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1.
PLoS One ; 15(1): e0228413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986185

RESUMO

Behavioural indicators of affective state, including burrowing, clinical scores and the Mouse Grimace Score have not yet been validated in mouse models of chronic gastrointestinal disease. Additionally, a comparison of these methods has not been characterised. This study aimed to determine which behavioural assessment was the optimal indicator of disease, evidenced by correlation with clinically-assessed measures, in an azoxymethane (AOM)/dextran sulphate sodium (DSS) mouse model of colitis-associated colorectal cancer. C57BL/6 mice were allocated to four groups (n = 10/group); 1) saline control, 2) saline+buprenorphine, 3) AOM+DSS+water, 4) AOM+DSS+buprenorphine. Mice were gavaged thrice weekly with water or buprenorphine (0.5mg/kg; 80µL) for 9 weeks. Disease activity index (DAI) was measured daily; burrowing and grimace analyses occurred on days -1, 5, 19, 26, 40, 47 and 61. Colonoscopies were performed on days 20, 41 and 62. All animals were euthanized on day 63. Burrowing activity and retrospective grimace analyses were unaffected (P>0.05), whilst DAI was significantly increased (P<0.05) in mice with colitis-associated colorectal cancer compared to normal controls. In addition, DAI was positively correlated with colonoscopically-assessed severity and tumour number (P<0.05). We conclude that traditional measures of DAI or clinical scoring provide the most reliable assessment of wellbeing in mice with colitis-associated colorectal cancer.


Assuntos
Azoximetano/efeitos adversos , Buprenorfina/administração & dosagem , Colite/complicações , Neoplasias Colorretais/complicações , Sulfato de Dextrana/efeitos adversos , Medição da Dor/métodos , Animais , Comportamento , Colite/induzido quimicamente , Colonoscopia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/psicologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Estudos Retrospectivos , Medição de Risco
2.
Am J Pathol ; 190(3): 674-688, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31972160

RESUMO

miRNAs, a well-known group of noncoding RNAs, contribute to the pathogenesis of multiple diseases, including colitis-associated cancer (CAC). Our recent findings indicate that proinflammatory cytokines up-regulate c-MYC level, which subsequently activates cullin 4A and 4B (CUL4A/4B) and CRL4DCAF4 E3 ligases and promotes ubiquitination of suppression of tumorigenicity 7 in CAC. Herein, we identified and proved that miR-34b-5p can directly target c-MYC. In vitro oncogenic phenotype analyses and in vivo tumor formation assay indicated that miR-34b-5p overexpression could markedly decrease cell proliferation, colony formation, cell invasion, and tumor volumes. Overexpression of c-MYC in vitro could reverse the oncogenic phenotypes caused by miR-34b-5p up-regulation. In addition, the down-regulation of miR-34b-5p in CAC was dependent on the coregulation of the inflammatory microenvironment and DNA methylation. Collectively, our findings demonstrate that intracellular inflammation and DNA hypermethylation suppress miR-34b-5p expression, which limits its inhibitory effect on c-MYC and initiates the downstream events, including the induction of CRL4DCAF4 E3 ligase activity. The activated CRL4DCAF4 E3 ligase ubiquitinates suppression of tumorigenicity 7 and results in its degradation, eventually leading to the CAC tumorigenesis.


Assuntos
Colite/complicações , Neoplasias do Colo/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular , Colite/enzimologia , Colite/patologia , Colo/enzimologia , Colo/patologia , Neoplasias do Colo/complicações , Neoplasias do Colo/enzimologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Metilação de DNA , Regulação para Baixo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Inflamação , Proteínas Proto-Oncogênicas c-myc/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
3.
Nat Commun ; 10(1): 4614, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601814

RESUMO

Autophagy is a central component of integrated stress responses that influences many inflammatory diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). While the core machinery is known, the molecular basis of the epigenetic regulation of autophagy and its role in colon inflammation remain largely undefined. Here, we report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for the homeostatic maintenance of intestinal epithelial cells (IECs) to prevent the inflammation and tumorigenesis. BRG1 emerges as a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7 and Wipi2, which are important for autophagosome biogenesis. Defective autophagy in BRG1-deficient IECs results in excess reactive oxygen species (ROS), which leads to the defects in barrier integrity. Together, our results establish that BRG1 may represent an autophagy checkpoint that is pathogenetically linked to colitis and is therefore likely a potential therapeutic target for disease intervention.


Assuntos
Autofagia/fisiologia , Colite/etiologia , Neoplasias Colorretais/etiologia , DNA Helicases/genética , Doenças Inflamatórias Intestinais/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Estudos de Casos e Controles , Colite/complicações , Colite/patologia , Neoplasias Colorretais/genética , DNA Helicases/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/patologia , Camundongos Knockout , Proteínas Nucleares/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo
4.
Life Sci ; 238: 116968, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628914

RESUMO

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.


Assuntos
Biomarcadores/metabolismo , Carcinogênese/patologia , Colite/complicações , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Fator 2 Relacionado a NF-E2/fisiologia , Animais , Azoximetano/toxicidade , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinógenos/toxicidade , Colite/induzido quimicamente , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
5.
Infect Immun ; 87(11)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31481410

RESUMO

Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohn's disease (CD). Mechanisms that favor fibrosis are not well understood, and therapeutic strategies are limited. Here we demonstrate that colitis-susceptible Il10-deficient mice develop inflammation-associated fibrosis when monoassociated with adherent/invasive Escherichia coli (AIEC) that harbors the yersiniabactin (Ybt) pathogenicity island. Inactivation of Ybt siderophore production in AIEC nearly abrogated fibrosis development in inflamed mice. In contrast, inactivation of Ybt import through its cognate receptor FyuA enhanced fibrosis severity. This corresponded with increased colonic expression of profibrogenic genes prior to the development of histological disease, therefore suggesting causality. fyuA-deficient AIEC also exhibited greater localization within subepithelial tissues and fibrotic lesions that was dependent on Ybt biosynthesis and corresponded with increased fibroblast activation in vitro Together, these findings suggest that Ybt establishes a profibrotic environment in the host in the absence of binding to its cognate receptor and indicate a direct link between intestinal AIEC and the induction of inflammation-associated fibrosis.


Assuntos
Colite/microbiologia , Escherichia coli/metabolismo , Fibrose/etiologia , Inflamação/microbiologia , Interleucina-10/metabolismo , Fenóis/metabolismo , Tiazóis/metabolismo , Animais , Aderência Bacteriana , Colite/complicações , Colite/patologia , Regulação Bacteriana da Expressão Gênica , Vida Livre de Germes , Humanos , Inflamação/patologia , Interleucina-10/genética , Camundongos , Camundongos Knockout , Mutação
6.
Neuropeptides ; 77: 101957, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400959

RESUMO

Irritable bowel syndrome patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting the involvement of an exaggerated signaling process in both visceral and somatic sensory pathways. Increasing evidence has shown that sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibers toward sensory neurons in dorsal root ganglia maintains and exacerbates the neuropathic and inflammatory pain, as well as colonic inflammation. The aim of the present study was to determine whether electroacupuncture could alleviate the visceral and secondary somatic hyperalgesia in colitis rats by suppressing the TH-IR expression in related dorsal root ganglia. After trinitrobenzene sulfonic acid irritation, rats developed inflammatory tissue damage in the distal colon, which was accompanied by visceral hypersensitivity and secondary hind paw hyperalgesia, as indicated by enhanced visceromotor response to colorectal distension and decreased mechanical and thermal withdrawal latency of the hind paw. Additionally, excessive TH-IR fibers sprouted toward calcitonin gene-related peptide immunoreactive sensory neurons, and TH-IR neurons also increased in the sixth lumbar dorsal root ganglia of colitis rats. Both electroacupuncture and guanethidine attenuated visceral and referred hind paw hyperalgesia by inhibiting the over-expression of TH-IR neurons and fibers in the sixth lumbar dorsal root ganglia. Moreover local inflammatory damage in the distal colon was restored after 7 days of electroacupuncture intervention. These results suggest that electroacupuncture relieved visceral and referred hind paw hypersensitivity in colitis rats by inhibiting TH expression in the sixth lumbar dorsal root ganglia.


Assuntos
Colite/complicações , Gânglios Espinais/metabolismo , Hiperalgesia/terapia , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Colite/metabolismo , Modelos Animais de Doenças , Eletroacupuntura , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Medição da Dor , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo
7.
Int J Cancer ; 145(11): 3126-3139, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31407335

RESUMO

Inflammation is currently considered a hallmark of cancer and plays a decisive role in different stages of tumorigenesis, including initiation, promotion, progression, metastasis and resistance to antitumor therapies. Colorectal cancer is a disease widely associated with local chronic inflammation. Additionally, extrinsic factors such as infection may beneficially or detrimentally alter cancer progression. Several reports have noted the ability of various parasitic infections to modulate cancer development, favoring tumor progression in many cases and inhibiting tumorigenesis in others. The aim of our study was to determine the effects of excreted/secreted products of the helminth Taenia crassiceps (TcES) as a treatment in a murine model of colitis-associated colon cancer (CAC). Here, we found that after inducing CAC, treatment with TcES was able to reduce inflammatory cytokines such as IL-1ß, TNF-α, IL-33 and IL-17 and significantly attenuate colon tumorigenesis. This effect was associated with the inhibition of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation. Furthermore, we determined that TcES interfered with LPS-induced NF-κB p65 activation in human colonic epithelial cell lines in a Raf-1 proto-oncogene-dependent manner. Moreover, in three-dimensional cultures, TcES promoted reorganization of the actin cytoskeleton, altering cell morphology and forming colonospheres, features associated with a low grade of aggressiveness. Our study demonstrates a remarkable effect of helminth-derived molecules on suppressing ongoing colorectal cancer by downregulating proinflammatory and protumorigenic signaling pathways.


Assuntos
Anti-Inflamatórios/administração & dosagem , Azoximetano/efeitos adversos , Colite/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Proteínas de Helminto/administração & dosagem , Taenia/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Neoplasias do Colo/etiologia , Modelos Animais de Doenças , Feminino , Proteínas de Helminto/farmacologia , Humanos , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , Camundongos , NF-kappa B/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Pharm ; 570: 118644, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31465837

RESUMO

Colitis-associated colorectal cancer (CAC) is a common malignancy that develops in chronically inflamed mucosa and is usually accompanied by metastases at other sites. Puerarin, a natural isoflavone isolated from the root of the Pueraria lobata (Willd.) Ohwi, has potential anti-colon cancer activity. However, the poor solubility and low bioavailability of puerarin has restricted its application in the pharmaceutical industry. In the present study, pH-responsive alginate microspheres loaded with puerarin were prepared by emulsification/internal gelation for targeted treatment of colitis-associated colorectal cancer. Herein, puerarin, as an active drug, could participate in the construction of alginate microspheres with hydrogen bonding. The microspheres exhibited pH-responsive release behavior with little release of puerarin in simulated gastric fluid and high amounts (approximately 55%) of release in simulated colonic fluid. A fluorescence tracer indicated microspheres had high retention time of more than 20 h in the colon. Meanwhile, puerarin-loaded alginate microspheres not only significantly decreased the inflammatory response by downregulating the levels of pro-tumorigenic cytokines, but they reduced tumorigenesis and metastasis by inhibiting epithelial-mesenchymal transitions in AOM/DSS-induced colitis-associated colorectal cancer in mice. The overall results suggested that puerarin-loaded alginate microspheres could effectively inhibit development of colonic tumors, which could be developed as a promising therapeutic strategy for colitis-associated colorectal cancer.


Assuntos
Carcinogênese/efeitos dos fármacos , Colite/complicações , Colo/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/etiologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/etiologia , Isoflavonas/farmacologia , Alginatos/química , Animais , Líquidos Corporais/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Isoflavonas/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microesferas
9.
BMJ Case Rep ; 12(8)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31444261

RESUMO

We report a case of juvenile dermatomyositis (JDM) with cytomegalovirus (CMV) colitis which was further complicated with perforation. The patient, a 6-year-old girl, was diagnosed with JDM 1 month prior to the current presentation. After 2 weeks of optimising her treatment with steroid, intravenous Ig and methotrexate, she was readmitted with diffuse abdominal pain. Erect abdominal X-ray revealed gas under diaphragm. An exploratory laparotomy showed perforation of the large intestine. A biopsy showed inclusion bodies of CMV with immunohistochemistry for CMV positive. Strong positive CMV DNA PCR from tissue specimen, positive IgG CMV and negative IgM CMV in blood suggested a reactivation of CMV. The treatment followed included surgery and strategic use of antiviral agents as well as immunomodulators. CMV enteritis with complications should also be suspected in optimally treated autoimmune disease patients, including JDM, when they present with abdominal symptoms.


Assuntos
Colite/diagnóstico , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , Dermatomiosite , Perfuração Intestinal/diagnóstico , Dor Abdominal/etiologia , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Criança , Colite/complicações , Colite/terapia , Colostomia , Terapia Combinada , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/terapia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Perfuração Intestinal/complicações , Perfuração Intestinal/terapia
10.
Inflammation ; 42(5): 1611-1621, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377948

RESUMO

Epidemiological studies showed that there was an inverse relationship between Helicobacter pylori (H. pylori) infection and the incidence of inflammatory bowel diseases (IBD). Our previous research indicated that the regulatory immune responses induced by H. pylori infection were not limited to gastric mucosa, and the balance of intestinal mucosal immunity was influenced. In this study, mice were infected with H. pylori SS1, and then colitis was induced by 3% dextran sulphate sodium (DSS), to investigate the role of the regulatory B cells in the effects of H. pylori infection on acute and chronic colitis. In acute and chronic colitis groups, DAI and colonic histological scores reduced significantly and colon length shorted less, the proinflammatory cytokines mRNA expression downregulated in colonic mucosa, and the percentages of CD19+IL-10+Breg cells were higher in the H. pylori/DSS co-treated groups compared with the DSS-treated groups. Our study suggests that H. pylori infection can alleviate the acute and chronic colitis induced by DSS, and CD19+IL-10+Breg cells may play a critical role in the alleviation of acute and chronic colitis following H. pylori infection.


Assuntos
Linfócitos B Reguladores/patologia , Proliferação de Células , Colite/prevenção & controle , Infecções por Helicobacter/prevenção & controle , Helicobacter pylori , Animais , Antígenos CD19/análise , Linfócitos B Reguladores/química , Colite/induzido quimicamente , Colite/complicações , Citocinas/metabolismo , Sulfato de Dextrana , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Interleucina-10/análise , Camundongos
11.
J Laparoendosc Adv Surg Tech A ; 29(10): 1285-1291, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464567

RESUMO

Background: Operative maneuvers to increase mesenteric length during ileal pouch-anal anastomosis (IPAA) are frequently utilized in adults, but limited data exist on the need for their use in children. Materials and Methods: A retrospective chart review of children (age <18) considered for IPAA creation at two affiliated tertiary referral centers from 2007 to 2017 was conducted, and patient factors, operative details, and 30-day postoperative complications were abstracted. Body mass index (BMI) was normalized to BMI percentile-for-age-and-sex and classified as underweight (BMI <5th percentile), healthy weight (5th ≤ BMI percentile <85th), or overweight/obese (BMI ≥85th percentile). Maneuvers were identified from operative notes. Univariate analysis and multivariable logistic regression were performed to determine independent factors associated with the use of maneuvers. Results: A total of 94 patients underwent attempt at IPAA creation, which was successful in 91 (97%). Fourteen (15%) of 91 patients were classified as overweight or obese. The 3 failures occurred secondary to inability to reach in 3 patients, with specific mention of patients' obesity in 2 and pouch ischemia in 1. Sixty (66%) patients required maneuvers to lengthen the mesentery. Overweight/obese patients required maneuvers more often than nonoverweight/obese patients (93% versus 61%, P = .03). There were no differences in 30-day maximum Clavien-Dindo scores between patients with and without maneuvers performed (P = .83). Being overweight/obese was an independent risk factor for requiring maneuvers (odds ratio: 9.3, 95% confidence interval: 1.1-82.8) after adjusting for age, sex, height, operative stage, and surgeon. Conclusion: Surgeons should be prepared to perform mesenteric lengthening maneuvers when operating on pediatric patients to ensure minimal tension on the IPAA, and more so when operating on obese children. Whether these maneuvers have an impact on long-term pouch function is undetermined.


Assuntos
Polipose Adenomatosa do Colo/cirurgia , Colite/cirurgia , Mesentério/cirurgia , Padrões de Prática Médica/estatística & dados numéricos , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Proctocolectomia Restauradora/métodos , Polipose Adenomatosa do Colo/complicações , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Colite/complicações , Feminino , Florida , Humanos , Lactente , Modelos Logísticos , Masculino , Minnesota , Obesidade Pediátrica/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
12.
Biomed Res Int ; 2019: 8020785, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317039

RESUMO

The intestinal microbiome plays a crucial role in promoting intestinal health, and perturbations to its constitution may result in chronic intestinal inflammation and lead to colorectal cancer (CRC). α-Ketoglutarate is an important intermediary in the NF-κB-mediated inflammatory pathway that maintains intestinal homeostasis and prevents initiation of intestinal inflammation, a known precursor to carcinoma development. The objective of this study was to assess the potential protective effects of α-ketoglutarate intervention against CRC development, which may arise due to its known anti-inflammatory and antitumour effects. CRC was induced in C57BL/6 mice using azoxymethane (AOM) and dextran sulfate sodium (DSS). Tumour frequency, histological rating, and colonic microbiota were assessed in colonic samples. The findings demonstrated that α-ketoglutarate offered significant protection against CRC development in mice. Furthermore, α-ketoglutarate also exhibited immunomodulatory effects mediated via downregulation of interleukin (IL)-6, IL-22, tumour necrosis factor (TNF)-α, and IL-1ß cytokines. Finally, intervention with α-ketoglutarate tended to minimise the frequency of opportunistic pathogens (Escherichia and Enterococcus) while increasing the populations of Akkermansia, Butyricicoccus, Clostridium, and Ruminococcus. Taken together, our findings show that dietary α-ketoglutarate intervention may protect against inflammation-related CRC.


Assuntos
Colite/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácidos Cetoglutáricos/farmacologia , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/microbiologia , Citocinas/genética , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/microbiologia , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Interleucinas/genética , Camundongos , NF-kappa B/genética
13.
Phytomedicine ; 63: 153011, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301538

RESUMO

BACKGROUND: Ilexgenin A (IA), the main bioactive compound from Ilex hainanensis Merr., has significant hypolipidemic activities. However, the effects of IA on colitis-associated colorectal cancer (CRC) and its mechanisms are still unknown. PURPOSE: The study was designed to evaluate the effect of IA on CRC and explore its underlying mechanisms. STUDY DESIGN: The effect of IA on colitis related CRC were evaluated in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice and the underlying mechanisms were revealed by metabolomics, which were further validated in vivo and in vitro. METHODS: The Balb/c mice were treated with AOM/DSS to induce CRC model and fed with normal diet with or without 0.02% IA. After the experimental period, samples of plasma were collected and analyzed by ultra-high-performance liquid chromatography/quadrupole time off light mass spectrometry (UHPLC-Q-TOF). Multivariate statistical tools were used to identify the changes of serum metabolites associated with CRC and responses to IA treatment. HT 29 and HCT 116 cells were stimulated by palmitate (PA) and cultured under hypoxia. Western blot, Q-PCR, and Immunofluorescence staining were performed to confirm the molecular pathway in vivo and in vitro. RESULTS: Our results showed IA significantly inhibited the inflammatory colitis symptoms such as disease activity index score, shortening of colon tissues and the increase of inflammatory cytokines. In metabolomic study, 31 potential metabolites associated with CRC were identified and 24 of them were reversed by IA treatment. Most of biomarkers were associated with arachidonic acid metabolism, glycerophospholipid catabolism, and phospholipid metabolism, suggesting lipid metabolism might be involved in the beneficial effect of IA on CRC. Furthermore, we also found IA could decrease the expressions of SREBP-1 and its target gene in the colon tissues of AOM/DSS mice. It could down-regulate the triglyceride (TG) content and the expressions of HIF1α, SREBP-1, FASN, and ACC in HT 29 and HCT 116 cells. The inhibitory effect of IA on SREBP-1 was also attenuated by desferrioxamine (DFX), suggesting HIF1α is involved in the regulation of IA on SREBP-1. CONCLUSION: IA prevents early colonic carcinogenesis in AOM/DSS mice and reprogramed lipid metabolism partly through HIF1α/SREBP-1.


Assuntos
Neoplasias Colorretais/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triterpenos/farmacologia , Animais , Anticarcinógenos/farmacologia , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , beta Catenina/genética
14.
Gac Med Mex ; 155(Suppl 1): S32-S37, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31182876

RESUMO

Introduction: In Mexico, seroprevalence of Entamoeba histolytica is 8.4%. The intestinal amebiasis in patients with acute leukemia of novo, after the start of chemotherapy (CT) in the Hematology Service of the CMN 20 de Noviembre is 12%, even if patients show a negative baseline coprological test. Objective: To find out if the administration of tinidazole, in patients with acute leukemia and negative coprological test, at the beginning of the CT, decreases the incidence of amoebic colitis during the induction to remission. Method: Prospective and not comparative study. Patients with de novo diagnosis of acute leukemia who initiate induction and initial coprological CT. Tinidazole was indicated, 2 g/day for 5 days in the first week of CT started. They were monitored until the induction was concluded and hematopoietic recovery started. Results: 38 patients, 15 women and 23 men with a mean age of 44 years (16-72), with acute lymphoblastic leukemia 19, myeloblastic 16 and promyelocytic 3. Cases without and with intestinal amebiasis were 35 and 3, respectively. Patients with amebiasis only received tinidazole for 3 days and it was given 2 days after the CT started. Conclusion: Tinidazole, in patients with acute de novo leukemia who initiate induction CT, is effective in the prevention of intestinal amebiasis, during the induction stage, if administered at 2 g/day, for five days, starting on day 1 of the CT.


Assuntos
Colite/prevenção & controle , Colite/parasitologia , Disenteria Amebiana/prevenção & controle , Tinidazol/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Colite/complicações , Disenteria Amebiana/complicações , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
15.
Int J Mol Sci ; 20(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195598

RESUMO

Inflammatory bowel diseases increase the risk of colorectal cancer and colitis-associated colorectal cancer (CAC). Tenascin-C, a matricellular protein, is highly expressed in inflammatory bowel diseases, especially colorectal cancer. However, the role of tenascin-C in the development of CAC is not yet fully understood. We previously showed that a peptide derived from tenascin-C, peptide TNIIIA2, induces potent and sustained activation of ß1-integrin. Moreover, we recently reported that peptide TNIIIA2 promotes invasion and metastasis in colon cancer cells. Here, we show the pathological relevance of TNIIIA2-related functional site for the development of CAC. First, expression of the TNIIIA2-containing TNC peptides/fragments was detected in dysplastic lesions of an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. In vitro experiments demonstrated that conditioned medium from peptide TNIIIA2-stimulated human WI-38 fibroblasts induced malignant transformation in preneoplastic epithelial HaCaT cells. Indeed, these pro-proliferative effects stimulated by peptide TNIIIA2 were abrogated by peptide FNIII14, which has the ability to inactivate ß1-integrin. Importantly, peptide FNIII14 was capable of suppressing polyp formation in the AOM/DSS model. Therefore, tenascin-C-derived peptide TNIIIA2 may contribute to the formation of CAC via activation of stromal fibroblasts based on ß1-integrin activation. Peptide FNIII14 could represent a potential prophylactic treatment for CAC.


Assuntos
Colite/complicações , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Progressão da Doença , Fibroblastos/metabolismo , Integrina beta1/metabolismo , Peptídeos/metabolismo , Tenascina/metabolismo , Animais , Azoximetano , Células CACO-2 , Proliferação de Células , Pólipos do Colo/patologia , Meios de Cultivo Condicionados/farmacologia , Sulfato de Dextrana , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/patologia , Humanos , Masculino , Camundongos Endogâmicos ICR , Comunicação Parácrina
16.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
17.
PLoS One ; 14(6): e0216393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242213

RESUMO

Although synbiotics may be effective in maintaining remission of inflammatory bowel disease, their anticarcinogenic effects are still debated. To address this issue, we evaluated the effects of synbiotics, probiotics, and prebiotics on tumorigenesis using a CDX2P-Cre; Apc+/flox mouse model harboring a colon-specific Apc knock out, which develops adenoma and adenocarcinoma of the colon. Dextran sodium sulfate (DSS)-administration promoted colonic tumor development in CDX2P-Cre; Apc+/flox mice, and these tumors were associated with loss of Apc heterozygosity, as confirmed by observation of well-differentiated adenocarcinomas with ß-catenin accumulation in tumor cell cytoplasm. Synbiotics-treatment suppressed dextran sodium sulfate-induced colitis in CDX2P-Cre; Apc+/flox mice, thereby reducing mortality, and inhibited tumorigenesis accelerated by DSS-administration. Conversely, neither probiotics nor prebiotics had any effect on inflammation and tumorigenesis. Lactobacillus casei and Bifidobacterium breve were detected in the fecal microbiota of probiotics-treated mice. Synbiotics-treatment suppressed DSS-induced expression of IL-6, STAT-3, COX-2, and TNF-α gene transcripts in normal colonic epithelium, indicating the possibility of suppressing tumor development. Importantly, these genes may be potential therapeutic targets in inflammation-associated colon cancer.


Assuntos
Carcinogênese/efeitos dos fármacos , Colite/complicações , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Simbióticos , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heterozigoto , Interleucina-6/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Microbiota/efeitos dos fármacos , Prebióticos , Probióticos/farmacologia , Fator de Transcrição STAT3/genética , Fator de Necrose Tumoral alfa/genética , beta Catenina/metabolismo
18.
BMC Bioinformatics ; 20(1): 271, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138124

RESUMO

BACKGROUND: Networks have been widely used to model the structures of various biological systems. The ultimate aim of research on biological networks is to steer biological system structures to desired states by manipulating signals. Despite great advances in the linear control of single-layer networks, it has been observed that many complex biological systems have a multilayer networked structure and extremely complicated nonlinear processes. RESULT: In this study, we propose a general framework for controlling nonlinear dynamical systems with multilayer networked structures by formulating the problem as a minimum union optimization problem. In particular, we offer a novel approach for identifying the minimal driver nodes that can steer a multilayered nonlinear dynamical system toward any desired dynamical attractor. Three disease-related biology multilayer networks are used to demonstrate the effectiveness of our approaches. Moreover, in the set of minimum driver nodes identified by the algorithm we proposed, we confirmed that some nodes can act as drug targets in the biological experiments. Other nodes have not been reported as drug targets; however, they are also involved in important biological processes from existing literature. CONCLUSIONS: The proposed method could be a promising tool for determining higher drug target enrichment or more meaningful steering nodes for studying complex diseases.


Assuntos
Doença , Redes Reguladoras de Genes , Algoritmos , Comunicação Celular , Colite/complicações , Colite/genética , Neoplasias do Colo/complicações , Neoplasias do Colo/genética , Bases de Dados como Assunto , HIV-1/fisiologia , Humanos , Dinâmica não Linear
19.
Anticancer Res ; 39(5): 2443-2446, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092437

RESUMO

BACKGROUND/AIM: TLR-4 Knock-out (KO) mice are protected from colitis-associated cancer in the established AOM/DSS mouse model. The aim of this study was to assess whether the TLR4 KO mice would still be protected from carcinogenesis after platelet depletion and transfusion with TLR4 wild-type platelets. MATERIALS AND METHODS: Thirty-two female C57BL6 mice were divided into 6 groups. Among the three groups that received Azoxymethane/Dextran Sulfate Sodium (AOM/DSS), one group included TLR4KO mice, which were depleted of their platelets and were then transfused with platelets from TLR4 wild-type mice. The other two groups included wild-type and TLR-4KO mice that only received AOM/DSS. RESULTS: All 6 animals in the KO group that underwent platelet depletion/transfusion succumbed. Three of them died before the administration of DSS and three in the week following DSS administration. In contrast, mice in the other two groups experienced less weight loss and only 1 mouse died in each of them. CONCLUSION: Platelet depletion/transfusion was detrimental in TLR-4 transgenic mice that received AOM/DSS.


Assuntos
Plaquetas/metabolismo , Colite/sangue , Neoplasias do Colo/sangue , Transfusão de Plaquetas/efeitos adversos , Receptor 4 Toll-Like/genética , Animais , Azoximetano/toxicidade , Plaquetas/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Colite/induzido quimicamente , Colite/complicações , Colite/genética , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout
20.
J Ethnopharmacol ; 241: 111981, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31146002

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis is one of the three high risk factors for colorectal cancer. Studies have found that about 20% of cancers are caused by repeated chronic inflammatory stimuli over a long period of time. Ulcer-related colorectal cancer is one of the main causes of death in patients with ulcerative colitis. At present, surgery is the first choice for the treatment of colorectal cancer, combined with radiotherapy and chemotherapy, which have serious side effects. However, reportedly, a compound prescription of Chinese traditional medicine Shaoyao Decoction (SYD) commonly used to treat damp-heat dysentery has anti-colorectal cancer effect. Thus this study described the effect of SYD to AOM/DSS-induced colon cancer model. AIM OF THE STUDY: In this study, modern biomedical approaches were employed for investigating the protective/preventive effects of SYD in mice with azoxymethane (AOM)/DSS-induced CRC. MATERIALS AND METHODS: The mice pretreated with AOM/DSS were randomly allocated to SYDL, SYDM, SYDH group and SASP (sulfasalazine) group. Mice without AOM/DSS treatment were randomly divided into PBS control group and SYD control group. RESULTS: It was found that SYD inhibited the production of inflammatory cytokines, TNF-α, IL-1ß, superoxide dismutase (SOD), and malonaldehyde (MDA), and increased the antioxidant indices, as measured by the mRNA expression of GR, TR, HO-1, γ-GCSc, γ-GCSm, NQO-1, UGT1A1, and UGT1A10 in AOM-treated mice. Particularly, the expressions rates of NF-κB and Ki-67 in the SYD-treated experimental groups were significantly lower than those in the model group, indicating that the proliferative ability of the CRC tissues was weaker in the SYD-treated experimental groups. Moreover, the positive levels of Nrf2 in the SYD-treated experimental groups were slightly higher than those in the model group, suggesting that SYD exhibited antioxidant activity. CONCLUSIONS: To sum up, our results suggest that SYD inhibits the development of acute/chronic colitis and prevents colitis-associated CRC by suppressing inflammation and preventing oxidative stress-induced cellular damage.


Assuntos
Anti-Inflamatórios , Anticarcinógenos , Antineoplásicos , Antioxidantes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/prevenção & controle , Medicamentos de Ervas Chinesas , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Colite/complicações , Colite/tratamento farmacológico , Colite/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
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