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During neocortical development, neural stem cells (NSCs) divide symmetrically to self-renew at the early stage and then divide asymmetrically to generate post-mitotic neurons. The molecular mechanisms regulating the balance between NSC self-renewal and neurogenesis are not fully understood. Using mouse in utero electroporation (IUE) technique and in vitro human NSC differentiation models including cerebral organoids (hCOs), we show here that regulator of cell cycle (RGCC) modulates NSC self-renewal and neuronal differentiation by affecting cell cycle regulation and spindle orientation. RGCC deficiency hampers normal cell cycle process and dysregulates the mitotic spindle, thus driving more cells to divide asymmetrically. These modulations diminish the NSC population and cause NSC pre-differentiation that eventually leads to brain developmental malformation in hCOs. We further show that RGCC might regulate NSC spindle orientation by affecting the organization of centrosome and microtubules. Our results demonstrate that RGCC is essential to maintain the NSC pool during cortical development and suggest that RGCC defects could have etiological roles in human brain malformations.
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Neocórtex , Células-Tronco Neurais , Animais , Diferenciação Celular , Camundongos , Neurogênese , NeurôniosRESUMO
OBJECTIVE: the aim of this study was to investigate the expression of integrin αvß6 in normal, hepatitis B, HBV-associated cirrhosis and HBV-associated HCC liver tissues. METHODS: immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to study the expression of integrin αvß6 in HBV-associated cirrhosis (n = 88), chronic hepatitis B ( n= 11), HBV-associated HCC (n = 84) and normal (n = 10) human liver tissues. RESULTS: the expression of integrin αvß6 was significantly upregulated in HBV-associated liver cirrhosis and the expression increased with an increase in severity of cirrhosis. Furthermore, it was moderately or weakly expressed in chronic hepatitis B and HBV-associated HCC liver tissues when compared to normal liver tissue. CONCLUSION: integrin αvß6 could be a predictive marker for the progression of liver cirrhosis associated with HBV infection. Further studies are needed to determine the association between the expression of integrin αvß6 in hepatitis B and HBV-associated HCC liver tissues.
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Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antígenos de Neoplasias/metabolismo , Vírus da Hepatite B , Hepatite B Crônica/complicações , Humanos , Integrinas/metabolismo , Cirrose Hepática/complicaçõesRESUMO
BACKGROUND: Schizophrenia (SCZ) is a complex, heritable, and devastating psychiatric disorder. Mutations in the members of ABC transporters have been associated with psychiatric illnesses. AIMS: In this study, we investigated whether 9 SNPs in ABCB1 (rs6946119, rs28401781, rs4148739, and rs3747802), ABCB6 (rs1109866, rs1109867, rs3731885, and rs3755047), and ABCG1 (rs182694) contribute to the risk of SCZ in a Han Chinese population. METHODS: We conducted a case-control study in a Han Chinese population, involving 1,034 SCZ patients and 1,034 unrelated healthy controls to genotype 9 SNPs. RESULTS: The analysis demonstrated that rs182694 of ABCG1 was significantly different between SCZ patients and controls as to allele (rs182694: p = 0.0070, χ2 = 7.27) and genotype frequencies (rs182694: p = 0.0013, χ2 = 13.35). CONCLUSIONS: Our findings support an association between ABCG1 polymorphism and SCZ in a Han Chinese population.
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Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Esquizofrenia/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Criança , China , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Schizophrenia is a kind of neurodevelopmental disease. Epidemiological data associates schizophrenia with prenatal exposure to famine. Relevant prenatal protein deprivation (PPD) rodent models support this result by observing decreasing prepulse inhibition, altered hippocampal morphology and impaired memory in offspring. All these abnormalities are highly consistent with the pathophysiology of schizophrenia. We developed a prenatal famine rat model by restricting daily diet of the pregnant rat to 50% of low protein diet. A metabolomics study of prefrontal cortex was performed to integrate GC-TOFMS and UPLC-QTOFMS. Thirteen controls and thirteen famine offspring were used to differentiate in PLS-DA (partial least squares-discriminate analysis) model. Furthermore, metabolic pathways and diseases were enriched via KEGG and HMDB databases, respectively. A total of 67 important metabolites were screened out according to the multivariate analysis. Schizophrenia was the most statistical significant disease (P = 0.0016) in our famine model. These metabolites were enriched in key metabolic pathways related to energy metabolism and glutamate metabolism. Based on these important metabolites, further discussion speculated famine group was characterized by higher level of oxidized damage compared to control group. We proposed that oxidative stress might be the pathogenesis of prenatal undernutrition which is induced schizophrenia.
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Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Estresse Oxidativo/fisiologia , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Esquizofrenia/metabolismo , Animais , Dieta com Restrição de Proteínas , Modelos Animais de Doenças , Feminino , Espectrometria de Massas , Metaboloma , Metabolômica , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers and is expected to become the second leading cause of cancer death by 2030. Despite extensive efforts to improve surgical treatment, limited progress has been made. Increasing evidence indicates that integrin ß6 plays a crucial role in carcinoma invasion and metastasis. However, the expression and role of ß6 in PDAC remain largely unknown. In the present study, we investigated the expression of ß6 in PDAC and its potential value as a prognostic factor and therapeutic target. ß6 upregulation was identified as an independent unfavorable prognostic indicator. Integrin ß6 markedly promoted the proliferation and invasion of pancreatic carcinoma cells and induced ETS1 phosphorylation in an ERK-dependent manner, leading to the upregulation of matrix metalloprotease-9, which is essential for ß6-mediated invasiveness of pancreatic carcinoma cells. Accordingly, small interfering RNA-mediated silencing of integrin ß6 markedly suppressed xenograft tumor growth in vivo. Taken together, our results suggest that integrin ß6 plays important roles in the progression of pancreatic carcinoma and contributes to reduced survival times, and may serve as a novel therapeutic target for the treatment of PDAC.
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Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Cadeias beta de Integrinas/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Proteína Proto-Oncogênica c-ets-1/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Cadeias beta de Integrinas/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Prognóstico , Proteína Proto-Oncogênica c-ets-1/biossíntese , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Colorectal cancer (CRC) displays a predilection for metastasis to liver. Although stromal cell-derived factor-1 (SDF-1)/CXCR4 plays an important role in the liver metastasis, the molecular mechanism still remains obscure. We previously reported that integrin αvß6 was implicated in the progression of CRC. However, no data are currently available on the cross talk between CXCR4 and αvß6. In the present study, we first demonstrated the cross talk between CXCR4 and αvß6 and their role in liver metastasis of CRC. We analyzed 159 human CRC samples and found that expression of CXCR4 and αvß6 was significantly associated with liver metastasis, and interestingly expression of αvß6 significantly correlated with expression of CXCR4. Both CXCR4 and αvß6 were highly expressed in metastatic CRC cell lines HT-29 and WiDr, whereas both of them were exiguous in non-metastatic cell line Caco-2. Furthermore, inhibition of αvß6 significantly decreased SDF-1α-induced cell migration in vitro. SDF-1/CXCR4 could upregulate αvß6 expression through phosphorylation of ERK and activation of Ets-1 transcription factor. In conclusion, we demonstrate that SDF-1/CXCR4 induces directional migration and liver metastasis of CRC cells by upregulating αvß6 through ERK/Ets-1 pathway. These data support combined inhibition of CXCR4 and αvß6 to prevent development of liver metastasis of CRC.
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Antígenos de Neoplasias/metabolismo , Movimento Celular , Quimiocina CXCL12/metabolismo , Neoplasias Colorretais/patologia , Integrinas/metabolismo , Neoplasias Hepáticas/secundário , Proteína Proto-Oncogênica c-ets-1/metabolismo , Receptores CXCR4/metabolismo , Antígenos de Neoplasias/genética , Apoptose , Western Blotting , Células CACO-2 , Proliferação de Células , Quimiocina CXCL12/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Citometria de Fluxo , Imunofluorescência , Células HT29 , Humanos , Técnicas Imunoenzimáticas , Integrinas/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores CXCR4/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Human brain organoids produce anatomically relevant cellular structures and recapitulate key aspects of in vivo brain function, which holds great potential to model neurological diseases and screen therapeutics. However, the long growth time of 3D systems complicates the culturing of brain organoids and results in heterogeneity across samples hampering their applications. We developed an integrated platform to enable robust and long-term culturing of 3D brain organoids. We designed a mesofluidic bioreactor device based on a reaction-diffusion scaling theory, which achieves robust media exchange for sufficient nutrient delivery in long-term culture. We integrated this device with longitudinal tracking and machine learning-based classification tools to enable non-invasive quality control of live organoids. This integrated platform allows for sample pre-selection for downstream molecular analysis. Transcriptome analyses of organoids revealed that our mesofluidic bioreactor promoted organoid development while reducing cell death. Our platform thus offers a generalizable tool to establish reproducible culture standards for 3D cellular systems for a variety of applications beyond brain organoids.
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Brain organoids provide a unique opportunity to model organ development in a system similar to human organogenesis in vivo. Brain organoids thus hold great promise for drug screening and disease modeling. Conventional approaches to organoid characterization predominantly rely on molecular analysis methods, which are expensive, time-consuming, labor-intensive, and involve the destruction of the valuable 3D architecture of the organoids. This reliance on end-point assays makes it challenging to assess cellular and subcellular events occurring during organoid development in their 3D context. As a result, the long developmental processes are not monitored nor assessed. The ability to perform non-invasive assays is critical for longitudinally assessing features of organoid development during culture. In this paper, we demonstrate a label-free high-content imaging approach for observing changes in organoid morphology and structural changes occurring at the cellular and subcellular level. Enabled by microfluidic-based culture of 3D cell systems and a novel 3D quantitative phase imaging method, we demonstrate the ability to perform non-destructive high-resolution imaging of the organoid. The highlighted results demonstrated in this paper provide a new approach to performing live, non-destructive monitoring of organoid systems during culture.
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Brain organoids represent a new model system for studying developmental human neurophysiology. Methods for studying the electrophysiology and morphology of single neurons in organoids require acute slices or dissociated cultures. While these methods have advantages (e.g., visual access, ease of experimentation), they risk damaging cells and circuits present in the intact organoid. To access single cells within intact organoid circuits, we have demonstrated a method for fixturing and performing whole cell patch clamp recording from intact brain organoids using both manual and automated tools. We demonstrate applied electrophysiology methods development followed by an integration of electrophysiology with reconstructing the morphology of the neurons within the brain organoid using dye filling and tissue clearing. We found that whole cell patch clamp recordings could be achieved both on the surface and within the interior of intact human brain organoids using both manual and automated methods. Manual experiments were higher yield (53 % whole cell success rate manual, 9 % whole cell success rate automated), but automated experiments were more efficient (30 patch attempts per day automated, 10 patch attempts per day manual). Using these methods, we performed an unbiased survey of cells within human brain organoids between 90 and 120 days in vitro (DIV) and present preliminary data on morphological and electrical diversity in human brain organoids. The further development of intact brain organoid patch clamp methods could be broadly applicable to studies of cellular, synaptic, and circuit-level function in the developing human brain.
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Encéfalo , Neurônios , Humanos , Neurônios/fisiologia , Encéfalo/fisiologia , Fenômenos Eletrofisiológicos , Técnicas de Patch-Clamp , OrganoidesRESUMO
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with a birth incidence of 1:6000 in the United States that is characterized by the growth of non-cancerous tumors in multiple organ systems including the brain, kidneys, lungs, and skin. Importantly, TSC is also associated with significant neurological manifestations including epilepsy, TSC-associated neuropsychiatric disorders, intellectual disabilities, and autism spectrum disorder. Mutations in the TSC1 or TSC2 genes are well-established causes of TSC, which lead to TSC1/TSC2 deficiency in organs and hyper-activation of the mammalian target of rapamycin signaling pathway. Animal models have been widely used to study the effect of TSC1/2 genes on the development and function of the brain. Despite considerable progress in understanding the molecular mechanisms underlying TSC in animal models, a human-specific model is urgently needed to investigate the effects of TSC1/2 mutations that are unique to human neurodevelopment. DATA SOURCES: Literature reviews and research articles were published in PubMed-indexed journals. RESULTS: Human-induced pluripotent stem cells (iPSCs), which capture risk alleles that are identical to their donors and have the capacity to differentiate into virtually any cell type in the human body, pave the way for the empirical study of previously inaccessible biological systems such as the developing human brain. CONCLUSIONS: In this review, we present an overview of the recent progress in modeling TSC with human iPSC models, the existing limitations, and potential directions for future research.
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Objective: Cholangiocarcinoma (CHOL) is a deadly cancer worldwide with limited available therapies. The aim of this study was to investigate key exosomal miRNAs and their functions in CHOL development. Methods: Serum exosomes were isolated from patients with CHOL and healthy controls, followed by miRNA sequencing for identifying differentially expressed miRNAs (DEMs) and their functions. Then, the expression of key DEMs was experimentally validated in exosomes from clinical CHOL patients and CHOL cells. The effects of overexpression of key DEMs on CHOL cell migration and proliferation were investigated. A key exosomal DEM miR-3124-5p was identified. The effects of overexpression or knockdown of exosomal miR-3124-5p on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were investigated. Moreover, the function of exosomal miR-3124-5p on tumor growth in vivo was explored. Results: A total of 632 exosomal DEMs were identified between CHOL and control samples. Target genes of DEMs were significantly enriched in pathways, such as the p53 signaling pathway. miR-3124-5p was upregulated in serum exosomes from CHOL patients and exosomes from CHOL cells, and overexpression of miR-3124-5p promoted RBE cell migration and viability. Moreover, overexpression of exosomal miR-3124-5p promoted the proliferation, migration, and angiogenesis of HUVECs, while knockdown of miR-3124-5p had the opposite effect. miR-3124-5p could target growth differentiation factor 11 (GDF11) and downregulate GDF11 expression. Furthermore, exosomal miR-3124-5p promoted tumor growth in vivo. Conclusions: Our findings revealed that exosome-encapsulated miR-3124-5p promoted the malignant progression of CHOL by targeting GDF11. Exosomal miR-3124-5p and GDF11 could be promising biomarkers or therapeutic targets for CHOL.
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BACKGROUND: Accumulated studies have pointed out the striking association between variants in or near APOC3, GCKR, PNPLA3, and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear. OBJECTIVES: This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. METHODS: Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within APOC3, GCKR, and PNPLA3 were genotyped using the MassARRAY® platform in a large Chinese Han sample comprising of 733 elderly NAFLD patients and 824 age- and ethnic-matched controls. Association and mediation analysis were employed by R. RESULTS: The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: P=0.004, Pcorr=0.020, OR [95%CI]= 0.69 [0.54-0.89]; rs780094: P=0.005, Pcorr=0.025, OR [95%CI]= 0.70 [0.55-0.90]). Particularly, an increased triglyceride level was observed in carriers of rs1260326 T allele (1.94±1.19 mmol/L) compared with non-carriers (1.73±1.05 mmol/L).no significant results were observed in rs780094. Notably, triglyceride levels had considerably indirect impacts on association between NAFLD and rs1260326 (ß =0.01, 95% CI: 0.01-0.02), indicating that 12.7% of the association of NAFLD with rs1260326 was mediated by triglyceride levels. CONCLUSIONS: Our results identified a prominent relationship between GCKR rs1260326 and NAFLD, and highlighted the mediated effect of triglyceride levels on the that association in the Chinese Han elderly.
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Hepatopatia Gordurosa não Alcoólica , Idoso , Estudos de Casos e Controles , China/epidemiologia , Predisposição Genética para Doença , Genótipo , Humanos , Lipase/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , TriglicerídeosRESUMO
DiGeorge Syndrome Critical Region Gene 8 (DGCR8) is a key component of the microprocessor complex governing the maturation of most microRNAs, some of which participate in schizophrenia and neural development. Previous studies have found that the 22q11.2 locus, containing DGCR8, confers a risk of schizophrenia. However, the role of DGCR8 in schizophrenia and the early stage of neural development has remained unknown. In the present study, we try to identify the role of DGCR8 in schizophrenia from human samples and animal models. We found that the G allele and GG genotype of rs3757 in DGCR8 conferred a higher risk of schizophrenia, which likely resulted from higher expression of DGCR8 according to our test of dual-luciferase reporter system. Employed overexpression model in utero and adult mice, we also revealed that the aberrant increase of Dgcr8 delayed neuronal migration during embryological development and consequently triggered abnormal behaviors in adult mice. Together, these results demonstrate that DGCR8 may play a role in the etiology of schizophrenia through regulating neural development.
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BACKGROUND: Transvaginal cholecystectomy has been performed successfully at several research institutions worldwide using natural orifice transluminal endoscopic surgery (NOTES) techniques. However, it is a growing new surgical concept in China. Several technical challenges hinder the safe clinical application of NOTES. This study investigated transvaginal endoscopic cholecystectomy performed with the assistance of a single umbilical trocar and achieved helpful initial clinical experience. METHODS: From May 2009 to April 2010, a total of 43 transvaginal human cholecystectomies were performed. A single umbilical trocar was used for safe access and laparoscopic assistance during the operation. After the gallbladder had been removed through the vagina, the colpotomy was closed with absorbable stitches under direct vision. In addition, Student's t-test was performed for two samples to estimate the superiority of NOTES over a conventional laparoscopic cholecystectomy (LC) operation. RESULTS: The procedure was successfully completed for all the patients. No intra- or post-operative complications occurred. The patients recovered promptly after surgery, and all were satisfied with ideal cosmetic outcomes. The postoperative pain, hospital stay, and cost of hospitalization with NOTES were much less than with conventional LC operations. CONCLUSIONS: Although endoscopic instruments specifically designed for NOTES are not available, the addition of an umbilical trocar is an optimal way to allow safe performance of NOTES procedures in an easily reproducible manner. The authors' initial experience demonstrates that this hybrid technique is potentially feasible and effective for reducing postoperative pain and recovery times while improving the cosmetic results of transvaginal cholecystectomy.
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Colecistectomia/métodos , Laparoscopia/métodos , Cirurgia Endoscópica por Orifício Natural/métodos , Adulto , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Colecistectomia/economia , Colelitíase/cirurgia , Estética , Feminino , Neoplasias da Vesícula Biliar/cirurgia , Hospitalização/economia , Humanos , Laparoscopia/economia , Tempo de Internação/estatística & dados numéricos , Pessoa de Meia-Idade , Cirurgia Endoscópica por Orifício Natural/economia , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/prevenção & controle , Pólipos/cirurgia , Instrumentos Cirúrgicos , VaginaRESUMO
Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development.
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Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/patologia , Neurogênese/genética , Prosencéfalo/patologia , Adulto , Encéfalo/patologia , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Fenômenos Eletrofisiológicos , Humanos , Masculino , Modelos Neurológicos , Neurogênese/efeitos dos fármacos , Neurônios/patologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/genética , Receptores de Glutamato Metabotrópico/efeitos dos fármacosRESUMO
Hepatocellular carcinoma (HCC) is one of the most aggressive malignant diseases and requires more effective prevention and treatment strategies. Mutations or overexpression of endoplasmic reticulum (ER) proteins have been frequently identified in a solid tumor, suggesting that ER proteins play an important role in tumor development. SEC61G, a component of Sec61 complex located in the membrane of the human ER, has been revealed a potential relevance in glioblastoma multiforme. Analyses from TCGA database showed that SEC61G was overexpressed in HCC. Additionally, the expression of SEC61G mRNA was associated with the survival time of HCC patients. We verified that the higher expression of SEC61G in HCC tissues than paracancerous tissues. Moreover, knockdown of SEC61G inhibited cell proliferation and induced cell apoptosis in vitro. Besides, SEC61G was required for cell migration and invasion, conferring a potential role for SEC61G in tumor transfer. Taken together, our results revealed the role of SEC61G in HCC cells. Further detailed understanding of the signaling networks underlying SEC61G involvement in HCC cells would make SEC61G as a viable therapeutic target for pharmaceutical intervention of HCC.
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Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Hepáticas/metabolismo , Oncogenes/fisiologia , Canais de Translocação SEC/biossíntese , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Canais de Translocação SEC/genética , Taxa de Sobrevida/tendênciasRESUMO
Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.
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Atresia Biliar/genética , Proteínas de Ligação a Calmodulina/genética , DNA/genética , Glipicanas/genética , Polimorfismo de Nucleotídeo Único , Atresia Biliar/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Glipicanas/metabolismo , Humanos , Lactente , Masculino , Locos de Características QuantitativasRESUMO
OBJECTIVE: We aimed to study the association among venlafaxine antidepressive outcome, NR3C2 gene polymorphisms and the change of two neuroendocrine hormones during treatment. METHODS: 195 Chinese Han major depressive disorder (MDD) patients were recruited and received a 6-week venlafaxine treatment in this study. Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) levels were measured at the beginning and at the end of treatment. Six single-nucleotide polymorphisms (SNPs) (NR3C2: rs1512325, rs1512342, rs2070951; NR3C1: rs6191, rs6196, rs10482614) were selected for high-throughput SNP genotyping. Allele and genotype frequencies of them were compared between remission and non-remission groups. RESULTS: We found that genotype frequency of the rs1512325 located in the NR3C2 gene was significantly different between remission and non-remission groups respectively (p < 0.05). Meanwhile, the frequency of the rs1512325 C-allele was significantly lower (p < 0.05) in remission group. The TSH concentration significantly increased after venlafaxine treatment in remission group (p < 0.05). CONCLUSION: The rs1512325 in NR3C2 gene and TSH concentration may be related to venlafaxine treatment outcome in Chinese Han MDD patients.
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Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Receptores de Mineralocorticoides/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Adulto , Alelos , Povo Asiático/genética , Transtorno Depressivo Maior/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Receptores de Mineralocorticoides/genética , Tireotropina/sangue , Resultado do TratamentoRESUMO
Background and Aims: Hirschsprung's disease (HSCR) is a rare genetically heterogeneous congenital disorder. A recent study based on whole genome sequencing demonstrated that common variants at four novel loci, which contained two intronic variants on CASQ2 and PLD1, and intergenic variants located between SLC4A7 and EOMES at 3p24.1, and between LINC01518 and LOC283028 at 10q11.21, were associated with HSCR susceptibility. To validate these associations with HSCR susceptibility, we performed a case-control study in a Han Chinese sample set. Methods: We selected four previously identified single nucleotide polymorphisms (SNPs) for replication, along with tag SNPs to cover the four associated regions. In total, 61 SNPs were genotyped in 420 HSCR patients and 1,665 healthy controls from the Han Chinese population. Results: None of the 14 tag SNPs in the CASQ2 gene region, including the previously associated rs9428225, showed an association with HSCR. Among the 24 tag SNPs from the SLC4A7-EOMES region at 3p24.1, rs2642925 [odds ratio (OR) = 1.41, 95% confidence interval (95% CI) = 1.10-1.79; P Additive = 0.007] and the previously associated SNP rs9851320 showed a suggestive association (OR = 1.22, 95% CI = 1.01-1.47; P Additive = 0.042). A non-synonymous SNP, rs2287579, in PLD1 showed a suggestive association with HSCR susceptibility (OR = 1.71, 95% CI = 1.18-2.46; P Additive = 0.004). Additionally, the previously associated PLD1 SNP rs12632766 showed a suggestive significance (OR = 1.20, 95% CI = 1.01-1.42, P Additive = 0.038). In the LINC01518-LOC283028 region at 10q11.21, three SNPs meet the study-wide significance threshold. Rs17153309 was the most associated SNP (OR = 1.60, 95% CI = 1.34-1.90; P Additive = 1.13 × 10-7). The previously associated SNP rs1414027 also showed significant association (OR = 1.43, 95% CI = 1.20-1.70, P Additive = 3.92 × 10-5). Two associated SNPs at 10q11.21 (rs1414027 and rs624804) were expression quantitative trait loci in digestive tract tissues from GTEx databases. Conclusions: Our results confirmed that variants of the LINC01518-LOC283028 region were associated with HSCR in the Han Chinese population. Additionally, the susceptibility of SNPs in the LINC01518-LOC283028 region were associated with the expression levels of nearby genes. These results provide new insight into the pathogenesis of HSCR.
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Norcantharidin has been used as an efficacious anticancer drug in China for many years, but its true mechanism remains poorly understood. Intriguingly, in an in vitro series study of anticancer drugs, we found that norcantharidin can effectively inhibit epithelial tumor cells from expressing integrin alphavbeta6. Our previous studies have confirmed that integrin alphavbeta6 is closely relevant to malignant epithelial cell tumor biology behavior, and it can promote cancer cells to invade and metastasize through a special alphavbeta6-extracellular signal-related kinase (ERK) direct signaling pathway. In this study, we investigated the relationship between the norcantharidin anticancer mechanism and integrin alphavbeta6. After HT-29 colon cancer cells were treated with norcantharidin, cell apoptosis increased remarkably. The expression of alphavbeta6 and the amount of p-ERK decreased substantially; simultaneously, the linkage between alphavbeta6 and ERK was barely detectable. However, the expression of other integrins and the levels of mitogen-activated protein kinase hardly changed. On these grounds, we presumed that norcantharidin induced HT-29 colon cancer cell apoptosis through the alphavbeta6-ERK signaling pathway. This finding elicited a novel strategy for targeting the whole alphavbeta6-ERK signal pathway, rather than simply blocking the combining site of alphavbeta6-ERK in colon cancer treatment.