Faruk Öktem

Lithium-induced renal toxicity in rats: Protection by a novel antioxidant caffeic acid phenethyl ester

Lithium carbonate used in the long-term treatment of manic-depressive illness has been reported to lead to progressive renal impairment in rats and humans. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygene species mediated oxidative stress in ischemia-reperfusion and toxic injuries. The beneficial effect CAPE on lithium-induced nephrotoxicity has not been reported yet. The purpose of this study was to examine a possible renoprotective effect of CAPE against lithium-induced nephrotoxicity in a rat model. Twenty-two adult male rats were randomly divided into three experimental groups, as follows: control group, lithium-treated group (Li), and lithium plus CAPE-treated group (Li+CAPE). Li were treated intraperitoneally (i.p.) with 25 mg/kg Li2CO3 solution in 0.9% NaCl twice daily for 4 weeks. CAPE was co-administered i.p. with a dose of 10 μM/kg/day for 4 weeks. Serum Li, blood urea nitrogen and plasma creatinine, urinary N-acetyl-β-D-glucosaminidase (NAG, a marker of renal tubular injury), and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in Li-treated rats. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Serum Li levels were found high in the Li and Li+CAPE groups. In Li-administrated rats, urinary NAG and renal MDA levels were increased according to control and Li+CAPE groups (p < 0.05). CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD, CAT and GSH-Px activities were decreased in Li-administrated animals; CAPE caused a significant increase in the activities of these antioxidant enzymes. In conclusion, CAPE treatment has a protective effect against Li-induced renal tubular damage and oxidative stress in a rat model.

Methotrexate-induced renal oxidative stress in rats : the role of a novel antioxidant caffeic acid phenethyl ester

The exact mechanisms of methotrexate-induced renal toxicity have not yet been determined. However, several hypotheses have been put forward, including oxidative stress. The aim of this study was to investigate the role of caffeic acid phenethyl ester (Caffeic Ester), a novel antioxidant, on methotrexate-induced renal oxidative stress in rats. Nineteen adult male rats were equally divided into three experimental groups as follows: control group, methotrexate-treated group, and methotrexate-/Caffeic Ester-treated group. A single dose of methotrexate (20 mg/kg) was administered intraperitoneally (ip). Caffeic Ester (10 mmol/kg) was administered ip, once daily for seven days. Malondialdehyde (MDA) levels (an index of lipid peroxidation) were used as a marker of oxidative stress-induced renal injury. Similarly, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were determined to evaluate the changes of antioxidant status in renal tissue. Methotrexate administration to control rats increased MDA levels (PB < 0.0001), but decreased SOD, CAT and GSH-Px activities in renal tissue (PB < 0.0001). Caffeic Ester-/methotrexate treatment caused a significant decrease in MDA levels (PB < 0.001), and caused an increase in SOD, CAT and GSH-Px activities when compared with methotrexate treatment alone (PB < 0.001, < 0.05, < 0.0001, respectively). In conclusion, methotrexate leads to a reduction in antioxidant enzymatic defense capacity and causes lipid peroxidation in renal tissue. Similarly, Caffeic Ester exhibits protective effects on methotrexate-induced renal oxidative impairment in rats.

A novel antioxidant agent caffeic acid phenethyl ester prevents long-term mobile phone exposure-induced renal impairment in rat

Caffeic acid phenethyl ester (CAPE), a flavonoid like compound, is one of the major components of honeybee propolis. It has been used in folk medicine for many years in Middle East countries. It was found to be a potent free radical scavenger and antioxidant recently. The aim of this study was to examine long-term applied 900 MHz emitting mobile phone-induced oxidative stress that promotes production of reactive oxygen species (ROS) and, was to investigate the role of CAPE on kidney tissue against the possible electromagnetic radiation (EMR)-induced renal impairment in rats. In particular, the ROS such as superoxide and nitric oxide (NO) may contribute to the pathophysiology of EMR-induced renal impairment. Malondialdehyde (MDA, an index of lipid peroxidation) levels, urinary N-acetyl-β-d-glucosaminidase (NAG, a marker of renal tubular injury) and nitric oxide (NO, an oxidant product) levels were used as markers of oxidative stress-induced renal impairment and the success of CAPE treatment. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in renal tissue were determined to evaluate the changes of antioxidant status. The rats used in the study were randomly grouped (10 each) as follows: i) Control group (without stress and EMR), ii) Sham-operated rats stayed without exposure to EMR (exposure device off), iii) Rats exposed to 900 MHz EMR (EMR group), and iv) A 900 MHz EMR exposed + CAPE treated group (EMR + CAPE group). In the EMR exposed group, while tissue MDA, NO levels and urinary NAG levels increased (p < 0.0001), the activities of SOD, CAT, and GSH-Px in renal tissue were reduced (p < 0.001). CAPE treatment reversed these effects as well (p < 0.0001, p < 0.001 respectively). In conclusion, the increase in NO and MDA levels of renal tissue, and in urinary NAG with the decrease in renal SOD, CAT, GSH-Px activities demonstrate the role of oxidative mechanisms in 900 MHz mobile phone-induced renal tissue damage, and CAPE, via its free radical scavenging and antioxidant properties, ameliorates oxidative renal damage. These results strongly suggest that CAPE exhibits a protective effect on mobile phone-induced and free radical mediated oxidative renal impairment in rats.

Comparative analysis of the protective effects of melatonin and caffeic acid phenethyl ester (CAPE) on mobile phone-induced renal impairment in rat.

Melatonin and caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, were recently found to be potent free radical scavengers and antioxidants. There are a number of reports on the effects induced by electromagnetic radiation (EMR) in various cellular systems. Mechanisms of adverse effects of EMR indicate that reactive oxygen species may play a role in the biological effects of this radiation. The present study was carried out to compare the protective effects of melatonin and CAPE against 900 MHz EMR emitted mobile phone-induced renal tubular injury. Melatonin was administered whereas CAPE was given for 10 days before the exposure. Urinary N-acetyl-β-D-glucosaminidase (NAG, a marker of renal tubular injury) and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in rats exposed to EMR. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Urinary NAG and renal MDA were increased in EMR exposed rats while both melatonin and CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD and GSH-Px activities were decreased in EMR exposed animals while melatonin caused a significant increase in the activities of these antioxidant enzymes but CAPE did not. Melatonin caused a significant decrease in urinary NAG activity and MDA levels which were increased because of EMR exposure. CAPE also reduced elevated MDA levels in EMR exposed renal tissue, but the effect of melatonin was more potent than that of CAPE. Furthermore, treatment of EMR exposed rats with melatonin increased activities of SOD and GSH-Px to higher levels than those of control rats. In conclusion, melatonin and CAPE prevent renal tubular injury by reducing oxidative stress and protect the kidney from oxidative damage induced by 900 MHz mobile phone. Nevertheless, melatonin seems to be a more potent antioxidant compared with CAPE in kidney. (Mol Cell Biochem 276: 31–37, 2005)

The activities of purine-catabolizing enzymes and the level of nitric oxide in rat kidneys subjected to methotrexate : Protective effect of caffeic acid phenethyl ester

The aim of this experimental study was to investigate the possible role of nitric oxide (NO) levels, and activities of adenosine deaminase (ADA) and xanthine oxidase (XO) in the pathogenesis of methotrexate-induced nephrotoxicity, and was the effect of caffeic acid phenethyl ester (CAPE), the potent free radical scavenger, in decreasing the toxicity. A total of 19 adult male rats were divided into three experimental groups, as follows: control group, MTX-treated group, and MTX+CAPE treated group. MTX were administered intraperitoneally (i.p.) with 20 mg/kg for single dose. CAPE was administered i.p. with a dose of 10 μmol//kg once daily for 7 days. The injection of MTX induced a significant increase in the activities of ADA and XO, and NO levels in renal tissue of rats (p < 0.0001). Co-treatment with CAPE caused a significantly decrease activities of ADA and XO, and the levels of NO in renal tissue (p < 0.0001). The results of this study revealed that NO, XO and ADA may play an important role in the pathogenesis of MTX-induced oxidative renal damage. CAPE may have protective potential in this process and it will become a promising drug in the prevention of this undesired side effect of MTX.

Melatonin reduces urinary excretion of N-acetyl-beta-D-glucosaminidase, albumin and renal oxidative markers in diabetic rats.

1 Increased oxidative stress has an important role in the pathogenesis of diabetic nephropathy. The aim of the present study was to evaluate diabetic nephropathy by determining markers of oxidative stress and the urinary excretion of N‐acetyl‐b‐d‐glucosaminidase (NAG), albumin and to investigate the possible protective effects of in vivo melatonin on renal tubular oxidative damage in diabetic rats. 2 Twenty‐six rats were randomly divided into three groups: (i) group I, control, non‐diabetic rats (n = 9); (ii) group II, untreated diabetic rats (n = 8); and (iii) group III, melatonin‐treated diabetic rats (n = 9). In groups II and III, diabetes developed 3 days after administration of a single dose of streptozotocin (35 mg/kg, i.p.). Thereafter, whereas the rats in group II received no treatment, rats in group III began to receive 10 mg/kg per day, i.p., melatonin for 8 weeks. Malondialdehyde (MDA), an index of lipid peroxidation, NAG and microalbumin in the urine, markers of renal tubular damage, were the parameters used for oxidative stress‐induced renal injury. Superoxide dismutase (SOD), xanthine oxidase (XO) and glutathione peroxidase (GSH‐Px) activities were determined to evaluate changes in the anti‐oxidant status of kidney tissue. 3 In untreated diabetic rats, urinary NAG, albumin and renal MDA levels were markedly increased compared with control rats (P < 0.0001). However, these parameters were reduced in diabetic rats by melatonin treatment (P < 0.0001). Urinary excretion of NAG was positively correlated with the microalbuminuria and renal MDA levels (r = 0.8; P < 0.0001). The SOD and XO activities in the untreated diabetic group were found to be significantly higher than those of the control group (P < 0.0001). Superoxide dismutase and XO activities decreased in melatonin‐treated rats compared with untreated diabetic rats (P < 0.002 and P < 0.023, respectively). However, the decrease did reach levels seen in control rats. There were no significant differences in GSH‐Px activity between the three groups. 4 Therefore, on the basis of these data, we suggest that urinary NAG, albumin excretion, XO activity and MDA levels are more valuable parameters showing the degree of renal tubular injury than classical markers of oxidative stress, including SOD and GSH‐Px, in diabetic rat kidneys. Melatonin has an ameliorating effect on oxidative stress‐induced renal tubular damage via its anti‐oxidant properties. Thus, it may be suggested that urinary NAG excretion and microalbuminuria may be important markers showing the degree of renal changes and the success of long‐term treatment of renal impairment with melatonin.

The comparition of the efficacy of two different probiotics in rotavirus gastroenteritis in children.

Objectives. The aim of the study is to compare the clinical effectiveness of the probiotics—Saccharomyces boulardii and Bifidobacterium lactis—in children who had been diagnosed with rotavirus gastroenteritis. Materials and methods. Seventy five patients aged between 5 months–5 years diagnosed as rotavirus gastroenteritis were included in the study. The patients diagnosed as rotavirus gastroenteritis by latex agglutination test in stool were divided into 3 groups of twenty-five patients each: First group was given oral rehydration therapy and rapid refeeding with a normal diet with Saccharomyces boulardii (spp. I-745), second group was given oral rehydration therapy and rapid refeeding with a normal diet with Bifidobacterium lactis (spp. B94, culture number:N°118529) and third group received only oral rehydration therapy and rapid refeeding with a normal diet. Results. The duration of diarrhea was shorter in the group given oral rehydration therapy and rapid refeeding with a normal diet with Bifidobacterium lactis and Saccharomyces boulardii than the group given only oral rehydration therapy and rapid refeeding with a normal diet. Conclusion. Bifidobacterium lactis has a complemental role in the treatment of rotavirus gatroenteritis and other probiotics may also have a beneficial effect in rotavirus gastroenteritis compared with the therapy included only oral rehydration therapy and rapid refeeding with a normal diet.

Determination of early urinary renal injury markers in obese children

BackgroundObesity is an important health issue, the prevalence of which is increasing in childhood. The aim of this study was to examine urinary renal injury markers in order to determine the renal effect of obesity and its comorbidities in a pediatric population.MethodsEighty-four obese children and 64 healthy control subjects were enrolled in the study. We checked their urine using N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and microalbumin as renal injury markers. Associations of renal damage markers with hypertension, an impaired glucose tolerance test, and insulin resistance were assessed.ResultsObese individuals had higher urinary NAG and KIM-1 values compared to those of healthy controls (p = 0.027, p = 0.026). There was no difference in urinary NGAL between obese and lean subjects (p = 0.885). Urinary renal injury markers were not statistically different in the obese group when checked for impaired glucose tolerance, insulin resistance, and hypertension (p > 0.05).ConclusionsThis study shows that urinary NAG and KIM-1 could be used as a screening method for detection of early renal damage in obese children.

Vitamin D Deficiency and Insufficiency in Obese Children and Adolescents and Its Relationship with Insulin Resistance

Objectives. We aimed to determine the relationship between insulin resistance and serum 25-hydroxyvitamin D (25-OHD) levels in obese children and their nonobese peers. Materials and Methods. Included in the study group were 188 obese children (aged 9–15 years), and 68 age- and gender-matched healthy children of normal weight as control group. Anthropomorphic data were collected on patients and fasting serum glucose, insulin, serum lipids, alanine aminotransaminase (ALT) and 25-OHD were measured. The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated in both groups. Results. The levels of 25-OHD in the obese group were significantly lower than those of the nonobese (P = 0.002). HOMA-IR, triglycerides, low-density lipoprotein, and ALT levels in the obese group were significantly higher than values of control group (P < 0.001 and P = 0.002, resp.). In the obese group, vitamin D deficiency, insufficiency, and sufficiency (25-OHD < 10 ng/dl, < 20, >10 ng/dl; > 20 ng/dl, resp.) were not correlated with HOMA-IR (r : −0.008, P = 0.935). HOMA-IR was negatively correlated with BMI, BMI SDS, and BMI%, and triglycerides, low-density lipoprotein, and ALT levels (P < 0.001). Conclusion. The insulin resistance of the obese subjects who were vitamin D deficient and insufficient did not statistically differ from those with vitamin D sufficiency. Low 25-hydroxyvitamin D levels were not related with higher insulin resistance in obese children and adolescents. In obese subjects, insulin resistance was affected more from BMI, BMI SDS, and BMI% than from 25-hydroxyvitamin D levels.

Effects of fluorosis on QT dispersion, heart rate variability and echocardiographic parameters in children.

OBJECTIVE Chronic fluoride poisoning is called fluorosis. The aim of the study was to investigate effects of fluorosis on cardiovascular system in children by measuring QT dispersion (QTd), corrected QT dispersion (QTcd), heart rate variability (HRV) and echocardiography findings. METHODS Thirty-five children with dental fluorosis and 26 children as control group were included in this cross-sectional study. Dean index was used for the clinical diagnosis. The fluoride levels of subjects measured by ion electrode method in spot urine higher than 0.6 ppm were included in the study. Serum electrolytes and thyroid function tests were analyzed. Electrocardiography (ECG), echocardiography and 24-hour ambulatory Holter monitorizations were applied, and all the data were analyzed for measuring HRV, and calculation of QTd and QTcd intervals. Corrected QT (QTc) intervals were determined with the Bazzett formula. Difference between the longest and shortest intervals was considered as dispersion. Statistical analysis was performed Kruskal-Wallis test and Pearson correlation test. RESULTS Low free thyroxine hormone (FT4) (Control Group, Group 2 1.11 (0.85-1.64) ng/dL, 0.96 (0.85-1.11) ng/dL, p<0.05), calcium (Control Group, Group 1, 2, 9.80 (9.30-10.70) mg/dL, 9.60 (8.90-10.70) mg/dL, 9.50 (8.90-10.10) mg/dL, p<0.05) and high serum sodium levels (Control Group, Group 2 139 (136-142) mEq/L, 141 (138-148) mEq/L, p<0.01), increased QT (Control Group, Group 2 329.8 (300.0-363.5) msec, 351.8 (318.0-372.0) msec, p<0.05) and QTc intervals (Control Group, Group I2 390.6 (309.0-418.5) msec, 366.8 (318.2-468.5) msec, p<0.05) were found in subjects with fluorosis. No significant difference was found with respect to echocardiography and HRV variables. CONCLUSION Endemic fluorosis is a risk factor for decrease in calcium and FT4 levels, increase in sodium levels and QT prolongation. These findings might be related with some cardiovascular system dysfunctions such as arrhythmias or syncope. Subjects with fluorosis should be monitored in terms of long QT and QTc intervals.