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BACKGROUND: The diagnosis of adolescent Depressive Disorder (DD) lacks specific biomarkers, posing significant challenges. This study investigates the potential of Niacin Skin Flush Response (NSFR) as a biomarker for identifying and assessing the severity of adolescent Depressive Disorder, as well as distinguishing it from Behavioral and Emotional Disorders typically emerging in childhood and adolescence(BED). METHODS: In a case-control study involving 196 adolescents, including 128 Depressive Disorder, 32 Behavioral and Emotional Disorders, and 36 healthy controls (HCs), NSFR was assessed. Depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) and anxious symptoms with the Generalized Anxiety Disorder 7-item scale (GAD-7). Pearson correlation analysis determined the relationships between NSFR and the severity of depression in DD patients. Receiver Operating Characteristic (ROC) was used to identify DD from BED integrating NSFR data with clinical symptom measures. RESULTS: The adolescent Depressive Disorder group exhibited a higher rate of severe blunted NSFR (21.4%) compared to BED (12.5%) and HC ( 8.3%). Adolescent Depressive Disorder with psychotic symptoms showed a significant increase in blunted NSFR (p = 0.016). NSFR had negative correlations with depressive (r = -0.240, p = 0.006) and anxious (r = -0.2, p = 0.023) symptoms in adolescent Depressive Disorder. Integrating NSFR with three clinical scales improved the differentiation between adolescent Depressive Disorder and BED (AUC increased from 0.694 to 0.712). CONCLUSION: The NSFR demonstrates potential as an objective biomarker for adolescent Depressive Disorder, aiding in screening, assessing severity, and enhancing insights into its pathophysiology and diagnostic precision.
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Niacina , Humanos , Adolescente , Depresión , Trastornos de Ansiedad/psicología , Estudios de Casos y Controles , BiomarcadoresRESUMEN
AIM: Blunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients. METHODS: Two independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT-PCR analysis, eQTL data, and Dual-Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR. RESULTS: The results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data. CONCLUSION: HCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In-depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.
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Niacina , Receptores Nicotínicos , Esquizofrenia , Humanos , Niacina/farmacología , Niacina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Endofenotipos , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Receptores Nicotínicos/genética , Receptores Nicotínicos/uso terapéutico , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/uso terapéuticoRESUMEN
BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia. METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome was the prediction of nonresponse. Nonresponse is defined as a < 20% reduction in the total scores of PANSS from baseline to endpoint. Severity ratings of mild, moderate, and severe illness corresponded to baseline PANSS total scores of 58, 75, and 95, respectively. RESULTS: At week 2, a reduction of < 5% in the PANSS total score showed the highest total accuracy in the severe and mild schizophrenia patients (total accuracy, 75.0% and 80.8%, respectively), and patients who were treated with the risperidone and amisulpride groups (total accuracy, 82.4%, and 78.2%, respectively). A 10% decrease exhibited the best overall accuracy in the moderate schizophrenia patients (total accuracy, 84.0%), olanzapine (total accuracy, 79.2%), and aripiprazole group (total accuracy, 77.4%). At week 4, the best predictive cut-off value was < 20%, regardless of the antipsychotic or severity of illness (total accuracy ranging from 89.8 to 92.1%). CONCLUSIONS: Symptom reduction at week 2 has acceptable discrimination in predicting later non-response to antipsychotics in schizophrenia, and a more accurate predictive cut-off value should be determined according to the medication regimen and baseline illness severity. The response to treatment during the next 2 weeks after week 2 could be further assessed to determine whether there is a need to change antipsychotic medication during the first four weeks. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (NCT03451734).
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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Olanzapina/uso terapéutico , Risperidona/uso terapéutico , Aripiprazol/uso terapéutico , Amisulprida/uso terapéutico , Resultado del TratamientoRESUMEN
Schizophrenia is a complex and highly heterogeneous mental illness with a prodromal period called clinical high risk (CHR) for psychosis before onset. Metabolomics is greatly promising in analyzing the pathology of complex diseases and exploring diagnostic biomarkers. Therefore, we conducted salivary metabolomics analysis in 83 first-episode schizophrenia (FES) patients, 42 CHR individuals, and 78 healthy controls with ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The mass spectrometry raw data have been deposited on the MetaboLights (ID: MTBLS3463). We found downregulated aromatic amino acid metabolism, disturbed glutamine and nucleotide metabolism, and upregulated tricarboxylic acid cycle in FES patients, which existed even in the CHR stage and became more intense with the onset of the schizophrenia. Moreover, differential metabolites can be considered as potential diagnostic biomarkers and indicate the severity of the different clinical stages of disease. Furthermore, three disordered pathways were closely related to peripheral indicators of inflammatory response, oxidative stress, blood-brain barrier damage, and salivary microbiota. These results indicate that the disorder of oral metabolism occurs earlier than the onset of schizophrenia and is concentrated and intensified with the onset of disease, which may originate from the dysbiotic salivary microbiota and cause the onset of schizophrenia through the peripheral inflammatory response and redox system, suggesting the importance of oral-brain connection in the pathogenesis of schizophrenia.
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Trastornos Psicóticos , Esquizofrenia , Biomarcadores , Humanos , Espectrometría de Masas , Metabolómica/métodos , Síntomas Prodrómicos , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: Brachydactyly type A1 (BDA1, OMIM 112500) is a rare inherited malformation characterized primarily by shortness or absence of middle bones of fingers and toes. It is the first recorded disorder of the autosomal dominant Mendelian trait. Indian hedgehog (IHH) gene is closely associated with BDA1, which was firstly mapped and identified in Chinese families in 2000. Previous studies have demonstrated that BDA1-related mutant IHH proteins affected interactions with its receptors and impaired IHH signaling. However, how the altered signaling pathway affects downstream transcriptional regulation remains unclear. RESULTS: Based on the mouse C3H10T1/2 cell model for IHH signaling activation, two recombinant human IHH-N proteins, including a wild type protein (WT, amino acid residues 28-202) and a mutant protein (MT, p.E95k), were analyzed. We identified 347, 47 and 4 Gli1 binding sites in the corresponding WT, MT and control group by chromatin immunoprecipitation and the overlapping of these three sets was poor. The putative cis regulated genes in WT group were enriched in sensory perception and G-protein coupled receptor-signaling pathway. On the other hand, putative cis regulated genes were enriched in Runx2-related pathways in MT group. Differentially expressed genes in WT and MT groups indicated that the alteration of mutant IHH signaling involved cell-cell signaling and cellular migration. Cellular assay of migration and proliferation validated that the mutant IHH signaling impaired these two cellular functions. CONCLUSIONS: In this study, we performed integrated genome-wide analyses to characterize differences of IHH/Gli1 downstream regulation between wild type IHH signaling and the E95K mutant signaling. Based on the cell model, our results demonstrated that the E95K mutant signaling altered Gli1-DNA binding pattern, impaired downstream gene expressions, and leaded to weakened cellular proliferation and migration. This study may help to deepen the understanding of pathogenesis of BDA1 and the role of IHH signaling in chondrogenesis.
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Braquidactilia/genética , Proteínas Hedgehog/genética , Mutación , Transcripción Genética/genética , Proteína con Dedos de Zinc GLI1/genética , Braquidactilia/patología , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Cadmium (Cd) is a ubiquitous environmental toxicant for aquatic animals. The freshwater crab, Sinopotamon henanense (S. henanense), is a useful model for monitoring Cd exposure since it is widely distributed in sediments whereby it tends to accumulate several toxicants, including Cd. In the recent years, the toxic effects of Cd in the hepatopancreas of S. henanense have been demonstrated by a series of biochemical analysis and ultrastructural observations as well as the deep sequencing approaches and gene expression profile analysis. However, the post-transcriptional regulatory network underlying Cd toxicity in S.henanense is still largely unknown. RESULTS: The miRNA transcriptional profile of the hepatopancreas of S. henanense was used to investigate the expression levels of miRNAs in response to Cd toxicity. In total, 464 known miRNAs and 191 novel miRNAs were identified. Among these 656 miRNAs, 126 known miRNAs could be matched with the miRNAs of Portunus trituberculatus, Eriocheir sinensis and Scylla paramamosain. Furthermore, a total of 24 conserved miRNAs were detected in these four crab species. Fifty-one differentially expressed miRNAs were identified in the Cd-exposed group, with 31 up-regulated and 20 down-regulated. Eight of the differentially expressed miRNAs were randomly selected and verified by the quantitative real-time PCR (qRT-PCR), and there was a general consistency (87.25%) between the qRT-PCR and miRNA transcriptome data. A total of 5258 target genes were screened by bioinformatics prediction. GO term analysis showed that, 17 GO terms were significantly enriched, which were mainly related to the regulation of oxidoreductase activity. KEGG pathway analysis showed that 18 pathways were significantly enriched, which were mainly associated with the biosynthesis, modification and degradation of proteins. CONCLUSION: In response to Cd toxicity, in the hepatopancreas of S. henanense, the expressions of significant amount of miRNAs were altered, which may be an adaptation to resist the oxidative stress induced by Cd. These results provide a basis for further studies of miRNA-mediated functional adaptation of the animal to combat Cd toxicity.
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Braquiuros/efectos de los fármacos , Braquiuros/genética , Cadmio/toxicidad , Hepatopáncreas/efectos de los fármacos , Hepatopáncreas/metabolismo , MicroARNs/genética , Animales , Braquiuros/metabolismo , Cadmio/metabolismo , Biología Computacional , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , TranscriptomaRESUMEN
OBJECTIVE: To identify pathogenic mutation in a Chinese family affected with hereditary spastic paraplegia (HSP) through genetic testing and a follow-up survey. METHODS: Whole exome sequencing was performed on DNA samples of two patients and one unaffected member to screen candidate mutations. Sanger sequencing was used to validate the suspected mutations in all ten family members. RESULTS: Four patients and three asymptomatic members (under 25 years old) carried a c.1771T>C mutation of the KIAA0196, while the other three asymptomatic members (over 40 years old) did not carry the mutation. The mutation was predicted to be "affect protein function", "probably damaging" and "disease causing" by SIFT, PolyPhen-2 and Mutation Taster, respectively. Three asymptomatic carriers were followed up and one of them developed HSP one year later, while the other two had no signs of the disease yet. CONCLUSION: The clinical phenotype of the c.1771T>C mutation of KIAA0196 has a considerable heterogeneity and this mutation may be a common pathogenic site of KIAA0196 mutations among Chinese patients with hereditary spastic paraplegia.
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Proteínas/genética , Paraplejía Espástica Hereditaria , Adulto , Pueblo Asiatico , Heterocigoto , Humanos , Mutación , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/genéticaRESUMEN
OBJECTIVE: To detect potential mutation in a large Chinese pedigree affected with congenital corneal dystrophy. METHODS: Two patients from the pedigree were subjected to whole exome sequencing to determine the candidate gene. Suspected mutation was verified in 13 additional members by directional Sanger sequencing. Ccorrelation between genotype and phenotype was explored. RESULTS: A missense mutation, c.1877A>C (p.His626Pro), was detected in exon 14 of the TGFBI gene in 8 patients from the pedigree, but not in five unaffected members and 100 unrelated healthy controls. Respectively, the mutation was predicted as "affecting protein function", "probably damaging" and "disease causing" by SIFT, PolyPhen-2 and MutationTaster. CONCLUSION: The c.1877A>C mutation of the TGFBI gene probably underlies the disease in this pedigree.
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Distrofias Hereditarias de la Córnea/genética , Proteínas de la Matriz Extracelular/genética , Factor de Crecimiento Transformador beta/genética , Adulto , Pueblo Asiatico/genética , Secuencia de Bases , China , Distrofias Hereditarias de la Córnea/metabolismo , Análisis Mutacional de ADN , Exones , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Linaje , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: microRNAs (miRNAs) have regulatory roles in various cellular processes, including apoptosis. Recently, X-linked inhibitor of apoptosis protein (XIAP) has been reported to be dysregulated in epithelial ovarian cancer (EOC). However, the mechanism underlying this dysregulation is largely unknown. METHODS: Using bioinformatics and a literature analysis, a panel of miRNAs dysregulated in EOC was chosen for further experimental confirmation from hundreds of miRNAs that were predicted to interact with the XIAP 3'UTR. A dual-luciferase reporter assay was employed to detect the interaction by cellular co-transfection of an miRNA expression vector and a reporter vector with the XIAP 3'UTR fused to a Renilla luciferase reporter. DAPI and TUNEL approaches were used to further determine the effects of an miR-137 mimic and inhibitor on cisplatin-induced apoptosis in ovarian cancer cells. RESULTS: We identified eight miRNAs by screening a panel of dysregulated miRNAs that may target the XIAP 3'UTR. The strongest inhibitory miRNA, miR-137, suppressed the activity of a luciferase reporter gene fused with the XIAP 3'UTR and decreased the levels of XIAP protein in SKOV3 ovarian cancer cells. Furthermore, forced expression of miR-137 increased cisplatin-induced apoptosis, and the depressed expression of miR-137 decreased cisplatin-induced apoptosis in SKOV3 and primary EOC cells. Consistently, the disruption of miR-137 via CRISPR/Cas9 inhibited apoptosis and upregulated XIAP in A2780 cells. Furthermore, the effect of miR-137 on apoptosis could be rescued by XIAP in SKOV3 cells. In addition, miR-137 expression is inversely correlated with the level of XIAP protein in both ovarian cancer tissues and cell lines. CONCLUSIONS: Our data suggest that multiple miRNAs can regulate XIAP via its 3'UTR. miR-137 can sensitise ovarian cancer cells to cisplatin-induced apoptosis, providing new insight into overcoming drug resistance in ovarian cancer.
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Apoptosis/genética , MicroARNs/fisiología , Neoplasias Ováricas/patología , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Regiones no Traducidas 3' , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Neoplasias Ováricas/genéticaRESUMEN
Colorectal epithelial cancer is one of the most common cancers in the world and its 5-year survival rate is still relatively low. Cytochrome P450 (CYP) enzymes in epithelial cells lining the alimentary tract play an important role in the oxidative metabolism of a wide range of xenobiotics, including (pro-)carcinogens and endogenous compounds. Although CYP2S1, a member of CYP family, strongly expressed in many extrahepatic tissues, the role of CYP2S1 in cancer remains unclear. To investigate whether CYP2S1 involves in colorectal carcinogenesis, cell proliferation was analyzed in HCT116 cells depleted of CYP2S1 using small hairpin interfering RNA. Our data show that CYP2S1 knockdown promotes cell proliferation through increasing the level of endogenous prostaglandin E2(PGE2). PGE2, in turn, reduces phosphorylation of ß-catenin and activates ß-catenin signaling, which contributes to the cell proliferation. Furthermore, CYP2S1 knockdown increase tumor growth in xenograft mouse model. In brief, these results demonstrate that CYP2S1 regulates colorectal cancer growth through associated with PGE2-mediated activation of ß-catenin signaling.
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Neoplasias Colorrectales/patología , Sistema Enzimático del Citocromo P-450/genética , Dinoprostona/metabolismo , beta Catenina/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/genética , Colon/citología , Neoplasias Colorrectales/genética , Dinoprostona/farmacología , Células HCT116 , Humanos , Ratones , Trasplante de Neoplasias , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal , Trasplante HeterólogoRESUMEN
Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI). However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap). Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1) some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2) in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects.
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Reposicionamiento de Medicamentos/métodos , Expresión Génica/efectos de los fármacos , Genómica/métodos , Farmacología/métodos , Ligandos , Preparaciones FarmacéuticasRESUMEN
Cell-free DNA (cfDNA) has been found to be elevated in patients with schizophrenia (SZ), potentially derived from activated apoptosis, but the underlying mechanisms remain unknown. Moreover, whether the concentrations of cfDNA are altered with disease stage has not been investigated, which limits its clinical application as an auxiliary diagnostic marker for SZ. Using an improved fluorescence correlation spectroscopy (FCS) method that does not require DNA extraction, we measured the molar concentrations of cfDNA in plasma samples of 191 patients with SZ, 78 patients with mood disorders (MD) and 65 healthy controls (HC). We also analyzed the cfDNA composition from either the nucleus or mitochondria, oxidation markers and biochemical indexes to explore the potential mechanistic associations of the increased cfDNA levels. We found that in SZ patients, the cfDNA levels were significantly increased (P = 0.003) regardless of the different disease stages or antipsychotic medication use. Furthermore, qPCR revealed that cell-free nuclear DNA (cf-nDNA) (P = 0.041) but not cell-free mitochondrial DNA (cf-mtDNA) was elevated in SZ patients. Moreover, decreased SOD activity in SZ patients (P = 0.005) was negatively correlated with cfDNA levels (P = 0.047), and fasting blood glucose was positively correlated with cfDNA levels in SZ patients (P = 0.013). Our study provides evidence to support that the elevated cfDNA may be a convenient, effective and stable trait indicator of SZ. Further analysis showed that it mainly came from nucleus, suggesting increased apoptosis, and potentially related to oxidative stress and high blood glucose levels in patients.
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BACKGROUND: Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (ω3) polyunsaturated fatty acids are a promising adjuvant therapy in adult depression. The primary objective of this study was to investigate the efficacy of adjuvant ω3 treatment on depressive symptoms in adolescent depression. Secondarily, we explored the effects of ω3 on cognitive function and memory and niacin skin flushing response (NSFR), as their robust associations with adolescent depression. METHODS: A total of 71 adolescents with depression (aged 13-24; 59.2 % female) were randomly assigned to receive ω3 plus Paxil (n = 34) or Paxil alone (n = 37) for 12 weeks. Primary outcome was depression severity according to scores on Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes were cognitive function and memory, and NSFR. RESULTS: Significant improvements in depressive symptoms over time (p = 0.00027 at week 12) were observed in the ω3 + Paxil group compared with Paxil group. Additionally, in the ω3 + Paxil group, significant improvements in memory over time, and greater cognitive function and NSFR were also observed compared with the Paxil group; the NSFR was negatively correlated with MADRS scores at baseline. LIMITATIONS: The trial was open label; thus, the outcome measures should be viewed as preliminary since inherent bias in outcomes due to the potential of a placebo effect. CONCLUSIONS: Our results demonstrate that adjuvant ω3 treatment is effective for reducing depressive symptoms as well as improving cognitive function, memory and the NSFR; these results suggest ω3 is a promising adjuvant treatment for adolescent depression.
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Niacina , Adulto , Adolescente , Femenino , Humanos , Masculino , Depresión/tratamiento farmacológico , Paroxetina , Cognición , Suplementos DietéticosRESUMEN
Genetic factors play important roles in the development of tuberculosis (TB). SP110 is a promising candidate target for controlling TB infections. However, several studies associating SP110 single nucleotide polymorphisms (SNPs) with TB have yielded conflicting results. This may be partly resolved by studying other genes associated with SP110, such as MYBBP1A and RELA. Here, we genotyped 6 SP110 SNPs, 8 MYBBP1A SNPs and 5 RELA SNPs in 702 Chinese pulmonary TB patients and 425 healthy subjects using MassARRAY and SNaPshot methods. Using SNP-based analysis with Bonferroni correction, rs3809849 in MYBBP1A [Pcorrected (cor) = 0.0038] and rs9061 in SP110 (Pcor = 0.019) were found to be significantly associated with TB. Furthermore, meta-analysis of rs9061 in East Asian populations showed that the rs9061 T allele conferred significant risk for TB [P = 0.002, pooled odds ratio (OR), 1.24, 95% confidence interval (CI) = 1.08-1.43]. The MYBBP1A GTCTTGGG haplotype and haplotypes CGACCG/TGATTG within SP110 were found to be markedly and significantly associated with TB (P = 2.00E-06, 5.00E-6 and 2.59E-4, respectively). Gene-based analysis also demonstrated that SP110 and MYBBP1A were each associated with TB (Pcor = 0.011 and 0.035, respectively). The logistic regression analysis results supported interactions between SP110 and MYBBP1A, indicating that subjects carrying a GC/CC genotype in MYBBP1A and CC genotype in SP110 possessed the high risk of developing TB (P = 1.74E-12). Our study suggests that a combination of SP110 and MYBBP1A gene polymorphisms may serve as a novel marker for identifying the risk of developing TB in the Chinese Han population.
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Pueblo Asiatico/genética , Heterocigoto , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Polimorfismo de Nucleótido Simple , Factor de Transcripción ReIA/genética , Tuberculosis Pulmonar/genética , Adulto , Anciano , Pueblo Asiatico/estadística & datos numéricos , China/epidemiología , Proteínas de Unión al ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Oportunidad Relativa , Proteínas de Unión al ARN , Factores de Riesgo , Factores de TranscripciónRESUMEN
Polyunsaturated fatty acids (PUFAs), especially long-chain PUFAs (LCPUFAs), are crucial for both the structural and functional integrity of cells. PUFAs have been reported to be insufficient in schizophrenia, and the resulting cell membrane impairments have been hypothesized as an etiological mechanism. However, the impact of PUFA deficiencies on the onset of schizophrenia remain uncertain. We investigated the associations between PUFAs consumption and schizophrenia incidence rates through correlational analyses and conducted Mendelian randomization analyses to reveal the causal effects. Using dietary PUFA consumption and national schizophrenia incidence rates in 24 countries, we found that incidence rates of schizophrenia were inversely correlated with arachidonic acid (AA) and ω-6 LCPUFA consumption (rAA = -0.577, p < 0.01; rω-6 LCPUFA = -0.626, p < 0.001). Moreover, Mendelian randomization analyses revealed that genetically predicted AA and gamma-linolenic acid (GLA) were protective factors against schizophrenia (ORAA = 0.986, ORGLA = 0.148). In addition, no significant relationships were observed between schizophrenia and docosahexaenoic acid (DHA) or other ω-3 PUFAs. These findings show that the deficiencies of ω-6 LCPUFAs, especially AA, are associated with schizophrenia risk, which sheds novel insight into the etiology of schizophrenia and a promising diet supplementation for the prevention and treatment of schizophrenia.
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Ácidos Grasos Omega-3 , Esquizofrenia , Humanos , Ácido Araquidónico , Análisis de la Aleatorización Mendeliana , Ácidos Grasos Insaturados/metabolismoRESUMEN
BACKGROUND: Depressive disorder (DD) affects approximately 20 % of adolescents worldwide, but it is underdiagnosed due to the lack of objective biomarkers. Niacin skin flushing response (NSFR) is an objective and noninvasive biomarker of adult depression; however, its effectiveness has not been assessed in adolescents. METHODS: This study included 198 adolescents with 50 % healthy controls (HC). Linear mixed-effects model and multiple linear regression analyses were performed to assess differences in NSFR between the DD and HC groups. Logistic regression models based on NSFR were constructed, and the area under curve (AUC) was calculated to evaluate the performance of models. Spearman correlations were calculated to assess the relationships between NSFR and disease duration and hormone levels associated with puberty. RESULTS: Adolescents with DD displayed significantly attenuated and delayed NSFR compared to HC. NSFR effectively distinguished DD patients from HC with AUC values of 0.719 (sensitivity = 0.844) and 0.721 (sensitivity = 0.829) determined in the discovery and validation sets, respectively. Within the DD group, the maximum degree of NSFR was negatively correlated with the disease duration (r = -0.28, p = 0.011), and the overall degree of NSFR was positively associated with prolactin (r = 0.29, p = 0.039) and thyroxine (r = 0.29, p = 0.027) levels. LIMITATIONS: Future investigations will be necessary to confirm our results in an independent sample set. CONCLUSIONS: This study provides the first evidence of the utility of NSFR as an objective auxiliary diagnostic biomarker for adolescent depression. It provides new clues to understand the pathophysiology of the disease, and helps promote precise diagnosis, treatment, and prognostic evaluation of adolescent depression.
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Niacina , Adulto , Humanos , Adolescente , Depresión , Rubor/inducido químicamente , Rubor/diagnóstico , Biomarcadores , Modelos LogísticosRESUMEN
Evidence has shown that the gut microbiota is closely related to the pathogenesis of schizophrenia, but temporal changes in the gut microbiota of patients with schizophrenia (SZ) during treatment remain unclear. Here, to evaluate temporal changes in the gut microbiota in schizophrenia, we performed whole-genome shotgun metagenomics on fecal samples from 36 healthy controls (HCs) and 19 baseline-period patients, and followed up with patients upon treatment. Compared to that in HCs, beta diversity in SZ was significantly distinct. The genera Bacteroides, Prevotella and Clostridium were the top 3 altered genera between SZ and HCs, and the Bacteroides-Prevotella ratio was significantly increased in SZ. Thirty-three percent of differentially abundant species were short-chain fatty acid (SCFA)-producing bacteria. Functional analysis showed that glucose and lipid metabolism of the gut microbiota was decreased in SZ compared with those in HCs. The abundances of two rate-limiting enzymes in glucose and lipid metabolism, phosphofructokinase (PFK) and acetyl-CoA carboxylase (ACC), were significantly decreased in SZ, and differentially abundant metabolism-related enzymes were significantly associated with SCFA-producing bacteria. Next, we found that the abundance of SCFA-producing bacteria also changed after treatment and that Clostridium was significantly negatively correlated with the total positive and negative syndrome scale (PANSS) score in patients. Functional analysis showed that glycoside hydrolase family 30 incrementally increased in abundance during treatment and were significantly associated with SCFA-producing bacteria. Our findings help to provide evidence for the role of gut microbiota in the occurrence and development of schizophrenia.
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Microbioma Gastrointestinal , Esquizofrenia , Humanos , Metabolismo de los Lípidos , Metagenómica , Glucosa , Bacterias/metabolismo , Ácidos Grasos Volátiles/metabolismoRESUMEN
Immunological/inflammatory factors are implicated in the development of psychosis. Complement is a key driver of inflammation; however, it remains unknown which factor is better at predicting the onset of psychosis. This study aimed to compare the alteration and predictive performance of inflammation and complement in individuals at clinical high risk (CHR). We enrolled 49 individuals at CHR and 26 healthy controls (HCs). Twenty-five patients at CHR had converted to psychosis (converter) by the 3-year follow-up. Inflammatory cytokines, including interleukin (IL)-1ß, 6, 8, 10, tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor levels, and complement proteins (C1q, C2, C3, C3b, C4, C4b, C5, C5a, factor B, D, I, H) were measured by enzyme-linked immunosorbent assay at baseline. Except for TNF- alpha, none of the inflammatory cytokines reached a significant level in either the comparison of CHR individuals and HC or between CHR-converters and non-converters. The C5, C3, D, I, and H levels were significantly lower (C5, p = 0.006; C3, p = 0.009; D, p = 0.026; I, p = 0.016; H, p = 0.019) in the CHR group than in the HC group. Compared to non-converters, converters had significantly lower levels of C5 (p = 0.012) and C5a (p = 0.007). None of the inflammatory factors, but many complement factors, showed significant correlations with changes in general function and symptoms. None of the inflammatory markers, except for C5a and C5, were significant in the discrimination of conversion outcomes in CHR individuals. Our results suggest that altered complement levels in the CHR population are more associated with conversion to psychosis than inflammatory factors. Therefore, an activated complement system may precede the first-episode of psychosis and contribute to neurological pathogenesis at the CHR stage.
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Proteínas del Sistema Complemento , Trastornos Psicóticos , Humanos , Citocinas/sangre , Citocinas/química , Inflamación/metabolismo , Trastornos Psicóticos/sangre , Trastornos Psicóticos/diagnóstico , Factores de Riesgo , Factor de Necrosis Tumoral alfa , Proteínas del Sistema Complemento/química , Complemento C1q/química , Complemento C3b/química , Complemento C4b/química , Complemento C5b/químicaRESUMEN
In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.
Asunto(s)
Agranulocitosis/inducido químicamente , Clozapina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Mapeo de Interacción de Proteínas/métodos , Benzodiazepinas/farmacología , Biomarcadores/metabolismo , Línea Celular Tumoral , Biología Computacional/métodos , Antagonistas del GABA/efectos adversos , Proteínas HSP70 de Choque Térmico/genética , Humanos , Olanzapina , Proteómica/métodos , Especies Reactivas de Oxígeno , Estudios Retrospectivos , Factores de RiesgoRESUMEN
In the past decade, a number of case-control studies have been conducted to investigate the relationship between the ATP-binding cassette transporter A1 (ABCA1) R219K polymorphism and coronary heart disease (CHD). However, the results have been inconclusive. The purpose of the present study is to investigate whether this polymorphism confers significant susceptibility to CHD using a meta-analysis. PubMed, Embase and CNKI database were searched to get the genetic association studies. Then data were extracted. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated. Moreover, subgroup and sensitive analysis were performed. In total, 9,437 cases and 16,270 controls were involved in the meta-analysis. The K219 was significantly associated with CHD (OR = 0.80, 95% CI 0.69-0.92, P(Z) = 0.001). However, significant heterogeneity was present. Further subgroup analysis suggested ethnicity explained much heterogeneity. In Asians, K219 showed a strong protective effect and the pooled OR was 0.69 (95% CI 0.55-0.86 P(Z) = 0.0009). While in Caucasians the result was not significant (OR = 0.87, 95% CI 0.73-1.04, P(Z) = 0.12). In conclusion, our results indicate that the ABCA1 R219K polymorphism is a protective factor of CHD in Asians, but not in Caucasians.