Evaluation of the effect of Exercise Trainings and CGRP receptor antagonist (BIBN 4096) on mitochondrial dynamic in the hippocampus of male Wistar rats.

BACKGROUND: Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS: In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist. Real-time PCR (2-ΔΔCT) and western blotting were employedto measure the expression of genes and protein, respectively. RESULTS: HIIT and ET significantly increased Bcl-2, Pgc-1α, Sirt3, and Nrf-1 gene expression in the hippocampal tissue (p < 0.05, p < 0.01, p < 0.01, and p < 0.001, respectively). ET-CGRPi and HIIT-CGRPi significantly increased Sirt3, Pgc-1α, and Nrf-1 gene expression compared to the control group (p < 0.05, p < 0.01, and p < 0.05, respectively). CONCLUSION: ET and HIIT-induced physiological alterations in the hippocampus. In fact, this modulation showed protective properties in the hippocampusvia up regulation of Bcl-2, Pgc-1α, Nrf-1, and Sirt3 gene expression. CGRPi did not cause gene or protein changes harmful to mitochondrial dynamic balance and apoptosis in the hippocampus of rats.

Beneficial effects of berberine against pulmonary complications of experimental pulmonary arterial hypertension in rats and some relevant mechanisms.

Pulmonary arterial hypertension (PAH) is a severe disease that leads to pulmonary vascular remodeling characterized by a rise in pulmonary vascular resistance and pressure. We assessed the effects of an herbal compound, berberine (BB), and some related mechanisms on PAH in rats. Male Wistar rats were assigned to seven groups: control, monocrotaline (MCT), MCT+vehicle, and MCT+BB (with doses of 10, 20, 30, and 40 mg/kg) groups. Three weeks after induction of PAH by MCT, treatment groups received daily intraperitoneal injections of vehicle or BB for 3 weeks. On Day 43, the right ventricular systolic pressure (RVSP, as an index of pulmonary arterial pressure) and the ratio of RV to LV+septum weight (as RV hypertrophy index, right ventricle hypertrophy [RHVI]) were measured. Inflammatory and oxidative stress indices and histopathology of the lungs were also assessed. RVSP (89.4 ± 8.2 vs. 23 ± 3.3), RVHI (0.63 ± 0.08 vs. 0.26 ± 0.04), and lung inflammatory cytokines TNF-α (2.03 ± 0.25 vs. 1.21 ± 0.3) and IL-6 (8.8 ± 0.59 vs. 6.3 ± 0.95) significantly increased in the MCT group compared to the control group. MCT also raised the level of Malondialdehyde (0.11 ± 0.01 vs. 0.09 ± 0.01) and diminished total antioxidant capacity (6.5 ± 0.51 vs. 8.3 ± 0.62), the activity of superoxide dismutase (1.19 ± 0.22 vs. 1.93 ± 0.2), glutathione peroxidase (0.02 ± 0.002 vs. 0.03 ± 0.005), catalase (2.1 ± 0.29 vs. 2.8 ± 0.20) and Bax/Bcl-2 ratio (0.41 ± 0.07 vs. 0.61 ± 0.09) in the lungs. Treatment with BB significantly recovered all of these alterations. BB ameliorated pulmonary vascular remodeling by decreasing inflammation and fibrosis and increasing apoptosis and antioxidant/oxidant balance. Therefore, this herbal derivative may be considered a therapeutic goal against PAH.

Probable role of the hyperpolarization-activated current in the dual effects of CB1R antagonism on behaviors in a Parkinsonism mouse model.

Recent evidence from genetic and pharmacological animal models of Parkinson's disease (PD) suggests alteration in activity of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) occurs following dopamine (DA) depletion. Further, based on data from our lab and others, the endocannabinoid system (ECBS) appears to be involved in PD-related processes. Therefore, we compared the motor and non-motor effects of an intracerebroventricular (i.c.v.) injection of the cannabinoid receptor type 1 (CB1R) agonist WIN 55,212-2 (WIN) and selective antagonist AM251 (AM) on motor and non-motor symptoms (NMS) of PD in a mouse model generated by an i.c.v. injection of 6-hydroxydopamine (6-OHDA). To provide further knowledge about the link between CB1R and the hyperpolarization-activated current (Ih), we conducted ex vivo investigations in the ventral tegmental area (VTA). In the current study, pharmacological antagonism of CB1R ameliorated explorative behaviors, balance, muscle strength, and passive avoidance memory deficits induced by 6-OHDA, however, anxious, and depressive-like behaviors were heightened. AM was also effective in reducing a 6-OHDA-induced TH level deficit. 6-OHDA exposure induced severe alterations in the spontaneous and evoked firing behavior of DA neurons, as evidenced by a significant increase in the mean number of spikes and a decrease in spike half-width, respectively. Interestingly, an increase in the amplitude of the sag voltage and in the amplitude of the steady state Ih current was seen. Consistent with an effect of increasing Ih, WIN exacerbated 6-OHDA-induced actions by further reducing the spike half-width and increasing the firing frequency. In addition, greater amplitudes of sEPSPs were elicited. The effects of 6-OHDA on sag voltage, Ih current amplitude, and firing frequency were reversed by administration of AM. These results suggest that ECBs might be involved in some of the 6-OHDA-induced electrophysiological alterations in VTA DA neurons in this animal model of PD. In addition, the CB1R antagonistic mechanism could be effective in modulating the devastating effects of 6-OHDA.

Moderate Endurance Training and MitoQ Improve Cardiovascular Function, Oxidative Stress, and Inflammation in Hypertensive Individuals: The Role of miR-21 and miR-222: A Randomized, Double-Blind, Clinical Trial.

OBJECTIVE: Hypertension (HTN) is among the leading causes of myocardial infarction, stroke, and kidney disease. The MitoQ supplement is a mitochondrial-targeted antioxidant that attenuates the generation of reactive oxygen species (ROS). miRNAs play an essential role in the pathophysiology of HTN. Regular aerobic exercise is recommended to decrease the risk of cardiovascular disease. We aimed to evaluate the effects of MitoQ supplementation and moderate endurance training (ET), alone and in combination, on cardiac function, blood pressure, the circulatory levels of miRNA-21 and miRNA-222, and oxidative status in individuals with HTN. MATERIALS AND METHODS: In a double-blind, randomized clinical trial (except for ET group), 52 male hypertensive subjects (40-55 years old) were randomly divided into four groups (n=13): Placebo, MitoQ (20 mg/day, oral), ET (Cycle ergometer, moderate intensity, 40-60% VO2 peak, three sessions/week for six weeks), and MitoQ+ET. Cardiac echocardiography indices, serum oxidative and inflammation status, and miRNAs 21 and 222 were assessed before and after interventions. RESULTS: Left ventricular mass [effect size (ES): -6.3, 95% confidence interval (CI): -11.2 to -1.4] and end-systolic/ diastolic diameters significantly improved in the intervention groups (ES: -0.05, 95% CI: -0.11 to 0.00 and -0.09, 95% CI: -0.16 to -0.02). Total serum antioxidant capacity (TAC) increased (ES: 36.0, 95% CI: 26.1 to 45.8), and malondialdehyde (MDA) (ES: -0.43, 95% CI: -0.53 to -0.32), IL-6 (ES: -1.6, 95% CI: -1.98 to -1.25), miR-21 (ES: -0.48, 95% CI: -0.61 to -0.35), and miR-222 (ES: -0.31, 95% CI: -0.44 to -0.18) significantly decreased in response to ET, MitoQ, and their combination. CONCLUSION: MitoQ and ET, individually and more pronouncedly in combination, can improve cardiovascular health in people with high blood pressure (BP) by reducing inflammation and increasing antioxidant defense, in association with reduction in circulatory miR-21 and miR-222 levels (registration number: IRCT20190228042870N1).

Effect of Combined Endurance Training and MitoQ on Cardiac Function and Serum Level of Antioxidants, NO, miR-126, and miR-27a in Hypertensive Individuals.

OBJECTIVES: Hypertension (HTN) is one of the most important risk factors for cardiovascular diseases. Despite advances in treatment and control of HTN, the prevalence of HTN is still increasing. MitoQ is a supplement that acts on mitochondria and attenuates reactive oxygen species (ROS), which plays an important role in cardiovascular health. miRNAs play an important role in the pathophysiology of HTN. We evaluated the effects of MitoQ supplementation and endurance training (ET), alone and in combination, on functional indices of the heart and serum levels of miR-126, miR-27a, antioxidants, and NO, in patients with HTN. METHODS: In a double-blind randomized clinical trial, 52 male participants (age 40-55 years) were randomly divided into four groups (n = 13) of placebo, MitoQ (20 mg/day, oral), ET (cycle ergometer, moderate intensity, 40-60% VO2 peak, heart rate 120-140 b/min, 45 min a day, three days/week for six weeks), and MitoQ+ET. Cardiac function indices were assessed by echocardiography before and after interventions. RESULTS: Systolic blood pressure (SBP) significantly decreased in all intervention groups (P < 0.001) while DBP (P < 0.01) and LV hypertrophy (P < 0.05) were significantly decreased only in the MitoQ+ET group. Serum levels of SOD, GPx, and NO and the level of miR-126 significantly increased in all treatment groups, while miR-27a reduced in the ET (P < 0.05) and MitoQ+ET (P < 0.01) groups. CONCLUSIONS: Compared to MitoQ and ET alone, their combination has more prominent improving effects on cardiac health and amelioration of BP in the patients with HTN. These effects are through miR-126 and miR-27a modulation and ameliorating mitochondrial ROS production.

Interaction of high-intensity endurance exercise and nandrolone on cardiac remodeling: role of adipo-cardiac axis.

OBJECTIVES: Given the cardiac pathological remodeling following to anabolic androgenic steroids (AASs) consumption, we examined the effect of chronic administration of nandrolone decanoate with high-intensity endurance exercise on the left ventricular hypertrophy index, levels of hydroxyproline, tumor necrosis factor-alpha (TNF-α), adiponectin (APN) and its receptors (AdipoR1 and AdipoR2) expression in rats' hearts. METHODS: The male Wistar rats randomly divided to six groups included the control (CTL), exercise (Ex), nandrolone (Nan), vehicle (Arach), trained vehicle (Ex + Arach), and trained nandrolone (Ex + Nan) groups that were treated for eight weeks. RESULTS: Nandrolone consumption significantly enhanced the hypertrophy index (p<0.05) and exercise intensified this effect. It also increased the level of cardiac hydroxyproline (p<0.001), however exercise completely masked this effect. The values of TNF-α protein and AdipoR1 protein significantly increased in trained nandrolone-treated (Ex + Nan) group in comparison with CTL group (p<0.05), however, did not show significant alteration in Nan or Ex groups. High-intensity endurance exercise significantly enhanced the AdipoR2 protein (p<0.05), but, co-administration of nandrolone with exercise prevented this effect. The mRNA expression of AdipoR1 significantly reduced in the animals that received nandrolone for eight weeks and exercise recovered this effect (p<0.001). CONCLUSIONS: Despite an additive effect of high-intensity endurance exercise plus nandrolone on TNF-α level, their effects on hydroxyproline and APN receptors expression is incompatible in heart of rat. It is suggests a part of beneficial regulatory role of endurance exercise against nandrolone induced heart remodeling may apply through modulation of APN system.

SIRT1 and Klotho expression in the heart and kidneys of rats with acute and chronic renovascular hypertension.

AIM: To evaluate Klotho and SIRT1 expression in the heart and kidneys of rats with acute and chronic renovascular hypertension. METHODS: Four and sixteen weeks after the induction of renovascular hypertension by clipping the left renal artery, systemic blood pressure, serum angiotensin II level, and the expression of Klotho and SIRT1 proteins and oxidative stress indices in the heart and kidneys were assessed. RESULTS: SIRT1 level was significantly reduced in the ischemic (left) kidney in acute and chronic phases of hypertension. In the heart, it decreased in the acute phase, but increased in the chronic phase. Klotho levels in the heart and kidneys did not change significantly in either hypertension phase. Superoxide dismutase (SOD) activity in the heart significantly decreased, and SOD, total antioxidant capacity, and malondialdehyde in the ischemic kidney significantly increased during the development of hypertension. Serum angiotensin II level significantly increased in the acute phase of hypertension. CONCLUSION: Development of renovascular hypertension was associated with a reduction of SIRT1 expression in the heart and ischemic kidney. As angiotensin II and SIRT1 counteract each other's expression, a SIRT1 reduction in the heart and kidney, along with the influence of systemic/local angiotensin II, seems to be partly responsible for hypertension development. A combination of SIRT1 agonists and angiotensin II antagonists may be considered for use in the treatment of renovascular hypertension.

Effects of short environmental enrichment on early-life adversity induced cognitive alternations in adolescent rats.

Early-life experiences, including parental care, affect cognitive performance later in life. Being exposed to early-life maternal separation (MS) increases susceptibility to stress-related psychopathology. Previous studies suggest that MS could induce learning and memory impairments. Since enriched environment (EE) provides more opportunities for exploration and social interaction, in the present study we evaluated the effects of a short EE paradigm with a duration of 13 days on cognitive abilities of maternally separated rats (MS; 180 min/day, postnatal day (PND) 1-21) during adolescence in four experimental groups: Control, Control+EE, MS, and MS+EE. Plasma corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels were also measured in experimental animals. We also studied the induction of long-term potentiation (LTP) in the slices of hippocampal CA1 area. The behavioral and electrophysiological assessments were started at PND 35. MS caused higher basal CORT levels in plasma and impaired spatial learning, memory, and social interaction. LTP induction was also impaired in MS rats and plasma BDNF levels were reduced in these animals. MS also induced more anxiety-like behavior. Short EE reduced plasma CORT levels had the potential to improve locomotor activity and anxiety-like behavior in MS+EE rats and reversed MS-induced impairments of spatial learning, memory, and social behavior. LTP induction and plasma BDNF levels were also enhanced in MS+EE rats. We concluded that short EE might be considered as a therapeutic strategy for promoting cognition.

Low-Frequency Stimulation Prevents Kindling-Induced Impairment through the Activation of the Endocannabinoid System.

BACKGROUND: Cannabinoid system affects memory and has anticonvulsant effects in epileptic models. In the current study, the role of cannabinoid 1 (CB1) receptors was investigated in amelioration of the effects of low-frequency stimulation (LFS) on learning and memory impairments in kindled rats. METHODS: Electrical stimulation of the hippocampal CA1 area was employed to kindle the animals. LFS was applied to the CA1 area in four trials following the last kindling stimulation. One group of animals received intraperitoneal injection of AM251 (0.1 µg/rat), a CB1 receptor antagonist, before the LFS application. Similarly, CB1 agonist WIN55-212-2 (WIN) was administrated to another group prior to LFS. The Morris water maze (MWM) and the novel object recognition (NOR) tests were executed 48 h after the last kindling stimulation to assess learning and memory. RESULTS: Applying LFS in the kindled+LFS group restored learning and memory impairments in the kindled rats. There was a significant difference between the kindled and the kindled+LFS groups in learning and memory. The application of AM251 reduced the LFS effects significantly. Adversely, WIN acted similarly to LFS and alleviated learning and memory deficits in the kindled+WIN group. In addition, WIN did not counteract the LFS enhancing effects in the KLFS+WIN group. CONCLUSIONS: Improving effects of LFS on learning and memory impairments are mediated through the activation of the endocannabinoid (ECB) system.

Serum microRNA-33 levels in pre-diabetic and diabetic patients.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and abnormal insulin secretion. MicroRNAs are small, non-coding RNAs that are able to affect cell biological functions and act as biomarkers for some diseases such as DM. In current study, we measured serum miR-33 in three groups (n = 15) as follows; non-diabetic control, pre-diabetic, and DM patients. Real-time PCR method was used to quantify miR-33 expression. miR-33 expression was significantly increased in pre-diabetic subjects compared to other two groups (p < 0.001). FBS (p < 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001), and TG (p = 0.026) were higher in diabetic subjects than the other two groups. In people that had high physical activity, the number of diabetic subjects were zero and most of them were in pre-diabetic group (p = 0.019). Serum miR-33 level significantly and positively correlated with pre-diabetic state (B = 2.67, p = 0.000), Sex (B = 1.03, p = 0.025), and FBS (B = 0.04, p = 0.036) and also miR-33 was significantly and negatively correlated with HOMA-IR (B = - 1.58, p = 0.04). These findings support the possible role of miR-33 to monitor pre-diabetes onset and progression. It needs to be evaluated in future studies with high number of participants to clarify its mechanism and diagnostic viability.

Electromagnetic field protects against cognitive and synaptic plasticity impairment induced by electrical kindling in rats.

Kindling results in abnormal synaptic potentiation and significant impairment in learning and memory. Electromagnetic field (EMF) effects on learning and memory in kindled animals and its effects on hippocampal neural activity are largely unknown. In the current study, the effects of EMF on learning and memory, as well as hippocampal synaptic plasticity, in kindled rats were investigated. EMF (10 mT; 100 Hz) was applied to fully kindled animals one hour/day for a period of one week. The behavioral and electrophysiological studies were performed 24 h following the EMF application. The kindled rats showed spatial learning deficits during the training phase of the Morris water maze (MWM) test. Moreover, there were increments in escape latency and path length compared to the sham group. The kindled rats spent less time in the target-quadrant probe test, indicating spatial memory impairment. Applying EMF to the KEMF group (kindling + EMF) restored learning and memory, and decreased escape latency and path length significantly compared to the kindled group. EMF alone had no significant effects on the learning and memory parameters. Based on the open field (OF) test results, EMF alone in the EMF group, but not in the kindled or the KEMF groups, decreased the total traveled distance and increased the spent time in the peripheral zone, compared to the sham group. Based on electrophysiological results, applying EMF in the KEMF group returned the ability of synaptic potentiation to the hippocampal CA1 area and high-frequency stimulation induced long-term potentiation (LTP). Accordingly, EMF can be considered a potential therapy for seizure-induced deficits in learning and memory.

Intranasal oxytocin administration facilitates the induction of long-term potentiation and promotes cognitive performance of maternally separated rats.

Maternal separation (MS) is known to induce permanent changes in the central nervous system and is associated with increased levels of anxiety and cognitive impairments. The neuropeptide oxytocin (OT) has been implicated in a broad spectrum of social and nonsocial and behaviors. Since it plays a significant role in learning and memory and enhances synaptic plasticity, we hypothesized that OT may affect MS-induced changes in synaptic plasticity and cognitive performance. Rat pups underwent MS protocol for 180 min/day from postnatal day (PND) 1-21. OT was administered intranasally (2 µg/µl, 7 days) to control and MS groups from PND 22-34. Plasma corticosterone (CORT) levels, anxiety-like behavior, sociability, learning and memory were measured in adolescent rats. In addition, extracellular evoked field excitatory postsynaptic potentials (fEPSP) were also recorded from hippocampal slices. MS induced higher plasma CORT levels and impaired social interaction, learning and memory. Moreover, MS reduced locomotor activity and increased anxiety-like behavior. Intranasal OT could overcome MS-induced deficits and promoted sociability, learning and memory of MS rats. OT also enhanced locomotor activity in the open field and decreased anxiety-like behavior. Obtained results showed that long term potentiation (LTP) was not induced in MS animals. However, OT injection overcame the MS-induced impairment in LTP generation in CA1 area of the hippocampus.

Effect of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide on cognitive deficits and hippocampal plasticity during nicotine withdrawal in rats.

Withdrawal from chronic nicotine has damaging effects on a variety of learning and memory tasks. Various Sulfonamides that act as carbonic anhydrase inhibitors have documented role in modulation of various cognitive, learning, and memory processing. We investigated the effects of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS) on nicotine withdrawal impairments in rats using Morris water maze (MWM), Novel object recognition, Passive avoidance, and open field tasks. Also, Brain-derived neurotrophic factor (BDNF) profiling and in vivo field potential recording were assessed. Rats were exposed to saline or chronic nicotine 3.8 mg/kg subcutaneously for 14 days in four divided doses, spontaneous nicotine withdrawal was induced by quitting nicotine for 72 h (hrs). Animals received 4-FBS at 20, 40, and 60 mg/kg after 72 h of withdrawal in various behavioral and electrophysiological paradigms. Nicotine withdrawal causes a deficit in learning and long-term memory in the MWM task. No significant difference was found in novel object recognition tasks among all groups while in passive avoidance task nicotine withdrawal resulted in a deficit of hippocampus-dependent fear learning. Anxiety like behavior was observed during nicotine withdrawal. Plasma BDNF level was reduced during nicotine withdrawal as compared to the saline group reflecting mild cognitive impairment, stress, and depression. Withdrawal from chronic nicotine altered hippocampal plasticity, caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results showed that 4-FBS at 40 and 60 mg/kg significantly prevented nicotine withdrawal-induced cognitive deficits in behavioral as well as electrophysiological studies. 4-FBS at 60 mg/kg upsurge nicotine withdrawal-induced decrease in plasma BDNF. We conclude that 4-FBS at 40 and 60 mg /kg effectively prevented chronic nicotine withdrawal-induced impairment in long term potentiation and cognitive performance.

Swimming Exercise Training Attenuates the Lung Inflammatory Response and Injury Induced by Exposing to Waterpipe Tobacco Smoke.

BACKGROUND: The use of waterpipe tobacco smoking (WTS) is on the rise throughout the world, especially among young people and even athletes. There is a belief among consumers that exercise prevents the harmful effects of hookah smoke on the body. We examined this belief by evaluation of lung injury following to concurrent WTS and swimming endurance training in male Wistar rats. METHODS: Animals were randomly divided to sedentary control (CTL) group, exercise training group (Ex group), sedentary WTS (S) group, and exercise plus WTS (S + Ex) group. FINDINGS: 8 weeks of WTS was associated with significant increase in serum level of cotinine, lung damage, reduction in alveolar number AN/SA (mm2) and increase in malondialdehyde (MDA) level of lung tissue. Combination of exercise with WTS significantly decreased these negative effects; however, it could not fully protect the lung from smoking damage. Waterpipe smoking (WPS) also significantly increased the pro-inflammatory cytokines of lung tissue such as tumor necrosis factor alpha (TNF-α) (P < 0.001), interleukin 1 beta (IL-1ß) (P < 0.010), and IL-6 (P < 0.050) in comparison with CTL group. Exercise training to some degree reduced the levels of pro-inflammatory cytokines and increased the level of IL-10 as an anti-inflammatory IL and glutathione peroxidase (GPX) activity in animals exposed to WTS. CONCLUSION: It is suggested that combination of mild to moderate exercise with WTS may attenuate the hookah smoking-induced lung damage. This effect partly is mediated through balancing of pro/anti-inflammatory and redox systems.

Effects of Endurance Exercise Training on Cardiac Dysfunction Induced by Waterpipe Tobacco Smoking.

BACKGROUND: There is an increasing popularity of waterpipe tobacco smoking (WTS) in youth and even in athletes worldwide. Despite the existence of evidence of the harmful effects of hookah smoke on various systems of the body, especially the cardiovascular system, its simultaneous effect with exercise training has not been well studied. We assessed the effects of WTS exposure with/without swimming exercise on blood pressure (BP), and heart histology and mechanical performance in male Wistar rats. METHODS: The animals were divided into 4 groups of sedentary control (CTL), waterpipe tobacco smoking (S), mild endurance swimming exercise training (Ex), and waterpipe smoking plus exercise (S + Ex). The duration of WTS and exercise was 8 weeks. FINDINGS: BP and heart rate (HR) did not show a significant difference among the groups. WTS increased the TNF-α level of the heart (P < 0.05 vs. CTL) and cardiac tissue lesions (P < 0.05 vs. CTL), and reduced +dP/dt max, -dp/dt max, and heart contractility indices (P < 0.01, P < 0.01, and P < 0.05, respectively, vs. CTL and Ex groups). It also increased the Tau index (P < 0.05 vs. CTL; P < 0.01 vs. Ex groups) of the left ventricle. However, the combination of exercise and WTS reduced the TNF-α level, improved the heart activity of superoxide dismutase (SOD) and catalase enzymes, and prevented the negative effects of smoking on heart function and morphology. CONCLUSION: Mild exercise prevents WTS-induced left ventricular systolic and diastolic dysfunction partly via improvement of antioxidants and attenuation of pro-inflammatory cytokines.

Impact of extremely low-frequency electromagnetic field (100 Hz, 100 G) exposure on human glioblastoma U87 cells during Temozolomide administration.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely dismal prognosis, a median survival is12 months. Temozolomide (TMZ) is an alkylating agent widely used to treat cancer, resistance to this drug is often found. One unexplored possibility for overcoming this resistance is a treatment based on concomitant exposure to electromagnetic fields (EMF) and TMZ. Indeed, many evidences show that EMF affects cancer cells and drug performance. Therefore, the present study was carried out to evaluate the potential synergistic effect of 100 µM TMZ and EMF (100 Hz, 100 G) on human glioma cell line U87 U87 cells with four experimental groups (I-IV) were exposed to ELF-EMF and TMZ for 120 and 144 h, as follows: (I) control; (II) ELF-EMF; (III) TMZ; (IV) ELF-PEMFs / TMZ. mRNA expression of genes such as (Nestin,CD133, Notch4 and GFAP) were investigated by Real-time PCR and western blot. We also evaluated, SOD activity, MDA and calcium concentration by ELISA assay. Co-treatment synergistically decreased the expression of Nestin,CD133, and Notch4 and increased the GFAP genes. We also observed an increase in Superoxide dismutase (SOD) activity, Malondialdehyde (MDA) and Ca2+concentration in comparison to controls.TMZ prevents cancer progression not only through the induction of cell death, but also by inducing differentiation in cancer cells. In addition, our data demonstrate ELF-EMF (100 Hz, 100 G) can significantly enhance the effects of TMZ on human glioblastoma U87 cell. These findings may open new window for future studies.

Early enriched environment prevents cognitive impairment in an animal model of schizophrenia induced by MK-801: Role of hippocampal BDNF.

Early life experience has long-lasting effects on brain and behaviour. This study aims to investigate the long-term effects of enriched environment (EE), which was imposed during the animals' development, on their recognition memory as well as hippocampal levels of brain-derived neurotrophic factor (BDNF), in an animal model of schizophrenia induced by chronic postnatal administration of MK-801. Forty male and female rat pups were separated in four distinct groups for each sex (n = 10). The rats were injected with MK-801 (1 mg/kg) or saline (1 cc/kg) on their postnatal days (P) 6-10. MK-801 and Control rats were maintained in standard or enriched cages (containing toys, tunnels, running wheels, and climbing frame), from their birth up to the time of behavioral experiments at P60. Neonatal challenge with MK-801 significantly impaired novel object recognition (NOR) in both male and female animals. EE exposure reversed the recognition memory only in male rats. MK-801 resulted in decreased levels of BDNF in the hippocampus, and EE exposure restored the decreased level. Our results provide evidence that BDNF plays an important role in pathophysiology of schizophrenia in the present animal model, and is a possible mechanism through which early EE can enhance the cognitive functions.

Anti-Inflammatory and Anti-Oxidative Effects of Myrtenol in the Rats with Allergic Asthma.

The aim of the present study was to investigate the effect of Myrtenol, the active ingredient of Myrtle on the oxidant and anti-oxidant indices and cytokines in the allergic asthma. Allergic asthma was induced by ovalbumin (OVA) sensitization and inhalation in four groups of rats; Control, Asthma, Asthma + Dexamethasone and Asthma + Myrtenol. Myrtenol (50mg/kg) or Dexamethasone (2.5mg/kg) was administered intraperitoneally for 7 consecutive days after OVA inhalation. At the end, histopathological parameters, and interleukins (Interleukin-10 (IL10), Interferon gamma (IFN-γ) , interleukin-1ß (IL-1ß), Tumor Necrosis Factor α (TNF-α)), and oxidative stress biomarkers, Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPX) in the lung and serum were measured by hematoxylin and eosin staining and ELISA method, respectively. Myrtenol reduced the pathological changes in the lungs and airway endothelium (P < 0.01), (P < 0.5). The level of IL-1ß (P < 0.05) and MDA in the serum and lung tissue (P < 0.01), (P < 0.05), and also the level of TNF-α (P < 0.05) in the lung tissue decreased in the Myrtenol group compared to the asthma group. Myrtenol increased the level of IL-10 (P < 0.05) and the activity of GPX in the lung tissue and serum (P < 0.001). Myrtenol may improve asthma by increasing the ratio of antioxidants to oxidants and reducing the ratio of pro-inflammatory to anti-inflammatory interleukins in the lung. Myrtenol is presented as a potent herbal medicine ingredient for the treatment of asthma.

The effect of different digoxin concentrations on heart tissue and antioxidant status in iron-overloaded rats.

BACKGROUND: Thalassaemia is a hereditary disorder and has an economic burden on patients and the government. The most prevalent complication in these patients is iron overload which is followed by cardiomyopathy. Digoxin is considered as a treatment against heart failure in thalassaemia. The present study evaluated the effect of two digoxin concentrations on iron content and antioxidative defense in cardiac tissue of iron-overloaded rats. METHODS: The study was conducted on 48 rats which were divided into 6 groups. Group 1 was the control group and did not receive any treatment and group 2 was the iron overload group. In addition groups 3 and 4 were the digoxin control groups which received 1 and 5 mg/kg/day of digoxin, respectively. Groups 5 and 6 received 1 and 5 mg/kg/day of digoxin plus iron-dextran, respectively. After 1 month, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), and total antioxidant status (TAS) were assessed in cardiac tissues. RESULTS: Co-administration of iron-dextran and digoxin (1 and 5 mg/kg/day) significantly increased SOD and TAS levels (P < 0.0010) and reduced MDA (P < 0.0010) in heart tissue compared to control and iron overload groups. GPX levels significantly reduced in groups 5 and 6 (iron + digoxin 1 (P < 0.0500) and iron + digoxin 5) (P < 0.0010) compared to the iron control group. CONCLUSION: Digoxin remarkably facilitates iron uptake by cardiomyocytes by affecting other channels such as L-type and T-type Ca2+ channels (LTCC and TTCC). Digoxin administration in the iron-overloaded rat model deteriorated antioxidative parameters and increased iron entry into heart tissue at higher doses. Therefore, in patients with beta thalassaemia major, digoxin must be administered with great care and serum iron and ferritin must be regularly monitored.

Cytotoxicity of carboplatin on human glioblastoma cells is reduced by the concomitant exposure to an extremely low-frequency electromagnetic field (50 Hz, 70 G).

Glioblastoma multiforme (GBM) is a malignant brain cancer that causes high mortality in patients. GBM responds weakly to the common cancer treatments such as chemotherapy and radiotherapy and even surgery. Carboplatin is an alkylating agent widely used to treat cancer. However, resistance to this drug is a common problem in its use in cancer treatment. Concomitant exposure to extremely low-frequency electromagnetic fields (ELF-EMFs) and carboplatin is one unexplored possibility for overcoming this resistance. Indeed, many lines of evidence show that EMF affects cancer cells and drug action. In this study, we evaluated the effect of concomitant administration of carboplatin and EMF (50 Hz, 70 G) and also concomitant administration of carboplatin and static magnetic field (SMF) (70 G) on human glioma cell line (U-87). The results showed that cotreatment reduced the efficiency of carboplatin in U-87 cells, by decreasing caspase-3 in comparison to drug groups. Overall, EMF reduced the apoptotic effect of carboplatin, possibly through a redox regulation mechanism. Therefore, we have to avoid coadministration of magnetic field (MF) and carboplatin in tumor area, because the MF decreased the toxicity of the drug. However, further studies are needed to reveal the action mechanism of this combination therapeutic method.