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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 800-805, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750821

RESUMO

Objective To investigate the role and mechanism of histone deacetylase 3 (HDAC3) in alcohol-induced inflammation and permeability of intestinal epithelial cells. Methods To select the proper concentration of alcohol, differentiated Caco-2 cells were treated with different concentrations (10, 25, 50, 100 and 200 mmol/L) of alcohol, and then cell viability was assayed by MTT assay; the mRNA and protein levels of HDAC3 were analyzed by real-time PCR and Western blot analysis. Differentiated Caco-2 cells were divided into three groups: control group, alcohol group (treatment with 50 mmol/L alcohol for 60 minutes), and alcohol combined with HDAC3 inhibitor group (pretreatment with 2 µmol/L RGFP966 1 hour before alcohol). ELISA was performed to detect tumor necrosis factor α (TNF-α) level in cell supernatant. Transepithelial electrical resistance (TER) was measured using a resistance meter. Western blot analysis was used to determine the protein levels relevant to tight junction (occludin and claudin-1) and NF-κB activation (IκB and phosphorylated NF-κBp65). Results Alcohol at 10, 25 and 50 mmol/L did not affect cell viability. The mRNA and protein expression levels of HDAC3 increased in a dose-dependent manner after alcohol treatment at these concentration s. Compared with the control group, TNF-α and phosphorylated NF-κBp65 levels increased, whereas TER and protein levels of occludin, claudin-1 and IκB decreased in the alcohol group. Compared with the alcohol group, TNF-α and phosphorylated NF-κBp65 levels were reduced, while TER and protein levels of occludin, claudin-1 and IκB were elevated in the alcohol combined with HDAC3 inhibitor group. Conclusion HDAC3 inhibition can attenuate alcohol-induced inflammation and permeability of intestinal epithelial cells, which may be related to the inactivation of NF-κB.


Assuntos
Etanol/efeitos adversos , Inibidores de Histona Desacetilases/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Fator de Transcrição RelA/antagonistas & inibidores , Células CACO-2 , Claudina-1/metabolismo , Histona Desacetilases , Humanos , Proteínas I-kappa B/metabolismo , Inflamação , Mucosa Intestinal/patologia , Ocludina/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa
2.
Surg Clin North Am ; 99(6): 1063-1082, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31676048

RESUMO

The roles of flexible endoscopy in the setting of inflammatory bowel disease include diagnosis, surveillance, and determining response to treatment and monitoring for the development of recurrence, dysplasia, or malignancy. Advanced techniques, such as chromoendoscopy and narrow band imaging, can be useful adjuncts when performing endoscopy in patients with inflammatory bowel disease. There are several roles for therapeutic endoscopy in the setting of inflammatory bowel disease, including endoscopic balloon dilation and endoscopic stricturotomy.


Assuntos
Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Progressão da Doença , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/terapia , Biópsia por Agulha , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Masculino , Imagem de Banda Estreita/métodos , Sensibilidade e Especificidade , Índice de Gravidade de Doença
3.
Arq Bras Cir Dig ; 32(3): e1451, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31644671

RESUMO

BACKGROUND: Hypovolemic shock is a common disease in polytrauma patients and may develop ischemia in various organs, increasing morbidity and mortality. The bowel is usually most affected by this condition. AIM: To evaluate the effects of copaiba oil on the intestinal mucosa's injury of rats submitted to hypovolemic shock. METHOD: Fifteen rats were divided into three groups: sham - simulated surgery; ischemia - animals submitted to hypovolemic shock; and copaiba - animals submitted to hypovolemic shock previously treated with copaiba oil. Mean blood pressure, arterial blood gas after shock induction, degree of intestinal lesion and villus length were evaluated. RESULTS: The sham presented the lowest values of lactate and PaCO2 and the highest values of mean arterial pressure, pH and bicarbonate in relation to the other groups. The degree of mesenteric lesion was zero in the sham group; 3.00±1.00 in the ischemia group; and 3.00±0.71 in the copaiba group. The villus length was 173.60±8.42 in the sham, 142.77±8.33 in the ischemia and 143.01±9.57 in the copaiba group. There was a significant difference between the sham and the other groups (p<0.05); however, there not significant difference between groups Ischemia and copaiba. CONCLUSION: Administration of copaiba oil did not reduce the intestinal mucosa lesion of rats after hypovolemic shock.


Assuntos
Anti-Inflamatórios/farmacologia , Fabaceae/química , Mucosa Intestinal/efeitos dos fármacos , Óleos Vegetais/farmacologia , Choque , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Íleo/patologia , Mucosa Intestinal/patologia , Isquemia/tratamento farmacológico , Masculino , Óleos Vegetais/química , Óleos Vegetais/uso terapêutico , Distribuição Aleatória , Ratos Wistar , Choque/tratamento farmacológico
4.
Acta Gastroenterol Belg ; 82(3): 375-378, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566324

RESUMO

BACKGROUND: Colorectal recurrent lesions after endoscopic mucosal resection (EMR) often contain severe fibrosis. In such lesions, repeat EMR is often difficult and endoscopic piecemeal mucosal resection (EPMR) has a high risk of repeated recurrence, while surgery is considered overtreatment. Whether ESD can be used safely and reliably to treat such difficult lesions has not been adequately verified. We analyzed the treatment outcomes of ESD for recurrent lesions after EMR. METHODS: Among 653 colorectal ESD conducted in our institution between April 2012 and August 2017, 27 consecutive patients underwent the procedure for recurrent lesions after EMR. Treatment outcomes including en bloc resection rate, R0 resection rate, and curative resection rate; complications were analyzed. RESULTS: Treatment outcomes of the 27 patients were as follows: en bloc resection rate 81.5%, R0 resection rate 74.1%, curative resection rate 74.1%, median procedure time 47 min (range 10‒210 min), perforation rate 0%, and delayed bleeding rate 3.7%. The corresponding rates for 626 patients who underwent colorectal ESD during the same period for lesions other than recurrence after EMR were 97.2%, 95.5%, 88.7%, 37 min (7-225 min), 0.5%, and 2.8%. There were no differences in complication rates. Treatment outcomes including en bloc resection rate were inferior in the recurrence group compared to non-recurrent group, but no local recurrence was found in all patients. CONCLUSIONS: Colorectal ESD is feasible for recurrent colorectal lesions after EMR. The procedure is safe and achieves good treatment outcomes with no local recurrence.


Assuntos
Neoplasias Colorretais/cirurgia , Ressecção Endoscópica de Mucosa/métodos , Mucosa Intestinal/cirurgia , Recidiva Local de Neoplasia/cirurgia , Colonoscopia , Neoplasias Colorretais/patologia , Estudos de Viabilidade , Humanos , Mucosa Intestinal/patologia , Resultado do Tratamento
5.
Nature ; 574(7779): 532-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645730

RESUMO

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.


Assuntos
Colo/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mutação , Sintomas Prodrômicos , Reto/citologia , Adenoma/genética , Adenoma/patologia , Idoso , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patologia , Transformação Celular Neoplásica , Células Clonais/citologia , Células Clonais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/metabolismo
6.
Toxicol Lett ; 316: 109-118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472180

RESUMO

Lithocholic acid (LCA) is both a secondary bile acid and a vitamin D receptor (VDR) ligand. The VDR is activated by 1,25-dihydroxy vitamin D3 and plays an important role in maintaining integrity of the intestinal mucosal barrier. LCA can also substitute for vitamin D to carry out the in vivo functions of vitamin D. However, it is unclear whether activation of the VDR by LCA affects mucosal barrier function. In the present study, we researched the protective effect of LCA on tumor necrosis factor-alpha (TNF-α)-induced intestinal epithelial barrier dysfunction in Caco-2 cells of the human epithelial intestinal adenocarcinoma cell line. Caco-2 cell monolayers were pretreated with LCA and then exposed to 100 ng/mL TNF-α. The results showed that LCA alleviated the decrease in transepithelial electrical resistance and the increase in FITC-Dextran flux induced by TNF-α. LCA ameliorated the TNF-α-induced decrease in protein expression and distribution of ZO-1, E-cadherin, Occludin, and Claudin-1, which are tight junction markers. Additionally, the LCA treatment effectively counteracted TNF-α-mediated downregulation of silent information regulator 1 (SIRT1), nuclear factor erythroid2-related factor 2 (Nrf2), and heme oxygenase-1, which are related to oxidative stress. Increases in NF-κB p-p65 and p-IκB-α induced by TNF-α were significantly inhibited by LCA. Considering all these, the present study indicates that LCA has a significant protective effect on TNF-α-induced injury of intestinal barrier function through the VDR and suggests that suppressing NF-κB signaling and activating the SIRT1/Nrf2 pathway might be one of the mechanisms underlying the protective effect of LCA.


Assuntos
Células Epiteliais/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Ácido Litocólico/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptores de Calcitriol/agonistas , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Células CACO-2 , Citoproteção , Impedância Elétrica , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Permeabilidade , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
7.
Medicine (Baltimore) ; 98(36): e17080, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490411

RESUMO

Although fecal calprotectin (Fcal) and the fecal immunochemical test (FIT) have been associated with endoscopic activity in ulcerative colitis (UC), the clinical implications of each marker depending on the mucosal status are not well known.A total of 174 results obtained from 128 patients with UC who simultaneously underwent colonoscopy and fecal tests were retrospectively evaluated from March 2015 to February 2018. The correlation and predictability of fecal markers as a surrogate marker of endoscopic activity, and the sensitivity, specificity, and predictive value of fecal tests for mucosal healing were statistically evaluated.Both fecal tests showed a statistically significant correlation with Mayo Endoscopic Subscore (MES) (Fcal: r = 0.678, P < .001 and FIT: r = 0.635, P < .001) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) (Fcal: r = 0.711, P < .001 and FIT: r = 0.657, P < .001). Fcal was statistically superior to FIT in predictive accuracy for endoscopic activity (area under the curve [AUC]: 0.863 vs 0.765 with MES, P < .001 and AUC; 0.847 vs 0.757 with UCEIS, P < .001). FIT was superior to Fcal in sensitivity for mucosal healing (98.0% vs 78.4% with MES, 94.9% vs 74.6% with UCEIS).Fcal and FIT were well correlated with endoscopic activity in UC and can be surrogate markers of mucosal inflammation. Depending on mucosal status, Fcal was more accurate in predicting the endoscopic activity in active inflammation, whereas FIT was more sensitive in predicting the achievement of mucosal healing.


Assuntos
Colite Ulcerativa/patologia , Mucosa Intestinal/patologia , Complexo Antígeno L1 Leucocitário/análise , Adolescente , Adulto , Idoso , Colite Ulcerativa/diagnóstico , Colonoscopia , Fezes/química , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto Jovem
8.
Int J Nanomedicine ; 14: 4491-4502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417254

RESUMO

Background: Selenium (Se) can exert antioxidative activity and prevent the body from experiencing oxidative injury. Biogenic Se nanoparticles (SeNPs) synthesized by probiotics possess relatively strong chemical stability, high bioavailability, and low toxicity, this makes them potential Se supplements. Previously, we demonstrated that SeNPs synthesized by Lactobacillus casei ATCC 393 can alleviate hydrogen peroxide (H2O2)-induced human and porcine intestinal epithelial cells' oxidative damage. However, the antioxidant mechanism remains unclear. Methods: The possible antioxidant mechanism and protective effect of SeNPs on intestinal epithelial permeability and mitochondrial function were evaluated by establishing an H2O2-induced oxidative damage model of human colon mucosal epithelial cells (NCM460) and conducting Nrf2 inhibitor interference experiments. Mitochondrial membrane potential (MMP), mitochondrial DNA content, adenosine triphosphate (ATP), ROS, and protein expression levels of Nrf2-related genes were determined. Mitochondrial ultrastructure was visualized by transmission electron microscopy. Results: An amount of 4 µg Se/mL of SeNPs synthesized by L. casei ATCC 393 alleviated increase of ROS, reduced ATP and MMP, and maintained intestinal epithelial permeability in NCM460 cells challenged by H2O2. In addition, SeNPs improved the protein levels of Nrf2, HO-1, and NQO-1. Moreover, SeNPs attenuated the damage of mitochondrial ultrastructure caused by oxidative stress. Nrf2 inhibitor (ML385) abolished the regulatory effect of SeNPs on intracellular ROS production. Conclusion: Data suggest that biogenic SeNPs synthesized by L. casei ATCC 393 can protect the intestinal epithelial barrier function against oxidative damage by alleviating ROS-mediated mitochondrial dysfunction via Nrf2 signaling pathway. Biogenic SeNPs are an attractive candidate for potential Se supplement agent in preventing oxidative stress-related intestinal disease by targeting mitochondria.


Assuntos
Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Lactobacillus casei/metabolismo , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Selênio/farmacologia , Animais , Antioxidantes/farmacologia , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Modelos Biológicos , Nanopartículas/ultraestrutura , Oxirredução , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Suínos
9.
Orv Hetil ; 160(34): 1327-1334, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31423827

RESUMO

Although celiac disease (gluten-sensitive enteropathy) is a relatively well known malady, yet is surrounded by several misconceptions. It is in fact, a multi-systemic autoimmune disorder with a wide spectrum of possible presentations, though most clinicians regard it as a solely gastrointestinal disease. Another misconception that it is a disease of paediatric age group. Thus, the diagnosis of adult or elderly patients is often delayed. Recognition of the disease in the adults can be challenging, as there are less pronounced gastrointestinal symptoms, and patients present with other manifestations (i.e., neurologic, cardiovascular, hepatobiliary, or hematologic involvement are common). As these extraintestinal manifestations are less well known among practicing physicians, here we propose a brief overview of these. We aimed to summarize the available literature on the extraintestinal manifestations associated with gluten sensitivity. Orv Hetil. 2019; 160(34): 1327-1334.


Assuntos
Autoimunidade , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Glutens/efeitos adversos , Adulto , Idoso , Criança , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia
10.
Vet Immunol Immunopathol ; 216: 109919, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446207

RESUMO

Mucosal surfaces such as the gastrointestinal tract, and skin are the front line of host defence and immunity against many pathogens. Gamma delta (γδ) T lymphocytes preferentially localize to the mucosal surfaces in several species including cattle, and are thought to play crucial roles in immunosurveillance and host defence, particularly against mycobacteria. Many γδ T cells are present in young calves, which is the period when calves are thought to be initially exposed to Mycobacterium avium subspecies paratuberculosis (Map). The role of mucosal γδ T cells in cattle, especially during host-pathogen interactions during early pre-clinical phases of infectious disease remains unclear. The purposes of this study were to investigate and characterize WC1+ and WC1neg γδ  T cell subsets in various segments of the gastrointestinal (GI) tract of young calves, and then to examine γδ  T cell subsets in the distal small intestine of calves after experimental intestinal Map infection by direct Peyer's patch inoculation. We show that in healthy calves, the relative proportion of γδ T cells is constant throughout the GI mucosa, though the ileum has significantly more γδ T cells. In the distal intestine, γδ T cells are mainly WC1neg and primarily located within the lamina propria of the jejunum and ileum. In Map-infected intestine, there are higher numbers of γδ T cells in the lamina propria and a greater proportion of WC1+ cells within the epithelial layer compared to control calves. While WC1neg γδ T cells preferentially localize to the distal small intestine of healthy calves, WC1+ γδ T cells are increased in the intestinal mucosa during Map infection, which is suggestive of effector cell function. Further, spectral microscopy and flow cytometry in tandem will lead to improved understanding of the functions of these cells during health and disease.


Assuntos
Doenças dos Bovinos/imunologia , Mucosa Intestinal/metabolismo , Glicoproteínas de Membrana/metabolismo , Mycobacterium avium subsp. paratuberculosis , Paratuberculose/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Bovinos , Sobrevivência Celular , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Mucosa Intestinal/patologia , Glicoproteínas de Membrana/genética , Paratuberculose/metabolismo
11.
Acta Cir Bras ; 34(6): e201900610, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31433001

RESUMO

PURPOSE: To identify whether the colon mucosa is affected by ten days of gastric restriction in an animal model. METHODS: An experimental model of gastric restriction was devised using rats. The animals were submitted to surgical gastrostomy, and a cylindrical loofah was inserted into the stomach. We studied 30 adult male Wistar rats divided into three groups: the stomach restriction group (R10); the sham group (S10), which underwent the same procedure except for the loofah insertion; and the control group (C10). The expression of neutral and acid mucins was evaluated using histochemical techniques. Goblet cells and protein content were compared between groups using generalized estimation equations (GEEs). Bonferroni's multiple comparison was applied to identify differences between the groups. All tests considered a 5% significance level. RESULTS: There was an increased expression of neutral mucins, acid mucins and goblet cells in the R10 group. Collagen was also enhanced in the R10 group. CONCLUSION: The colon mucosa is affected by ten days of gastric restriction in an animal model, increasing neutral mucins, acid mucins and collagen content with trophic maintenance.


Assuntos
Privação de Alimentos , Mucosa Intestinal/metabolismo , Mucinas/metabolismo , Animais , Colo , Gastrostomia , Mucosa Intestinal/patologia , Masculino , Modelos Animais , Ratos , Ratos Wistar , Fatores de Tempo
12.
J Drugs Dermatol ; 18(8): 832-834, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424717

RESUMO

INTRODUCTION: While psoriasis, psoriatic arthritis, and Crohn's Disease (CD) all share a common central pathogenesis pathway and a wide overlap of treatment regime, discrepancies still exist and are highlighted by the variability in the effectiveness of certain immunomodulating agents. Etanercept, for example, has been shown to be ineffective in CD due to its inability to induce T-cell apoptosis in the intestinal mucosa. CASE: We describe the case of a 37-year-old man with a 20-year history of psoriatic arthritis. The patient presented with abdominal pain, watery diarrhea with mild hematochezia, and a reported 24-pound unintentional weight loss over the past five months. Of note, the patient began treatment with etanercept five months earlier after discontinuation of infliximab for his psoriatic arthritis symptoms. Colonoscopy with terminal ileum intubation revealed active colitis and intestinal biopsy results showed marked ulcerations and non-caseating granulomas, indicative of CD. Etanercept was subsequently discontinued and the patient was started on ustekinumab, leading to remission of both his psoriatic arthritis and new onset CD. DISCUSSION: Because the concurrent existence of psoriatic arthritis and IBD is becoming increasingly appreciated in recent literature, healthcare providers should have a high index of suspicion in patients with psoriasis and psoriatic arthritis presenting with unusual intestinal symptoms. Etanercept is intestinally inactive and should be used in caution in patients with psoriasis and psoriatic arthritis, as it may unmask underlying CD in this predisposed patient population. Dermatologists should also be aware of recent studies suggesting that etanercept directly contributes to the development of CD by altering the inflammatory cytokine milieu. Lastly, ustekinumab was successful in relieving our patient's cutaneous, joint, and gastrointestinal symptoms and may be considered an effective treatment option in patients suffering from both psoriasis and CD or the paradoxical induction of one disease entity secondary to treatment of the other.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Doença de Crohn/induzido quimicamente , Etanercepte/efeitos adversos , Adulto , Biópsia , Colonoscopia , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino
13.
Nature ; 571(7765): 398-402, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292548

RESUMO

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche1,2. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α)3, and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.


Assuntos
Envelhecimento , Senescência Celular , Esterases/metabolismo , Mucosa Intestinal/patologia , Celulas de Paneth/metabolismo , Regeneração , Envelhecimento/fisiologia , Animais , Senescência Celular/fisiologia , Esterases/antagonistas & inibidores , Esterases/biossíntese , Feminino , Humanos , Mucosa Intestinal/fisiologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , PPAR alfa/metabolismo , Celulas de Paneth/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Nicho de Células-Tronco , Células-Tronco/patologia , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt
14.
Nat Commun ; 10(1): 2919, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266962

RESUMO

Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRASG12V in mouse intestinal organoids, while transgenic BRAFV600E activates ERK in all cells. Quantitative network modelling from perturbation data reveals that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of ERK in the intestine. Furthermore, we find that oncogenic KRAS, together with ß-Catenin, favours expansion of crypt cells with high ERK activity. Our experiments highlight key differences between oncogenic BRAF and KRAS in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.


Assuntos
Neoplasias do Colo/enzimologia , Mucosa Intestinal/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Transgênicos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Especificidade da Espécie
15.
Am J Forensic Med Pathol ; 40(4): 376-380, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31306168

RESUMO

Barotrauma-associated perforation of the colon is not common and usually occurs due to the passage of compressed air through the anus. Most of the cases are accidental and done for fun often at the victim's workplace. Therefore, it is necessary that the workers should be made aware of the dangers of the equipment they regularly use at their workplace. Here, we describe one such case where a rice mill worker died when compressed air through an air pump pipe entered his rectum. His chief complaint was abdominal pain and breathing difficulty. Computed tomography scan of the abdomen and thorax showed pneumoperitoneum, pneumomediastinum, and soft tissue emphysema. There was a complete tear in the rectosigmoid junction of the colon. The mucosa was deeply hemorrhagic and congested. Histopathology of this segment showed hemorrhagic necrosis of the mucosa.


Assuntos
Colo/lesões , Ar Comprimido/efeitos adversos , Perfuração Intestinal/etiologia , Exposição Ocupacional/efeitos adversos , Colo/diagnóstico por imagem , Colo/patologia , Evolução Fatal , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/patologia , Humanos , Mucosa Intestinal/patologia , Perfuração Intestinal/diagnóstico por imagem , Perfuração Intestinal/patologia , Masculino , Enfisema Mediastínico/diagnóstico por imagem , Necrose , Peritonite/etiologia , Pneumoperitônio/diagnóstico por imagem , Tomografia Computadorizada por Raios X
17.
Medicine (Baltimore) ; 98(26): e16131, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261535

RESUMO

BACKGROUND: The FOS gene is located on human chromosome 14q21-31 and encodes the nuclear oncoprotein c-Fos. This study analyzed the correlation between the FOS noncoding region rs7101 and rs1063169 polymorphisms and colorectal cancer susceptibility and prognosis. METHODS: We analyzed the FOS genotypes in 432 colorectal cancer patients and 315 healthy subjects by PCR/Sanger sequencing. Survival was analyzed by Kaplan-Meier and Cox regression analysis. Western blot was used to detect the expression of c-Fos protein in cancer tissues and adjacent tissues in colorectal cancer patients with different genotypes. RESULTS: The presence of a T allele at rs7101 and a T allele at rs1063169 in FOS carried a higher risk of colorectal cancer [adjusted odds ratio (OR) = 1.237, 95% confidence interval (95% CI) = 1.131-1.346, P ≤ .001 and adjusted OR = 1.218, 95% CI = 1.111-1.327, P ≤ .001, respectively]. c-Fos protein levels were significantly higher in variant cancer tissues than in normal mucosa tissues (P < .05), and c-Fos proteins levels were also higher in homozygous variant cancer tissues than in heterozygous variant cancer tissues. The 3-year survival rate of patients with wild-type FOS was higher than that of patients with variant FOS (P < .05). CONCLUSION: The rs7101 and rs1063169 polymorphisms in the noncoding region of FOS are associated with the risk of developing colorectal cancer and the progression of colorectal cancer, which may be because the mutation enhances the expression of c-Fos protein to promote the incidence and development of colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Seguimentos , Expressão Gênica , Interação Gene-Ambiente , Estudos de Associação Genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
18.
Gastroenterology ; 157(4): 1019-1031.e7, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279870

RESUMO

BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.


Assuntos
Anti-Inflamatórios/administração & dosagem , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Ustekinumab/administração & dosagem , Cicatrização/efeitos dos fármacos , Adulto , Anti-Inflamatórios/efeitos adversos , Biópsia , Doença de Crohn/patologia , Esquema de Medicação , Endoscopia Gastrointestinal , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Quimioterapia de Indução , Mucosa Intestinal/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Ustekinumab/efeitos adversos
19.
Gastroenterology ; 157(4): 1007-1018.e7, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279871

RESUMO

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Endoscopia Gastrointestinal , Fármacos Gastrointestinais/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Imagem por Ressonância Magnética , Cicatrização/efeitos dos fármacos , Adulto , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Biópsia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Qualidade de Vida , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
Gastroenterology ; 157(4): 1093-1108.e11, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325428

RESUMO

BACKGROUND & AIMS: Inflammation, injury, and infection up-regulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice. METHODS: We generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published data sets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn's disease. RESULTS: Histologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor to inhibit activation of NOTCH1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn's disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1, and aryl hydrocarbon receptor, but reduced levels of SLC2A5. CONCLUSIONS: In mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn's disease patients. We propose that IDO1 contributes to intestinal homeostasis.


Assuntos
Bactérias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Microbioma Gastrointestinal , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Doenças Inflamatórias Intestinais/enzimologia , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/microbiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Notch/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Estudos de Casos e Controles , Linhagem Celular , Linhagem da Célula , Modelos Animais de Doenças , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Genótipo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/deficiência , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/genética , Receptores Notch/genética , Via Secretória , Transdução de Sinais , Células-Tronco/enzimologia , Células-Tronco/microbiologia , Células-Tronco/patologia
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