الفهرس 
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Abstract
SUMMARY
Hepatocellular carcinoma (HCC) is an aggressive cancer. It
is one of the most frequent primary cancers at which its
incidence rate has been increased to become the fifth most
common malignancy worldwide and the third leading cause
of cancer-related deaths. The development of cancer is
a multistep and multiphase process. chronic hepatic
inflammation and oxidative stress are involved in the HCC
pathogenesis. Cancer chemoprotection is based on the use
of exogenous agents, mostly phytochemicals, to enhance
endogenous mechanisms against various stages of cancer
development.
Many countries used fenugreek as a traditional
dietary element. As a medicinal herb, fenugreek has proven
activity against hepatotoxicity. The present study aimed to
evaluate the antihepatocarcinogenesis activity of fenugreek
seed aqueous extract (FSAE, 6 g/kg body weight, orally
and daily for 14 weeks) and the diosgenin (DIOS,
a steroidal saponin of fenugreek seeds, 36 mg/kg body
weight, orally and daily for 14 weeks) in presence/absence
of a chemotherapy on HCC rats model. The HCC rat model
was induced by one intraperitoneal injection every 2 weeks
of diethylnitrosamine (DEN, 100 mg/kg body weight) for
14 consecutive weeks. Cyclophosphamide (CP, 20 mg/kg
body weight, intraperitoneal injection, twice/week for
6 consecutive weeks starting from the 9th week) was used
as chemotherapy in this study. Moreover, the present study
examined any harmful and toxic effects caused by
consumption of the FSAE and DIOS in healthy rats.
The results of the present study showed that the HCC
control group had a significant decrease (P<0.001,
compared with the healthy control group) in the body
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weight, the cell density of central lymphoid organs (bone
marrow and thymus), the concentration of serum proteins
(total protein, albumin and total globulins) and antiinflammatory
cytokine (interleukin (IL)-10), the hepatic
reduced glutathione (GSH) concentration, and the activity
of hepatic antioxidant enzymes: catalase (CAT),
glutathione peroxidase (GPx), glutathione reductase (GR)
and superoxide dismutase (SOD). While, it showed
a significant increase (P<0.001, compared with the healthy
control group) in the liver relative weight, clotting time,
prothrombin time, the concentration of serum α-fetoprotein,
bilirubin (total and direct) and proinflammatory cytokines
(IL-1β and tumour necrosis factor (TNF)-α), the serum
markers of tissue injury (transaminases (ALAT and
ASAT), alkaline phosphatase (ALP), -glutamyl transferase
(γ-GT) activities), the activity of hepatic glutathione-Stransferase
(GST), the count of bone marrow
micronucleated polychromatic erythrocytes (MnPCEs), and
DNA fragmentation. Moreover, the HCC control group
showed upregulation in the expression of hepatic caspase-3,
caspase-9 and p53, in addition to, serious histopathological
changes in liver including disorganization of the hepatic
strands, an irregularly dilation of the blood sinusoids and
the central vein, swollen in hepatocytes with necrotic areas,
and lymphocytes infiltration as compared with the healthy
control group.
FSAE and diosgenin in presence/absence of CP
significantly reduced (P<0.05-0.001) the relative liver
weight, clotting time, prothrombin time, the concentration
of serum bilirubin (total and direct), α-fetoprotein, TNF-α
and IL-1β, the activity of serum transaminases (ALAT and
ASAT), ALP and γ-GT, the hepatic GST activity, the count
of bone marrow MnPCEs and DNA fragmentation, as well
as downregulated the expression of hepatic caspase-3,
Summary
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caspase-9 and p53, in the HCC rat model. In addition,
FSAE and diosgenin in presence/absence of CP
significantly increased (P<0.05-0.001) the body weight,
thymus and bone marrow cells density, the concentration of
serum total proteins and IL-10, the hepatic GSH
concentration, and the activity of hepatic antioxidant
enzymes (CAT, GPx, GR and SOD) in the HCC rat model.
The concentration of serum albumins and globulins as well
as the histopathological changes in liver were mainly
improved in the HCC groups that received FSAE plus CP
or DIOS plus CP only. In general, the antihepatocarcinogenesis
activity of CP plus either FSAE or
diosgenin was more than that of CP alone. Moreover, the
antihepatocarcinogenesis activity of diosgenin was slightly
more than that of FSAE, especially in presence of CP.
On the other hand, the results obtained in this study
affirmed that treatment of adult male Wistar albino rats
with either FSAE or DIOS significantly increased (P<0.01-
0.001) the hepatic GSH concentration and serum IL-10
concentration, which may be beneficial in improving the
antioxidant defence system and treatment of inflammation.
Administration of FSAE or DIOS did not significantly
change other biochemical, immunological and molecular
parameters measured in healthy rats in this study. In
addition, the mortality rate for FSAE- or DIOS-treated rats
was 0% in this study, indicating that the used doses of
FSAE or DIOS are generally safe.
In conclusion, both FSAE and diosgenin were safe
and effective in reducing the hepatocarcinogenesis and
augmented the therapeutic activity of CP in the HCC rat
model. Possible mechanisms for the anticarcinogenesis
activities of FSAE and DIOS shown in the present study in
the HCC rat model are their ability to modulate hepatic
inflammation, oxidative stress, genotoxicity and apoptosis.