الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Breast cancer (BC) is the most frequent cancer in women all over the world. It is the second leading cause of cancer related death cases among women. Tamoxifen is widely used for the treatment of hormone-responsive BC because of two significant advantage: it is inexpensive and is well tolerated. Tamoxifen therapy has been linked to the development of fatty liver. Recently, multiple reports have also associated TAM with cognitive impairment in breast cancer patients.
Luteolin, a natural flavonoid, has been traditionally used for treating various inflammatory disorders including liver diseases, cognitive impairments and cancer.
This study aimed to evaluate the potential protective effect of luteolin in TAM-induced cognitive deficits and liver steatosis.
Animals
Eight-week-old male albino rats weighing about (150–200 g) were obtained from an animal breeding facility (National Research Center, Giza, Egypt). The animals were housed in cages at a constant temperature of 25°C under 12 h day/night cycle.
They were given free access to food pellets and water ad libitum and left to acclimatize the laboratory environment for 1 week before the experiment. All the experimental procedures were approved by the Research Ethics Committee, Faculty of Pharmacy, Ain Shams University, Egypt under the memorandum no 82.
Experimental Design:
Rats were grouped into five groups (8 rats/group) as the following.
group I: Was considered as a control group and received daily subcutaneous (S.C.) injection of sesame oil containing 10% benzoyl alcohol for 7 days.
group II: Was considered as diseased group, they were exposed daily to
S.C. injections of TAM at a dose of 1mg/kg (dissolved in sesame oil containing 10% benzoyl alcohol) for 7days as previously described.
group III: Was considered as treated group and received daily oral gavage of luteolin at a dose of 20 mg/kg dissolved in 10% DMSO in normal saline concomitantly with S.C injection of TAM (1mg/kg) for 7days.
group IV: Received oral gavage of luteolin at a dose of 40 mg/kg concomitantly with S.C injection of TAM (1mg/kg) for 7days.
group V: Received daily oral gavage of luteolin (40mg/kg) for 7days. The dose of luteolin was chosen in accordance with a previous on NAFLD.
Twenty-four hours after the last injection the behavioral tests were conducted on all groups. Rats were sacrificed after 3 days from the last injection and blood samples were collected from the retro-orbital plexus and allowed to clot. Serum was separated by cold centrifugation of the blood at 4000 rpm for 20 minutes, and then stored at -80°C for subsequent use in the following tests. The following tissues; liver and brain tissues were dissected and washed with ice-cold saline either fixed in 10% formalin or stored at - 80°C for subsequent biochemical and for the histopathological examinations.
Behavioral tests Locomotor assessment test Passive Avoidance test
Y maze test
Histopathological examination Assessment of serum transaminases
Serum concentrations of alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) were determined.
Assessment of serum lipids profiles: total cholesterol (TC) and triglyceride (TG).
Assessment of liver tissue inflammatory markers: tumor necrosis factor- alpha (TNF-α), interleukin-1Beta (IL 1-β) and Transforming growth factor Beta(TGF-β).
Assessment of protein expression: hepatic β-catenin and glycogen synthase kinase 3 (GSK-3β) protein expression.
Results: Luteolin significantly alleviated behavioral defects in TAM- induced cognitive impairment rats. Assertively, luteolin significantly reversed histopathological neurodegeneration in the cortex and the hippocampal areas in TAM induced models. Furthermore, luteolin attenuated hepatic steatosis. Luteolin cotreatment decreased hepatotoxic serum markers (AST and ALT).
Besides, it reversed increased hyperlipidemia (TG). As an anti-inflammatory agent, luteolin improved increase hepatic inflammatory markers (TNF-α, IL-
1β, TGF-β) accompanied by increasing β-catenin protein expression in TAM induced fatty liver.
Conclusions This study showed that luteolin improved cognitive impairment and fatty liver associated with TAM administration. Thus, adding luteolin with TAM will beneficially guard against neurodegeneration and liver steatosis induced by TAM treatment. Besides, this study suggested β-catenin as a novel promising therapeutic candidate in reducing TAM- induced fatty liver, however, future mechanistic studies are required to confirm our finding.