Hypoxia causes important changes of extracellular matrix biomarkers and ADAMTS proteinases in the adriamycin-induced renal fibrosis model.

AIM: Renal fibrosis is a common cause of renal dysfunction with chronic kidney diseases. This process is characterized by excessive production of extracellular matrix (ECM) or inhibition of ECM degradation. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteinases, which are widely presented in mammals, have very critical roles in ECM remodelling. We aimed to study the role of ADAMTS proteinases and some of the ECM markers in the pathogenesis of renal fibrosis and to investigate the effects of hypoxia on these biomarkers. METHODS: In addition to the control group, Adriamycin (ADR) treated rats were divided into four groups as ADR, sham and two hypoxia groups. Renal nephropathy was assessed biochemical assays, pathological and immunohistochemical staining methods. The expression of ADAMTSs and mRNA were determined using Western blotting and real-time PCR, respectively. RESULTS: Renal dysfuntion and tissue damage in favour of ECM accumulation and renal fibrosis were observed in the ADR group. This was approved by remarkable changes in the expression of ADAMTS such as increased ADAMTS-1, -12 and -15. In addition, it was found that hypoxia and duration of hypoxia enhanced markers of tubulointerstitial fibrosis in the rat kidney tissues. Also, expression differences especially in ADAMTS-1, -6 and -15 were observed in the hypoxia groups. The variable and different expression patterns of ADAMTS proteinases in the ADR-induced renal fibrosis suggest that ADAMTS family members are involved in the development and progression of fibrosis. CONCLUSION: The expression changes of ADAMTS proteinases in kidney and association with hypoxia have potential clues to contribute to the early diagnosis and treatment options of renal fibrosis.

Effects of quercetin on methotrexate-induced nephrotoxicity in rats.

OBJECTIVE: This experimental study was conducted to elucidate the possible protective/therapeutic effects of quercetin against methotrexate (Mtx)-induced kidney toxicity with biochemical and histopathological studies. METHODS: Twenty-four adult male rats were randomly divided into four groups, as follows: control group (saline intraperitoneally (i.p.), 9 days), Mtx group (20 mg/kg i.p., single dose), Mtx + quercetin group (50 mg/kg quercetin was orally administered 2 days before and 6 days after Mtx administration) and only quercetin group (50 mg/kg oral, 9 days). Structural changes were evaluated by hematoxylin-eosin and periodic acid-Schiff stainings. Apoptotic changes were investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and caspase-3 antibody. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured in tissue and plasma samples. RESULTS: Mtx compared with the control group, there was significant increase in nephrotoxic tissue damage findings, in addition to apoptotic index (APOI) and caspase-3 expression ( p < 0.05). Mtx + quercetin group revealed significantly lower histopathological damage and APOI and caspase-3 expression decreased when compared to Mtx group. MDA levels were increased in Mtx group compared to others, and by the use of quercetin, this increase was significantly reduced. SOD levels were higher in Mtx group than others. This increase was evaluated as a relative increase arising from oxidative damage caused by Mtx. CONCLUSION: As a result, Mtx administration may involve oxidative stress by causing structural and functional damage in kidney tissue in rats. Quercetin reduced the Mtx-induced oxidative stress through its antioxidant properties and so quercetin may be promising to alleviate Mtx-induced renal toxicity.

Protective Effect of Alpha Lipoic Acid on Rat Sciatic Nerve Ischemia Reperfusion Damage.

BACKGROUND: Alpha lipoic acid is a potent antioxidant that plays numerous roles in human health. This study examined the effect of ALA on rat sciatic nerve ischemia reperfusion damage. AIMS: Protective effect of alpha lipoic acid (ALA) on sciatic nerve following ischemia-reperfusion in rats was investigated by using light microscopy and biochemical methods. Provided that the protective effect of ALA on sciatic nerve is proven, we think the damage to the sciatic nerve that has already occurred or might occur in patients for various reasons maybe prevented or stopped by giving ALA in convenient doses. STUDY DESIGN: Animal experiment. METHODS: Forty-two adult male Sprague-Dawley rats (250-300 grams) were used in this study. Rats were randomly divided into six groups including one control (Group 1), one sham (Group 2), two ischemia-reperfusion (Groups 3 and 4) and two treatment groups (Groups5 and 6). Doses of 60 and 100 mg/kg ALA were given (Group 5 and 6) intra peritoneally twice, 1 and 24 hours before the ischemia to each treatment group. Ischemia was carried out the abdominal aorta starting from the distal part of the renal vein for two hours followed by reperfusion for three hours. In immunohistochemical methods, fibronectin immunoreactivity was analyzed. For biochemical analyses, the tissues were taken in eppendorf microtubes and superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) enzyme activities as well as malondialdehyde (MDA) and nitricoxide (NO) levels were measured. RESULTS: Fibronectin was observed to have increased significantly in the ischemia group; on the other hand, it was observed to have decreased in parallel to the doses in the ALA groups. Biochemical studies showed that SOD and GSHPx declined with ischemia-reperfusion, but the activities of these enzymes were increased in the treatment groups in parallel with the dose. It was found that increased MDA levels with ischemia-reperfusion were decreased in parallel with ALA dose. There were no statistically significant changes in NO. CONCLUSION: Increased fibronectin observed after ischemia/reperfusion of rat sciatic nerve is reduced after the administration of ALA. This indicates that the function of fibronectin, to reconnect cut nerve segments and regenerate nerves, is more prominent than its function in tissue healing after ischemia. ALA administered before ischemia decreases MDA and increases SOD and GSHPx. We think that ALA may protect against the pathological changes in ischemic nerve and may be used to devise more efficient treatments.

Age-related volumetric changes in pancreas: a stereological study on computed tomography.

PURPOSE: (1) To explore age-related changes in the volume of the pancreas on computed tomography (CT) images calculated by the method of Cavalieri. (2) To investigate the relationship between these changes and body mass index (BMI), gender, abdominal diameter, abdominal skinfold thickness. METHODS: We retrospectively reviewed abdominal CT examinations of 272 adults between the ages of 20-88 years. There were seven groups of patients, with 40 patients (only ninth decade has 32 patients) for each decade. RESULTS: Pancreatic volume (PV) was found to be 63.68 ± 15.08 cm(3) in females, 71.75 ± 15.99 cm(3) in males (mean value of both groups, 67.71 ± 16.03 cm(3)). Maximum value of PV was found in the fourth decade in females, males and also for mean of both groups (73.50, 84.21 and 78.85 cm(3), respectively). PV remained constant until ~60 years of age. Thereafter, it gradually decreased in both genders. There was a negative correlation between PV and age (p < 0.001, r: -0.473). We found positive correlation between PV and BMI, sagittal abdominal diameter (SAD), transverse abdominal diameter (TAD), anterior subcutaneous adipose tissue thicknesses (ASAT), posterior subcutaneous adipose tissue thicknesses (PSAT), bilateral subcutaneous adipose tissue thicknesses (BSAT). CONCLUSIONS: Quantitative data may allow clinicians to better estimate age-related PV changes and help them in decision making.

Histological assessment of skin grafts stored in amniotic fluid and saline.

We investigated the efficacy of amniotic fluid as a substance in which to store grafts; it is rich in nutrients, proteins, and growth factors, and has well-known antimicrobial features. We compared it with the widely-used and practical saline. Split-thickness grafts 4 × 4 cm were prepared from the back of 20 rats and divided into four groups (n = 5 each). The rolled grafts were wrapped in gauze dampened with saline or amniotic fluid and placed into refrigerators in sterile containers for storage. On days 7, 14, 21, and 28, histological examinations were made. A semiquantitative evaluation of the histological damage to the skin was made by scoring its degree of severity. Compared with saline, histological scores in the grafts stored in amniotic fluid were found to be significantly lower on the 14th, 21st, and 28th days (p values on days 14, 21, and 28; cell swelling: 0.014, 0.006, and 0.005, respectively; nuclear swelling: 0.003, 0.006, and 0.007, respectively; nuclear pleomorphism: 0.004, 0.005, and 0.003, respectively; nuclear haloes: 0.015, 0.005, and 0.005, respectively; nuclear pyknosis: 0.003, 0.005, and 0.003, respectively; dermo-epidermal clefting: 0.005, 0.003, and 0.003, respectively; eosinophilia and mitosis: 0.003, 0.006, and 0.004, respectively; dermal collagen: 0.003, 0.003, and 0.003, respectively). Amniotic fluid maintained preservation better for skin grafts than saline. Comparison with other modern storage media would be beneficial.

Novel approach for the prevention of contrast nephropathy.

OBJECTIVE: To date, there is no effective treatment of contrast medium (CM)-induced nephropathy. Multiple studies documented a protective role of hydration and N-acetylcystein (NAC) as prophylactic agents against CM-induced nephropathy in a high-risk population. In the present study, we investigated a new antioxidant agent, caffeic acid phenethyl ester (CAPE), and compare with NAC against contrast nephropathy. METHODS: Forty-two adult male rats were divided into six experimental groups, which were control, injected with intravenous (i.v.) CM, injected with i.p. CAPE, injected with i.p. NAC, injected with i.v. CM pretreated with i.p. CAPE, injected with i.v. CM pretreated with i.p. NAC. CAPE and NAC were given daily throughout the study. All rats were deprived of water for 24h at the third day of the study and then contrast medium was administered to CM, CAPECM and NACCM groups. The rats were sacrificed at the fifth day. Oxidant-antioxidant status was determined in renal tissues. The severity of injury was scored with a light microscope in renal tissue. Plasma creatinine levels were measured. RESULTS: Renal injury scores were higher in CAPECM and NACCM groups than in control, CAPE and NAC groups, but lower than the CM group. Likewise, creatinine levels of CAPECM and NACCM groups were higher than the control groups but they were significantly lower than the level of the CM group. Creatinine levels of the NACCM group were significantly higher than the CAPECM group. Malondialdehyde levels were significantly lower in CAPECM and NACCM groups than the CM group. CONCLUSION: CAPE might protect renal structure and functions as well as NAC against CM injury.

The neuroprotective effect of dexmedetomidine in the hippocampus of rabbits after subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage is a serious condition, often accompanied by cerebral vasospasm, which may lead to brain ischemia and neurologic deterioration. We evaluated if dexmedetomidine has neuroprotective effects in the hippocampus of vasospastic SAH rabbits or not. MATERIALS AND METHODS: Eighteen New Zealand rabbits were taken. An experimental SAH model was formed by injecting 0.9 mL of autologous arterial blood per 1 kg of body weight to the cisterna magna of 12 rabbits. Craniotomy was performed in the control group (n = 6) except performing experimental SAH. Rabbits in the SAH-alone (n = 6) group were infused with 5 mL.kg(-1).h(-1) 0.9% sodium chloride, and rabbits (n = 6) in the SAH-dexmedetomidine group were infused with 5 microg.kg(-1).h(-1) dexmedetomidine for 2 hours, 48 hours after SAH was established. Rabbits of all groups were sacrificed via penthotal 24 hours after dexmedetomidine administration. Brains were removed immediately, and hippocampal tissues were blocked from the right hemisphere for histopathologic study. In addition to this, hippocampal tissues of left hemispheres were dissected for biochemical analyses to evaluate MDA levels, activity of XO, and SOD. RESULTS: The histopathologic study showed that dexmedetomidine may have a neuroprotective effect in SAH-induced hippocampal injuries. The biochemical parameters support the neuroprotective effect of dexmedetomidine (P < .05). CONCLUSION: Our study showed that dexmedetomidine may have a neuroprotective effect in the hippocampus of vasospastic SAH rabbits.

The neuroprotective effect of fish n-3 fatty acids in the hippocampus of diabetic rats.

INTRODUCTION: Diabetes mellitus may lead to functional and structural changes in the brain. Fish oil is a rich source of n-3 essential fatty acids (EFA) such as eicosapentaenoic and docosahexoenoic acids. We examined the neuroprotective effects of fish n-3 EFA in the hippocampus of diabetic rats. MATERIALS AND METHODS: Nineteen adult male rats were divided into three groups. Group I (control; n = 6) was fed a normal rat diet. Group II (diabetic; n = 6) was fed a normal rat diet and streptozotocin (STZ) was administered to induce diabetes mellitus. Group III (n-3 + diabetic; n = 7) was fed a normal rat diet and fish n-3 EFA (Marincap, 0.4 g/kg/day) for 8 weeks and STZ was administered to induce diabetes mellitus. The levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) and catalase (CAT) were measured in the left hippocampus after the animals were sacrificed. The right hemisphere was completely blocked. The sections were stained with Cresyl Violet and apoptotic neurons were counted in the hippocampus. RESULTS: The levels of MDA and activities of SOD and CAT increased in diabetic rats compared to control rats. However, the levels of MDA and activities of SOD and CAT decreased in n-3 + diabetic rats compared to diabetic rats. Also, the number of apoptotic neurons increased in diabetic rats compared to control rats and decreased in n-3 + diabetic rats compared to diabetic rats. CONCLUSIONS: Fish n-3 EFA reduces oxidative stress and induces apoptotic changes in the hippocampus of STZ-diabetic rats. The addition of fish n-3 EFA to diets may be useful to prevent functional and structural changes to cerebral centers due to diabetes mellitus.

Oedema risk of endotracheal intubation in rabbits with cessation of steroid therapy.

Rebound oedema of tissues is a well defined complication of cessation of steroid therapy. Tapering of systemic corticosteroid regimens in short course steroid therapy is considered unnecessary in most circumstances in acute exacerbation of chronic obstructive pulmonary diseases, presence of laryngeal rebound edema is obscure in this situation. We studied whether or not laryngeal oedema increases after intubation when intubation is established after cessation of steroid therapy. Thirty-six rabbits were randomly divided into six groups. We administered 1 mg/kg methyl prednisolone intraperitoneally to four steroid groups for ten days. Another group received serum physiologic for ten days and last group was sham control that was intubated only. Rabbits that received steroid therapy were intubated and separated into groups one day, one week, two weeks, and a month after the cessation of steroid therapy. Airway area and percentage of cross sectional area of larynx lumen to their own larynx tissues surrounded by thyroid cartilage and oesophagus were studied by stereological methods. Larynx lumen area of one week steroid group was significantly narrower and percentage of cross sectional area of larynx lumen to their own larynx tissues surrounded by thyroid cartilage and oesophagus was significantly larger than sham control. Rebound oedema forms in larynx with abrupt cessation of steroid therapy in rabbits. Clinical safe time for intubation after abrupt cessation of steroid therapy is also defined with our study. These results suggest that one week after the cessation of steroid therapy may be a hazardous time for tracheal intubation.

Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats.

BACKGROUND: Oxidative stress has an important role in the pathogenesis of doxorubicin-induced hepatotoxicity. The aim of this study was to investigate the hepatoprotective effects of erdosteine, an antioxidant agent, on doxorubicin-induced hepatotoxicity. METHODS: Rats were divided into control, doxorubicin alone (20 mg/kg, i.p.) and doxorubicin plus erdosteine (50 mg/kg/day, oral) groups. At the end of the 10(th) day, liver tissues were removed for light microscopy and analysis. The levels of tissue protein carbonyl content, malondialdehyde and nitric oxide, as well as the activities of superoxide dismutase, catalase, were determined. RESULTS: The tissue of the doxorubicin group showed some histopathological changes such as necrosis, hepatocyte degeneration, sinusoidal dilatation, hemorrhage and vascular congestion and dilatation. In the doxorubicin plus erdosteine group, histopathological evidence of hepatic damage was markedly reduced. Biochemical parameters were consistent with histological parameters. CONCLUSIONS: Doxorubicin caused hepatotoxicity, and erdosteine treatment prevented lipid peroxidation and protein oxidant in liver tissue.

Esophageal muscle cell interaction with biopolymers.

BACKGROUND: The in vitro interactions of esophageal smooth muscle cells (SMCs) with synthetic absorbable polymers were tested and artificial muscle tissues harvested from subcutaneous implantation were examined. MATERIAL/METHODS: Esophageal tissue samples from adult and fetal (25-day gestational age) rabbits were cut into small pieces and cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum. Growing cells were identified as SMCs by immunostaining for anti-actin and anti-myosin antibodies. Equal volumes of agar gel and medium were mixed and used for 3-D culture. 5x10(5) cells and 1 mg polyglycolic acid (PGA) and poly-lactide-co-glycolide acid (PLGA) fibers were seeded in six-well tissue culture plates. On days 2 and 7 growing cells were counted by a hemocytometer and cell-polymer interactions were evaluated with light microscopy. Adult and fetal SMCs were seeded onto the PGA and PLGA scaffolds, cultivated for two weeks, and implanted subcutaneously on the backs of the rabbits. Cell-polymer implants were retrieved after four weeks and muscle formation was evaluated histologically and immunohistochemically. RESULTS: Growing cells stained positive for actin and myosin proteins. Cell-polymer interactions were poor after 24 hours, whereas intensive attachment to the fibers was detected 48 hours following cultivation. Both fiber materials supported cell proliferation. PLGA scaffolds improved muscle formation more efficiently than PGA, and fetal and adult SMCs showed similar mass quality. CONCLUSIONS: Scaffolds are important as cell-carrying vehicles, and material-cell interactions should be tested before application. A 3-D culture prepared with agar gel and medium is practical for testing material toxicity.

The protective effect of fish n-3 fatty acids on cerebral ischemia in rat hippocampus.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of cerebral injury after ischemia-reperfusion (I/R). Fish n-3 essential fatty acids (EFA), contain eicosapentaenoic acids (EPA) and docosahexoenoic acids (DHA), exhibit antioxidant properties. DHA is an important component of brain membrane phospholipids and is necessary for the continuity of neuronal functions. EPA prevents platelet aggregation and inhibits the conversion of arachidonic acid into thromboxane A(2) and prostaglandins. They have been suggested to be protective agents against neurological and neuropsychiatric disorders. In this study, the neuroprotective effects of fish n-3 EFA on oxidant-antioxidant systems and number of apoptotic neurons of the hippocampal formation (HF) subjected to cerebral I/R injury was investigated in Sprague-Dawley rats. Six rats were used as control (Group I). Cerebral ischemia was produced by occlusion of both the common carotid arteries combined with hypotension for 45 min, followed by reperfusion for 30 min, in rats either on a standard diet (Group II) or a standard diet plus fish n-3 EFA (Marincap((R)), 0.4 g/kg/day, by gavage) for 14 days (Group III). At the end of procedures, the rats were sacrificed and their brains were removed immediately. The levels of malonedialdehyde (MDA) and nitric oxide (NO) and activities of superoxide dismutase (SOD) and catalase (CAT) were measured in left HF. In addition, the number of apoptotic neurons was counted by terminal transferase dUTP nick end labelling (TUNEL) assay in histological samples of the right HF. We found that SOD activities and MDA levels increased in Group III rats compared with Group II rats. On the other hand, CAT activities and NO levels were found to be decreased in Group III rats compared with Group II rats. Additionally, the number of apoptotic neurons was lower in Group III in comparison with Group II rats. The present findings suggest that fish n-3 EFA could decrease the oxidative status and apoptotic changes in ischemic rat hippocampal formation. Dietary supplementation of n-3 EFA may be beneficial to preserve or ameliorate ischemic cerebral vascular disease.

Effects of formaldehyde exposure on granule cell number and volume of dentate gyrus: a histopathological and stereological study.

The hippocampal formation is a complex region of the brain related to memory and learning. The purpose of the present study was to determine whether exposure of neonatal rats to formaldehyde (FA) had either early or delayed effects on the numbers of granule cells in the dentate gyrus (DG). After birth, the neonatal male Wistar rats were exposed throughout a 30-day period to various concentrations of FA: 0 (control group), 6 ppm (low concentration group) and 12 ppm (high concentration group). This was done by placing them for 6 h/day and 5 days per week in a glass chamber containing FA vapor. Then, five animals from each group were anesthetized and decapitated on postnatal day (PND) 30, and the remaining five animals were sacrificed on PND 90 by intracardiac perfusion using 10% neutral buffered FA solution. The Cavalieri principle of stereological approaches was used to determine the volume of the DG in these sections. The optical fractionator counting method was used to estimate the total number of granule cells in the DG. The appearance of granule cells was normal under light microscopy in all PND 30 and PND 90 groups. There were significant age-related reductions in the volume of the DG at PND 90 irrespective of which group was examined. Significant age-related neuron loss was also determined at PND 90 compared to that at PND 30. Rats treated with a high concentration FA were found to have fewer granule cells than either the animals treated with a low concentration FA or the control group (p<0.01 and p<0.01, respectively) at PND 90 but not at PND 30. These findings clearly indicate that granule cells in the DG may be vulnerable to stress and the concentration of FA to which they are exposed during early postnatal life, and also that a neurotoxic effect of high dose FA on cell number is only seen after a long time period. These results may explain why some disorders do not appear until later life.

Ginkgo biloba inhibits bleomycin-induced lung fibrosis in rats.

Oxidative stress has been implicated in the pathogenesis of bleomycin-induced lung fibrosis and many antioxidant agents have been studied for prevention and treatment of the disease in animals and humans. We therefore examined whether Ginkgo biloba (Gb), a flavonoid-rich antioxidant, inhibits bleomycin-induced lung fibrosis in rats. Male Sprague-Dawley rats were given a single dose of bleomycin (2.5 mg/kg, intratracheally) in pulmonary fibrosis groups and saline in controls. First dose of Gb was given a day before the bleomycin injection and continued until sacrifice. At day 14, fibrotic changes in lung were estimated to occur by Aschoft's criteria and lung hydroxyproline content. Bleomycin challenge provoked severe pulmonary fibrosis with marked increase in hydroxyproline content of lung tissue and typical histological findings, which is prevented by Gb. Hydroxyproline level was significantly higher (13.51+/-0.87 mg/g dried tissue) in bleomycin treated rats than controls (9.2+/-1.33), and its level was remained to the control levels (7.38+/-0.76) in rats treated with prophylactic Gb. On the other hand, bleomycin injection significantly reduced activities of glutathione peroxidase, superoxide dismutase and catalase in lung tissue which is prevented by Gb. Also, bleomycin injection resulted in a marked increase of malondialdehyde and nitrite level which is attenuated by Gb. The data suggest that Gb has a potent antioxidant activity in the model of bleomycin-induced lung fibrosis in rats, and therefore has a potent antifibrotic activity against bleomycin-induced lung fibrosis model in rats.

Protein oxidation and lipid peroxidation after renal ischemia-reperfusion injury: protective effects of erdosteine and N-acetylcysteine.

Oxygen radicals have roles in the renal ischemia-reperfusion (IR) injury usually encountered in several conditions such as renal transplantation. The aim of this study was to investigate the effects of erdosteine and N-acetylcysteine (NAC) on the oxidant/antioxidant status and microscopy of renal tissues after IR injury. Male Sprague-Dawley rats were randomly assigned to four groups: control untreated rats, IR (30 min ischemia and 120 min reperfusion), IR + NAC (i.p.; 180 mg/kg) and IR + erdosteine (oral; 50 mg/kg/day for 2 days before experiments) groups. After unilateral renal IR, the right kidney was rapidly excised and sectioned vertically into two pieces for microscopic examination and biochemical analysis. Erdosteine and NAC treatment did not cause any significant change in the activity of superoxide dismutase (SOD) in comparison with the IR group, even if the SOD activity increased in IR groups than in the control group. Catalase (CAT) activity was decreased in the IR group in comparison with control and IR + erdosteine groups (P<0.05), whereas it was higher in the IR + erdosteine group than in the IR + NAC group (P<0.05). Xanthine oxidase (XO) activity was higher in all the IR-performed groups than in the control group (P<0.05). Thiobarbituric acid-reactive substances (TBARS) level and protein carbonyl (PC) content were increased after IR injury (P<0.05). Erdosteine or NAC treatments ameliorated these increased TBARS and PC contents in comparison with the IR group (P<0.05). Light microscopy of the IR group showed tubular dilatation, tubular necrosis and vacuole formation in epithelial cells. Erdosteine but not NAC apparently reduced the renal tissue damage. The pathological damage score after IR was significantly reduced after erdosteine treatment (P<0.05), but not after NAC treatment. In conclusion, renal IR resulted in oxidative damage as seen in biochemical lipid peroxidation and protein oxidation results with aggravated tubular necrosis. Erdosteine and NAC treatments improved the biochemical results of IR injury. However, on microscopic evaluations, animals receiving erdosteine showed a great reduction in renal damage when compared with the NAC group.

Preventive effect of melatonin on bleomycin-induced lung fibrosis in rats.

Oxidative stress has an important role in the pathogenesis of idiopathic pulmonary fibrosis. Melatonin has direct and indirect free radical-detoxifying activity. The present study investigated whether melatonin treatment attenuates bleomycin-induced lung fibrosis in rats. A group of rats was given one dose of bleomycin while the control animals were given saline. The first dose of melatonin (4 mg/kg/day) was given 2 days before the bleomycin injection. At day 14, fibrotic changes were evaluated using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a 2.7-fold rise in the fibrosis score that was decreased 65% by melatonin (P < 0.05) and a 1.4-fold increase in hydroxyproline content which was completely prevented by melatonin. Protein carbonyl and thiobarbituric acid reactive substances levels, which were significantly elevated in the bleomycin treated rats, were significantly attenuated by melatonin. Bleomycin administration significantly reduced the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue. The reduction in CAT activity was prevented by melatonin but SOD and GSH-Px were not influenced. These results revealed that melatonin may prevent the development of bleomycin-induced lung fibrosis via the repression of protein and lipid peroxidation.

Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats.

BACKGROUND: Nephrotoxicity is one of the important side effects of antracycline antibiotics. The aim of this study was to investigate the effects of caffeic acid phenethyl ester (CAPE), an antioxidant agent, against nephrotoxicity induced by doxorubicin (DXR). METHODS: The rats were divided into control, CAPE alone, doxorubicin (20 mg/kg, i.p.) and doxorubicin plus CAPE (10 micromol/kg/day, i.p.) groups. At the end of the 10th day, kidney tissues were removed for light microscopy and analysis. The levels of tissues protein carbonyl content (PC), malondialdehyde (MDA) and nitric oxide (NO) as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and myeloperoxidase (MPO) were determined. Plasma oxidants and antioxidants were also measured. RESULTS: The activities of CAT and GSH-Px were decreased as well as myeloperoxidase, NO, MDA and PC were increased in renal tissue of doxorubicin group compared with the other groups. Plasma GSH-Px activity was higher in doxorubicin plus CAPE group than the others and plasma MDA level was higher in doxorubicin group than the other groups. There were glomerular vacuolization, tubular desquamation, loss of brush border, and adhesion to Bowman's in the light microscopy in the kidneys of doxorubicin group. The tubules and brush border were almost normal and some of the glomerulus was filled with fine vacuoles in CAPE treated rats. CONCLUSION: Doxorubicin caused renal injury and CAPE treatment prevented lipid peroxidation and protein oxidation in renal tissue and partially preserved glomerulus and tubules.

Cisplatin-induced acute renal failure is ameliorated by erdosteine in a dose-dependent manner.

The aim of this study was to investigate the optimum dosage of erdosteine to ameliorate cisplatin-induced nephrotoxicity. Three different doses of erdosteine at 25, 50 and 75 mg kg(-1) were studied in rats. Intraperitoneal administration of 7 mg kg(-1) cisplatin led to acute renal failure, as indicated by kidney histology and increases in plasma creatinine and blood urea nitrogen (BUN) levels. At 5 days after cisplatin injection the BUN level was increased significantly from 15.1 +/- 4.3 to 126.7 +/- 152.6 mg dl(-1) and plasma creatinine levels increased from 0.37 +/- 0.005 to 1.68 +/- 1.9 mg dl(-1). When the rats were administered 50 and 75 mg kg(-1) erdosteine 24 h before cisplatin injection that was continued until sacrifice (total of 6 days), the BUN and creatinine levels remained similar to control levels and the grade of histology was similar. Erdosteine at doses of 50 and 75 mg kg(-1) ameliorates cisplatin-induced renal failure. The optimum dose of erdosteine may be 50 mg kg(-1) in this study.

Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats.

The prevention of doxorubicin (DXR)-induced cardiotoxicity may be helpful to improve future DXR therapy. The aim of this study was to investigate the cardio-protective effects of caffeic acid phenethyl ester (CAPE), an antioxidant agent, on DXR-induced cardiotoxicity. Rats were divided into three groups and treated with saline, DXR and DXR + CAPE. Rats were treated with CAPE (10 micromol x kg(-1) day(-1) i.p.) or saline starting 2 days before a single dose of DXR (20 mg x kg(-1) i.p.). Ten days later, haemodynamic measurements were performed and the hearts were excised for biochemical analyses and microscopic examination. The heart rate and mean blood pressure were higher and the pulse pressure was lower in the DXR group than in the other two groups. The administration of DXR alone resulted in higher myeloperoxidase activity, lipid peroxidation and protein carbonyl content than in the other groups. The activities of superoxide dismutase and catalase were higher in DXR and DXR + CAPE groups than in the saline group. Rats in the DXR + CAPE group had increased catalase activity in comparison with the DXR group and high glutathione peroxidase activity in comparison with the other two groups. There was severe disruption of mitochondrial fi ne structure in the electron microscopy of the DXR group. In contrast, myocardial microscopy appeared nearly normal in the DXR + CAPE group (as de fi ned at the electron microscopic level). In light of these in vivo haemodynamic, enzymatic and morphological results, we conclude that CAPE pretreatment significantly attenuated DXR-induced cardiac injury, possibly with its antioxidant effects.