Beneficial effects of carnosine and carnosine plus vitamin E treatments on doxorubicin-induced oxidative stress and cardiac, hepatic, and renal toxicity in rats.

OBJECTIVE: Oxidative stress plays an important role in doxorubicin (DOX)-induced toxicity. Carnosine (CAR) is a dipeptide with antioxidant properties. The aim of this study was to evaluate the decreasing or preventive effect of CAR alone or combination with vitamin E (CAR + Vit E) on DOX-induced toxicity in heart, liver, and brain of rats. METHODS: Rats were treated with CAR (250 mg kg(-1) day(-1); intraperitoneally (i.p.)) or CAR + Vit E (equals 200 mg kg(-1) α-tocopherol; once every 3 days; intramuscularly) for 12 consecutive days. On the 8th day of treatment, rats were injected with a single dose of DOX (30 mg kg(-1), i.p.). Serum cardiac troponin I (cTnI), urea, and creatinine levels; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities; and oxidative stress parameters in tissues were measured. We also determined thiobarbituric acid reactive substances, diene conjugate, protein carbonyl (PC), and glutathione levels and antioxidant enzyme activities. RESULTS: DOX resulted in increased serum cTnI, ALT, AST, urea, and creatinine levels and increased lipid peroxide and PC levels in tissues. CAR or CAR + Vit E treatments led to decreases in serum cTnI levels and ALT and AST activities. These treatments reduced prooxidant status and ameloriated histopathologic findings in the examined tissues. CONCLUSION: Our results may indicate that CAR alone, especially in combination with Vit E, protect against DOX-induced toxicity in heart, liver, and kidney tissues of rats. This was evidenced by improved cardiac, hepatic, and renal markers and restoration of the prooxidant state and amelioration of histopathologic changes.

Volatile solvent abuse caused glomerulopathy and tubulopathy in street children.

Substance misuse among street children is a significant problem in developing countries. Volatile substances are the most abused agents. According to case reports, chronic renal diseases are common among substance-abusing street children. In this study, we examined the renal findings of 42 volatile substance-abusing street children and compared them with results from 49 healthy children (control). The street children's weight, height, and blood pressure were lower than the controls' (P < 0.05). However, their blood alkaline phosphatase and creatinine phosphokinase levels were higher (P < 0.05), and total blood protein, creatinine, and phosphorus levels were lower than the controls' (P < 0.05). Furthermore, the street children's glomerular filtration rates were within normal limits (P < 0.05), their urinary N-acetyl-beta-glucosaminidase (NAG), beta(2)-microglobulin, microalbumin, protein, calcium, phosphorus, sodium, potassium, and chloride excretions were higher, and tubular phosphate reabsorption were lower than the controls' (P < 0.05). Volatile substances have been charged with causing distal tubular disease, but increased urinary protein, NAG, beta(2)-microglobulin, microalbumin, and electrolyte excretions also result from glomerular, proximal, and distal tubular influences. We believe that increased volatile substance products in the renal parenchyma are responsible for glomerular and tubular damage. Volatile substance-abusing street children should be examined for glomerular and proximal tubular function and distal tubular acidosis.

Do vitamin E and selenium have beneficial effects on trinitrobenzenesulfonic acid-induced experimental colitis.

The balance between oxidant and antioxidant systems may be important in the pathogenesis and/or maintenance of tissue injury in ulcerative colitis. This study was designed to evaluate the effects of vitamin E and selenium supplementations on tissue injury and oxidative stress in trinitrobenzenesulfonic acid-induced ulcerative colitis in rats. Trinitrobenzenesulfonic acid administration severely changed the normal architecture of the colon and significantly increased the levels of malondialdehyde, protein carbonyl, and xantine oxidase (P < 0.001) in the colon homogenates of these rats. Supplementation of selenium to the trinitrobenzenesulfonic acid-treated rats neither improved the histopathological findings nor decreased the levels of malondialdehyde and protein carbonyl. Vitamin E supplementation reduced the levels of malondialdehyde and protein carbonyl but did not improve the colonic lesions. Supplementation of vitamin E + selenium significantly reduced both the severity of colonic lesions and the levels of malondialdehyde and protein carbonyl. In conclusion, we suggest that antioxidants and specific micronutrients may have beneficial effects in the treatment of ulcerative colitis.

An increase in lipoprotein oxidation and endogenous lipid peroxides in serum of obese women.

Endogenous malondialdehyde and diene conjugate levels, the susceptibility of apolipoprotein B-containing lipoproteins to copper-induced lipid peroxidation, and antibody titer against oxidized low-density lipoproteins were increased, but serum antioxidant activity was unchanged in obese women. Serum cholesterol, low-density lipoproteincholesterol, and trigliceride levels were also elevated, but high-density lipoprotein-cholesterol levels remained unchanged in obese women. In vitro, oxidation of apolipoprotein B-containing lipoproteins and levels of antibody against oxidized low-density lipoprotein correlated with body mass index, serum total cholesterol, and low-density lipoproteincholesterol levels in obese women. These results indicate that obesity is associated with increases in endogenous lipid peroxides, oxidation of low-density lipoproteins, and lipids in serum.

Could honey have a place in colitis therapy? Effects of honey, prednisolone, and disulfiram on inflammation, nitric oxide, and free radical formation.

BACKGROUND/AIMS: The purpose of this study was to investigate the potential therapeutic roles of honey, prednisolone and disulfiram in an experimental model of inflammatory bowel disease. Another aspect of the study was to find out whether these substances have any effect on nitric oxide (NO) and free radical production. METHODS: After the induction of colitis with trinitrobenzene sulfonic acid in 64 male rats, physiological saline, honey, prednisolone and disulfiram enemas were applied to the rats once daily for 3 days (acute treatment groups) or 7 days (chronic treatment groups). Control groups received only saline enemas. Rats were killed on the 4th or 8th days and their colonic mucosal damage was quantitated using a scoring system. Acute and chronic inflammatory responses were determined by a mucosal injury score, histological examination and measurement of the myeloperoxidase (MPO) activity of tissues. The content of malonylaldehyde (MDA) and NO metabolites in colon homogenates was also measured to assess the effects of these substances on NO and free oxygen radical production. RESULTS: Estimation of colonic damage by mucosal injury scoring was found to be strongly correlated with the histologic evaluation of colon specimens. On the other hand, mucosal injury scores were not correlated with MPO, MDA or NO values. There were significant differences between the MPO results of chronic-control and chronic-honey groups, as well as chronic-control and chronic-prednisolone groups (p = 0.03 and p = 0.0007). The acute honey, prednisolone, and disulfiram groups had significantly lower MDA results compared to the acute control group (p = 0.04, p = 0.02, and p = 0.04). In terms of NO, there was no significant difference between the treatment and control groups. NO was found to have a strong relationship with MDA (p = 0.03) and MPO values (p = 0.001). On the other hand, MPO results were not found to be correlated with MDA values (p > 0.05). CONCLUSIONS: MPO activity is not directly proportional to the severity of the inflammation, but it may only determine the amount of neutrophil in the tissues. Inflammatory cells are not the sole intensifying factor in colitis. Therefore, mucosal injury scores may not correlate well with MPO activities. In an inflammatory state NO and MPO levels have a strong relationship, since NO is released from the neutrophils. In an inflammatory model of colitis, intrarectal honey administration is as effective as prednisolone treatment. Honey may have some features in the treatment of colitis, but this issue requires further investigation. Honey, prednisolone and even disulfiram also have some value in preventing the formation of free radicals released from the inflamed tissues. Prednisolone may also have some possible benefits in the inhibition of NO production in colitis therapy.

Glutathione S-transferase-pi in malignant tissues and plasma of human colorectal and gastric cancers.

PURPOSE: In this study, 16 paired samples of colorectal and gastric cancers and adjacent non-neoplastic tissues were analysed for the determination of glutathione S-transferase (GST) activities and the expression of GST-pi. METHODS: Western blotting procedure as well as plasma GST-pi levels were used. RESULTS: GST activities were found to be increased in malignant tissues of patient compared with adjacent normal tissues. A significant correlation was detected between GST activity and GST-pi expression in malignant tissues of patients. Plasma GST-pi levels increased in patients compared to aged-matched control subjects. When the patients were grouped according to TNM stage, GST-pi expression in malignant tissues as well as plasma GST-pi levels were higher in patients with more advanced tumor stages. CONCLUSIONS: Our results indicate that GST-pi expression in malignant tissues and plasma GST-pi levels in human colorectal and gastric cancers increased depending on the stages of tumor.

Increased lipid and protein oxidation and DNA damage in patients with chronic alcoholism.

Increased oxidative stress has been speculated to be one possible mechanism of ethanol toxicity. This study evaluates malondialdehyde (MDA) and protein carbonyl content in serum as markers of oxidative stress and DNA damage in lymphocytes in the same patients with chronic alcoholism. Patients with chronic alcoholism showed a significant increase in MDA levels and protein carbonyl content of their serum as compared with non-alcoholic control subjects. Increases in endogenous and H2O2-induced DNA damage were also observed in lymphocytes of patients with chronic alcoholism. In addition, there were significant correlations between endogenous and H2O2-induced DNA damage and serum MDA or protein carbonyl content in patients with chronic alcoholism. These results clearly indicate the presence of oxidative stress in patients with chronic alcoholism.

The effect of selenium and/or vitamin E treatments on radiation-induced intestinal injury in rats.

Cytotoxic effects of ionizing radiation on gastrointestinal epithelium may be related to oxidative stress. In this study, we wanted to investigate the effects of selenium, vitamin E and selenium plus vitamin E pretreatments prior to whole abdominal irradiation on intestinal injury. Irradiation caused increased lipid peroxide and decreased GSH levels in the intestine. Intestinal superoxide dismutase and glutathione peroxidase activities were increased, but glutathione transferase activity decreased following irradiation. Selenium and/or vitamin E pretreatments ameliorated these disturbances in prooxidant-antioxidant balance. This amelioriation has been verified with histopathological findings. These results indicate that antioxidant pretreatments prior to irradiation may have some beneficial effects against irradiation-induced intestinal injury.

Superoxide dismutase activity and the effects of NBQX and CPP on lipid peroxidation in experimental spinal cord injury.

The endogenous activity of the neuroprotective enzyme superoxide dismutase (SOD) and the amount of lipid peroxidation in the early phase of experimental spinal cord injury, together with the effects of N-methyl-D-aspartate (NMDA) antagonist CPP and non-NMDA antagonist NBQX on lipid peroxidation were evaluated. The clip compression model was used for the production of a standardized spinal cord trauma. SOD activity and malondialdehyde (MDA) levels--as an indicator of lipid peroxidation--were determined in the injured segment of the spinal cord 30 and 60 min after injury. SOD activity did not change in this period, whereas MDA levels at 30 and 60 min after trauma were significantly elevated. Intrathecal administration of CPP or NBQX 15 min after injury produced statistically significant reductions in MDA elevation 60 min after injury. NBQX was found to be more effective than CPP. These results demonstrated that intrathecal local application of excitatory amino acid receptor antagonists can protect the spinal cord from secondary damage caused by the generation of lipid peroxides in experimental spinal cord injury.

The role of stimulated lipid peroxidation and impaired calcium sequestration in the enhancement of cocaine induced hepatotoxicity by ethanol.

The purpose of this study was to investigate possible mechanism of cocaine-induced hepatotoxicity and its potentiation by ethanol in mice. Ethanol (2 g/kg) and/or cocaine (25 mg/kg) injections were given as binge model (five injections in 3 days). Cocaine administration with or without ethanol caused an increase in lipid peroxidation in liver homogenate and its subcellular fractions. The greatest increases were observed in mitochondrial fraction following cocaine plus ethanol treatment. Also, glutathione (GSH) levels were increased in liver homogenate and its mitochondrial fractions after cocaine and cocaine plus ethanol treatment. Microsomal calcium sequestration was found to decrease in all treatments. These results suggest that increased lipid peroxidation and decreased microsomal calcium sequestration in the liver may play a possible role cocaine-induced hepatotoxicity and its potentiation by ethanol.

Plasma nitric oxide metabolites and lipid peroxide levels in preeclamptic pregnant women before and after delivery.

It has been suggested that oxidative stress may cause endothelial dysfunction and that endothelial dysfunction may lead to hypertension by reduced release of vasodilating agents such as nitric oxide (NO). In this study, we investigated the relationship between serum NO and lipid peroxides in preeclamptic and normal pregnant women before and after delivery. Plasma from women with preeclampsia had significantly lower nitrate/nitrite concentrations and significantly higher lipid peroxide levels than normal pregnant women before the delivery. Lipid peroxide levels were significantly elevated in preeclamptic placenta. After delivery in the preeclamptic group the plasma concentration of nitrate/nitrite was increased and plasma thiobarbituric acid reactive substance levels decreased, while these parameters remained unchanged in the normal pregnants women. These results indicate that high levels of lipid peroxides in the circulation may be the cause of lowered NO synthesis and hypertension observed in preeclamptic women.

In vitro effects of peroxynitrite on human spermatozoa.

In the present study, the in vitro effects of peroxynitrite on sperm motility, lipid peroxidation and sulfhydryl content were examined. Sperm percentage motility and movement characteristics were assessed by a computer-assisted system. Lipid peroxidation was measured by determining malondialdehyde levels using the thiobarbituric acid (TBA) method. Sperm sulfhydryl content was measured by a spectrophotometric method based on reduction of 5,5'-dithiobis-(2-nitrobenzoic acid) by sulfhydryl groups. Percentage motility, movement characteristics and sulfhydryl content decreased significantly in peroxynitrite-treated samples compared to decomposed peroxynitrite-treated samples. Lipid peroxidation in peroxynitrite-treated samples was significantly higher than in decomposed peroxynitrite-treated samples. These results indicate that peroxynitrite anion may cause sperm dysfunction through lipid peroxidation stimulation and total SH depletion.

Superoxide dismutase activity and the effect of N-methyl-D-aspartate antagonists on lipid peroxidation in the early phase of cold injury.

Free radicals, lipid peroxidation and excitatory amino acids have been implicated in the secondary mechanisms of traumatic brain injury. We used the cold injury model in rats to assess the endogenous activity of the protective enzyme superoxide dismutase (SOD) and the lipid peroxidation level in the contused tissue at an early phase of injury. Furthermore, we treated the rats with two different N-methyl-D-aspartate receptor antagonists, namely MK-801 and CPP, and evaluated their effect on lipid peroxidation in the contused tissue. Rats were divided into four groups: sham, control, treatment 1 and treatment 2 groups (n= 16 for each group). Thirty and 60 min after craniectomy or injury, tissue samples were removed. SOD activity didn't change in this period. However, lipid peroxidation in terms of malondialdehyde (MDA) amount showed a significant increase at 60 min. Fifteen minutes after injury, MK-801 (1 mg/kg), CPP (10 mg/kg) or saline (1 ml) were applied intraperitoneally in treatment 1, treatment 2 and the control groups. Treatment with MK-801 attenuated MDA levels, whereas treatment with CPP did not. The protective effect of MK-801 achieved statistical significance. These results demonstrate that SOD activity does not change in the early period of cold injury. Moreover, these results show that lipid peroxidation increases after 60 min of cold injury, and treatment with MK-801 15 min after injury can prevent this elevation.

Protective effect of the N-methyl-D-aspartate receptor antagonists, MK-801 and CPP on cold-induced brain oedema.

Cold injury model in rat was used to determine the effect of treatment with the competitive NMDA antagonists CPP and the non-competitive NMDA antagonist MK-801 in cerebral oedema. MK-801 was applied in doses of 1 mg/kg and CPP of 10 mg/kg, 15 min. after injury. Control animals received 1 ml saline at the same time interval after injury. Tissue samples from the core and periphery of the lesion of the injured hemisphere and from the symmetrical location of the undamaged contralateral hemisphere were removed 24 hours after injury. Blood brain barrier permeability, brain water content and tissue specific gravity values were determined. MK-801 was found beneficial for reducing the oedema and restore the blood brain barrier permeability at the penumbral zone of the lesion, whereas both MK-801 and CPP were found ineffective for prevention of oedema accumulation at the core of the lesion.

Nitric oxide and radiation enteritis.

OBJECTIVE: To investigate the changes in intestinal nitric oxide (NO) and myeloperoxidase (MPO) concentrations, the rate of endotoxaemia, and intestinal mucosal structure in rats after irradiation of the abdomen and to find out the effect of Nomega-nitroarginine methyl ester (L-NAME) inhibition NO synthesis. SETTING: Medical school, Turkey. DESIGN: Experimental study. MATERIAL: 46 Wistar-albino rats. INTERVENTIONS: In Group I (n = 12), rats underwent abdominal irradiation alone. In Group II (n = 12), they underwent abdominal irradiation and were given L-NAME orally for 3 days before and 3 days after irradiation. In Group III (n = 12), rats had abdominal irradiation and were given L-NAME orally for 3 days after irradiation. Group IV (n = 10) were controls and were untreated. The irradiation procedure consisted of a single shot of 1000 cGy to the abdomen and L-NAME was given 30 mg/kg/day orally in the drinking water. MAIN OUTCOME MEASURES: Intestinal mucosal MPO and nitrite, and plasma endotoxin concentrations. Changes in villous height and number were recorded. RESULTS: In groups II and III, MPO and NO2- concentrations decreased significantly compared with group I. Mucosal integrity was protected in both groups treated with L-NAME (groups II and III) in contrast to the group given irradiation without treatment (group I). CONCLUSION: These results suggest that the NO pathway contributes to the inflammatory response of radiation enteritis. Inhibition of NO synthesis may have a beneficial effect in the treatment of inflammation caused by irradiation.

Imbalance between lipid peroxidation and antioxidant status in preeclampsia.

Lipid peroxidation and the antioxidant system were investigated in the plasma and placenta of normal and preeclamptic pregnant women. A significant increase in thiobarbituric acid reactive substance (TBARS), significant decreases in total thiol (t-SH) content and superoxide dismutase (SOD) activity, and unchanged vitamin C levels and glutathione peroxidase (GPx) activity were observed in the plasma of preeclamptic women compared to women with normal pregnancies. In placentas from preeclamptic women TBARS levels were significantly elevated, while glutathione and vitamin C levels and GPx, glutathione S-transferase and SOD activities were decreased. After delivery, the elevated TBARS values decreased significantly and the reduced SOD activity and t-SH contents increased significantly. We concluded that preeclampsia is associated with an imbalance between lipid peroxides and the antioxidant system.

The effects of interferon-alpha on serum lipid peroxidation and total thiol content in patients with chronic active hepatitis-C.

Chronic hepatitis develops in at least half of the patients with acute hepatitis C. Although there is currently no effective therapy for chronic hepatitis C (CHC), it is reported that Interferon-alpha (IFN alpha) has some beneficial effects. It has been suggested that changes in the oxidant-antioxidant balance may take decisive role in the progression of liver damage in viral hepatitis and IFN alpha might be effective in the treatment of liver damage by improving the antioxidant system. In the present study, when the patients with chronic active hepatitis-C (CAH-C) were compared to controls, serum thiobarbituric acid reactive substance (TBARS) levels and glutathione peroxidase (GPx) activity as well as transaminase activities were increased, but total sulfhydryl (t-SH) contents were decreased Following IFN alpha treatment three times a week for a period of 6 months, it has been observed that elevated TBARS levels and GPx activity were decreased and reduced t-SH contents were increased significantly in patients with chronic active hepatitis-C (CAH-C). According to our results, these findings suggests that oxidative stress may play an important role in HCV induced liver injury and IFN alpha may be useful in treatment by reducing the oxidative stress.

Effects of thymosin alpha-1 on erythrocyte lipid levels and erythrocyte membrane (Na(+)-K+)-ATPase activity in experimental hypercholesterolemia.

Thymosin alpha-1 is an active polypeptide isolated from thymus. This polypeptide is widely used in the diagnosis and treatment of many diseases, especially immune diseases. In this present study, we examined the effects of thymosin alpha-1 on plasma and erythrocyte lipid levels and the changes in erythrocyte membrane (Na+, K+)ATPase activity in hypercholesterolemic rabbits. The erythrocyte lipid levels decreased, whereas the erythrocyte membrane (Na+, K+)ATPase activity increased significantly in these rabbits after thymosin alpha-1 injection. These findings suggest that thymosin alpha-1 is effective on both the lipid level and erythrocyte membrane (Na+, K+)ATPase activity.

Evaluation of the changes in serum lipid profile and ferritin concentrations in relation to body ascorbic acid status in healthy pre- and postmenopausal women.

The aim of this work was to study the relationship between body ascorbic acid (AA) status and serum lipid profile and ferritin concentrations in healthy pre- and postmenopausal women. The mean leukocyte and plasma ascorbate values in postmenopausal women were found to be significantly low but within acceptable ranges as compared to premenopausal women. According to these results, plasma and leukocyte AA concentrations decreased after the cessation of ovarian hormone production. In addition, significant increases in total cholesterol, triglyceride and LDL-cholesterol but a significant decrease in HDL-cholesterol were observed in postmenopausal women as compared to premenopausal women. A close positive relationship was found between plasma and leukocyte AA and body iron status in postmenopausal women. The findings were prominent especially in the subgroup of postmenopausal women with low body AA status. Thus, it is concluded that women having low body AA concentrations might have a predisposition for iron depletion.

Thymosin alpha 1 protects liver and aorta from oxidative damage in atherosclerotic rabbits.

The thymus hormones were reported to be effective on lipid peroxidation and the antioxidant system. Thymus plays a broader role than just regulating the immune system. Thymosin alpha 1 is the first subgroup extracted from thymosin F5 and has higher biological activity than thymosin F5. In the present study, we have examined the effects of thymosin alpha 1 on lipid levels and lipid peroxidation and glutathione (GSH) content in the plasma, liver and aorta tissues of atherosclerotic rabbits. At the end of thymosin alpha 1 treatment, we determined the lipid levels and lipid peroxidation of the plasma, liver and aorta tissues and hepatic subcellular fractions in these rabbits. Our results demonstrated that thymosin alpha 1 might normalize changed lipid levels and increased lipid peroxides and also elevate decreased GSH in the plasma, liver and aorta tissues of atherosclerotic rabbits. Results of this study suggest that thymosin alpha 1 may be beneficial to prevent and/or to treat atherosclerosis.