الفهرس 
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Abstract
Summary
Histamine H2 receptor antagonists are commonly prescribed medications and are known to be well tolerated. Ranitidine is a H2 receptor antagonist which is a widely used over-the-counter antacid medication (Weissman et al., 2018). Ranitidine (RA) is a histamine type 2 receptor antagonist (H2 blocker) which is widely used for treatment of acid-peptic disease and heartburn. It has been linked to rare instances of clinically apparent acute liver injury. It is white to pale yellow, crystalline, practically odorless powder, sensitive to light and moisture. Melts at about 140°C with decomposition. The empirical formula is C13H22N4O3S.HCl (Abd Elrasoul et al., 2020).
Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine. (Zakrzewski et al., 2019). Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be isolated easily from many sources such as bone marrow, adipose tissue or umbilical cord (Dabrowska et al., 2021). MSCs have shown great potential in the regenerative medicine field, MSCs have been shown to be effective therapy in liver diseases (Perico et al.,2013).
Sweet red pepper (Capsicum annuum L) is an important vegetable used for our daily consumption. Peppers are good sources of vitamins C, E, provitamin A, and carotenoids, it also contains various phenolics and flavonoids (Materska and Perucka 2005). Capsinoids (capsiate, dihydrocapsiate, and nordihydrocapsiate) are capsaicin-like compounds found in a nonpungent type of red pepper (sweet pepper) (Matsushita et al., 2021). Capsinoids possesses antioxidant and anti-inflammatory properties and is a proven dietary antioxidant in various ailments (Koneru et al., 2018). Therefore, the present study was done to investigate the curative effect of CA or / and MSCs against RA induced toxicity in liver rats.
The doses selected in the present investigation were 300 mg/kg day for ranitidine, single intravenous injection for stem cells (2×106 cell) and 60mg/kg b. wt./day) for capsiate (Capsinoids). 60 male Wister albino rats weighting 130-150g were divided into six groups ten rats each according the following regimen: -
1- Normal control group: orally received distilled water (GI).
2-Capsinoid control group: orally received Capsinoid (CA) (60mg/kg b. wt. /day) for 4 weeks (GII).
3-Ranitidine (RA) group: orally received ranitidine (300 mg/kg b. wt. /day) for 6 weeks (GIII).
4-Capsinoid therapeutic group: received oral doses of ranitidine (300 mg/kg b. wt. /day) for 6 weeks then orally administered Capsinoid (60mg/kg b. wt./day) for another 4 weeks (GIV).
5-Mesenchymal stem cells (MSCs) therapeutic group: received oral doses of ranitidine (300 mg/kg b. wt. /day) for 6 weeks then administered single intravenous injection of stem cells (2×106 cell) (GV).
6-(MSCs + CA) therapeutic group: received oral doses of ranitidine (300 mg/kg b. wt./ day) for 6 weeks then administered MSCs + CA (GVI).
At the end of treatment, the animals were sacrificed, and then the mean body weight, liver and relative liver weights were calculated. The blood samples were collected and centrifuged for biochemical analysis. Then the liver specimens obtained from the control and treated rats were prepared to be examined histologically in addition to estimation of oxidative stress and comet test. The results obtained from the present investigation can be summarized as follows:
Total body weight, liver and relative liver weights
In the present study, the mean body weights of RA rats significantly decreased as compared to the control group. A considerable improvement was observed in CA, MSCs and mixture groups. On the other hand, a slight increase in the mean and relative liver weights were found in RA rats, some improvements were observed in MSCs, CA and mixture groups.
Biochemical parameters
Liver enzymes and protein profile
Normal rats showed more or less constant levels of serum ALT, AST, GGT and bilirubin during the course of the study. On the other hand, in RA group, a significant elevation was realized in ALT, AST, GGT and bilirubin (direct, total) levels as compared with control group. A considerable improvement was observed in CA, MSCs and mixture groups. Moreover, serum total protein and albumin levels were significant decreased in RA group, while a significant improvement was observed in CA, MSCs and mixture groups.
Lipid profile
RA group (GII) showed significant elevation of serum levels of cholesterol, TG, LDL and VLDL and significant reduction of HDL was recorded as compared to control group (GI). some improvements were observed in CA, MSCs and mixture groups.
Complete Blood Count
Administration of RA in (GII) resulted in significant increase in white blood cells count and significant decrease in RBCs, Hb, PLT and hematocrit compared to control. While some improvements took place in the groups treated with CA (GIV) and MSCs (GV) Moreover, a strong improvement was recorded in CA+MSCs rats (GVI).
Immunity measurements
Administration of RA (GII) resulted in significant increase in the serum of pro-inflammatory cytokines TNF-α and IL-12, serum CRP and proapoptotic factor serum Casp-3 levels, while significant decrease in serum post- inflammatory cytokine IL-10 and Anti-apoptotic factor Bcl2 level. A considerable improvement was observed in CA, MSCs and mixture groups.
Oxidative stress parameters
Current study showed that intoxication of rats with ranitidine induced hepatotoxicity represented by induction of oxidative stress in hepatic tissues as it increased hepatic tissue contents of MDA while it deceased hepatic tissues contents of GSH and SOD. While a considerable improvement was observed in CA, MSCs and mixture groups.
Comet parameters
Comet %
The control rats designated more or less constant figures during the study period. On the other hand, in RA group a strong elevation was realized in comet percent as compared with the control group. A considerable improvement was observed in CA therapeutic group in comet percent. Also, minimal improvement occurred in the comet% of MSCs therapeutic group as compared with the control group. On the other hand, strong improvement occurred in the comet % of therapeutic rats by mixture of CA and MSCs.
Head diameter
The control rats designated more or less constant figures during the study period. On the other hand, in RA group a strong decrease was recorded in head diameter as compared with the control group. A considerable improvement was observed in CA therapeutic group. Also, minimal improvement occurred in the head diameter of MSCs therapeutic group as compared with the control group. On the other hand, strong improvement occurred in the head diameter of therapeutic rats by mixture of CA and MSCs.
% DNA in head
The control rats designated more or less constant figures during the study period. On the other hand, in RA group a strong decrease was recorded in % DNA in head as compared with the control group. A considerable improvement was observed in CA therapeutic group. Also, minimal improvement occurred in % DNA in head of MSCs therapeutic group as compared with the control group. On the other hand, strong improvement occurred in % DNA in head of therapeutic rats by mixture of CA and MSCs.
Tail length
The control rats designated more or less constant figures during the study period. On the other hand, in RA group a strong increase was recorded in tail length as compared with the control group. A considerable improvement was observed in CA therapeutic group in tail length. Also, minimal improvement occurred in tail length of MSCs therapeutic group. On the other hand, strong improvement occurred in tail length of therapeutic rats by mixture of CA and MSCs as compared with the control group.
% DNA in tail
The control rats designated more or less constant figures during the study period. On the other hand, in RA group a strong increase was recorded in % DNA in tail. A considerable improvement was observed in CA therapeutic group in % DNA in tail. Also, minimal improvement occurred in % DNA in tail of MSCs therapeutic group as compared with the control group. On the other hand, strong improvement occurred in % DNA in tail of therapeutic rats by mixture of CA and MSCs.
Tail moment
The control rats designated more or less constant figures during the study period. On the other hand, in RA group a strong increase was recorded in tail moment as compared with the control group. Minimal improvement occurred in tail moment of CA therapeutic group. A considerable improvement was observed in MSCs therapeutic group in tail moment. On the other hand, strong improvement occurred in tail moment of therapeutic rats by mixture of MSCs and CA as compared with the control group.
Histological studies
Microscopical studies of the liver
Examination of liver sections of the control animals showed regular histoarchitecture of the liver parenchyma with well designated hepatocytes, sinusoids and central veins. In RA rats a marked degree of deterioration of the liver tissue has been displayed. The parenchymal liver tissue had apparently lost most of their characteristic architectural organization, and the great majority of the constituent hepatocytes became detached from each other. Minimal improvement occurred in CA therapeutic group, regenerative changes within hepatic cells occurred, while some cells appeared binucleated and cytoplasmic vacuolation in hepatocytes persisted. In MSCs therapeutic group, the photomicrographs of liver sections showed a slight improvement within hepatic cells and cytoplasmic vacuolation. No Abreus alteration was observed fallowed mixed treatment with CA & MSCs as compared to treatment with either alone.
Conclusions:
It could be stated now that RA as a drug has serious noxious and deleterious impacts on the body organs, also revealed that, RA produced oxidative stress and this was associated with impairment in liver functions and tissue architecture. These impacts will be reflected in improper functioning, not only of the liver, but also of the whole body in general. Also, from the present findings that the previously reported therapeutic effects of CA and MSCs against RA toxicity to liver injury could also be exhibited when they are given orally after exposure to RA. In view of the findings of this study, it may be concluded that MSCs and CA possess the ability to reverse RA induced liver oxidative injury as well as to regulate the metabolic activities and may be considered as therapeutic agent against RA induced toxic effects.
In conclusion, there are numerous sources of free radicals that, in excess, may have deleterious effects on the human body. This study suggests that MSCs and CA have therapeutic effects on oxidative stress caused hepatic injury induced by RA. The therapeutic effect of the mixture is more potent than those of MSCs or CA only.