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1.
Medicine (Baltimore) ; 98(48): e18127, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770243

RESUMO

This study aimed to examine the association between colorectal cancer and zolpidem use in Taiwan.A case-control study was conducted using the database of Taiwan National Health Insurance Program from 2000 to 2013. Participants aged 20 to 84 years with newly diagnosed colorectal cancer were selected as the cases. Sex-matched and age-matched participants without colorectal cancer were randomly selected as the matched controls. The odds ratio and 95% confidence interval for colorectal cancer associated with zolpidem use were calculated by the multivariable logistic regression model.There were 4912 cases with colorectal cancer and 4912 matched controls without colorectal cancer. The mean age was 63 years and 58% were male participants. After adjustment for co-variables, the multivariable logistic regression model disclosed that there was no statistical association between colorectal cancer and zolpidem use (adjusted OR 1.05, 95% CI 0.95-1.15).No statistical association can be detected between colorectal cancer and zolpidem use in Taiwan.


Assuntos
Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/epidemiologia , Medicamentos Indutores do Sono/efeitos adversos , Zolpidem/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Factuais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
2.
Life Sci ; 237: 116895, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610204

RESUMO

To evaluate the effect of a probiotic on the aggressiveness of a chemically induced colorectal tumor in rats. Twenty-five male Fisher 344 rats, 250 g, provided with feed and water ad libitum, were randomly divided into 5 groups (5 rats/group): GControl, no treatment; GTumor, tumor induction; GTumor+5FU, tumor induction, 5-Fluorouracil applied; GTumor+Prob, induction of the tumor, supplemented with probiotic; GTumor+5-FU+Prob, tumor induction, 5-Fluorouracil applied, supplemented with probiotic. For tumor induction 20 mg/kg of 1,2-dimethylhydrazine was applied intraperitoneally over 4 weeks, followed by an interval of 15 days, and then repeated for a further 4 weeks. Five weeks after the final dose of the carcinogen, treatment was initiated with 5-Fluorouracil (15 mg/kg, intraperitoneally/week) and a commercial probiotic (1 × 109 CFU, daily/gavage). Data were analyzed by One Way Variance Analysis and means compared by Dunnett's test. GraphPad Prism statistical software was used. The histopathological analyzes were evaluated by the chi-square test. A 5% type-I error was considered statistically significant. Compared with the GTumor, the GTumor+Prob (p < 0.0373) and GTumor+5-FU+Prob (p < 0.0003) demonstrated an attenuated effect on the aggressiveness of the colorectal tumor, with a reduction in the count of Aberrant Crypt foci; and a lower percentage of malignant neoplastic lesions in the GTumor+Prob (40% low grade tubular adenoma, 40% carcinoma in situ, 20% low grade adenocarcinoma) and GTumor+5-FU+Prob (40% low grade tubular adenoma and 60% carcinoma in situ). Probiotic supplementation has the potential to decrease the formation of aberrant crypts and ameliorate tumor malignancy, enhancing the antitumor effect of 5-Fluorouracil chemotherapy in colic segments.


Assuntos
Neoplasias Colorretais/prevenção & controle , Suplementos Nutricionais , Dimetilidrazinas/toxicidade , Probióticos/administração & dosagem , Animais , Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Masculino , Ratos , Ratos Endogâmicos F344
3.
Immunology ; 158(1): 35-46, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31429085

RESUMO

Chronic inflammation may drive development of cancer as observed in inflammation-induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti-tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein-1 (PD-1)/PD-L1 signalling pathway is currently at the forefront in the development of anti-tumour immunity-based therapies for multiple malignancies. By blocking the immune-checkpoint of activated T-cells, it is possible to rewire the adaptive resistance induced by the PD-1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy-modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T-cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis and colitis-associated CRC. In addition, we examined the expression of PD-1 and its ligands PD-L1 and PD-L2 as well as other molecular targets related to T-cell exhaustion. We found a significant increase in PD-1 expression on all examined mucosal T-cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD-L1 and PD-L2 mRNA expression throughout the AOM/DSS regime. Blocking PD-1 signalling with an anti-PD1 antibody did not affect the tumour burden in the AOM/DSS-treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune-mediated toxicity. This raises a concern for patients with colitis-associated CRCs and should be further investigated.


Assuntos
Azoximetano , Colite/metabolismo , Colo/metabolismo , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana , Mucosa Intestinal/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Animais , Antígeno B7-H1/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Colo/imunologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Mucosa Intestinal/imunologia , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Fenótipo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Linfócitos T/imunologia , Regulação para Cima
4.
Zhonghua Zhong Liu Za Zhi ; 41(6): 421-428, 2019 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-31216827

RESUMO

Objective: To evaluate the feasibility of intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI MRI) in the evaluation of tumor vascular normalization in a mouse model of colorectal cancer induced by recombinant human endostatin (rhES). Methods: The CT26 colorectal cancer xenograft model of BALB/c mice were established and divided into rhES group and control group, with 20 mice in each group. The mice of rhES group were intravenously injected with rhES 5 mg·kg(-1)·d(-1) once daily for 12 days, while the mice of the control group were intravenously injected with the same volume of 0.9% saline. 5 mice of rhES group and control group were randomly selected to perform IVIM-DWI MRI as following times: before treatment and four, eight, twelve days after treatment. The parameters of IVIM-DWI were recorded, including true diffusion coefficient(D), pseudo-diffusion coefficient (D(*)) and perfusion fraction (f). Meanwhile, microvessel density (MVD), pericyte coverage and tumor perfusion in tumor tissues were detected by immunofluorescence, respectively. Results: The tumor volumes of control group and rhES group before treatment were (154.42±24.65) mm(3) and (174.24±28.27)mm(3,) respectively, without statistically significant difference (P=0.440). From day 2 to day 12 after treatment, the tumor volume of rhES group was significantly smaller than that of control group (all P<0.05). There were no statistical significances of D value between the rhES group and control group before and after treatment (all P>0.05). The D(*) values of the rhES group were (10.940±2.834)×10(-3)mm(2)/s and (12.940±2.801)×10(-3)mm(2)/s in day 4 and 8 after treatment respectively, significantly higher than (6.980±1.554)×10(-3)mm(2)/s and (7.898±1.603)×10(-3)mm(2)/s of control group (P<0.05). Moreover, compared with control group, the D(*) value of rhES group was significantly lower in day 12 (6.848±1.460)×10(-3)mm(2)/s vs (9.950±2.596)×10(-3)mm(2)/s, (P<0.05). The f value of rhES group in day 8 was (0.226±0.021)%, significantly higher than (0.178±0.016)% of control group (P<0.01). The MVD of rhES group was significantly lower than that of control group (P<0.05), while the pericyte coverage and tumor perfusion of rhES group were significantly higher than those of control group in day 4 and 8 after treatment (all P<0.05). In addition, we found D(*) value of IVIM-DWI in rhES group was significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.354, r=0.555, r=0.559, all P<0.05). Meanwhile, the f value in rhES group was also significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.391, r=0.538, r=0.315, all P<0.05). Conclusions: IVIM-DWI MRI can effectively evaluate the vascular normalization in rhES-induced CT26 colorectal tumor.The parameters D(*) and f are closely related to intratumorally microvessel density, pericyte coverage and perfusion, which can effectively monitor the occurrence of tumor vascular normalization time.


Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Neovascularização Patológica/diagnóstico por imagem , Animais , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/induzido quimicamente , Modelos Animais de Doenças , Endostatinas/toxicidade , Estudos de Viabilidade , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/toxicidade
5.
Cancer Sci ; 110(7): 2156-2165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31099450

RESUMO

The incidence of colorectal cancer (CRC) has been on the rise, which is linked to the increasing prevalence of obesity, based on global epidemiological evidence. Although chronic inflammation is implicated in tumor development, the mechanisms underlying obesity-associated CRC remain unknown. Here, we sought to identify the inflammatory cytokines and their roles in obesity-related colorectal tumorigenesis using cytokine array analyses in a mouse model. Colorectal tumorigenesis was induced through i.p. injection of azoxymethane once a week for 6 weeks in 6-week-old female WT C57Black/6J mice and the obesity diabetes model mouse KK/TaJcl, KK-Ay/TaJcl. The formation of aberrant crypt foci and colorectal tumors were more frequent in obese mice compared with WT mice, and both serum interleukin (IL)-13 and IL-13 receptor (R) expression in the normal intestinal mucosal epithelium were significantly increased in the obese mice. Furthermore, addition of IL-13 to a human CRC cell line and a human colon organoid culture altered the phenotype of intestinal epithelial cells. Knockdown experiments further revealed that IL-13Rα1 dominantly induced mucosal proliferation. Collectively, These results suggest an association between anti-inflammatory cytokines and colorectal carcinogenesis, and provide new research directions for cancer prevention strategies. In particular, inflammation provoked by obesity, notably by increased expression of the cytokine IL-13, could play an important role in the carcinogenesis of obesity-related CRC.


Assuntos
Focos de Criptas Aberrantes/patologia , Azoximetano/efeitos adversos , Neoplasias Colorretais/patologia , Interleucina-13/sangue , Obesidade/complicações , Regulação para Cima , Focos de Criptas Aberrantes/induzido quimicamente , Focos de Criptas Aberrantes/metabolismo , Animais , Azoximetano/administração & dosagem , Proliferação de Células , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/imunologia , Absorção Peritoneal , Receptores de Interleucina-13/sangue , Transdução de Sinais
6.
Biochem Pharmacol ; 164: 139-151, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981879

RESUMO

Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17ß-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1ß and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERß) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.


Assuntos
Azoximetano/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Estradiol/uso terapêutico , Ovariectomia/efeitos adversos , Animais , Neoplasias Colorretais/sangue , Estradiol/sangue , Feminino , Camundongos , Camundongos Endogâmicos ICR , Ovariectomia/tendências , Distribuição Aleatória
7.
Acta Cir Bras ; 34(2): e201900207, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30843940

RESUMO

PURPOSE: To evaluate red propolis, gum arabic and L-lysine activity on colorectal preneoplastic lesions induced by azoxymethane (AOM). METHODS: The study featured 4 control groups (I-IV) and 4 experimental groups (V-VIII), totaling 48 rats. Once a week for 2 weeks, animals on control groups received saline, while animals in experimental groups received azoxymethane (15 mg/kg i.p.). The follow up along 16 weeks included daily oral gavage to administer water (I and V), L-lysine (150 mg/kg)(II and VI), própolis (100mg/5ml/kg)(III and VII), or gum arabic (5ml/kg)(IV and VIII). Was performed surgery on the animals in the end of this time in order to collect blood for biological assays (TBARS, GSH), followed by their sacrifice to tissue extract. RESULTS: Oxidative stress (TBARS) and the number of aberrant crypt foci (ACF) in distal colon were lower using própolis (p<0.01 for both parameters). Gum arabic reduced preneoplastic lesions (ACF ≤ 4 crypts) on distal colon and on the entire colon (p<0.05). CONCLUSIONS: Red propolis reduced AOM-induced oxidative stress (TBARS) and total number of ACF in the distal colon. L-lysine neither protected against nor enhanced AOM-induced ACF. Gum arabic reduced the number of ACF.


Assuntos
Neoplasias Colorretais/prevenção & controle , Goma Arábica/farmacologia , Lisina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Lesões Pré-Cancerosas/prevenção & controle , Própole/farmacologia , Animais , Azoximetano , Carcinógenos , Neoplasias Colorretais/induzido quimicamente , Modelos Animais de Doenças , Masculino , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos Wistar
8.
Methods Mol Biol ; 1960: 215-225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30798535

RESUMO

Mouse models have proved essential for generating a mechanistic understanding of human disease processes. The azoxymethane/interleukin-10 knockout (AOM/Il10-/-) model is a powerful tool for assessing the effects of intestinal microbiota and inflammation on colon tumorigenesis. This model of colitis-associated colorectal cancer (CAC) is particularly relevant to inflammatory bowel disease (IBD)-associated colon cancer and recapitulates many of the molecular effects underlying inflammation's influence on human colorectal cancer. The model utilizes inflammation-susceptible Il10-/- mice injected intraperitoneally (i.p.) with the colon-specific carcinogen AOM. AOM and its metabolites cause mutagenesis and colorectal tumorigenesis in an inflammation-dependent manner, which in Il10-/- mice is driven by the presence and composition of the intestinal microbiota. Here we describe bacterial colonization with the pathobiont Escherichia coli strain NC101, cancer initiation with AOM, bacterial quantification, and histologic assessment of inflammation and cancer.


Assuntos
Azoximetano/toxicidade , Colite/complicações , Neoplasias Colorretais/etiologia , Interleucina-10/deficiência , Animais , Colite/metabolismo , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Vida Livre de Germes , Inflamação/imunologia , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/metabolismo , Intestinos/imunologia , Camundongos Knockout
9.
Immunopharmacol Immunotoxicol ; 41(2): 207-213, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706742

RESUMO

Objective: Inflammatory bowel disease (IBD) is generally considered as a major risk factor in the progression of colitis-associated colorectal cancer (CAC). Previous studies have indicated that the composition of gut microflora may be involved in CAC induction and progress. Bacteroides fragilis (BF) is a Gram-negative anaerobe belonging to colonic symbiotic bacteria of the host. This study was aimed to investigate the protective role of BF in a colorectal cancer (CRC) model induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in germ-free (GF) mice. Materials and methods: Total 22 GF mice were divided into two groups: GF and BF group. Half of the GF mice were colonized with BF for 28 days before CRC induction by AOM/DSS. Results: BF colonization increased animal survival (100%). Cecum weight and cecum/body weight ratio significantly decreased in BF/AOM/DSS group. Interestingly, there was a significant decrease in tumor number and tumor incidence in the BF/AOM/DSS group as compared to the GF/AOM/DSS group. The adenocarcinoma/adenoma incidence and histologic score were also decreased in the BF/AOM/DSS group. In addition, immunohistochemistry staining found decreased numbers of cell proliferation (PCNA) and inflammatory cell (granulocytes) infiltration in the colon mucosa of the BF group. The ß-catenin staining in the BF/AOM/DSS group had fewer and weaker positive signal expressions. Taking together, the BF colonization significantly ameliorated AOM/DSS-induced CRC by suppressing the activity of cell proliferation-related molecules and reducing the number of inflammatory cells. Conclusions: Symbiotic BF may play a pivotal role in maintaining the gastrointestinal immunophysiologic balance and regulating anti-tumorigenesis responses.


Assuntos
Azoximetano/toxicidade , Bacteroides fragilis/imunologia , Colite , Neoplasias Colorretais , Sulfato de Dextrana/toxicidade , Vida Livre de Germes , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Masculino , Camundongos
10.
Nutrients ; 11(2)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769854

RESUMO

The present research combines real data and parameters found in recent literature that were used to design realistic scenarios demonstrating the potential effects (benefits and costs) of the World Health Organization (WHO)'s risk communication regarding the consumption of processed meat, which was proven to be associated with an increased risk of colorectal cancer (CRC) in an International Agency for Research on Cancer (IARC)/WHO report. The impact of the risk communication of processed meat consumption was simulated using Monte Carlo microsimulation models. The results showed that a 1% reduction in the number of high-level processed meat consumers may lead to a yearly decrease in CRC cases of 406.43 (IC 95%: -243.94, 1056.81), while the more extreme scenario of a 15% reduction may lead to 2086.62 fewer cases (IC 95%: 1426.66, 2746.57). On the other hand, if demand contraction in the processed meat sector resulted in a 0.1% loss in employment, one could expect 27.23 all-cause mortalities attributable to job loss (IC 95%: 16.55, 37.80). This simulation study demonstrates that caution should be taken when implementing public awareness campaigns, particularly when the prevention message is not straightforward.


Assuntos
Neoplasias Colorretais/induzido quimicamente , Produtos da Carne/efeitos adversos , Animais , Comunicação , Dieta/estatística & dados numéricos , Preferências Alimentares , Humanos , Método de Monte Carlo , Fatores de Risco
11.
BMC Cancer ; 19(1): 94, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30665389

RESUMO

BACKGROUND: Stress has been suggested as a promoter of tumor growth and development. Glucocorticoids (GCs) are the main stress hormones and widely prescribed as drugs. However, the effect of GCs on the development and progression of colorectal carcinoma (CRC) is unclear. METHODS: We evaluated the effect of corticosterone (CORT) on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in the colorectum of C57BL/6 strain mice. Plasma level of CORT was detected by radioimmunoassay. The expression of proliferation markers (Ki-67 and PCNA), nuclear factor (NF)-κB p65 and phosphoto-p65 (P-p65), as well as cyclooxygenase (COX)-2 were determined by immunohistochemistry. Inflammation in colorectum was evaluated by histopathology. RESULTS: CORT feeding in drinking water of mice not only significantly elevated plasma CORT concentration, but also significantly increased the incidence and neoplasms burden (number and size of neoplasms) in colorectum. CORT also significant enhanced the expression of cell proliferation marker (Ki-67 and PCNA), NF-κB p65 and P-p65 as well as COX-2 in colorectal neoplasm of AOM/DSS-treated mice. CONCLUSION: In this study, we have found for the first time that CORT at stress level potentially promotes the growth and development of AOM/DSS-induced colorectal adenoma and carcinoma in mice. Up-regulation of NF-κB and COX-2 may be involved in the promoting effect of CORT.


Assuntos
Azoximetano/toxicidade , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana/toxicidade , Glucocorticoides/toxicidade , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/metabolismo , Ciclo-Oxigenase 2/biossíntese , Sinergismo Farmacológico , Humanos , Imuno-Histoquímica , Antígeno Ki-67/biossíntese , Masculino , Camundongos Endogâmicos C57BL , Antígeno Nuclear de Célula em Proliferação/biossíntese , Fator de Transcrição RelA/biossíntese
12.
Nat Prod Res ; 33(18): 2722-2725, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29683343

RESUMO

Allicin is the major biologically active compounds of freshly crushed garlic. It has been reported to inhibit the proliferation and promote the apoptosis of multiple colorectal cancer cells. However, the anti-colorectal cancer effect of Allicin has not been verified by in vivo studies. In the present study, we investigated the effect of Allicin on azoxymethane/dextran sodium sulfate (AOM/DSS) colorectal cancer mouse model and explore the underlying possible mechanism. Our result showed that Allicin could inhibit colonic tumorigenesis of AOM/DSS mice in vivo. In vitro study showed that Allicin promoted the apoptosis and suppressed the survival and proliferation of HCT116 cells. The molecular mechanism is related to the suppression of STAT3 signaling activation. Thus, our data provide further support for Allicin as a potential favorable supplement for human colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Ácidos Sulfínicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Azoximetano/toxicidade , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana/toxicidade , Células HCT116 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
13.
Clin Transl Oncol ; 21(2): 220-231, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29956073

RESUMO

PURPOSE: The aim of this study is to explore the roles of ß-catenin, decorin, septin-7, and S100A10 expression in colorectal cancer development. METHODS: Twenty-five BALB/c mice were divided into five groups; four groups were administrated N,N-dimethylhydrazine for 0, 10, 15, and 20 weeks, and one group was administrated normal saline for 20 weeks. The colons were collected for histopathological analysis. Protein samples prepared from the frozen colon tissues of mice treated with N,N-dimethylhydrazine for the different time points were evaluated using the isobaric tags for relative and absolute quantification (iTRAQ) labeling technique coupled with the 2D liquid chromatography-tandem mass spectrometry analysis. Based on the proteomic analysis results, immunohistochemical staining of ß-catenin, decorin, septin-7, and S100A10 was performed in paraffin-embedded mice colorectal tissue, and 53 cases of human hereditary polyposis colorectal cancer samples. RESULTS: Colorectal cancer was observed in mice treated with N,N-dimethylhydrazine for 20 weeks, and adenomas were observed in mice subjected to the 10-, and 15-week treatments. Seventy-two differentially expressed proteins were involved in the development of cancer as per the iTRAQ and spectrometry analysis. In normal epithelium, adenoma, and cancer from human hereditary polyposis colorectal cancer, S100A10 expression (c2 = 100.989, P = 0.000) was highest in cancer, whereas decorin (c2 = 12.852, P = 0.002) and septin-7 (c2 = 66.519, P = 0.002) expressions were highest in the normal epithelium, which was confirmed via immunohistochemical staining. CONCLUSIONS: The subcellular localization of ß-catenin and decorin, septin-7, and S100A10 expressions are associated with the development of colorectal cancer in mice after N,N-dimethylhydrazine treatment and in human hereditary polyposis colorectal cancers.


Assuntos
Polipose Adenomatosa do Colo/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Adulto , Animais , Anexina A2/análise , Anexina A2/biossíntese , Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Decorina/análise , Decorina/biossíntese , Dimetilidrazinas/toxicidade , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Proteômica/métodos , Proteínas S100/análise , Proteínas S100/biossíntese , Septinas/análise , Septinas/biossíntese , beta Catenina/análise , beta Catenina/biossíntese
14.
Immunology ; 156(1): 56-68, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171602

RESUMO

B lymphocytes, known as antibody producers, mediate tumor cell destruction in the manner of antibody-dependent cell-mediated cytotoxicity; however, their anti-tumor function seems to be weakened during tumorigenesis, while the underlying mechanisms remain unclear. In this study, we found that IgG mediated anti-tumor effects, but IgG-producing B cells decreased in various tumors. Considering the underlying mechanism, glycometabolism was noteworthy. We found that tumor-infiltrating B cells were glucose-starved and accompanied by a deceleration of glycometabolism. Both inhibition of glycometabolism and deprivation of glucose through tumor cells, or glucose-free treatment, reduced the differentiation of B cells into IgG-producing cells. In this process, special AT-rich sequence-binding protein-1 (SATB1) was significantly silenced in B cells. Down-regulating SATB1 by inhibiting glycometabolism or RNA interference reduced the binding of signal transducer and activator of transcription 6 (STAT6) to the promoter of germline Cγ gene, subsequently resulting in fewer B cells producing IgG. Our findings provide the first evidence that glycometabolic inhibition by tumorigenesis suppresses differentiation of B cells into IgG-producing cells, and altering glycometabolism may be promising in improving the anti-tumor effect of B cells.


Assuntos
Adenocarcinoma/imunologia , Linfócitos B/metabolismo , Neoplasias Colorretais/imunologia , Glucose/metabolismo , Neoplasias Pulmonares/imunologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neoplasias/imunologia , Idoso , Animais , Azoximetano , Linfócitos B/imunologia , Células Cultivadas , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/genética , Fator de Transcrição STAT6/metabolismo
15.
J Gastroenterol Hepatol ; 34(7): 1182-1192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30357910

RESUMO

BACKGROUND AND AIM: Chronic inflammation is a major contributor to the initiation and progression of cancers. Lactobacillus helveticus NS8, which was originally separated from fermented koumiss, exhibited anti-inflammatory functions in our prior studies. In this study, NS8 was investigated for its potential to prevent colitis-associated colorectal cancer (CAC). METHODS: The protective effects of NS8 against CAC was explored by employing the azoxymethane plus dextran sodium sulfate-induced carcinogenesis mouse model. The prevalences of T cells expressing specific inflammatory cytokines were measured by flow cytometry at the early stage of CAC. Inflammatory modulation by NS8 was also tested in the Caco2-Raw264.7 cell co-culture system. The alternations in the intestinal microbiota following the health-inflammation-cancer sequence were analyzed by 16S rDNA sequencing. RESULTS: Oral intake of NS8 lactobacilli clearly reduced tumor number and the degree of hyperplasia. The increased proliferation of enterocytes at the early stage of CAC was significantly suppressed by NS8, while the level of apoptosis was elevated. The anticancer effects of NS8 were associated with its anti-colitis outcomes before tumor formation. NS8 significantly suppressed the activation of NF-κB and upregulated the anti-inflammatory cytokine IL-10. Further analysis revealed the marked downregulation of IL-17-producing T cells by NS8. Furthermore, NS8 modulated intestinal dysbiosis by promoting beneficial commensal microbes while suppressing cancer-associated microbes. Notably, Bacteroides acidifaciens was the most sensitive commensal bacteria to NS8 intervention. CONCLUSION: These results provide insight into the protective effects of L. helveticus NS8 against colorectal cancer.


Assuntos
Colite/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Microbioma Gastrointestinal , Intestinos/microbiologia , Lactobacillus helveticus/crescimento & desenvolvimento , Probióticos , Animais , Apoptose , Azoximetano , Células CACO-2 , Proliferação de Células , Técnicas de Cocultura , Colite/induzido quimicamente , Colite/imunologia , Colite/microbiologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Citocinas/imunologia , Sulfato de Dextrana , Disbiose , Humanos , Mediadores da Inflamação/imunologia , Intestinos/imunologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Linfócitos T/imunologia
16.
Cancer Epidemiol Biomarkers Prev ; 28(1): 99-109, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275115

RESUMO

BACKGROUND: Heterocyclic amines (HCA) are potent carcinogenic substances formed in meat. Because of their mutagenic activity, they may increase the risk of colorectal adenomas, which are the precursors of colorectal cancer, one of the most prevalent cancers worldwide. The aim of this meta-analysis was to synthesize the knowledge about the intake of HCAs and its associations with CRA. METHODS: We conducted a systematic search in PubMed and EMBASE. We used odds ratios (OR); or relative risks, RR) from every reported intake and compared the highest versus lowest level of dietary HCAs. In addition, we assessed a dose-response relationship. RESULTS: Twelve studies on HCA intake and risk of CRA were included in our analysis. We observed a statistically significant association when comparing top versus bottom intake category of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP; OR = 1.20; 95% confidence interval (CI) = 1.12-1.29], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx; OR = 1.20; 95% CI = 1.08-1.34), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx; OR = 1.16; 95% CI = 1.05-1.27), benzo(a)pyrene (BaP; OR = 1.15; 95% CI = 1.04-1.27), and mutagenicity index (OR = 1.22; 95% CI = 1.06-1.41). Furthermore, we observed a significant dose-response effect for PhIP, MeIQx, and mutagenicity index. CONCLUSIONS: This meta-analysis suggests that there is a positive association of HCAs, BaP, mutagenicity index with risk of CRA. In addition, our dose-response analyses showed an increased risk of CRA for PhIP, MeIQx, and mutagenicity index. IMPACT: This study provides evidence for a positive association between the dietary intake of meat mutagens and CRA risk.


Assuntos
Adenoma/induzido quimicamente , Aminas/toxicidade , Neoplasias Colorretais/induzido quimicamente , Compostos Heterocíclicos/toxicidade , Mutagênicos/efeitos adversos , Carne Vermelha/efeitos adversos , Adenoma/etiologia , Adulto , Idoso , Benzo(a)pireno/toxicidade , Neoplasias Colorretais/etiologia , Dieta/efeitos adversos , Feminino , Humanos , Imidazóis/toxicidade , Masculino , Carne/efeitos adversos , Carne/análise , Pessoa de Meia-Idade , Mutagênicos/toxicidade , Razão de Chances , Quinoxalinas/toxicidade , Carne Vermelha/análise
17.
Mucosal Immunol ; 12(1): 188-199, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279515

RESUMO

Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-ß via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-ß)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.


Assuntos
Colite/imunologia , Neoplasias Colorretais/imunologia , Doenças Inflamatórias Intestinais/imunologia , Ácidos Linoleicos Conjugados/metabolismo , Macrófagos/imunologia , PPAR gama/metabolismo , Linfócitos T/imunologia , Ácido Aminossalicílico/metabolismo , Animais , Carcinogênese , Células Cultivadas , Colite/induzido quimicamente , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/genética , Fator de Crescimento Transformador beta/metabolismo
18.
Crit Rev Food Sci Nutr ; 59(3): 488-505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28925728

RESUMO

Repeated heating of vegetable oils at high temperatures during cooking is a very common cooking practice. Repeatedly heated cooking oils (RCO) can generate varieties of compounds, including polycyclic aromatic hydrocarbons (PAH), some of which have been reported as carcinogenic. RCO is one of the commonly consumed cooking and frying medium. These RCO consumption and inhalation of cooking fumes can pose a serious health hazard. Taking into account exploratory study, the present review aims to provide the consumption of RCO and its fumes cause the high incidence of genotoxic, mutagenic, tumorogenic and various cancers. The information on RCO and its fumes were collected through a library database and electronic search (ScienceDirect, PubMed, and Google Scholar). Remarkable studies demonstrated that the health adverse effects of RCO and its cooking fumes have been often attributed to their detrimental properties and ease to genotoxic, mutagenic and carcinogenic activities. RCO and its cooking fumes were found to enhance the incidence of aberrant cells, including breaks, fragments, exchanges and multiple chromosomal damages and micronuclei in a dose-dependent manner. Furthermore, the large consumption of RCO has been associated with a number of malignancies, including lung, colorectal, breast, and prostate cancers. The present review provides additional insights into the polluting features of PAHs produced various cancers via cooking activities in indoor environments.


Assuntos
Culinária/métodos , Temperatura Alta , Neoplasias/induzido quimicamente , Óleos Vegetais/química , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Animais , Neoplasias da Mama/induzido quimicamente , Carcinógenos/síntese química , Neoplasias Colorretais/induzido quimicamente , Feminino , Humanos , Neoplasias Pulmonares/induzido quimicamente , Masculino , Mutagênicos , Neoplasias/epidemiologia , Hidrocarbonetos Policíclicos Aromáticos/análise , Neoplasias da Próstata/induzido quimicamente , Fatores de Risco
19.
Gastroenterology ; 156(4): 1112-1126, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30472235

RESUMO

BACKGROUND & AIMS: Wnt signaling contributes to the development of colorectal cancer (CRC). We studied interactions between lysine demethylase 4D (KDM4D or JMJD2D) and ß-catenin, a mediator of Wnt signaling, in CRC cell lines and the effects on tumor formation in mice. METHODS: We obtained colorectal tumor specimens and surrounding nontumor colon tissues (controls) from patients undergoing surgery in China; levels of JMJD2D were measured by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in CRC (CT26, HCT116, and SW480 cells) using small hairpin RNAs, and cells were analyzed with viability, flow cytometry, colony formation, and transwell migration and invasion assays. Cells were also grown as tumor xenografts in nude mice or injected into tail veins or spleens of mice, and metastases were measured. We performed promoter activity, co-immunoprecipitation, and chromatin immunoprecipitation assays. We also performed studies with Apcmin/+ and JMJD2D-knockout mice; these mice were crossed, and colorectal tumor formation in offspring (Apcmin/+Jmjd2d+/+ and Apcmin/+Jmjd2d-/-) was analyzed. JMJD2D-knockout and wild-type (control) mice were given azoxymethane followed by dextran sodium sulfate to induce colitis-associated CRC; some mice were given the JMJD2D inhibitor 5-chloro-8-hydroxyquinoline (5-c-8HQ) or vehicle to examine the effects of 5-c-8HQ on intestinal tumor formation. RESULTS: Levels of JMJD2D were significantly higher in human colorectal tumors than in control tissues and correlated with levels of proliferating cell nuclear antigen. JMJD2D knockdown reduced CRC cell proliferation, migration, and invasion, as well as growth of xenograft tumors and formation of metastases in mice. JMJD2D was required for expression of ß-catenin in CRC cell lines; ectopic expression of JMJD2D increased the promoter activities of genes regulated by ß-catenin (MYC, CCND1, MMP2, and MMP9). We found that JMJD2D and ß-catenin interacted physically and that JMJD2D demethylated H3K9me3 at promoters of ß-catenin target genes. JMJD2D-knockout mice developed fewer colitis-associated colorectal tumors than control mice, and their tumor tissues had lower levels of ß-catenin, MYC, cyclin D1, and proliferating cell nuclear antigen than tumors from control mice. Apcmin/+Jmjd2d-/- mice developed fewer and smaller colon tumors than Apcmin/+ mice. Mice given 5-c-8HQ developed smaller and fewer colitis-associated tumors, with lower levels of cell proliferation, than mice given vehicle. Apcmin/+ mice given 5-c-8HQ also developed fewer tumors in intestines and colons than mice given vehicle. CONCLUSIONS: Levels of the histone demethylase JMJD2D are increased in human colorectal tumors compared with nontumor colon tissues. JMJD2D interacts with ß-catenin to activate transcription of its target genes and promote CRC cell proliferation, migration, and invasion, as well as formation of colorectal tumors in mice.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Histonas/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , beta Catenina/metabolismo , Animais , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular/genética , Cloroquinolinóis/farmacologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Ciclina D1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Metilação , Camundongos , Camundongos Knockout , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Transcrição Genética , Ensaio Tumoral de Célula-Tronco , Via de Sinalização Wnt , beta Catenina/genética
20.
Biol Pharm Bull ; 41(12): 1797-1803, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504681

RESUMO

High-dose vitamin C administration has been reported to exhibit antitumor effect in various mouse models of cancer. However, the underlying mechanism of antitumor effect against colorectal cancer remains to be elucidated. In this study, we investigated the antitumor effect of high-dose vitamin C in a mouse model of chronic inflammation-associated colorectal cancer induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). After cancer induction, the mice were administered vitamin C and/or irinotecan. Because irinotecan is a key drug in colorectal cancer treatment, it was used for comparison in this study. We examined reactive oxygen species (ROS) and interleukin-6 (IL-6) levels in the plasma of mice, as well as collagen type I and caspase-1 expression and neutrophil and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cell counts in the colon tissue. Vitamin C and/or irinotecan administration decreased the plasma level of ROS and IL-6 and increased the expression of collagen type I and caspase-1. Furthermore, it increased neutrophil and TUNEL-positive cell counts. The most significant changes in the parameters analyzed were observed when both vitamin C and irinotecan were administered.


Assuntos
Antineoplásicos/uso terapêutico , Ácido Ascórbico/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Irinotecano/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Ácido Ascórbico/administração & dosagem , Azoximetano , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Sulfato de Dextrana , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Interleucina-6/sangue , Irinotecano/administração & dosagem , Masculino , Camundongos Pelados , Espécies Reativas de Oxigênio/sangue
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