الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Cisplatin (CIS) is widely used in cancer treatment, while
hepatotoxicity is one of its side effects. Although there is no
consensus as to the mechanism of CIS-induced hepatotoxicity, the
two most widely recognized views are the shift of the antioxidant
balance towards oxidative stress and acceleration of apoptosis. In
this study, ferulic acid and/or LDR were investigated with regard to
their protective effects against cisplatin-induced hepatotoxicity in
rats. The possible mechanisms underlying these effects were also
discussed. In this investigation, eighty male albino rats were
involved. Rats were divided into eight equal groups (10 rats each)
identified as follow:
group 1 (NC): Healthy group this group served as Normal
control.
group 2 (FA): Ferulic acid group; rats of this group were
received FA (dissolved in saline) orally in a dose equivalent to
40 mg/kg body weight daily for 19 consecutive days via oral
tube.
group 3 (LDR): Low dose of γ-irradiation (LDR) group; rats’
whole-body of this group were submitted to fractionated dose
of γ-irradiation (two doses each dose 0.25Gy up to 0.5Gy).
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Summary and Conclusion
group 4 (FA+LDR): Ferulic acid and low dose of γ-irradiation
group; rats of this group were received FA (40 mg/kg body
weight, orally via oral tube) daily for 19 consecutive days, one
hour after the last treatment, rats’ whole-body were submitted
to 0.25Gy γ-irradiation on the 14th and 18th day from FA
administration.
group 5 (CIS): Cisplatin (CIS) group; rats of this group were
injected intraperitoneally with CIS (2 mg/kg body weight)
daily for five successive days.
group 6 (CIS + FA): Cisplatin and ferulic acid group; rats of this
group were received FA (40 mg/kg body weight, orally via
oral tube) daily for 19 successive days. Start from the 15th to
19th day of FA administration, each rat was injected
intraperitoneally with CIS (2 mg/kg body weight) daily for 5
consecutive days.
group 7 (CIS + LDR): Cisplatin and low dose of γ-irradiation
group; rats’ whole-body of this group were submitted to a
single dose of γ-radiation (0.25Gy) 24h pre-cisplatin injection,
followed by injection with CIS (2 mg /kg body weight) daily
for 5 consecutive days. One hour later from CIS administration,
rats were exposed to a second single dose of γ-radiation (0.25
Gy) at the 4th day.
group 8 (CIS+FA+LDR): Cisplatin and ferulic acid and low
dose of γ-irradiation group; rats of this group were received
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Summary and Conclusion
FA (40 mg/kg body weight, orally via oral tube) daily for 19
consecutive days; one hour after the last treatment, rats’ wholebody were submitted to two doses of (0.25 Gy) of gamma
irradiation at 14th and 18th day; one hour later, rats were
injected with CIS (2 mg/kg body weight) for 5 consecutive
days from the 15th to 19th day of FA administration.
At the end of experimental period, all animals were sacrificed
24 hr after the last treatment. Serum and liver tissue were
subjected to the following analysis:
Blood serum was withdrawn from animals for the analysis of
liver function enzymes e.g ALT and AST.
Liver was excised for the analysis of oxidative stress
biomarkers (MDA, SOD and CAT) in tissue homogenate. In
addition, the expression of NF-ҡB-P65, IL-1β, Caspase-1 and
COX-2 mRNA was measured in liver tissue using qRT-PCR.
A part of excised tissues was used for the estimation of NO
free radical concentration by using ESR. In addition,
histological examinations were performed to confirm the
biochemical data also, immunohistochemistery analysis (IHC)
for the active caspase-3 was carried out.
The results of the current work are summarized as follows
The electron spin resonance analysis revealed a significant
high levels of NO free radical content in the hepatic tissue of
CIS intoxicated rats, compared to the control group. Applying
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Summary and Conclusion
FA and /or LDR and their combination with CIS, significantly
ameliorated the NO free radical concentration compared to
CIS group.
The biochemical findings indicated that CIS induced hepatic
injury which was manifested by the significant elevation of
ALT and AST activities in serum of CIS group versus the
control group. In contrast, treating CIS-intoxicated animals
with either FA or LDR or their combinations significantly
reduced the activities of hepatic enzymes as compared to CIS
group.
Exposing normal rats to LDR caused a slight elevation in the
hepatic MDA level with slight reduction in the antioxidant
enzymes (CAT and SOD).
Intraperitoneal injection of CIS to normal rats induced
oxidative stress and lipid peroxidation in normal hepatic tissue
evidenced by the significant augmentation in the level of
hepatic MDA with the significant reduction in the activities of
CAT and SOD. On the opposite side, applying different
treatments of FA or LDR or their combinations with CIS
alleviated the examined parameters compared to CIS treated
group. The combined treatment of FA and LDR was the most
effective.
The molecular investigation indicated the down regulation of
NF-ҡB-P65 and caspase-1 gene expression level in the hepatic
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Summary and Conclusion
tissues of CIS-intoxicated rats. On the other hand, the
expression level of IL-1β and COX-2 genes were up-regulated
in the same group. Treating CIS injected rats with either FA,
LDR or their combination modulated the expression levels of
the studied genes.
The immunohistochemical study revealed that CIS treatment
induced apoptosis in the normal liver tissue through the
enhancement of the expression level of active caspase-3
protein compared to the control group. However, coadministration of FA and/or LDR with CIS prevents the
apoptotic effect of CIS by modulating the expression level of
hepatic active caspase-3 protein compared to CIS group.
Histopathological examination of liver tissue of CIS-treated
rats showed marked structural changes including sever
steatosis, pyknotic nuclei also multiple inflammatory areas. On
the opposite side, FA and/or LDR treatments ameliorate the
CIS hepatic toxicity.
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Summary and Conclusion
6- CONCLUSION
In conclusion, this research delivers a new strategy for the
attenuation of CIS-induced liver injury in cancer patients
receiving CIS drug, as the present findings ascertained the
hepato-protective effect of ferulic acid and/or low dose of γirradiation against CIS hepatotoxicity by mitigation oxidative
stress, improving the endogenous antioxidant system, decreasing
caspase-3 activity and inhibiting inflammatory pathways.
However, before a conclusive statement might be made on the
potential usefulness of this adjunct therapy, there is a need for
further studies on a cancer model.