Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/métodos , Pomadas/administração & dosagem , Seio Pilonidal/cirurgia , Cicatrização/efeitos dos fármacos , Administração Tópica , Adolescente , Adulto , Alginatos/administração & dosagem , Aloe , Colostro , Feminino , Glicerol/administração & dosagem , Humanos , Ácido Hialurônico/administração & dosagem , Itália , Masculino , Pessoa de Meia-Idade , Pomadas/química , Período Pós-Operatório , Resultado do Tratamento , Adulto JovemRESUMO
Tumor necrosis factor-α (TNF-α) inhibitors are highly effective in suppressing inflammation in ankylosing spondylitis (AS) patients, and operate by suppression of TFN-α and downstream immunological pathways. To determine the mechanisms of action of TNF-α inhibitors in AS patients, we used transcriptomic and bioinformatic approaches on peripheral blood mononuclear cells from AS patients pre and post treatment. We found 656 differentially expressed genes, including the genome-wide significant AS-associated genes, IL6R, NOTCH1, IL10, CXCR2 and TNFRSF1A. A distinctive gene expression profile was found between male and female patients, mainly because of sex chromosome-linked genes and interleukin 17 receptor C, potentially accounting for the differences in clinical manifestation and treatment response between the genders. In addition to immune and inflammation regulatory pathways, like intestinal immune network for IgA production, cytokine-cytokine receptor interaction, Ras signaling pathway, allograft rejection and hematopoietic cell lineage, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that infection-associated pathways (influenza A and toxoplasmosis) and metabolism-associated pathways were involved in response to TNF-α inhibitor treatment, providing insight into the mechanism of TNF-α inhibitors.
Assuntos
Espondilite Anquilosante/genética , Transcriptoma , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/metabolismoRESUMO
Analysis of classical mouse mutations has been useful in the identification and study of many genes. We previously mapped Sox18, encoding an SRY-related transcription factor, to distal mouse chromosome 2. This region contains a known mouse mutation, ragged (Ra), that affects the coat and vasculature. Here we have directly evaluated Sox18 as a candidate for Ra. We found that Sox18 is expressed in the developing vascular endothelium and hair follicles in mouse embryos. Furthermore, we found no recombination between Sox18 and Ra in an interspecific backcross segregating for the Ra phenotype. We found point mutations in Sox18 in two different Ra alleles that result in missense translation and premature truncation of the encoded protein. Fusion proteins containing these mutations lack the ability to activate transcription relative to wild-type controls in an in vitro assay. Our observations implicate mutations in Sox18 as the underlying cause of the Ra phenotype, and identify Sox18 as a critical gene for cardiovascular and hair follicle formation.
Assuntos
Anormalidades Cardiovasculares/genética , Folículo Piloso/anormalidades , Proteínas de Grupo de Alta Mobilidade/genética , Mutação Puntual/genética , Fatores de Transcrição/genética , Alelos , Animais , Anormalidades Cardiovasculares/patologia , Análise Mutacional de DNA , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Ligação Genética , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Proteínas de Grupo de Alta Mobilidade/biossíntese , Hibridização In Situ , Endogamia , Camundongos , Camundongos Mutantes , Neovascularização Fisiológica/genética , Fenótipo , RNA Mensageiro/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Receptores Proteína Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento/biossíntese , Receptores de Fatores de Crescimento/deficiência , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento do Endotélio Vascular , Recombinação Genética , Fatores de Transcrição SOXF , Fatores de Transcrição/biossíntese , Ativação TranscricionalRESUMO
Wnt genes have been implicated in a range of developmental processes in the mouse including the patterning of the central nervous system and limbs. Reported here for the first time is the expression of Wnt2 in the early heart field of 7.5-8.5 dpc (days post-coitum) mouse embryos, making Wnt2 a potentially useful gene marker for the early stages of heart development. Expression was also detected in the allantois from 8.0 dpc and at later stages in the placenta and umbilicus. Mice deficient in Wnt2, generated by gene targeting, displayed runting and approximately 50% died perinatally. Histological analysis revealed alterations in the size and structure of placentas from these mice from 14.5 dpc. The placental defects were associated primarily with the labyrinthine zone and included oedema and tissue disruption and accumulation of maternal blood in large pools. There was also an apparent decrease in the number of foetal capillaries and an increase in the amount of fibrinoid material in the Wnt2 mutant placentas. These results suggest that Wnt2 is required for the proper vascularisation of the mouse placenta and the placental defects in Wnt2-deficient mice result in a reduction in birthweight and perinatal lethality.