Effect of Carvacrol on histological analysis and expression of genes involved in an animal model of multiple sclerosis.

BACKGROUND: The most common non-traumatic neurological disease in young- and middle-aged adults is multiple sclerosis (MS), leading to central nervous system (CNS) atrophy and neurological disorders with loss of myelin and axonal degeneration. Due to the inadequate efficiency of common treatments, some natural products with antioxidant properties such as Carvacrol have been considered. OBJECTIVE: the present study aimed to investigate carvacrol's anti-inflammatory and therapeutic effects on MS symptoms in healthy and experimental autoimmune encephalomyelitis (EAE) induced female Lewis rats. METHODS: The study was performed in three groups of Lewis rats: control group, EAE model, and EAE treated with carvacrol (carvacrol-treated group). The treatment group received 25 mg/kg of carvacrol intraperitoneally daily. Histologic examination and expression analysis of pro-inflammatory genes (Interleukin-1 and 17 (IL-1 and IL-17), Nuclear Factor Kappa B Cells (NF-κB) and Tumor Necrosis Factor-α (TNF-α)), myelin repair, and also regeneration genes (Myelin basic protein (MBP), Oligodendrocyte Transcription Factor 2 (OLIG2) and Platelet-Derived Growth Factor Receptor α (PDGFR-α)) were carried out. Gene studies, Hematoxylin and Eosin (H&E), and Luxol fast blue stain were performed in the lumbar region of the spinal cord. RESULTS: The EAE clinical scores in the carvacrol-treated group were lower than in untreated rats (P < 0.001). The expression of two genes, IL-17 and MBP, was confirmed using fluorescence immunohistochemistry (FIHC). A significant decrease was observed in NF-κB and IL-17, and IL-1 gene expression. The MBP and OLIG2 gene expression was increased in the carvacrol-treated group (p < 0.001). In EAE, PDGFR-α expression increased about four times. However, carvacrol administration did not affect PDGFR-α and TNF-α gene expression. In this treatment, H&E staining of spinal cord regions showed a significant decrease in inflammatory cell infiltration. Moreover, immunostaining analysis demonstrated a considerable increase in MBP and a reduction in IL-17 secretion. CONCLUSION: The results showed that carvacrol administration reduces the entry of inflammatory cells into the CNS by stimulating myelination-related processes employing increasing the expression of genes involved in myelin repair and reducing the expression of inflammatory genes. Our findings confirm that carvacrol improves the clinical and pathological symptoms of EAE through its therapeutic and modification properties as a potential adjunctive therapy and needs to be studied more.

Comparison of Vitamin D, Neurofeedback, and Neurofeedback Combined with Vitamin D Supplementation in Children with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Nowadays, some treatments such as neurofeedback and Vitamin D Supplementation are of great importance in the treatment of attention-deficit/hyperactivity disorder (ADHD). To determine the efficacy of the combined treatment, the present trial was conducted to investigate the effectiveness of each one of them with combined neurofeedback and vitamin D supplementation in the reduction of ADHD symptom in children suffering from this disorder. METHODS: In this study from March 2020 to June 2020, we enrolled a total of 120 patients (6-15 years old) who were referred to the Mehr psychiatric hospital (affiliated to Lorestan University of Medical Sciences). Patients were then randomly categorized into three experimental groups and one control group. The first, the second, and the third experimental groups consumed vitamin D pearl, neurofeedback combined with vitamin D, and neurofeedback for 12 weeks, respectively. The control group was given no treatment. Vitamin D serum level was evaluated at baseline, 4, 8, and 12 weeks in all participants. For data collection, the Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) was applied. The obtained information was analyzed using repeated measure variance analysis. RESULTS: The mean scores were significantly different across the groups. Repeated measure variance analysis showed that the mean score was lower in the combined group in comparison with the other three groups (P<0.05). CONCLUSION: Combined treatment could be considered as more effective compared to separate treatments. In addition, in this study, by applying the combined intervention, the duration of treatment decreased significantly.

Biosynthesis of titanium dioxide nanoparticles using Hypericum perforatum and Origanum vulgare extracts and their main components, hypericin and carvacrol as promising antibacterial agents.

OBJECTIVE: To evaluate the anti-bacterial activities of titanium dioxide (TiO) nanoparticles of Origanum (O.) vulgare and Hypericum (H.) perforatum extracts, carvacrol and hypericin against Staphylococcus (S.) aureus. METHODS: In this study, TiOnanoparticles of O. vulgare and H. perforatum extracts, carvacrol and hypericin, were prepared and their antibacterial effects were evaluated against Staphylococcus (S.) aureus. In this study, scanning electron microscope, fourier transform infrared spectrometer, atomic force microscopy, dynamic light scattering and zeta potential were used to investigate the structure of synthesized drugs. RESULTS: Anti-bacterial activity of synthesized NPs was tested by minimum inhibitory concentration (MIC), minimum bactericidal concentration and disc diffusion method. MICs of TiO-NPs synthesized using O. vulgare, H. perforatum, carvacrol and hypericin and TiO were obtained 250, 62.5, 250, and 250, and 500 µg/mL, respectively. The MBCs for all of these were obtained 1000 µg/mL. CONCLUSION: Green-synthesized of TiO nanoparticles provides a promising approach to the use of O. vulgare and H. perforatum, carvacrol and hypericin as novel agents and safer antibacterial compounds, especially anti-S. aureus compounds.

Applying Vasopressin-Pre-Conditioned Human Adipose Mesenchymal Stem Cells Improves Heart Condition after Transplantation into Infarcted Myocardium.

Transplantation of H-AdMSCs may improve heart function after MI. AVP is a neurohypophyseal hormone that reduces cardiovascular damage. This study investigated the role of AVP preconditioning in the survival of MSCs and their effect on myocardial repair in the MI rats. H-AMSCs were isolated and incubated for 3 days. The expression of oxytocin and vasopressin receptors was evaluated by Real-time-PCR. Forty male Wistar rats were divided into 4 groups: control, sham, ASC and AVP-ASC. Ischemia was established by ligation of LAD coronary artery. Electrocardiography, fibrosis, angiogenesis, and apoptosis in myocardium were determined after 7 days. Results showed that preconditioned MSCs significantly increased cardiac function when compared with group that received non-preconditioned MSCs. This was associated with significantly reduced fibrosis, increased vascular density, and decreased resident myocyte apoptosis. Results indicate that AVP preconditioned MSCs can be consider a novel approach to management of MI.

The role of vasopressin V1A and oxytocin OTR receptors in protective effects of arginine vasopressin against H2O2-induced oxidative stress in H9C2 cells.

BACKGROUND: Oxidative stress, has been shown to play an important role in the pathophysiology of cardiac remodelling and heart failure. The aim of study is effect of arginine vasopressin (AVP) on apoptosis of cardiomyocyte via its receptors. MATERIALS AND METHODS: The cell viability effect of AVP in H9C2 cardiomyocytes was assayed using the MTT method. The transcription and translation level of apoptosis genes (Bax, Bcl-2, caspase-3) were discovered with qRT-PCR and western blotting. RESULTS: The results showed that vasopressin could reduce apoptosis in cardiomyocytes cell line through downregulation of caspase-3, BAX and upregulation of Bcl-2 (p < .001). Also, there was a decrease in anti-apoptosis effect of vasopressin when V1A and OTR receptors were blocked with their antagonists. DISCUSSION: These results suggest that activation of V1A and OTR receptors in H9C2 cells mediate protective effect of vasopressin via regulating apoptosis marker that lead to cell survival under conditions of stress oxidative.Key pointAVP may contribute to the improvement of heart ischaemia through its actions on V1A and OTR receptors.

Effect of fluoxetine treatment on neurotoxicity induced by lysolecithin in male rats.

Demyelination disorder is an unusual pathologic event, which occurs in the central nervous system (CNS). Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects the CNS, and it is the leading cause of disability in young adults. Lysolecithin (LPC) is one of the best toxin-induced demyelination models. In this study, a suitable model is created, and the effect of fluoxetine treatment is examined on this model. In this case, it was assumed that daily fluoxetine treatment had increased the endogenous remyelination in the LPC model. This study was focused on investigating the influence of the fluoxetine dose of 5 or 10 mg/kg per day for 1 and 4 weeks on LPC-induced neurotoxicity in the corpus callosum region. It was performed as a demyelinating model in male Wistar rats. After 3 days, fluoxetine was injected intraperitoneally (5 or 10 mg/kg per day) for 1 and 4 weeks in each group. After completing the treatment course, the corpus callosum was removed to examine the gene expression and histological analysis was performed. The results of the histopathological study of hematoxylin and eosin staining of the corpus callosum showed that in 1 and 4-week treatment groups, fluoxetine has reduced the level of inflammation at the LPC injection site (5 and 10 mg/kg per day). Fluoxetine treatment in the luxol fast blue (LFB) staining of the corpus callosum has been led to an increase in myelination capacity in all doses and times. The results of the genetic study showed that the fluoxetine has significantly reduced the expression level of tumor necrosis factor-α, nuclear factor κß, and induced nitric oxide synthase in comparison with the untreated LPC group. Also, the fluoxetine treatment has enhanced the expression level of the forkhead box P3 (FOXP3) gene in comparison with the untreated group. Fluoxetine has increased the expression level of myelination and neurotrophic genes such as myelin basic protein (MBP), oligodendrocyte transcription factor 2 (OLIG2), and brain-derived neurotrophic factor (BDNF). The outcomes demonstrated that fluoxetine reduces inflammation and strengthens the endogenous myelination in the LPC-induced demyelination model; however, supplementary studies are required for specifying the details of its mechanisms.

Effect of Nectaroscordum koelzi Methanolic Extract on Acute and Chronic Inflammation in Male Mice.

INTRODUCTION: The present study deals with the effect of Nectaroscordum koelzi fruit extract on acute and chronic inflammation. METHODS: A total of 84 NMRI mice were used in this study. The effect of the extract on acute inflammation was analyzed by increasing vascular permeability via acetic acid and xylene induced ear edema among mice. The extract was evaluated in terms of effects on chronic inflammation by means of the cotton pellet test among mice. For the assessment of inflammation degree, the mice paw edema volume was measured by the plethysmometric test. RESULTS: The findings showed that the extract was effective on acute inflammation induced by acetic acid in mice. In the xylene ear edema, N. koelzi extract indicated a significant activity in mice. In the cotton pellet method, the methanol extract produced a significant reduction in comparison with the control and dexamethasone. Mice paw edema volume decreased with the extract. CONCLUSION: In general, the data from the experiments indicated that the methanol extract of N. koelzi has an anti-inflammatory effect on acute and chronic inflammation. However, the exact contributing mechanisms have not been investigated for the pharmacological effects.

Prevalence of self-medication in university students: systematic review and meta-analysis.

BACKGROUND: Self-medication can lead to serious consequences but its overall prevalence in students is not known. AIMS: The aim of this study was to determine the prevalence of self-medication in students through a systematic review and meta-analysis of studies on the prevalence of self-medication in students across the world. METHODS: PubMed/MEDLINE, EMBASE, ISI/Web of Science and Google Scholar were searched up to October 2017. Studies reporting the prevalence of self-treatment in university students were selected. Data recorded included year of publication, country where the study was conducted, sample size, prevalence of self-medication, sex and mean age of students, and faculty of students (medical or non-medical). A random-effect model was used to determine effect size with a 95% confidence interval (CI). Heterogeneity across studies was assessed with the I2 test. A sensitivity analysis assessed stability of the findings. RESULTS: A total of 89 studies were included in the analysis, which comprised 60 938 students. The overall prevalence of self-medication in university students was 70.1% (95% CI: 64.3-75.4%). Female students self-medicated more often than male students: odds ratio = 1.45 (95% CI%: 1.17-1.79). The prevalence of self-medication in medical students (97.2%) was higher than in non-medical students (44.7%). The I2 test indicated high, statistically significant heterogeneity. The sensitivity analysis showed that the results were stable. CONCLUSION: The prevalence of self-medication among students worldwide is high. Programmes on the risks of self-medication and increasing control and monitoring of the sale of drugs are recommended. Facilitating students' access to doctors and health centres could reduce self-medication in students.

Protective effects of honey, Apis mellifera meda skorikov, on ischemia-reperfusion induced muscle injury / Efectos protectores de la miel, Apis mellifera meda skorikov, sobre la lesión muscular inducida por isquemia-reperfusión

Honey is a natural antioxidant that its protective effects have been proven against ischemia-reperfusion (IR) injury. The aim of this study was to evaluate the ameliorative effect of Persian Honey, Apis mellifera meda skorikov, on gastrocnemius muscle IR injury. Eighty adult male Sprague-Dawley rats weighing 250-300 g were used. They were divided into ten groups (N=8 per group). The ischemia was conducted with a silk suture 6-0 using the slipknot technique. All groups were rendered in ischemic for 3 h, and reperfused for various times of 3 days (3-day reperfusion), 7 days (7-day reperfusion), 14 days (14-day reperfusion), and 28 days (28-day reperfusion). Half of the groups had experimental honey (5 %) treatment immediately after ischemia. After reperfusion, the rats, based on the grouping, were killed with high doses of anesthetic, and the gastrocnemius muscles were removed and fixed. After the tissue processing, the evaluation of edema and mast cells infiltration was performed with hematoxylin-eosin and toluidine blue staining, respectively. TNF-α was detected with immunohistochemistry method. The amount of TNF-α as an index of acute inflammatory except the 3rd day significantly decreased on the other day of reperfusion (7th, 147th and 287th days). The mast cells infiltration was significantly decreased on 77th and 147th days. The tissue edema was decreased significantly in honey administrated group in the comparison with placebo groups. Honey administration can reduce damage caused by ischemia-reperfusion in the rat gastrocnemius muscle.

La miel es un antioxidante natural; sus efectos protectores han sido probados contra la lesión por isquemiareperfusión (IR). El objetivo de este estudio fue evaluar el efecto de mejora de la miel persa Apis mellifera meda skorikov, en la lesión por IR del músculo gastrocnemio. Se utilizaron 80 ratas Sprague-Dawley macho adultas con un peso entre 250 y 300 g divididas en diez grupos (N = 8 por grupo). La isquemia se realizó con una sutura de seda 6-0 utilizando la técnica slipknot permaneciendo isquémicos durante 3 h. La reperfusión se realizó durante varios tiempos de 3 días, 7 días (reperfusión de 7 días), 14 días (reperfusión de 14 días) y 28 días (28 días reperfusión). La mitad de los grupos recibió tratamiento experimental con miel (5 %) inmediatamente después de la isquemia. Después de la reperfusión, las ratas, fueron sacrificadas con altas dosis de anestésico, y los músculos gastrocnemios fueron removidos y fijados. Después de procesar el tejido, se realizó la evaluación del edema y la infiltración de mastocitos se realizó con tinción de hematoxilina-eosina y azul de toluidina, respectivamente. TNF-α se detectó con el método de inmunohistoquímica. La cantidad de TNF-α como índice de inflamación inflamatoria aguda, excepto en el tercer día, disminuyó significativamente al día siguiente de la reperfusión (7, 14 y 28 días). La infiltración de mastocitos disminuyó significativamente a los 7 y 14 días. El edema tisular disminuyó significativamente en el grupo administrado con miel en comparación con los grupos placebo. El tratamiento con miel puede reducir el daño causado por la isquemia-reperfusión en el músculo gastrocnemio de la rata.

Antinociceptive effects of green synthesized copper nanoparticles alone or in combination with morphine.

OBJECTIVE: The aim of this study was to evaluate the antinociceptive effect of biosynthetic copper nanoparticles from aqueous extract of Capparis spinosa fruit. METHODS: In this study, green synthesis of copper nanoparticles (CuNPs) was performed using C. spinosa extract according to the method described previously. The synthesized CuNPs were characterized using the UV-vis spectroscopy, Fourier transforms of infrared (FTIR), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX). The antinociceptive effect of CuNPs was evaluated by tail-flick, hot-plate, and rotarod tests following the oral administration of mice with CuNPs at the concentrations of 25, 50, and 75 mg/kg for two weeks. RESULTS: The obtained maximum peak at the wavelength of 414 nm demonstrated the biosynthesis of the copper nanoparticles. SEM approved the particle size of CuNPs between 17 and 41 nm. The statistical analyses of the data of hot plate and tail-flick tests showed the potent analgesic effect of biosynthetic CuNPs. In this regard, the antinociceptive effect of at the doses of 75 mg/kg and 25 mg/kg plus morphine was significantly higher in comparison with the control group receiving morphine alone (P < 0.05). No significant (p > 0.05) difference was observed after the administration of CuNPs at the doses of 25, 50, and 75 mg/kg in the sensory-motor test. CONCLUSION: The present investigation demonstrated the analgesic effects of CuNPs especially in combination with morphine. These findings can provide a new strategy for producing new antinociceptive medications in the future.

Sleep Disturbances Rate among Medical and Allied Health Professions Students in Iran: Implications from a Systematic Review and Meta-Analysis of the Literature.

Medicine and healthcare professions are prestigious and valued careers and, at the same time, demanding, challenging, and arduous jobs. Medical and allied health professions students, experiencing a stressful academic and clinical workload, may suffer from sleep disturbances. In Iran, several studies have been conducted to explore the prevalence rate among medical and healthcare professions students. The aim of this systematic review and meta-analysis was to quantitatively and rigorously summarize the existing scholarly literature, providing the decision- and policy-makers and educators with an updated, evidence-based synthesis. Only studies utilizing a reliable psychometric instrument, such as the Pittsburgh sleep quality index (PSQI), were included, in order to have comparable measurements and estimates. Seventeen investigations were retained in the present systematic review and meta-analysis, totaling a sample of 3586 students. Studies were conducted between 2008 and 2018 and reported an overall rate of sleep disturbances of 58% (95% confidence interval or CI 45-70). No evidence of publication bias could be found, but formal analyses on determinants of sleep disturbances could not be run due to the dearth of information that could be extracted from studies. Poor sleep is highly prevalent among Iranian medical and healthcare professions students. Based on the limitations of the present study, high-quality investigations are urgently needed to better capture the determinants of poor sleep quality among medical and healthcare professions students, given the importance and the implications of such a topic.

Sustained release of silibinin-loaded chitosan nanoparticle induced apoptosis in glioma cells.

In this study, a chitosan nanoparticle formulation was synthesized for loading silibinin as a sustained-release drug system to evaluate its effects on apoptosis in C6 glioma cells. This synthesized nanoparticle was analyzed by measurement methods including Fourier transform infrared (FTIR), field emission-scanning electron microscopy (FE-SEM), dynamic light scattering (DLS), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The formation and amorphization of nanoparticle were confirmed by FTIR and XRD analysis, respectively. The mean diameter of silibinin-loaded chitosan nanoparticles (SCNP) was 50 ± 7 and 188.6 ± 0.17 nm by using FE-SEM and DLS, respectively. In addition, the positive zeta potential of nanoparticles was +11.5. Rhodamine-conjugated SCNP analysis showed the internalization of silibinin to C6 glioma cells. The cytotoxicity assay indicated that the nanoformulation of silibinin was toxic to C6 glioma cells. Although SCNP significantly increased the expression of the both apoptotic genes in C6 cells, Bax and caspase3, it did not have any significant effect on the level of the antiapoptotic gene, Bcl2. In contrast, SCNP did not have any toxic effect on H9C2 cells. In conclusion, the results of the current study indicated that SCNP can be considered as a sustained-release drug system for future cell-based therapeutic strategies.

Cancer stem cells and nanotechnological approaches for eradication.

Cancer stem cells (CSCs) are currently known as the main cause of tumor recurrence. After chemotherapy is completed, CSCs proliferate and then differentiate to generate new tumor tissues. Similar to normal stem cells, this non-uniformly distributed cell population in the tumor tissue has self-renewal capacity and is responsible for survival of the tumor and difference in its genetic and metabolic characteristics. Followed by gene instability in CSCs, new phenotypic markers are aberrantly expressed in CSCs subpopulation. Hence, some of the surface markers and metabolic pathways that are upregulated in CSCs may be applied as specific targets for development of diagnostic and therapeutic approaches. In this review article, the distinctive properties of CSCs including signal pathways implicated in self-renewal and surface markers were discussed. Moreover, targeting CSCs based on their specific properties using nanodrugs was reviewed.

The efficacy of Crocus sativus (Saffron) versus placebo and Fluoxetine in treating depression: a systematic review and meta-analysis.

Background: Depression represents a serious public health concern, imposing a high burden, both in epidemiological and clinical terms. Crocus sativus (Saffron) is a herbal remedy that has anti-cancer, anti-oxidant, anti-inflammatory and anti-platelet properties. However, the exact mechanisms of Saffron in treating depression are not yet clear. This study was conducted to evaluate the effectiveness of Saffron versus placebo and Fluoxetine in the treatment of depressed patients. Methods: Different bibliographic thesauri, namely the Cochrane Library, Scopus, PubMed/MEDLINE, Centre for Reviews and Dissemination (CRD), EMBASE, and ISI/Web of Science (WoS) were searched up to May 2018. Effect sizes were computed as Standardized Mean Differences (SMD) with their 95% confidence interval (CI). To evaluate the heterogeneity among the studies, I2 test was carried out. Results: Eight studies were included. The SMD was -0.86 (95% CI: -1.73 to 0.00) concerning the comparison of Saffron with placebo. The SMD was found to be 0.11 (95% CI: -0.20 to 0.43) concerning the comparison of Saffron with Fluoxetine. In both sensitivity analyses, the results did not statistically change, confirming the stability of the findings. Conclusion: The findings of this study showed that Saffron administration was well comparable with Fluoxetine and placebo.

The synergistic effect of hydroalcoholic extracts of Origanum vulgare, Hypericum perforatum and their active components carvacrol and hypericin against Staphylococcus aureus.

AIM: This study was designed to evaluate the synergistic activities of hydroalcoholic extracts of medicinal plants Origanum vulgare and Hypericum perforatum and their active components, carvacrol and hypericin against Staphylococcus aureus. METHODS: The synergistic effects of the plants, as well as carvacrol and hypericin, were examined using a checkered method against S. aureus (ATCC 12600). RESULTS: A fractional inhibitory concentration of 0.5 was obtained for combination of O. vulgare and H. perforatum and 0.49 for combination of the active ingredients carvacrol and hypericin, both of which indicated a synergistic effect. CONCLUSION: This preliminary evaluation demonstrated a synergistic property of O. vulgare and H. perforatum extracts in treating S. aureus infection. This study indicates that combination of the plants, as well as combination of carvacrol and hypericin, might be used as a new antibacterial strategy against S. aureus.

Phytochemical Profiles and Antibacterial Activities of Hydroalcoholic Extracts of Origanum vulgare and Hypericum perforatum and Carvacrol and Hypericin as a Promising Anti-Staphylococcus aureus.

OBJECTIVES: Staphylococcus aureus, a Gram-positive bacteria, is ranked second among the causes of hospital infections and is one of the three main causes of food poisoning. In recent times, the spread of antibiotic resistance in S. aureus has become very worrisome. Therefore, research for new effective drugs is important. The present study aims to investigate the phytochemical profiles and antibacterial effects of hydroalcoholic extracts of Origanum vulgare (Lamiaceae family) and Hypericum perforatum (Clusiaceae family) and their active compounds on S. aureus (ATCC 12600) in vitro. METHODS: The identification of phytochemical compounds in both plants was performed by Highperformance liquid chromatography (HPLC), headspace-solid-phase microextraction (HS-SPME) and Fourier-transform infrared spectroscopy (FTIR). To investigate microbial susceptibility, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and disc diffusion method (DAD) were used. Finally, the results of the study were compared with methicillin. RESULTS: Of the 42 combinations of O. vulgare, carvacrol (48%) and of the 38 combinations of H. perforatum, hypericin (46.2%) were the most abundant. The MIC, MBC and DAD of O. vulgare and H. perforatum, carvacrol, hypericin and methicillin were 625, 625, 312.5, 78.12 and 384 µg/mL, 10000, 10000, 2500, 2500 and 384 µg/mL, and 15.66 ± 4.49, 12.66 ± 0.47 and 22 ± 0.81 mm, respectively. CONCLUSION: Due to the significant effects of O. vulgare and H. perforatum and their active components against S. aureus, it is expected that in the future, hypericin, carvacrol and their derivatives can be used as effective antibacterial agents against S. aureus.

Brain Derived Neurotrophic Factor Modification of Epileptiform Burst Discharges in a Temporal Lobe Epilepsy Model.

INTRODUCTION: Transforming Growth Factor-Beta 1 (TGF-ß1) is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS), by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-ß1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-ß1 and susceptibility to IS. METHODS: Male Wistar rats were divided into sham (receiving phosphate buffered saline within dorsal hippocampus), pilocarpine (epileptic model of TLE), single injection BDNF (epileptic rats which received single high dose of BDBF within dorsal hippocampus), and multiple injections BDNF (epileptic rats which received BDNF in days 10, 11, 12, and 13 after induction of TLE) groups. Their electrocorticogram was recorded and amplitude, frequency, and duration of spikes were evaluated. RESULTS: Amplitude and frequency of epileptiform burst discharges were significantly decreased in animals treated with BDNF compared to pilocarpine group. CONCLUSION: Our findings suggested that BDNF may modulate the epileptic activity in the animal model of TLE. In addition, it may have therapeutic effect for epilepsy. More studies are necessary to clarify the exact mechanisms of BDNF effects.

Curcumin as a double-edged sword for stem cells: dose, time and cell type-specific responses to curcumin.

BACKGROUND: The beneficial effects of curcumin which includes its antioxidant, anti-inflammatory and cancer chemo-preventive properties have been identified. Little information is available regarding the optimal dose and treatment periods of curcumin on the proliferation rate of different sources of stem cells. METHODS: In this study, the effect of various concentrations of curcumin on the survival and proliferation of two types of outstanding stem cells which includes bone marrow stem cells (BMSCs) and adult rat neural stem/progenitor cells (NS/PCs) at different time points was investigated. BMSCs were isolated from bilateral femora and tibias of adult Wistar rats. NS/PCs were obtained from subventricular zone of adult Wistar rat brain. The curcumin (0.1, 0.5, 1, 5 and 10 µM/L) was added into a culture medium for 48 or 72 h. Fluorescent density of 5-bromo-2'-deoxyuridine (Brdu)-positive cells was considered as proliferation index. In addition, cell viability was assessed by MTT assay. RESULTS: Treatment of BMSCs with curcumin after 48 h, increased cell survival and proliferation in a dose-dependent manner. However, it had no effect on NSCs proliferation except a toxic effect in the concentration of 10 µM of curcumin. After a 72 h treatment period, BMSCs and NS/PCs survived and proliferated with low doses of curcumin. However, high doses of curcumin administered for 72 h showed toxic effects on both stem cells. CONCLUSIONS: These findings suggest that curcumin survival and proliferative effects depend on its concentration, treatment period and the type of stem cells. Appropriate application of these results may be helpful in the outcome of combination therapy of stem cells and curcumin.

Regulation of connexin 43 and microRNA expression via ß2-adrenoceptor signaling in 1321N1 astrocytoma cells.

Connexin 43 (Cx43) is the main gap junction protein in astrocytes and exerts the same effects on growth inhibition in astrocytoma and glioma as microRNA-146a (miR-146a) in glioma. ß2-adrenergic receptor (AR) signaling modulates Cx43 expression in myocytes via components downstream of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). However, it remains to be elucidated how expression of Cx43 is modulated in astrocytes. In the present study, 1321N1 astrocytoma cells were treated with ß2-AR signaling agents in order to evaluate the expression of Cx43 and miRNAs. RNA and protein were extracted from the cells for use in reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The results revealed that clenbuterol increased miR-146a level and upregulated Cx43 expression via cAMP/PKA at the mRNA and protein level. Pre-inhibition of adenyl cyclase decreased expression of Cx43 and miR-146a. PKA activation and overexpression of miR-146a in A-1321N1 cells increased the expression of Cx43. ß2-AR stimulation and 6Bnz, a PKA activator, suppressed oncomiRs miR-155 and miR-27a, while 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, an Epac activator, increased their levels. The current findings demonstrated that ß2-AR signaling has growth inhibitory effects via modulation of the cAMP/PKA pathway in A-1321N1 cells through increasing the expression level of Cx43 and miR-146a as well as decreasing miR-155 and miR-27a levels. Thus, stimulation of the ß2-AR and PKA signaling pathway may be a useful approach for astrocytoma therapy.

cAMP-Epac Pathway Stimulation Modulate Connexin-43 and MicroRNA-21 Expression in Glioma Cells.

INTRODUCTION: Malignant astrocytic gliomas are the most common and lethal brain malignancies due to their refractory to the current therapies. Nowadays, molecular targeted therapy has attracted great attention in treatment of glioma. Connexin 43 (Cx43) and micro ribonucleic acid-21(miR-21) are among molecules that are involved in glioma development and progression. These molecules showed potential to be as target molecules with regard to glioma. Some studies have reported that cyclic adenosine monophosphate (cAMP) signaling could be effective on Cx43 and miR-21 in tissues other than in brain. We investigate possible relationship between ß-adrenergic receptor and its newly described downstream, exchange protein directly activated by cAMP (Epac) signaling pathway and expression of Cx43 and miR-21 in low (1321N1) and high grade (U87MG) glioma cell lines. METHODS: We treated cells with ß-adrenergic agonist and Epac activator with and without adenyl cyclase inhibitor. Cx43 and miR-21 expression were measured with real-time PCR. RESULTS: Our data showed that in 1321N1 cells, ß-adrenergic-Epac pathway stimulation up and down-regulated Cx43 and miR-21 expression respectively. Whereas, in U87MG cells these interventions had no effect on Cx43 and miR-21 expression. DISCUSSION: These findings demonstrate that low grade astrocytoma cells have better response to our pharmacological interventions.