Increased serum midkine levels in autism spectrum disorder patients.

BACKGROUND: Midkine (MK) is a heparin binding growth factor and is involved in neurogenesis, neural development and neuroprotection. Additionally, MK may contribute to cancer development and pathogenesis of neurodegenerative disorders and schizophrenia. Considering these effects of MK, this study researched whether MK is involved in autism spectrum disorders (ASD) pathogenesis. METHODS: We evaluated serum MK levels of 38 patients with ASD and 32 healthy control group. MK levels were measured with ELISA, while ASD severity was assessed with Childhood Autism Rating Scale. RESULTS: Our data showed that the serum MK concentration in ASD patients (mean ± SD, 11.51 ± 8.53 pg/ml) is significantly higher than healthy controls (mean ± SD, 6.19 ± 3.94 pg/ml) (p = 0.007). CONCLUSIONS: According to these results, MK may play a role in ASD pathogenesis.

Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects.

OBJECTIVE: To evaluate the serum levels of zonulin, which regulates tight junctions between enterocytes and is a physiological modulator controlling intestinal permeability, in patients with autism spectrum disorders (ASDs). STUDY DESIGN: Serum zonulin levels were determined in 32 patients with ASD and 33 healthy controls using an enzyme-linked immunosorbent assay. The severity of ASD symptoms was assessed with the Childhood Autism Rating Scale. RESULTS: Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL). There was a positive correlation between zonulin levels and Childhood Autism Rating Scale score when all subjects were assessed (r = 0.523; P < .001). CONCLUSIONS: This study suggests that zonulin, which regulates intestinal permeability, plays a role in the development of symptoms of ASD.

Early term effect of ureterorenoscopy (URS) on the Kidney: research measuring NGAL, KIM-1, FABP and CYS C levels in urine.

AIM: URS is a very commonly used procedure for treatment of ureter stones. Increased hydrostatic pressure in the collecting system linked to fluids used during the procedure may cause harmful effects on the kidney. The aim of this study is to determine whether the URS procedure has a negative effect on the kidney by investigating NGAL, KIM-1, FABP and Cys C levels in urine. MATERIAL AND METHODS: This study included 30 patients undergoing ureterorenoscopy (URS) for ureter stones. Urine samples were collected 5 times; before the URS procedure (control) and at 1, 3, 5 and 12 hours following the procedure. NGAL, KIM-1, FBAP and Cys C levels were measured in urine and compared with the control values. RESULTS: The NGAL levels in urine before the procedure and at 1, 3, 5 and 12 hours after the procedure were 34.59±35.34; 62.72±142.32; 47.15±104.48; 45.23±163.16 and 44.99±60.79ng/mL, respectively (p=0.001). Similarly, the urinary KIM-1, FABP and Cys C levels were found to increase compared to control values; however this increase did not reach statistical significance (p >0.05). CONCLUSIONS: After the URS procedure, there were important changes in NGAL, FABP, KIM-1 and Cys C levels. These changes reached statistical significance for NGAL, but did not reach significance for the other parameters. In conclusion, the URS procedure significantly affects the kidney; however, this effect disappears over time.

The effect of tadalafil therapy on kidney damage caused by sepsis in a polymicrobial septic model induced in rats: a biochemical and histopathological study.

INTRODUCTION: Sepsis is an inflammatory reaction to bacteria involving the whole body and is a significant cause of mortality and economic costs. The purpose of this research was to determine whether tadalafil exhibits a preventive effect on sepsis in a septic model induced in rats with cecal ligation and puncture (CLP). MATERIALS AND METHODS: Rats were randomly separated into groups, 10 rats in each: (i) a sham (control) group, (ii) an untreated sepsis group, (iii) a sepsis group treated with 5mg/kg tadalafil and (iv) a sepsis group treated with 10mg/kg tadalafil. A polymicrobial sepsis model was induced in rats using CLP. Rats were sacrificed after 16h, and blood and kidney tissues were collected for biochemical and histopathological study. RESULTS: Levels of the inflammatory parameter IL-6 decreased significantly in the sepsis groups receiving tadalafil in comparison with the untreated sepsis group (p < 0.05). In terms of histopathology, inflammation scores investigated in kidney tissues decreased significantly in the sepsis groups receiving tadalafil compared to the untreated sepsis group (p < 0.05). In addition, levels of creatinine and cystatin C measured in septic rats receiving tadalafil were lower by a clear degree than in septic rats (p < 0.05). CONCLUSION: In this study, tadalafil exhibited a preventive effect for sepsis-related damage by suppressing inflammation in serum and kidney tissue of septic rats in a polymicrobial sepsis model induced with CLP.

Effect of sugammadex, rocuronium and sevoflurane on oxidative stress and apoptosis in cerebral ischemia reperfusion model in rats.

OBJECTIVE: Cerebral ischemia-reperfusion (I/R) injury causes neurological dysfunction and cell death. Sugammadex, as a large molecule, is normally difficult to pass through the blood-brain barrier (BBB). In ischemia, molecules can pass into the brain tissue. In this study, we aimed to evaluate the effect of sugammadex in the presence of cerebral I/R damage in rats with a general anesthesia model with sevoflurane and rocuronium. METHODS: Rats were divided into 7 groups; Group 1 (Control), Group 2 (Sham), Group 3 (Sevoflurane), Group 4 (Sugammadex), Group 5 (Sevoflurane + Rocuronium), Group 6 (Sevoflurane + Sugammadex), Group 7 (Sevoflurane + Rocuronium + Sugammadex). Brain tissues of rats with cerebral I/R damage with bilateral carotid occlusion were removed. Tissue Malondialdehyde (MDA), Myeloperoxidase (MPO), and Superoxide dismutase (SOD) levels were examined with ELISA and apoptosis was examined by Caspase-3. RESULTS: The number of caspase-3 positive cells decreased the most in Group 4 compared to the other groups. Group 4's mean MDA and MPO levels were lower than Group 2. There was no significant difference in terms of SOD levels. CONCLUSION: The apoptotic effect of sugammadex was lowest compared to other agent groups, and it did not increase oxidative damage as much as the other groups.

The BDNF-TrkB signaling pathway is partially involved in the neuroprotective effects of hydrogen sulfide in Parkinson's disease.

Recent studies have demonstrated that hydrogen sulfide (H2S) has a neuroprotective effect in neurodegenerative diseases. It is possible that this effect is supported by brain-derived neurotrophic factor (BDNF). Our aim is to examine the effects of H2S on neural damage in Parkinson's disease (PD) and to reveal the role of the BDNF-TrkB pathway in its possible effect. PD model was created with 1-methyl-phenyl-1,2,3,6-tetrahydropyridine (MPTP). C57BL/6 breed male mice were randomly divided into six groups: control, K252a, MPTP, MPTP + K252a, MPTP + NaHS, and MPTP + NaHS + K252a. TrkB receptor antagonist K252a and sodium hydrosulfide (NaHS) as a H2S donor were administered intraperitoneally. An increase was observed in the motor behavior tests in MPTP group, but NaHS treatment shortened the time spent on the balance beam and pole tests. It was also noticed that the BDNF-pathway played a role in the shortening of this period. Mice that received NaHS were found to have less MPTP-induced cellular damage. A positive effect of BDNF was also detected in the protection of these neurons. BDNF levels in the SN were significantly increased in MPTP group, compared to control group. Tissue CBS levels decreased in the groups that received K252a, compared to MPTP group. The findings of the present study display that the BDNF-TrkB pathway partially plays a role in the protective effect of H2S in the experimental mouse model of PD. This effect is probably due to changes in intracellular signaling pathways, rather than TrkB receptor expression.

Exercise-induced changes in renal URAT1 activity and expression in rats.

During exercise, the plasma urate levels and urinary excretion increase due to the enhanced purine degradation in skeletal muscle. Although urate transporter-1 (URAT1) is the main transporter responsible for the reabsorption of filtered urate, potential changes in its activity and expression during exercise have not been studied yet. Therefore, the effect of heavy muscle activity on renal URAT1 activity and expression was investigated in this study. Wistar rats were used in the study and the experimental design consisted of three groups: a control group, an exercise group where animals were exhausted once a day for 5 days, and a hyperuricemia group, which was induced by an uricase inhibitor, oxonic acid. URAT1 activity measurements were performed in isolated proximal tubule segments and expression of URAT1 mRNA and protein levels were determined by the reverse transcription polymerase chain reaction and western blot analyses, respectively. Increased citrate synthase activity in soleus muscle of exercised animals proved the efficiency of our exercise protocol. Proteinuria, glucosuria, and hypoglycemia were observed only in exercised animals; however, plasma and urinary urate levels were found to be elevated in both exercising and hyperuricemia groups. Moreover, in both of the groups URAT1 transporter activity was found to be increased despite the significant decrease in URAT1 protein levels. Considering the similar changes of urate metabolism observed in both exercising and hyperuricemic rats, our results suggest that exercise-induced changes in URAT1 expression and activity depend on the increased urate concentration in plasma.

The effect of heavy muscle activity on renal cytoresistance in rats.

Cytoresistance is the term used to describe the response of the proximal tubule cells to various stress inducers via cholesterol accumulation. However, the role of extensive exercise as a renal insult has not been examined. In this study, the effect of heavy muscle activity on proximal tubule cytoresistance was investigated. Results obtained from rats subjected to running a treadmill for five days were compared to those of controls. Extensive muscle activity-induced soleus citrate synthase and blood lactate elevation were associated with normal MAP, RBF, and GFR. Blood electrolytes and cholesterol levels remained unchanged, whereas the total and free cholesterol accumulations in the proximal tubule cells of the exercised group were higher than controls. Cholesterol-loaded tubules were more resistant (as proved by LDH release) to an ATP-depleted/calcium overloaded second stress. These data clearly demonstrate that heavy muscle activity induces cholesterol accumulation in the proximal tubules of kidney, without influencing ATP generation.

The nephrotoxicity risk in rats subjected to heavy muscle activity.

When the body is exposed to insults, the kidneys exhibit adaptive changes termed renal cytoresistance, characterized by cholesterol accumulation in the membranes of the tubule cells. However, heavy muscle activity has not yet been accepted as one of the stressors that could lead to cytoresistance. In order to study the renal functional characteristics of animals exposed to heavy muscle activity, rats were subjected to exhaustive treadmill exercise for 5 days and their data was compared to those of sedentary controls. It was found that in exercised rats, blood lactate, muscle citrate synthase and proximal tubule peroxynitrite levels were all elevated, suggesting the presence of oxidative stress in the proximal tubule segments. However, mean arterial pressure, renal blood flow, glomerular filtration rate, fractional excretion of sodium and potassium, and organic anion excretion remained normal. Despite unchanged blood cholesterol levels, cholesterol loading in the proximal tubule segments, especially the free form, and decreased lactate dehydrogenase release from cytoresistant proximal tubule segments indicated the development of renal cytoresistance. However, this resistance did not seem to have protected the kidneys as expected because organic anion accumulation associated with glycosuria and proteinuria, in addition to the elevated urinary cholesterol levels, all imply the presence of an impaired glomerular permeability and reabsorption in the proximal tubule cells. Therefore, we suggest that in response to heavy muscle activity the tubular secretion may remain intact, although cytoresistance in the proximal tubule cells may affect the tubular reabsorptive functions and basolateral uptake of substances. Thus, this differential sensitivity in the cytoresistance should be taken into account during functional evaluation of the kidneys. Key pointsThe cholesterol loading and decreased LDH release from PTSs isolated from exhausted rats indicate the heavy muscle activity induced renal cytoresistance.Heavy muscle activity-induced renal cytoresistance did not preserve the kidney functions.Organic anion accumulation as well as failure in the absorptive capacity of the tubule cells suggest the presence of some biochemical changes and elevated vulnerability of kidneys against nephrotoxic agents in rats subjected to heavy muscle activity.

Nitrite may serve as a combination partner and a biomarker for the anti-cancer activity of RRx-001.

BACKGROUND: RRx-001 is an anti-cancer immunotherapeutic that increases the sensitivity of drug resistant tumors via multiple mechanisms which involve binding to hemoglobin and enhancing nitrite reductase activity of deoxyhemoglobin. OBJECTIVE: In the present study, the effect of clinically used doses of RRx-001 on erythrocyte deformability was examined. METHODS: A dose dependent effect of RRx-001 (1-1000 micro molar) on erythrocyte deformability was measured by ektacytometer under hypoxia (n = 8). Low dose RRx-001 (20 micro molar) in the presence of ODQ (1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one), L-NAME (L-NG-Nitroarginine methyl ester) or nitrite were examined both in normoxia and hypoxia. Intracellular nitric oxide (NO) levels were measured fluorometrically with DAF-FM-DA. RESULTS: Higher doses of RRx-001 (100, 1000 micro molar) significantly decreased erythrocyte deformability under hypoxia (p < 0.01; p < 0.05, respectively). RRx-001 (20 micro molar), alone or in combination with ODQ or L-NAME, did not change deformability. However, RRx-001 and nitrite caused an increase in deformability (p < 0.01) under hypoxia. RRx-001 induced NO production was more pronounced in the presence of nitrite (p < 0.05). CONCLUSIONS: Co-administration of RRx-001 and nitrite under hypoxic conditions results in a significant increase in erythrocyte deformability that is related to increased NO production. We suggest that measurement of serum nitrite level in RRx-001 treated cancer patients should be routinely undertaken and supplemented if levels are low for maximal activity.

Endoplasmic reticulum stress in the livers of BDNF heterozygous knockout mice.

Context: Involvement of endoplasmic reticulum (ER) stress and brain-derived neurotrophic factor (BDNF) in hepatic lipid metabolism has been reported previously. Objective: The effects of chronic BDNF deficiency on ER stress response in the livers were examined in this study. Methods: BDNF(+/-) mice, characterised by BDNF deficiency, and their wild-type (WT) littermates were used. The ER stress was induced by tunicamycin (Tm) (0.5 mg/kg, intraperitoneal). Animals were divided into four groups; WT, WT + Tm, BDNF(+/-), and BDNF(+/-)+Tm. Results: At the basal conditions, BDNF deficiency did not affect hepatic cell death or lipid accumulation. However, during ER stress, BDNF(+/-)+Tm group showed increased apoptosis, GADD153 immunostaining, sterol regulatory element-binding protein-1c (SREBP-1c) level, and steatosis compared to the WT + Tm group. Conclusion: Endogenous BDNF might be protective against apoptosis through GADD153 suppression and steatosis via SREBP-1c suppression during ER stress. This effect of BDNF might be clinically important for type 2 diabetes and obesity, which are related with both ER stress and BDNF deficiency.

Renal response to tunicamycin-induced endoplasmic reticulum stress in BDNF heterozygous mice.

BACKGROUND: The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported. OBJECTIVES: The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress. MATERIAL AND METHODS: Brain-derived neurotrophic factor heterozygous knockout mice (BDNF(+/-)) and their wild-type (WT) littermates were used. The animals were divided into 4 groups: WT, BDNF(+/-), WT+Tm, and BDNF(+/-)+Tm (n = 7 in each group). After 3 days of saline or Tm injection (0.5 mg/kg; intraperitoneally (i.p.)), renal BDNF, glucose-regulated protein 78 (GRP78), and caspase-12 levels as well as serum BDNF concentration were measured with enzyme-linked immunosorbent assay (ELISA). In the kidney sections, hematoxylin & eosin (H&E) staining, GADD153 immunostaining and TUNEL staining were performed. Serum creatinine levels were measured as an indicator of renal function. RESULTS: Circulating and tissue BDNF levels were significantly lower in the BDNF(+/-) and BDNF(+/-)+Tm groups. Renal levels of GRP78 and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the WT+Tm and BDNF(+/-)+Tm groups. However, apoptosis was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.01). Similarly, GADD153 staining was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.05). Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/-)+Tm group. Serum creatinine concentrations were significantly higher in the WT+Tm (p < 0.05) and BDNF(+/-)+Tm (p < 0.05) groups. CONCLUSIONS: This study showed that endogenous BDNF may play a protective role in kidneys against ER stress-induced apoptosis via the suppression of GADD153. As a result, BDNF and related signaling pathways could be considered for therapeutic/protective approaches in kidney disorders.

Positive outcomes of phosphodiesterase type 5 inhibitor on histopathologic and biochemical changes induced by ureteral obstruction.

OBJECTIVES: We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO). METHODS: The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T). RESULTS: Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss.The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-ß (TGF-ß) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-ß decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T. CONCLUSION: The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-ß in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.

IGF-1 receptor cleavage in hypertension.

Increased protease activity causes receptor dysfunction due to extracellular cleavage of different membrane receptors in hypertension. The vasodilatory effects of insulin-like growth factor-1 (IGF-1) are decreased in hypertension. Therefore, in the present study the association of an enhanced protease activity and IGF-1 receptor cleavage was investigated using the spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto (WKY) controls (n = 4). Matrix metalloproteinase (MMP) activities were determined using gelatin zymography on plasma and different tissue samples. WKY aorta rings were incubated in WKY or SHR plasma with or without MMP inhibitors, and immunohistochemistry was used to quantify the densities of the alpha and beta IGF-1 receptor (IGF-1R) subunits and to determine receptor cleavage. The pAkt and peNOS levels in the aorta were investigated using immunoblotting as a measure of IGF-IR function. Increased MMP-2 and MMP-9 activities were detected in plasma and peripheral tissues of SHRs. IGF-1R beta labeling was similar in both groups without plasma incubation, but the fraction of immunolabeled area for IGF-1R alpha was lower in the endothelial layer of the SHR aorta (p < 0.05). A 24-h incubation of WKY aorta with SHR plasma did not affect the IGF-1R beta labeling density, but reduced the IGF-1R alpha labeling density in the endothelium (p < 0.05). MMP inhibitors prevented this decrease (p < 0.01). Western blot analyses revealed that the pAkt and peNOS levels under IGF-1-stimulated and -unstimulated conditions were lower in SHRs (p < 0.05). A reduced IGF-1 cellular response in the aorta was associated with the decrease in the IGF-1R alpha subunit in the SHR hypertension model. Our results indicate that MMP-dependent receptor cleavage contributed to the reduced IGF-1 response in SHRs.

The effect of trimetazidine on renal oxidative stress in partial and complete ureteral obstructions in a rat model.

BACKGROUND/AIM: Renal oxidative stress occurs in ureteral obstructions. The purpose of this study was to investigate the effect of the antioxidant and antiischemic agent trimetazidine (TMZ) on oxidative stress following ureteral obstruction. MATERIALS AND METHODS: Ten groups were established. Sham groups were checked as controls after 1 and 3 weeks. The other 8 groups had partial or complete ureteral obstruction while receiving or not receiving trimetazidine (TMZ) at 5 mg/kg daily and were evaluated after either 1 week or 3 weeks. Creatinine and cystatin C measurements were performed in the serum. Malondialdehyde, myeloperoxidase, catalase, and glutathione peroxidase activity were measured in renal tissue and serum. RESULTS: In the 1-week groups, tissue malondialdehyde, serum myeloperoxidase, and glutathione peroxidase activity increased significantly with obstruction and TMZ use compared to the control group (P < 0.005). In the 3-week TMZ group, cystatin C, tissue malondialdehyde, serum and tissue myeloperoxidase, and tissue glutathione peroxidase differed significantly (P < 0.05). There was no significant difference in all parameters after 3 weeks of partial obstruction (P > 0.05), with only serum malondialdehyde being significantly elevated (P < 0.05). CONCLUSION: TMZ did not exhibit a renal oxidative stress-lowering effect in obstruction. It causes mild impairment of renal functions in obstruction. Patients using TMZ must be closely monitored in terms of kidney function in the event of any ureteral obstruction.

Evaluation of serum Neuron-specific enolase, S100B, myelin basic protein and glial fibrilliary acidic protein as brain specific proteins in children with autism spectrum disorder.

OBJECTIVE: Brain specific-proteins are not found in other tissues and measurement non-invasively in the blood may identify structurally and functionally damaged brain regions and identify the severity and prognosis of neuropsychiatric diseases. For this reason, we aimed to evaluate serum brain-specific protein values as brain damage markers in children with autism spectrum disorder (ASD). METHOD: 35 children with ASD and 31 healthy subjects were included in the study. Sociodemographic form and Childhood Autism Rating Scale (CARS) were applied to each subject. Serum neuron specific enolase (NSE), S100B, Myelin basic protein (MBP) and Glial fibrillary acidic protein (GFAP) values ​​were measured with ELISA. RESULTS: There was no significant difference between the two groups for NSE, MBP and S100B values (p=0.242; p=0.768; p=0.672, respectively). However, GFAP values ​​in the patient group were statistically significantly higher (mean±SD: 0.463±0.392ng/ml) than in the healthy control group (mean±SD: 0.256±0.111ng/ml) (p<0.001). In addition, there was a significant positive correlation between serum GFAP values ​​and CARS score in all subjects and in the patient group (r=0.599; p<0.001 and r=0.380; p=0.024, respectively). CONCLUSIONS: While serum NSE, MBP, and S100B values cannot be considered as biomarkers for ASD, GFAP may be a biomarker and is suggested as a possible indicator of autism severity.

Dietary silica modifies the characteristics of endothelial dilation in rat aorta.

Considering the importance of nitric oxide generation in the regulation of vessel tone, reduced endothelial nitric oxide synthase (eNOS) expression in alveolar macrophages exposed to short-term silica (Si) suggests the possibility of Si-induced changes in endothelial functions. In this experimental study, the functional changes of the endothelial cells were investigated in the aortic rings of rats subjected to 50 mg Si/kg body weight in their drinking water for 8 days. Norepinephrine elicited contractility and dilation response to acetylcholine (ACh) was significantly high in the aortic rings of Si-treated group. Alteration in receptor-independent endothelial response to A23187 in the aortic rings of Si-exposed rats was less obvious, but sodium nitroprusside (SNP)-elicited dilation was reduced significantly. A23187-induced relaxation was fully eliminated with N-nitro-L-arginine methyl ester (L-NAME) pretreatment, whereas 19.24 +/- 4.36% of ACh response was L-NAME resistant and eliminated with 10-5 M tetraethylammonium (TEA). Despite a significant reduction in the share of NO, the contribution of indomethacine (IND)-sensitive relaxation to ACh response remained unchanged in Si group. As a result, our findings demonstrated that Si both modifies the characteristics of endothelial relaxants and attenuates smooth muscle cell responsiveness to NO. Si-induced reduced NO association with elevated endothelium-derived hyperpolarizing factor (EDHF) in response to ACh, together with reduced NO sensitization, might have clinical importance in cardiovascular pathology.

Effect of nitric oxide on ammoniagenesis in rats.

AIM: This in vitro study using rat cortical slices, isolated proximal tubules and mitochondria was conducted to investigate the effect of exogenous and endogenous nitric oxide on ammoniagenesis. METHODS AND RESULTS: The cortical slices were incubated with phosphate-buffered saline containing 1 mML-glutamine at 37 degrees C andglutamine-stimulated ammoniagenesis which was further elevated with 10(-7)M ANGII showed a time-dependent decrease during 2 h. 10(-4)M L-NAME or 10(-5)ML-canavanin caused a similar ammonia elevation to that of ANGII, whereas the addition of 10(-5)M SNAP attenuated the ammonia-increasing effects of ANGII and L-NAME. Basal or exogenous NO without significantly affecting glutamine uptake of the slices seemed to convert the glutamine deamidation pathway to transamination, since L-NAME increased the ammonia to glutamine ratio from 0.87 +/- 0.08 mol/mol to 1.03 +/- 0.04 (p < 0.01). L-NAME increased both ammoniagenesis and mitochondrial oxygen consumption but SNAP depressed them. Endogenous NO reduced ammoniagenesis without changing the mitochondrial permeability transition pore (PTP), whereas exogenous NO-induced attenuation in ammoniagenesis was associated with elevated PTP in a CsA-sensitive manner. CONCLUSION: These results demonstrated that in rat kidney, basal NO depresses mitochondrial oxygen consumption and attenuates ammoniagenesis without affecting PTP; however, exogenous NO inhibits ammonia production by disturbing PTP in isolated mitochondria.

The effect of oral and intraurethral trimetazidine use on urethral healing.

OBJECTIVES: We aimed to study the effect of trimetazidine (TMZ) on urethral wound repair. MATERIALS AND METHODS: A total of 52 male rats were used; 8 groups were formed: 1-week and 3-week control (C1, C3), sham (S1, S3), oral (OT1, OT3), and intraurethral TMZ (IUT1, IUT3) groups. Serum and urine total antioxidant capacity (TAC), total oxidant capacity (TOC), and 8-hydroxy-deoxy-guanosine (8-OHdG) were studied. Hematoxyline-Eosin was used for the histopathological study. In addition, tumor necrosis factor alpha (TNF- α), interleukin 1α, and ß levels were compared across groups by an immunohistochemical method. RESULTS: There were significant differences between C3 and IUT3, OT3 and IUT3 with respect to serum TAC in 3-week groups (P=0.013; P =0.001). Serum TOC levels were significantly different between C3 and IUT3; S3 and OT3; and OT3 and IUT3 groups (P =0.024; P =0.019; P =0.000, respectively). Serum 8-OHdG levels were significantly different between C3 and OT3 groups (P=0.033). In the immunohistochemical examination, C1 and OT1; C1 and IUT1; and S1, S3, OT1, OT3, IUT1 groups were significantly different with respect to IL-1ß staining (P=0.007; P =0.000; P=0.009), while there was a significant difference between C3 and S3 with respect to IL-1ß (P =0.000). CONCLUSION: TMZ increased urinary total oxidant level; while increasing serum TAC levels in the long-term. It also reduced serum TAC levels in urethral use and caused an increase in serum TOC levels with minimal effects on DNA injury and repair. No effect was detected on IL1 α and TNF, but partially reduced the effect on IL-1 ß levels.