الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
 |  | from | 270 |  |  |
| | | from | 270 | | |
Abstract
The current study was carried out on adult male albino rats to examine the possible therapeutic effects of resveratrol and/or quercetin on some biochemical and haematological parameters linked to diethylnitrosamine (DENA)-induced tuomor inflammation, angiogenesis, hepatocellular carcinoma and coagulation-fibrinolysis abnormalities.
This work which was included two experiments. In the first experiment, the animals were classified into two main groups:
A. Control group (C): thirty one rats served as normal control and were treated with vehicle intraperitoneally, received 1 ml normal saline (0.9 % NaCl).
B. Hepatocellular carcinoma group (HCC): ninety four rats received intraperitoneal injection of DENA 100 mg/kg of body weight dissolved in normal saline (0.9% NaCl) solution once per week for three weeks. One week after the final dose of DENA. The rats received an intraperitoneal injection of PB 100 mg/kg once per day for 7 successive days.
At the completion of the 7 days treatments, 10 rats from each group were sacrificed by rapid decapitation after 24 hrs of the last dose of administrations and their blood samples were collected in clean dry test tube for determination of: Serum used for biochemical studies and plasma, (added sodium citrate or EDTA blood) used for haematological studies. For measurements the levels of serum α-feto protein (AFP), and liver functions parameters (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT)), total protein and albumin. Vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin- 6 (IL-6), cyclooxygenase-2(COX-2), α1-antitrypsin, glutathione oxidized (GSSG), heparanase, neutrophil elastase, endostatin, glutathione (GSH) and GSH/GSSG ratio. WBCs, platelets, monocyte, neutrophil percentage, lymphocyte percentage, prothrombin time (PT), partial thromboplastin time (PTT), thrombin antithrombin complex (TAT), fibrin degradation product (FDP), α2-macroglobulin, thrombin time (TT), fibrinogen, plasminogen and antithrombin, (AT)
In the second experiment, the remaining of normal control animal rats was served as control rats group (group A) (twenty one rats), while the remaining eighty four HCC rats will further sub divided in to the following groups (each group contains 21 rats):
group B HCC rats.
group B–1 HCC rats that received intraperitoneal quercetin (50 mg/kg/day) for 2, 4, and 8 weeks.
group B-2 HCC rats intraperitoneal administered resveratrol (50 mg/kg/day) for 2, 4, and 8 weeks.
group B-3 HCC rats injected intraperitoneal resveratrol (50 mg/kg/day) and quercetin (50 mg/kg/day) for 2, 4, and 8 weeks.
At the end of each period of experiment, 7 rats from each above group were sacrificed and measurement criteria mentioned above after 2, 4, and 8 weeks.
DENA / PB induced a significant increase in the serum levels of AFP, and liver functions parameters AST, ALT, ALP, LDH and GGT. A significant decreases in total protein and albumin levels in HCC model group as compared with the normal group.
A marked increases in the activities of VEGF, MMP-2, MMP-9, TNF-α, IL-1β, IL-6, COX-2, α1-antitrypsin, GSSG, heparanase and neutrophil elastase while there were significant decreases in endostatin, GSH and GSH/GSSG ratio levels in HCC model group.
Hematological effects of DENA and PB showed increases in the count of WBCs, platelets, monocyte, and neutrophil percentage. Furthermore, there was decreased in lymphocyte percentage and significant increases in PT, PTT, TAT, FDP, α2-macroglobulin, TT and fibrinogen. The HCC model group showed significant decreases in plasminogen and AT as compared to normal group.
The supplementation of resveratrol or quercetin to HCC rats group led to a significant decrease in the concentration of AFP, AST, ALT, ALP, LDH and GGT. A marked increase occurred in the concentration of total protein and albumin in HCC rats group were treated with resveratrol or quercetin. Decreases in the levels of VEGF, MMP-2, MMP-9, TNF-α, IL-1β, IL-6, COX-2, α1-antitrypsin, GSSG, heparanase and neutrophil elastase and significant increase in levels of endostatine, GSH and GSH/GSSG ratio. Maximum correction were recorded in the HCC rats group which treated with both resveratrol and quercetin at the end of the experiment (8 weeks).
A significant decrease occurred in the count of WBCs, platelets, monocyte, neutrophil percentage and increase in lymphocyte percentage. A marked decrease in the levels of PT, PTT TAT, FDP, α2-macroglobulin, TT and fibrinogen after rats were treated with resveratrol or quercetin in relation to control rats group. The attenuation was more pronounced after HCC rats group were received a mixture of quercetin and resveratrol and this correction depended on the time of treatment at the end of experiment (8 weeks).
DENA / PB induced a high significant decrease in plasminogen and AT levels. A marked increase occurred in plasminogen and AT levels after rats were treated with resveratrol or quercetin as compared to HCC rats group. It is clear from the data recorded that maximum best correction was occurred in HCC rats group which treated with both quercetin and resveratrol depending on the time of treatment.
Accordingly, from the above results it was noticed that in all parameters under investigation the maximum improvement was noticed in the last intervals (8 weeks) after the rats were treated with mixture of resveratrol and quercetin and this indicated that improvement in this study depended on time and therapeutic effects of resveratrol and quercetin together. Thus, the current investigation was designed to examine the possible therapeutic effects of resveratrol and/or quercetin in treating the hepatocellular carcinoma and related oxidative stress, inflammation, angiogenesis, and coagulation-fibrinolysis abnormalities caused by administration of DENA ∕PB in rats and resveratrol and/or quercetin led to a significant amelioration effects on the haematological and biochemical changes results from hepato-carcinogenesis by DENA ∕PB.
In conclusion, this study demonstrated that resveratrol and quercetin through its marked antioxidant activity coupled with favorable hemodynamic effects salvages DENA ∕PB hepato-carcinogenesis and oxidative stress, inflammation, angiogenesis, and coagulation-fibrinolysis abnormalities depending on resveratrol and quercetin together and time of treatment. So, this study recommends that HCC therapy should be preceded and followed up by natural products, derived from plant sources. The use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenesis is considered an important way for confronting HCC. The conventional therapy of hepatocarcinoma including chemotherapy, radiation, surgical resection and ablation gives little hope for restoration of health because of poor diagnosis and serious side effects. Therefore, developing more effective and less toxic anticancer agents, including natural products, is necessary to prevent or retard the process of hepatocarcinogenesis. Finally, it can be concluded that combination of quercetin with resveratrol using in treatment of HCC, The two phenol exert their synergistic effect through different mechanisms with 50 mg/kg b.wt. quercetin with resveratrol for 8 weeks proved to have a better therapeutic effects against DENA ∕PB hepatocarcinogenesis than 50 mg resveratrol or quercetin alone . Therefore, 50mg resveratrol and quercetin might open a new therapeutic possibility in patients with HCC.