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Temporal lobe epilepsy (TLE), which is one of the most common neurological diseases, is accompanied by a high incidence of psychiatric disorders. Among these psychiatric disorders, anxiety is one of the major psychiatric comorbidi...
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Temporal lobe epilepsy (TLE), which is one of the most common neurological diseases, is accompanied by a high incidence of psychiatric disorders. Among these psychiatric disorders, anxiety is one of the major psychiatric comorbidities in epilepsy patients. However, anxiety in epilepsy patients often remains unrecognized and untreated. It is believed that the inhibitory networks of gamma-aminobutyric acid (GABA) neurotransmission play pivotal roles in the modulation of emotion and mood responses in both physiological and pathological conditions. The impairment of neurotransmission mediated by GABAergic signaling is related to the pathophysiology of anxiety. However, it remains unclear whether and how GABAergic signaling modulates anxiety responses in the context of an epileptic brain. In the present study, we sought to determine the role of inhibitory networks of GABAergic signaling in the anxiety-like behavior of epileptic mice. Our results show epileptic mice exhibited increased anxiety-like behavior, and this increased anxiety-like behavior was accompanied by a decrease in GABAergic interneurons and an increase in GABA type A receptor (GABA(A)R) beta 3 subunit (GABRB3) expression in the hippocampus. Furthermore, the activation of GABA(A)Rs produced an anxiolytic-like effect, while the inhibition of GABA(A)Rs elicited an anxiogenic-like effect in the epileptic mice, suggesting that the alteration of GABAergic signaling is associated with anxiety-like behavior in epileptic mice. Thus, targeting GABAergic signaling in the epileptic brain may provide an effective anxiolytic treatment in epilepsy patients.
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Decreased inhibition plays an extremely important role in pathogenesis of autism spectrum disorder (ASD). Therefore, we aimed to determine whether expression levels of the gamma-aminobutyric acid type A receptor beta 3 subunit (GA...
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Decreased inhibition plays an extremely important role in pathogenesis of autism spectrum disorder (ASD). Therefore, we aimed to determine whether expression levels of the gamma-aminobutyric acid type A receptor beta 3 subunit (GABA(A)R beta 3), K+-Cl- cotransporter 2 (KCC2), and Na+-K+-Cl- cotransporter 1 (NKCC1) related to inhibition transmission are changed in a sodium valproate-induced rat model of ASD. Decreased expression levels of membrane GABA(A)R beta 3 (m-GABA(A)R beta 3) and KCC2 as well as increased endocytosis of GABA(A)Rs were found in the model group. However, there were no significant differences in expression of total GABA(A)R beta 3 and NKCC1 between the control and model groups. In addition, we observed growth retardation, impaired spatial memory, limited exploration, increased anxiety, and reduced sociability in the model group. These results suggest alterations in m-GABA(A)R beta 3 levels, KCC2 levels, and trafficking of GABA(A)Rs in rats prenatally exposed to valproic acid and advance our understanding of the pathogenesis of ASD. (C) 2017 Elsevier B.V. All rights reserved.
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Diazepam could regulate immune system and inflammation, which might be a potential therapeutic agent for pulmonary fibrosis in clinic. This study showed that diazepam reversed LPS-induced inhibition of cell proliferation and promo...
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Diazepam could regulate immune system and inflammation, which might be a potential therapeutic agent for pulmonary fibrosis in clinic. This study showed that diazepam reversed LPS-induced inhibition of cell proliferation and promotion of cell apoptosis. Of note, LPS specifically induced Caspase-11 dependent cell pyroptosis, which were significantly attenuated by diazepam or pyroptosis inhibitor necrosulfonamide (NSA) treatment. In addition, alpha 4- and alpha 5-subunits of GABA(A)Rs were highly expressed in human bronchial 16HBE cells, human pulmonary epithelial cells (BEAS-2B) and pulmonary epithelial cells isolated from mice (mPECs). Further results showed that only knock-down of alpha 4-GABA(A)Rs abrogated the effects of diazepam on LPS induced cell pyroptosis, apoptosis and proliferation. Similiarly, either diazepam or NSA treatment could alleviate development of LPS induced inflammatory reactions and pulmonary fibrosis in mice, which were abrogated by synergistically knocking down alpha 4-GABA(A)Rs. Taken together, diazepam alleviated LPS-induced cell pyroptosis and development of pulmonary fibrosis in mice by activating alpha 4-GABA(A)Rs.
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The endoplasmic reticulum-Golgi intermediate compartment protein-53 (ERGIC-53, aka LMAN1), which cycles between the endoplasmic reticulum (ER) and Golgi, is a known cargo receptor for a number of soluble proteins. However, whether...
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The endoplasmic reticulum-Golgi intermediate compartment protein-53 (ERGIC-53, aka LMAN1), which cycles between the endoplasmic reticulum (ER) and Golgi, is a known cargo receptor for a number of soluble proteins. However, whether LMAN1 plays a role as a trafficking factor in the central nervous system is largely unknown. Here, we determined the role of LMAN1 on endogenous protein levels of the Cys-loop superfamily of neuroreceptors, including gamma-aminobutyric acid type A receptors (GABA(A)Rs), 5-hydroxytryptamine (serotonin) type 3 (5-HT3) receptors, and nicotinic acetylcholine receptors (nAChRs). Knockdown of LMAN1 reduces the surface trafficking of endogenous beta 3 subunits of GABA(A)Rs in mouse hypothalamic GT1-7 neurons. Furthermore, Western blot analysis of brain homogenates from LMAN1 knockout mice demonstrated that loss of LMAN1 decreases the total protein levels of 5HT(3)A receptors and gamma 2 subunits of GABA(A)Rs. LMAN1 knockout regulates the ER proteostasis network by upregulating ERP44 without changing calnexin levels. Interestingly, despite the critical role of the glycan-binding function of LMAN1 in its other known cargo clients, LMAN1 interacts with GABA(A)Rs in a glycan-independent manner. In summary, LMAN1 is a trafficking factor for certain neuroreceptors in the central nervous system. This is the first report of LMAN1 function in membrane protein trafficking. (C) 2019 Elsevier Inc. All rights reserved.
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Cadmium (Cd) is a pervasive carcinogen and environmental endocrine disruptor. We studied the changes in learning and memory of offspring mice, whose mothers were exposed to 10 mg Cd/L via the drinking water during pregnancy and la...
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Cadmium (Cd) is a pervasive carcinogen and environmental endocrine disruptor. We studied the changes in learning and memory of offspring mice, whose mothers were exposed to 10 mg Cd/L via the drinking water during pregnancy and lactation period, as well as the changes of testosterone and estrogen levels, serum Cd levels, the histopathological changes and the changes in the mRNA and protein levels of different subunits of gamma-aminobutyric acid receptor subtype A subunits (GABAARs) in the hippocampus at the prepuberty, puberty, young adult, and adult stages.At birth, Cd had no obvious effect on mice offspring as statistically accessed based on their body weight, body length, and tail length (all p > 0.05). After grouped, the serum Cd levels increased in the three exposed groups more than in the normal control group at stages (all p < 0.05). Only serum estradiol of female offspring at age 7 weeks was significantly decreased compared with other groups (all p < 0.05). Histopathological results showed that the arrangement of the cells in hippocampal CA1 area of mice offspring was significantly sparse in the exposed groups compared with the control group.At 5 and 7 weeks, two Cd-exposed groups showed prolonged escape latency and exploring time for the platform compared with the normal group in the Morris water maze (all p < 0.05). Only increased protein expression of GABA(A)R alpha 5 was found in the Cd group at these two ages. At age 12 weeks, similar impaired learning and memory of female mice, and decreased protein expression of GABA(A)R was found in Cd-exposed groups.Collectively, low-dose Cd had no effect on the growth of mice offspring but affected their learning and memory, especially female offspring, at puberty, young adulthood, and adulthood through changed structure in the hippocampal CAl area and protein expression of GABA(A)R5 and GABA(A)RS.
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Mutations that result in the defective trafficking of gamma 2 subunit containing GABA(A) receptors (gamma 2-GABA(A)Rs) are known to reduce synaptic inhibition. Whether perturbed clustering of non-mutated GABA(A)Rs similarly reduce...
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Mutations that result in the defective trafficking of gamma 2 subunit containing GABA(A) receptors (gamma 2-GABA(A)Rs) are known to reduce synaptic inhibition. Whether perturbed clustering of non-mutated GABA(A)Rs similarly reduces synaptic inhibition in vivo is less clear. In this study we provide evidence that the loss of postsynaptic gamma 2-GABA(A)Rs upon postnatal ablation of gephyrin, the major scaffolding protein of inhibitory postsynapses, from mature principal neurons within the forebrain results in reduced induction of long-term potentiation (LTP) and impaired network excitability within the hippocampal dentate gyrus. The preferential reduction in not only synaptic gamma 2-GABA(A)R cluster number at dendritic sites but also the decrease in gamma 2-GABA(A)R density within individual clusters at dendritic inhibitory synapses suggests that distal synapses are more sensitive to the loss of gephyrin expression than proximal synapses. The fact that these mice display behavioural features of anxiety and epilepsy emphasises the importance of postsynaptic gamma 2-GABA(A)R clustering for synaptic inhibition. (C) 2016 Elsevier Inc. All rights reserved.
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Communication between individual GABAergic cells and their target neurons is mediated by synapses and, in the case of neurogliaform cells (NGFCs), by unitary volume transmission. Effects of non-synaptic volume transmission might i...
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Communication between individual GABAergic cells and their target neurons is mediated by synapses and, in the case of neurogliaform cells (NGFCs), by unitary volume transmission. Effects of non-synaptic volume transmission might involve non-neuronal targets, and astrocytes not receiving GABAergic synapses but expressing GABA receptors are suitable for evaluating this hypothesis. Testing several cortical interneuron types in slices of the rat cerebral cortex, we show selective unitary transmission from NGFCs to astrocytes with an early, GABA(A) receptor and GABA transporter-mediated component and a late component that results from the activation of GABA transporters and neuronal GABA(B) receptors. We could not detect Ca2+ influx in astrocytes associated with unitary GABAergic responses. Our experiments identify a presynaptic cell-type-specific, GABA-mediated communication pathway from individual neurons to astrocytes, assigning a role for unitary volume transmission in the control of ionic and neurotransmitter homeostasis.
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BACKGROUND: The second leading cause of cancer-related death in women is breast cancer. Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. In the metabolism of xeno...
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BACKGROUND: The second leading cause of cancer-related death in women is breast cancer. Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. In the metabolism of xenobiotic, cytochrome P450s or monooxygenases perform an important function by catalysing the hydroxylation reaction. In this study, the susceptibility and genetic polymorphisms of CYP450 isoenzymes was investigated that may have an etiological role in breast cancer. AIM: The main purpose of this study was to evaluate the association of CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP2C8 (rs1058930), and CYP19A1 (rs749292) polymorphisms with the risk of breast cancer in Mazandaran province. MATERIAL AND METHODS: This cross-sectional case-control study were recruited 72 patients and 51 healthy individuals and was performed between March 2018 to May 2018 in the Oncology Department at Imam Hospital in Sari city, Iran. Peripheral blood samples were collected in EDTA tube, and DNA extraction was performed using the salting-out method and WizPrep extraction kits. Breast cancer patients with known clinicopathological characters and healthy women as control group were genotyped for genes polymorphisms by PCR-RFLP technique, using restriction enzymes. Chi-square, Fisher exact test and Logistic regression model, were applied for statistical analysis. RESULTS: The results of the experiments showed that there was a significant relationship between two groups and the age of the patients is significantly higher than the control group (p = 0.044). According to the chi-square and Fisher exact test, education, pregnancy, menopause status and oppose were significant between the two groups. Based on using a logistic regression model in two normalized and age-adjusted models to finding relationship between the genotypes of each gene and breast cancer risk, it was determined that in the CYP2C8 genotype, those who have the CG allele have a 7.74 degree increased risk of breast cancer (CI = 95% 0.95-62.5) and in the CYP19A1 gene, individuals with GA genotype, increased risk of breast cancer (CI = %95 1.52-27.21), about the CYP1B1 gene, people with two genotypes of CG + GG had higher risk of breast cancer (CI = %95 1.19-5.71) and allele G has decreased risk of breast cancer in this gene (P = 0.0271), also allele G in CYP2C8 gene had the protective effect (P = 0.02). In the age-adjusted model, for the CYP2C8 gene, GG genotype increased risk of breast cancer (CI = %95 1.11-75.84) as well as, the CG + GG genotype in CYP1B1 gene (CI = %95 1.31-6.57). CONCLUSION: Our results confirm the association between CYP2C8 (rs1058930), CYP19A1 (rs749292) and CYP1B1 (rs1056836) gene polymorphisms and increased risk of breast cancer in women in Mazandaran province.
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Abstract Background Cytokines regulate the expression of inflammatory molecules which destabilize the atheromatic plaques. This study focuses on studying the association of inflammatory cytokine polymorphisms like TNF-α ? 308 (G/...
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Abstract Background Cytokines regulate the expression of inflammatory molecules which destabilize the atheromatic plaques. This study focuses on studying the association of inflammatory cytokine polymorphisms like TNF-α ? 308 (G/A), TNF-β + 252 (A/G), IL-6 ? 174 (G/C) and IL-6 ? 597 (G/A), and IFN-? + 874 (T/A) with coronary artery disease (CAD) among north Indian patients. Materials and methods 143 CAD and 137 normal healthy controls were recruited in this study. DNA extraction was carried out by high salting out method. TNF-α ? 308 (G/A) (rs1800797), TNF-β + 252 (A/G) (rs909253), IL-6 ? 174 (G/C) (rs1800795), IL6 ? 597 (G/A) (rs1800797), and IFN-? + 874 (T/A) (rs2430561) SNPs were genotyped by TaqMan?SNP genotyping assays. Different statistical analyses were performed using SPSS v 22.0 and SNPStats. p ≤ 0.05 was considered significant. Results Significant risk association with CAD was found for TNF-α ? 308 (G/A) “A” allele (OR = 5.6, CI 1.8–17.4, p = 0.001) and TNF-β + 252 (A/G) “G” allele (OR = 3.4, CI = 1.9–6.0, p < 0.001). However, no statistical significance was found for IL-6 ? 174 (G/C) or IL6 ? 597 (G/A), with CAD. TNF-α ? 308 (G/A), and TNF-β + 252 (A/G) haplotype “GG” “AG” increased CAD risk significantly (GG haplotype, adjusted OR = 2.6, CI 1.4–5.0, p = 0.003 and AG haplotype OR = 8.5, CI 2.2–33.35, p = 0.002) after adjustments for age, sex, TC, TG, HDL, APOB, smoking and diet. Discussion The present study found significant risk association for TNF-α ? 308 (G/A), and TNF-β + 252 (A/G) genotypes, alleles and haplotypes, with CAD in a North Indian population. Highlights ? Strong independent effects of TNF-α ? 308 and TNF-β + 252 loci on CAD risk ? Haplotype AG increases CAD risk by 8.5 times in North Indian population. ? IL-6 polymorphisms have no significant effect on CAD in this population. ? Genetic analysis of these and other inflammatory genes in CAD are warranted. ]]>
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Aim: The purpose of our study was to analyze association of miRNAs 146aG/C(2910164) and 196a2C/T(11614913) polymorphism with breast cancer (BC) risk for women of Azeri ethnicity in Iran. Materials & methods: In the current case (n =?200)–control (n =?200) study, miRNAs 146aG/C(2910164) and 196a2C/T(11614913) were investigated for allelic and genotypic levels via the PCR-restriction fragment length polymorphism technique. Results: The statistical analysis showed a significant relation between CC genotype of rs11614913(196a2) (codominant, odds ratio (OR) =?0.58, p?=?0.02236; recessive, OR?=?2.92, p?=?0.016...
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Aim: The purpose of our study was to analyze association of miRNAs 146aG/C(2910164) and 196a2C/T(11614913) polymorphism with breast cancer (BC) risk for women of Azeri ethnicity in Iran. Materials & methods: In the current case (n =?200)–control (n =?200) study, miRNAs 146aG/C(2910164) and 196a2C/T(11614913) were investigated for allelic and genotypic levels via the PCR-restriction fragment length polymorphism technique. Results: The statistical analysis showed a significant relation between CC genotype of rs11614913(196a2) (codominant, odds ratio (OR) =?0.58, p?=?0.02236; recessive, OR?=?2.92, p?=?0.01695; overdominant, OR?=?0.44, p?=?0.0113) and BC susceptibility. The subgroup analysis of mentioned polymorphism declared the significant correlation (p?≤?0.05) of the positive abortion, regular menstruation, positive human epidermal receptor-2 and positive estrogen receptor with BC susceptibility in CC genotype. Conclusion: The existence of a C-allele at miRNA 196a2(11614913) elevates women's BC susceptibility in Azeri ethnicity in Iran.
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