Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 17.027
Filtrar
3.
Nat Commun ; 12(1): 1067, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594081

RESUMO

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.


Assuntos
Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Glicoproteínas de Membrana/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Fezes , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunoglobulina A/metabolismo , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL , Pâncreas/patologia , Proteínas Recombinantes/farmacologia , Fatores de Transcrição/metabolismo , Regulação para Cima/genética
5.
Adv Exp Med Biol ; 1278: 141-190, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523448

RESUMO

Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Tolerância Imunológica , Recém-Nascido , Inflamação , Mucosa Intestinal , Linfócitos T Reguladores
6.
Nat Commun ; 12(1): 836, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547321

RESUMO

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3ß inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.


Assuntos
Colite/genética , Glicogênio Sintase Quinase 3 beta/genética , Homeostase/genética , Interleucina-33/genética , Proteínas de Membrana/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Criança , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Feminino , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Células HT29 , Homeostase/efeitos dos fármacos , Humanos , Interleucina-33/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Dodecilsulfato de Sódio/administração & dosagem
7.
BMJ Case Rep ; 14(1)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33408109

RESUMO

An 85-year-old man with Child-Pugh A cirrhosis secondary to non-alcoholic steatohepatitis presented to casualty with four days of painless haematochezia with dark blood without haemodynamic compromise. This was in the setting of receiving stereotactic body radiation therapy (SBRT) as treatment for his hepatocellular carcinoma (HCC).He was found to have haemorrhagic radiation colitis which was treated with argon plasma coagulation (APC). Our case demonstrates the importance of considering radiation induced colitis as a cause for painless lower gastrointestinal bleeding in patients with a background of radiation therapy for HCC. Earlier review of the imaging and consideration of this differential could have prevented the need for repeat hospitalisations and would have led to prompt colonoscopy and diagnosis.


Assuntos
Carcinoma Hepatocelular/radioterapia , Colite/diagnóstico , Hemorragia Gastrointestinal/diagnóstico , Neoplasias Hepáticas/radioterapia , Lesões por Radiação/diagnóstico , Radiocirurgia/efeitos adversos , Idoso de 80 Anos ou mais , Coagulação com Plasma de Argônio , Biópsia , Carcinoma Hepatocelular/patologia , Colite/etiologia , Colite/patologia , Colite/cirurgia , Colo/diagnóstico por imagem , Colo/patologia , Colo/efeitos da radiação , Colo/cirurgia , Colonoscopia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Lesões por Radiação/etiologia , Lesões por Radiação/cirurgia , Tomografia Computadorizada por Raios X
8.
Nat Commun ; 12(1): 261, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431850

RESUMO

Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn's disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients without NOD2 mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis.


Assuntos
Doença de Crohn/metabolismo , Imunoglobulina A Secretora/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Colite/microbiologia , Colite/patologia , Doença de Crohn/patologia , Humanos , Lectinas Tipo C/metabolismo , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Nódulos Linfáticos Agregados/metabolismo , Transporte Proteico , Salmonella/fisiologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Transcitose
9.
Int J Nanomedicine ; 16: 345-357, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33488076

RESUMO

Background: Our previous study found that deletion of Sorting nexin 10 (SNX10) can protect against colonic inflammation and pathological damage induced by dextran sulfate sodium (DSS). This inspired us that modulation of SNX10 expression in colonic epithelial cells might represent a promising therapeutic strategy for inflammatory bowel disease (IBD). Methods: Effective delivery of siRNA/shRNA to silence genes is a highly sought-after means in the treatment of multiple diseases. Here, we encapsulated SNX10-shRNA plasmids (SRP) with polylactide-polyglycolide (PLGA) to make oral nanoparticles (NPs), and then applied them to acute and chronic IBD mice model, respectively. The characteristics of the nanoparticles were assayed and the effects of SRP-NPs on mouse IBD were evaluated. Results: High-efficiency SNX10-shRNA plasmids were successfully constructed and coated with PLGA to obtain nanoparticles, with a particle size of 275.2 ± 11.4mm, uniform PDI distribution, entrapment efficiency of 87.6 ± 2.5%, and drug loading of 13.11 ± 1.38%, displayed dominant efficiency of SNX10 RNA interference in the colon. In both acute and chronic IBD models, SRP-NPs could effectively reduce the loss of mice body weight, relieve the intestinal mucosal damage and inflammatory infiltration, inhibit the expression of inflammatory cytokines IL-1ß, IL-23, TNF-α, and down-regulate the expression of toll-like receptors (TLRs) 2 and 4. Conclusion: Oral nanoparticles of SNX10-shRNA plasmid displayed dominant efficiency of SNX10 RNA interference in the colon and ameliorate mouse colitis via TLR signaling pathway. SNX10 is a new target for IBD treatment and nanoparticles of SNX10-shRNA plasmid might be a promising treatment option for IBD.


Assuntos
Colite/terapia , Portadores de Fármacos/química , Terapia Genética/métodos , Nanopartículas/química , Plasmídeos/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Administração Oral , Animais , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Camundongos , Interferência de RNA , RNA Interferente Pequeno/química , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Cell Host Microbe ; 29(1): 10-12, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33444552

RESUMO

Intestinal immunoglobulin (Ig)A binds to distinct commensals and pathobionts, but do these IgA-coated bacterial communities define clinical characteristics of inflammatory disease? In this issue of Cell Host & Microbe, Shapiro et al. comprehensively analyze IgA-coated bacteria in new onset inflammatory bowel disease (IBD), revealing their potential in guiding precision therapy and diagnostic stratification.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Microbiota , Diamante , Humanos , Imunoglobulina A , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética
12.
J Ethnopharmacol ; 264: 113243, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32781258

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is an autoimmune disease. Although the mortality rate of UC is not very high, it has a considerable morbidity rate and an unsatisfactory cure rate. Without effective treatment, UC is likely to develop into colon cancer. Kuijieling (KJL) is an effective empirical formula to treat UC in the clinical setting, and it has been proven to have curative effects against UC. AIM OF THE STUDY: In a previous study, we demonstrated that KJL could suppress NOD-like receptor protein 3 (NLRP3) to reduce inflammatory cytokines and alleviate UC. In this study, we investigated the mechanism of KJL in more detail, from the perspective of pyroptosis. MATERIALS AND METHODS: We established a dextran sulfate sodium-induced UC mouse model and RAW264.7 cells to measure different indicators with different experimental methods. The efficiency of KJL was evaluated by measuring the length and unit weight of mouse colons, and assessment of pathological injury was performed using HE staining. We detected different expression levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, gasdermin-D C-terminal domain (GSDMD-C), gasdermin-D N-terminal domain (GSDMD-N), IL-1ß, and IL-18 in colon tissues and cells using RT-qPCR and western blotting. Immunohistochemistry was used for tissues and immunofluorescence for cells to confirm protein expression. IL-1ß and IL-18 were measured with enzyme-linked immunosorbent assay in serum, tissue, and cell culture supernatant. MiR-223 was detected using RT-qPCR. RESULTS: After administration of KJL suspension, colon damage in KJL groups was milder than in model groups. ASC, caspase-1, IL-1ß, and IL-18 mRNA levels in colon tissue were decreased to different degrees in the KJL groups. Protein expression of NLRP3, caspase-1, GSDMD-N, IL-1ß, and IL-18 in vivo decreased significantly in the KJL groups. In addition, Mir-223 level decreased in colon tissue of the KJL groups. In vitro, NLRP3, ASC, caspase-1, GSDMD-N, IL-1ß, and IL-18 levels decreased to varying degrees, at both mRNA and protein levels. Mir-223 was lower in the KJL groups than in the model group. Furthermore, KJL was shown to regulate the level of miR-223, which returned to normal after its expression was inhibited or promoted, and the levels of associated indicators also returned to normal after transfection. CONCLUSIONS: KJL is able to inhibit pyroptosis to alleviate UC, but these suppression effects were not mediated through miR-223 regulation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/toxicidade , Piroptose/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Colite/metabolismo , Colite/patologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Piroptose/fisiologia , Células RAW 264.7 , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
13.
J Ethnopharmacol ; 264: 113280, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32822821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus and Codonopsis pilosula which are two Chinese medicinal herbs are often combinedly used as monarch drugs in Traditional Chinese Medicine (TCM) prescriptions to treat ulcerative colitis (UC). However, the exact mechanisms and effective constituents of the two herbs remain unclear. AIM OF THE STUDY: Polysaccharides are the main active ingredients of the two medicinal herbs and some specific polysaccharides extracted from the two medicinal herbs have been proven effective in relieving colitis. Hence, we speculated that polysaccharides of the two medicinal herbs may be the material basis for compatibility in TCM prescriptions to treat UC. In the research, total polysaccharides of A. membranaceus and C. pilosula extractum, named AERP and CERP respectively, were administrated to 2.5% dextran sulfate sodium (DSS)-induced acute colitis mice by dosing alone and in combination to test this hypothesis. MATERIALS AND METHODS: 5-aminosalicylic acid (5-ASA, 100 mg/kg/d) was selected as the positive drug. The basic indexes of colitis mice including body weight, stool bleeding, stool consistency and colon lengths were recorded. In addition, tissue inflammatory factors, mucosa-associated proteins, fecal short chain fatty acids (SCFAs) and gut microbiota were also analyzed. RESULTS: The co-administration of AERP and CERP at specific doses could improve the clinical symptoms, reestablish the immune balance, and alleviate colonic mucosal injury in colitis mice. The unique efficacy of co-administration relied on activation of the aryl hydrocarbon receptor (AhR) and up-regulation of isovaleric acid and butyrate. In addition, the structure of intestinal flora was recovered in the co-administration group. CONCLUSION: Our research proved the efficacy after co-administration of total polysaccharides from A. membranaceus and C. pilosula on colitis mice which provided a theoretical basis for their compatibility in TCM prescriptions to treat UC.


Assuntos
Astragalus propinquus , Codonopsis , Colite/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Animais , Colite/metabolismo , Colite/patologia , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação
14.
Sci Total Environ ; 750: 143085, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33182181

RESUMO

Microplastics (MPs) are ubiquitous contaminants in the environment and can be transferred along the food chain, thus causing adverse effects in organisms, even human beings. Therefore, it is of practical importance to identify the environmental risks of MPs, which could lead to a significant impact on public health. In addition to the healthy population, there are large numbers of patients with chronic diseases around the world whose responses to MPs are understudied, representing a significant knowledge gap within the health risk assessment of MPs. In this study, the response sensitivity to MPs of mice with acute colitis was compared with that of healthy mice. The mice were fed water containing polystyrene microplastics (PS MP) at a concentration of 500 µg/L for 28 days. The results showed that PS MP exposure induced inflammatory effects and exerted great disturbance on liver metabolites. Moreover, exposure to PS MP exaggerated dextran sodium sulfate (DSS)-induced acute colitis, as well as lipid disorders, as verified by typical inflammatory factor expression and triglyceride accumulation. The increased intestinal permeability of mice with acute colitis caused by exposure to PS MP may be responsible for the upregulated adverse effects. The results of this study suggest that populations with chronic diseases might be more sensitive to environmental contamination, which should be considered during health risk assessments.


Assuntos
Colite , Poluentes Químicos da Água , Animais , Colite/induzido quimicamente , Humanos , Fígado , Camundongos , Microplásticos , Plásticos , Poliestirenos , Poluentes Químicos da Água/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA