Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 15.629
Filtrar
1.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199160

RESUMO

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
2.
Anticancer Res ; 41(7): 3261-3270, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230120

RESUMO

BACKGROUND/AIM: Chronic inflammation generates large quantities of reactive oxygen and nitrogen species that damage DNA. DNA repair is important for cellular viability and genome integrity. MATERIALS AND METHODS: Expression levels of the DNA repair proteins OGG1, XPA, MLH1, PARP1, and XRCC6, which function in base excision repair, nucleotide excision repair, mismatch repair, single-strand break repair and double-strand break repair, respectively, were assessed using immunohistochemistry in ulcerative colitis and sporadic colorectal cancer biopsies. Levels of oxidative/ nitrosative stress biomarkers were also assessed. RESULTS: Ulcerative colitis and colorectal cancer lesions expressed significantly higher levels of all DNA repair proteins and oxidative/ nitrosative stress biomarkers compared to normal colonic mucosa. Ulcerative colitis had the highest XPA and XRCC6 expression. CONCLUSION: Oxidative/nitrosative stress is prevalent in the colon of both diseases. Nucleotide excision repair and non-homologous end-joining double-strand break repair may be compromised in colorectal cancer, but not in ulcerative colitis.


Assuntos
Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , DNA/genética , Estresse Nitrosativo/genética , Estresse Oxidativo/genética , Biomarcadores Tumorais/genética , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Humanos , Mucosa Intestinal/patologia , Oxirredução
3.
Anticancer Res ; 41(7): 3511-3517, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230146

RESUMO

BACKGROUND/AIM: We previously found crypts in symmetric fission (CSF) and in asymmetric fission (CAF) in colectomy-specimens with ulcerative colitis. We now analyzed CSF and CAF (CSAF) in biopsies from 80 patients with inflammatory bowel disease (IBD) without dysplasia or carcinoma. PATIENTS AND METHODS: One unselected double-biopsy from affected endoscopic areas was investigated in the 80 cases. RESULTS: A total of 353 crypts in fission were found. The median number of CAF/biopsy was 3.7 and for CSF/biopsy, 0.7 (p<0.00001). CONCLUSION: CSAF often occur in unselected biopsies from patients with IBD. Whereas the increased frequency of CSF might mirror a compensatory mechanism of crypt production in areas occupied by inflammation, CAF reflects a pathological aberration of cryptogenesis, probably generated by somatic mutations. The biological significance of CAF in IBD without dysplasia or carcinoma, deserves to be further investigated.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Biópsia/métodos , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias do Colo/patologia , Feminino , Humanos , Inflamação/patologia , Mucosa Intestinal/patologia , Masculino , Suécia
4.
Anticancer Res ; 41(7): 3567-3572, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230152

RESUMO

BACKGROUND/AIM: Medullary carcinoma (MC) of the colon is a rare subtype of colorectal adenocarcinoma (CRC) with unique histomorphology and frequent mismatch repair (MMR) deficiency. MC with exclusive squamous differentiation has not been reported. We report an unusual case of MC with squamous differentiation and tested this differentiation potential in other MMR-deficient CRC cases. CASE REPORT: A 68-year-old woman presented with a large ascending colon mass and biopsy showed squamoid tumor morphology with immunoprofile concerning for squamous cell carcinoma (SCC). She underwent right hemicolectomy. Immunohistochemistry and next-generation sequencing (NGS) were performed for tumor classification. Macroscopically, the tumor was large and locally advanced. It metastasized to the lung without lymph node metastasis. Microscopically, the tumor cells were monotonous with cytological features of both MC and SCC. Immunostains were diffusely positive for p40 and CK5/6, but negative for other lineage markers including CDX2, CK20, and SATB2. The tumor was MMR deficient with loss of MLH1 and PMS2. NGS confirmed BRAF V600E mutation. In comparison, a tissue microarray comprising 64 previously diagnosed MMR deficient CRC was tested for squamous differentiation, and only 1 case showed focal CK5/6 expression, but none was positive for p40. CONCLUSION: MC with exclusive squamous differentiation not only posed significant diagnostic challenges, but also unveiled unrecognized differentiation plasticity in this tumor type.


Assuntos
Carcinoma Medular/patologia , Carcinoma de Células Escamosas/patologia , Diferenciação Celular/fisiologia , Neoplasias do Colo/patologia , Idoso , Carcinoma Medular/genética , Carcinoma de Células Escamosas/genética , Diferenciação Celular/genética , Colo/patologia , Neoplasias do Colo/genética , Feminino , Humanos , Mutação/genética
5.
Nutrients ; 13(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209042

RESUMO

BACKGROUND AND AIMS: Altering dietary ferrous sulphate (FS) consumption exacerbates a murine model of colitis and alters the intestinal microbiome. We investigated the impact of oral ferric maltol (FM) and FS on mice with dextran sodium sulphate (DSS) induced colitis, and the microbiome of patients with iron deficiency. METHODS: Mice had acute colitis induced, with 2% DSS for 5 days, followed by water. During this period, groups of mice were fed standard chow (200 ppm iron, SC, n = 8), or SC with 200ppm FS supplementation (n = 16, FSS), or SC with 200 ppm FM supplementation (n = 16, FMS). Clinical, pathological and microbiome assessments were compared at days 1 and 10. Fecal bacterial gDNA was extracted and the microbiome assessed by sequencing. Statistical inferences were made using MacQIIME. Principal Coordinates Analysis were used to visualize beta-diversity cluster analysis. Ten patients with IDA were treated with FS, and six with inactive inflammatory bowel disease received FM, supplements for four weeks: pre- and mid-treatment fecal samples were collected: the microbiome was assessed (see above). RESULTS: In mice, after DSS treatment, there was a decrease in many genera in the SC and FSS groups: Lactobacillales increased in mice that received FMS. In humans, FS treatment led to an increase in five genera, but FM was not associated with any measurable change. The severity of DSS-induced colitis was greater with FSS than FMS. CONCLUSIONS: This study demonstrates differential and unique influences of ferric maltol and ferrous sulphate supplements on intestinal microbiota. These differences might contribute to the different side effects associated with these preparations.


Assuntos
Compostos Férricos/administração & dosagem , Compostos Férricos/farmacologia , Compostos Ferrosos/farmacologia , Pironas/administração & dosagem , Pironas/farmacologia , Administração Oral , Animais , Biodiversidade , Peso Corporal/efeitos dos fármacos , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Ferro/metabolismo , Camundongos Endogâmicos C57BL , Filogenia
6.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069352

RESUMO

Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNFα led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NFκB signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESI-MS/MS analysis of DAC/TNFα-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNFα-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.


Assuntos
Colite Ulcerativa/genética , Interleucinas/genética , Interleucinas/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Linhagem Celular , Colite/genética , Colo/patologia , Metilação de DNA/genética , Epigênese Genética/genética , Expressão Gênica/genética , Humanos , Interleucina-12/metabolismo , Mucosa Intestinal/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/genética , Espectrometria de Massas em Tandem/métodos , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069671

RESUMO

Inflammatory bowel disease is characterized by the infiltration of immune cells and chronic inflammation. The immune inhibitory receptor, CD200R, is involved in the downregulation of the activation of immune cells to prevent excessive inflammation. We aimed to define the role of CD200R ligand-CD200 in the experimental model of intestinal inflammation in conventionally-reared mice. Mice were given a dextran sodium sulfate solution in drinking water. Bodyweight loss was monitored daily and the disease activity index was calculated, and a histological evaluation of the colon was performed. TNF-α production was measured in the culture of small fragments of the distal colon or bone marrow-derived macrophages (BMDMs) cocultured with CD200+ cells. We found that Cd200-/- mice displayed diminished severity of colitis when compared to WT mice. Inflammation significantly diminished CD200 expression in WT mice, particularly on vascular endothelial cells and immune cells. The co-culture of BMDMs with CD200+ cells inhibited TNF-α secretion. In vivo, acute colitis induced by DSS significantly increased TNF-α secretion in colon tissue in comparison to untreated controls. However, Cd200-/- mice secreted a similar level of TNF-α to WT mice in vivo. CD200 regulates the severity of DSS-induced colitis in conventionally-reared mice. The presence of CD200+ cells decreases TNF-α production by macrophages in vitro. However, during DDS-induced intestinal inflammation secretion of TNF-α is independent of CD200 expression.


Assuntos
Antígenos CD/genética , Inflamação/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Antígenos CD/metabolismo , Colite/patologia , Colo/patologia , Citocinas/metabolismo , Células Endoteliais/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Inflamação/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/fisiopatologia , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/imunologia
8.
Nat Commun ; 12(1): 3464, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103493

RESUMO

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinogênese/patologia , Diferenciação Celular , Sobrevivência Celular , Colo/patologia , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Feto/patologia , Inflamação/patologia , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
9.
J Agric Food Chem ; 69(25): 7093-7103, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34152136

RESUMO

The worldwide prevalence of obesity has significantly increased over the past few decades. It is currently believed that obesity is a risk factor for developing inflammatory bowel disease. Pterostilbene (PTS), a naturally occurring stilbene from blueberries, is known to have anticancer, anti-inflammation, antifibrosis, and antiobesity effects. The preventive effect of PTS on the susceptibility of high-fat diet (HFD) to dextran sulfate sodium (DSS)-induced colitis in mice was investigated. Beginning at 5 weeks of age, C57BL/6J mice were fed a normal diet, 50% HFD alone, or containing PTS, and DSS (2.5%, w/v) was given in drinking water at week 9 and week 11. The results demonstrated that PTS significantly attenuated HFD and DSS-induced plasma interleukin-6 accumulation. Moreover, PTS suppressed HFD/DSS-induced formation of aberrant crypt foci and reduced the colon weight-to-length ratio in HFD/DSS-induced colitis mice. Furthermore, PTS inhibited interleukin-1ß (IL-1ß), the C/EBP homologous protein (CHOP), cyclooxygenase-2, and transforming growth factor beta-1 (TGF-ß1)/mothers against decapentaplegic homolog 2 expression and maintained mucin2 (Muc2) and E-cadherin expressions. In addition, post-treatment with PTS also decreased the colon weight-to-length ratio and loss of Muc2. Moreover, the CHOP, IL-1ß, matrix metalloproteinase-2, and TGF-ß1 expressions were significantly decreased in HFD/DSS-induced colitis mice after post-treatment with PTS. In conclusion, the results of the present study suggest that PTS is of significant interest for the prevention of HFD/DSS-induced colitis in C57BL/6J mice.


Assuntos
Colite , Estilbenos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colo/patologia , Sulfato de Dextrana , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fibrose , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Metaloproteinase 2 da Matriz , Camundongos , Camundongos Endogâmicos C57BL
10.
Medicine (Baltimore) ; 100(25): e26460, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160447

RESUMO

RATIONALE: Acute hemorrhagic necrotizing enterocolitis (AHNE) is a rapidly progressive and extremely dangerous disease. Here we report a rare case caused by Vibrio cholerae (V cholerae). PATIENT CONCERNS: A 70-year-old man was admitted to our emergency department because of a sudden loss of consciousness. DIAGNOSES: On admission with severe toxic shock, the patient presented with elevated body temperature, decreased blood pressure, abdominal tenderness and rebound pain, predominantly on the right side. Computed tomography showed swelling and thickening of the right colon and peritoneal effusion. Necrosis was found in the hepatic flexure of the colon. On the basis of these results, the patient was diagnosed with AHNE. INTERVENTIONS AND OUTCOMES: After fluid resuscitation, an exploratory laparotomy was performed immediately. The procedure was successful. Despite antibiotic therapy, the patient's clinical condition progressively deteriorated and he died of multi-organ failure on day 3 after admission. LESSONS: AHNE is a rapidly progressive and extremely dangerous disease. Here we report a case of AHNE caused by non-O1/non-O139 V cholerae infection. The clinical features, phenotypic analyses and the presence of a panel of known virulence genes in the isolated strain are described. To the best of our knowledge, this is the first report of V cholerae causing severe AHNE, which is of profound pedagogical significance.


Assuntos
Cólera/diagnóstico , Enterocolite Necrosante/diagnóstico , Insuficiência de Múltiplos Órgãos/microbiologia , Vibrio cholerae não O1/patogenicidade , Idoso , Antibacterianos/uso terapêutico , Cólera/complicações , Cólera/microbiologia , Cólera/terapia , Colo/diagnóstico por imagem , Colo/microbiologia , Colo/patologia , Colo/cirurgia , Enterocolite Necrosante/complicações , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/terapia , Evolução Fatal , Hidratação , Humanos , Masculino , Tomografia Computadorizada por Raios X , Vibrio cholerae não O1/isolamento & purificação
12.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066976

RESUMO

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor's fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1ß-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1ß-mediated crosstalk between both cell types. We silenced IL1ß in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1ß is overexpressed in cocultured tumor cells. IL1ß enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1ß-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFß1-driven NCFs. IL1ß induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1ß-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1ß-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Inflamação/patologia , Interleucina-1beta/metabolismo , Transdução de Sinais , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-1beta/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/metabolismo , Ensaio Tumoral de Célula-Tronco
13.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063173

RESUMO

Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (ApcMin/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 107 CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in ApcMin/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/ß-catenin signaling pathway in the colon of ApcMin/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in ApcMin/+ mice.


Assuntos
Polipose Adenomatosa do Colo/metabolismo , Bifidobacterium bifidum/citologia , Carcinogênese/patologia , Células Imobilizadas/citologia , Neoplasias Colorretais/patologia , Lactobacillus gasseri/citologia , Quercetina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Colo/patologia , Contagem de Colônia Microbiana , Neoplasias Colorretais/genética , Metabolismo Energético/efeitos dos fármacos , Fezes/microbiologia , Comportamento Alimentar , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Sangue Oculto , Tamanho do Órgão/efeitos dos fármacos , Probióticos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
14.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063607

RESUMO

Angiotensin II (Ang II) regulates colon contraction, acting not only directly on smooth muscle but also indirectly, interfering with myenteric neuromodulation mediated by the activation of AT1 /AT2 receptors. In this article, we aimed to explore which mediators and cells were involved in Ang II-mediated colonic contraction in the TNBS-induced rat model of colitis. The contractile responses to Ang II were evaluated in distinct regions of the colon of control animals or animals with colitis in the absence and presence of different antagonists/inhibitors. Endogenous levels of Ang II in the colon were assessed by ELISA and the number of AT1/AT2 receptors by qPCR. Ang II caused AT1 receptor-mediated colonic contraction that was markedly decreased along the colons of TNBS-induced rats, consistent with reduced AT1 mRNA expression. However, the effect mediated by Ang II is much more intricate, involving (in addition to smooth muscle cells and nerve terminals) ICC and EGC, which communicate by releasing ACh and NO in a complex mechanism that changes colitis, unveiling new therapeutic targets.


Assuntos
Angiotensina II/genética , Colite/genética , Doenças Inflamatórias Intestinais/genética , Sistema Renina-Angiotensina/genética , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Colite/fisiopatologia , Colo/metabolismo , Colo/patologia , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Humanos , Doenças Inflamatórias Intestinais/patologia , Células Intersticiais de Cajal/metabolismo , Células Intersticiais de Cajal/patologia , Masculino , Contração Muscular/genética , Contração Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Óxido Nítrico/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Transmissão Sináptica/genética
15.
FASEB J ; 35(7): e21701, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143529

RESUMO

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease. Although visceral hypersensitivity (VH) and disturbed gastrointestinal motility are typical pathophysiological features of IBS, the pathological mechanisms underlying this disease remain unclear. Serotonin system abnormalities are considered to play an important role in the pathomechanisms of IBS. Here, we hypothesize that similar alterations, including VH and colonic motility, induced by serotonin transporter (SERT) knockout result from altered serotonin signaling. We sought to determine the molecular mechanism underlying VH and colonic dysmotility induced by SERT knockout. We found that female SERT (slc6a4)-knockout (KO; ie, slc6a4-/- ) rats exhibited lower pain pressure thresholds (PPTs) than wild-type (WT; ie, slc6a4+/+ ) rats in response to colorectal distension (CRD). Significantly increased fecal pellet output and reduced concentration of serum tryptophan were observed in the female SERT KO rats. The concentrations of 5-hydroxytryptamine (5-HT) in platelet-rich plasma (PRP) and serum in SERT KO rats were lower than those in WT rats, but the numbers of enterochromaffin cells (ECs) and the concentrations of 5-HT in colon of SERT KO rats were higher than those of WT rats. Finally, increased expression levels of 5-HT1B receptors, 5-HT2C receptors, 5-HT3A receptors, 5-HT3B receptors, 5-HT6 receptors, 5-HT7 receptors, and glycosylated dopamine transporters (DATs) were found in the female SERT KO rats. We concluded that alterations in the serotonin system induced by the knockout of slc6a4 might result in VH and accelerated gastrointestinal motility in female SERT KO rats, which can be used as an animal model of IBS.


Assuntos
Colo/patologia , Motilidade Gastrointestinal , Hipersensibilidade/patologia , Síndrome do Intestino Irritável/patologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Serotonina/metabolismo , Animais , Animais Geneticamente Modificados , Colo/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/metabolismo , Ratos , Ratos Sprague-Dawley
16.
Int J Biol Macromol ; 182: 2024-2036, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34087293

RESUMO

In this study, ramulus mori polysaccharide (RMP) was encapsulated into Poly (lactic-co-glycolicacid) (PLGA) to form PLGA-RMP (PR). The aim of study is to investigate anti-inflammatory effects of PR. The particle size of PR nanoparticles was approximately 205.6 ± 1.86 nm. PR nanoparticles showed significant therapeutic effects on colitis mice model, evidenced by attenuation of the loss of body weight, reduction of the DAI score, and restoration of the colon length. From the histopathological analysis, alleviation of the histopathological damage, less production of IFN-γ and IL-6, and improvement of IL-10 were observed with the treatment of PR. Meanwhile, the treatment of PR not only promoted the expression of ZO-1 and occludin, but also improved the contents of acetate, propionate, and butyrate in the colitis colon. Furthermore, PR extenuated the reduction of the diversity and richness of gut microbiota induced by DSS, and decreased the ratio of Firmicutes to Bacteroidetes while increasing the proportion of Clostridium XIVa, Mucispirillum, and Paraprevotella in the gut microbiota. What's more, PR nanoparticles attenuated the metabolic disorders in the colitis colon induced by DSS. These results indicated that PR nanoparticles could serve as a potent nanomedicine to treat IBD and be used as potential prebiotics.


Assuntos
Anti-Inflamatórios/farmacologia , Morus/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polissacarídeos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/microbiologia , Colite/fisiopatologia , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/fisiopatologia , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polissacarídeos/uso terapêutico , Eletricidade Estática , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologia
17.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066339

RESUMO

Trefoil factor family peptides (TFF1, TFF2, TFF3), together with mucins, are typical exocrine products of mucous epithelia. Here, they act as a gastric tumor suppressor (TFF1) or they play different roles in mucosal innate immune defense (TFF2, TFF3). Minute amounts are also secreted as endocrine, e.g., by the immune and central nervous systems. As a hallmark, TFF peptides have different lectin activities, best characterized for TFF2, but also TFF1. Pathologically, ectopic expression occurs during inflammation and in various tumors. In this review, the role of TFF peptides during inflammation is discussed on two levels. On the one hand, the expression of TFF1-3 is regulated by inflammatory signals in different ways (upstream links). On the other hand, TFF peptides influence inflammatory processes (downstream links). The latter are recognized best in various Tff-deficient mice, which have completely different phenotypes. In particular, TFF2 is secreted by myeloid cells (e.g., macrophages) and lymphocytes (e.g., memory T cells), where it modulates immune reactions triggering inflammation. As a new concept, in addition to lectin-triggered activation, a hypothetical lectin-triggered inhibition of glycosylated transmembrane receptors by TFF peptides is discussed. Thus, TFFs are promising players in the field of glycoimmunology, such as galectins and C-type lectins.


Assuntos
Inflamação/metabolismo , Inflamação/patologia , Fatores Trefoil/metabolismo , Animais , Colo/patologia , Humanos , Mediadores da Inflamação/metabolismo , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/patologia , Fatores Trefoil/química
18.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072552

RESUMO

Indirect evidence has determined the possibility that microplastics (MP) induce constipation, although direct scientific proof for constipation induction in animals remains unclear. To investigate whether oral administration of polystyrene (PS)-MP causes constipation, an alteration in the constipation parameters and mechanisms was analyzed in ICR mice, treated with 0.5 µm PS-MP for 2 weeks. Significant alterations in water consumption, stool weight, stool water contents, and stool morphology were detected in MP treated ICR mice, as compared to Vehicle treated group. Also, the gastrointestinal (GI) motility and intestinal length were decreased, while the histopathological structure and cytological structure of the mid colon were remarkably altered in treated mice. Mice exposed to MP also showed a significant decrease in the GI hormone concentration, muscarinic acetylcholine receptors (mAChRs) expression, and their downstream signaling pathway. Subsequent to MP treatment, concentrations of chloride ion and expressions of its channel (CFTR and CIC-2) were decreased, whereas expressions of aquaporin (AQP)3 and 8 for water transportation were downregulated by activation of the mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB signaling pathway. These results are the first to suggest that oral administration of PS-MP induces chronic constipation through the dysregulation of GI motility, mucin secretion, and chloride ion and water transportation in the mid colon.


Assuntos
Constipação Intestinal/diagnóstico , Constipação Intestinal/etiologia , Microplásticos/efeitos adversos , Fenótipo , Poliestirenos/efeitos adversos , Animais , Comportamento Animal , Biomarcadores , Fenômenos Químicos , Cloretos/metabolismo , Colo/patologia , Colo/ultraestrutura , Modelos Animais de Doenças , Suscetibilidade a Doenças , Hormônios Gastrointestinais/metabolismo , Motilidade Gastrointestinal , Bombas de Íon/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Microplásticos/química , Mucinas/metabolismo , Poliestirenos/química , Transdução de Sinais , Água/metabolismo
19.
BMJ ; 373: n877, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947661

RESUMO

OBJECTIVE: To assess the risk of colorectal cancer (CRC) in first degree relatives (parents and full siblings) of patients with precursor lesions (polyps) for CRC. DESIGN: Case-control study. SETTING: Linkage to the multi-generation register and gastrointestinal ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) histopathology cohort in Sweden. PARTICIPANTS: 68 060 patients with CRC and 333 753 matched controls. MAIN OUTCOME MEASURES: Multivariable adjusted odds ratios of CRC according to the number of first degree relatives with a colorectal polyp and the histology of polyps and age at diagnosis in first degree relatives. Subgroup analysis was also performed according to age at CRC diagnosis and evaluated the joint association of family history of colorectal polyps and family history of CRC. RESULTS: After adjusting for family history of CRC and other covariates, having a first degree relative with a colorectal polyp (8.4% (5742/68 060) in cases and 5.7% (18 860/333 753) in controls) was associated with a higher risk of CRC (odds ratio 1.40, 95% confidence interval 1.35 to 1.45). The odds ratios ranged from 1.23 for those with hyperplastic polyps to 1.44 for those with tubulovillous adenomas. To better put this risk in perspective, the age specific absolute risk of colon and rectal cancers was estimated according to family history of polyps based on the 2018 national CRC incidence in Sweden. For example, the absolute risk of colon cancer in individuals aged 60-64 years with and without a family history of colorectal polyp was, respectively, 94.3 and 67.9 per 100 000 for men and 89.1 and 64.1 per 100 000 for women. The association between family history of polyps and CRC risk was strengthened by the increasing number of first degree relatives with polyps (≥2 first degree relatives: 1.70, 1.52 to 1.90, P<0.001 for trend) and decreasing age at polyp diagnosis (<50 years: 1.77, 1.57 to 1.99, P<0.001 for trend). A particularly strong association was found for early onset CRC diagnosed before age 50 years (≥2 first degree relatives: 3.34, 2.05 to 5.43, P=0.002 for heterogeneity by age of CRC diagnosis). In the joint analysis, the odds ratio of CRC for individuals with two or more first degree relatives with polyps but no CRC was 1.79 (1.52 to 2.10), with one first degree relative with CRC but no polyps was 1.70 (1.65 to 1.76), and with two or more first degree relatives with both polyps and CRC was 5.00 (3.77 to 6.63) (P<0.001 for interaction). CONCLUSIONS: After adjusting for family history of CRC, the siblings and children of patients with colorectal polyps are still at higher risk of CRC, particularly early onset CRC. Early screening for CRC might be considered for first degree relatives of patients with polyps.


Assuntos
Pólipos do Colo/epidemiologia , Neoplasias Colorretais/epidemiologia , Anamnese , Lesões Pré-Cancerosas/epidemiologia , Reto/patologia , Crianças Adultas/estatística & dados numéricos , Idade de Início , Idoso , Estudos de Casos e Controles , Colo/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Feminino , Humanos , Masculino , Programas de Rastreamento/organização & administração , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Sistema de Registros/estatística & dados numéricos , Medição de Risco/estatística & dados numéricos , Fatores Sexuais , Irmãos , Suécia/epidemiologia
20.
Ann Clin Lab Sci ; 51(2): 271-276, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941570

RESUMO

Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of ß-catenin, and the phosphorylated form of GSK-3ß were detectable in both areas, and GSK-3ß was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/ß-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property.


Assuntos
Proteína Morfogenética Óssea 2/genética , Transição Epitelial-Mesenquimal/fisiologia , Ossificação Heterotópica/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Idoso , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Osteoblastos/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...