الفهرس 
Hepatocellular carcinoma (HCC)Only 14 pages are availabe for public view
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Abstract
Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. The disease is associated with environmental exposure to hepatitis B virus and hepatitis C virus and Diethyl nitrosamine (DEN) that found in many consumed foods and reported as inducer for cancer in animals and humans. New anti-cancer drugs has been developed because of the reality that cancer cells, which are resistant to current chemotherapy, will eventually dominate the cells population and cause mortality. Melatonin is one among the categories of compounds having various therapeutic and pharmacological effects against hepatocarcinoma HepG2 cell line. MSCs based cell therapy has emerged as a promising therapeutic strategy. Great advance have been made using MSCs to treat cancer but the low viability of transplanted MSCs severely limits the efficiency of MSCs therapy. Melatonin has been given before MSCs injection as a new strategy to improve viability and MSCs homing to treat HCC 6.2. Aim of the work This study aimed to compare between the therapeutic effect of melatonin and MSCs on experimentally induced HCC in adult female rats. It also aimed to assess the role of antioxidant, cell cycle arrest, apoptotic, and anti-inflammatory factors. 6.3. Materials and methods HCC has been induced by injection with a single dose of DEN (200 mg/kg body weight) interperitonial and control group received saline only. The DEN-treated animals were administered with repeated doses of 2-acetyamino fluorine (150 mg/kg body weight) orally for 6 days alternatively that served as promoting agent. HCC rats were treated by melatonin (MLT) which was given intraperitoneal a dose of (50 mg/kg) for 8 days and a single dose of MSCs (1X106 cells/rat) was intravenously injected for each HCC rat. A total number of sixty four female rats were divided into eight groups and eight animals for each group as follows: control (Cnt), MLT, MSCs, MLT+MSCs, HCC, HCC+MLT, HCC+MSCs, and HCC+MLT+MSCs. After 24 week, all animals were killed and blood samples were withdrawn. To evaluate the desired aims, a biochemical tests to measure alanine transaminase (ALT), alkaline phosphatase (ALP), total protein level and antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), Glutathione peroxidase (GPX) and oxidative stress MDA. Relative gene expression by real-time PCR for apoptotic, cell cycle arrest, antioxidant and inflammatory genes were also detected. Liver tissues were preserved in 10% formalin for histological and immunohistochemical analysis. 6.4. Results The results demonstrated that treatment by melatonin could improve viability and function of BMMSCs. Injection of BMMSCs after repeated doses of melatonin of 50 mg/kg rat for 8 days showed increased activities of the antioxidant enzymes as, CAT, SOD, GPx and decreased lipid peroxidation marker (MDA) along with improved liver function as revealed by reduction of ALT, ALP enzymes and increase total protein. Also treatment by melatonin resulted in up regulation expression of apoptotic, cell cycle arrest, antioxidant genes, and down regulation of relative expression of inflammatory genes. The treatment by melatonin showed improved histological liver architecture and showed significant decrease in hepatic foci as revealed by reduction of glutathione S-transferase placental form (GSTP) immunostain as well as an interesting increase of cellular apoptosis as revealed by decreased proliferating cell nuclear antigen (PCNA) immunostain, Bcl-2 and PD-L1. Homing of male MSCs were confirmed by male sry gene at females liver section and immunohistochemical for CD105 MSCs On other hand, there was no significant difference between treatment between MLT or BMMSCs; while combination between MLT and MSCs showed more improvement than each one alone. 6.5. Conclusion and recommendation Here, demonstrated that given MLT before MSCs fostered the viability and therapeutic potential of MSCs possibly, through inhibition of oxidative stress in tumor microenvironment and improvement homing of cells. This new strategy showed better therapeutic outcomes and could improve BMMSCs-based therapy for HCC, so we recommend further studies on the effect of MLT and MSCs as therapeutic system on HCC.