Characterization of gut microbiota profile in Iranian patients with bipolar disorder compared to healthy controls.

Introduction: The human gut microbiota plays a crucial role in mental health through the gut-brain axis, impacting central nervous system functions, behavior, mood, and anxiety. Consequently, it is implicated in the development of neuropsychiatric disorders. This study aimed to assess and compare the gut microbiota profiles and populations of individuals with bipolar disorder and healthy individuals in Iran. Methods: Fecal samples were collected from 60 participants, including 30 bipolar patients (BPs) and 30 healthy controls (HCs), following rigorous entry criteria. Real-time quantitative PCR was utilized to evaluate the abundance of 10 bacterial genera/species and five bacterial phyla. Results: Notably, Actinobacteria and Lactobacillus exhibited the greatest fold change in BPs compared to HCs at the phylum and genus level, respectively, among the bacteria with significant population differences. Ruminococcus emerged as the most abundant genus in both groups, while Proteobacteria and Bacteroidetes showed the highest abundance in BPs and HCs, respectively, at the phylum level. Importantly, our investigation revealed a lower Firmicutes/Bacteroidetes ratio, potentially serving as a health indicator, in HCs compared to BPs. Conclusion: This study marks the first examination of an Iranian population and provides compelling evidence of significant differences in gut microbiota composition between BPs and HCs, suggesting a potential link between brain functions and the gut microbial profile and population.

Alteration of TRIM33 Expression at Transcriptional and Translational Levels is Correlated with Autism Symptoms.

As a complex neurodevelopmental disorder, autism affects children in three major cognitive domains including social interactions, language learning and repetitive stereotyped behaviors. Abnormal regulation of cell proliferation in the brain during the embryonic period via the TGF-ß signaling pathway and TRIM33 gene that encodes a protein with a corepressor and regulatory role in this pathway has been considered as an etiology for autism. Here, we investigated the association of a variation of TRIM33 with autism symptoms at levels of mRNA and protein expression. We used Autism Diagnostic Interview-Revised (ADI-R) and Childhood Autism Rating Scale (CARS) as behavioral diagnostic tools. Normal and autistic children were genotyped for a TRIM33 polymorphism (rs11102807), and then expression was assessed at transcriptional and translational levels. Results demonstrated that the frequency of the homozygous A allele (AA genotype of rs11102807) was significantly higher in children with autism (P < 0.001), whereas carriers of the G allele were mostly among healthy individuals. Children homozygous for the rs11102807 A allele were associated with an increase in CARS and ADI-R scores, indicating a significant correlation with autism symptoms. TRIM33 gene expression at both mRNA (P < 0.01) and protein (P < 0.001) levels was significantly higher in controls compared to autistic children. A remarkable association between higher TRIM33 gene expression at the transcriptional level and lower scores for both CARS and ADI-R was observed in non-autistic children. It seems that rs11102807 modulates the function and expression of the TRIM33 gene, implying that the A allele may increase the risk of autism in children by reducing gene expression and altering the TGF-ß signaling pathway.

Longitudinal Effects of Bumetanide on Neuro-Cognitive Functioning in Drug-Resistant Epilepsy.

Antiepileptic drugs (AEDs) have repeatedly shown inconsistent and almost contradictory effects on the neurocognitive system, from substantial impairments in processing speed to the noticeable improvement in working memory and executive functioning. Previous studies have provided a novel insight into the cognitive improvement by bumetanide as a potential antiepileptic drug. Through the current investigation, we evaluated the longitudinal effects of bumetanide, an NKCC1 co-transporter antagonist, on the brain microstructural organization as a probable underlying component for cognitive performance. Microstructure assessment was completed using SPM for the whole brain assay and Freesurfer/TRACULA for the automatic probabilistic tractography analysis. Primary cognitive operations including selective attention and processing speed, working memory capacity and spatial memory were evaluated in 12 patients with a confirmed diagnosis of refractory epilepsy. Participants treated with bumetanide (2 mg/ day) in two divided doses as an adjuvant therapy to their regular AEDs for 6 months, which followed by the re-assessment of their cognitive functions and microstructural organizations. Seizure frequency reduced in eight patients which accompanied by white matter reconstruction; fractional anisotropy (FA) increased in the cingulum-cingulate gyrus (CCG), anterior thalamic radiation (ATR), and temporal part of the superior longitudinal fasciculus (SLFt) in correlation with the clinical response. The voxel-based analysis in responder patients revealed increased FA in the left hippocampus, right cerebellum, and right medial temporal lobe, while mean diffusivity (MD) values reduced in the right occipital lobe and cerebellum. Microstructural changes in SLFt and ATR accompanied by a reduction in the error rate in the spatial memory test. These primary results have provided preliminary evidence for the effect of bumetanide on cognitive functioning through microstructural changes in patients with drug-resistant epilepsy.

TCF4 and GRM8 gene polymorphisms and risk of schizophrenia in an Iranian population: a case-control study.

TCF4 and GRM8, two significant genes involved in the normal nervous development and glutamate pathway, are thought to be involved in the pathogenesis of schizophrenia (SCZ). We aimed to explore the association of TCF4 and GRM8 gene polymorphisms with risk of SCZ. The rs8766 in TCF4 and rs712723 in GRM8 were selected for genotyping in a set of Iranian case-control samples including 215 patients and 220 matched healthy controls using polymerase chain reaction-restriction fragment length polymorphism. Although rs8766 increased the OR, we found that rs8766 allele and genotype frequencies were not significantly different between case and control groups and a significant association cannot be suggested for the selected SNP. However, allele C and genotype CC (allele C: OR 1.48, 95% CI 1.13-1.94; genotype CC: OR 1.71, 95% CI 1.09-2.68) of rs712723 polymorphism was found to have a significant association with risk of SCZ. Frequency of allele C (P = 0.003) and genotype CC (P = 0.017) was higher in the schizophrenic patients, while allele T (P = 0.003) and genotype TT (P = 0.028) frequencies were found lower in patients. Our findings indicate that rs712723 in GRM8 may play an important role in the pathogenesis of SCZ. However, our conclusion needs to be confirmed in other population.

Integrated analysis of the genetic basis of suicidal behavior: what has been shown by structural genetic studies so far.

OBJECTIVE: In recent decades, the role of genetic factors in the predisposition to suicidal behavior has attracted considerable attention. Although each genetic investigation appears to be valuable, no one study on its own can comprehensively explain the etiology of suicidal behavior. METHODS: In this study, using a broad literature review, we found the suicide-associated gene coexpression network. In addition, cytoband, molecular function, biological process, cellular component, tissue-based expression, and disease/disorder enrichment analyses were carried out to determine the most central cellular and molecular infrastructures involved in suicidal behavior. RESULTS: The reconstructed network consisted of 104 genes, including 91 previously known genes and 13 novel genes, and 354 interactions. Topological analysis showed that in total, CCK, INPP1, DDC, and NPY genes are the most fundamental hubs in the network. We found that suicide genes are significantly concentrated within chromosomes 11 and 6. Further analysis showed that monoaminergic signal transduction, especially through GPCRs, in the cingulate gyrus, superior prefrontal gyrus, dorsal striatum, and the cerebellum are the main, deficient routes in suicide. Moreover, it turned out that genetically, suicidal behavior is more likely in patients with mood and affective disorders. CONCLUSION: Like other behavioral disorders, suicide has a complex and multifactorial basis and at present, the only approaches to the integrated study of such disorders are computer-based methods. The results of such studies, although subject to a degree of uncertainty, however, can pave the way for future basic and clinical studies.

Association of transcription factor 4 (TCF4) gene mRNA level with schizophrenia, its psychopathology, intelligence and cognitive impairments.

Schizophrenia (SCZ), is considered as one of the most debilitating mental disorders around the world. Symptom-based clinical interview and numerous tests have been used to evaluate the diagnosis and also cognitive disturbances in patients with SCZ. All these tests measure phenotype-based functions. Thus, it seems accurate diagnosis of such complex disorders must rely on more valid and reliable factors. In this study, we evaluated the association of transcription factor 4 (TCF4) gene mRNA level in peripheral blood with SCZ, and also its psychopathology, cognitive and intellectual impairments. In this study, using real-time PCR, we compared TCF4 mRNA level between the case (70 unmedicated schizophrenia patients) and healthy control (n = 72) groups. In addition, all subjects underwent Psychopathology (PANSS) and cognitive and intelligence (WAIS, WMS, Stroop, WCST) assessments, and scores were compared between the two groups. Also, to determine the effect of TCF4 expression on psychopathology, cognitive and intellectual functions, the correlation between expression level and test scores was measured. The correlation between gene expression and age of onset and duration of the disorder was evaluated as well. Our results showed that the TCF4 mRNA level, psychopathology, cognitive and intellectual functions were significantly different in all, male, and female patients compared to healthy participants. Additionally, it was found that TCF4 level is positively correlated with scores of WAIS and WMS and is negatively correlated with Stroop and WCST errors and PANSS score. Our results showed that the mRNA level of TCF4 may be associated with SCZ, its psychopathology, IQ and cognitive impairments in an Iranian group of patients with SCZ. These results may help to better understanding the TCF4 role in the psychopathogenesis of SCZ and also may shed some light on the ongoing works conducted on peripheral biomarker-based diagnosis of complicated mental disorders.

Obsessive-compulsive disorder, which genes? Which functions? Which pathways? An integrated holistic view regarding OCD and its complex genetic etiology.

Obsessive-compulsive disorder (OCD) is characterized by recurrent obtrusive and repetitive acts typically occurred following anxiety. In the last two decades, studies done on the gene sequences, large-scale and point mutations and gene-gene, gene-environment and gene-drug interactions have led to the discovery of hundreds of genes associated with OCD. Although each gene in turn is a part of the etiology of this disorder; however, OCD, like other mental disorders is complex and a comprehensive and integrated view is necessary to understand its genetic basis. In this study, through an extensive review of existing published studies, all genes associated with OCD were found. Then, in order to integrate the results, all the interactions between these genes were explored and the achievement was represented as an interactive genetic network. Furthermore, the reconstructed network was analyzed. It was found that GRIN2A, GRIN2B and GRIA2 are the most central nodes in the network. Functional and pathway enrichment analysis showed that glutamate-related pathways are the main deficient systems in patients with OCD. By studying genes shared between OCD and other diseases, it was cleared that OCD, epilepsy and some types of cancer have the most number of shared genes. The results of this study, in addition to reviewing the available results as a comprehensive and integrated manner, provide new hypotheses for future studies.

Association Between Neuregulin-1 Gene Variant (rs2439272) and Schizophrenia and Its Negative Symptoms in an Iranian Population.

Objective: Although the etiology of schizophrenia is unknown, it has a significant genetic component. A number of studies have indicated that neuregulin-1 (NRG1) gene may play a role in the pathogenesis of schizophrenia. In this study, we examined whether the rs2439272 of NRG1 is associated with schizophrenia and its negative symptoms in an Iranian population. Method: Rs2439272 was genotyped in 469 participants including 276 unrelated patients with schizophrenia and 193 healthy controls. The association of genetic risk with negative symptoms (by using panss) was examined in the total, male and female samples. COCAPHASE and CLUMP22 programs were used to compare the allele and genotype frequencies, and general linear regression was used to analyze the quantitative dependent variables by the selected variant. Results: In this study, it was revealed that the G allele of rs2439272 might be an allele with the increased risk of developing schizophrenia, especially in the male participants. In addition, significant differences were found between the G allele and GG genotype frequencies, and negative symptoms in the total and male participants. Conclusion: Our results supported the association between rs2439272 in NRG1 gene and risk of schizophrenia and its negative symptoms in an Iranian population. .

Comparing the effects of fluoxetine and imipramine on total cholesterol, triglyceride, and weight in patients with major depression.

BACKGROUND: There are some reports on the effects of antidepressants on metabolic syndrome. However, our search in the previously published literature showed a lack of information on the comparison of the effects of different classes of antidepressants on lipid profile. Therefore, this study was aimed to compare the effects of fluoxetine and imipramine on serum total cholesterol (TC) and triglyceride (TG) as well as body weight (BW) in patients with major depressive disorder. METHODS: Fifty one patients, 18 to 70 years of age, with major depressive disorder complied with the criteria of this preliminary, open-label clinical trial. Subjects received either imipramine (75-200 mg/day) or fluoxetine (20-40 mg/day) for 8 weeks. Total cholesterol and TG levels, as well as BW were compared at baseline with those at weeks 4 and 8. Data was analyzed by SPSS software version 16.0. RESULTS: In the fluoxetine group, TC levels decreased from 165.71 mg/dL to 156.71 mg/dL at week 4 (P = 0.07), and to 143.94 mg/dL at week 8 (P = 0.16); TG levels decreased from 129.35 mg/dL to 115.88 mg/dL at week 4 (P <0.001), and to 110.41 mg/dL at week 8 (P = 0.56). In the imipramine group, TC levels increased from 169.10 mg/dL to 178.69 mg/dL at week 4 (P = 0.07), and to 208.69 mg/dL at week 8 (P < 0.001) while TG levels increased from 111.73 mg/dL to 128.83 mg/dL at week 4 (P = 0.005), and to 160.90 mg/dL at week 8 (P < 0.001). BW was significantly increased in the imipramine group at weeks 4 and 8. In the fluoxetine group, BW was non-significantly decreased from 75.69 ± 7.97 Kg (baseline) to 75.67 ± 8.01 Kg at week 4 (P = 0.88), and to 75.22 ± 8.67 Kg at week 8 (P = 0.20), while in the imipramine group, BW had significant increases from 72.53 ± 8.55 Kg (baseline) to 73.95 ± 8.61 mg/dL at week 4 (P < 0.001), and to 75.13 ± 8.34 mg/dL at week 8 (P < 0.001).Repeated measures ANOVA showed significant effects on both TC and TG levels as well as on BW in all patients receiving imipramine. However, in patients on fluoxetine, repeated measures ANOVA showed significant effects of this medication only on TC levels in males. CONCLUSIONS: Monitoring TC and TG and BW is recommended before starting imipramine in depressed patients with increased risk for cardiovascular disease. Fluoxetine may be the preferred agent in those with high or borderline high lipid levels.

Association between ABCB1-T1236C polymorphism and drug-resistant epilepsy in Iranian female patients.

BACKGROUND: One third of epileptic patients are resistant to several anti-epileptic drugs (AED). P-glycoprotein (P-gp) is an efflux transporter encoded by ATP-binding cassette subfamily B member 1 (ABCB1) gene that excludes drugs from the cells and plays a significant role in AEDs resistance. Over-expression of P-gp could be a result of polymorphisms in ABCB1 gene. We studied the association of T129C and T1236C single-nucleotide polymorphisms (SNP) of ABCB1 gene with drug-resistant epilepsy in Iranian epileptics. METHODS: DNA samples were obtained from 200 healthy controls and 332 epileptic patients, of whom 200 were drug responsive and 132 drug resistant. The frequencies of the genotypes of the two SNP were determined by polymerase chain reaction followed by restriction fragment length polymorphism. RESULTS: No significant association was found between T129C and T1236C genotypes and drug-resistant epilepsy neither in adults nor in children. However, the risk of drug resistance was higher in female patients with 1236CC (P = 0.02) or CT (P = 0.008) genotype than in those with TT genotype. The risk of drug resistance was also higher in patients with symptomatic epilepsies with 1236CC (P = 0.02) or CT (P = 0.004) genotype than in those with TT genotype. The risk of drug resistance was lower in patients with idiopathic epilepsies with 129TT genotype (P = 0.001) than in those with CT genotype. CONCLUSION: Our results indicate that T1236C polymorphism is associated with drug resistance in Iranian female epileptic patients. Replication studies with large sample sizes are needed to confirm our results.