Permissive role of cytosolic pH acidification in neurodegeneration: A closer look at its causes and consequences.

The maintenance of cytosolic pH in its physiological range is required for normal neuronal activity, and even minor alterations can have serious consequences. This Review summarizes the current understanding of the conditions that are associated with cytosolic pH disruption and that lead to abnormal cytosolic acidification. Oxidative stress results in cytosolic acidification, and this plays a crucial role in the emergence of apoptosis in protein misfolding and excitotoxicity, ultimately leading to irreversible neuronal damage. Through the identification of mechanisms by which intraneuronal pH acidification promotes neurodegeneration, we may identify new approaches for preventing and treating neurodegenerative disorders. © 2016 Wiley Periodicals, Inc.

Amyloid-beta: a crucial factor in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia which affects people older than 60 years of age. In AD, the dysregulation of the amyloid-beta (Aß) level leads to the appearance of senile plaques which contain Aß depositions. Aß is a complex biological molecule which interacts with many types of receptors and/or forms insoluble assemblies and, eventually, its nonphysiological depositions alternate with the normal neuronal conditions. In this situation, AD signs appear and the patients experience marked cognitional disabilities. In general, intellect, social skills, personality, and memory are influenced by this disease and, in the long run, it leads to a reduction in quality of life and life expectancy. Due to the pivotal role of Aß in the pathobiology of AD, a great deal of effort has been made to reveal its exact role in neuronal dysfunctions and to finding efficacious therapeutic strategies against its adverse neuronal outcomes. Hence, the determination of its different molecular assemblies and the mechanisms underlying its pathological effects are of interest. In the present paper, some of the well-established structural forms of Aß, its interactions with various receptors and possible molecular and cellular mechanisms underlying its neurotoxicity are discussed. In addition, several Aß-based rodent models of AD are reviewed.

Up-regulation of TLR2 and TLR4 in high mobility group Box1-stimulated macrophages in pulpitis patients.

OBJECTIVES: High Mobility Group Box1 (HMGB1) is a nonhistone, DNA-binding protein that serves a crucial role in regulating gene transcription and is involved in a variety of proinflammatory, extracellular activities. The aim of this study was to explore whether HMGB1 stimulation can up-regulate the expression of Toll-like Receptor 2 (TLR2) and Toll-like Receptor 4 (TLR4) on macrophages from pulpitis and to clarify the subsequent events involving Th17 cells and Th17 cell-associated cytokine changes. MATERIALS AND METHODS: Having prepared dental pulp tissues of pulpitis and healthy controls, macrophage were isolated and cultured. Macrophages were thereafter stimulated by HMGB1 time course. RT-QPCR, flowcytometer, immunofluorescence, Western blotting, and ELISA techniques were used in the present research. RESULTS: Our results showed that the expression of TLR2 and TLR4 on macrophages stimulated with HMGB1 increased in pulpitis compared with controls (macrophages without HMGB1 stimulation) with a statistical significance (P<0.001). In addition, the levels of IL-17, IL-23, and IL-6 in supernatants from cultured macrophages stimulated with HMGB1 from pulpitis increased, and NF-kB, the downstream target of TLR2 and TLR4, also showed a marked elevation after macrophages' stimulation by HMGB1. CONCLUSION: The evidence from the present study suggests that the enhanced TLR2 and TLR4 pathways and Th17 cell polarization may be due to HMGB1 stimulation in pulpitis.

Antidepressant-like effect of modafinil in mice: Evidence for the involvement of the dopaminergic neurotransmission.

BACKGROUND: Modafinil is a wake-promoting agent that provides wide ranges of neurological effects. There is evidence that it can produce antidepressant effects. This study investigated the antidepressant effect of modafinil in the tail suspension (TST) in mice. METHODS: Different doses of modafinil was intraperitoneally (ip) administrated and then animals were subjected to TST and/or open field test (OFT). Moreover, the implication of the dopaminergic neurotransmission in modafinil's antidepressant effect was studied. For this purpose, animals were pretreated with haloperidol (non-selective dopamine receptor antagonist), or SCH23390 and sulpiride (the dopamine D1 and D2 receptor antagonist, respectively), then were assessed by TST. The possible effect of sub-effective dose of modafinil in combination with sub-therapeutic doses of standard antidepressants was also evaluated in separate groups. RESULTS: Modafinil (75 mg/kg, ip) produced antidepressant effect in TST, as compared to a control group, without any alterations in ambulation in OFT. Pretreatment of mice with haloperidol (0.2mg/kg, ip) and sulpride (50mg/kg, ip) blocked the anti-immobility effect of modafinil (75 mg/kg, ip). We also found that the administration of SCH23390 (0.05 mg/kg, sc) couldn't antagonize the antidepressant effects of modafinil. In addition, a sub-effective dose of modafinil (50mg/kg, ip) potentiated the sub-effective doses of standard antidepressants including of bupropion (1mg/kg, ip), fluoxetine (1mg/kg, ip) and imipramine (0.1mg/kg, ip) and reduced immobility time in TST. CONCLUSION: Results show that modafinil induced an antidepressant property in TST and this effect apparently was mediated through interaction with the dopaminergic (D2 receptors) system.

Efficacy of Combination Therapy of Statin and Vitamin C in Comparison with Statin in the Prevention of Post-CABG Atrial Fibrillation.

PURPOSE: Atrial fibrillation (AF) is the most frequent arrhythmia that follows coronary artery bypass graft (CABG). Patients developing postoperative AF (POAF) have significantly higher mortality rates. The consistent prophylactic effectiveness of statins and vitamin C are well-accepted; however, no evaluation on combined therapy has been performed. We aimed at assessing the efficacy of combination therapy with statin and vitamin C in comparison with statin alone in the prevention of post CABG-AF. METHODS: In a randomized double blind clinical trial, 120 candidates of CABG were recruited in Tabriz Madani Educational Center in a 15-month period of time. Patients were randomized into two groups of 60 receiving oral atorvastatin (40mg) plus oral vitamin C (2g/d operation day and 1g/d for five consequent days) for intervention group and oral atorvastatin (40mg) for control group. Occurrence of post CABG AF was compared between the two groups. RESULTS: There were 60 patients, 43 males and 17 females with a mean age of 61.0±11.5 (29-78) years, in the intervention group and sixty patients, 39 males and 21 females with a mean age of 60.5±11.3 (39-81) years, in the control group. The post CABG AF occurred in 6 cases (10%) in the interventional group and 15 patients (25%) in the controls (P=0.03, odds ratio=0.33, 95% confidence interval 0.12-0.93). CONCLUSION: Based on our findings, combination prophylaxis against post CABG AF with oral atorvastatin plus vitamin C is significantly more effective than single oral atorvastatin.

Iran's Bushehr Earthquake at a Glance.

On 9 April 2013, an earthquake of 6.1 magnitude hit southwestern Iran near the city of Khvormuj and the towns of Kaki and Shonbeh in Bushehr province. The official disaster mitigation committee took immediate actions to coordinate rescue teams equipped with 24-hour medical air assistance. Overall, 160 victims were transferred to and treated in the Khvormuj hospital, while 139 survivors were transferred to the hospitals in Bushehr for specialized care. The survivors have been settled in temporary shelters with adequate primary supplies. Considering the hot climate of the area, immediate measures should be taken in order to avoid any further casualties particularly heatstroke, dehydration, diarrheal and vector-borne diseases.

Does adenotonsillectomy alter IGF-1 and ghrelin serum levels in children with adenotonsillar hypertrophy and failure to thrive? A prospective study.

OBJECTIVES: Adenotonsillar hypertrophy (ATH) contributes to upper airway obstruction and recurrent tonsillitis in children. The aim of this study was to evaluate the effect of adenotonsillectomy on serum IGF-1 and ghrelin levels in children with ATH failure to thrive. METHODS: Forty pre-pubertal children with more than 5 years of age (6.57 ± 1.284 years) suffering from ATH, sleep disorder breathing, snoring, open mouth breathing and growth retardation were studied. Blood samples were taken eight hours after fasting and weight and height were measured by SECA instrument. Blood samples were centrifuged immediately and the extracted sera were stored at -70 °C in Eppendorf vials. IGF-1 and ghrelin were measured by ELISA kit. Patients with adenotonsillectomy indication underwent adenotonsillectomy and serum levels of IGF-1 and ghrelin were measured 12 months after operation. RESULTS: Weight, height and BMI were increased significantly after operation (P < 0.001). Serum IGF-1 and ghrelin levels increased significantly after operation compared to before operation (P < 0.001). CONCLUSION: Growth retardation in children with adenotonsillar hypertrophy is related to lower serum IGF-1 levels. Ghrelin levels increase before the meals and ghrelin increases hunger and food intake. The results obtained from our study confirmed that weight, height and BMI increase significantly following adenotonsillectomy; this could in turns prevent undesirable and irreversible physiological changes that occur due to adenotonsillar hypertrophy. Adenotonsillectomy in children with adenotonsillar hypertrophy and failure to thrive increases IGF-1 and Ghrelin serum levels which might contribute to the improvement in the growth pattern of the children.