الفهرس 
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Abstract
This study aimed to evaluate the effect of modulating glucose metabolism on DAB-induced HCC in mice through the inhibition of glycolysis by Phloretin and the activation of gluconeogenesis by Dexamethasone.
Mice were divided into 8 study groups: normal control, HCC-induced untreated, normal + PH, normal + DEXA, HCC-induced + DMSO, HCC-induced + PH, HCC-induced + DEXA, and HCC-induced + combined PH+DEXA treatment.
After treatment period, relative expression for the Caspase-3, Cyclin D1, Beclin 1, Cytokeratin 18, Glucose transporter 2, and Phosphoenolpyruvate carboxykinase genes and ATP concentration were measured. Furthermore, serum ALT, AST, and random blood sugar were also measured for all mice groups. Histopathological examination of liver sections was also performed to assess the effect of treatment on the histology of the tumor. Finally, molecular in silico investigations were performed to further identify potential targets for both PH and DEXA that might further explain novel mechanisms leading to their anti-cancer effects, individually or in combination.
• Results:
1- PH and DEXA treatments caused a statistically significant increase in Caspase-3 expression levels individually and in combination in all treated groups and a higher effect was detected after DEXA treatment.
2- PH and DEXA treatments caused a statistically significant decrease in Cyclin D1 expression levels individually and in combination in all treated groups.
3- PH and DEXA caused a statistically significant decrease in Beclin1 expression levels individually and in combination in all treated groups.
4- PH and DEXA caused a statistically significant decrease in Cytokeratin-18 expression individually and in combination in all treated groups and a higher effect was detected after the combination of treatments.
5- PH and DEXA caused a statistically significant decreased Glucose transporter 2 expression levels individually and in combination in all treated groups.
6- PH and DEXA treatment caused a statistically significant increased PEPCK expression individually, but when combined PEPCK decreased to normal.
7- DEXA treatment increased ATP concentration, but when combined with PH, ATP level was significantly decreased.
8- Histopathological studies confirmed molecular analysis results, indicating DEXA treatment as the best treatment for HCC-induced animals compared to other single treatments and untreated animals, The Phloretin-based combination effectively reversed malignant tissue and restored normal hepatic architecture.
9- Molecular docking analysis showed that PH can bind to the target site of GLUT2 and therefore inhibit its actions.
10- Molecular in silico docking analysis suggested that DEXA can bind to the target site of retinoid X receptors (RXRα), therefore explaining a potentially novel mechanism for the activation of gluconeogenesis by DEXA through the inhibition of RXRα binding to PEPCK.