Impact of morin-5'-sulfonic acid sodium salt on cyclophosphamide-induced gastrointestinal toxicity in rats.

BACKGROUND: The aim of this study was to evaluate the effect of morin-5'-sulfonic acid sodium salt (NaMSA) on cyclophosphamide-induced gastrointestinal changes in rats. METHODS: Rats received intragastrically 0.9% saline (group C), cyclophosphamide (15 mg/kg) (group CX), NaMSA (100 mg/kg) (group M) or cyclophosphamide (15 mg/kg) with NaMSA (100 mg/kg) (group M-CX), respectively, for 10 days. RESULTS: No histological lesions were observed in the liver and the large intestine in the control group and group receiving NaMSA. In the cyclophosphamide-treated group, a generalized blurred trabecular structure, hepatocyte apoptosis, focal and diffuse necrosis were noticed in the liver and atypia of epithelial cells or adenoma were noticed in the large intestine. In the group receiving both cyclophosphamide and NaMSA, hepatocyte apoptosis in the liver was observed less frequently. Histological examination of the small intestine revealed: low-grade dysplasia adenoma in the C, M, CX and M-CX group (in 44%, 0%, 100%, and 55.6% of specimens, respectively) with adenocarcinoma in 55.6% of specimens in the cyclophosphamide-receiving group only. Adenoma with high-grade dysplasia was observed in the control and NaMSA-receiving group with a similar frequency (22%). In addition to the histological evaluation, blood cell count parameters, as well as total protein concentration, blood glucose level, amylase, ALT, AST and GGTP activities were evaluated. Cyclophosphamide impaired weight gain, decreased blood cell count parameters and total protein concentration, and increased the GGTP activity. Those changes were not reversed by NaMSA. CONCLUSIONS: Summing up, NaMSA may protect against some cyclophosphamide-induced histological abnormalities in the gastrointestinal tract, including intestinal neoplasia in rats.

Application of Cornelian Cherry Iridoid-Polyphenolic Fraction and Loganic Acid to Reduce Intraocular Pressure.

One of the most common diseases of old age in modern societies is glaucoma. It is strongly connected with increased intraocular pressure (IOP) and could permanently damage vision in the affected eye. As there are only a limited number of chemical compounds that can decrease IOP as well as blood flow in eye vessels, the up-to-date investigation of new molecules is important. The chemical composition of the dried Cornelian cherry (Cornus mas L.) polar, iridoid-polyphenol-rich fraction was investigated. Loganic acid (50%) and pelargonidin-3-galactoside (7%) were found as the main components. Among the other constituents, iridoid compound cornuside and the anthocyans cyanidin 3-O-galactoside, cyanidin 3-O-robinobioside, and pelargonidin 3-O-robinobioside were quantified in the fraction. In an animal model (New Zealand rabbits), the influence of loganic acid and the polyphenolic fraction isolated from Cornelian cherry fruit was investigated. We found a strong IOP-hypotensive effect for a 0.7% solution of loganic acid, which could be compared with the widely ophthalmologically used timolol. About a 25% decrease in IOP was observed within the first 3 hours of use.

The impact of morin, a natural flavonoid, on cyclophosphamide-induced changes in the oxidative stress parameters in rat livers.

BACKGROUND: Cyclophosphamide (CPX) has many adverse effects, partly due to oxidative stress induction in various tissues. Morin is one of the natural flavonoids with strong antioxidant properties. OBJECTIVES: The aim of the current research was to estimate the influence of morin on changes in antioxidant parameters in rat livers after cyclophosphamide administration. MATERIAL AND METHODS: The study was performed on Wistar rats. The rats in Group C received 0.9% saline; those in Group CX received cyclophosphamide (CPX); and those in Group M-CX received CPX with morin. Cyclophosphamide and morin were given by gastric gavage for 10 consecutive days at doses of 15 mg/kg and 100 mg/kg, respectively. Malondialdehyde (MDA) and glutathione (GSH) concentrations, superoxide dismutase (SOD) activity and catalase (CAT) activity were determined in liver tissue homogenates. RESULTS: CPX caused a significant decrease in SOD activity and GSH levels, but only the latter was fully restored by morin. There were no significant differences in CAT activity in the various groups. CPX also insignificantly decreased MDA levels, which was aggravated by co-administration of morin. CONCLUSIONS: The results obtained indicate that morin may exert some protective action on CPX-induced changes in the antioxidant state in rat livers.

Age-related changes in ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion.

BACKGROUND: Liver function is affected during ischemia/reperfusion (IR). We evaluated the effect of the aging process on selected parameters determining the NO level in rat liver subjected to IR. METHODS: The animals were divided into the C-2 and the IR-2 group of young rats (2-4 months old) and the C-12 and the IR-12 group of older rats (12-14 months old). Livers belonging to the IR-2 and the IR-12 group were subjected to partial ischemia (60 min) and reperfusion (4 h). Blood samples were obtained after surgeries to estimate the activity of aminotransferases, as well as just before ischemia and during reperfusion (15, 120, and 240 min) to estimate concentration of arginine (Arg) and its derivatives: asymmetric and symmetric dimethylarginine (ADMA, SDMA). After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and protein concentration of inducible nitric oxide synthase (iNOS) were measured in liver homogenates. RESULTS: In the IR-2 group ADMA level increased the most between 15 and 120 min of reperfusion and was the highest of all the groups (0.72±0.2 µmol/l). In the IR-12 group ADMA level decreased significantly and was lower compared to all the other groups at 15 min (0.42±0.2 µmol/l) and to IR-2 at 120 (0.52±0.1 µmol/l) and 240 min (0.38±0.1 µmol/l) of reperfusion. Only the IR-2 group SDMA level increased significantly between 15 (0.75±0.9 µmol/l) and 240 min (1.0±1.2 µmol/l) of reperfusion. At the beginning of the surgery the Arg level was significantly higher in young rats (C-2: 102.1±35.7 µmol/l; IR-2: 114.63±28.9 µmol/l) than in older ones (C-12: 41.88±44.7 µmol/l; IR-12: 28.64±30.6 µmol/l). In the C-2 group the Arg level (77.41±37.5 µmol/l) and Arg/ADMA (A/A) ratio (138.03±62.8 µmol/l) were significantly higher compared to the ischemic groups at 15 min and to all the other groups at 120 (Arg: 47.17±31.7 µmol/l; A/A: 88.28±66.2 µmol/l) and 240 min (Arg: 43.87±21.9 µmol/l; A/A: 118.02±106.3 µmol/l). In the IR-2 group Arg level (11.4±12.0 µmol/l) and A/A ratio (16.11±16.2 µmol/l) decreased significantly at 15 min and during the next phase of reperfusion the levels of those parameters were low, comparably to those in IR-12. As a result of IR, a decrease in DDAH activity and an increase in iNOS protein concentration were observed only in the young rats. CONCLUSIONS: We found that in the non-ischemic groups the Arg level may be affected by the aging process. Under IR conditions, important changes in DDAH-ADMA-NO pathway were observed only in young livers.

Influence of ezetimibe on ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion.

BACKGROUND: We evaluated effect of ezetimibe on selected parameters determining NO level in rat liver subjected to ischemia reperfusion (IR). METHODS: Rats received ezetimibe (5 mg/kg) (groups E0 and EIR) or saline solution (groups C0 and CIR) intragastrically for 21 days. Then, the livers of CIR and EIR underwent ischemia (60 min) and reperfusion (4 h). Blood samples were obtained before surgery to estimate activities of aminotransferases, and just before ischemia and during reperfusion to estimate asymmetric and symmetric dimethylarginine (ADMA, SDMA) and arginine (Arg) levels. After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and endothelial nitric oxide synthase (eNOS) protein concentration were measured in liver homogenates. DDAH and protein arginine methyltransferase (PRMT) mRNA were quantified by real-time PCR in liver tissue samples. RESULTS: In CIR, the ADMA level was significantly higher compared to all other groups in 30 min and to E0 group in 120 min of reperfusion. In EIR, ADMA was low, compared to non-ischemic groups. At 30 and 120 min of reperfusion, in non-ischemic groups the level of Arg and Arg/ADMA ratio were significantly higher than in ischemic groups and E0 was the group with the highest levels of those parameters of all. In CIR, eNOS protein concentration was significantly lower than in ezetimibe-treated groups. Activity of DDAH was significantly higher in E0 than in non-treated groups. In ischemic groups, DDAH mRNA expression was significantly higher than in non-ischemic ones and PRMT mRNA expression was significantly higher in C0 than in all other groups. CONCLUSIONS: Influence of ezetimibe on ADMA/DDAH/NO pathway demonstrated in this work may suggest protective properties of this drug on rat livers injured by IR and, to a lower extent, on livers non-subjected to IR.

Effect of cyclophosphamide and morin-5'-sulfonic acid sodium salt, alone or in combination, on ADMA/DDAH pathway in rats.

BACKGROUND: The aim of the study was to evaluate the effect of cyclophosphamide (CPX) and morin-5'-sulfonic acid sodium salt (NaMSA) on plasma asymmetric dimethylarginine (ADMA) level and dimethylarginine dimethylaminohydrolase (DDAH) activity in rat liver. METHODS: The study was performed on Wistar rats receiving normal saline, CPX (15 mg/kg/day), NaMSA (100 mg/kg/day) or both CPX and NaMSA for 10 consecutive days. RESULTS: Significant decrease in ADMA level was found in all groups when compared to the control. DDAH activity in the liver was significantly higher in CX group compared to the control group. CONCLUSION: Obtained results of ADMA/DDAH pathway parameters require further research.