Aggravating effect of atorvastatin on indomethacin-induced gastric injury: Focus on PGE2, TNF-α, neutrophils and iNOS.

Statins are suggested to possess healing properties due to their antioxidant and antiinflammatory effects in animal ulcer models. In contrary, a clinical report indicated the formation of gastric ulcer by the use of atorvastatin. In this study, we aimed to investigate the effects of atorvastatin (0.5, 5 and 50mg/kg, p.o.) after single (acute) and multiple (subchronic, 5 days) applications on indomethacin-induced gastric ulcer in rats. In both acute and subchronic models high dose atorvastatin (50mg/kg), unlike to lower doses (0,5 and 5mg/kg), significantly aggravated ulcer lesions induced by indomethacin (30 mg/kg) although, a direct ulcerogenic influence was lacking. Proulcerogenic effect of atorvastatin are likely to be associated with decreased mucosal defense mechanisms (GSH and PGE2), and increased neutrophil infiltration and proinflammatory factors (TNF-a and iNOS) possibly via independently from mevalonate pathway. Thus, atorvastatin therapy should be monitorized in patients for an increased risk of gastric ulcer particularly when used concomitantly with NSAIDs.

Expressions of some vital molecules: glioblastoma multiforme versus normal tissues.

OBJECTIVE: The aim of this study was to assess plasma and/or tissue levels of adhesion and apoptotic molecules, cytokines, nitric oxide metabolites, levels of lipid peroxidation, myeloperoxidase and superoxide dismutase in patients with glioblastoma multiforme and controls. METHODS: All the molecules were evaluated in 25 tumors and 30 controls: 15 were normal healthy subjects for plasma and 15 were normal brain tissues that were collected during autopsy. Commercially available kits for measurements were used. RESULTS: Superoxide dismutase was significantly lower in tumors, while all other molecules were significantly elevated compared to the controls (p=0.0001). Superoxide dismutase negatively correlated with plasma interleukin-1beta (p=0.04) and plasma Fas (p=0.016). Plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 correlated positively with plasma 3-nitrotyrosine (p=0.019) and nitrite/nitrate (p=0.019), respectively. Furthermore, plasma interleukin-1beta also positively correlated with plasma nitrite/nitrate (p=0.003). DISCUSSION: These results suggest that there is a complex relationship between pro- and anti-apoptotic molecules in glioblastoma multiforme pathogenesis. Thus, targeting multiple pathways with advanced chemotherapeutic agents or radiotheraupetic regimens following total resections might be helpful in patients with glioblastoma multiforme since preventing a single pathway does not seem to be reasonable.

Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis.

Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia to Sprague-Dawley rats (200-250 g; n = 7-8 per group). Control rats received an equal volume of saline intratracheally. In the treatment groups, the rats were treated with either sildenafil citrate (10 mg/kg per day; subcutaneously) or saline for 14 days. Another group of rats were administered subcutaneously with N(G)-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg in 0.9% NaCl) 5 min after sildenafil injections. After decapitation, the lungs were excised and taken for microscopic evaluation or stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity, and for the assessment of apoptosis. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. In the group with lung fibrosis, the lung tissue was characterized by microscopic lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and apoptosis. Serum TNF-alpha and IL-1beta levels were higher in the lung fibrosis group compared to control values. Sildenafil reversed tissue MDA levels, MPO activity and serum pro-inflammatory cytokine levels, and preserved GSH content although its effect on the extent of tissue lesion and apoptosis was not statistically significant. Treatment with l-NAME reversed the effect of sildenafil on GSH content. In conclusion, sildenafil citrate administration to rats with bleomycin-induced lung fibrosis seems to be beneficial via prevention of lipid peroxidation, cytokine production and/or release and neutrophil accumulation.

Influence of intermittent hypobaric exposure on SOD and TBARS levels in trained rats.

Live high train low (LHTL) is a well-known training model for preparation of competitions. In this study, the thiobarbituric acid reacting substances (TBARS) levels and superoxide dismutase (SOD) activity were determined in heart, lung and muscle tissues of rats. They were intermittently exposed to hypobaric pressure of 523 mmHg, corresponding to an altitude of 3,000 m, and they performed swim training at sea level. Two groups of male rats were trained to swim for thirty minutes a day and 4 days a week, lasting 9 weeks. Two groups were exposed to hypobaria for 120 min a day and 4 days a week for 9 weeks in pressure cabin. In heart tissue, TBARS levels of normobaric trained (NbT) group was higher (P < 0.05) than those of the normobaric sedentary (control) group. TBARS levels of hypobaric trained (HbT) group was higher than those of the control and hypobaric sedentary (Hb) groups (P < 0.001; P < 0.01, respectively). TBARS levels of lung tissue of HbT group was also higher than those of the same groups (control; P < 0.01, Hb; P < 0.05, respectively). In muscle tissue, TBARS levels of HbT group was higher than those of the sedentary groups (control; P < 0.001, Hb; P < 0.05, respectively). SOD activity of heart tissue of HbT group was higher (P < 0.001) than that of the other groups. In lung tissue, SOD activity of control group was lower than that of the other groups (HbT; P < 0.001, NbT; P < 0.01, Hb; P < 0.01, respectively). In muscle tissue, SOD activity of HbT group was higher (P < 0.01) than that of the control group. The results of this study suggest that intermittent hypobaric exposure may augment exercise-induced oxidative stress in heart, lung and muscle of trained rats.

The effect of sildenafil, a phosphodiesterase-5 inhibitor, on acetic acid-induced colonic inflammation in the rat.

BACKGROUND AND AIM: Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. METHODS: Colitis was induced by intrarectal administration of 1 mL of 5% acetic acid to Sprague-Dawley rats (200-250 g; n = 7-8/group). Control rats received an equal volume of saline intrarectally. In treatment groups, the rats were treated with either sildenafil citrate (5 mg/kg/day; subcutaneously) or saline for 3 days. After decapitation, distal colon was weighed and scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and oxidant production. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. RESULTS: In the colitis group, the colonic tissue was characterized by lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and oxidant production. Serum TNF-alpha and IL-1beta levels were higher in the colitis group compared to control values. Sildenafil reversed these inflammatory parameters nearly back to control values. CONCLUSIONS: Sildenafil citrate administration to rats with acetic acid-induced colitis seems to be beneficial via prevention of lipid peroxidation, oxidant generation, cytokine production and neutrophil accumulation.

Effects of erucic acid supplemented feeding on chronic doxorubucin toxicity in rats.

One of the undesired complications of the chemotherapy with doxorubicin is cardiotoxicity. Cardiac effect of erucic acid, which is a member of omega-9 fatty acid, is investigated on doxorubicin treatment in this study. Forty-eight rats were divided into eight groups and each group contained six rats. First group rats were fed with milk. In the third and fifth groups we fed rats with milk supplemented 0.5% and 5% erucic acid respectively. The groups 2, 4, 6 were fed as the groups 1, 3, 5 respectively; we injected 2 mg/kg twice weekly intraperitoneal doxorubicin to these groups whereas we injected isovolumous normal saline to the groups 1, 3, 5. Two other groups (groups 7 and 8) were fed with standard pellet. Group 8 received 2 mg/kg doxorubicin twice weekly; group 7 received normal saline. After 4 weeks hearts were isolated and mounted on a Langendorff apparatus perfused by modified Tyrode solution. Surviving rats were significantly less in erucic acid + doxorubicin groups at the end of the treatment period (p<0.05). No significant difference was found between groups for malondialdehyde, catalase, cytochrome c oxidase and isolated heart measurements. Concomitant application of erucic acid and doxorubicin showed profound toxicity.

Expression of hypoxia inducible factor-1alpha in tumors of patients with glioblastoma multiforme and transitional meningioma.

Hypoxia-inducible factor-1 alpha (HIF-1alpha) is the major transcriptional factor involved in the adaptive response to hypoxia. The aim of this study was to assess HIF-1alpha in 22 patients with transitional meningioma (TM) and 26 patients with glioblastoma multiforme (GBM). HIF-1alpha was assessed using a commercially available enzyme-linked immunosorbent assay-based HIF-1 transcription factor assay. Levels of HIF-1alpha in TM and GBM were measured using optical density at 450nm, and median values were found to be 0.35 for TM and 0.37 OD for GBM, respectively. There was no statistically significant difference between the two types of tumor (p=0.264). These findings indicate that HIF-1alpha is elevated in both TM and GBM, suggesting that although hypoxia is one of the most important and powerful stimuli for HIF-1alpha elevation and consequently angiogenesis, other mechanisms may play roles in HIF-1alpha stimulation in benign brain tumors such as TM.

The effects of vitamin E on lipid peroxidation, nitric oxide production and superoxide dismutase expression in hyperglycemic rats with cerebral ischemia-reperfusion injury.

OBJECTIVES: Recent studies have revealed that nitric oxide (NO) in concert with lipid peroxidation (LP) may play an important role in pathophysiological mechanism(s) of cerebral ischemia. In addition, hyperglycemia exaggerates the pathological changes during cerebral ischemia. The purpose of this study was to investigate the effects of vitamin E (VE) on LP, NO production, and superoxide dismutase (SOD) expression in hyperglycemic rats after cerebral ischemiareperfusion injury. MATERIALS AND METHODS: Malondialdehyde (MA) (indicator of LP) in plasma and brain tissue, total nitrite/nitrate (metabolites of nitric oxide) in plasma, nitrite in brain tissue, and SOD in red blood cells were detected and the results were compared before and after VE administration in hyperglycemic rats with cerebral ischemia-reperfusion injury induced by two common carotid artery occlusions. RESULTS: Ischemia-reperfusion injury together with hyperglycemia caused elevation in NO metabolites and MA levels and this elevation was more p rominent in hyperglycemic rats. SOD was also increased in ischemiareperfusion, and VE administration had positive effects on the SOD level. In addition, VE administration caused a significant decrease in NO metabolite levels after ischemia-reperfusion injury. CONCLUSIONS: These results suggest that prophylaxis with VE may have positive effects on reducing cerebral damage after stroke in patients with diabetes mellitus.

Relationship between DNA damage and total antioxidant capacity in patients with transitional meningioma.

PURPOSE: The purpose of this study was to assess oxidative DNA damage and total antioxidant capacity (TAC) in patients with transitional meningioma (TM) and to compare the results with normal brain tissues. PATIENTS AND METHODS: Oxidative DNA damage and TAC were evaluated in TM extracted from 22 patients and in normal brain tissues of 15 subjects who underwent autopsy within first 4h of death. Oxidative DNA damage was assessed by measuring 8-hydroxy-2-deoxyguanosine (8-OH-dG) using the 8-OH-dG enzyme immunoassay kit, a quantitative assay for 8-OH-dG, and TAC was analyzed using the ImAnOx colorimetric test system for the determination of antioxidative capacity. The results were compared between two groups and any correlation between 8-OH-dG and TAC was sought. RESULTS: The median level of TAC in TM (135nmol/gwet tissue) was remarkably lower than in normal brain tissue (298nmol/gwet tissue). The difference was statistically significant (p=0.00001). In contrast, oxidative DNA damage was significantly higher in patients with TM (71.61ng/gwet tissue) than in controls (34.71ng/gwet tissue). Again, the difference was statistically significant (p=0.00001). We also found a negative correlation between oxidative DNA damage and TAC (p<0.001). CONCLUSION: These findings show that the degree of oxidative DNA damage is increased and TAC is decreased in TM and oxidative DNA damage is negatively correlated with the levels of TAC.

Detection of caspase-3, neuron specific enolase, and high-sensitivity C-reactive protein levels in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The purpose of this study is to explore whether or not the levels of caspase-3 (Casp3), neuron-specific enolase (NSE), and high-sensitivity C-reactive protein (hsCRP) were elevated in cerebrospinal fluid (CSF) and serum of patients after aneurysmal subarachnoid hemorrhage (SAH). METHODS: This prospective clinical study consisted of 20 patients who experienced recent aneurysmal SAH and 15 control patients who experienced hydrocephalus without any other central nervous system disease. CSF and serum samples obtained within the first 3 days, and on the fifth and seventh days of SAH were assayed for Casp3, NSE, and hsCRP by using enzyme-linked immunosorbent assay. RESULTS: Levels of Casp3, NSE, and hsCRP in the CSF (P = 0.00001, P = 0.00001, and P <0.003, respectively) and in the serum (P = 0.00001, P <0.01, and P = 0.00001, respectively) of SAH patients were found to be elevated when compared with controls with normal pressure hydrocephalus. CONCLUSION: The authors have demonstrated the synchronized elevation of Casp3, NSE, and hsCRP in both CSF and serum of patients with aneurysmal SAH. Further studies with a large number of patients are recommended to more accurately determine the roles of these molecules in aneurysmal SAH.

Glutathione peroxidase, glutathione reductase and protein oxidation in patients with glioblastoma multiforme and transitional meningioma.

PURPOSE: The aim of this study was to assess glutathione peroxidase (GPx), glutathione reductase (GRx) and protein oxidation (POx) levels in patients with glioblastoma multiforme (GBM) and transitional meningioma (TM) and to compare with normal brain tissues. METHODS: GPx, GRx and POx levels were measured in 48 brain tumors obtained during surgery and 15 normal brain tissues that were collected during autopsy. Results were compared between two groups. RESULTS: GPx and GRx activities were significantly lower in GBM and TM when compared to controls and the difference was statistically significant (P = 0.0001). Furthermore, the decrease in enzyme activities was more evident in GBM than in TM. In contrast, POx levels were found to be higher in both GBM and TM compared to controls and showed statistically significant difference (P = 0.00001). Increase in POx levels was clearer in GBM than TM. CONCLUSIONS: GPx and GRx decreased and POx increased significantly in both GBM and TM when compared to normal brain tissues. Further, clinical studies with a larger patient population are required to show the role(s) of antioxidant enzymes in brain tumors more accurately.

GSM base station electromagnetic radiation and oxidative stress in rats.

The ever increasing use of cellular phones and the increasing number of associated base stations are becoming a widespread source of nonionizing electromagnetic radiation. Some biological effects are likely to occur even at low-level EM fields. In this study, a gigahertz transverse electromagnetic (GTEM) cell was used as an exposure environment for plane wave conditions of far-field free space EM field propagation at the GSM base transceiver station (BTS) frequency of 945 MHz, and effects on oxidative stress in rats were investigated. When EM fields at a power density of 3.67 W/m2 (specific absorption rate = 11.3 mW/kg), which is well below current exposure limits, were applied, MDA (malondialdehyde) level was found to increase and GSH (reduced glutathione) concentration was found to decrease significantly (p < 0.0001). Additionally, there was a less significant (p = 0.0190) increase in SOD (superoxide dismutase) activity under EM exposure.

YKL-40 levels in the cerebrospinal fluid and serum of patients with aneurysmal subarachnoid hemorrhage: preliminary results.

YKL-40 is a newly discovered matrix protein thought to be secreted during the acute stages of inflammation. Clinical studies have revealed that YKL-40 has growth factor and potent migration factor activity for cells involved in inflammation and tissue remodeling processes. It has recently been speculated that YKL-40 may serve as a specific serologic marker of neutrophil function at the site of acute tissue inflammation. We aimed to quantify the levels of YKL-40 in both cerebrospinal fluid and serum of ten consecutive patients with aneurysmal subarachnoid hemorrhage and to speculate on the origin of this glycoprotein. The levels were also compared with ten control patients with hydrocephalus. We found that patients with aneurysmal subarachnoid hemorrhage had significantly higher YKL-40 levels in both cerebrospinal fluid and serum than controls. The authors believe that YKL-40 is expressed in cerebrospinal fluid due to stress on neural structures while a damaged blood-brain barrier allows entry of neutrophils and macrophages from the systemic circulation.

Cerebrospinal fluid superoxide dismutase and serum malondialdehyde levels in patients with aneurysmal subarachnoid hemorrhage: preliminary results.

OBJECTIVES: Experimental studies provide evidence that oxidative damage plays a role in the development of vasospasm after aneurysmal subarachnoid hemorrhage (SAH) but data from human studies is still limited. The purpose of this study was to investigate the time course of cerebrospinal fluid (CSF) superoxide dismutase (SOD) and serum malondialdehyde (MDA) changes in patients with aneurysmal SAH. METHODS: SOD in CSF and MDA in the serum were detected on days 1-3, 5 and 7 after aneurysmal SAH in 21 patients, and the results were compared with 15 patients with hydrocephalus. The results were also compared with those of clinical parameters including the patient's outcome at 6 months. RESULTS: The mean CSF SOD levels were lower and serum MDA levels were higher than the controls. Patients with a high amount of blood within the cisterns had a trend to decreased SOD while increasing MDA levels. CONCLUSION: These preliminary results suggest that the levels of antioxidants are decreased after the onset of SAH in the early period, possibly because of increased oxidative stress. Reactive oxygen-mediated oxidative damage may play an important role in inflammation after SAH.

Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage.

OBJECT: The aim of this study was to explore whether levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in the cerebrospinal fluid (CSF) and serum of patients after aneurysmal subarachnoid hemorrhage (SAH). METHODS: This prospective clinical study focused on 21 patients who had recently suffered an SAH due to aneurysmal rupture and 15 control patients with hydrocephalus who had no other central nervous system disease. Cerebrospinal fluid and serum samples obtained within the first 3 days and on the 5th and 7th days of SAH were assayed for ICAM-1 and VCAM-1 by using quantitative enzyme-linked immunosorbent assays. Levels of soluble forms of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.009) in the patients' CSF and those of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.00001) in their serum were found to be elevated after SAH compared with levels in the CSF and serum of control patients with hydrocephalus. In addition, when the authors compared the increased levels of adhesion molecules in the CSF and serum of patients after SAH, the only statistically insignificant difference that they found was between the levels of VCAM-1 in serum obtained on Days 5 and 7 after SAH (p = 0.27). CONCLUSIONS: Adhesion molecules are a group of macromolecules that may participate in the inflammatory process, a common pathway leading to vasospasm after SAH. Leukocyte adherence to the vascular endothelium, which is induced by adhesion molecules, has been believed to be the initial signal of the development of vasospasm. The authors have demonstrated the synchronized elevation of two adhesion molecules in both CSF and serum following aneurysmal SAH. Blocking of ICAM-1 as well as VCAM-1 by monoclonal antibodies post-SAH may provide a beneficial effect on vasospasm.

The effect of halofuginone, a specific inhibitor of collagen type 1 synthesis, in the prevention of esophageal strictures related to caustic injury.

BACKGROUND: To assess the effects of halofuginone, a specific inhibitor of synthesis of collagen type 1, which is the major constituent of fibrosis, on esophageal stricture formation due to caustic ingestion. METHODS: Sixty rats were divided into four equal groups: control group; sham laparotomy group; caustic injury without treatment group; caustic injury with halofuginone treatment group. Caustic injuries were done by 50% sodium hydroxide. Halofuginone was administered by the first postoperative day. All animals were sacrificed on day 21; and the results were evaluated by hydroxyproline levels, stenosis index, lumen diameter, histopathological evaluation, wall thickness, and animal weights. RESULTS: Mortality differences were significant comparing group 3 with group 1 and 2 (P = 0.006) and group 4 (P = 0.03). According to hydroxyproline levels, the differences are significantly higher (P <0.001) comparing group 3 with group 1, 2, and 4. The P value was considered significant in all other parameters (P <0.001) for all the groups but group 1 versus group 2 (P >0.05). CONCLUSIONS: Halofuginone, a specific inhibitor of collagen type 1 synthesis, significantly reduced esophageal stricture occurrence.

Nitric oxide levels in rat cortex, hippocampus, cerebellum, and brainstem after impact acceleration head injury.

Nitric oxide (NO) is a potential mediator of secondary brain injury in the settings of cerebral ischemia and inflammation. Traumatic brain injury (TBI) alters the levels of stable end products of NO metabolism. We investigated these changes and attempted to identify brain regions that were unique with regard to NO production in the period immediately after TBI. The experiment involved assaying nitrite-nitrate concentrations in the rat cortex, cerebellum, hippocampus, and brainstem after impact-acceleration head injury. Five rats comprised the sham-operated (control) group, five sustained mild head injury (MHI), and five sustained severe head injury (SHI). There was a uniform decline in the tissue concentrations of NO metabolites in all four brain regions in both injured groups. There were no significant differences in the concentrations of NO metabolites among the various sites tested in the MHI group; however, there appeared to be a relationship between degree of decline in NO levels and amount of trauma sustained by a given region in the SHI group. In these rats, NO dropped to the lowest levels in the brain region where the direct trauma was most severe. The results suggest that nitrite-nitrate levels in these four brain regions fall below normal in the first 5 min after impact trauma. This decrease may, in part, be related to reduced activity of all nitric oxide synthase isoforms, which would cause a drop in the levels of NO metabolites. We believe that this decline may be linked to, and may even cause, the global decrease in cerebral blood flow that occurs in the initial stages of TBI.