Molecular mechanisms of microRNAs in glioblastoma pathogenesis.

Glioblastoma (GBM) is human's most prevalent and severe brain cancer. Epigenetic regulators, micro(mi)RNAs, significantly impact cellular health and disease because of their wide range of targets and functions. The "epigenetic symphony" in which miRNAs perform is responsible for orchestrating the transcription of genetic information. The discovery of regulatory miRNA activities in GBM biology has shown that various miRNAs play a vital role in disease onset and development. Here, we summarize our current understanding of the current state-of-the-art and latest findings regarding the interactions between miRNAs and molecular mechanisms commonly associated with GBM pathogenesis. Moreover, by literature review and reconstruction of the GBM gene regulatory network, we uncovered the connection between miRNAs and critical signaling pathways such as cell proliferation, invasion, and cell death, which provides promising hints for identifying potential therapeutic targets for the treatment of GBM. In addition, the role of miRNAs in GBM patient survival was investigated. The present review, which contains new analyses of the previous literature, may lead to new avenues to explore in the future for the development of multitargeted miRNA-based therapies for GBM.

The Role of Inhaled Estradiol and Myrtenol, Alone and in Combination, in Modulating Behavioral and Functional Outcomes Following Traumatic Experimental Brain Injury: Hemodynamic, Molecular, Histological and Behavioral Study.

BACKGROUND: Traumatic brain injury (TBI) is an important and growing cause of disability worldwide, and its cognitive consequences may be particularly significant. This study assessed the neuroprotective impacts of estradiol (E2), myrtenol (Myr), and the combination of the two on the neurological outcome, hemodynamic parameters, learning and memory, brain-derived neurotrophic factor (BDNF) level, phosphoinositide 3-kinases (PI3K/AKT) signaling, and inflammatory and oxidative factors in the hippocampus after TBI. METHODS: Eighty-four adult male Wistar rats were randomly divided into 12 groups with seven rats in each (six groups to measure intracranial pressure, cerebral perfusion pressure, brain water content, and veterinary coma scale, and six groups for behavioral and molecular studies): sham, TBI, TBI/vehicle, TBI/Myr, TBI/E2, and TBI/Myr + E2 (Myr 50 mg/kg and E2 33.3 µg/kg via inhalation for 30 min after TBI induction). Brain injury was induced by using Marmarou's method. Briefly, a 300-g weight was dropped down from a 2-m height through a free-falling tube onto the head of the anesthetized animals. RESULTS: Veterinary coma scale, learning and memory, brain water content, intracranial pressure, and cerebral perfusion pressure were impaired following TBI, and inflammation and oxidative stress were raised in the hippocampus after TBI. The BDNF level and PI3K/AKT signaling were impaired due to TBI. Inhalation of Myr and E2 had protective effects against all negative consequences of TBI by decreasing brain edema and the hippocampal content of inflammatory and oxidant factors and also by improving BDNF and PI3K/AKT in the hippocampus. Based on these data, there were no differences between alone and combination administrations. CONCLUSIONS: Our results propose that Myr and E2 have neuroprotective effects on cognition impairments due to TBI.

Myrtenol Ameliorates Recognition Memories' Impairment and Anxiety-Like Behaviors Induced by Asthma by Mitigating Hippocampal Inflammation and Oxidative Stress in Rats.

INTRODUCTION: Asthma is related to neurochemical alterations which affect brain functions and lead to anxiety and cognitive dysfunctions. Myrtenol has sparked considerable interest due to its pharmacological effects, especially for the remediation of chronic disorders. Thus, the present research was designed to evaluate the impacts of myrtenol on anxiety-like behaviors, cognitive declines, inflammation, and oxidative stress in the hippocampus of asthmatic rats. METHODS: Rats were allocated to five groups: control, asthma, asthma/vehicle, asthma/myrtenol, and asthma/budesonide. Asthma was elicited in the rats by ovalbumin, and the animals were then exposed to myrtenol inhalation. Anxiety-like behavior and memory were assessed by elevated plus maze (EPM) and novel object and location recognition tests. Interleukins (interleukin-6, -17, and -10), tumor necrosis factor α (TNF-α), and oxidative stress biomarkers such as malondialdehyde (MDA), superoxide dismutase (SOD), Glutathione peroxidase (GPX), and total antioxidant capacity (TAC) in the hippocampus were assessed by the ELISA method. RESULTS: The levels of IL-6, IL-17, TNF-α, and MDA decreased, but GPX, SOD, and TAC levels increased in the hippocampus of asthmatic animals due to myrtenol inhalation. CONCLUSION: Myrtenol diminished asthma-induced anxiety-like behaviors and cognitive deficits in asthmatic rats; these effects might have been typically mediated by a reduction in inflammation and oxidative stress.

Neuroprotective effects of lovastatin against traumatic spinal cord injury in rats.

BACKGROUND: Lovastatin, as a drug of statins subgroup, has been conceptualized to have anti-inflammatory, antioxidant, and anti-apoptotic properties. Accordingly, the present study aimed to investigate the neuroprotective ramification of lovastatin on spinal cord injury (SCI). MATERIAL AND METHODS: Seventy-five female adult Wistar rats were divided into five groups (n = 15). In addition to non-treated (Control group) and laminectomy alone (Sham group), SCI animals were randomly assigned to non-treated spinal cord injury (SCI group), treated with 2 mg/kg of lovastatin (Lova 2 group), and treated with 5 mg/kg of lovastatin (Lova 5 group). At the end of the study, to evaluate the treatments, MDA, CAT, SOD, and GSH factors were evaluated biochemically, apoptosis and gliosis were assessed by immunohistochemical while measuring caspase-3 and GFAP antibodies, and inflammation was estimated by examining the expression of IL-10, TNF-α, and IL-1ß genes. The stereological method was used to appraise the total volume of the spinal cord at the site of injury, the volume of the central cavity created, and the density of neurons and glial cells in the traumatic area. In addition, Basso-Beattie-Bresnehan (BBB) and narrow beam test (NBT) were utilized to rate neurological functions. RESULTS: Our results exposed the fact that biochemical factors (except MDA), stereological parameters, and neurological functions were significantly ameliorated in both lovastatin-treated groups, especially in Lova 5 ones, compared to the SCI group. The expression of the IL-10 gene was significantly upregulated in both lovastatin-treated groups compared to the SCI group and was considerably heighten in Lova 5 group. Expression of TNF-α and IL-1ß, as well as the rate of apoptosis and GFAP positive cells significantly decreased in both lovastatin treated groups compared to the SCI group, and it was more pronounced in the Lova 5 ones. CONCLUSION: Overall, using lovastatin, especially at a dose of 5 mg/kg, has a dramatic neuroprotective impact on SCI treatment.

The effects of neurosteroid allopregnanolone on synaptic dysfunction in the hippocampus in experimental parkinsonism rats: An electrophysiological and molecular study.

The dopaminergic system is a powerful candidate targeted for changes of synaptic plasticity in the hippocampus. Higher incidence of Parkinson's disease (PD) in men than women indicates the influence of sex hormones on the PD development. Previous studies have shown that neurodegenerative diseases such as PD are related to the decline of Allopregnanolon (Allo), a metabolite of progesterone; it is also well known that learning and memory are influenced by oscillations in steroidal hormones. Although abnormalities in hippocampal plasticity have been observed in the toxic models of PD, effects of Allo on hippocampal LTP and hippocampal synaptic protein levels, which play an important role in maintaining the integrity of neural connections, have never been analyzed thus far. Experimental groups subjected to the long-term potentiation (LTP) were studied in the CA1 area of the hippocampus. In addition, the levels of hippocampal postsynaptic density protein 95 (PSD-95), neurexin-1 (Nrxn1) and neuroligin (Nlgn) as synaptic molecular components were determined by immunoblotting. Although dopamine denervation did not alter basal synaptic transmission and pair-pulse facilitation of field excitatory postsynaptic potentials (fEPSPs), the induction and maintenance of LTP were impaired in the CA1 region. In addition, the levels of PSD-95, Nrxn1 and Nlgn were significantly decreased in the hippocampus of 6-OHDA-treated animals. Such abnormalities in synaptic electrophysiological aspects and protein levels were abolished by the treatment with Allo. These findings showed that partial dopamine depletion led to unusual synaptic plasticity in the CA1 as well as the decrease in synaptic proteins in the hippocampus. Our results demonstrated that Allo ameliorated these deficits and preserved pre- and post-synaptic proteins. Therefore, Allo may be an effective factor in maintaining synaptic integrity in the mesolimbic pathway.

Protective effects of atorvastatin and rosuvastatin on 3,4-methylenedioxymethamphetamine (MDMA)-induced spatial learning and memory impairment.

3,4-Methylenedioxymethamphetamine (MDMA) or "Ecstasy", which has been used for recreational purposes, is shown to impair memory and brain functions. Statins, beyond their efficient cholesterol-lowering impact through inhibition of HMG-COA reductase enzyme, possess multiple actions referred to as pleiotropic effects. In this regard, we aimed to investigate the neuroprotective effects of atorvastatin and rosuvastatin on MDMA-induced neurotoxicity. Adult male Wistar rats received atorvastatin (5, 10, and 20 mg/kg; orally) and rosuvastatin (5, 10, 20 mg/kg; orally) for 21 consecutive days. Then, spatial memory and learning were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally injected with MDMA (2.5, 5, and 10 mg/kg) 30 min before the first training session in 4 training days of MWM task. Afterward, rats were euthanized and their hippocampuses were dissected to evaluate reactive oxygen species (ROS) production, lipid peroxidation (LPO), and caspase-3 and -9 activities. Our findings showed that MDMA (5 and 10 mg/kg) significantly impaired spatial memory functions and dramatically increased ROS production, LPO, and caspase-3 and -9 activities compared to control. Also, atorvastatin (5, 10, and 20 mg/kg) and rosuvastatin (20 mg/kg) significantly improved memory performances and inhibited the elevation of ROS, LPO, and caspase-3 and -9 activities induced by MDMA. In conclusion, the results indicated that MDMA-induced cognitive impairment is followed by oxidative stress and activation of apoptotic pathways in the hippocampus. However, atorvastatin and rosuvastatin suppressed these deleterious consequences of MDMA and revealed protective effects against activation of pathways leading to cell damage.

In Vitro Anti-cancer Activity of Adipose-Derived Mesenchymal Stem Cells Increased after Infection with Oncolytic Reovirus.

Purpose: Reovirus type 3 Dearing (ReoT3D), a wild type oncolytic virus (OV) from the Reoviridae family, kills KRAS mutant cancer cells. However, the use of OVs has faced with some limitations such as immune responses, and delivery of OVs to the tumor sites in systemic therapy. To solve this, and also to increase the anti-cancer effects of these OVs, mesenchymal stem cells (MSCs) might be used as an effective vehicle for OVs delivery. In this study, we examined the anti-cancer effects of human adipose derived-MSCs (AD-MSCs) as a vehicle of ReoT3D against human glioblastoma cells. Methods: Here, AD-MSCs were characterized and toxicity of ReoT3D on them was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Then, capability of AD-MSCs for virus production was assessed by real-time polymerase chain reaction (PCR), and different in vitro anti-cancer experiments were applied for our anti-cancer purposes. Results: Our results from toxicity assay revealed that the isolated and provoked AD-MSCs were resistant to nontoxic concentration multiplicity of infection (MOI) >1 pfu/cells of ReoT3D. In addition, the results indicated that AD-MSCs were susceptible for virus life cycle complementation and were capable for production of virus progenies. Furthermore, our results showed that AD-MSCs had oncolysis effects and increased the anti-cancer effects of ReoT3D. Conclusion: AD-MSCs as a susceptible host for oncolytic reovirus could increase the anti-cancer activity of this OV against glioblastoma multiforme (GBM) cell line.

Apelin-13 prevents hippocampal synaptic plasticity impairment in Parkinsonism rats.

The hippocampus is involved in learning and memory for novel information and implicated within the cognitive dysfunction in Parkinson's disease. Long-term potentiation (LTP), the most type of synaptic plasticity, is the base of learning and memory. We evaluated the consequences of apelin-13 on early long-term potentiation (E-LTP) in the Cornu Ammonis (CA1) area of the hippocampus and synaptic hippocampal protein expression of postsynaptic density protein 95 (PSD-95) and dopaminergic receptor (DR1) of the rat model of Parkinsonism. 6-hydroxydopamine (6-OHDA) was infused within the right substantia nigra. Intra-nigral transfusion of apelin-13 (1, 2, and 3 µg/rat) was performed one week after the 6-OHDA injection. Using hematoxylin and eosin staining, the pathological changes in the substantia nigra neurons were examined. In Vivo field excitatory postsynaptic potentials were recorded in the CA1 region one month after the apelin injection. The PSD-95 and DR1 protein levels were assessed by western blotting. The mRNA expression level of DR1 was also measured by real-time PCR. 6-OHDA meaningfully disrupted short-term memory and LTP, and altered the expression levels of the above-mentioned proteins in the hippocampus. The results suggest that apelin-13 (especially at 3 µg/rat) significantly ameliorates the E-LTP impairment and attenuates the changes in hippocampal synaptic proteins in 6-OHDA-treated rats.

Expression Levels of miR-127-3p and miR-144-3p in Gastric Cancer and their Relationships with Clinicopathological Parameters.

BACKGROUND: Previous studies demonstrated the critical role of miRNAs in carcinogenesis. Aberrant expression of miR-127-3p and miR-144-3p have been revealed in several types of cancers. METHODS: Expression levels of miR-127-3p and miR-144-3p were detected in the plasma of patients with gastric cancer (GC) using fluorescent quantitative polymerase chain reaction to recognize potential non-invasive biomarkers for GC and evaluated the relationship between their expression and clinicopathological parameters of GC. RESULTS: The results showed miR-127-3p and miR-144-3p expression levels were significantly decreased in plasma of GC patients (p = 0.003 and p < 0.001, respectively) and the expression level of miR-144-3p was associated with tumor-node-metastasis (TNM) staging. In addition, receiver operating characteristic (ROC) curve analysis indicated the area of miR-127-3p and miR-144-3p under the ROC curve for GC diagnosis were 0.664 and 0.741, re-spectively (p < 0.05). CONCLUSIONS: The expression levels of miR-127-3p and -144-3p were downregulated in the plasma of GC patients that may participate in the pathological process of GC and act as potential tumor biomarkers.

Interleukin 7 receptor T244I polymorphism and the multiple sclerosis susceptibility: a meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is recognized as the most prevalent chronic inflammatory neurological disorder diagnosed in young adults. Recent evidence suggests that the T244I polymorphism of the IL7Rα gene (rs6897932) May influence MS susceptibility; however, individual studies have provided conflicting and controversial results. Therefore, this meta-analysis was conducted to assess the association between the IL7R T244I polymorphism and the risk of MS. METHOD: An extensive search for published literature up to May 2019 was accomplished in the electronic databases, and 28 studies consisting of 16,260 MS patients and 18,335 controls were included. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to investigate the strength of association. RESULTS: The results of the present meta-analysis represented significant association between the IL7R T244I polymorphism and MS susceptibility. (recessive model: OR = 1.126, 95% CI 1.026-1.236, P = .012; dominant model: OR = 1.172, 95% CI 1.024-1.341, P = .021; homozygous model: OR = 1.213, 95% CI 1.038-1.417, P = .015; and allelic model: OR = 1.109, 95% CI 1.025-1.200, P = .010, respectively). In the subgroup analysis according to region, our findings showed significant association in Europe. However, no association was found in Middle East. CONCLUSION: The current meta-analysis demonstrated that the C allele of IL7R T244I polymorphism might be a risk factor for the MS susceptibility in Europe but not in Middle East.

Protective impacts of erythropoietin on myelinization of oligodendrocytes and schwann cells in CNS and PNS following cuprizone-induced multiple sclerosis- histology, molecular, and functional studies.

BACKGROUND: Multiple sclerosis (MS) is known as one of the chronic inflammatory diseases characterized by lesions in the central nervous system (CNS) and peripheral nervous system(PNS) resulting in serious cognitive or physical disabilities as well as neurological disorders. Thus, protective effects of erythropoietin(EPO) on myelinization of oligodendrocytes and schwann cells respectively in CNS and PNS following MS induced by cuprizone (CPZ) administration in young female mice. METHODOLOGY: To meet the objectives of this study; a chow with 0.2 % CPZ was used to feed young female C57BL/6 J mice for six weeks. After three weeks, EPO (5000 IU/kg body weight) was administered via daily intra-peritoneal injection for simultaneous treatment of the mice. Measurement of latency and amplitude of the compound muscle action potential (CMAP) of gastrocnemius muscle was also performed every week during a six-week demyelination interval, and then examinations were fulfilled on the histological sections of the brain and sciatic nerve. Therefore, we focused on the removal of the sciatic and sciatic nerve specimens and analysis of the use of the stereological procedures, western blot, immuno-histochemistry, and gene expression. RESULTS: According to the results of this study, MBP levels increased in oligodendrocytes (OLs) in the treated mice. Moreover, EPO could concurrently enhance motor coordination and muscle activity. Analysis showed the significant enhancement of the gene expression of MBP, MAG, and S100, as well as stereological variables in the treatment group in comparison with the cuprizone (CPZ) group. CONCLUSION: Findings could help further understand the alleviation of the detrimental impacts of CPZ using the OLs that would be capable of increasing the level of S100, MAG, and MBP.

Chronic Exposure to Morphine Leads to a Reduced Affective Pain Response in the Presence of Hyperalgesia in an Animal Model of Empathy.

BACKGROUND: Empathy is the capability to represent the mental and emotional states of other subjects. Previous studies have demonstrated a possible correlation between morphine addiction and altered empathy response in morphine-addicted subjects. This study was performed to evaluate the effect of chronic morphine exposure as an animal model of morphine addiction on empathic changes in affective and sensory pain. METHODS: Adult male Wistar rats (3 months old) were used for the current study. Animals were grouped in cages of two (n = 8 for each group) and one animal was selected as the pain observer group. Pain observer animals received either saline or morphine (10 mg/kg, twice daily for 8 days). At ninth day, formalin [50 µg, 5%, subcutaneous (SC)] was injected into the hindpaw of the cagemate and placed inside the cage. Elevated plus maze (EPM) and open field test (OFT) were recruited to evaluate anxiety; hot plate and tail flick tests were used to assay sensory pain. Conditioned place aversion (CPA) was also measured as indicator of affective pain component. FINDINGS: Chronic morphine exposure led to a reduced level of anxiety in EPM and OFT assays. An opioid-induced hyperalgesia was observed in the sensory pain assays, while there was a reduced affective pain in the CPA paradigm in morphine-treated animals. CONCLUSION: It might be plausible that chronic morphine exposure might alter empathy for pain through affective and not sensory pain pathways.

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.

Role of Opioid System in Empathy-like Behaviours in Rats.

BACKGROUND: Empathy is defined as the ability to simulate the mental states of others. Recent studies have demonstrated empathy-like behaviors in other animals including rats and mice. The objective of the current study was to evaluate the effect of acute administration of morphine and naloxone on cognition and nociception changes following observing conspecifics undergoing nociceptive stimulus. METHODS: Adult male Wistar rats were used (n = 8 for each group). One cagemate received formalin injection into the hindpaw five times within a nine-day period and the other cagemate observed the pain while being pretreated with saline, morphine, or naloxone [10 mg/kg, intraperitoneal (i.p.)]. Pain behaviors, anxiety-like behaviour, locomotion, balance and muscle strength were evaluated in the observer animals. FINDINGS: Observing a cagemate in pain increased anxiety-like behavior and reduced thermal pain threshold in the observer animals. Administration of morphine reversed these effects and naloxone did not affect the responses. CONCLUSION: Results of the current study reveal an important role for opioid receptors (ORs) in empathy for pain, so that activation of this system dampens the empathy-like responses.

Neurosteroid allopregnanolone attenuates cognitive dysfunctions in 6-OHDA-induced rat model of Parkinson's disease.

Cognitive deficits have an extensive influence on the quality of life of the Parkinson's disease (PD) patients. Previous studies have shown that lack of steroid hormones have an important role in the development of PD. Therefore, in this study the effects of neurosteroid allopregnanolone (Allo) on the PD-induced cognitive disorders were assessed. To simulate PD, 6-hydroxydopamine (6-OHDA) was injected into the rat's substantia nigra. Allo (5 and 20mg/kg, orally) were administered on the day after the 6-OHDA injection and continued during the entire treatment period (two months). Cognitive behaviors were assessed by Moris water maze (MWM), novel object recognition (NOR) and object location tasks. The data indicated that Allo significantly improved the 6-OHDA-induced cognitive impairment which revealed by the reduction of time spent to find out platform (escape latency) and the increase of retention time in MWM test and also with increase in the exploration index in NOR and object location tasks. Present study strongly supports the pro-cognitive property of allopregnanolone in PD.

Ecstasy-induced caspase expression alters following ginger treatment.

INTRODUCTION: Exposure to 3-4, methylenedioxymethamphetamine (MDMA) leads to cell death. Herein, we studied the protective effects of ginger on MDMA- induced apoptosis. METHODS: 15 Sprague dawley male rats were administrated with 0, 10 mg/kg MDMA, or MDMA along with 100mg/kg ginger, IP for 7 days. Brains were removed to study the caspase 3, 8, and 9 expressions in the hippocampus by RT-PCR. Data was analyzed by SPSS 16 software using the one-way ANOVA test. RESULTS: MDMA treatment resulted in a significant increase in caspase 3, 8, and 9 as compared to the sham group (p < 0.001). Ginger administration however, appeared to significantly decrease the same (p < 0.001). DISCUSSION: Our findings suggest that ginger consumption may lead to the improvement of MDMA-induced neurotoxicity.

BMSC and CoQ10 improve behavioural recovery and histological outcome in rat model of Parkinson's disease.

OBJECTIVE: This study assessed the ability of a combination treatment of bone marrow stromal cell (BMSC) graft and oral coenzyme (CoQ10) in a rat model of Parkinson's disease (PD) as an appropriate substitute for current Parkinson treatments. The combination treatment was compared to sole treatments of BMSC and CoQ10. MATERIALS AND METHODS: In this experimental study, there were six groups of male Wistar rats: control, sham, lesion, CoQ10, graft BMSC and graft BMSC plus CoQ10. Oral administration of CoQ10 began 1 week before the PD and continued during the entire treatment period. To simulate PD, we injected 6 hydroxydopamine (6OHDA) in rats. BMSC were labelled by 5-bromo-2'-deoxyuridine (Brdu) before transplantation. We assessed behaviour before PD, 2 weeks after PD and 8 weeks after cell transplantation. At the end of the second month of treatment, immunohistochemistry, histology and molecular studies were performed. RESULTS: Behavioural assessment of the CoQ10 group and BMSC group indicated equal recovery in comparison with the lesion group (P<0.01), while the combined treatment of BMSC and CoQ10 showed considerably better recovery compared with the lesion group (P<0.001). There were no signs of gliosis and graft rejection. Immunohistochemistry analysis of Brdu indicated that cells were alive after 2 months of application in host tissue. Cell counts showed significantly greater numbers of neural cells in the combination treatment of BMSC and CoQ10 compared to the other groups. Tyrosine hydroxylase (TH) gene expression levels in the combined therapy group was significantly more than the other experimental groups (P<0.001). CONCLUSION: The combined use of two neuroprotective treatments and cell replacement therapy can be effective in the treatment of PD, at least in experimental settings.