ALT, AST and LDH, urea and creatinine as compared to MTX-treated group.
3. In our study, pre-treatment with PHL showed hepatic and renal protective potential evidenced by the ability of PHL to ameliorate the progression of the inflammation and manifested by significantly decreased serum levels of COX-2 and TNFα as compared to MTX-treated group.
4. Phloridzin showed strong antioxidant capacity, which demonstrated by a significant raising in hepatic and renal TAC, a significant elevation in hepatic and renal content of GSH, and significantly reduced hepatic and renal TBARS and NO2- contents. Moreover, significantly elevated hepatic and renal antioxidant enzymes CAT, GST and SOD activities.
5. In addition, PHL showed anti-apoptotic activity in the hepatic and renal tissues, which demonstrated by a significant downregulation of hepatic and renal mRNA caspase-3 expression. Furthermore, pre-treatment with PHL showed a reduction in the mortality rate of MTX-treated rats demonstrated by the ability of PHL to ameliorate hepatic and renal injury caused by MTX. Finally, PHL showed alleviation in histopathological changes which strongly consistent with biochemical findings.