Effect of transcranial near-infrared photobiomodulation on cognitive outcomes in D-galactose/AlCl3 induced brain aging in BALB/c mice.

Brain photobiomodulation (PBM) therapy (PBMT) modulates various biological and cognitive processes in senescence rodent models. This study was designed to investigate the effects of transcranial near-infrared (NIR) laser treatment on D-galactose (D-gal)/aluminum chloride (AlCl3) induced inflammation, synaptic dysfunction, and cognitive impairment in mice. The aged mouse model was induced by subcutaneously injecting D-gal (60 mg/kg/day) followed by intragastrically administering AlCl3 (200 mg/kg/day) for 2 months. NIR PBM (810 nm laser, 32, 16, and 8 J/cm2) was administered transcranially every other day (3 days/week) for 2 months. Social, contextual, and spatial memories were assessed by social interaction test, passive avoidance test, and Lashley III maze, respectively. Then, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and synaptic markers including growth-associated protein 43 (GAP-43), post-synaptic density-95 (PSD-95), and synaptophysin (SYN) levels were measured in the hippocampus using western blot method. Behavioral results revealed that NIR PBM at fluencies of 16 and 8 J/cm2 could reduce D-gal/AlCl3 impaired social and spatial memories. Treatment with NIR attenuated neuroinflammation through down-regulation of TNF-α and IL-6. Additionally, NIR significantly inhibited the down-regulation of GAP-43 and SYN. The results indicate that transcranial PBM at the fluencies 16 and 8 J/cm2 effectively prevents cognitive impairment in mice model of aging by inhibiting the production of the inflammatory cytokines and enhancing synaptic markers.

Clinical Association between Phospho-AKT Expression with Clinicopathological Characteristics of Gastrointestinal Cancer Patients: A Meta-Analysis.

Deregulation of AKT (protein kinase B) is frequently observed in human malignancies including gastrointestinal (GI) cancers. Here we have reviewed the association between AKT phosphorylation (activation) and clinical and pathological characteristics of patients with GI cancer. Articles in the EMBASE, PubMed, Cochrane Library, and Web of Science databases were searched up to July 2018. Eighteen studies comprising 1,698 patients with 5 different cancer types were included in the meta-analysis. In the pooled analysis, AKT phosphorylation was positively correlated with tumor size (r = 0.14, 95% CI: 0.06-0.22; P < 0.001), tumor grade (r = 0.08, 95% CI: 0.02-0.14; P < 0.009), tumor stage (r = 0.19, 95% CI: 0.13-0.24; P < 0.001), lymph node status (r = 0.18, 95% CI: 0.09-0.25; P < 0.001) and the presence of distant metastasis (r = 0.14, 95% CI: 0.06-0.22; P < 0.001) in the patients with GI cancer. These findings support the potential clinical value of AKT as a prognostic marker and therapeutic target in patients with GI carcinomas.

The genetic factors contributing to hypospadias and their clinical utility in its diagnosis.

Hypospadias is among the most common congenital malformations in male neonates. It results from abnormal penile and urethral development, but is a multifactorial disorder that is highly heterogeneous, with several genetic and environmental determinants. Monogenic and chromosomal abnormalities are present in approximately 30% of cases, although the genetic factors contributing to hypospadias remain unknown in 70% of cases. While defects in androgen synthesis can lead to this malformation, mutational analyses have shown several genes, such as sonic hedgehog, fibroblast growth factors, bone morphogenetic proteins, homeobox genes, and the Wnt family, are involved in the normal development of male external genitalia. Mutations in the genes of penile development (e.g., HOX, FGF, Shh) and testicular determination (e.g., WT1, SRY), luteinizing hormone receptor, and androgen receptor have also been proposed to be implicated in hypospadias. Here we review the recent advances in this field and discuss the potential genes that could determine the risk of hypospadias.

Therapeutic potency of oncolytic virotherapy-induced cancer stem cells targeting in brain tumors, current status, and perspectives.

Brain tumors are the most common form of solid tumors in children and is presently a serious therapeutic challenge worldwide. Traditional treatment with chemotherapy and radiotherapy was shown to be unsuccessful in targeting brain tumor cancer stem cells (CSCs), leading to recurrent, treatment-resistant secondary malignancies. Oncolytic virotherapy (OV) is an effective antitumor therapeutic strategy which offers a novel, targeted approach for eradicating pediatric brain tumor CSCs by utilizing mechanisms of cell killing that differ from conventional therapies. A number of studies and some clinical trials have therefore investigated the effects of combined therapy of radiations or chemotherapies with oncolytic viruses which provide new insights regarding the effectiveness and improvement of treatment responses for brain cancer patients. This review summarizes the current knowledge of the therapeutic potency of OVs-induced CSCs targeting in the treatment of brain tumors for a better understanding and hence a better management of this disease.

Gold nanoparticle and polyethylene glycol in neural regeneration in the treatment of neurodegenerative diseases.

Gold nanoparticles (GNs) have unique characteristics, for example, stability, biocompatibility, small dimensions, and low toxicity. Several clinical applications have been suggested for GNs, such as diagnosis, imaging, and drug delivery. GNs absorb infrared light, indicating their potential value for imaging. There is growing evidence showing the therapeutic application of GN for drug delivery because of their interaction with the blood-brain barrier and DNA, the latter being associated with their genotoxic effects. GN can also be stimulated to produce high local temperatures, indicating their potential value in photodynamic therapy in the treatment of tumors. The aim of the current review is to summarize the potential applications of GNs in the biomedical field, specifically in neurodegenerative diseases.

Rosa canina L. methanolic extract prevents heat stress-induced memory dysfunction in rats.

NEW FINDINGS: What is the central question of this study? Heat stress has harmful effects on the brain structure and synaptic density via induction of oxidative stress and neuroinflammation, which result in neuronal damage in the hippocampus and thereby cognitive impairments. In this study, we investigate the effect of Rosa canina treatment on cognitive function in heat stress-exposed rats and its underlying mechanisms. What is the main finding and its importance? We show that R. canina improves cognitive deficits induced by heat stress by attenuation of oxidative stress and neuroinflammation and by upregulation of synaptic proteins in the hippocampus. ABSTRACT: The aim of the study was to evaluate the effects of aqueous methanolic extract of Rosa canina (RC) dried fruits on oxidative stress, inflammation, synaptic degeneration and memory dysfunction induced by heat stress (HS) in rats. Sixty adult male Wistar rats were randomly divided into five groups as follows: the control group received normal saline (NS); the HS group was exposed to heat stress (43°C) for 15 min once a day for 2 weeks; and HS+R groups were exposed to heat stress and received one of three doses (250, 500 or 1000 mg kg-1 ) of RC methanolic extract for 2 weeks. A passive avoidance test and a Y-maze test were performed to assess learning and memory. The levels of reactive oxygen species were assessed. The serum cortisol concentration and hippocampal total antioxidant capacity, superoxide dismutase and glutathione peroxidase were also detected using spectrophotometry. The protein expressions of c-Fos, heat-shock protein-70, tumour necrosis factor-α, growth-associated protein 43, post-synaptic density-95 and synaptophysin were evaluated in the hippocampal tissue. The results showed that RC significantly improved cognitive dysfunction induced by HS, which was accompanied by downregulation of tumour necrosis factor-α and upregulation of growth-associated protein 43 and synaptophysin proteins in the hippocampus of HS-exposed rats. Furthermore, RC significantly attenuated serum cortisol concentrations and upregulated heat shock protein-70 and c-Fos in the hippocampus. In addition, the administration of RC attenuated reactive oxygen species levels and enhanced antioxidant defense in the hippocampus. These findings indicate that RC attenuated the deleterious effect of HS on cognition through its antioxidant properties and by enhancing synaptic function and plasticity.

ß-Lapachone attenuates cognitive impairment and neuroinflammation in beta-amyloid induced mouse model of Alzheimer's disease.

Oxidative stress and neuroinflammation are critically involved in amyloid beta (Aß) induced cognitive impairments. ß-Lapachone (ß-LAP) is a natural activator of NAD(P)H quinone oxidoreductase 1 (NQO1) which has antioxidant and anti-inflammatory properties.This study investigated the effect of ß-LAP administration on Aß-induced memory deficit, oxidative stress, neuroinflammation, and apoptosis cell death in the hippocampus. Forty BALB/c mice were allocated into control, sham, ß-LAP (ßL), Aß, and Aß + ßL groups. Intracerebroventricular injection of Aß1-42 was used to induce Alzheimer's disease (AD) model. Mice in the ßL and Aß + ßL groups were treated with ß-LAP (10 mg/kg, i.p) for 4 days. Results revealed that ß-LAP attenuated memory impairment in the Aß-received mice, as measured in the novel object recognition (NOR) and Barnes maze tests. Moreover, Aß resulted in inflammasome activation evident by enhanced caspase-1 immunoreactivity and interleukin-1 beta (IL-1ß) protein levels. However, ß-LAP could markedly reduce reactive oxygen species (ROS) production and down-regulate mRNA expression of NLRP3 inflammasome and protein levels of cleaved caspase 1 and IL-1ß. Additionally, ß-LAP-treated mice showed increased SIRT1 levels and NAD+/NADH ratio in the hippocampus. These results were followed by fewer number of TUNEL-positive cell, reduced hippocampal atrophy and neuronal loss in the hippocampal dentate gyrus (DG). These results indicated that the protective effect of ß-LAP against AD-associated cognitive deficits is partially through its strong antioxidant and anti-inflammatory actions.

Cardioprotective effect of Rosa canina L. methanolic extract on heat shock induced cardiomyocyte injury: An experimental study.

Introduction: Overexposure to heat conditions can affect the functioning of the cardiovascular system and may promote cardiovascular disorders. Heat shock induced myocardial injury via increasing endoplasmic reticulum response-mediated apoptosis. This study investigated the impact of pretreatment with Rosa canina (RC), a natural antioxidant, on myocardial damage induced by heat stress exposure and underlying mechanisms in cardiomyocytes in rats. Methods: Sixty adult male Wistar rats were allocated into five groups, including Control: received normal saline (NS), Heat Stress (HS), and HS+RC groups. Animals in the HS groups were subjected to heat stress (43 ºC) for 15 minutes once a day for two weeks. Animals in the HS+RC groups received three doses of RC (250, 500, and 1000 mg/mL) one hour before being subjected to heat shock. The endoplasmic reticulum (ER) transmembrane kinases, including PKR-like endoplasmic reticulum kinase (PERK), immunoreactivity of CCAAT/enhancer-binding protein homologous protein (CHOP), and eukaryotic translation initiation factor 2-alpha (eIF2α) as well as caspase 8 were detected by Western blot. The levels of reactive oxygen species (ROS) were assessed. Moreover, histopathological changes and apoptosis were also assayed in the heart tissue by using histopathological and TUNEL assays. Results: Heat exposure increased the level of ROS and induced oxidative damage in the heart tissue. The results demonstrated that RC administration decreased the overproduction of ROS induced by heat stress in cardiomyocytes. Moreover, heat stress up regulated the expression of p-PERK, p-eIF2α,and CHOP protein while pretreatment with RC decreased expression of ER stress-related markers in cardiomyocytes. Besides, RC diminished heat stress-induced cellular damage and apoptosis associated with inhibition of caspase 8 activation, a pro-apoptotic protein in cardiomyocytes. Conclusion: These findings indicate that RC exerts a protective effect on heart tissue, at least in part,through inactivation of PERK/eIF2α/CHOP pathway or inhibition of ER stress and oxidative stress triggeredapoptosis in cardiomyocytes induced by heat stress.

Changes in Cognitive Functions Following Violent and Football Video Games in Young Male Volunteers by Studying Brain Waves.

INTRODUCTION: This research investigated the effects of violent and football video games on cognitive functions, cortisol levels, and brain waves. METHODS: A total of 64 participants competed in a single-elimination tournament. Saliva samples of all players were obtained before and after the games for the assessment of cortisol levels. The cognitive performances of the players were also assessed by paced auditory serial addition test. Moreover, the electroencephalogram recording was conducted during the games. RESULTS: The results showed that salivary cortisol levels significantly decreased after playing both games. Also, playing the football game increased reaction time, whereas decreased sustained attention and mental fatigue. CONCLUSION: Conversely, following playing a violent game, the reaction time decreased, and sustained attention and mental fatigue increased. Furthermore, the results of the EEG recording revealed that playing a violent game engaged more brain regions than the football game. In conclusion, playing violent game more effectively improved cognitive performances in the players than the football game.

Association of 5-lipoxygenase activating protein gene polymorphism and stroke: A study from north east of Iran.

Background: Stroke is a multifactorial disorder and a major cause of morbidity and mortality around the world. There are growing numbers of candidate gene pathways which are thought to be associated with stroke. Genes involved in lipid metabolism are important issues in stroke studies. Studying different polymorphisms in these genes are becoming an interest for researchers. 5-lipoxygenase activating protein (ALOX5AP) is one of these genes. Different studies have provided different relations between ALOX5AP promoter polymorphism (rs17222919) and stroke. In the present study, we have evaluated this gene polymorphism in a population in north east of Iran. Methods: This case-control study took place in Ghaem Hospital, Mashhad, Iran. Patients with computed tomography (CT) or magnetic resonance imaging (MRI) confirmation for ischemic stroke were enrolled in this study and considered as case group. Healthy persons without ischemic stroke were control group. During 1-year period of this study, ALOX5AP gene polymorphism in 200 healthy patients (control group) as well as 228 patients with stroke (case group) was evaluated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: All of 428 persons (228 cases and 200 healthy controls) enrolled in this study. The genotype and allele frequency was significantly different between both groups (P = 0.001 and P = 0.003, respectively). A total number of 54 patients had G allele in case group in contrast to 27 ones in control group. Also, 174 patients in case group had T allele and 173 persons had this allele in control group. In compression of TT genotype, the risk of developing stroke in GG and TG genotypes increased by 3.998 and 1.643, respectively. Also the risk of ischemic stroke with G allele would increase by 2.128. Conclusion: According to our results, ALOX5AP promoter polymorphism (rs17222919) is related to increased ischemic stroke in Iranian population.

Photobiomodulation and Coenzyme Q10 Treatments Attenuate Cognitive Impairment Associated With Model of Transient Global Brain Ischemia in Artificially Aged Mice.

Disturbances in mitochondrial biogenesis and bioenergetics, combined with neuroinflammation, play cardinal roles in the cognitive impairment during aging that is further exacerbated by transient cerebral ischemia. Both near-infrared (NIR) photobiomodulation (PBM) and Coenzyme Q10 (CoQ10) administration are known to stimulate mitochondrial electron transport that potentially may reverse the effects of cerebral ischemia in aged animals. We tested the hypothesis that the effects of PBM and CoQ10, separately or in combination, improve cognition in a mouse model of transient cerebral ischemia superimposed on a model of aging. We modeled aging by 6-week administration of D-galactose (500 mg/kg subcutaneous) to mice. We subsequently induced transient cerebral ischemia by bilateral occlusion of the common carotid artery (BCCAO). We treated the mice with PBM (810 nm transcranial laser) or CoQ10 (500 mg/kg by gavage), or both, for 2 weeks after surgery. We assessed cognitive function by the Barnes and Lashley III mazes and the What-Where-Which (WWWhich) task. PBM or CoQ10, and both, improved spatial and episodic memory in the mice. Separately and together, the treatments lowered reactive oxygen species and raised ATP and general mitochondrial activity as well as biomarkers of mitochondrial biogenesis, including SIRT1, PGC-1α, NRF1, and TFAM. Neuroinflammatory responsiveness declined, as indicated by decreased iNOS, TNF-α, and IL-1ß levels with the PBM and CoQ10 treatments. Collectively, the findings of this preclinical study imply that the procognitive effects of NIR PBM and CoQ10 treatments, separately or in combination, are beneficial in a model of transient global brain ischemia superimposed on a model of aging in mice.

Near-infrared photobiomodulation combined with coenzyme Q10 for depression in a mouse model of restraint stress: reduction in oxidative stress, neuroinflammation, and apoptosis.

This study was aimed to evaluate the effects of near-infrared (NIR) photobiomodulation (PBM) combined with coenzyme Q10 (CoQ10) on depressive-like behavior, cerebral oxidative stress, inflammation, and apoptosis markers in mice. To induce a depressive-like model, mice were subjected to sub-chronic restraint stress for 5 consecutive days. NIR PBM (810 nm laser, 33.3 J/cm2) and/or CoQ10 (500 mg/kg/day, gavage) were administered for five days concomitantly with immobilization. Behavior was evaluated by the forced swim test (FST), tail suspension test (TST), and open field test (OFT). Mitochondrial membrane potential as well as oxidative stress, neuroinflammatory, and markers of apoptosis were evaluated in the prefrontal cortex (PFC) and hippocampus (HIP). The serum levels of pro-inflammatory cytokines, cortisol, and corticosterone were also measured. PBM or CoQ10, or the combination, ameliorated depressive-like behaviors induced by restraint stress as indicated by decreased immobility time in both the FST and TST. PBM and/or CoQ10 treatments decreased lipid peroxidation and enhanced total antioxidant capacity (TAC), GSH levels, GPx and SOD activities in both brain areas. The neuroinflammatory response in the HIP and PFC was suppressed, as indicated by decreased NF-kB, p38, and JNK levels in PBM and/or CoQ10 groups. Intrinsic apoptosis biomarkers, BAX, Bcl-2, cytochrome c release, and caspase-3 and -9, were also significantly down-regulated by both treatments. Furthermore, both treatments decreased the elevated serum levels of cortisol, corticosterone, TNF-α, and IL-6 induced by restraint stress. Transcranial NIR PBM and CoQ10 therapies may be effective antidepressant strategies for the prevention of psychopathological and behavioral symptoms induced by stress.

Cerebrolysin attenuates ethanol-induced spatial memory impairments through inhibition of hippocampal oxidative stress and apoptotic cell death in rats.

The present study investigates the potential neuroprotective effect of cerebrolysin (CBL), a combination of neurotrophic factors, on the cognitive and biochemical alterations induced by chronic ethanol administration in rats. The animals were divided into five groups as follows: control; ethanol (4 g/kg, for 30 days) plus normal saline (Ethanol + NS); ethanol plus CBL 1 mL/kg (Ethanol + CBL 1), ethanol plus CBL 2.5 mL/kg (Ethanol + CBL 2.5); and ethanol plus CBL 5 mL/kg (Ethanol + CBL 5). The Morris water maze (MWM) test was performed to assess cognitive impairment. The status of the lipid peroxidation marker MDA, antioxidant capacity, as well as alterations of the apoptotic factors such as Bcl-2, BAX, and cleaved caspase-9 and -3, were evaluated in the hippocampus. The results showed that CBL treatment not only normalized the increased MDA levels in the alcoholic rats and enhanced antioxidant defense, but also reduced the Bax/Bcl-2 ratio and cleaved caspase-9 and -3 in the hippocampus. These results were parallel with improvement in spatial memory performance in the MWM test. The findings of the present study provide evidence for the promising therapeutic effect of CBL in chronic ethanol consumption through counteracting oxidative stress and apoptosis markers.

Nicotine Modulates Cognitive Function in D-Galactose-Induced Senescence in Mice.

Here, we tested the claim that nicotine attenuates the signs of brain dysfunction in the model of brain aging induced by D-galactose (DGal) in mice. We administered nicotine at doses of 0.1, 0.5 and 1 mg/kg by the subcutaneous (s.c.) or at 0.1 mg/kg by the intranasal (i.n.) routes in mice that had received DGal at the dose of 500 mg/kg subcutaneous (s.c.) for 6 weeks. We assessed animal withdrawal signs as the number of presented somatic signs, thermal hyperalgesia, elevated plus maze (EPM) and open field tests. We evaluated spatial memory and recognition with Barnes maze and novel object recognition (NOR) tests. We tested brain tissue for reactive oxygen species (ROS), mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor and nerve growth factor levels. Nicotine administration in model groups (0.5 mg/kg s.c. and 0.1 mg/kg i.n. doses) significantly attenuated impairment of spatial and episodic memories in comparison to normal saline-received model group. These doses also reduced mito-oxidative damage as well as apoptosis and raised neurotrophic factors level in model groups in comparison to normal saline-received model group. The 1 mg/kg s.c. dose nicotine revealed withdrawal signs compared with the other nicotine-received groups. Nicotine at specific doses and routes has the potential to attenuate age-related cognitive impairment, mito-oxidative damage, and apoptosis. The doses raise neurotrophic factors without producing withdrawal signs.

Cerebrolysin attenuates hyperalgesia, photophobia, and neuroinflammation in a nitroglycerin-induced migraine model in rats.

Chronic migraine dramatically affects the quality of life in the migraineurs. This study examined the effect of chronic cerebrolysin (CBL) treatment on the migraine-associated symptoms in a rat model of migraine. Experiments were carried out on 8 weeks, male Wistar rats. Chronic migraine was modeled by injection (10 mg/kg, i.p) of nitroglycerin (NTG) on days 3, 5, 7, and 9. CBL (2.5 and 5 ml/kg, i.p.) was injected every day for 10 days. Mechanical and thermal withdrawal thresholds of the hind paw were examined by von Frey hairs and hot plate, respectively. Head grooming behavior was evaluated one hour following injection of NTG. Light-aversive behaviors were determined in the modified elevated plus-maze (EPM) on even days and in the light/dark box on odd days. After behavioral experiments, blood concentrations of calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), tumor necrosis factor-a (TNF-α), and interleukin-1ß (IL-1ß) were assessed by rat specific enzyme-linked immunosorbent assay (ELISA) kits. Our results indicated that NTG significantly increased migraine-related behavioral and molecular symptoms in the animals, whereas CBL treatment markedly reduced mechanical and thermal hyperalgesia, head grooming, and light-aversive behaviors induced by NTG. Also, blood levels of CGRP, PACAP, and pro-inflammatory cytokines (TNF-α and IL-1ß) significantly decreased by CBL administration. Chronic CBL treatment showed antinociceptive and light-aversive reducing effects in the NTG-induced animal model of chronic migraine and may represent a valuable therapy for those suffering from migraine.

Transcranial near-infrared photobiomodulation attenuates memory impairment and hippocampal oxidative stress in sleep-deprived mice.

Sleep deprivation (SD) causes oxidative stress in the hippocampus and subsequent memory impairment. In this study, the effect of near-infrared (NIR) photobiomodulation (PBM) on learning and memory impairment induced by acute SD was investigated. The mice were subjected to an acute SD protocol for 72 h. Simultaneously, NIR PBM using a laser at 810 nm was delivered (once a day for 3 days) transcranially to the head to affect the entire brain of mice. The Barnes maze and the What-Where-Which task were used to assess spatial and episodic-like memories. The hippocampal levels of antioxidant enzymes and oxidative stress biomarkers were evaluated. The results showed that NIR PBM prevented cognitive impairment induced by SD. Moreover, NIR PBM therapy enhanced the antioxidant status and increased mitochondrial activity in the hippocampus of SD mice. Our findings revealed that hippocampus-related mitochondrial damage and extensive oxidative stress contribute to the occurrence of memory impairment. In contrast, NIR PBM reduced hippocampal oxidative damage, supporting the ability of 810 nm laser light to improve the antioxidant defense system and maintain mitochondrial survival. This confirms that non-invasive transcranial NIR PBM therapy ameliorates hippocampal dysfunction, which is reflected in enhanced memory function.