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1.
Medicine (Baltimore) ; 98(39): e17334, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574870

RESUMO

RATIONALE: Subacute combined degeneration (SCD) is a disease caused by decreased vitamin B12 intake or metabolic disorders. It is more common in the elderly and rarely seen in children. Here, we report 2 pediatric cases of SCD in late-onset cobalamin C (CblC) deficiency. PATIENT CONCERNS: The patients complained of unsteady gait. Their physical examination showed sensory ataxia. Magnetic resonance imaging showed classic manifestations of SCD. The serum vitamin B12 level was normal, but urine methylmalonic acid and serum homocysteine levels were high. DIAGNOSIS: The pathogenic gene was confirmed as MMACHC. The 2 patients each had 2 pathogenic mutations C.482 G>A and C.271dupA and C.365A>T and C.609G>A in this gene. They were diagnosed with combined methylmalonic acidemia and homocysteinemia-CblC subtype. INTERVENTIONS: The patients were treated with methylcobalamin 500 µg intravenous injection daily after being admitted. After the diagnosis, levocarnitine, betaine, and vitamin B12 were added to the treatment. OUTCOMES: Twelve days after treatment, the boy could walk normally, and his tendon reflex and sense of position returned to normal. The abnormal gait seemed to have become permanent in the girl and she walked with her legs raised higher than normal. LESSONS: To the best of our knowledge, this is the first report of 2 cases of isolated SCD in children with late-onset CblC disorder. Doctors should consider that SCD could be an isolated symptom of CblC disorder. The earlier the treatment, the lower the likelihood of sequelae.


Assuntos
Proteínas de Transporte/genética , Homocistinúria , Degeneração Combinada Subaguda , Deficiência de Vitamina B 12/congênito , Vitamina B 12/análogos & derivados , Adolescente , Ataxia/diagnóstico , Ataxia/etiologia , Ataxia/terapia , Encéfalo/diagnóstico por imagem , Criança , Feminino , Homocisteína/sangue , Homocistinúria/diagnóstico , Homocistinúria/genética , Humanos , Injeções Intravenosas , Transtornos de Início Tardio , Imagem por Ressonância Magnética/métodos , Masculino , Ácido Metilmalônico/urina , Mutação , Degeneração Combinada Subaguda/diagnóstico , Degeneração Combinada Subaguda/etiologia , Degeneração Combinada Subaguda/fisiopatologia , Degeneração Combinada Subaguda/terapia , Resultado do Tratamento , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/genética , Complexo Vitamínico B/administração & dosagem
3.
Life Sci ; 234: 116771, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421084

RESUMO

AIMS: We aimed to elucidate the effects and mechanisms of MAT1 in the progression of osteosarcoma, especially for its lung metastasis. MAIN METHODS: CCK-8 and flow cytometry assays were carried out to detect the proliferation and apoptosis of osteosarcoma cells. Wound healing and transwell assays were used to determine cell migration and invasion abilities. Real time quantitative PCR (RT-PCR) and western blot technologies were applied to detect the expression levels of RNA and protein, respectively. KEY FINDS: The results showed that both the mRNA and protein expression levels of MAT1 were elevated in osteosarcoma tissues with lung metastasis and metastatic lung tissues, particularly in the metastatic lung tissues, as compared to the osteosarcoma tissues without lung metastasis. High expression level of MAT1 in osteosarcoma patients showed a negative association with the overall survival. In addition, upregulation of MAT1 induced significant increases in cell growth, migration and invasion and an obvious inhibition in cell apoptosis in osteosarcoma MG63 and 143B cells, as well as elevated AKT1 expression level. Moreover, knockdown of AKT1 obviously impaired MAT1-mediated promotions in cell migration and invasion in vitro, as well as repressed tumor growth and reduced the number of metastatic lung tumors in xenografted nude mice. SIGNIFICANCE: This study reveals that high expression of MAT1 closely related to the poor prognosis and malignant clinical process of osteosarcoma patients. MAT1 serves as a promoter in the lung metastasis of osteosarcoma through increasing AKT1 expression. Our study may provide a potent therapeutic target for the lung metastasis of osteosarcoma.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Neoplasias Ósseas/patologia , Proteínas de Transporte/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/genética , Regulação para Cima , Adulto Jovem
4.
Braz J Med Biol Res ; 52(8): e8522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365696

RESUMO

Pancreaticobiliary maljunction (PBM) is associated with high risk of epithelial atypical growth and malignant transformation of the bile duct or gallbladder. However, overall changes in genetic expression have not been examined in children with PBM. Genome-wide expression was analyzed using peripheral blood samples from 10 children with PBM and 15 pediatric controls. Differentially expressed genes (DEGs) were identified using microarray. Bioinformatics analysis was conducted using Gene Ontology and KEGG analyses. The top 5 in the up-regulated genes in PBM were verified with qRT-PCR. Receiver operator characteristic curve analysis was conducted to evaluate the predictive accuracy of selected genes for PBM. The microarray experiments identified a total of 876 DEGs in PBM, among which 530 were up-regulated and the remaining 346 were down-regulated. Verification of the top 5 up-regulated genes (TYMS, MYBPC1, FUT1, XAGE2, and GREB1L) by qRT-PCR confirmed the up-regulation of MYBPC1 and FUT1. Receiver operating characteristic curve analysis suggested that FUT1 and MYBPC1 up-regulation could be used to predict PBM, with the area under the curve of 0.873 (95%CI=0.735-1.000) and 0.960 (95%CI=0.891-1.000), respectively. FUT1 and MYBPC1 were up-regulated in children with PBM, and could be used as potential biomarkers for PBM.


Assuntos
Ductos Biliares/anormalidades , Proteínas de Transporte/genética , Fucosiltransferases/genética , Perfilação da Expressão Gênica , Ductos Pancreáticos/anormalidades , Regulação para Cima/genética , Neoplasias dos Ductos Biliares/etiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Dilatação Patológica/complicações , Dilatação Patológica/congênito , Feminino , Neoplasias da Vesícula Biliar/etiologia , Humanos , Lactente , Masculino , Análise em Microsséries
5.
Arch Virol ; 164(10): 2559-2563, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321587

RESUMO

Polymorphisms in the microsomal triglyceride transfer protein (MTTP) gene were genotyped in individuals who were chronically infected with hepatitis C virus (HCV). In the 236 patients, the frequencies of risk alleles of the -164T/C (rs1800804), -400A/T (rs1800803) and H297Q (rs2306985) polymorphisms were 0.30, 0.41 and 0.50, respectively. A significant association between the risk alleles of the -164T/C and -400A/T polymorphisms combined with HCV genotype 3 infection and the occurrence of steatosis was detected (p = 0.004 and p = 0.032), suggesting that a combination of host and viral factors can potentially be used to predict hepatic steatosis.


Assuntos
Proteínas de Transporte/genética , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Predisposição Genética para Doença , Hepacivirus/classificação , Hepatite C Crônica/complicações , Hepatite C Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Técnicas de Genotipagem , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Histocitoquímica , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
6.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
7.
Oncology ; 97(3): 180-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31330520

RESUMO

BACKGROUND: Hormone receptor-positive breast cancer accounts for nearly two-thirds of breast cancer cases; it ultimately acquires resistance during endocrine treatment and becomes more aggressive. This study evaluated the role of developmental endothelial locus (Del)-1 in tamoxifen-resistant (TAM-R) breast cancer. METHODS: Del-1 expression in recurrent TAM-R breast cancer tissue was evaluated and compared to that in the original tumor tissue from the same patients. Del-1 expression was also evaluated in TAM-R cells by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assay. The effects of Del-1 knockdown on the proliferation, migration, and invasion of TAM-R cells was assessed with wound-healing and Matrigel transwell assays. RESULTS: Del-1 was more highly expressed in recurrent breast cancer as compared to the original tumor tissues before initiation of endocrine treatment. Del-1 mRNA was upregulated in TAM-R and small interfering RNA-mediated knockdown of Del-1 suppressed the migration and proliferation of TAM-R cells while partly restoring TAM sensitivity. And the TAM resistance was recovered by knockdown of Del-1. CONCLUSIONS: TAM-R breast cancer is characterized by Del-1 overexpression and tumor progression can be inhibited by Del-1 depletion, which restores TAM sensitivity. Thus, therapeutic strategies that target Del-1 may be effective for the treatment of hormone-resistant breast cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Proteínas de Transporte/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Tamoxifeno/farmacologia , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interferência de RNA , RNA Interferente Pequeno
8.
J Sci Food Agric ; 99(14): 6582-6588, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328268

RESUMO

BACKGROUND: This study was conducted to investigate effects of dietary zinc methionine (Zn-Met) supplementation on laying performance, zinc (Zn) status, intestinal morphology, and Zn transporters in laying hens compared with zinc sulfate (ZnSO4 ). A total of 384 Hyline Grey laying hens (38 weeks old) with similar performance (1.42 ± 0.07 kg) were randomly allotted to four dietary treatments and fed with a basal diet (control) or the basal diet supplemented with Zn, either as Zn-Met at 40 and 80 mg Zn/kilogram diet or as ZnSO4 at 80 mg Zn/kilogram diet, for 10 weeks. RESULTS: There was no difference in egg weight, egg production, feed intake, and feed conversation ratio among all groups (P > 0.05). Compared with the control, Zn contents were increased (P < 0.05) in the liver, duodenum, and jejunum of laying hens fed diets supplemented with different Zn sources. There was no difference (P > 0.05) in Zn contents in liver, duodenum, and jejunum between diets supplemented with Zn-Met or ZnSO4 at 80 mg Zn/kilogram diet. Compared with the control and the ZnSO4 group (80 mg Zn/kilogram diet), supplementation with Zn-Met of 80 mg Zn/kilogram diet increased (P < 0.05) villus height, villus area, and villus height/crypt depth ratio but reduced (P < 0.05) crypt depth in jejunum. Expression of metallothionein messenger RNA of jejunum in the group fed a diet containing Zn-Met (80 mg Zn/kilogram diet) was higher (P < 0.05) than that in the control. CONCLUSION: These results indicated that Zn-Met has positive effects on the Zn status of liver, duodenum, and jejunum, intestinal morphology, and metallothionein messenger RNA expression in jejunum of laying hens compared with ZnSO4 . © 2019 Society of Chemical Industry.


Assuntos
Proteínas de Transporte/genética , Galinhas/crescimento & desenvolvimento , Galinhas/metabolismo , Intestinos/crescimento & desenvolvimento , Metionina/análogos & derivados , Compostos Organometálicos/administração & dosagem , Zinco/metabolismo , Ração Animal/análise , Animais , Proteínas de Transporte/metabolismo , Galinhas/genética , Suplementos Nutricionais/análise , Ovos/análise , Feminino , Intestinos/efeitos dos fármacos , Metionina/administração & dosagem , Metionina/metabolismo , Compostos Organometálicos/metabolismo , Zinco/análise
9.
J Med Microbiol ; 68(7): 1053-1058, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31169483

RESUMO

BACKGROUND: Streptococcus pyogenes is the most common cause of bacterial pharyngitis. Genotyping of emm is useful for molecular epidemiological survey of S. pyogenes. Antibiotic resistance data are needed for empirical treatments. METHODS: In total, 358 children in Changwon, Korea who had pharyngitis symptoms were subjected to throat cultures to isolate S. pyogenes in 2017. emm genotyping was performed by direct sequencing. An antibiotic susceptibility test was performed using the disk diffusion method for erythromycin (ERY), clindamycin (CLI), tetracycline (TET) and ofloxacin (OFX). Screening for macrolide resistance phenotype and its determinants was performed for the ERY-resistant strains. RESULTS: A total of 190 strains (53.1 %) of S. pyogenes were isolated from 358 children. The most frequent emm genotype was emm4 (53.2 %), followed by emm89 (12.6 %), emm28 (11.6 %) and emm1 (10 %). Antibiotic resistance rates to ERY, CLI, TET and OFX were 3.2 %, 2.6 %, 1.1 % and 2.6%, respectively. There were five isolates of the cMLSB phenotype having the ermB gene and one M phenotype harbouring the mefA gene. CONCLUSIONS: The distribution of emm genotypes was quite different from those previously reported in Korea. emm4 accounted for more than 50  % of the genotypes. Macrolide resistance rates remained very low, but five of six ERY-resistant strains displayed the cMLSB phenotype.


Assuntos
Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Transporte/genética , Farmacorresistência Bacteriana/genética , Faringite/epidemiologia , Faringite/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/genética , Adolescente , Antibacterianos/farmacologia , Criança , Pré-Escolar , Genótipo , Humanos , República da Coreia/epidemiologia , Infecções Estreptocócicas/epidemiologia , Streptococcus pyogenes/efeitos dos fármacos
10.
Chem Commun (Camb) ; 55(60): 8868-8871, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31240288

RESUMO

New evidence on the role of H2S as a gasotransmitter suggests that the true signalling effectors are polysulfides. Both oxidized polysulfides and hydropolysulfides were synthesized and their presence in S. cerevisiae was observed for the first time. A single gene-deletant approach allowed observation of the modulation of polysulfide species and levels.


Assuntos
Gasotransmissores/análise , Saccharomyces cerevisiae/química , Sulfetos/análise , Proteínas de Transporte/genética , Cistationina beta-Sintase/genética , Cistationina gama-Liase/genética , Gasotransmissores/síntese química , Gasotransmissores/metabolismo , Deleção de Genes , Metabolômica/métodos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Sulfetos/síntese química , Sulfetos/metabolismo
11.
Parasit Vectors ; 12(1): 317, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234897

RESUMO

Glycophorins are heavily glycosylated sialoglycoproteins of human and animal erythrocytes. In humans, there are four glycophorins: A, B, C and D. Glycophorins play an important role in the invasion of red blood cells (RBCs) by malaria parasites, which involves several ligands binding to RBC receptors. Four Plasmodium falciparum merozoite EBL ligands have been identified: erythrocyte-binding antigen-175 (EBA-175), erythrocyte-binding antigen-181 (EBA-181), erythrocyte-binding ligand-1 (EBL-1) and erythrocyte-binding antigen-140 (EBA-140). It is generally accepted that glycophorin A (GPA) is the receptor for P. falciparum EBA-175 ligand. It has been shown that α(2,3) sialic acid residues of GPA O-glycans form conformation-dependent clusters on GPA polypeptide chain which facilitate binding. P. falciparum can also invade erythrocytes using glycophorin B (GPB), which is structurally similar to GPA. It has been shown that P. falciparum EBL-1 ligand binds to GPB. Interestingly, a hybrid GPB-GPA molecule called Dantu is associated with a reduced risk of severe malaria and ameliorates malaria-related morbidity. Glycophorin C (GPC) is a receptor for P. falciparum EBA-140 ligand. Likewise, successful binding of EBA-140 depends on sialic acid residues of N- and O-linked oligosaccharides of GPC, which form a cluster or a conformational structure depending on the presence of peptide fragment encompassing amino acids (aa) 36-63. Evaluation of the homologous P. reichenowi EBA-140 unexpectedly revealed that the chimpanzee homolog of human glycophorin D (GPD) is probably the receptor for this ligand. In this review, we concentrate on the role of glycophorins as erythrocyte receptors for Plasmodium parasites. The presented data support the long-lasting idea of high evolutionary pressure exerted by Plasmodium on the human glycophorins, which emerge as important receptors for these parasites.


Assuntos
Proteínas de Transporte/metabolismo , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Glicoforina/metabolismo , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Proteínas de Transporte/genética , Glicoforina/genética , Humanos , Ligantes , Merozoítos , Pan troglodytes , Ligação Proteica , Proteínas de Protozoários/genética , Receptores de Superfície Celular/genética
12.
Nat Commun ; 10(1): 2678, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213601

RESUMO

Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/metabolismo , Melanoma Experimental/imunologia , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Neoplasias Cutâneas/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
13.
Nat Commun ; 10(1): 2828, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249301

RESUMO

H2A.Z variant has emerged as a critical player in regulating plant responses to environment; however, the mechanism by which H2A.Z mediates this regulation remains unclear. In Arabidopsis, H2A.Z has been proposed to have opposite effects on transcription depending on its localization within the gene. These opposite roles have been assigned by correlating gene expression and H2A.Z enrichment analyses but without considering the impact of possible H2A.Z post-translational modifications. Here, we show that H2A.Z can be monoubiquitinated by the PRC1 components AtBMI1A/B/C. The incorporation of this modification is required for H2A.Z-mediated transcriptional repression through a mechanism that does not require PRC2 activity. Our data suggest that the dual role of H2A.Z in regulating gene expression depends on the modification that it carries, while the levels of H2A.Z within genes depend on the transcriptional activity.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Histonas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Histonas/genética , Complexo Repressor Polycomb 1/genética , Ubiquitinação
14.
Eur J Endocrinol ; 181(2): 103-119, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31200363

RESUMO

Context: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective: Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients: A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions: This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.


Assuntos
Hipogonadismo/congênito , Hipogonadismo/genética , Mutação , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Brasil/epidemiologia , Proteínas de Transporte/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos , Glicoproteínas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/epidemiologia , Imunoglobulinas/genética , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/epidemiologia , Síndrome de Kallmann/genética , Fator de Transcrição MSX1/genética , Masculino , Proteínas de Membrana/genética , Fatores de Transcrição Otx/genética , Linhagem , Receptores de Grelina/genética , Ribonucleoproteínas/genética , Adulto Jovem
15.
Photochem Photobiol Sci ; 18(7): 1685-1699, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31166333

RESUMO

The UVR8 photoreceptor in Arabidopsis thaliana is specific for ultraviolet-B (UV-B; 280-315 nm) radiation and its activation leads to a number of UV-B acclimation responses, including the accumulation of flavonoids. UVR8 participates in a signaling cascade involving COP1 and HY5 so that the absence of any of these components results in a reduction in the ability of a plant to accumulate flavonoids in response to UV; Cop1 mutants show high dropouts and hy5-ks50 hyh double mutants show very low levels of flavonoids. The predominant phenolics in Arabidopsis thaliana are sinapic acid derivatives as well as non-aclyated quercetin and kaempferol di- and triglycosides containing glucose and rhamnose as glycosylated sugar moieties. How this flavonoid profile in Arabidopsis thaliana is affected by UV radiation, how rapidly these changes occur in changing UV conditions, and which components of the UV-B signalling pathway are involved in rapid UV acclimatization reactions is poorly understood. In the present study, we examined these questions by characterizing the flavonoid profiles of Arabidopsis thaliana signalling mutants and wild types grown under different UV levels of constant UV-B+PAR ratios and then transferring a subset of plants to alternate UV conditions. Results indicate that flavonoid accumulation in Arabidopsis thaliana is triggered by UV and this response is amplified by higher levels of UV but not by all compounds to the same extent. The catechol structure in quercetin seems to be less important than the glycosylation pattern, e.g. having 2 rhamnose moieties in determining responsivity. At low UV+PAR intensities the introduction of UV leads to an initial tendency of increase of flavonoids in the wild types that was detected after 3 days. It took 7 days for these changes to be detected in plants grown under high UV+PAR intensities suggesting a priming of PAR. Thus, the flavonoid profile in Arabidopsis thaliana is altered over time following exposure to UV and PAR, but the functional significance of these changes is currently unclear.


Assuntos
Arabidopsis/efeitos da radiação , Flavonoides/metabolismo , Transdução de Sinais/efeitos da radiação , Raios Ultravioleta , Arabidopsis/química , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cromatografia Líquida de Alta Pressão , Proteínas Cromossômicas não Histona/metabolismo , Flavonoides/análise , Mutagênese , Folhas de Planta/química , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação , Espectrometria de Massas por Ionização por Electrospray , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
16.
Photochem Photobiol Sci ; 18(7): 1675-1684, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31218318

RESUMO

UV-B exposure of plants regulates expression of numerous genes concerned with various responses. Sudden exposure of non-acclimated plants to high fluence rate, short wavelength UV-B induces expression via stress-related signaling pathways that are not specific to the UV-B stimulus, whereas low fluence rates of UV-B can regulate expression via the UV-B photoreceptor UV RESISTANCE LOCUS 8 (UVR8). However, there is little information about whether non-stressful, low fluence rate UV-B treatments can activate gene expression independently of UVR8. Here, transcriptomic analysis of wild-type and uvr8 mutant Arabidopsis exposed to low fluence rate UV-B showed that numerous genes were regulated independently of UVR8. Moreover, nearly all of these genes were distinct to those induced by stress treatments. A small number of genes were expressed at all UV-B fluence rates employed and may be concerned with activation of eustress responses that facilitate acclimation to changing conditions. Expression of the gene encoding the transcription factor ARABIDOPSIS NAC DOMAIN CONTAINING PROTEIN 13 (ANAC13) was studied to characterise a low fluence rate, UVR8-independent response. ANAC13 is induced by as little as 0.1 µmol m-2 s-1 UV-B and its regulation is independent of components of the canonical UVR8 signaling pathway COP1 and HY5/HYH. Furthermore, UV-B induced expression of ANAC13 is independent of the photoreceptors CRY1, CRY2, PHOT1 and PHOT2 and phytochromes A, B, D and E. ANAC13 expression is induced over a range of UV-B wavelengths at low doses, with maximum response at 310 nm. This study provides a basis for further investigation of UVR8 and stress independent, low fluence rate UV-B signaling pathway(s).


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Raios Ultravioleta , Proteínas de Arabidopsis/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas Cromossômicas não Histona/genética , Criptocromos/genética , Criptocromos/metabolismo , Transdução de Sinais/efeitos da radiação , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
18.
Zhonghua Yi Xue Za Zhi ; 99(21): 1664-1668, 2019 Jun 04.
Artigo em Chinês | MEDLINE | ID: mdl-31189268

RESUMO

Objective: To investigate the relationship of STOX1expression and pathogenesis of early onset preeclampsia. Methods: 65 cases of preeclampsia women who delivered in Shanghai Pudong Hospital from October 2015 to June 2018, were recruited, which included 31 cases with early onset preeclampsia (early onset group, gestational week<34 weeks) and 34 patients with late onset preeclampsia (late onset group, gestational week ≥34 weeks). 34 cases women who received caesarean section because of pelvic structural deformities, breech presentation, macrosomia and social factors were included as the control group(gestational week ≥34 weeks) were selected as control group.The expression and localization of STOX1 mRNA and protein in placenta of three groups of maternal were evaluated by immunohistochemistry SP, RT-qPCR and Western blotting. Results: (1) The expression of STOX1 in placenta mainly distributed in the cytoplasm of placental syncytiotrophoblasts, cytotrophoblasts, vascular endothelial and mesenchymal cells, a few in the cell nucleus.The staining intensity of STOX1 in early onset group was significantly stronger than that in late onset group, the staining intensity of the late onset group was similar to that of the control group. The positive expression rates of STOX1protein in early onset group, late onset group and control group were 96.8%(30/31), 70.6%(24/34), 67.6%(23/34) respectively, which was higher in early onset group than that in late onset group(P=0.005). There was no statistical difference of STOX1 level between the late onset group and the control group(P=0.793). (2)Relative expression of STOX1 mRNA in early onset group, late onset group and control group were 0.054 3±0.003 5,0.037 5±0.000 7,0.035 2±0.000 4 respectively, which was significantly higher in early onset group than that in late onset group(P<0.05), while there was no statistical difference between the late onset group and the control group(P>0.05).(3)Relative expression level of STOX1 protein in early onset group, late onset group and control group were 0.78±0.04,0.59±0.020 and 0.54±0.018 respectively, which is higher in early onset group than that in late onset group(P<0.05). There was no statistical difference of STOX1 level between the late onset group and the control group(P>0.05). Conclusions: The pathogenesis of early onset and late onset preeclampsia may be different. Up-regulated expression of STOX1 in placenta may be associated with the pathogenesis of early onset preeclampsia.


Assuntos
Proteínas de Transporte/genética , Pré-Eclâmpsia , Estudos de Casos e Controles , Cesárea , China , Feminino , Humanos , Placenta , Pré-Eclâmpsia/genética , Gravidez , Trofoblastos
20.
Nat Methods ; 16(7): 633-639, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235883

RESUMO

Mammalian genomes are folded into tens of thousands of long-range looping interactions. The cause-and-effect relationship between looping and genome function is poorly understood, and the extent to which loops are dynamic on short time scales remains an unanswered question. Here, we engineer a new class of synthetic architectural proteins for directed rearrangement of the three-dimensional genome using blue light. We target our light-activated-dynamic-looping (LADL) system to two genomic anchors with CRISPR guide RNAs and induce their spatial colocalization via light-induced heterodimerization of cryptochrome 2 and a dCas9-CIBN fusion protein. We apply LADL to redirect a stretch enhancer (SE) away from its endogenous Klf4 target gene and to the Zfp462 promoter. Using single-molecule RNA-FISH, we demonstrate that de novo formation of the Zfp462-SE loop correlates with a modest increase in Zfp462 expression. LADL facilitates colocalization of genomic loci without exogenous chemical cofactors and will enable future efforts to engineer reversible and oscillatory loops on short time scales.


Assuntos
Regulação da Expressão Gênica , Engenharia de Proteínas , Animais , Proteínas de Transporte/genética , Células Cultivadas , Fatores de Transcrição Kruppel-Like/genética , Luz , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , RNA Guia/genética
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