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Olive leaves as potential source for drug discovery in cholesterol, diabetes and human breast cancer
Hèdia Jemai, Zouhaier Bouallagui, Ines Feki, Mohamed Bouaziz, Junkuy Han, Hiroko Isoda and Sami Sayadi

Throughout the history, olive (Olea europea L.) leaves have been explored for the treatment of hypertension and other therapeutic uses. In this work we are investigating the potential hypocholesterolemic, anti-diabetic and anti-tumoral activities of an olive leaves extract from the chemlali olive cultivar largely cultivated in the south of Tunisia.

A series of models in vitro were setted-up. Firstly, the lipid-lowering and the antioxidative activities of oleuropein, oleuropein aglycone and hydroxytyrosol- rich extracts in rats fed a cholesterol-rich diet were tested. Wistar rats fed a standard laboratory diet or cholesterol- rich diets for 16 weeks were used. The cholesterol-rich diet induced hyperlipidemia resulting in the elevation of total cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C). Administration of polyphenol- rich olive leaves extracts significantly lowered the serum levels of TC, TG and LDL-C and increased the serum level of high density lipoprotein cholesterol (HDL-C). Furthermore, the content of TBARS in liver, heart, kidneys and aorta decreased significantly after oral administration of polyphenol- rich olive leaves extracts compared with those of rats fed a cholesterol-rich diet. In addition, these extracts increased the serum antioxidant potential and the hepatic CAT and SOD activities.
In second experiments, the antidiabetic activity of olive leaves extracts was investigated. Diabetes in Wistar rats was induced by intra- peritoneal injections of alloxan. Diabetic rats showed hyperglycaemia, hypercholesterolemia, increased lipid peroxidation and depletion in the antioxidant enzymes activities. The administration, for 4 weeks, of oleuropein and hydroxytyrosol rich extracts, leading to 8 and 16 mg/kg b. w of each compound, significantly decreased the serum glucose and cholesterols levels and restored the antioxidant perturbations.

In vitro cytotoxic effects against MCF7 cells were examined using MTT and neutral red tests. The anti-tumor acti vities were further investigated by flow cytometry and western blotting. Cytotoxicity assays resulted in a dose dependent inhibition of MCF7 cells growth. This inhibition was due to the growth arrest in the G0/G1 phase. The understanding of the molecular mechanism by which olive leaves extract arrested cell growth showed a down-expression of the peptidyl-prolyl cis-trans isomerase Pin1 which in turns decreased the expression of a G1 key protein; Cyclin D1. Besides the cell cycle arrest was not associated to the apoptosis as no cleavage for the PARP protein was detected. Additionally, the over-expression of c-jun might be an argument in favour of the cell survival.

Thus, olive leaves extract could be a potential alternative in cholesterol, diabetes and cancer therapy as well as a talented probable source of food and cosmetic additives.