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1.
BMC Genet ; 20(1): 10, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651074

RESUMO

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.


Assuntos
Braquidactilia/genética , Proteínas Hedgehog/genética , Mutação , Transcrição Gênica/genética , Proteína GLI1 em Dedos de Zinco/genética , Braquidactilia/patologia , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Transdução de Sinais/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 584-587, 2019 Jun 10.
Artigo em Zh | MEDLINE | ID: mdl-31055811

RESUMO

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.


Assuntos
Proteínas/genética , Paraplegia Espástica Hereditária , Adulto , Povo Asiático , Heterozigoto , Humanos , Mutação , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/genética
3.
Exp Cell Res ; 331(2): 377-86, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25557876

RESUMO

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.


Assuntos
Neoplasias Colorretais/patologia , Sistema Enzimático do Citocromo P-450/genética , Dinoprostona/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Colo/citologia , Neoplasias Colorretais/genética , Dinoprostona/farmacologia , Células HCT116 , Humanos , Camundongos , Transplante de Neoplasias , Fosforilação , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Transplante Heterólogo
4.
Nutrients ; 15(5)2023 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-36904193

RESUMO

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.


Assuntos
Ácidos Graxos Ômega-3 , Esquizofrenia , Humanos , Ácido Araquidônico , Análise da Randomização Mendeliana , Ácidos Graxos Insaturados/metabolismo
5.
J Affect Disord ; 324: 69-76, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36521667

RESUMO

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.


Assuntos
Niacina , Adulto , Humanos , Adolescente , Depressão , Rubor/induzido quimicamente , Rubor/diagnóstico , Biomarcadores , Modelos Logísticos
6.
Schizophr Bull ; 48(5): 1125-1135, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35751100

RESUMO

BACKGROUND AND HYPOTHESIS: Multiple lines of clinical, biochemical, and genetic evidence suggest that disturbances of membrane lipids and their metabolism are probably involved in the etiology of schizophrenia (SCZ). Lipids in the membrane are essential to neural development and brain function, however, their role in SCZ remains largely unexplored. STUDY DESIGN: Here we investigated the lipidome of the erythrocyte membrane of 80 patients with SCZ and 40 healthy controls using ultra-performance liquid chromatography-mass spectrometry. Based on the membrane lipids profiling, we explored the potential mechanism of membrane phospholipids metabolism. STUDY RESULTS: By comparing 812 quantified lipids, we found that in SCZ, membrane phosphatidylcholines and phosphatidylethanolamines, especially the plasmalogen, were significantly decreased. In addition, the total polyunsaturated fatty acids (PUFAs) in the membrane of SCZ were significantly reduced, resulting in a decrease in membrane fluidity. The accumulation of membrane oxidized lipids and the level of peripheral lipid peroxides increased, suggesting an elevated level of oxidative stress in SCZ. Further study of membrane-phospholipid-remodeling genes showed that activation of PLA2s and LPCATs expression in patients, supporting the imbalance of unsaturated and saturated fatty acyl remodeling in phospholipids of SCZ patients. CONCLUSIONS: Our results suggest that the mechanism of impaired membrane lipid homeostasis is related to the activated phospholipid remodeling caused by excessive oxidative stress in SCZ. Disordered membrane lipids found in this study may reflect the membrane dysfunction in the central nervous system and impact neurotransmitter transmission in patients with SCZ, providing new evidence for the membrane lipids hypothesis of SCZ.


Assuntos
Esquizofrenia , Ácidos Graxos Insaturados/metabolismo , Homeostase , Humanos , Lipídeos de Membrana , Fosfolipídeos/metabolismo
7.
Biomed Pharmacother ; 144: 112281, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34624676

RESUMO

Schistosomiasis is a serious parasitic infection caused by Schistosoma. The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (α-SMA) and of collagen assessed by quantitative PCR, Western blot and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1-treated Schistosoma-infected mice for RNA-sequencing analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in the transdifferentiation of HSCs to myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression levels of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg-induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum.


Assuntos
Antifibróticos/farmacologia , Azepinas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Janus Quinase 2/metabolismo , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Schistosoma japonicum/patogenicidade , Esquistossomose/tratamento farmacológico , Triazóis/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/parasitologia , Células Estreladas do Fígado/patologia , Interações Hospedeiro-Patógeno , Fígado/enzimologia , Fígado/parasitologia , Fígado/patologia , Cirrose Hepática/enzimologia , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Fosforilação , Esquistossomose/enzimologia , Esquistossomose/parasitologia , Esquistossomose/patologia , Transdução de Sinais
8.
J Psychiatr Res ; 137: 14-21, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33640722

RESUMO

Recent evidence supports an association between lipid metabolism dysfunction and the pathology of schizophrenia which has led to the search for peripheral blood-based biomarkers. The purpose of this study was to investigate the proteins involved in lipid metabolism (especially apolipoprotein) and to explore their potential as biomarkers for schizophrenia. Using multiple reaction monitoring mass spectrometry (MRM-MS), we quantified 22 proteins in serum samples of 109 healthy controls (HCs) and 111 patients with schizophrenia (SCZ), who were divided into discovery and validation sets. We found serum apolipoprotein A4 (ApoA4) to be significantly decreased in SCZ patients compared to HCs (p=1.61E-05). Moreover, the serum ApoA4 level served as an effective diagnostic tool, achieving area under the receiver operating characteristic curves (AUROC) of 0.840 in the discovery set and 0.791 in the validation set. Additionally, apolipoprotein F (ApoF), angiotensinogen (AGT), and alpha1-antichymotrypsin (ACT) levels were significantly higher in patients with schizophrenia than in healthy controls. These proteins combined with ApoA4, provided higher diagnostic accuracy for schizophrenia in the discovery set (AUROC=0.901) and in the validation set (AUROC=0.879). Our results suggest that the serum level of ApoA4 is a novel potential biomarker for schizophrenia. The proteins identified in this study expand the pool of biomarker candidates for schizophrenia and may be linked to the underlying mechanism of the disease.


Assuntos
Esquizofrenia , Apolipoproteínas A , Área Sob a Curva , Biomarcadores , Humanos
9.
NPJ Schizophr ; 7(1): 51, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711862

RESUMO

Schizophrenia is a debilitating mental disorder and often has a prodromal period, referred to as clinical high risk (CHR) for psychosis, prior to the first episode. The etiology and pathogenesis of schizophrenia remain unclear. Despite the human gut microbiome being associated with schizophrenia, the role of the oral microbiome, which is a vital player in the mouth-body connection, is not well understood. To address this, we performed 16S rRNA gene sequencing to investigate the salivary microbiome in 85 patients with drug-naïve first-episode schizophrenia (FES), 43 individuals at CHR, and 80 healthy controls (HCs). The salivary microbiome of FES patients was characterized by higher α-diversity and lower ß-diversity heterogeneity than those of CHR subjects and HCs. Proteobacteria, the predominant phylum, was depleted, while Firmicutes and the Firmicutes/Proteobacteria ratio was enriched, in a stepwise manner from HC to CHR to FES. H2S-producing bacteria exhibited disease-stage-specific enrichment and could be potential diagnostic biomarkers for FES and CHR. Certain salivary microbiota exhibited disease-specific correlation patterns with symptomatic severities, peripheral pro-inflammatory cytokines, thioredoxin, and S100B in FES. Furthermore, the metabolic functions from inferred metagenomes of the salivary microbiome were disrupted in FES, especially amino acid metabolism, carbohydrate metabolism, and xenobiotic degradation. This study has established a link between salivary microbiome alterations and disease initiation and provided the hypothesis of how the oral microbiota could influence schizophrenia.

10.
EBioMedicine ; 64: 103239, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33581645

RESUMO

BACKGROUND: Schizophrenia (SZ) is a severe mental disease with highly heterogeneous clinical manifestations and pathological mechanisms. Schizophrenia is linked to abnormalities in cell membrane phospholipids and blunting of the niacin skin flush response, but the associations between these phenotypes and its molecular pathogenesis remain unclear. This study aimed to describe the PLA2/COX pathway, the key link between phospholipids and niacin flush, and to illustrate the pathogenic mechanisms in schizophrenia that mediate the above phenotypes. METHODS: A total of 166 patients with schizophrenia and 54 healthy controls were recruited in this study and assigned to a discovery set and a validation set. We assessed the mRNA levels of 19 genes related to the PLA2/COX cascade in leukocytes by real-time PCR. Plasma IL-6 levels were measured with an ELISA kit. Genetic association analysis was performed on PLA2G4A and PTGS2 to investigate their potential relationship with blunted niacin-skin response in an independent sample set. FINDINGS: Six of the 19 genes in the PLA2/COX pathway exhibited significant differences between schizophrenia and healthy controls. The disturbance of the pathway indicates the activation of arachidonic acid (AA) hydrolysis and metabolization, resulting in the abnormalities of membrane lipid homeostasis and immune function, further increasing the risk of schizophrenia. On the other hand, the active process of AA hydrolysis from cell membrane phospholipids and decreased transcription of CREB1, COX-2 and PTGER4 may explain the reported findings of a blunted niacin response in schizophrenia. The significant genetic associations between PLA2G4A and PTGS2 with the niacin-skin responses further support the inference. INTERPRETATION: These results suggested that the activation of AA hydrolysis and the imbalance in COX-1 and COX-2 expression are involved in the pathogenesis of schizophrenia and blunting of the niacin flush response. FUNDING: This work was supported by the National Key R&D Program of China (2016YFC1306900, 2016YFC1306802); the National Natural Science Foundation of China (81971254, 81771440, 81901354); Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018ZDA40, YG2019GD04, YG2016MS48); Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420500); Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500); and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); China Postdoctoral Science Foundation (2018M642029, 2018M630442, 2019M661526, 2020T130407); Natural Science Foundation of Shanghai (20ZR1426700); and Startup Fund for Youngman Research at SJTU (19 × 100040033).


Assuntos
Suscetibilidade a Doenças , Regulação da Expressão Gênica , Fosfolipases/genética , Prostaglandina-Endoperóxido Sintases/genética , Esquizofrenia/etiologia , Adulto , Biomarcadores , Estudos de Casos e Controles , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fosfolipases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Esquizofrenia/metabolismo , Adulto Jovem
11.
Mitochondrion ; 60: 150-159, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34375734

RESUMO

As an essential post-translational modification, acetylation participates in various cellular processes and shows aberrances during tumorigenesis. Owing to its modification substrate, acetyl-CoA, acetylation is postulated as a depot for acetyl groups and evolve to build a connection between epigenetics and metabolism. Here we depict a distinct acetylome atlas of hepatocellular carcinoma from the perspectives of both protein acetylation and acetyl-CoA metabolism. We found that tumor acetylome demonstrated a compartment-dependent alteration that the acetylation level of mitochondrial proteins tended to be decreased while nuclear proteins were highly acetylated. In addition, elevated expression of ATP-citrate synthase (ACLY) was observed in tumors, which would facilitate histone acetylation by transporting mitochondrial acetyl coenzyme A to the nucleus. A hypothetical model of the oncogenic acetylome was proposed that growing demands for histone acetylation in tumor cells would drive the relocalization of acetyl-CoA to the nucleus, which may contribute to the global deacetylation of mitochondrial proteins to support the nuclear acetyl-CoA pool in an ACLY-dependent manner. Our findings are thought-provoking on the potential linkage between epigenetics and metabolism in the progression of tumorigenesis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Mitocôndrias Hepáticas/metabolismo , Acetilcoenzima A/metabolismo , Acetilação , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal
12.
Schizophr Res ; 230: 53-60, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33677199

RESUMO

AIM: Schizophrenia and affective disorders all show high heterogeneity in clinical manifestations. A lack of objective biomarkers has long been a challenge in the clinical diagnosis of these diseases. In this study, we aimed to investigate the performance of niacin skin flushing in schizophrenia and affective disorders and determine its clinical potential as an auxiliary diagnostic marker. METHODS: In this case-control study, niacin skin-flushing tests were conducted in 613 patients (including 307 schizophrenia patients, 179 bipolar disorder patients, and 127 unipolar depression patients) and 148 healthy controls (HCs) with a modified method. Differences in niacin skin-flushing responses were compared with adjustment for gender, BMI, age, nicotine dependence, alcohol consumption and educational status. A diagnostic model was established based on a bivariate cut-off. RESULTS: Schizophrenia and affective disorders showed similar performance of niacin bluntness, characterized by attenuated flushing extent and reduced flushing rate. An innovative bivariate cut-off was established according to these two features, by which we could identify -patients with either schizophrenia or affective disorders from HCs with a sensitivity of 55.28%, a specificity of 83.56% and a positive predictive value of 93.66%. CONCLUSIONS: The niacin-induced skin flushing was prevalently blunted in patients with schizophrenia or affective disorders, indicating a promising potential as an auxiliary diagnostic marker in risk prediction and clinical management of these disorders. Additionally, the niacin-blunted subgroup implies a common biological basis in the investigated disorders, which provokes new thoughts in elucidating the pathological mechanisms.


Assuntos
Niacina , Esquizofrenia , Biomarcadores , Estudos de Casos e Controles , Humanos , Transtornos do Humor/diagnóstico , Transtornos do Humor/etiologia
13.
Antioxid Redox Signal ; 33(10): 679-688, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32578452

RESUMO

Schizophrenia is a chronic, disabling, and complex mental illness, of which the pathogenesis remains elusive. To provide clues for the pathogenesis and etiology of schizophrenia, we performed serum metabolic profiling in 54 patients with schizophrenia and 54 matched healthy controls using Fourier transform-ion cyclotron resonance-mass spectrometry. Based on 94 differential metabolites identified, we discovered two dysregulated metabolic pathways in schizophrenia, including the upregulated arachidonic acid-related pathway and the downregulated aromatic amino acid-related pathway. Moreover, carnitine was identified as a promising diagnostic biomarker for schizophrenia with an area under the curve of 0.997. Given the antioxidant and pro-oxidant properties of these altered metabolites, these results pointed to an imbalance of the redox homeostasis in schizophrenia, which was further confirmed by a remarkable elevation of 8-hydroxydeoxyguanosine (8-OHdG), a reactive oxidative stress marker. Furthermore, correlation analyses demonstrated that 8-OHdG was negatively correlated with antioxidant biliverdin and positively related to oxidation products, 9-hydroxylinoleic acid and o-tyrosine, and that total antioxidant capacity was positively associated with antioxidant acetylcarnitine in schizophrenia. Our results lead to the hypothesis that the disturbed metabolic characteristics reveal enhanced oxidative stress, which in turn results in the damage of lipids, proteins, and DNA and ultimately promotes the development of schizophrenia.


Assuntos
Biomarcadores/sangue , Metaboloma , Metabolômica , Estresse Oxidativo , Esquizofrenia/sangue , Humanos , Masculino , Redes e Vias Metabólicas , Metabolômica/métodos , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
14.
Antioxid Redox Signal ; 31(8): 579-588, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31126188

RESUMO

Although several underlying etiologic implications for schizophrenia (SZ) have been proposed, the cross talk between them is rarely explored systematically. The aim of the present study was to illustrate the pathogenic mechanism of SZ through describing a systematical pathophysiology network using proteomic signatures in first-episode SZ patients. A total of 3152 proteins were identified in leukocytes, and 475 of these proteins were significantly altered in SZ. Functional analysis revealed that cell redox homeostasis was dramatically disrupted, demonstrated as upregulated glycolysis, mitochondrial oxidative phosphorylation, and thioredoxin-centered antioxidant system. We also identified an activated complement system and caspase-independent apoptosis. In addition, increased pyruvate and lactate levels and decreased lactate-to-pyruvate ratios were observed in plasma of SZ patients. The results here lead to the hypothesis that increased oxidative stress is caused by metabolic upregulation and complement activation, which induces protein damage and cell apoptosis, thus contributing to the development of SZ. Antioxid. Redox Signal. 31, 579-588.


Assuntos
Leucócitos/metabolismo , Fenótipo , Proteômica , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Adolescente , Adulto , Antioxidantes/metabolismo , Apoptose , Biomarcadores , Ativação do Complemento , Suscetibilidade a Doenças , Metabolismo Energético , Feminino , Glicólise , Humanos , Imunidade , Masculino , Mitocôndrias/metabolismo , Modelos Biológicos , Oxirredução , Fosforilação Oxidativa , Estresse Oxidativo , Proteoma , Proteômica/métodos , Fatores de Risco , Esquizofrenia/diagnóstico , Adulto Jovem
15.
Psychiatry Res ; 273: 782-787, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31207866

RESUMO

Evidence indicates that abnormal phospholipase A2 (PLA2) levels and niacin insensitivity are present in individuals with schizophrenia. This study was designed to determine whether differences in plasma calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) exist between those with schizophrenia and healthy controls, and to explore the correlation between PLA2s and the niacin skin reaction in schizophrenic patients. We performed ELISA experiments to measure the concentrations of plasma iPLA2 and cPLA2 and we conducted a series of niacin skin tests on schizophrenic patients from the Chinese Han population. In addition, a meta-analysis of the relationship between PLA2 and schizophrenia was conducted. The plasma concentration of iPLA2 in patients with schizophrenia was significantly higher than that in healthy controls while the plasma concentration of cPLA2 did not differ. The meta-analysis also revealed that the activity level of iPLA2 in individuals with schizophrenia was higher than that in healthy controls, whereas that of cPLA2 was not. Furthermore, a significant positive correlation was found between the concentration of iPLA2 and the score for the skin flushing response within 20 min. The abnormal plasma iPLA2 concentration and its relationship with the niacin skin test in schizophrenic patients has contributed to a deeper understanding of the pathology of schizophrenia, which may in turn provide new insights into the clinical diagnoses and treatment of schizophrenia.


Assuntos
Fosfolipases A2 do Grupo VI/sangue , Fosfolipases A2 Citosólicas/sangue , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Adulto , Animais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Transl Psychiatry ; 8(1): 104, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29795286

RESUMO

Cell-free DNA (cfDNA), which is primarily released following cell death, has been described and developed to serve as an effective biomarker in autoimmune diseases which may share the pathogenesis with schizophrenia. In this study, we hypothesized and explored whether the concentrations and size distributions of cfDNA are abnormal in schizophrenia. A total of 65 patients with schizophrenia (SZ), 29 patients with mood disorders (MD) and 62 matched healthy controls (HC) were included in the study. Fluorescence correlation spectroscopy was used to assay the molar concentrations and size distributions of cfDNA. Fluorometric quantification and quantitative real-time PCR (qPCR) were performed to verify the results. The cfDNA levels were approximately two-fold higher in the SZ group ((29 ± 15) nM) than in the healthy controls ((15 ± 9) nM; P-value = 0.00062), but the levels in patients with MD were not significantly different from those in the healthy controls ((17 ± 10) nM; P-value = 0.343). According to the size distribution analysis, cfDNA in schizophrenia patients was composed of shorter DNA molecules and showed an apoptosis-like distribution pattern. Our study shows the elevated levels and short sizes of cfDNA in schizophrenia patients, which provide direct evidences supporting increased apoptotic activity in the disease. cfDNA may be developed to serve as an auxiliary diagnostic marker for the disease in the future.


Assuntos
Ácidos Nucleicos Livres/análise , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Transtornos do Humor/sangue , Espectrometria de Fluorescência
17.
Schizophr Bull ; 44(4): 896-907, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29077970

RESUMO

Schizophrenia (SZ) is a devastating mental disease caused by complex genetic and environmental factors. The pathological process and clinical manifestation of SZ are heterogeneous among patients, which hampers precise diagnosis and treatment of the disease. Since no objective marker for SZ has been established today, to identify a subgroup of the patients with homogeneous biochemical traits will provide a new angle for both researchers and clinicians to understand and manage the disease. In this study, we employed the niacin skin-flushing test in Chinese population and confirmed a niacin-blunted subgroup of SZ patients distinguishable from mood disorders (MD) and normal individuals. This subgroup accounted for 30.67% of the total SZ patients with a specificity of 88.37% in male subjects and 83.75% in female subjects. We support the notion that bluntness in niacin skin test might reflect abnormalities in membrane fatty acid composition, which could be induced by increased PLA2 enzyme activity, in vivo oxidative stress or lipid metabolism imbalance in SZ. Further studies are encouraged to clarify the molecular origins of niacin-bluntness in SZ, which would provide extra clues for etiological research in schizophrenia and for new targeted treatment.


Assuntos
Biomarcadores , Transtornos do Humor/diagnóstico , Niacina/farmacologia , Esquizofrenia/diagnóstico , Vasodilatadores/farmacologia , Adulto , China , Eritema/induzido quimicamente , Feminino , Humanos , Masculino , Niacina/administração & dosagem , Sensibilidade e Especificidade , Testes Cutâneos/normas , Vasodilatadores/administração & dosagem
18.
Oncotarget ; 7(41): 66679-66688, 2016 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-27556505

RESUMO

Housekeeping proteins are essential endogenous controls for normalization as they are expected to be stably expressed. However, the stability of the expression level of housekeeping proteins needs to be assessed considering various experimental conditions. Our study evaluated the degree of variability of 7 commonly used housekeeping proteins with regard to their potential utility as normalizers in 56 pairs of matched colorectal adenocarcinoma (CRC) tissue samples and 6 pairs of hepatocellular carcinoma (HCC) tissue samples using multiple reaction monitoring (MRM) and Western blot analyses. A comprehensive experimental design and strict statistical analysis revealed that the expression levels of these 7 housekeeping proteins were not as stable as expected and they all exhibited upregulations to varying degrees in both the CRC and the HCC tissue samples. Consequently, we verified that using the amount of total protein instead of that of an individual protein can serve as a preferable control for studies of protein expression that require normalization.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Hepáticas/metabolismo , Proteômica/métodos , Actinas/metabolismo , Adenocarcinoma/diagnóstico , Idoso , Carcinoma Hepatocelular/diagnóstico , Neoplasias Colorretais/diagnóstico , Proteínas de Ligação a DNA , Feminino , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Matriz Nuclear/metabolismo , Fatores de Transcrição de Octâmero/metabolismo , Proteínas de Ligação a RNA/metabolismo , Padrões de Referência , Proteínas Ribossômicas/metabolismo , Tubulina (Proteína)/metabolismo , Regulação para Cima
19.
Sci Rep ; 6: 33078, 2016 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-27609465

RESUMO

Oxaliplatin displays a wide spectrum of antitumor activities and is widely used in the treatment of metastatic colorectal cancer (CRC). However, tumor responses to this agent are variable, and the underlying mechanisms are poorly understood. In the present study, oxaliplatin was found to strongly inhibit the growth of HCT116 cells harboring wild-type p53 but to only weakly inhibit SW480 cells, HT29 cells or p53-/- HCT116 cells, which all lack p53 expression. Administration of oxaliplatin significantly induced p53 accumulation and enhanced expression of CYP2S1 in HCT116 cells with wild-type p53. CYP2S1 knockdown conferred a cell survival advantage after oxaliplatin treatment to cells harboring wild-type p53 in vitro and in vivo. Interestingly, enzyme immunoassays, TOPFlash/FOPFlash reporter activity assays and western blotting analysis demonstrated oxaliplatin-mediated downregulation of PGE2 and Wnt/ß-catenin signaling in a manner dependent on p53. Moreover, oxaliplatin treatment of mice with subcutaneous tumor xenografts drastically reduced the volume of wild-type p53 HCT116 tumors but had no effect on isogenic p53-/- HCT116 tumors. These results suggest that oxaliplatin exerts its inhibitory effects in human CRC cells via upregulation of CYP2S1 expression in a p53-dependent manner.


Assuntos
Neoplasias Colorretais , Sistema Enzimático do Citocromo P-450/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Piridinas/farmacologia , Proteína Supressora de Tumor p53 , Regulação para Cima/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Sistema Enzimático do Citocromo P-450/genética , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
Sci Rep ; 6: 23791, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27030512

RESUMO

The 14-3-3 family, which is composed of seven distinct members in humans, plays important roles in the cell cycle, apoptosis, synaptic plasticity and neuronal differentiation and migration. Previous genetic and post-mortem gene expression studies have linked this family to schizophrenia. However, the direction of gene expression changes in these studies has been inconsistent, and reports of 14-3-3 gene expression in living schizophrenic patients are still lacking. Here, we assessed 14-3-3 gene and protein expression levels in peripheral blood leukocytes from drug-naïve first-episode schizophrenic patients and matched controls. mRNA and protein expression levels were quantified by qRT-PCR and UPLC-MRM/MS, respectively. Expression analysis revealed four downregulated and one upregulated mRNA transcripts as well as five downregulated protein levels of 14-3-3 isoforms in schizophrenia. Moreover, significant positive correlations between 14-3-3 mRNA and protein expression levels were found in schizophrenia, and we also identified negative correlations between ε, θ and ζ isoform expression levels and positive symptoms of schizophrenia. Our results suggest that gene and protein expression levels for the 14-3-3 family are dysregulated in schizophrenia, perhaps owing to specific regulatory mechanisms, and we also suggest that expression of the 14-3-3ε, θ and ζ isoform genes could be useful indicators of disease severity.


Assuntos
Proteínas 14-3-3/genética , Leucócitos Mononucleares/metabolismo , RNA Mensageiro/genética , Esquizofrenia/genética , Proteínas 14-3-3/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/patologia , Masculino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Índice de Gravidade de Doença , Transdução de Sinais
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