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1.
Medicine (Baltimore) ; 99(12): e19553, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195964

RESUMO

New endoscopic resection techniques are constantly being developed for gastric adenoma, which can be classified as low or high grade according to the Vienna classification. However, long-term data on gastric adenoma (e.g., removal or follow-up after resection via endoscopy) remain lacking.We retrospectively analyzed 133 cases with gastric adenoma that underwent endoscopic resection from January 2010 to November 2018. We analyzed the risk factors and frequency of patients with synchronous and metachronous lesions after endoscopic resection for gastric adenoma and followed them for more than 2 years.One hundred six (79.7%) and 27 patients (20.3%) received endoscopic resection (ER) once and more than twice, respectively. Compared with the initial endoscopic biopsy pathological results, the upgraded and downgraded histological discrepancy rates were 10.5% (n = 14) and 3.0% (n = 4) after resection, respectively. The mean time to synchronous/metachronous recurrence was 2.23 years. The average lesion size at first procedure was larger in the multiple ER group than in the single ER group (2.00 vs 1.10 cm; P = .040). Eleven (8.3%) and 16 patients (12.0%) had recurred synchronous and metachronous lesions, respectively. In the multivariate Cox analysis of the recurrence group, intestinal metaplasia (hazard ratio, 2.761; 95% confidence interval, 1.117-6.820; P = .028) and lesion size (hazard ratio, 1.607; 95% confidence interval, 1.082-2.385; P = .019) were independent factors for receiving endoscopic resection more than twice.If patients have severe intestinal metaplasia or large size of lesion at endoscopic resection for gastric adenoma, periodic observation is necessary.


Assuntos
Adenoma/cirurgia , Ressecção Endoscópica de Mucosa/métodos , Neoplasias Gástricas/patologia , Adenoma/classificação , Idoso , Feminino , Seguimentos , Humanos , Incidência , Intestinos/patologia , Masculino , Metaplasia , Pessoa de Meia-Idade , Recidiva , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/cirurgia
2.
Gene ; 736: 144421, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32018014

RESUMO

5-Aminolevulinic acid synthase (ALAS) is the rate-limiting enzyme in the biosynthesis of heme, a prosthetic group that is found in hemoproteins, including those involved in molting. To better understand the roles of ALAS in L. vannamei (LvALAS), we analyzed its sequence and tissue distribution, the effects of age and bacterial infection on its gene expression, and the effects of LvALAS gene silencing. We also examined the expressions of three hemoproteins, the cytochrome oxidase subunit I (COX I) and subunit IV (COX IV) and catalase. Three LvALAS splicing variants were found in the hepatopancreas, with the main splicing variant having an open reading frame that encodes 532 aa. LvALAS transcripts were found in each of the eleven tissues tested in this study, with the highest gene expression in the intestine. The transcript abundances of LvALAS, COX I and COX IV in the hepatopancreas and stomach tended to decrease with age. LvALAS and catalase gene expressions significantly increased in the stomach after V. parahaemolyticus infection. LvALAS gene expression in the hepatopancreas, stomach and intestine (12- and 24-hours post-injection) was relatively lower in dsALAS-injected shrimp than in PBS-injected shrimp. All the PBS-injected shrimp molted after 8-10 days while no molting activity was observed in the dsALAS-injected shrimp group within the 14 days post-injection period. Our results provide evidence that (1) only the housekeeping form of ALAS exists in L. vannamei; LvALAS gene expression (2) decreases with age and (3) increases after bacterial infection; and (4) an ALAS-dependent pathway is necessary for proper molting in L. vannamei.


Assuntos
5-Aminolevulinato Sintetase/genética , Proteínas de Artrópodes/genética , Expressão Gênica/genética , Penaeidae/genética , Sequência de Aminoácidos , Ácido Aminolevulínico/metabolismo , Animais , Clonagem Molecular/métodos , Hepatopâncreas/metabolismo , Hepatopâncreas/patologia , Intestinos/patologia , Penaeidae/patogenicidade , Filogenia , Alinhamento de Sequência , Estômago/patologia
3.
Nat Commun ; 11(1): 543, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992714

RESUMO

Health care-associated infections such as Pseudomonas aeruginosa bacteremia pose a major clinical risk for hospitalized patients. However, these systemic infections are presumed to be a "dead-end" for P. aeruginosa and to have no impact on transmission. Here, we use a mouse infection model to show that P. aeruginosa can spread from the bloodstream to the gallbladder, where it replicates to extremely high numbers. Bacteria in the gallbladder can then seed the intestines and feces, leading to transmission to uninfected cage-mate mice. Our work shows that the gallbladder is crucial for spread of P. aeruginosa from the bloodstream to the feces during bacteremia, a process that promotes transmission in this experimental system. Further research is needed to test to what extent these findings are relevant to infections in patients.


Assuntos
Bacteriemia/microbiologia , Bacteriemia/transmissão , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/transmissão , Pseudomonas aeruginosa/patogenicidade , Animais , Bacteriemia/patologia , Modelos Animais de Doenças , Epitélio/microbiologia , Fezes/microbiologia , Feminino , Vesícula Biliar/microbiologia , Vesícula Biliar/patologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/patologia , Humanos , Intestinos/microbiologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pneumonia/microbiologia , Infecções por Pseudomonas/patologia , Sistemas de Secreção Tipo III
5.
Cancer Sci ; 111(1): 137-147, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724799

RESUMO

As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3-K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase-inactive Erbb3K740M homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium-induced colitis, the kinase-inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin-1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the ApcMin mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Intestinos/patologia , Organoides/metabolismo , Organoides/patologia , Receptor ErbB-3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Organoides/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Pólipos/tratamento farmacológico , Pólipos/patologia , Inibidores de Proteínas Quinases/farmacologia
6.
Gut ; 69(2): 252-263, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31092589

RESUMO

OBJECTIVE: To study the role of α4ß7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4ß7 inhibition with regard to intestinal wound healing. DESIGN: We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4ß7 integrin. RESULTS: Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4ß7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4ß7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4ß7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. CONCLUSION: In addition to reported effects on lymphocytes, anti-α4ß7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Integrinas/fisiologia , Intestinos/patologia , Monócitos/fisiologia , Cicatrização/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Quimiotaxia de Leucócito/fisiologia , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/fisiopatologia , Integrinas/antagonistas & inibidores , Integrinas/sangue , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Cicatrização/efeitos dos fármacos , Adulto Jovem
7.
Dis Colon Rectum ; 63(2): 200-206, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31842162

RESUMO

BACKGROUND: Tobacco smoking is a known risk factor for recurrence of Crohn's disease after surgical resection. OBJECTIVE: This study assessed the effect of smoking cessation on long-term surgical recurrence after primary ileocolic resection for Crohn's disease. DESIGN: A retrospective review of a prospectively maintained database was conducted. SETTINGS: Patient demographic data and medical and surgical details were combined from 2 specialist centers. After ethical approval, patients were contacted in case of missing data regarding smoking habit. PATIENTS: All patients undergoing ileocolic resection between 2000 and 2012 for histologically confirmed Crohn's disease were included. Those with previous intestinal resection, strictureplasty for Crohn's disease, leak after ileocolic resection, or who were never reversed were excluded. MAIN OUTCOME MEASURES: The primary end point was surgical recurrence measured by Kaplan-Meier survival analysis and secondary medical therapy at time of follow-up. RESULTS: Over a 12-year period, 290 patients underwent ileocolic resection. Full smoking data were available for 242 (83%) of 290 patients. There were 169 nonsmokers (70%; group 1), 42 active smokers at the time of ileocolic resection who continued smoking up to last follow-up (17%; group 2), and 31 (13%) who quit smoking after ileocolic resection (group 3). The median time of smoking exposure after ileocolic resection for group 3 was 3 years (interquartile range, 0-6 y), and median follow-up time for the whole group was 112 months (9 mo; interquartile range, 84-148 mo). Kaplan-Meier survival analysis showed a significantly higher surgical recurrence rate for group 2 compared with group 3 (16/42 (38%) vs 3/31 (10%); p = 0.02; risk ratio = 3.9 (95% CI, 1-12)). In addition, significantly more patients in group 2 without surgical recurrence received immunomodulatory maintenance therapy compared with group 3 (12/26 (46%) vs 4/28 (14%); p = 0.01; risk ratio = 3.2 (95% CI, 1-9)). LIMITATIONS: The study was limited by its retrospective design and small number of patients. CONCLUSIONS: Smoking cessation after primary ileocolic resection for Crohn's disease may significantly reduce long-term risk of surgical recurrence and is associated with less use of maintenance therapy. See Video Abstract at http://links.lww.com/DCR/B86. ¿DEJAR DE FUMAR REDUCE LA RECURRENCIA QUIRÚRGICA DESPUÉS DE LA RESECCIÓN ILEOCÓLICA PRIMARIA PARA LA ENFERMEDAD DE CROHN?: Fumar tabaco es un factor de riesgo conocido para la recurrencia de la enfermedad de Crohn después de la resección quirúrgica.Evaluar el efecto de dejar de fumar en la recurrencia quirúrgica a largo plazo después de la resección ileocólica primaria para la enfermedad de Crohn.Revisión retrospectiva de una base de datos mantenida prospectivamente.Se combinaron datos demográficos del paciente, así como detalles médicos y quirúrgicos de dos centros especializados. Después de la aprobación ética, se contactó a los pacientes en caso de falta de datos sobre el hábito de fumar.Todos los pacientes sometidos a resección ileocólica entre 2000 y 2012 por enfermedad de Crohn confirmada histológicamente. Se excluyeron aquellos con resección intestinal previa, estenosis por enfermedad de Crohn, fuga después de resección ileocólica o que nunca se revirtieron.La principal variable fue la recurrencia quirúrgica medida por análisis de supervivencia de Kaplan-Meier, terapia médica secundaria en el momento del seguimiento.Durante un período de 12 años, 290 pacientes fueron sometidos a resección ileocólica. Se dispuso de datos completos sobre el tabaquismo para 242/290 (83%). Hubo 169 no fumadores (70%) (grupo 1), 42 (17%) fumadores activos en el momento de la resección ileocólica que continuaron fumando hasta el último seguimiento (grupo 2) y 31 (13%) que dejaron de fumar después de resección ileocólica (grupo 3). La mediana del tiempo de exposición al tabaquismo después de la resección ileocólica para el grupo 3 fue de 3 años (IQR 0-6) y la mediana del tiempo de seguimiento para todo el grupo fue de 112 meses (9 años) (IQR 84-148). El análisis de supervivencia de Kaplan-Meier mostró una tasa de recurrencia quirúrgica significativamente mayor para el grupo 2 en comparación con el grupo 3 (16/42 (38%) frente a 3/31 (10%), p = 0.02; razón de riesgo 3.9 (IC 95% 1-12)). Además, un número significativamente mayor de pacientes del grupo 2 sin recurrencia quirúrgica recibieron terapia de mantenimiento inmunomoduladora en comparación con el grupo 3 (12/26 (46%) frente a 4/28 (14%), p = 0.01; razón de riesgo 3.2 (IC 95% 1-9)).Diseño retrospectivo y pequeño número de pacientes.Dejar de fumar después de la resección ileocólica primaria para la enfermedad de Crohn puede reducir significativamente el riesgo a largo plazo de recurrencia quirúrgica y se asocia con un menor uso del tratamiento de mantenimiento. Consulte Video Resumen en http://links.lww.com/DCR/B86. (Traducción-Dr. Gonzalo Federico Hagerman).


Assuntos
Doença de Crohn/cirurgia , Intestinos/cirurgia , Reoperação/estatística & dados numéricos , Abandono do Hábito de Fumar/métodos , Adolescente , Adulto , Idoso , Anastomose Cirúrgica , Doença de Crohn/epidemiologia , Doença de Crohn/patologia , Feminino , Seguimentos , Humanos , Imunomodulação/fisiologia , Exposição por Inalação/efeitos adversos , Intestinos/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Abandono do Hábito de Fumar/estatística & dados numéricos , Análise de Sobrevida , Adulto Jovem
8.
Ulus Travma Acil Cerrahi Derg ; 25(6): 545-554, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31701499

RESUMO

BACKGROUND: Sepsis can be defined as a life-threatening organ dysfunction due to a dysregulated host response to infection. In sepsis, the coagulation cascade is activated and the balance shifts to the procoagulant side. Recently, the use of protein C is proposed for the treatment of sepsis. Another therapeutic agent that has been intensively studied is tri-iodothyronine. METHODS: This study aimed to compare the effects of activated protein C and tri-iodothyronine, which are administered at a single dose to sepsis-induced rats at the late phase. Leukocyte, platelet, hemoglobin and antithrombin-III concentrations and histopathological changes in the small intestine, liver and lung were evaluated at 24 hours. RESULTS: Single-dose intraperitoneal recombinant human APC (activated protein C) has a partial curative effect on hematological parameters in the late phase, while it is possible to state that it has significant therapeutic effects on hepatic and intestinal tissues, but more remarkably on the lung tissue. Tri-iodothyronine is also considered to be used for the treatment and has a strong potential to be a therapeutic agent. CONCLUSION: We observed that the T3 hormone has significantly limited and reduced the sepsis-related damage to hepatic and intestinal tissues, but especially the lung tissue. Tri-iodothyronine can be a good alternative to APC, which is partially allowed due to high cost and complication of bleeding in the treatment of sepsis.


Assuntos
Proteína C , Sepse , Tri-Iodotironina , Animais , Modelos Animais de Doenças , Hemoglobinas/análise , Intestinos/efeitos dos fármacos , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Proteína C/farmacologia , Proteína C/uso terapêutico , Ratos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Tri-Iodotironina/farmacologia , Tri-Iodotironina/uso terapêutico
9.
Life Sci ; 239: 116886, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678286

RESUMO

Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.


Assuntos
Células Enterocromafins/metabolismo , Células Enterocromafins/fisiologia , Hiperplasia/patologia , Animais , Colo/metabolismo , Humanos , Hiperplasia/metabolismo , Inflamação/metabolismo , Intestinos/patologia , Síndrome do Intestino Irritável/metabolismo , Serotonina/metabolismo , Estresse Fisiológico/fisiologia
10.
Life Sci ; 239: 117021, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678552

RESUMO

OBJECTIVES: Clematichinenoside AR (AR) is a saponin extracted for traditional Chinese medicine with the effects of improving the expression of tight junction (TJ) proteins and mediating anti-inflammatory activities. However, its effect on Crohn's disease (CD) is still unknown. We aimed to investigate the impact of AR on CD-like colitis and determine the mechanism underlying its effects. METHODS: Interleukin-10 gene knockout (Il-10-/-) mice (male, fifteen weeks old) with spontaneous colitis were allocated to the positive control and AR-treated (32 mg/kg AR administered every other day by gavage for 4 weeks) groups. Wild-type (WT) mice (male, fifteen weeks old) composed the negative control group. The effects of AR on intestinal barrier function and structure and T cell responses as well as the potential mechanisms underlying these effects were investigated. RESULTS: AR treatment significantly improved spontaneous colitis in Il-10-/- mice as demonstrated by reductions in the inflammatory score, disease activity index (DAI) and levels of inflammatory factors. The effects of AR on colitis in Il-10-/- mice were related to protecting intestinal barrier function and maintaining immune system homeostasis (regulatory T cell (Treg)/T helper 17 (Th17) cell balance). The anticolitis effect of AR may partly act by downregulating PI3K/Akt signaling. CONCLUSIONS: AR may have therapeutic potential for treating CD in humans.


Assuntos
Colite/tratamento farmacológico , Colite/genética , Interleucina-10/genética , Intestinos/patologia , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Translocação Bacteriana/efeitos dos fármacos , Colite/patologia , Citocinas/metabolismo , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
12.
EMBO J ; 38(21): e101346, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31566767

RESUMO

The regenerative activity of adult stem cells carries a risk of cancer, particularly in highly renewable tissues. Members of the family of inhibitor of apoptosis proteins (IAPs) inhibit caspases and cell death, and are often deregulated in adult cancers; however, their roles in normal adult tissue homeostasis are unclear. Here, we show that regulation of the number of enterocyte-committed progenitor (enteroblast) cells in the adult Drosophila involves a caspase-mediated physiological apoptosis, which adaptively eliminates excess enteroblast cells produced by intestinal stem cells (ISCs) and, when blocked, can also lead to tumorigenesis. Importantly, we found that Diap1 is expressed by enteroblast cells and that loss and gain of Diap1 led to changes in enteroblast numbers. We also found that antagonistic interplay between Notch and EGFR signalling governs enteroblast life/death decisions via the Klumpfuss/WT1 and Lozenge/RUNX transcription regulators, which also regulate enteroblast differentiation and cell fate plasticity. These data provide new insights into how caspases drive adult tissue renewal and protect against the formation of tumours.


Assuntos
Apoptose , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Enterócitos/patologia , Receptores ErbB/metabolismo , Intestinos/patologia , Receptores de Peptídeos de Invertebrados/metabolismo , Receptores Notch/metabolismo , Células-Tronco/patologia , Animais , Caspases , Diferenciação Celular , Linhagem da Célula , Proteínas de Drosophila/genética , Enterócitos/metabolismo , Receptores ErbB/genética , Feminino , Homeostase , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Receptores de Peptídeos de Invertebrados/genética , Receptores Notch/genética , Transdução de Sinais , Células-Tronco/metabolismo
13.
Ecotoxicol Environ Saf ; 186: 109782, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31614302

RESUMO

Considering the short life-cycle property, Caenorhabditis elegans is a suitable animal model to evaluate the long-term effects of microgravity stress on organisms. Canonical Wnt/ß-catenin signaling is evolutionarily conserved in various organisms. We here investigated the response of canonical Wnt/ß-catenin signaling pathway to microgravity stress in nematodes. We observed the noticeable response of canonical Wnt/ß-catenin signaling to microgravity stress. In contrast, we did not detect the obvious response of non-canonical Wnt/ß-catenin signaling to microgravity stress. The canonical ß-catenin BAR-1 acted in the intestine to regulate the response to simulated microgravity. Moreover, in the intestine, we identified a signaling cascade of canonical Wnt/ß-catenin signaling pathway in response to simulated microgravity, and this signaling cascade contained Frizzled receptor MIG-1, Disheveled protein DSH-2, GSK3A/GSK-3, and ß-catenin transcriptional factor BAR-1. Our data suggests an important protective response of canonical Wnt/ß-catenin signaling to simulated microgravity in nematodes.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas do Citoesqueleto/metabolismo , Intestinos/patologia , Estresse Fisiológico , Ausência de Peso , Via de Sinalização Wnt/fisiologia , Animais , Caenorhabditis elegans/metabolismo , Modelos Biológicos
14.
Parasit Vectors ; 12(1): 486, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619276

RESUMO

BACKGROUND: In the animal production sector, enteritis is responsible for serious economic losses, and intestinal parasitism is a major stress factor leading to malnutrition and lowered performance and animal production efficiency. The effect of enteric parasites on the gut function of teleost fish, which represent the most ancient bony vertebrates, is far from being understood. The intestinal myxozoan parasite Enteromyxum leei dwells between gut epithelial cells and causes severe enteritis in gilthead sea bream (Sparus aurata), anorexia, cachexia, growth impairment, reduced marketability and increased mortality. METHODS: This study aimed to outline the gut failure in this fish-parasite model using a multifaceted approach and to find and validate non-lethal serum markers of gut barrier dysfunction. Intestinal integrity was studied in parasitized and non-parasitized fish by immunohistochemistry with specific markers for cellular adhesion (E-cadherin) and tight junctions (Tjp1 and Cldn3) and by functional studies of permeability (oral administration of FITC-dextran) and electrophysiology (Ussing chambers). Serum samples from parasitized and non-parasitized fish were analyzed using non-targeted metabolomics and some significantly altered metabolites were selected to be validated using commercial kits. RESULTS: The immunodetection of Tjp1 and Cldn3 was significantly lower in the intestine of parasitized fish, while no strong differences were found in E-cadherin. Parasitized fish showed a significant increase in paracellular uptake measured by FITC-dextran detection in serum. Electrophysiology showed a decrease in transepithelial resistance in infected animals, which showed a diarrheic profile. Serum metabolomics revealed 3702 ions, from which the differential expression of 20 identified compounds significantly separated control from infected groups in multivariate analyses. Of these compounds, serum inosine (decreased) and creatine (increased) were identified as relevant and validated with commercial kits. CONCLUSIONS: The results demonstrate the disruption of tight junctions and the loss of gut barrier function, a metabolomic profile of absorption dysfunction and anorexia, which further outline the pathophysiological effects of E. leei.


Assuntos
Enterite/veterinária , Doenças dos Peixes/parasitologia , Metabolômica , Myxozoa/patogenicidade , Doenças Parasitárias em Animais/parasitologia , Dourada/parasitologia , Animais , Caderinas/metabolismo , Claudina-3/metabolismo , Creatina/sangue , Dextranos/metabolismo , Modelos Animais de Doenças , Eletrofisiologia , Enterite/parasitologia , Ensaio de Imunoadsorção Enzimática , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Imuno-Histoquímica , Inosina/sangue , Mucosa Intestinal/metabolismo , Intestinos/parasitologia , Intestinos/patologia , Doenças Parasitárias em Animais/patologia , Permeabilidade , Proteína da Zônula de Oclusão-1/metabolismo
15.
Medicine (Baltimore) ; 98(39): e17079, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574807

RESUMO

Advancements in diagnostic modalities have improved the diagnosis of meconium peritonitis (MP) both in utero and ex utero. This study aimed to determine the efficacy of prompt prenatal and postnatal diagnoses of MP on the postnatal outcomes of these patients.We conducted a retrospective chart review of neonates with MP admitted to the Mackay Memorial Hospital Systems from 2005 to 2016. The prenatal diagnoses, postnatal presentations, surgical indications, operative methods, types of MP, operative findings, associated anomalies, morbidities, patient outcomes, and survival rates were analyzed. Morbidities included postoperative adhesion ileus, bacteremia, and short bowel syndrome. We also performed subgroup analyses of the morbidity and survival rates of prenatally versus postnatally diagnosed patients, as well as inborn versus outborn neonates.Thirty-seven neonates with MP were enrolled. Of this number, 24 (64.9%) were diagnosed prenatally. Twenty-two (59.5%) were born preterm. The most common prenatal sonographic findings included fetal ascites followed by dilated bowel loops. Abdominal distention was the most frequent postnatal symptom. Thirty-four (91.9%) neonates underwent surgery, whereas 3 were managed conservatively. Volvulus of the gastrointestinal tract was the most frequent anatomic anomaly. The total morbidity and survival rates were 37.8% and 91.9%, respectively. The morbidity and survival rates did not differ significantly between prenatally and postnatally diagnosed patients (37.5% vs 33.3%, P = 1.00; 91.7% vs 92.3%, P = 1.00, respectively). Inborn and outborn patients did not differ in terms of morbidity and survival rates (27.3% vs 53.3%, P = .17; 100% vs 80.0%, P = .06, respectively).Although not statistically significant, inborn MP neonates had higher survival rates when compared with outborn MP neonates. Prompt postnatal management at tertiary centers seemed crucial.


Assuntos
Mecônio , Peritonite/diagnóstico por imagem , Ultrassonografia Pré-Natal , Ascite/etiologia , Dilatação Patológica/etiologia , Diagnóstico Precoce , Feminino , Humanos , Recém-Nascido , Volvo Intestinal/etiologia , Intestinos/patologia , Avaliação de Resultados da Assistência ao Paciente , Peritonite/complicações , Peritonite/mortalidade , Peritonite/terapia , Gravidez , Estudos Retrospectivos , Taxa de Sobrevida , Tempo para o Tratamento
16.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540496

RESUMO

Crohn's disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD), are autoimmune diseases characterized by chronic inflammation within the gastrointestinal tract. Debromohymenialdisine is an active pyrrole alkaloid that is well known to serve as a stable and effective inhibitor of Chk2. In the present study, we attempted to investigate the anti-inflammatory properties of (10Z)-debromohymenialdisine (1) isolated from marine sponge Stylissa species using an intestinal in vitro model with a transwell co-culture system. The treatment with 1 attenuated the production and gene expression of lipopolysaccharide (LPS)-induced Interleukin (IL)-6, IL-1ß, prostaglandin E2 (PGE2), and tumor necrosis factor-α in co-cultured THP-1 macrophages at a concentration range of 1-5 µM. The protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were down-regulated in response to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation into the nucleus in cells. In addition, we observed that 1 markedly promoted the nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) and subsequent increase of heme oxygenase-1 (HO-1) expression. These findings suggest the potential use of 1 as a pharmaceutical lead in the treatment of inflammation-related diseases including IBD.


Assuntos
Organismos Aquáticos/química , Azepinas/farmacologia , Colite Ulcerativa , Doença de Crohn , Intestinos/patologia , Poríferos/química , Pirróis/farmacologia , Animais , Azepinas/química , Células CACO-2 , Técnicas de Cocultura , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Dinoprostona/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pirróis/química , Células THP-1
17.
Nat Commun ; 10(1): 4365, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554796

RESUMO

Epithelia are exposed to diverse types of stress and damage from pathogens and the environment, and respond by regenerating. Yet, the proximal mechanisms that sense epithelial damage remain poorly understood. Here we report that p38 signaling is activated in adult Drosophila midgut enterocytes in response to diverse stresses including pathogenic bacterial infection and chemical and mechanical insult. Two upstream kinases, Ask1 and Licorne (MKK3), are required for p38 activation following infection, oxidative stress, detergent exposure and wounding. Ask1-p38 signaling in enterocytes is required upon infection to promote full intestinal stem cell (ISC) activation and regeneration, partly through Upd3/Jak-Stat signaling. Furthermore, reactive oxygen species (ROS) produced by the NADPH oxidase Nox in enterocytes, are required for p38 activation in enterocytes following infection or wounding, and for ISC activation upon infection or detergent exposure. We propose that Nox-ROS-Ask1-MKK3-p38 signaling in enterocytes integrates multiple different stresses to induce regeneration.


Assuntos
Proteínas de Drosophila/metabolismo , Intestinos/fisiopatologia , MAP Quinase Quinase 3/metabolismo , MAP Quinase Quinase Quinases/metabolismo , NADPH Oxidases/metabolismo , Regeneração/fisiologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Animais Geneticamente Modificados , Infecções Bacterianas/microbiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Enterócitos/metabolismo , Enterócitos/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Intestinos/microbiologia , Intestinos/patologia , MAP Quinase Quinase 3/genética , MAP Quinase Quinase Quinases/genética , NADPH Oxidases/genética , Estresse Oxidativo , Regeneração/genética , Células-Tronco/metabolismo , Células-Tronco/microbiologia , Estresse Mecânico , Proteínas Quinases p38 Ativadas por Mitógeno/genética
18.
Pediatr Surg Int ; 35(12): 1339-1343, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31555862

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases in infancy. Hypoxia is known as one of the major risk factors for the development of NEC. Endothelin, known to regulate vasoconstriction, has two receptors (A and B). However, the role of endothelin receptor B (EDNRB) in neonatal intestinal injury remains unclear. We aimed to investigate whether EDNRB is involved in NEC pathophysiology. METHODS: Following ethical approval (#44032), EDNRB hetero knockout mice pups (EDNRB±) and their wild-type (WT) littermates were studied. NEC was induced from postnatal day 5-9 (P5-P9) by hypoxia, gavage feeding of formula and administration of lipopolysaccharide. On P9, the ileum was harvested. RESULTS: NEC induction in WT mice was associated with mucosal injury. However, EDNRB± NEC mice had reduced mucosal injury. Similarly, EDNRB± mice had significantly lower expression of IL-6 mRNA compared to WT NEC mice. Pimonidazole immunostaining was also significantly lower in EDNRB± compared to WT NEC, suggesting reduced tissue hypoxia. CONCLUSIONS: Partial knockout of EDNRB results in reduced NEC severity and reduced tissue hypoxia. Intestinal perfusion and hypoxia are important elements of NEC pathogenesis. These findings are relevant to the understanding of NEC pathophysiology and to the development of novel preventive strategies for NEC.


Assuntos
Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Receptor de Endotelina B/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Humanos , Recém-Nascido , Intestinos/patologia , Camundongos , Camundongos Knockout
19.
Biomed Pharmacother ; 118: 109258, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545283

RESUMO

Gypenosides (GP) are a type of traditional Chinese medicine (TCM) extracted from plants and commonly applied for treatment of metabolic diseases. This study aims to explore the effects of GP extracts on alleviating non-alcoholic fatty liver disease (NAFLD). In this experiment, C57BL/6 J mice were randomly assigned into normal diet control (ND), HFHC (high-fat and high-cholesterol) and HFHC + GP (GP) groups. Mice in HFHC group were fed HFHC diet combined with fructose drinking water for 12 weeks to induce the animal model of NAFLD, followed by ordinary drinking water until the end of the experiment. In the HFHC + GP group, mice were fed HFHC diet combined with fructose drinking water for 12 weeks, followed by GP-containing drinking water till the end. Mouse body weight was measured weekly. After animal procedures, mouse liver and serum samples were collected. It is shown that GP administration reduced body weight, enhanced the sensitivity to insulin resistance (IR) and decreased serum levels of ALT, AST and TG in NAFLD mice. In addition, GP treatment alleviated steatohepatitis, and downregulated ACC1, PPARγ, CD36, APOC3 and MTTP levels in mice fed with HFHC diet. Furthermore, GP treatment markedly improved intestinal microbiota, and reduced relative abundance ratio of Firmicutes / Bacteroidetes in the feces of NAFLD mice. Our results suggested that GP alleviated NAFLD in mice through improving intestinal microbiota.


Assuntos
Progressão da Doença , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/microbiologia , Animais , Biodiversidade , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Regulação para Baixo/efeitos dos fármacos , Gynostemma/química , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Resistência à Insulina , Intestinos/efeitos dos fármacos , Intestinos/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
20.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547531

RESUMO

Misfolded and abnormal ß-sheets forms of wild-type proteins, such as cellular prion protein (PrPC) and amyloid beta (Aß), are believed to be the vectors of neurodegenerative diseases, prion and Alzheimer's disease (AD), respectively. Increasing evidence highlights the "prion-like" seeding of protein aggregates as a mechanism for pathological spread in AD, tauopathy, as well as in other neurodegenerative diseases, such as Parkinson's. Mutations in both PrPC and Aß precursor protein (APP), have been associated with the pathogenesis of these fatal disorders with clear evidence for their pathogenic significance. In addition, a critical role for the gut microbiota is emerging; indeed, as a consequence of gut-brain axis alterations, the gut microbiota has been involved in the regulation of Aß production in AD and, through the microglial inflammation, in the amyloid fibril formation, in prion diseases. Here, we aim to review the role of microbiome ("the other human genome") alterations in AD and prion disease pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/microbiologia , Precursor de Proteína beta-Amiloide/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiologia , Proteínas PrPC/metabolismo , Doença de Alzheimer/patologia , Humanos , Intestinos/patologia
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