Endoplasmic reticulum stress produced by Thapsigargin affects the occurrence of spike-wave discharge by modulating unfolded protein response pathways and activating immune responses in a dose-dependent manner.

The Endoplasmic Reticulum (ER) is associated with many cellular functions, from post-transcriptional modifications to the proper folding of proteins, and disruption of these functions causes ER stress. Although the relationship between epileptic seizures and ER stress has been reported, the contribution of ER stress pathways to epileptogenesis is still unclear. This study aimed to investigate the possible effects of ER stress-related molecular pathways modulated by mild- and high-dose Thapsigargin (Tg) on absence epileptic activity, CACNA1H and immune responses in WAG/Rij rats. For this purpose, rats were divided into four groups; mild-dose (20 ng) Tg, high-dose (200 ng) Tg, saline, and DMSO and drugs administered intracerebroventriculary. EEG activity was recorded for 1 h and 24 h after drug administration following the baseline recording. In cortex and thalamus tissues, GRP78, ERp57, GAD153 protein changes (Western Blot), Eif2ak3, XBP-1, ATF6, CACNA1H mRNA expressions (RT-PCR), NF-κB and TNF-α levels (ELISA) were measured. Mild-dose-Tg administration resulted in increased spike-wave discharge (SWD) activity at the 24th hour compared to administration of saline, and high-dose-Tg and it also significantly increased the amount of GRP78 protein, the expression of Eif2ak3, XBP-1, and CACNA1H mRNA in the thalamus tissue. In contrast, high-dose-Tg administration suppressed SWD activity and significantly increased XBP-1 and ATF6 mRNA expression in the thalamus, and increased NF-κB and TNF-α levels. In conclusion, our findings indicate that Tg affects SWD occurrence by modulating the unfolded protein response pathway and activating inflammatory processes in a dose-dependent manner.

The role of hepcidin, GDF15, and mitoferrin-1 in iron metabolism of polycythemia vera and essential thrombocytosis patients

Background/aim: GDF15, hepcidin and mitoferrin-1 (mfrn-1) are proteins involved in systemic iron regulation. There are no studies in the literature demonstrating the serum mfrn-1 levels in polycythemia vera (PV) and essential thrombocythemia (ET) patients. The aim of this study was to investigate GDF15, hepcidin and mfrn-1 levels in PV and ET patients. Materials and methods: Ten PV, 17 ET patients, and 27 healthy controls (HCs) were enrolled. GDF15, hepcidin and mfrn-1 values were measured with enzyme-linked immunosorbent assay (ELISA). Results: GDF15 levels were higher in the myeloproliferative neoplasm (MPN) group (P = 0.002). Hepcidin levels were not different between MPN patients and HCs. The mfrn-1 levels were lower in MPN patients (P = 0.039). Hepcidin, GDF15, and mfrn-1 levels were not different between PV and ET patients. mfrn-1 levels were lower in ET patients than HCs (P = 0.038). Conclusion: Increased erythropoiesis in MPNs may lead to high GDF15 levels in these patients. However, hepcidin was not suppressed despite the increased GDF15 levels and erythropoiesis in these patients. Decrease in mfrn-1 in MPNs can be the result of its increased turnover due to increased myelopoiesis. It can be hypothesized that similar hepcidin levels in patients and controls and low mfrn-1 levels in patients may be a defense mechanism against erythroid activity and thromboembolic complications.

Antagonism of adenosinergic system decrease SWD occurrence via an increment in thalamic NFkB and IL-6 in absence epilepsy.

Epilepsy is a major pathological condition, characterized by recurrent seizures and affecting approximately 1% of the population. Many studies have shown a relationship between epilepsy and inflammation. The adenosinergic system contributes to inflammation and epilepsy by regulating the release of neurotransmitters through its various receptors. This study investigates the effect of agonist and antagonist of adenosinergic system on seizure activity and cytokine levels in the WAG/Rij strain, a genetic animal model of absence epilepsy. The WAG/Rij rats used in our study were assigned to saline, Tween 20, adenosine, and caffeine groups. Tripolar electrodes were implanted on the skull, and EEG activities recorded for 3 h. ELISA was used to determine the NFkB, TNF-α, IL-1ß, and IL-6 levels in the cortical and thalamic brain regions, as well as the TNF-α, IL-1ß, and IL-6 levels in the blood samples. Administration of caffeine to rats resulted in a decreased SWD number at 30 and 60 min as determined by EEG recording after baseline (p < .05), and a significant increase in NFkB and IL-6 levels in the thalamic tissue (p < .05). Administration of adenosine to rats did not change seizures and cytokine levels. Our results show that an increase in thalamic IL-6 and NFkB levels may related with a decrement in absence epilepsy. This study clearly shows the contribution of adenosinergic system in absence seizure in WAG/Rij rats. These results also support the importance of the thalamus on occurrence of SWD in the thalamocortical loop.

Effect of nitric oxide synthase inhibitors in acute lung injury due to blunt lung trauma in rats.

BACKGROUND: This study aims to investigate the effects of blunt lung trauma performed in experimental rat model on lung tissue and blood as well as proinflammatory cytokines, oxidant-antioxidant enzymes and histopathological parameters after Ngamma-nitro-L-arginine methyl ester and N-iminoethyl-L-ornithine administration. METHODS: The study included 50 adult male Wistar albino rats (weighing 350 to 400 g). Rats were randomly allocated into four groups. Except in the control, moderate-level pulmonary contusion was created in all other groups. Intraperitoneal saline solution was performed in groups 1 and 2, 25 mg.kg-1 Ngamma-nitro-L-arginine methyl ester in group 3, and 20 mg.kg-1 N-iminoethyl-L-ornithine in group 4. Blood and lung tissues were studied biochemically and histopathologically. RESULTS: Best outcomes were recorded statistically significantly in groups with administration of Ngamma-nitro-L-arginine methyl ester and N-iminoethyl-L-ornithine when malondialdehyde response, mucous and histopathological values were examined. Significant improvement was detected in superoxide dismutase values in the group with administration of competitive nitric oxide synthase inhibitor Ngamma-nitro-L-arginine methyl ester. Nitric oxide values were substantially decreased in N-iminoethyl-L-ornithine group, while no significance was detected. CONCLUSION: Free oxygen radicals and lipid peroxidation played a role in pulmonary contusion after blunt lung trauma. According to biochemical and histopathological outcomes, effects of inflammation were decreased and protective effects were formed with administration of both Ngammanitro- L-arginine methyl ester and N-iminoethyl-L-ornithine.

The Effects of Adenosinergic Modulation on Cytokine Levels in a Pentylenetetrazole-Induced Generalized Tonic-Clonic Seizure Model.

OBJECTIVE: It has been suggested that the adenosinergic system and cytokines play a role in the pathogenesis of epilepsy. Although the role of the adenosinergic system in the modulation of seizure activity is well known, the mechanism of this modulation needs to be described in detail. We performed this study to determine the contribution of the proinflammatory cytokines to the generalized seizure activity during adenosine and caffeine treatment. METHODS: We induced generalized tonic-clonic seizures with the administration of 60 mg/kg pentylenetetrazole (PTZ) in male Wistar Albino rats. Adenosine (500 mg/kg) or caffeine (5 mg/kg) was administered before PTZ injection. We monitored seizure activity and then determined the TNF-α, IL-1ß, and IL-6 levels in the cortical and thalamic brain regions of rats by ELISA. RESULTS: Adenosine pretreatment significantly extended seizure latency (p < 0.05), but did not affect seizure duration and entry time to stage 4 seizure. Caffeine pretreatment did not change seizure latency and seizure duration. PTZ treatment did not change brain cytokine levels significantly (p > 0.05) compared to the control group. Whereas adenosine pretreatment decreased brain TNF-α, IL-1ß, and IL-6 levels significantly (p < 0.05), caffeine pretreatment reduced brain cytokine levels slightly but nonsignificantly (p > 0.05). CONCLUSION: Our results show that there is a clear relation between adenosinergic system and brain tissue cytokine levels. Our findings indicated that TNF-α, IL-1ß, and IL-6 participate in the pathogenesis of generalized seizures, and the inhibition of TNF-α, IL-1ß, and IL-6 with adenosinergic modulation may decrease seizure severity.

Low serum insulin-like growth factor-1 in patients with erectile dysfunction.

OBJECTIVE: Endothelial dysfunction and microvascular damage play a crurical role in the pathogenesis of erectile dysfunction (ED). Insulin-like growth factor-1 (IGF-1) is one of the growth factors that have a wide range of biologic effects. IGF-1 is an important mediator of cell growth, differentiation and transformation in various tissues. The purpose of the current study was to determine the association between IGF-1 levels and ED. MATERIALS AND METHODS: All men were evaluated for ED and divided into two groups: 80 patients suffering from ED for > 1 year and 80 subjects without ED were enrolled as a control group in this study. Diagnosis of ED was based on the International Index of Erectile Function Score-5. IGF-1 levels were measured in serum by an automated chemiluminescence immunoassay. The relationship between IGF-1 levels and ED scores in patients was statistically evaluated. RESULTS: The mean age of patients in ED group was 60.4 ± 11.3 years and 55.4 ± 9.6 in control group. The plasma IGF-1 levels were significantly lower in ED than in control group (96.5 ± 38.3 and 132.5 ± 53.3 ng/ mL, respectively, P < 0.001). The IGF-1 levels were positively correlated with ED score (r = 0.623, P < 0.01). CONCLUSION: In this study serum IGF-1 levels were found to be associated with endothelial dysfunction that predicts ED. Serum IGF-1 level appears to be a specific predictor of ED, and it might be used in early prediction of ED in male population.

OBJECTIFS: La dysfonction endothéliale et les altérations vasculaires jouent un rôle crucial dans la pathogenèse de la dysfonction érectile (DE). L'Insulin-like Growth Factor-1 (IGF-1) est l'un des facteurs de croissance qui ont un vaste champ d'effets biologiques. IGF-1 est un médiateur important de la croissance, différentiation et transformation cellulaires dans différents tissus. Le but de la présente étude était de rechercher une association entre les taux d'IGF-1 et la dysfonction érectile. MATÉRIEL ET MÉTHODES: La dysfonction érectile a été évaluée chez tous les hommes, constitués en 2 groupes : 80 patients souffrant de DE depuis plus d'un an, et 80 sujets sans DE recrutés comme groupe témoin dans l'étude. Le diagnostic de DE était basé sur le score 5 de l'Index International de la Fonction Erectile. Les taux d'IGF-1 ont été mesurés par immunodosage automatisé par chemiluminescence. La relation entre les taux d'IGF-1 et le score de la DE a été statistiquement évaluée. RÉSULTATS: L'âge moyen des patients du groupe DE était de 60.4±11.3 ans et de 55.4±9.6 dans le groupe témoin. Les taux plasmatiques d'IGF-1 étaient significativement plus bas dans le groupe DE que chez les témoins (respectivement 96.5±38.3 et 132.5±53.3 ng/mL, P < 0.001). Les taux d'IGF-1 étaient positivement corrélés au score de la DE (r = 0.623, P < 0.01). CONCLUSIONS: Nos résultats indiquent que les taux sériques d'IGF-1 sont associés à une dysfonction endothéliale qui prédit la DE. L'IGF-1 sérique apparaît être un prédicteur spécifique de la DE, et il pourrait être utilisé pour une prédiction précoce de la DE dans la population masculine.

Protective effect of hydrogen sulfide on renal injury in the experimental unilateral ureteral obstruction

Introduction/Objective: Ureteral obstruction is a common pathology and causes kidney fibrosis and dysfunction at late period. In this present study, we investigated the antifibrotic and antiinflammatory effects of hydrogen sulfide on kidney damage after unilateral ureteral obstruction (UUO) in rats. Materials and Methods: 24 rats were divided into four groups. Group 1 was control, group 2 was sham, group 3 included rats with UUO and group 4 rats with UUO which were given sodium hydrogen sulfide (NaHS)-exogenous donor of hydrogen sulfide (intraperitoneally 56μmoL/kg/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. Tubular necrosis, mononuclear cell infiltration and interstitial fibrosis were determined histopathologically in a part of the kidneys; nitric oxide (NO), malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined in the other part of the kidneys. Urea-creatinine levels were investigated by blood analysis. Statistical analyses were made by the Chi-square test and one-way analysis of variance (ANOVA). Results: There was no significantly difference for urea-creatinine levels among groups. Pathologically, there was serious tubular necrosis and fibrosis in group 3 and there was significantly decreasing of tubular necrosis and fibrosis in group 4 (p<0.005). Also, there was significantly increase of NO and MDA levels and decrease of GSH levels in group 3 compared to other groups (p<0.005). Conclusions: hydrogen sulfide prevents kidney damage with antioxidant and antiinflammatory effect.

Protective effect of hydrogen sulfide on renal injury in the experimental unilateral ureteral obstruction.

INTRODUCTION/OBJECTIVE: Ureteral obstruction is a common pathology and causes kidney fibrosis and dysfunction at late period. In this present study, we investigated the antifibrotic and antiinflammatory effects of hydrogen sulfide on kidney damage after unilateral ureteral obstruction (UUO) in rats. MATERIALS AND METHODS: 24 rats were divided into four groups. Group 1 was control, group 2 was sham, group 3 included rats with UUO and group 4 rats with UUO which were given sodium hydrogen sulfide (NaHS)-exogenous donor of hydrogen sulfide (intraperitoneally 56 µmoL/kg/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. Tubular necrosis, mononuclear cell infiltration and interstitial fibrosis were determined histopathologically in a part of the kidneys; nitric oxide (NO), malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined in the other part of the kidneys. Urea-creatinine levels were investigated by blood analysis. Statistical analyses were made by the Chi-square test and one-way analysis of variance (ANOVA). RESULTS: There was no significantly difference for urea-creatinine levels among groups. Pathologically, there was serious tubular necrosis and fibrosis in group 3 and there was significantly decreasing of tubular necrosis and fibrosis in group 4 (p<0.005). Also, there was significantly increase of NO and MDA levels and decrease of GSH levels in group 3 compared to other groups (p<0.005). CONCLUSIONS: hydrogen sulfide prevents kidney damage with antioxidant and antiinflammatory effect.

Protective effect of hydrogen sulfide on gentamicin-induced renal injury.

OBJECTIVE: We evaluated the potential protective effect of hydrogen sulfide (H2S) against GEN-induced nephrotoxicity in rats. MATERIALS AND METHODS: Twenty-four rats were randomly divided into four groups, each consisting of six animals as follows: (1) the rats were control, (2) intraperitoneally injected with GEN 14 consecutive days (100 mg/kg/day), (3) treated with GEN plus %0.9 saline intraperitoneally for 14 days and (4) treated with GEN plus sodium hydrogen sulfide (NaHS)-exogenous H2S donor (56 µmol/kg/day) for 14 days. After 15 days, rats were sacrificed and their kidneys were taken and blood analysis was performed. Twenty-four hours urine collections were obtained in standard metabolic cages a day before the rats were sacrificed. Tubular necrosis and interstitial fibrosis scoring were determined histopathologically in a part of kidneys; nitric oxide (NO), malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined in the other part of kidneys. Statistical analyses were made by the chi-squared test and one-way analysis of variance. RESULTS: Serum urea and creatinine levels were significantly higher in rats treated with GEN alone, than the rats in control and GEN + NaHS groups. The GSH levels in renal tissue of only GEN-treated rats were significantly lower than those in control group, and administration of NaHS to GEN-treated rats significantly increased the level of GSH. The group that was given GEN and NaHS had significantly lower MDA and NO levels in kidney cortex tissue than those that was given GEN alone. In rats treated with GEN + NaHS, despite the presence of mild tubular degeneration and tubular necrosis are less severe, and glomeruli maintained a better morphology when compared with GEN group. DISCUSSION: We can say that H2S prevent kidney damage with antioxidant and anti-inflammatory effect.