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Monocyte chemoattractant protein-1 (MCP-1) has been proposed as a contributory factor in pathophysiology of schizophrenia. The aim of the current study was to explore the possible association of the MCP-1-2518A/G genetic polymorphism and plasma levels of MCP-1 in patients with paranoid schizophrenia. The MCP-1-2518A/G (rs1024611) polymorphism and blood levels of MCP-1 in patients with paranoid schizophrenia and healthy subjects were evaluated and compared. One hundred and three chronic patients with paranoid schizophrenia treated with neuroleptics and 105 healthy subjects were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and their MCP-1 plasma levels were measured by a solid-phase enzyme-linked immunosorbent assay (ELISA). When comparisons were made between patients and controls, the frequency of the MCP-1-2518*G minor allele (35% vs 23%, p=0.009, OR=1.77, 95% CI: 1.1-2.04) and also of the MCP-1-2518*G carriers (60% vs 40%, p=0.003, OR=2.27, 95% CI: 1.13-2.01) were higher in patients. The mean value of the MCP-1 plasma level in patients with schizophrenia was significantly higher than in controls. Interestingly, the patients with the GG genotype had the highest MCP-1 level (711.4 ± 211.4 pg/ml), followed by those with the AG genotype (472.1 ± 135.8 pg/ml) and AA (372.4 ± 180.2 pg/ml) homozygotes. In conclusion, we report here the association of the -2518A/G genetic polymorphism and increased plasma levels of MCP-1 with schizophrenia and nominate -2518*G minor allele as a risk factor for schizophrenia in Armenian population.
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Quimiocina CCL2/metabolismo , Esquizofrenia/metabolismo , Adulto , Antipsicóticos/uso terapéutico , Armenia , Estudios de Casos y Controles , Quimiocina CCL2/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
BACKGROUND: Schizophrenia is a complex, multifactorial psychiatric disorder. Our previous findings indicated that altered functional activity of the complement system, a major mediator of the immune response, is implicated in the pathogenesis of schizophrenia. In order to explore whether these alterations are genetically determined or not, in the present study we evaluated the possible association of complement C1Q component gene variants with susceptibility to schizophrenia in Armenian population, focusing on four frequent single nucleotide polymorphisms (SNPs) of C1QA and C1QB genes. METHODS: In the present study four SNPs of the complement C1Q component genes (C1QA: rs292001, C1QB rs291982, rs631090, rs913243) were investigated in schizophrenia-affected and healthy subjects. Unrelated Caucasian individuals of Armenian nationality, 225 schizophrenic patients and the same number of age- and sex-matched healthy subjects, were genotyped. Genotyping was performed using polymerase chain reaction with sequence-specific primers (PCR-SSP) and quantitative real-time (qRT) PCR methods. RESULTS: While there was no association between C1QA rs292001, C1QB rs913243 and rs631090 genetic variants and schizophrenia, the C1QB rs291982*G minor allele was significantly overrepresented in schizophrenic patients (G allele frequency 58%) when compared to healthy subjects (46%, OR = 1.64, p(corr) = 0.0008). Importantly, the susceptibility for schizophrenia was particularly associated with C1QB rs291982 GG genotype (OR = 2.5, p(corrected) = 9.6E-5). CONCLUSIONS: The results obtained suggest that C1QB gene may be considered as a relevant candidate gene for susceptibility to schizophrenia, and its rs291982*G minor allele might represent a risk factor for schizophrenia at least in Armenian population. Replication in other centers/populations is necessary to verify this conclusion.
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Complemento C1q/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Población Blanca/genética , Adulto , Alelos , Armenia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/epidemiologíaRESUMEN
BACKGROUND: Whereas the complement system alterations contribute to schizophrenia, complement receptors and regulators are little studied. We investigated complement receptor type 1 (CR1) expression on blood cells, the levels of circulating immune complexes (CIC) containing ligands of CR1, C1q complement protein and fragments of C3 complement protein (C1q-CIC, C3d-CIC), and CR1 C5507G functional polymorphism in schizophrenia patients and controls. RESULTS: We found an increased C1q-CIC level and CR1 expression on blood cells, elevated number of CR1 positive erythrocytes and reduced number of CR1 positive lymphocytes and monocytes in patients compared to controls. No difference in the levels of C3d-CIC between groups was observed. Higher CR1 expression on erythrocytes in CC genotype versus CG+GG for both groups was detected, whereas no difference was observed for other cell populations. Our results indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level. CONCLUSIONS: Our study for the first time indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level. Further studies in other ethnic groups are needed to replicate these findings.
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In the present study, we evaluated functional activity of the alternative pathway of complement in schizophrenia by measuring the alternative pathway hemolytic activity (AH50) of complement as well as hemolytic activity of the complement C3 component (C3H50) in the blood of patients with schizophrenia and healthy subjects. To assess the influence of neuroleptic treatment on measured parameters, both drug-free and medicated patients were examined. In addition, correlation analysis between AH50 and C3H50 has been performed. The results of the present study clearly demonstrate upregulation of the alternative complement cascade in schizophrenia and activator effect of neuroleptics on complement alternative pathway. Based upon the results obtained we hypothesize that hyperactivation of the alternative complement pathway in schizophrenia is stimulated by apoptotic cells.
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Complemento C3/análisis , Vía Alternativa del Complemento , Esquizofrenia/sangre , Adulto , Antipsicóticos/uso terapéutico , Ensayo de Actividad Hemolítica de Complemento , Femenino , Hemólisis , Humanos , Masculino , Esquizofrenia/tratamiento farmacológicoRESUMEN
BACKGROUND: In the present study we assessed the functional state of the major mediator of the immune response, the complement system, in post-traumatic stress disorder (PTSD). METHODS: Thirty one PTSD patients within 13 years from traumatic event and the same number of sex- and age-matched healthy volunteers were involved in this study. In the blood serum of the study subjects hemolytic activities of the classical and alternative complement pathways, as well as the activities of the individual complement components have been measured. Correlation analysis between all measured parameters was also performed. RESULTS: According to the results obtained PTSD is characterized by hyperactivation of the complement classical pathway, hypoactivation of the complement alternative pathway and overactivation of the terminal pathway. CONCLUSIONS: The results obtained provide further evidence on the involvement of the inflammatory component in pathogenesis of PTSD.
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INTRODUCTION: Cryoglobulins are abnormal immune complexes where both the antigens and the antibodies are immunoglobulins. The ability of cryoglobulins to bind C-reactive protein and low density lipoproteins, activate complement, and stimulate production of tumor necrosis factor-alpha generates interest in studying cryoglobulins in ischemic stroke. MATERIALS AND METHODS: We determined blood levels of cryoglobulins in patients with ischemic stroke at different time points of stroke onset and identified the composition of cryoglobulins isolated from the blood on the first day of stroke onset. RESULTS: On days 1-14, significantly elevated levels of cryoglobulins were detected with the maximum level on day 3. DISCUSSION: Determination of immunoglobulin (Ig) content of cryoglobulins revealed the presence of a mixture of polyclonal IgG, IgA, and IgM, C3 complement protein and its activation split products, C1q complement protein, pathogenic lipoprotein-X, and beta-lipoprotein. CONCLUSION: We suggest that cryoglobulins are involved in post-ischemic inflammatory response through activation of the complement cascade and cytokines production.
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Complejo Antígeno-Anticuerpo/metabolismo , Crioglobulinas/metabolismo , Accidente Cerebrovascular/metabolismo , Anciano , Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/inmunología , Complemento C1q/química , Complemento C1q/inmunología , Complemento C1q/metabolismo , Complemento C3/química , Complemento C3/inmunología , Complemento C3/metabolismo , Crioglobulinas/química , Crioglobulinas/inmunología , Femenino , Humanos , Inmunoquímica , Lipoproteína X/química , Lipoproteína X/inmunología , Lipoproteína X/metabolismo , Lipoproteínas LDL/química , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Masculino , Persona de Mediana Edad , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/fisiopatología , Factores de TiempoRESUMEN
OBJECTIVE: In the present work the concentration of abnormal immune complexes, cryoglobulins (Cgs), in the blood of schizophrenic patients was determined, and immunochemical composition of these complexes was studied. PATIENTS AND METHODS: Eighty multiple-episode schizophrenia-affected subjects (55 medicated, 25 drug-free) and 40 healthy controls were involved in the study. Cgs were isolated by exposure of blood serum samples to precipitation at low temperature followed by extensive washings of Cg-enriched pellets. The immunochemical composition of Cgs was analyzed using different electrophoretic and immunoblotting systems. RESULTS: Significantly increased blood serum levels of type III Cgs were detected in all schizophrenia-affected subjects, as compared to controls. We also revealed the presence of C1q and C3 complement proteins and their activation products in Cgs isolated from the blood of schizophrenic patients. CONCLUSIONS: The results of the present study suggest that Cgs are involved in schizophrenia-associated upregulated immune response by binding the complement proteins, activating the complement cascade and triggering aberrant apoptosis.
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Complejo Antígeno-Anticuerpo/sangre , Crioglobulinas/inmunología , Esquizofrenia , Adolescente , Adulto , Apoptosis/fisiología , Complemento C1q/inmunología , Complemento C3/inmunología , Femenino , Humanos , Sistema Inmunológico/fisiología , Persona de Mediana Edad , Esquizofrenia/sangre , Esquizofrenia/inmunologíaRESUMEN
Partial and/or complete deficiency of the complement protein C4 is associated with autoimmune and infectious diseases. Infectious or autoimmune processes may have a role in schizophrenia. Previous reports suggest abnormalities in the complement C4B isotype in schizophrenia and other mental disorders. We assessed C4A and C4B isotypes and serum C4B protein concentration in Armenian schizophrenic patients. Although there was no difference in frequency of C4BQ0, C4B serum protein level was significantly decreased in the schizophrenic patients compared with healthy controls.
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Complemento C4b/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: The aim of the current study was to assess the proteolytic activities of collectin-bound MASP-1 and MASP-2 in the blood of patients with ischaemic stroke, as well as the association of their six genetic polymorphisms (rs3203210, rs28945070, rs28945073 in MASP1 gene and rs2273343, rs12711521, rs147270785 in MASP2 gene) with this pathology. METHODS: In total, 250 patients and 300 healthy subjects were involved in this study. MBL-associated serine protease (MASP)-1 and MASP-2 activities were measured using in-house developed immunofluorescent and enzyme-linked immunosorbent assays, respectively. Sequence specific primer PCR was used to study the association of MASP1 and MASP2 genetic polymorphisms with ischaemic stroke. RESULTS: The results obtained demonstrate that the activities of collectin-bound MASP-1 and MASP-2 in patients with ischaemic stroke are significantly higher than those in healthy subjects (p<0.001). According to the data obtained for genotyping, the rs3203210 polymorphism in the MASP1 gene and the rs147270785 polymorphism in the MASP2 gene are associated with ischaemic stroke (p<0.0001). CONCLUSIONS: In conclusion we suggest that the complement lectin pathway serine proteases, MASP-1 and MASP-2, can be associated with ischaemic stroke development risk and may participate in pathological events leading to post-ischaemic brain damage. Moreover rs3203210 and rs147270785 single nucleotide polymorphisms in the MASP1 and MASP2 genes, respectively, are strongly associated with ischaemic stroke, and the minor rs3203210*C and rs147270785*A alleles of these polymorphisms may be considered as protective factors for ischameic stroke, at least in the Armenian population.
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Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/enzimología , Accidente Cerebrovascular/genética , Adulto , Anciano , Armenia , Biomarcadores/sangre , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Humanos , Masculino , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Accidente Cerebrovascular/diagnósticoRESUMEN
BACKGROUND AND PURPOSE: Ischemic brain injury induces both functional and structural disarray affecting the blood-brain barrier (BBB) which in return aggravates stroke outcomes. Complement system and its bioactive proteins are important molecular responders to ischemia. C5a protein along with its receptor C5a receptor 1 is a key component of this system with potent pro-inflammatory and chemoattractant properties. The purpose of this study is to investigate the role of C5a protein and its receptor which are believed to participate in the inflammatory response that follows ischemic insult. MATERIALS AND METHODS: To mimic an ischemic in vivo event in which C5a may contact brain endothelial cells after injury, we studied oxygen-glucose deprivation (OGD) followed by reperfusion in brain microvascular endothelial cells (b.End. 3) by only added C5a at the time of reperfusion. Cell death and viability were estimated by trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, respectively. Tight junction protein zonula occluden (ZO-1) levels were analyzed by Western blot analysis, and nitric oxide (NO) was assessed using the Griess reagent. RESULTS: Brain-derived endothelial cell was susceptible to OGD-induced injury in a duration-dependent manner as was the presence of ZO-1 protein. However, the addition of C5a protein had no notable effects even when used at high concentrations up to 100 nM. While OGD led to reduction in ZO-1 protein levels, no change was seen following the addition of C5a. Finally, OGD led unexpectedly to small decreases in NO generation, but this was again unaltered by C5a. CONCLUSIONS: Our study suggests that complement system protein C5a may not have a direct role in the disruption of BBB, following brain ischemia. This is in contrary with previous literature that suggests a possible role of this protein in the inflammatory response to ischemia.
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There is considerable evidence to suggest a role for complement in the pathogenesis of schizophrenia, but the data related to the classical pathway complement activity in patients with schizophrenia are conflicting. In the present study, the total hemolytic activity of the complement and the activities of individual complement components, C1, C2, C3 and C4, were determined in the blood serum of schizophrenic patients with positive family history of the disease and healthy subjects. In comparison to the healthy subjects, the mean values of the hemolytic activities of the C1, C3 and C4 complement components in the serum of the schizophrenic patients were significantly higher, and the mean value of the hemolytic activity of the C2 complement component was significantly lower. However, no significant difference was found between the mean values of the total hemolytic activity of complement in schizophrenic patients and healthy subjects. The C3 hemolytic activity was 2.17 times higher in medicated patients than in drug-free patients. Within each group examined no significant difference was found between smokers and non-smokers or between males and females. The results of this study suggest that the pathogenesis of schizophrenia is associated with alterations in activities of complement classical pathway components.
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Vía Clásica del Complemento/inmunología , Proteínas del Sistema Complemento/análisis , Proteínas del Sistema Complemento/inmunología , Esquizofrenia/sangre , Esquizofrenia/inmunología , Adulto , Femenino , Humanos , MasculinoRESUMEN
Defects in synaptic plasticity play a key role in pathophysiology of schizophrenia. Pathomechanisms responsible for synaptic plasticity alterations in schizophrenia are very complicated and not well defined. Transcription factor c-Fos plays an important role in regulation of synaptic plasticity. In the present study we evaluated the association of rs7101 and rs1063169 single nucleotide polymorphisms (SNPs) of c-Fos encoding gene (FOS) with schizophrenia. A total of 604 DNA samples of schizophrenia-affected and healthy subjects of Armenian ancestry were genotyped using polymerase chain reaction with sequence-specific primers. Also, comparative determination of the blood levels of c-Fos protein in schizophrenia patients and controls was performed using the enzyme-linked immunosorbent assay. Potential interaction between protein level and genotypes as well as relationships between genotypes/protein level and clinical-demographic characteristics of schizophrenia patients were assessed. The results obtained demonstrated that mutant allele of FOS rs1063169 SNP is negatively associated with schizophrenia and may be nominated as a protective factor for this disorder. On the other hand, according to our results, the FOS rs7101T mutant allele is positively associated with schizophrenia and, therefore, may be considered as a risk factor for this disorder. In addition, decreased c-Fos plasma levels in schizophrenia patients compared to controls were found. In conclusion, the results of this study suggest that FOS is among the candidate genes of schizophrenia and that changes in the expression of c-Fos protein may contribute to molecular pathomechanisms of schizophrenia-related alterations in synaptic plasticity.
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Predisposición Genética a la Enfermedad , Plasticidad Neuronal/genética , Proteínas Proto-Oncogénicas c-fos/genética , Esquizofrenia/genética , Adulto , Anciano , Alelos , Armenia/epidemiología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Esquizofrenia/epidemiología , Esquizofrenia/patologíaRESUMEN
Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by recurrent thrombosis and pregnancy morbidity in association with the presence of antiphospholipid antibodies. Growing evidence supports the involvement of monocytes in APS pathogenesis. Inflammatory activation of monocytes promotes thrombus formation and other APS complications. However, mechanisms underlying their activation are poorly investigated. We aimed to determine transcriptional activity of monocytes after exposing them to low concentrations of lipopolysaccharide (LPS) and LPS + adenosine triphosphate (ATP) using comparative qRT-PCR. The results showed that LPS significantly increased transcriptional levels of TLR2, IL-23, CCL2, CXCL10, IL-1ß, and IL-6 in APS cells, while, in cells from healthy donors, LPS resulted in IL-6 and STAT3 elevated mRNAs. Double stimulation of the cells resulted in decreased mRNA levels of NLRP3 in monocytes isolated from healthy donors and CCL2, IL-1ß in APS cells. By contrast, TLR2 mRNAs were elevated in both investigated groups after culture of the cells with LPS + ATP. Thus, the findings indicate increased sensitivity of APS cells to LPS that may contribute to thrombus formation and enhance development or progression of autoimmune processes. Low concentrations of ATP diminish LPS-induced inflammatory state of APS monocytes which might be a potential mechanism which regulates inflammatory state of the cells.
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Adenosina Trifosfato/farmacología , Síndrome Antifosfolípido/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Adulto , Anticipación Genética/efectos de los fármacos , Estudios de Casos y Controles , Quimiocina CCL2/metabolismo , Quimiocina CXCL10 , Femenino , Humanos , Interleucinas/metabolismo , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/metabolismo , Receptor Toll-Like 2/metabolismoRESUMEN
The main goal of this study was to establish how the inflammation caused by infection with two different Salmonella enterica serotypes, S. Typhimurium and S. Enteritidis, may lead to the predisposition to allergy as measured by total IgE level in the blood. Infection by S. Typhimurium did not affect the systemic IgE concentration while in S. Enteritidis-infected patients there was a significant 3.5-fold increase. This effect was especially profound in patients >4 years old, with up to the 8-fold increase above the norm. The degree of dysbiosis in these two infections measured with the comparative counts of cultivated bacteria showed an inverse relationship with the IgE concentration. Earlier we reported the elevated level of IL-17 in patients infected by S. Enteritidis. In the current study a significant correlation was found between the concentrations of IL-17 and IgE suggesting a possible role played by this cytokine in triggering the production of IgE in response to S. Enteritidis infection.
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Anticuerpos Antibacterianos/sangre , Inmunoglobulina E/sangre , Salmonella enteritidis/inmunología , Salmonella typhimurium/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Humanos , Lactante , Interleucina-17/sangre , Persona de Mediana Edad , Adulto JovenRESUMEN
To determine if clinical diabetes is associated with disruption of the blood-brain barrier (BBB) and/or brain injury, enzyme-linked immunoassays and Western blots were used to measure serum levels of S100B, NSE and their auto-antibodies in type 1 and type 2 diabetic subjects. Serum S100B concentrations in type 2 diabetic subjects, but not in type 1 diabetic subjects, were significantly lower than those found in healthy controls. There were no significant differences in serum NSE levels of either type 1 or type 2 diabetics compared to healthy controls. However, there was a significant increase in antibodies to NSE in both type 1 and type 2 diabetic subjects compared to controls, whereas diabetics and controls had equally very low levels of anti S100B auto-antibodies. These studies suggest that diabetes in humans may be associated with alterations in the BBB integrity that allow the emergence of antibodies against neuronal antigens.
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Astrocitos/metabolismo , Diabetes Mellitus/diagnóstico , Factores de Crecimiento Nervioso/sangre , Neuronas/metabolismo , Fosfopiruvato Hidratasa/sangre , Proteínas S100/sangre , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Western Blotting/métodos , Niño , Diabetes Mellitus/sangre , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
OBJECTIVES: The purpose of this review is to analyse, sum up and discuss the available literature on the role of inflammation and inflammatory cytokines in the pathogenesis of schizophrenia. METHODS: An electronic literature search of peer-reviewed English language articles using Pubmed was undertaken. These articles together with those published by us provided the background for the present review. RESULTS: An overview of the available literature on this issue clearly demonstrated the alterations in mRNA and protein expression levels of several proinflammatory and chemotactic cytokines in patients with schizophrenia. Importantly, some of these changes are genetically determined. It was noteworthy that, depending on the study population, some variations of the data obtained are detected. CONCLUSIONS: Altered inflammatory cytokine production, both genetically and environmentally determined, is implicated in schizophrenia and contributes to disease-associated low-grade systemic inflammation. Proinflammatory and chemotactic cytokines and their receptors may represent additional therapeutic targets for treatment of schizophrenia.
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Citocinas/inmunología , Mediadores de Inflamación/inmunología , Esquizofrenia/inmunología , Citocinas/genética , Humanos , Esquizofrenia/genéticaRESUMEN
OBJECTIVES: A growing number of studies implicate brain-derived neurotrophic factor (BDNF), an important promoter of synaptic transmission and neural plasticity, in the pathogenesis of schizophrenia. However, the existing data are controversial, that may reflect population differences between studied groups. DESIGN AND METHODS: In the present study we performed a comparative analysis of BDNF plasma levels and its relation with rs6265 (G196A; Val66Met) polymorphism of BDNF gene (BDNF) in schizophrenia-affected and healthy subjects (controls) of the Armenian population. To check the influence of antipsychotics on BDNF plasma levels both medicated and non-medicated patients were involved in this study. Patients with paranoid form of schizophrenia chronically treated with typical antipsychotics (n=103), age- and sex-matched controls (n=105), and 25 antipsychotic-naive first-episode schizophrenia patients were involved. The levels of BDNF in the blood plasma were measured with a solid-phase enzyme-linked immunosorbent assay. RESULTS: Decreased plasma levels of BDNF in both medicated and non-medicated schizophrenia patients compared to controls were observed. No significant difference in BDNF levels between medicated and non-medicated patients was detected. It was also detected that, compared to individuals homozygous for the standard allele (G/G) of rs6265, carriers of the rs6265 minor allele (A/G+A/A), which is significantly more frequent in schizophrenia patients than in controls, had decreased BDNF levels. CONCLUSIONS: The data obtained suggested that the pathogenesis of schizophrenia is characterized by genetically predetermined decreased blood levels of BDNF. These results indicated that genetically determined alterations of neuroimmune modulators may be among the risk factors of schizophrenia and contribute to disease-specific pathologic changes in functional activity of both the neuronal synaptic plasticity and the immune system.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Esquizofrenia/sangre , Adulto , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/genéticaRESUMEN
Schizophrenia (SCZ) is a multifactorial chronic and disabling mental disease. The specific genetic variants contributing to disease complex phenotype are largely unknown. Growing amount of evidence suggested that aberrant synaptic connectivity contributes to SCZ pathogenesis. From this point of view, complexin-2, a presynaptic regulatory protein, represents here a special interest, since it has been recently shown that genetic variants of the CPLX2 gene may affect current cognitive performance in patients with SCZ. A specific objective of this study was to evaluate if tagging single nucleotide polymorphisms (rs3892909, rs1366116) of gene encoding complexin-2 protein (CPLX2) linked to SCZ and to examine their relationships with complexin-2 blood levels. DNA samples of 260 patients with SCZ and 260 sex- and age-matched healthy controls were genotyped for the selected polymorphisms by application of polymerase chain reaction with sequence-specific primers, and concentration of complexin-2 in the blood plasma was determined using the enzymelinked immunosorbent assay. All study subjects were unrelated Armenians. According to the obtained results, in the patients group both the frequency distribution and carriage rate of the CPLX2 rs1366116*T minor allele were higher than in controls. On the contrary, the frequency distribution and carriage rate of the CPLX2 rs3892909*T minor allele in control group were higher than in patients. This data suggested that the presence of the CPLX2 rs1366116*T allele increases susceptibility to SCZ, whereas the rs3892909*T allele of the CPLX2 decreases the risk of SCZ. Furthermore, we found that CPLX2 rs1366116*T heterozygosity is associated with earlier disease onset. No difference between complexin-2 plasma levels in patients and controls and no significant interaction between complexin-2 plasma levels and CPLX2 genotypes in both groups were observed. In summary, we concluded that the CPLX2 rs1366116*T variant represents a risk factor of SCZ, and that, at the same time, the CPLX2 rs3892909*T variant is protective against SCZ.
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Proteínas Adaptadoras del Transporte Vesicular/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Proteínas Adaptadoras del Transporte Vesicular/sangre , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/sangre , Riesgo , Esquizofrenia/sangre , Esquizofrenia/epidemiología , Adulto JovenRESUMEN
Altered immune response, including low-grade inflammatory processes, is involved in the pathogenesis of schizophrenia, a chronic psychiatric disorder with complex etiology. Distinct gene variants of a number of pro-inflammatory and chemotactic cytokines together with their receptors associate with this disorder. Interleukin-2 receptor gamma (IL-2RG) represents an important signaling component of many interleukin receptors and so far, no data on the functional state of this receptor in schizophrenia have been reported. The aim of this study was to investigate mRNA expression of the IL2RG gene (IL2RG) in schizophrenia patients in comparison with healthy subjects (controls). Total RNA was isolated from peripheral blood of 66 schizophrenia patients and 99 healthy subjects of Armenian population. The mRNA expression was determined by quantitative real-time polymerase chain reaction (RT-PCR) using PSMB2 as housekeeping gene. IL2RG mRNA expression was upregulated in peripheral blood of patients in comparison with controls (patients vs. controls, median [interquartile range]: 2.080 [3.428-1.046] vs. 0.324 [0.856-0.000], p<0.0001). In conclusion, our findings suggest that over-expression of the IL2RG gene may be implicated in altered immune response in schizophrenia and contribute to the pathomechanisms of this disorder.
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Subunidad gamma Común de Receptores de Interleucina/genética , Receptores de Interleucina-2/genética , Esquizofrenia/genética , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/sangre , ARN Mensajero/genética , Esquizofrenia/inmunología , Esquizofrenia/fisiopatologíaRESUMEN
Promising studies suggest that defects in synaptic plasticity detected in schizophrenia may be linked to neurodevelopmental and neurodegenerative abnormalities and contribute to disease-associated cognitive impairment. We aimed to clarify the role of the synaptic plasticity regulatory proteins, nerve growth factor (NGF) and its receptor (NGFR) in the pathogenesis of schizophrenia by comparative analysis of their blood levels and functional single nucleotide polymorphisms (SNPs) in genes encoding these proteins (NGF and NGFR) in schizophrenia-affected and healthy subjects. Relationships between the selected SNPs' genotypes and NGF and NGFR plasma levels were also assessed. Our results demonstrated a positive association between schizophrenia and the NGF rs6330 as well as the NGFR rs11466155 and rs2072446 SNPs. Also, a negative association between this disorder and NGF rs4839435 as well as NGFR rs734194 was found. In both, haloperidol-treated and antipsychotic-free patients decreased blood levels of the NGF and NGFR were found, and a positive interrelation between rs6330 and rs2072446 carriage and decreased NGF and NGFR levels, respectively, was revealed. In conclusion, our results demonstrate association of schizophrenia with the rs6330, rs4839435 and rs734194, rs11466155, rs2072446 as well as with the decreased blood levels of corresponding proteins. Our findings indicate the implication of alterations in NGFR and NGFR genes in schizophrenia, particularly, in defects of synaptic plasticity. Furthermore, the data obtained suggests that at least in Armenian population the NGF rs6330*T and NGFR rs11466155*T, rs2072446*T alleles might be nominated as risk factors, whereas the NGF rs4839435*A and NGFR rs734194*G alleles might be protective against developing schizophrenia.