الفهرس 
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Abstract
Chia (Salvia hispanica L.) seeds showed multiple biological activities. Doxorubicin (DOX) is one of the effective chemotherapy drugs for liver cancer treatment. Resistance to DOX is one of its limitations beside its adverse effects. Invitro study aimed to investigate the effect of the combination of chia seeds oil (CSO) and Chia seeds omega (CS- omega) with DOX on the tumor suppressor miRNAs and doxorubicin-metabolizing enzyme CYP-3A4, and multidrug resistance-associated protein (MRP1) in HepG2 cells. The results indicated that CS omega showed a non-significant effect on the cytotoxicity of DOX. While, the combined treatment CSO/DOX 5μg/ml/12.2μg/ml respectively led to increased HepG2 cells sensitivity to DOX as concluded from its higher cytotoxicity. Doxorubicin induced CYP-3A4, MRP1 and their corresponding mRNAs, while CSO inhibited both of their expression and proteins in DOX-treated cells. CSO induced tumor suppressor miRNAs. DOX was found to downregulated miR-122 and let-7/b/e and elevated let-7a expression , while CSO/DOX upregulated let-7/b/e, miR-34a, and miR-122 (which inhibits MRP1) and downregulate let-7a that may lead to increase apoptosis. Invivo study aimed to investigate the influence of CSO and CS omega on DOX-induced resistance and antioxidant status. CSO and CS Omega showed an improvement significantly in oxidative stress biomarkers by increasing in GSH levels, CAT activities, decreasing MDA levels in liver, kidney and heart tissues.Treatment with CSO and CS Omega led to a significant decrease in ALT, GGT, LDH , AST activitires, creatinine and uric acid concentrations. Histopathological examinations were confirmed these findings. In the liver tissues, miR-122 showed asignificant inhibition in DOX group compared to the control group. On contrary, CSO/DOX group resulted in a remarkable induction in the tumor suppressor miR-122 as compared to DOX-treated group. Moreover, miRNA let-7a expression was explored in different rat groups. DOX-treated group showed a dramatic induction in the expression of let-7a, compared to the control group, while the combined treatment with CSO/DOX group resulted in a notable inhibition in let-7a compared to DOX-treated group. Generally, A concentration of 30% IC50 (12.2μg/ml) combined with CSO (5µg/ml) for 24h resulted in a higher cytotoxic effect of doxorubicin and a significant induction to all of the tested tumor suppressor miRNAs but to variable extents. CSO effectively re-sensitized HepG2 cells to liposomal –doxorubicin via inhibiting MRP-1 and CYP-3A4, which increase in vivo doxorubicin bioavailability and decrease its therapeutic dose to diminish its adverse effects. CSO is capable of re-sensitized hepatic cells to doxorubicin effectively via inhibiting MRP1 and CYP3A4. Moreover, CSO inhibited hepatic resistance to DOX via inducing miR-122 and inhibiting let-7a. Additionally, CSO can potentiate DOX cytotoxicity and control the hepatic cells via inhibition c-MYC.