H. Ramazan Yilmaz

Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism

BACKGROUND There is evidence that oxygen free radicals play an important role in the pathophysiology of many neuropsychiatric disorders. Although it has not been investigated yet, several recent studies proposed that nitric oxide (NO) and other parameters related to oxidative stress may have a pathophysiological role in autism. METHODS We assessed the changes in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and thiobarbituric acid-reactive substances (TBARS) levels in plasma as well as NO levels in red blood cells (RBC) in patients with autism (n=27) compared to age- and sex-matched normal controls (n=30). RESULTS In the autistic group, increased RBC NO levels (p<0.0001) and plasma GSH-Px activity (p<0.0001) and unchanged plasma TBARS levels and SOD activity were detected. CONCLUSIONS These findings indicate a possible role of increased oxidative stress and altered enzymatic antioxidants, both of which may be relevant to the pathophysiology of autism.

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.

The activities of liver adenosine deaminase, xanthine oxidase, catalase, superoxide dismutase enzymes and the levels of malondialdehyde and nitric oxide after cisplatin toxicity in rats: protective effect of caffeic acid phenethyl ester.

The aim of this experimental study was to investigate the effects of caffeic acid phenethyl ester (CAPE), an antioxidant agent, on cisplatin-induced hepatotoxicity through adenosine deaminase (AD), xanthine oxidase (XO), catalase (CAT), superoxide dismutase (SOD) activities and malondialdehyde (MDA) and nitric oxide (NO) levels in liver tissue of rats. Wistar albino rats were divided into three groups: control group (n-6), cisplatin group (n-9) and CAPE+cisplatin group (n-8). All the chemicals used were applied intraperitoneally. Spectrophotometric methods were used to determine the activities of the above-mentioned enzymes in the liver tissue. NO level and XO activity were found to be increased in the cisplatin group compared to the control group. NO level was found to be decreased in the cisplatin+CAPE group in comparison with the cisplatin group. There was no significant change in the activity of XO between the cisplatin and cisplatin+CAPE groups. The activity of SOD was lower in the cisplatin group than both the control and cisplatin+CAPE groups. There was no significant change in the activity of CAT between the control and cisplatin groups. CAT activity was increased in the cisplatin+CAPE group compared to the cisplatin group. The AD activity and MDA level remained unchanged in all groups. The results obtained suggested that CAPE significantly attenuated the hepatotoxicity as an indirect target of cisplatin in an animal model of cisplatin-induced nephrotoxicity.

Effects of v-3 essential fatty acids against formaldehyde-induced nephropathy in rats:

The aim of this study was to examine the toxicity of formaldehyde (FA) on the kidney and the protective effects of v-3 essential fatty acids against these toxic effects. Twenty-one male Wistar rats were divided into three groups. Rats in Group I comprised the controls, while the rats in Group II were injected every other day with FA. Rats in Group III received v-3 fatty acids daily while exposed to FA. At the end of the 14-day experimental period, all rats were killed by decapitation and the kidneys removed. Some of the kidney tissue specimens were used for determination of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and malondialdehyde (MDA) levels. The remaining kidney tissue specimens were used for light microscopic evaluation. The levels of SOD and GSH-Px were significantly decreased, and MDA levels were significantly increased in rats treated with FA compared with those of the controls. Furthermore, in the microscopic examination of this group, glomerular and tubular degeneration, vascular congestion and tubular dilatation were observed. However, increased SOD and GSH-Px enzyme activities, and decreased MDA levels were detected in the rats administered v-3 fatty acids while exposed to FA. Additionally, kidney damage caused by FA was decreased and structural appearance was similar to that of the control rats in this group. In conclusion, it was determined that FA-induced kidney damage was prevented by administration of v-3 essential fatty acids.

The effects of ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity.

This study was carried out to determine if Ginkgo Biloba Extract (GBE or Egb 761) exerts a beneficial effect against cisplatin-induced renal failure in rats. Sprague Dawley rats were divided into four groups. The first group (control) received orally 1 mL/kg/day of 0.9% saline by an oral carrier vehicle on days 1 to 10. The second group was injected with 7 mg/kg cisplatin intraperitoneally (i.p.) on the fourth day, once only. The third group (vit E=cisplatin) was administered 10 mg/kg/day i.p. vit E on 1 to 10 days with one dose of i.p. cisplatin (7 mg/kg) injection on the fourth day. The fourth group (GBE=cisplatin) was given GBE orally at 100 mg/mL/kg started on the first day up to the tenth day with one dose of cisplatin (7 mg/kg) injection on the fourth day. Cisplatin was found to lead a statistically significant increase in plasma BUN and creatinine levels, as well as urine micro total protein (MTP) levels, leading to acute renal failure (ARF) in rats. Renal xanthine oxidase (XO) activities increased in all groups (statistically significant in cisplatin=GBE-treated rats; P≤0.001). Adenosine deaminase (AD) activities were increased in cisplatin-treated rats, and decreased in cisplatin=GBE-treated (PB≤0.041) and cisplatin=vit E-treated (PB≤0.005) rats, compared to controls. Malondialdehyde (MDA), nitric oxide (NO) levels and myeloperoxidase (MPO) activities were increased in the kidney tissue of cisplatin-treated rats. Vit E improved plasma creatinine and urine MTP levels, together with tissue MDA, NO levels, and MPO activities. But GBE had no statistically significant effect on those parameters. These results indicate that increased XO, AD and MPO activities, as well as MDA and NO levels play a critical role in cisplatin nephrotoxicity. GBE has been shown to protect against cisplatin-induced nephrotoxicity. Toxicology and Industrial Health 2006; 22: 125-130.

Anticlastogenic effect of caffeic acid phenethyl ester on cisplatin-induced chromosome aberrations in rat bone marrow cells.

Caffeic acid phenethyl ester (CAPE) is an antioxidant that can scavenge free radicals and protect cellular macromolecules, including DNA and proteins, from oxidative damage induced by various agents. The protective effect of CAPE on cisplatin-induced chromosome aberrations has been determined in rat bone marrow cells. The animals were pretreated with a single dose of CAPE (10 μmol/kg body weight [b.w.]) injected intraperitoneally (i.p.) 24 hours before the administration of cisplatin and then sacrificed 24 hours after the cisplatin administration. Cisplatin was administered to rats either alone (5 mg/kg b.w., i.p.) or after CAPE treatment. CAPE has led to a statistically significant decrease in the total number of chromosomal aberrations and abnormal metaphases induced by cisplatin when compared with only cisplatin given groups. We have concluded that CAPE could prevent cisplatin-induced chromosome aberrations by establishing a potent free radical scavenger effect.

Caffeic acid phenethyl ester protects against amphotericin B induced nephrotoxicity in rat model.

The present study was conducted to investigate whether caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has a protective effect on amphotericin B induced nephrotoxicity in rat models. Male Wistar-Albino rats were randomly divided into four groups: (I) control group (n = 10), (II) CAPE group (n = 9) which received 10 μmol/kg CAPE intraperitoneally (i.p.), (III) amphotericin B group (n = 7) which received one dose of 50 mg/kg amphotericin B, and (IV) amphotericin B plus CAPE group (n = 7) which received 10 μmol/kg CAPE i.p. and one dose of 50 mg/kg amphotericin B. The left kidney was evaluated histopathologically for nephrotoxicity. Levels of malondialdehyde (MDA), nitric oxide (NO), enzyme activities including catalase (CAT), and superoxide dismutase (SOD) were measured in the right kidney. Histopathological damage was prominent in the amphotericin B group compared to controls, and the severity of damage was lowered by CAPE administration. The activity of SOD, MDA, and NO levels increased and catalase activity decreased in the amphotericin B group compared to the control group (P = 0.0001, P = 0.003, P = 0.0001, and P = 0.0001, resp.). Amphotericin B plus CAPE treatment caused a significant decrease in MDA, NO levels, and SOD activity (P = 0.04, P = 0.02, and P = 0.0001, resp.) and caused an increase in CAT activity compared with amphotericin B treatment alone (P = 0.005). CAPE treatment seems to be an effective adjuvant agent for the prevention of amphotericin B nephrotoxicity in rat models.

Vitreoscilla hemoglobin renders Enterobacter aerogenes highly susceptible to heavy metals.

When expressed in heterologous microorganisms Vitreoscilla hemoglobin (VHb) acts as oxygen storage and causes a higher oxygen uptake. In this study, the effect of this protein on growth, sensitivity and antioxidant properties of Enterobacter aerogenes exposed to metal stress was investigated. The strain expressing VHb was more sensitive to mercury and cadmium as the minimal inhibitory concentration (MIC) for these metals was up to 2-fold lower in this strain than the host and the recombinant strain carrying a comparable plasmid. At lower concentrations than MIC, the metals partially limited growth and caused an inhibition proportional to metal concentration applied. The growth pattern of VHb expressing strain was also distinctly different from other two non-hemoglobin strains. The hemoglobin containing strain showed substantially higher superoxide dismuates (SOD) activity than the non-hemoglobin strains, while catalase levels were similar in all strains. All strains exposed to copper, however, showed similar MIC values, growth patterns, and SOD and catalase levels.

Manganese superoxide dismutase, glutathione peroxidase and catalase gene polymorphisms and clinical outcomes in acute kidney injury

Abstract Introduction The aim of this study was to evaluate the potential association of single gene polymorphisms of manganese superoxide dismutase (MnSOD), glutathione peroxidase 1 (GPX1) and catalase (CAT) with clinical outcomes of acute kidney injury (AKI). Materials and methods Ninety AKI patients and 101 healthy volunteers were included in the study. Determination of MnSOD rs4880, GPX1 rs1050450 and CAT rs769217 polymorphisms was performed using real-time polymerase chain reaction amplification. The duration of hospitalization of AKI patients, dialysis and intensive care requirements, sepsis, oliguria and in-hospital mortality rates were assessed. Results The MnSOD, GPX1 and CAT genotypes and allele frequencies of AKI patients did not differ significantly from those of healthy controls. In patients with a T allele in the ninth exon of the CAT gene, intensive care requirements were greater than those of patients with the CC genotype (p = 0.04). In addition, sepsis and in-hospital mortality were observed significantly more frequently in patients with a T allele in the ninth exon of the CAT gene (p = 0.03). Logistic regression analysis determined that bearing a T allele was the primary determinant of intensive care requirements and in-hospital mortality, independent of patient age, gender, presence of diabetes and dialysis requirements (OR 6.10, 95% CI 1.34–27.81, p = 0.02 and OR 10.25, 95% CI 1.13–92.80, p = 0.04, respectively). Conclusion Among AKI patients in the Turkish population, hospital morbidity and mortality were found to be more frequent in patients bearing a T allele of the rs769217 polymorphism of the CAT gene.

Effect of 2,4-dichlorophenoxyacetic acid on the activities of some metabolic enzymes for generating pyridine nucleotide pool of cells from mouse liver:

2,4-Dichlorophenoxyacetic acid (2,4-D), which is a plant auxin analogue, is lethal to broad leaved weeds within days at high dosages and is considered as having low toxicity to mammals. Some studies have reported that exposure to this compound may cause damage to organs such as liver. The aim of this study was to investigate the effects of 2,4-D in mouse liver on chromosomes as well as hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) which are required for the generation of the pyridine nucleotide pool. The experiments were carried out with a 2,4-D group, an ethanol control for 2,4-D, and saline group for ethanol control group on three generations of mice. Only female parents were given 2,4-D during the gestation period, lactation period and for 33 days following the lactation period. In females of the first cross, 2,4-D caused a significant increase in the activity of LDH, and ethanol alone caused a significant increase in the activities of HK and LDH. In the male offspring of the first cross maternal, 2,4-D caused a significant increase in the activity of LDH, and ethanol alone caused a significant decrease in the activity of 6PGD. In the female offspring of the first cross maternal, ethanol caused a significant increase in the activities of G6PD and MDH. In the female offsprings of the third cross maternal, 2,4-D caused a significant increase in the activity of MDH. No gross morphological changes were observed in internal organs, such as liver, kidney and spleen of the affected animals. Also, a chromosomal study from bone marrow cells indicated no anomalies in chromosomal sets and structures. As a result, 2,4-D had an effect on the first cross maternal and their offsprings. The compound did not affect the parameters studied except MDH enzyme activity in the second and third generation of mice.