Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.567
Filtrar
1.
Vet Pathol ; 57(5): 642-652, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32880235

RESUMO

In the small intestine, localized innate mucosal immunity is critical for intestinal homeostasis. Porcine epidemic diarrhea virus (PEDV) infection induces villus injury and impairs digestive function. Moreover, the infection might comprise localized innate mucosal immunity. This study investigated specific enterocyte subtypes and innate immune components of weaned pigs during PEDV infection. Four-week-old pigs were orally inoculated with PEDV IN19338 strain (n = 40) or sham-inoculated (n = 24). At day post inoculation (DPI) 2, 4, and 6, lysozyme expression in Paneth cells, cellular density of villous and Peyer's patch microfold (M) cells, and the expression of polymeric immunoglobulin receptor (pIgR) were assessed in the jejunum and ileum by immunohistochemistry, and interleukin (IL)-1ß and tumor necrosis factor (TNF)-α were measured in the jejunum by ELISA. PEDV infection led to a decrease in the ratios of villus height to crypt depth (VH-CD) in jejunum at DPI 2, 4, and 6 and in ileum at DPI 4. The number of villous M cells was reduced in jejunum at DPI 4 and 6 and in ileum at DPI 6, while the number of Peyer's patch M cells in ileum increased at DPI 2 and then decreased at DPI 6. PEDV-infected pigs also had reduced lysozyme expression in ileal Paneth cells at DPI 2 and increased ileal pIgR expression at DPI 4. There were no significant changes in IL-1ß and TNF-α expression in PEDV-infected pigs compared to controls. In conclusion, PEDV infection affected innate mucosal immunity of weaned pigs through alterations in Paneth cells, villous and Peyer's patch M cells, and pIgR expression.


Assuntos
Infecções por Coronavirus/veterinária , Imunidade Inata , Mucosa Intestinal/imunologia , Vírus da Diarreia Epidêmica Suína , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Citocinas/análise , Íleo/imunologia , Íleo/patologia , Íleo/virologia , Mucosa Intestinal/química , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Jejuno/imunologia , Jejuno/patologia , Jejuno/virologia , Receptores de Imunoglobulina Polimérica/metabolismo , Suínos , Desmame
2.
PLoS One ; 15(8): e0236657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760089

RESUMO

Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-ß: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.


Assuntos
Colo/metabolismo , Doença de Crohn/metabolismo , Íleo/metabolismo , Canais de Cátion TRPV/metabolismo , Fumar Tabaco/efeitos adversos , Adulto , Idoso , Animais , Células CACO-2 , Colo/patologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HT29 , Humanos , Íleo/patologia , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pesquisa Médica Translacional , Ácido Trinitrobenzenossulfônico
3.
Am J Gastroenterol ; 115(8): 1236-1245, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32759621

RESUMO

INTRODUCTION: It is unclear how baseline endoscopic characteristics in Crohn's disease (CD) affect the ability to achieve endoscopic remission (ER). We aimed to determine the endoscopic prognostic factors that influence achieving ER in CD. DESIGN: This post hoc analysis of SONIC (NCT00094458; YODA #2019-3980) evaluated baseline and week 26 endoscopy indices in 172 patients using the CD Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for CD. The impact of baseline ulcer depth and size on achieving week 26 ER was assessed using multivariate logistic regression models adjusted for confounders. RESULTS: The ER rate of ileal ulcers was significantly lower than ER rates throughout the colon (P < 0.0001). Ileal ulcers >2 cm were less likely to achieve ER compared with smaller ulcers {odds ratio (OR) 0.31 (95% confidence interval [CI] 0.11-0.89), P = 0.03}. Similarly, rectal ulcers >2 cm were associated with reduced odds of week 26 ER (OR 0.26 [95% CI 0.08-0.80], P = 0.02). Ulcer size in other colonic segments did not affect the achievement of week 26 ER. Deep ileal and rectal ulcers >2 cm compared with smaller or superficial ulcers were even less likely to achieve week 26 ER (ileum: OR 0.10, 95% CI 0.02-0.68, P = 0.02; rectum: OR 0.12, 0.02-0.82, P = 0.03). High baseline Simple Endoscopic Score for CD (≥16) or CDEIS scores (≥12) did not affect achieving week 26 ER. DISCUSSION: Patients with larger and deep ulcers in the ileum or rectum may have difficulty achieving ER. Overall degree of endoscopic inflammation as measured numerically by endoscopic scores does not affect the likelihood of achieving week 26 ER.


Assuntos
Doença de Crohn , Íleo/patologia , Reto/patologia , Índice de Gravidade de Doença , Adulto , Colonoscopia , Feminino , Humanos , Masculino , Prognóstico
4.
PLoS One ; 15(7): e0236300, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702056

RESUMO

Breadfruit is a traditional staple crop from Pacific islands with the potential to improve worldwide food security and mitigate diabetes. Flour produced from breadfruit is a gluten-free, low glycemic index, nutrient dense and complete protein option for modern foods but basic scientific knowledge of health impacts of a breadfruit-based diet in animals and humans was lacking. We designed a series of studies to provide basic and fundamental data on impacts of a breadfruit-based diet through an in vitro and in vivo model. Cooked breadfruit flour was digested through a multi-stage enzyme digestion model to estimate protein digestibility in comparison to wheat flour. Breadfruit protein was found to be easier to digest than wheat protein in the enzyme digestion model. The flour digestions were applied to Caco-2 cells to test the cytotoxicity and to measure the immunogenicity through cytokine expression. No significant differences were observed for immune factors and cytokines (IL-4, IL-10, IL-8, TNF-α, IFN-γ) on Caco-2 cells between the breadfruit and wheat groups. A breadfruit-based rodent chow was formulated by substitution of all of the wheat in the standard formulation with breadfruit. The diets were isocaloric, nutrient equivalent and used to feed male and female C57BL/6 mice for 21 days. No sign of malnutrition, discomfort, illness or death was observed among the mice because of the diet. The histology and the cytokine expression of the mice ileum from both groups were analyzed and showed similar results. The expression of major bacteria was measured in the colon and showed similar results. Mice fed the breadfruit diet had a significantly higher growth rate and body weight than standard diet fed mice. No negative health outcomes were observed in studies with in vitro or in vivo models and breadfruit flour is a healthy alternative to other starches for modern foods.


Assuntos
Artocarpus/química , Farinha , Abastecimento de Alimentos , Alimentos , Animais , Composição Corporal/efeitos dos fármacos , Células CACO-2 , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Dieta , Fezes/química , Humanos , Íleo/efeitos dos fármacos , Íleo/patologia , Interleucina-1beta/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Minerais/análise , Óxido Nítrico Sintase Tipo II/metabolismo
5.
Lancet Gastroenterol Hepatol ; 5(10): 900-907, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32619413

RESUMO

BACKGROUND: The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group. METHODS: In this retrospective follow-up study, we collected data from patients who participated in the LIR!C trial, a multicentre randomised controlled trial that compared quality of life after surgical resection versus infliximab in adult patients with non-stricturing and immunomodulator-refractory ileocaecal Crohn's disease. From Jan 1 to May 1, 2018, we collected follow-up data from the time from enrolment in the LIR!C trial until the last visit at either the gastrointestinal surgeon or gastroenterologist. In this study, outcomes of interest were need for surgery or repeat surgery or anti-TNF therapy, duration of treatment effect, and identification of factors associated with the duration of treatment effect. Duration of treatment effect was defined as the time without need for additional Crohn's disease-related treatment (corticosteroids, immunomodulators, biologics, or surgery). FINDINGS: We collected long-term follow-up data for 134 (94%) of 143 patients included in the LIR!C trial, of whom 69 were in the resection group and 65 were in the infliximab group. Median follow-up was 63·5 months (IQR 39·0-94·5). In the resection group, 18 (26%) of 69 patients started anti-TNF therapy and none required a second resection. 29 (42%) patients in the resection group did not require additional Crohn's disease-related medication, although 14 (48%) of these patients were given prophylactic immunomodulator therapy. In the infliximab group, 31 (48%) of 65 patients had a Crohn's disease-related resection, and the remaining 34 patients maintained, switched, or escalated their anti-TNF therapy. Duration of treatment effect was similar in both groups, with a median time without additional Crohn's disease-related treatment of 33·0 months (95% CI 15·1-50·9) in the resection group and 34·0 months (0·0-69·3) in the infliximab group (log-rank p=0·52). In both groups, therapy with an immunomodulator, in addition to the allocated treatment, was associated with duration of treatment effect (hazard ratio for resection group 0·34 [95% CI 0·16-0·69] and for infliximab group 0·49 [0·26-0·93]). INTERPRETATION: These findings further support laparoscopic ileocaecal resection as a treatment option in patients with Crohn's disease with limited (affected segment ≤40 cm) and predominantly inflammatory terminal ileitis for whom conventional treatment is not successful. FUNDING: None.


Assuntos
Ceco/cirurgia , Doença de Crohn/terapia , Íleo/cirurgia , Laparoscopia/métodos , Corticosteroides/uso terapêutico , Adulto , Ceco/patologia , Análise Custo-Benefício/métodos , Doença de Crohn/etiologia , Feminino , Seguimentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Íleo/patologia , Fatores Imunológicos/uso terapêutico , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
6.
Nat Commun ; 11(1): 3755, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709874

RESUMO

Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders.


Assuntos
Disbiose/imunologia , Inflamação/patologia , Intestinos/patologia , Células T Invariáveis Associadas à Mucosa/patologia , Obesidade/metabolismo , Tecido Adiposo/patologia , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Disbiose/complicações , Microbioma Gastrointestinal , Teste de Tolerância a Glucose , Íleo/patologia , Inflamação/complicações , Mucosa Intestinal/patologia , Intestinos/diagnóstico por imagem , Ligantes , Contagem de Linfócitos , Macrófagos/metabolismo , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/diagnóstico por imagem , Fenótipo , Pterinas/farmacologia , Receptores de Antígenos de Linfócitos T/metabolismo
7.
Acta Cir Bras ; 35(4): e202000401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555935

RESUMO

PURPOSE: To evaluate the effect of N-Acetylcysteine (NAC) in newborn rats submitted to hypoxia and reoxygenation (H/R) conditions in an experimental model of necrotizing enterocolitis. METHODS: Eight pregnant rats and their 70 cubs were used (5 groups) and exposed to H/R conditions and received NAC at different times. The animals in the H/R groups were placed in a gas chamber (100% CO2) for 10 minutes and then reoxygenated for 10 minutes (100% O2), twice a day for the first three days of life, with a six-hour span between events. On the third day of life, the animals were anesthetized, laparotomized and the intestines were resected. RESULTS: The H/R and NAC groups showed changes in the intestinal wall in relation to the number, height and width of the villi when compared to the control group (p<0.0001), but with better preservation of structures in the NAC group. There were no differences between groups regarding the number (%) of mitoses. CONCLUSION: The administration of NAC decreased the lesions in the intestinal wall of rats submitted to H/R, therefore suggesting that this drug can be used to prevent the development of necrotizing enterocolitis in newborns.


Assuntos
Acetilcisteína/farmacologia , Enterocolite Necrosante/prevenção & controle , Hipóxia/patologia , Íleo/efeitos dos fármacos , Íleo/patologia , Substâncias Protetoras/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
8.
Ann R Coll Surg Engl ; 102(8): e198-e201, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32538111

RESUMO

Colorectal cancer metastasis to the retroperitoneum, especially solitary metastasis allowing curative resection, is rare. We report a case of complete resection of retroperitoneal metachronous solitary metastasis from caecal cancer without distant metastasis. An 80-year-old woman with caecal cancer underwent laparoscopic ileocaecal resection with regional lymph node dissection. According to the eighth edition of the TNM classification, the pathological diagnosis was stage IIA (T3N0M0). Six months following the surgery, computed tomography revealed a solitary mass of 2cm diameter, dorsal to the right kidney. A second procedure for the removal of the tumour was performed. The lesion was pathologically diagnosed as a metachronous solitary retroperitoneal metastasis from caecal cancer. The patient is surviving and free from recurrence 17 months following the second procedure.


Assuntos
Neoplasias do Ceco/patologia , Ceco , Íleo , Neoplasias Retroperitoneais , Idoso de 80 Anos ou mais , Ceco/diagnóstico por imagem , Ceco/patologia , Ceco/cirurgia , Feminino , Humanos , Íleo/diagnóstico por imagem , Íleo/patologia , Íleo/cirurgia , Laparoscopia , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/secundário , Neoplasias Retroperitoneais/cirurgia
9.
J Virol ; 94(17)2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32554697

RESUMO

Coronaviruses (CoVs) have repeatedly emerged from wildlife hosts and infected humans and livestock animals to cause epidemics with significant morbidity and mortality. CoVs infect various organs, including respiratory and enteric systems, as exemplified by newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The constellation of viral factors that contribute to developing enteric disease remains elusive. Here, we investigated CoV interferon antagonists for their contribution to enteric pathogenesis. Using an infectious clone of an enteric CoV, porcine epidemic diarrhea virus (icPEDV), we generated viruses with inactive versions of interferon antagonist nonstructural protein 1 (nsp1), nsp15, and nsp16 individually or combined into one virus designated icPEDV-mut4. Interferon-responsive PK1 cells were infected with these viruses and produced higher levels of interferon responses than were seen with wild-type icPEDV infection. icPEDV-mut4 elicited robust interferon responses and was severely impaired for replication in PK1 cells. To evaluate viral pathogenesis, piglets were infected with either icPEDV or icPEDV-mut4. While the icPEDV-infected piglets exhibited clinical disease, the icPEDV-mut4-infected piglets showed no clinical symptoms and exhibited normal intestinal pathology at day 2 postinfection. icPEDV-mut4 replicated in the intestinal tract, as revealed by detection of viral RNA in fecal swabs, with sequence analysis documenting genetic stability of the input strain. Importantly, icPEDV-mut4 infection elicited IgG and neutralizing antibody responses to PEDV. These results identify nsp1, nsp15, and nsp16 as virulence factors that contribute to the development of PEDV-induced diarrhea in swine. Inactivation of these CoV interferon antagonists is a rational approach for generating candidate vaccines to prevent disease and spread of enteric CoVs, including SARS-CoV-2.IMPORTANCE Emerging coronaviruses, including SARS-CoV-2 and porcine CoVs, can infect enterocytes, cause diarrhea, and be shed in the feces. New approaches are needed to understand enteric pathogenesis and to develop vaccines and therapeutics to prevent the spread of these viruses. Here, we exploited a reverse genetic system for an enteric CoV, porcine epidemic diarrhea virus (PEDV), and outline an approach of genetically inactivating highly conserved viral factors known to limit the host innate immune response to infection. Our report reveals that generating PEDV with inactive versions of three viral interferon antagonists, nonstructural proteins 1, 15, and 16, results in a highly attenuated virus that does not cause diarrhea in animals and elicits a neutralizing antibody response in virus-infected animals. This strategy may be useful for generating live attenuated vaccine candidates that prevent disease and fecal spread of enteric CoVs, including SARS-CoV-2.


Assuntos
Infecções por Coronavirus/imunologia , Coronavirus/imunologia , Interferons/imunologia , Vírus da Diarreia Epidêmica Suína/imunologia , Vacinas Atenuadas/imunologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Betacoronavirus/imunologia , Chlorocebus aethiops , Infecções por Coronavirus/prevenção & controle , Diarreia/patologia , Diarreia/virologia , Modelos Animais de Doenças , Endorribonucleases/antagonistas & inibidores , Fezes/virologia , Íleo/patologia , Imunidade Inata , Jejuno/patologia , Pandemias , Pneumonia Viral/imunologia , Vírus da Diarreia Epidêmica Suína/genética , RNA Replicase , RNA Viral , Suínos , Doenças dos Suínos/virologia , Células Vero , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
10.
Nat Med ; 26(6): 919-931, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32451498

RESUMO

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Microbioma Gastrointestinal/imunologia , Íleo/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Oxaliplatina/farmacologia , Adenocarcinoma/imunologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Apoptose/imunologia , Bacteroides fragilis , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Firmicutes , Microbioma Gastrointestinal/fisiologia , Humanos , Íleo/imunologia , Íleo/microbiologia , Íleo/patologia , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/imunologia , Vigilância Imunológica/efeitos dos fármacos , Vigilância Imunológica/imunologia , Interleucina-12/imunologia , Mucosa Intestinal , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
11.
Nat Commun ; 11(1): 1995, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332732

RESUMO

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.


Assuntos
Artrite Reumatoide/prevenção & controle , Permeabilidade da Membrana Celular/efeitos dos fármacos , Disbiose/complicações , Haptoglobinas/antagonistas & inibidores , Mucosa Intestinal/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Precursores de Proteínas/antagonistas & inibidores , Adulto , Animais , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Experimental/prevenção & controle , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Translocação Bacteriana/efeitos dos fármacos , Translocação Bacteriana/imunologia , Células CACO-2 , Permeabilidade da Membrana Celular/imunologia , Estudos de Coortes , Estudos Transversais , Disbiose/imunologia , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Haptoglobinas/metabolismo , Voluntários Saudáveis , Humanos , Íleo/citologia , Íleo/efeitos dos fármacos , Íleo/microbiologia , Íleo/patologia , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Precursores de Proteínas/sangue , Precursores de Proteínas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-32348179

RESUMO

The serotonin transporter (SERT) functions to regulate the availability of serotonin (5-HT) in the brain and intestine. An intestine-specific mRNA variant arising from a unique transcription start site and alternative promoter in the SERT gene has been identified (iSERT; spanning exon 1C). A decrease in SERT is implicated in several gut disorders, including inflammatory bowel diseases (IBD). However, little is known about mechanisms regulating the iSERT variant, and a clearer understanding is warranted for targeting SERT for the treatment of gut disorders. The current studies examined the expression of iSERT across different human intestinal regions and investigated its regulation by HNF4α (hepatic nuclear factor-4α), a transcription factor important for diverse cellular functions. iSERT mRNA abundance was highest in the human ileum and Caco-2 cell line. iSERT mRNA expression was downregulated by loss of HNF4α (but not HNF1α, HNF1ß, or FOXA1) in Caco-2 cells. Overexpression of HNF4α increased iSERT mRNA concomitant with an increase in SERT protein. Progressive promoter deletion and site-directed mutagenesis revealed that the HNF4α response element spans nucleotides -1,163 to -1150 relative to the translation start site. SERT mRNA levels in the intestine were drastically reduced in the intestine-specific HNF4α-knockout mice relative to HNF4αFL/FL mice. Both HNF4α and SERT mRNA levels were also downregulated in mouse model of ileitis (SAMP) compared with AKR control mice. These results establish the transcriptional regulation of iSERT at the gut-specific internal promoter (hSERTp2) and have identified HNF4α as a critical modulator of basal SERT expression in the intestine.


Assuntos
Células Epiteliais/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Ileíte/metabolismo , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Células CACO-2 , Modelos Animais de Doenças , Células Epiteliais/patologia , Fator 4 Nuclear de Hepatócito/deficiência , Fator 4 Nuclear de Hepatócito/genética , Humanos , Ileíte/genética , Ileíte/patologia , Íleo/patologia , Mucosa Intestinal/patologia , Masculino , Camundongos Knockout , Regiões Promotoras Genéticas , Elementos de Resposta , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transcrição Genética
13.
J Surg Res ; 252: 116-124, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32278965

RESUMO

BACKGROUND: Proximal (duodenal) small bowel adenocarcinomas have a worse prognosis than distal (jejuno-ileal) tumors, but differences in patient, tumor, and treatment factors between locations remain unclear. METHODS: Patients in the National Cancer Database with surgically resected pathologic stage I-IV small bowel adenocarcinomas between 2004 and 2015 were analyzed. Clinical stage IV patients were excluded. RESULTS: Proximal tumors (n = 3767) were more likely to be higher grade (OR 1.52, CI 1.22-1.85 for moderately; OR 1.83, CI 1.49-2.33 for poorly differentiated, P < 0.01 for both) and have positive lymph nodes (OR 2.04, CI 1.30-3.23, P < 0.01), while distal tumors (n = 3252) were likely to be larger (OR 1.31, CI 1.07-1.60 for size > 5 cm, P < 0.01). Proximal tumors were associated with worse overall survival (OS) and stage-specific survival compared with distal tumors (all P < 0.01). Cox regression analysis of the entire cohort showed worse survival with community versus academic cancer programs, higher comorbidity scores, pathologic stage IV, poorly differentiated histology, positive nodal or margin status, and proximal location, while female gender, larger tumor size, and chemotherapy predicted better survival. On separate Cox regression analyses of each location, neoadjuvant chemotherapy was associated with better OS in the proximal cohort (HR 0.70, CI 0.55-0.88, P < 0.01), while adjuvant chemotherapy was associated with better OS for both proximal (HR 0.49, CI 0.42-0.57, P < 0.01) and distal tumors (HR 0.68, CI 0.57-0.81, P < 0.01). CONCLUSIONS: Proximal small bowel adenocarcinomas are associated with worse overall and stage-specific survival. This may be due to tumor biologic differences as proximal tumors were more likely to have higher grade. Future studies should further investigate differences between proximal and distal tumors to guide targeted treatment algorithms.


Assuntos
Adenocarcinoma/mortalidade , Neoplasias Duodenais/mortalidade , Neoplasias do Íleo/mortalidade , Neoplasias do Jejuno/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Quimiorradioterapia Adjuvante , Neoplasias Duodenais/patologia , Neoplasias Duodenais/terapia , Duodeno/patologia , Duodeno/cirurgia , Feminino , Humanos , Neoplasias do Íleo/patologia , Neoplasias do Íleo/terapia , Íleo/patologia , Íleo/cirurgia , Neoplasias do Jejuno/patologia , Neoplasias do Jejuno/terapia , Jejuno/patologia , Jejuno/cirurgia , Estimativa de Kaplan-Meier , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento
14.
Environ Toxicol ; 35(9): 982-990, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32333507

RESUMO

In this work, we aimed to evaluate the adverse effects and the mechanism of intestinal barrier caused by titanium dioxide nanoparticles (TiO2 NPs). Here, the effects of two different dosages (300 and 1200 mg/kg) of TiO2 NPs on female mice (n = 5) were investigated. After 28-day oral exposure, the results of Ti content were significantly increased in the ileum in comparison with the control. The histopathological structure index of the ileum was significantly changed after TiO2 NPs exposure; villi height and crypt depth were decreased and increased, respectively. Meanwhile, TiO2 NPs treatment also significantly altered the transcription levels of genes. First, the GATA-3 and STAT-4 were upregulation and downregulation, respectively. Second, gene expressions of the Zonula Occludens-1, claudin (CLDN)-12, occludin, and myosin light chain kinase were significantly upregulated, while the CLDN-3 was decreased. Finally, the caspase-3, caspase-9, and caspase-12 were upregulated. The results of TUNEL staining indicated apoptosis in the ileum. In general, TiO2 NPs treatment significantly changed the intestine physical barrier in a dose-dependent manner. The toxicity of TiO2 NPs could be through the imbalance in the Th1/Th2.


Assuntos
Apoptose/efeitos dos fármacos , Íleo/efeitos dos fármacos , Nanopartículas/toxicidade , Equilíbrio Th1-Th2/efeitos dos fármacos , Titânio/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Íleo/imunologia , Íleo/metabolismo , Íleo/patologia , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Propriedades de Superfície , Titânio/química , Titânio/farmacocinética
15.
Ann Hematol ; 99(5): 1121-1128, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32130472

RESUMO

AIM:  To measure histological villous atrophy and to clarify the diagnostic accuracy of endoscopic villous atrophy in gastrointestinal graft-versus-host disease. METHODS:  Data for patients who underwent upper and/or lower endoscopic examinations after hematopoietic stem cell transplantation were retrospectively collected. In study 1, group A included 56 patients in whom GI-GVHD was histologically confirmed and group B included 60 patients in whom GI-GVHD was not histologically confirmed. Group C included 59 patients before HSCT. The lengths of villi and crypts in the duodenum and terminal ileum were histologically measured. In study 2, the diagnostic accuracies of villous atrophy of the duodenum and of the terminal ileum using magnifying endoscopy were evaluated. RESULTS:  In study 1, the lengths of villi and the villi/crypt (V/C) ratios of the duodenum and terminal ileum in group A were significantly smaller than those in the other groups (p < 0.05). V/C ratio was moderately correlated with clinical severity, histological grades, and endoscopic grades in the terminal ileum. In study 2, the diagnostic accuracies of magnified images for villous atrophy were 83.8% in the duodenum and 94.9% in the terminal ileum. CONCLUSION:  Magnifying endoscopy enables evaluation of villous atrophy and is useful for optical biopsy of GVHD.


Assuntos
Duodenopatias/patologia , Duodeno/patologia , Endoscopia Gastrointestinal , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Doenças do Íleo/patologia , Íleo/patologia , Mucosa Intestinal/patologia , Adolescente , Adulto , Idoso , Aloenxertos , Atrofia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Toxicol Appl Pharmacol ; 394: 114956, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171571

RESUMO

Proper enterocytic proliferation/differentiation, besides providing adequate adherens junctions (AJ) integrity, are responsible for strengthening of the gut barrier that acts as a first line defense against endotoxemia. However, the preferential role of the underlying PI3K/Akt (PKB) axis in triggering enterocytic proliferation/differentiation signaling and AJ assembly is still obscure in sepsis. Additionally, the potential involvement of dipeptidyl peptidase (DPP)-IV in cholestatic sepsis has not yet been reported. Common bile duct ligation (CBDL) insult was performed in adult male Sprague-Dawley rats except for sham operated animals; three doses of vildagliptin (VLD3, 10 and 30 mg/kg/d; p.o) were administered for 10 consecutive days post CBDL. VLD3/10/30 dose-dependently decreased DPP-IV and elevated GLP-1, IGF-1, PI3K, pS473-Akt (PKB), pS9-GSK-3ß, pS133-CREB and cyclin-D1. VLD3/10 reduced fever, portal/aortic endotoxin and IgG, body weight loss as well as ileal NF-κB, TNF-α, MPO, TBARS, subepithelial/pericryptal and submucosal collagen deposition, vimentin immunoreactivity, N-cadherin, Zeb1 and pY654-ß-catenin but increased E-cadherin, NPSH and colon/spleen indices - effects that were quite the opposite of VLD30. Accordingly, maintaining proper enterocytic proliferation/differentiation and phosphorylation inputs consequent to adequate DPP-IV inhibition is integral to AJ assembly in cholestatic sepsis; however, perturbed signals by excessive suppression of the enzyme activity induce toxic effects manifested as AJ disassembly and EMT, hence gut leakage and overt endotoxemia.


Assuntos
Colestase/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Enterócitos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Sepse/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colestase/tratamento farmacológico , Ducto Colédoco/lesões , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Íleo/patologia , Ligadura , Masculino , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Vildagliptina/farmacologia , Vimentina/metabolismo , Perda de Peso/efeitos dos fármacos
17.
Korean J Gastroenterol ; 75(1): 46-49, 2020 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-31986573

RESUMO

Intussusception is a medical condition, in which a proximal part of the intestine folds into the distal intestine. Adult intussusceptions are rare and account for approximately 5% of all cases of intussusceptions. The anatomical leading points include tumors, diverticulums, polyps, and strictures in 80-90% of adult intussusceptions, and 65% of colon intussusceptions and 30% of small bowel intussusceptions originate from malignant tumors. Treatments for adult intussusception have not been established, but most cases require surgical treatment. The gastrointestinal tract is the most common extranodal site for non-Hodgkin lymphoma. The symptoms are mostly non-specific, but they rarely lead to complications, such as bleeding, perforation, and intussusception. Furthermore, few cases of primary gastrointestinal lymphomas causing intussusception have been reported. This paper reports a case of small bowel diffuse large B cell lymphoma that caused ileocolic intussusception in a 69-year-old woman with no medical history. She underwent a small bowel resection and received six cycles of adjuvant chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Since then, she has been in complete remission.


Assuntos
Doenças do Íleo/diagnóstico , Intussuscepção/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Idoso , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Endoscopia Gastrointestinal , Humanos , Doenças do Íleo/complicações , Íleo/patologia , Intussuscepção/complicações , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Tomografia Computadorizada por Raios X
19.
Am J Case Rep ; 21: e917759, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31988272

RESUMO

BACKGROUND The incidence of neuroendocrine tumors (NETs) has increased in recent years. They can affect every area of the human body that presents cells with a secretory function. In this report, we focus on gastrointestinal NETs. The small bowel (SI) is the most affected area and SI-NETs have recently become more common than adenocarcinomas. Inside the small intestine, the appendix suffers from this pathology more than other organs. CASE REPORT Our case report deals with a 70 years-old man with extensive abdominal pain due to ingestion of an apricot kernel. A CT abdominal scan showed, around the kernel, a mechanical ileus with inflammation of the distal ileum and thickening of the intestinal wall. During the operation, we replaced laparoscopy with mini-laparotomy, performing an ileocecectomy due to suspicion of a tumor lesion. The histopathological exam revealed a well-differentiated neuroendocrine tumor (NET G1) of the distal ileum. CONCLUSIONS This case report shows that SI-NETs can be found in cases of small bowel occlusion. Depending on the size and distinction, such patients can have good survival rates.


Assuntos
Neoplasias Intestinais/diagnóstico , Intestino Delgado/patologia , Tumores Neuroendócrinos/diagnóstico , Dor Abdominal , Idoso , Apêndice/patologia , Humanos , Íleo/patologia , Achados Incidentais , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico
20.
J Surg Res ; 246: 584-590, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31653414

RESUMO

BACKGROUND: Primary gastrointestinal stromal tumor (GIST)-mimicking gynecologic masses are easily misdiagnosed. This study aimed to investigate the clinicopathological features, management, and prognosis of primary GIST mimicking as gynecologic mass. METHODS: Clinicopathological and survival data of GIST mimicking as gynecologic mass admitted to our center from January 2005 to December 2017 were retrospectively analyzed. RESULTS: Thirty-eight patients were included. The most common primary tumor site was the jejunoileum (n = 33, 86.9%), and 33 patients (86.9%) were classified as high recurrence risk. The short-term outcomes of operative incision length (P = 0.004), time to gas passage (P = 0.002), and hospital stay (P = 0.012) with laparoscopy-assisted resection were significantly shorter than those with open resection, showing no significant differences of long-term outcomes. With a median follow-up of 56 mo for 31 patients (81.6%), 18 (58.1%) received adjuvant therapy with imatinib. The 5-year disease-free survival and disease-specific survival of pelvic high-risk GIST was 37.0% and 48.3%, respectively; both were significantly lower than those of the other female high-risk group (both P < 0.05). CONCLUSIONS: GIST mimicking as gynecologic mass is not uncommon, most originate from the jejunoileum and have a high risk of recurrence. Laparoscopy-assisted resection may be preferable for more favorable short-term outcomes. Compared with the other female high-risk GIST, pelvic high-risk GIST has a significantly worse prognosis; a longer duration of adjuvant therapy with imatinib than recommended may be beneficial.


Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/diagnóstico , Mesilato de Imatinib/uso terapêutico , Laparoscopia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Quimioterapia Adjuvante/métodos , Diagnóstico Diferencial , Intervalo Livre de Doença , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/terapia , Neoplasias dos Genitais Femininos/diagnóstico , Humanos , Íleo/patologia , Íleo/cirurgia , Jejuno/patologia , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA