Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether [BDE-47] and 2,2',4,5'-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.
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PMID:Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background. 2328 49

A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5-HT2A) receptors. Most of the tetracyclic compounds exhibited higher affinities for D2 and 5-HT1A receptors than l-SPD, while compound 23 e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23 d and 23 e were more potent than l-SPD at D3 receptor. According to the functional assays, 23 d and 23 e were demonstrated as full antagonists at D1 and D2 receptors and full agonists at 5-HT1A receptor. Since the combination of D2 antagonism and 5-HT1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents.
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PMID:Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l-SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles. 2530 66

Schizotypy captures the underlying genetic vulnerability to schizophrenia. However, the genetic underpinnings of schizotypy remain unexplored. The authors examined the relationship between single nucleotide poly-morphisms (SNPs) and schizotypy. A sample of 137 subjects (43 healthy controls, 34 subjects with schizotypal personality disorder [SPD], 32 with borderline personality disorder, and 25 with other personality disorders) completed the Schizotypal Personality Questionnaire (SPQ). Subjects were genotyped using a custom array chip. Principal component analysis was used to cluster SPQ variables. Linear regression tested for associations between dimensional schizotypy and SNPs. Logistic regression tested for associations between SNPs and SPD diagnosis. There were significant associations between the minor alleles of three SNPs within the glycine receptor alpha 1 subunit (GLRA1) and the disorganized schizotypy dimension, even after Bonferroni correction. There were no significant associations between any SNPs and the categorical SPD diagnosis. Glycine receptor pathways may have an impact on dimensional traits of psychosis.
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PMID:Dimensional Traits of Schizotypy Associated With Glycine Receptor GLRA1 Polymorphism: An Exploratory Candidate-Gene Association Study. 2875 85

Abnormalities in temporal and frontal cortical volume, white matter tract integrity, and hemispheric asymmetry have been implicated in schizophrenia-spectrum disorders. Schizotypal personality disorder can provide insight into vulnerability and protective factors in these disorders without the confounds associated with chronic psychosis. However, multimodal imaging and asymmetry studies in SPD are sparse. Thirty-seven individuals with SPD and 29 healthy controls (HC) received clinical interviews and 3T magnetic resonance T1-weighted and diffusion tensor imaging scans. Mixed ANOVAs were performed on gray matter volumes of the lateral temporal regions involved in auditory and language processing and dorsolateral prefrontal cortex involved in executive functioning, as well as fractional anisotropy (FA) of prominent white matter tracts that connect frontal and temporal lobes. In the temporal lobe regions, there were no group differences in volume, but SPD had reduced right>left middle temporal gyrus volume asymmetry compared to HC and lacked the right>left asymmetry in the inferior temporal gyrus volume seen in HC. In the frontal regions, there were no differences between groups on volume or asymmetry. In the white matter tracts, SPD had reduced FA in the left sagittal stratum and superior longitudinal fasciculus, and increased right>left asymmetry in sagittal stratum FA compared to HC. In the SPD group, lower left superior longitudinal fasciculus FA was associated with greater severity of disorganization symptoms. Findings suggest that abnormities in structure and asymmetry of temporal regions and frontotemporal white matter tract integrity are implicated in SPD pathology.
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PMID:Frontal and temporal cortical volume, white matter tract integrity, and hemispheric asymmetry in schizotypal personality disorder. 2945 12

We have previously argued that the current borderline personality disorder (BPD) diagnosis is over-inclusive and clinically and conceptually impossible to distinguish from the schizophrenia spectrum disorders. This study involves 30 patients clinically diagnosed with BPD as their main diagnosis by three BPD dedicated outpatient treatment facilities in Denmark. The patients underwent a careful and time-consuming psychiatric evaluation involving several senior level clinical psychiatrists and researchers and a comprehensive battery of psychopathological scales. The study found that the vast majority of patients (67% in DSM-5 and 77% in ICD-10) in fact met the criteria for a schizophrenia spectrum disorder, i.e., schizophrenia (20%) or schizotypal (personality) disorder (SPD). The schizophrenia spectrum group scored significantly higher on the level of disorders of core self as measured by the Examination of Anomalous Self-Experiences Scale (EASE). The BPD criterion of "identity disturbance" was significantly correlated with the mean total score of EASE. These findings are discussed in the light of changes from prototypical to polythetic diagnostic systems. We argue that the original prototypes/gestalts informing the creation of BPD and SPD have gone into oblivion during the evolution of polythetic criteria.
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PMID:Exploring schizophrenia spectrum psychopathology in borderline personality disorder. 3128 25


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