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Thank you

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by

mirhan makled

on 5 July 2015

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Transcript of Thank you

Thank you
All My Praise, Gratitude & Thanks to Allah.

Thanks to My Supervisors.

Special Acknowledgement to My Family

My Sincere Thanks to All Staff Members and Colleagues in Pharmacology and Toxicology Department.

DATS
possesses anti-oxidant and anti-inflammatory effects which were evident in its ability to protect against GalN/LPS-induced FHF, and APAP-induced ALF.

Protective effect of DATS may be mediated
mainly
by its ability to release H2S which scavenges proinflammatory oxidants and inhibits leuckocyte migration to inflamed areas.

In addition to its ability to upregulate phase II enzyme (GST) and downregulate CYP2E1.

DATS also reduces NO and TNF-α production.
BML-111
also possesses both anti-inflammatory and anti-oxidant effects, these effects were shown only in the model where ALF was induced by APAP.

These effects could be explained
mainly
by the ability of BML-111 to inhibit neutrophils migration, and subsequently prevent neutrophil-mediated tissue injury.

In addition to its ability to inhibit expression of proinflammatory genes and decrease production of proinflammatory cytokines as TNF-α.

It also decreases NO production.

Agmatine
possesses both anti-inflammatory and anti-oxidant effects; this was shown in both models.

This could be attributed
mainly
to its ability to inhibit NO release either directly or indirectly.

In addition to its ability to suppress proinflamatory cytokine release as TNF-α.

It also scavenges ROS which may be attributed to its nucleophilic structure.
Summary
&
Conclusions

Results
Material & Methods
This study was performed to investigate the efficacy of agmatine,
BML-111
and
DATS
against acute liver damage induced by
GalN/LPS
and
APAP.
Aim of the work
H2S scavenges proinflammatory oxidants such NO, ONOO−, HOCL, O2-, and H2O2.

In addition, it reduces TNF-alpha level and reduces adhesion and rolling of circulating leukocytes in inflamed microvasculature.

It also reduces NO production
DATS is a major compound in garlic oil (41.5%) and is easily obtained from freshly crushed garlic cloves.

MOA:

DATS, along with other garlic derived organic polysulfides, acts as a stable hydrogen sulfide (H2S) donor when it reacts with biological thiols such as glutathione.
Diallyltrisulfide (DATS)
Activation of ALX leads to inhibition of neutrophils migration, hence preventing neutrophil-mediated tissue injury and stimulation of the clearance of apoptotic neutrophils in a non phlogistic fashion.

It attenuates TNF- alpha production.

It also inhibits NO production

BML-111 is a commercially stable formyl peptide receptor-2 (FPR-2) agonist and even more potent compared with the original LXA4 molecule.

MOA:

It elicits antiinflammatory and proresolving actions through the specific G-protein coupled receptor, ALX, that is primarily expressed on neutrophils and monocytes.
BML-111
Following exposure to toxic doses of APAP, physiological detoxifying pathways (glucuronidation, sulfation, and renal excretion)
are depleted and APAP enters cytochrom-P450 metabolism, which in turn yields an abundant production of the toxic metabolite, NAPQI.

When NAPQI production exceeds GSH detoxification capacity, NAPQI covalently binds to various cell proteins resulting in subsequent loss of activity or function and eventual cell death and lysis.
APAP is a safe and effective analgesic when used at therapeutic doses.

An overdose of APAP can induce sever hepatotoxicity in experimental animals and in human.

It is well-known that APAP exerts hepatotoxic effects in a dose-dependent manner
Paracetamol (APAP) induced acute liver injury
ALF is the clinical manifestation of sudden and severe hepatic injury.

After abrupt loss of hepatic metabolic and immunological function caused by massive or submassive liver necrosis, it leads to hepatic encephalopathy, coagulopathy, and, in many cases, progressive multiorgan failure.
ALF is a serious disease. Without adequate treatment the mortality is high.

Various etiological factors may lead to ALF, and it may be very difficult to identify the cause in an individual case.

ALF is the final common pathway for a variety of liver insults.
Acute liver failure
In addition, the liver degrades or conjugates numerous toxic substances and drugs, but it can be overwhelmed by such substances and damaged.

Now days, millions of people throughout the world suffer from many hepatic disorders.

Among these hepatic disorders, acute hepatitis is one of the most prevalent hepatic disorders and occurs at alarming rate.
Introduction
II- Study of the potential protective effects of agmatine, BML-111 and DATS on
APAP
- induced acute liver injury in male Swiss albino mice
I- Study of the potential protective effects of agmatine, BML-111 and DATS on
GalN/LPS
-induced fulminant hepatic failure in male Swiss albino mice

II- Study of the potential protective effects of agmatine, BML-111 and DATS on
APAP
- induced acute liver injury in male Swiss albino mice

8 hr after GalN/LPS injection, blood and liver samples were obtained to estimate the following parameters:
I- Study of the potential protective effects of agmatine, BML-111 and DATS on
GalN/LPS
-induced fulminant hepatic failure in male Swiss albino mice

Agmatine is a polyamine that is synthesized after decarboxylation of l-arginine by ADC.

MOA:

Agmatine directly inhibits the activity of iNOS and indirectly inhibits the expression of iNOS by suppressing the activation of NF-kB.

It also attenuates the production of TNF-alpha and its cytotoxic effects.
Agmatine
GalN/LPS-induced fulminant hepatic failure
GalN, a hepatocyte-specific inhibitor of RNA synthesis, is known to sensitize animals to lethal effects of LPS and thus inducing FHF in experimental animal models.
Liver
The liver is the largest mass of glandular tissue in the body and the largest internal organ.

The liver plays an important role in the metabolism of glucose, nutrients and vitamins.

Many circulating plasma proteins are produced
and secreted by the liver.
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of APAP group

6- TNF-α level in liver homogenate
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of APAP group

5- Total nitrite and nitrate in serum
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of APAP group

3- Serum ALP
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of GalN/LPS group

6- TNF-α level in liver homogenate
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of GalN/LPS group

5- Total nitrite and nitrate in serum
2- Serum AST
Data were expressed as the mean ± SEM of 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of GalN/LPS group
1- Serum ALT
Thesis submitted by:
Mirhan N. Makled
Mansoura University
Faculty of Pharmacy
Dept. of Pharmacology and Toxicology

2- Serum AST
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of APAP group
1- Serum ALT
Dr.
Dina S. El-Agamy
Lecturer of Pharmacology and Toxicology,
Faculty of Pharmacy, Mansoura University.

Dr.
Nariman M. Gamiel
Emeritus Professor of Pharmacology and Toxicology,
Faculty of Pharmacy, Mansoura University.

&
Under the supervision of
iii) SOD
ii) GSH
i) MDA
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of APAP group

4- Oxidative stress in liver homogenate

iii) SOD
ii) GSH
i) MDA
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of GalN/LPS group
4- Oxidative stress in liver homogenate
GalN/LPS + BML-111
GalN/LPS
GalN/LPS + DATS
DMSO
GalN/LPS +agmatine
Control
7- Histopathology of liver
APAP + DATS
APAP + agmatine
APAP+ BML-111
Control
Control and DMSO groups, showing normal liver architecture; APAP showing severe centrilobular focal necrosis, apoptosis and inflammation; APAP + agmatine, showing only a minimal degree of necrosis and inflammation; APAP + DATS, showing minimal necrosis and inflammation; APAP + BML-111 showing marked decrease in hepatic inflammation and necrosis. HE, magnification 100×

DMSO
7- Histopathology of liver
Experimental design and treatments
Group 6:
(8 animals)
BML-111
(1 mg/kg, I.P.)
55 Swiss albino mice were divided into six groups as the following:
Agmatine, BML-111 and DATS were given twice daily
for 5 consecutive days before APAP injectin)
55 Swiss albino mice were divided into six groups as the following:
Experimental Design and Treatments
12 hr after APAP injection, blood and liver samples were obtained to estimate the following parameters:
Study of the Efficacy of Some Natural and Synthetic Compounds
against Experimentally Induced Liver Damage
Serum
AST level
ALT level
ALP level
total nitrite/nitrate
level


Hepatic
MDA content
SOD activity
GSH level
TNF-a level

Histopathological examination of liver following H&E staining.
Group 2:
(8 animals)
0.1%
DMSO
Group 5:
(8 animals)
DATS
(14 µmol/kg, I.P.)
Group 3:
(15 animals)
APAP
(500 mg/kg, I.P. )
Single dose

Group 1:
(8 animals)
Vehicle
(PBS)
Group 4:
(8 animals)
agmatine
(14 mg/kg, I.P.)
Serum
AST level
ALT level
ALP level
total nitrite/nitrate
level


Hepatic
MDA content
SOD activity
GSH level
TNF-a level

Histopathological examination of liver following H&E staining.
3- Serum ALP
Control and DMSO groups, showing normal liver architecture; GalN/LPS showing severe centrilobular necrosis, apoptosis and inflammation; GalN/LPS + agmatine, showing only a moderate degree of necrosis and inflammation; GalN/LPS + DATS, showing minimal necrosis and inflammation; GalN/LPS + BML-111 showing marked inflammation and necrosis. HE, magnification 100×.

Group 6:
(8 animals)
BML-111
(1 mg/kg, I.P.)
Agmatine, BML-111 and DATS were given 30 min. prior to challenge with GalN/LPS
Group 2:
(8 animals)
0.1%
DMSO
Group 5:
(8 animals)
DATS
(14 µmol/kg, I.P.)
Group 3:
(15 animals)

GalN (800 mg/Kg, I.P.) and LPS (50 µg/Kg, I.P.) single dose
Group 1:
(8 animals)
Vehicle
(PBS)
Group 4:
(8 animals)
agmatine
(14 mg/kg, I.P.)
Data were expressed as the mean ± SEM 8 mice.
Statistical analysis of mean values was done using ANOVA followed by Tukey-Kramer`s test.
* P less than 0.05 Significantly different from the corresponding mean value of control group.
# P less than 0.05 Significantly different from the corresponding mean value of GalN/LPS group
4- Oxidative stress in liver homogenate
APAP
GalN exerts its hepatotoxic effects by depleting hepatic uridine nucleotides due to formation of UDP-GalN derivative
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