RESUMEN
Decrease of pancreatic ß cells leads to diabetes. In an inducible cAMP early suppressor (ICER-Iγ) transgenic mouse model of severe type 2 diabetes with reduced insulin production and depleted ß cells, supplementation with high concentrations of 17ß-estradiol (E2) markedly enhances ß-cell proliferation and normalizes glucose levels. The current study explored the underlying mechanisms leading to a dynamic increase of ß cells and pathologic changes in diabetic mice exposed to E2. Gene expression profiling of pancreatic islets of 6-month-old ICER-transgenic mice recovering from diabetes due to elevated E2 levels identified growth regulation by estrogen in breast cancer 1 (Greb1) as a gene significantly up-regulated during the recovery phase. To substantiate this, ß-cell-specific Greb1-deficient mice were generated, and Greb1 was shown to be essential for recovery of depleted ß cells in diabetic mice. Graft growth and glucose lowering were observed in 50 islets with increased Greb1 expression transplanted adjacent to E2 pellets beneath the kidney capsule of streptozotocin-induced diabetic mice. Greb1 expression due to a drastic increase in exogenous or endogenous E2 was transient and closely correlated with changes in E2-related and some cell cycle-related genes. These findings provide new insights into in vivo proliferation of deficient ß cells and suggest the possibility of new therapeutic approaches targeting pancreatic ß cells that could revolutionize the concept of diabetes treatment, which has been considered difficult to cure completely.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratones , Animales , Estradiol/farmacología , Proliferación Celular , Ratones Transgénicos , GlucosaRESUMEN
Diabetic nephropathy (DN), once manifested, is unlikely to completely recover. Factors that influence DN progression were explored by investigating the process of glomerulosclerosis and interstitial fibrosis and chronological changes in glucose, albuminuria, hyperfiltration, and expressions of sodium-glucose cotransporter 2 (SGLT2) and hypoxia-inducible factors (HIFs) up to 50 weeks in inducible cAMP early repressor transgenic mice, a model of severe DN. Long-term intervention with the SGLT2 inhibitor canagliflozin or islet transplantation or heminephrectomy was used. Inducible cAMP early repressor transgenic mice exhibited progressive diabetic glomerulosclerosis and mild interstitial fibrosis, and expressed extensive HIF-1α and HIF-2α in glomerulus and tubules, with sustained hyperfiltration up to 50 weeks. Canagliflozin ameliorated glomerulosclerosis/interstitial fibrosis gradually and reduced HIF overexpression. Islet-transplanted mice exhibited no amelioration. None of the heminephrectomized diabetic mice survived the hyperfiltration overload, but all of the canagliflozin-treated mice survived with re-expressions of HIF-1α and HIF-2α. These results suggest that persistent glomerular hyperfiltration might initiate glomerular injury, and persistent overexpression of HIFs could promote the development of glomerulosclerosis and interstitial fibrosis. Canagliflozin attenuated both changes. Oxidative stress or hypoxia was undetectable in this model. The abnormal expression of HIF-1α and HIF-2α may be a potential therapeutic target for preventing glomerulosclerosis and interstitial fibrosis.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Canagliflozina , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Fibrosis , Glucosa , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratones , Ratones Transgénicos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17ß-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by ß-cellspecific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes. Here, we examined whether DN in male ICER-Tg mice is rescued by adjusting the androgen-to-E2 ratio to approximate that in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX), E2 pellet implantation, or both. E2 pellet implantation at an early stage of DN with or without ORX caused a rapid drop in blood glucose and a dramatic increase in ß-cell number, and it markedly inhibited DN progression [namely, E2 reduced glomerulosclerosis, collagen 4 deposition and albuminuria, and prevented hyperfiltration]. Furthermore, E2 pellet implantation was more effective than ORX alone and induced a remarkable improvement, even when initiated at advanced-stage DN. In contrast, induction of normoglycemia by islet transplant in ICER-Tg mice eliminated albuminuria but was less effective than E2 + ORX in reducing glomerulosclerosis, collagen 4 deposition, and hyperfiltration. These findings indicate that E2 treatment is effective, even after establishment of DN, whereas glucose normalization alone does not improve sclerotic lesions. We propose that E2 intervention is a potential therapeutic option for DN.
Asunto(s)
Andrógenos/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/etiología , Estradiol/sangre , Animales , Glucemia/análisis , Masculino , Ratones , Ratones TransgénicosRESUMEN
OBJECTIVE: A diet high in sugars may promote colorectal carcinogenesis, but it remains uncertain whether high intake of sugars or sucrose confers increased risk of colorectal cancer. The authors investigated the associations of sugars and sucrose intake with colorectal cancer risk in a community-based case-control study in Japan. METHODS: The study subjects comprised 816 incident cases of colorectal cancer and 815 community controls. Consumption frequencies and portion sizes of 148 food and beverage items were ascertained by a computer-assisted interview. The authors used the consumption of 29 food items to estimate sugars and sucrose intake. The odds ratios of colorectal cancer risk according to intake categories were obtained using a logistic regression model with adjustment for potential confounding variables. RESULTS: Overall, intakes of sugars and sucrose were not related to colorectal cancer risk either in men or women. The association between sugars intake and colorectal cancer risk differed by smoking status and alcohol use in men, but not in women. In men, sugars intake tended to be associated with colorectal cancer risk inversely among never-smokers and positively among male ever-smokers (interaction p=0.01). Sugars intake was associated with an increased risk among men with no alcohol consumption, but was unrelated to the risk among male alcohol drinkers (interaction p=0.02). Body mass index did not modify the association with sugars intake in either men or women. CONCLUSION: Sugars intake was associated with increased risk of colorectal cancer among smokers and non-alcohol drinkers in men selectively.
Asunto(s)
Neoplasias Colorrectales/etiología , Sacarosa en la Dieta , Fructosa , Adenocarcinoma/epidemiología , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Bebidas , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Dieta , Sacarosa en la Dieta/administración & dosificación , Sacarosa en la Dieta/efectos adversos , Femenino , Fructosa/administración & dosificación , Fructosa/efectos adversos , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores Sexuales , Fumar/efectos adversos , Fumar/epidemiología , Encuestas y CuestionariosRESUMEN
Estrogen receptor (ER)-ß signaling has generally been implicated in protection against colorectal cancer. The ER-ß gene cytosine-adenine (ESR2 CA) repeat polymorphism was reported to be associated with colorectal cancer, although showing contradicting results probably caused by ethnicity or age distribution of the subjects. We investigated the association between this polymorphism and the colorectal cancer risk in a community-based case-control study in Japan (685 cases/778 controls), including only subjects younger than 75. The effect modifications of the body mass index (BMI) and isoflavone intake were also examined. ESR2 CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labeled primers. CA repeat alleles were classified into short (S) allele (<22 repeats) and long (L) allele (≥ 22 repeats). Subjects were divided into three genotype groups (SS/SL/LL). The risk of colon cancer, but not of rectal cancer, was increased with an increasing number of L alleles among postmenopausal women; age-adjusted odds ratio (OR) for SL and LL genotypes compared with the SS genotype were 1.78 and 2.91, respectively (trend p = 0.002). Increased risks of colon cancer associated with the L allele were more evident among postmenopausal women with low BMI (<25 kg m(-2)) or with high isoflavone intake. Such associations were not observed among men or premenopausal women. Having longer ESR2 CA repeat increases colon cancer risk among postmenopausal women younger than 75, possibly with modification of BMI and isoflavone intake. Aging and estrogenic condition may be important in the colon cancer pathogenesis associated with ESR2 CA repeat polymorphism.
Asunto(s)
Neoplasias Colorrectales/genética , Receptor beta de Estrógeno/genética , Isoflavonas/administración & dosificación , Alelos , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
Microsomal epoxide hydrolase (EPHX1) plays an important role in the activation and detoxification of polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Polymorphisms in exon 3 (Y113H) and exon 4 (H139R) of the EPHX1 have been associated with enzyme activity. We investigated the risk of colorectal cancer in relation to the EPHX1 Y113H and H139R polymorphisms and assessed effect modifications of cigarette smoking and the other covariates. The interaction between the EPHX1 polymorphisms and selected genetic polymorphisms was also examined. We used data from Fukuoka Colorectal Cancer Study, a community-based case-control study, including 685 cases and 778 controls. In-person interviews were conducted to assess lifestyle factors. The EPHX1 Y113H and H139R polymorphisms were determined by the TaqMan assay and the polymerase chain reaction-restriction fragment length polymorphism, respectively. Neither of the two polymorphisms nor the imputed EPHX1 phenotype was associated with colorectal cancer risk. Cigarette smoking and alcohol intake showed no effect modification on the association with the EPHX1 polymorphisms or the imputed EPHX1 phenotype. Increased risks of colorectal cancer associated with the 113Y allele and imputed EPHX1 phenotype were observed among individuals with high body mass index (BMI; ≥25.0 kg/m(2)), but not among those with low BMI (<25.0 kg/m(2)). The risk decreased with an increasing number of the 139R allele in the null genotypes of GSTM1/GSTT1. It is unlikely that the EPHX1 polymorphisms play an important role in colorectal carcinogenesis. The observed interactions of the EPHX1 polymorphisms with BMI and the GSTM1/GSTT1 genotypes warrant further investigation.
Asunto(s)
Neoplasias Colorrectales/etiología , Epóxido Hidrolasas/genética , Polimorfismo Genético , Fumar , Anciano , Alelos , Índice de Masa Corporal , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , RiesgoRESUMEN
It has long been a matter of interest whether antioxidant vitamins are protective against colorectal cancer as well as human cancers in general, but epidemiological evidence is inconclusive. We investigated associations of dietary intakes of retinol and antioxidant vitamins with colorectal cancer risk in 816 incident cases of histologically confirmed colorectal cancer and 815 controls randomly selected for the Fukuoka colorectal cancer study in Japan. Dietary intakes were assessed by a PC-assisted interview regarding 148 food items. Statistical adjustment was made for body mass index, physical activity, calcium, and n-3 fatty acid intake and other factors. Retinol intake was significantly, inversely associated with colorectal cancer risk; the odds ratio for the highest vs. lowest was 0.55 (95% CI: 0.35, 0.88; P (trend) = 0.01) in women, but a modest increase in the risk was observed among men with the highest intake of retinol. Liver was the major source of retinol intake and showed similar associations with colorectal cancer risk in men and women. Intake of carotenes, vitamin C, and vitamin E were not related to colorectal cancer risk in either men or women. The study did not support a hypothesis that dietary intake of antioxidant vitamins is protective in the development of colorectal cancer.
Asunto(s)
Antioxidantes/farmacología , Ácido Ascórbico/administración & dosificación , Carotenoides/administración & dosificación , Neoplasias Colorrectales/prevención & control , Vitamina A/administración & dosificación , Vitamina E/administración & dosificación , Anciano , Dieta , Ácidos Grasos Omega-3 , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Oportunidad RelativaRESUMEN
BACKGROUND: X-ray cross-complementing group 1 (XRCC1) polymorphisms affect DNA repair capacity and may therefore be of importance in colorectal carcinogenesis. Alcohol consumption, an important risk factor for colorectal cancer, may induce carcinogenesis through DNA damage caused by the toxic effects of alcohol or its metabolites. Therefore, we examined the associations of XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms with colorectal cancer and the impact of the association between alcohol consumption and colorectal cancer risk. METHODS: This case-control study in Fukuoka, Japan including 685 cases and 778 controls. The cases were incident patients with histologically confirmed colorectal adenocarcinoma. The controls were randomly selected community subjects. RESULTS: The XRCC1 399Gln/Gln genotype was significantly associated with colorectal cancer risk (adjusted odds ratio [OR] 1.57, 95% CI 1.01-2.42; relative to 399Arg/Arg genotype). The association was strongest in individuals with high alcohol consumption. The Arg280His polymorphism modified the association between alcohol consumption and colorectal cancer risk (interaction P = 0.049). The OR of colorectal cancer in individuals with the 280His allele was 0.45 (95% CI 0.26-0.78) as compared with the 280Arg/Arg genotype limited to the 399Gln allele (interaction P = 0.001). The adjusted ORs for 399Gln/Gln-280Arg/Arg-194Arg/Arg and 399Arg/Gln-280Arg/Arg-194Arg/Trp were 1.71 (95% CI 1.02-2.87) and 1.57 (95% CI 1.05-2.33), respectively, with 399Arg/Arg-280Arg/Arg-194Arg/Arg as reference (interaction P = 0.418). CONCLUSIONS: The findings are additional evidence that individuals with the XRCC1 399Gln/Gln genotype have an increased risk of colorectal cancer, and that XRCC1 polymorphisms have an important role in colorectal cancer risk associated with alcohol consumption or gene-gene interaction.
Asunto(s)
Adenocarcinoma/genética , Consumo de Bebidas Alcohólicas/epidemiología , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético/genética , Adenocarcinoma/epidemiología , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Femenino , Genotipo , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
Prevention of immune rejection without immunosuppression is the ultimate goal of transplant immunobiology. One way to achieve this in cellular transplantation, such as with islet transplantation, is to create a favorable local environment at the transplant site. In the current study, we found that C57BL/6 mice with streptozotocin-induced diabetes remained normoglycemic for >1 year after transplantation of BALB/c islets without immunosuppression when the inguinal subcutaneous white adipose tissue (ISWAT) was the site of transplantation and when the site was pretreated with basic fibroblast growth factor. Mechanistically, mesenchymal stem cells (MSCs) expanded in the ISWAT after the treatment was found to produce transforming growth factor-ß (TGF-ß), and prevention of islet allograft rejection could be achieved by cotransplantation with syngeneic MSCs isolated from the ISWAT after the treatment, which was abolished by anti-TGF-ß antibody treatment. Importantly, TGF-ß-producing cells remained present at the site of cotransplantation up to the end of observation period at 240 days after transplantation. These findings indicate that prevention of islet allograft rejection without immunosuppression is feasible with the use of syngeneic TGF-ß-producing MSCs expanded in the ISWAT after the treatment with bFGF, providing a novel strategy for prevention of islet allograft rejection without immunosuppression.
Asunto(s)
Diabetes Mellitus Experimental , Trasplante de Islotes Pancreáticos , Aloinjertos , Animales , Diabetes Mellitus Experimental/terapia , Factor 2 de Crecimiento de Fibroblastos/farmacología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Terapia de Inmunosupresión , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Grasa SubcutáneaRESUMEN
Pancreatic islet transplantation is a highly promising approach for the treatment of insulin-dependent diabetes mellitus. However, the procedure remains experimental for several reasons, including its low efficiency caused by the early graft loss of transplanted islets. We demonstrate that Gr-1+CD11b+ cells generated by transplantation and their IFN-gamma production triggered by Valpha14 NKT cells are an essential component and a major cause of early graft loss of pancreatic islet transplants. Gr-1+CD11b+ cells from Valpha14 NKT cell-deficient (Jalpha281-/-) mice failed to produce IFN-gamma, resulting in efficient islet graft acceptance. Early graft loss was successfully prevented through the repeated administration of alpha-galactosylceramide, a specific ligand for Valpha14 NKT cells, resulting in dramatically reduced IFN-gamma production by Gr-1+CD11b+ cells, as well as Valpha14 NKT cells. Our study elucidates, for the first time, the crucial role of Gr-1+CD11b+ cells and the IFN-gamma they produce in islet graft rejection and suggests a novel approach to improving transplantation efficiency through the modulation of Valpha14 NKT cell function.
Asunto(s)
Rechazo de Injerto/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antígeno CD11b/inmunología , Citometría de Flujo , Inmunohistoquímica , Interferón gamma/inmunología , Hígado/citología , Hígado/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Quimiocina/inmunologíaRESUMEN
The development of a new plasma biomarker for early detection would be necessary to improve the overall outcome of colorectal cancer. Here we report the identification and validation of the ninth component of complement (C9) as a novel plasma biomarker for colorectal cancer by cutting-edge proteomic technologies. Plasma proteins were enzymatically digested into a large array of peptides, and the relative quantity of a total of 94,803 peptide peaks was compared between 31 colorectal cancer patients and 59 age/sex-matched healthy controls using 2D image-converted analysis of liquid chromatography and mass spectrometry. The selected biomarker candidates were validated in 345 subjects (115 colorectal cancer patients and 230 age/sex-matched healthy controls) using high-density reverse-phase protein microarrays. Plasma levels of Apo AI and C9 in colorectal cancer patients significantly differed from healthy controls with P values of 7.94×10(-4) and 1.43×10(-12) (Student's t-test), respectively. In particular, C9 was elevated in patients with colorectal cancer, including those with stage-I and -II diseases (P=3.01×10(-3) and P=1.13×10(-5) , respectively). Although the significance of the present study must be validated in an independent clinical study, the increment of plasma C9 may be applicable to the early detection of colorectal cancer.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/diagnóstico , Complemento C9/análisis , Análisis por Matrices de Proteínas/métodos , Espectrometría de Masas en Tándem/métodos , Anciano , Apolipoproteína A-I/sangre , Área Bajo la Curva , Neoplasias Colorrectales/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , ProteómicaRESUMEN
OBJECTIVE: It has been suggested that soy food and isoflavone intake may be protective against the risk of colorectal cancer. However, epidemiologic evidence remains sparse and inconsistent. We addressed this issue in the Fukuoka Colorectal Cancer Study. MATERIAL AND METHODS: The study subjects were the 816 incident cases of histologically confirmed colorectal cancer and 815 community controls. Intakes of soy foods and isoflavones were assessed by in-person interview using a computer-assisted dietary method. Logistic regression analysis was applied to estimate odds ratio (OR) and 95% confidence interval (CI) of colorectal cancer with adjustment for dietary intakes of calcium and n-3 polyunsaturated fatty acids as well as for body mass index, physical activity, alcohol use, and other lifestyle factors. RESULTS: Energy-adjusted intakes of soy foods (dry weight) and isoflavones were inversely associated with colorectal cancer risk in men and postmenopausal women, but not in premenopausal women. The multivariate-adjusted OR for the highest versus lowest quintile was 0.65 (95% CI 0.41-1.03, p for trend = 0.03) for soy foods and 0.68 (95% CI 0.42-1.10, p for trend = 0.051) for isoflavones in men. The corresponding values for postmenopausal women were 0.60 (95% CI 0.29-1.25, p for trend = 0.053) and 0.68 (95% CI 0.33-1.40, p for trend = 0.049). The site-specific analysis showed inverse associations of soy foods (p for trend = 0.007) and isoflavones (p for trend = 0.02) with rectal cancer in men. CONCLUSION: The findings add to epidemiologic evidence for protective effects of soy foods and isoflavones in colorectal carcinogenesis.
Asunto(s)
Neoplasias Colorrectales/epidemiología , Dieta , Isoflavonas/administración & dosificación , Alimentos de Soja , Anciano , Ingestión de Alimentos , Femenino , Humanos , Incidencia , Entrevistas como Asunto , Japón/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Posmenopausia , RiesgoRESUMEN
OBJECTIVE: Tumor protein p53 gene and its negative regulator, murine double minute 2 homolog are important components for cell-cycle arrest and apoptosis. An arginine-to-proline substitution at codon 72 in the p53 gene is reported to decrease apoptotic potential, while a thymine-to-guanine polymorphism at nucleotide 309, named SNP309, of murine double minute 2 gene increases transcription of the gene. These two polymorphisms therefore may be of importance in colorectal carcinogenesis. The relation of these polymorphisms to colorectal cancer risk was addressed in the Fukuoka Colorectal Cancer Study. METHODS: We genotyped the two polymorphisms in 685 incident cases of colorectal cancer and 778 community controls by the polymerase chain reaction-restriction fragment length polymorphism method. Statistical adjustment was made for sex and age. RESULTS: The proline allele of p53 gene and the guanine allele of SNP309 were each associated with a small, statistically non-significant increase in the odds ratio of colorectal cancer; the adjusted odds ratio (95% confidence interval) for arginine/proline and proline/proline genotypes combined versus arginine/arginine genotype of p53 gene was 1.23 (0.99-1.52) and that for thymine/guanine and guanine/guanine genotypes combined versus thymine/thymine genotype of SNP309 was 1.27 (0.98-1.63). Individuals harboring the proline allele of p53 gene and the guanine allele of SNP309 showed an odds ratio of 1.67 (95% confidence interval, 1.11-2.51). CONCLUSIONS: Codon 72 polymorphism of p53 and SNP309 in combination may confer an increased risk of colorectal cancer.
Asunto(s)
Pueblo Asiatico/genética , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/genética , Genes p53/genética , Polimorfismo de Longitud del Fragmento de Restricción , Proteínas Proto-Oncogénicas c-mdm2/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Japón/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co-transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co-transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co-transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP-1 were selected as candidate crucial factors using the Bio-Plex system, beneficial effects were partially counteracted by anti-insulin receptor antibodies. In conclusion, this study demonstrated that islet co-transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.
Asunto(s)
Hepatocitos/trasplante , Trasplante de Islotes Pancreáticos , Animales , Supervivencia Celular , Exosomas/metabolismo , Hepatocitos/citología , Masculino , Modelos Biológicos , Ratas Endogámicas F344 , Albúmina Sérica/metabolismoRESUMEN
Plasma proteome analysis requires sufficient power to compare numerous samples and detect changes in protein modification, because the protein content of human samples varies significantly among individuals, and many plasma proteins undergo changes in the bloodstream. A label-free proteomics platform developed in our laboratory, termed "Two-Dimensional Image Converted Analysis of Liquid chromatography and mass spectrometry (2DICAL)," is capable of these tasks. Here, we describe successful detection of novel prolyl hydroxylation of alpha-fibrinogen using 2DICAL, based on comparison of plasma samples of 38 pancreatic cancer patients and 39 healthy subjects. Using a newly generated monoclonal antibody 11A5, we confirmed the increase in prolyl-hydroxylated alpha-fibrinogen plasma levels and identified prolyl 4-hydroxylase A1 as a key enzyme for the modification. Competitive enzyme-linked immunosorbent assay of 685 blood samples revealed dynamic changes in prolyl-hydroxylated alpha-fibrinogen plasma level depending on clinical status. Prolyl-hydroxylated alpha-fibrinogen is presumably controlled by multiple biological mechanisms, which remain to be clarified in future studies.
Asunto(s)
Proteínas Sanguíneas/química , Fibrinógeno/química , Procolágeno-Prolina Dioxigenasa/química , Proteómica/métodos , Adenocarcinoma/sangre , Estudios de Casos y Controles , Línea Celular Tumoral , Cromatografía Liquida/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Procesamiento de Imagen Asistido por Computador , Espectrometría de Masas/métodos , Neoplasias Pancreáticas/sangre , Proteoma , Interferencia de ARNRESUMEN
BACKGROUND: It is uncertain whether smoking is related to colorectal cancer risk. Cytochrome P-450 CYP1A1, glutathione-S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1) are important enzymes in the metabolism of tobacco carcinogens, and functional genetic polymorphisms are known for these enzymes. We investigated the relation of cigarette smoking and related genetic polymorphisms to colorectal cancer risk, with special reference to the interaction between smoking and genetic polymorphism. METHODS: We used data from the Fukuoka Colorectal Cancer Study, a population-based case-control study, including 685 cases and 778 controls who gave informed consent to genetic analysis. Interview was conducted to assess lifestyle factors, and DNA was extracted from buffy coat. RESULTS: In comparison with lifelong nonsmokers, the odds ratios (OR) of colorectal cancer for <400, 400-799 and > or = 800 cigarette-years were 0.65 (95% confidence interval [CI], 0.45-0.89), 1.16 (0.83-1.62) and 1.14 (0.73-1.77), respectively. A decreased risk associated with light smoking was observed only for colon cancer, and rectal cancer showed an increased risk among those with > or = 400 cigarette-years (OR 1.60, 95% CI 1.04-2.45). None of the polymorphisms under study was singly associated with colorectal cancer risk. Of the gene-gene interactions studied, the composite genotype of CYP1A1*2A or CYP1A1*2C and GSTT1 polymorphisms was associated with a decreased risk of colorectal cancer, showing a nearly statistically significant (Pinteraction = 0.06) or significant interaction (Pinteraction = 0.02). The composite genotypes of these two polymorphisms, however, showed no measurable interaction with cigarette smoking in relation to colorectal cancer risk. CONCLUSIONS: Cigarette smoking may be associated with increased risk of rectal cancer, but not of colon cancer. The observed interactions between CYP1A1 and GSTT1 polymorphisms warrant further confirmation.
Asunto(s)
Adenocarcinoma/etiología , Neoplasias Colorrectales/etiología , Citocromo P-450 CYP1A1/genética , Glutatión Transferasa/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Polimorfismo Genético , Fumar/efectos adversos , Adenocarcinoma/etnología , Adenocarcinoma/genética , Adulto , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Japón/epidemiología , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Few studies have addressed the relation between dietary patterns and colorectal cancer in Japan. We investigated dietary patterns in relation to colorectal cancer risk in a community-based case-control study. The association with dietary patterns was also examined for different sites of colorectal cancer. Data were derived from the Fukuoka Colorectal Cancer Study, including 800 cases and 775 controls interviewed from September 2000 to December 2003. The cases were admitted to one of the participating hospitals for the first surgical treatment during this period. We identified dietary patterns using principal component analysis of intakes of twenty-nine items of food groups and specific foods. Quartile categories of each dietary pattern were used, and non-dietary lifestyle factors and total energy intake were adjusted for in the analysis. We identified three dietary patterns: prudent, high-fat and light-meal patterns. The prudent dietary pattern characterised by high intakes of vegetables, fruits, seafoods and soya foods showed a nearly significant protective association with the overall risk of colorectal cancer (trend P = 0.054), and it was statistically significantly related to a decreased risk of distal colon cancer (trend P = 0.002), but not to that of either proximal colon or rectal cancer. The high-fat and light-meal dietary patterns were not materially related to the overall or site-specific risk of colorectal cancer. In summary, a prudent dietary pattern was associated with a decreased risk of colorectal cancer, especially with that of distal colon cancer, in a fairly large case-control study in Japan.
Asunto(s)
Neoplasias del Colon/prevención & control , Neoplasias Colorrectales/prevención & control , Dieta , Anciano , Pueblo Asiatico , Estudios de Casos y Controles , Neoplasias del Colon/etiología , Neoplasias Colorrectales/etiología , Dieta/normas , Femenino , Conductas Relacionadas con la Salud , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Análisis de Componente PrincipalRESUMEN
OBJECTIVE: Despite much evidence from laboratory work, epidemiological evidence remains elusive regarding the role of dietary fiber in colorectal carcinogenesis. We investigated associations of dietary fiber and source foods with colorectal cancer risk in the Fukuoka Colorectal Cancer Study, a community-based case-control study. MATERIAL AND METHODS: The study subjects were 816 incident cases of colorectal cancer and 815 community controls. Nutrient and food intakes were estimated on the basis of a computer-assisted interview regarding 148 dietary items. Odds ratios of colorectal cancer according to quintile categories of energy-adjusted intakes of dietary fiber and food groups were obtained with adjustment for non-dietary factors and dietary intakes of calcium and n-3 fatty acids. RESULTS: Total, soluble and insoluble dietary fibers were not measurably associated with overall risk or subsite-specific risk of colorectal cancer. By contrast, rice consumption was associated with a decreased risk of colorectal cancer (trend p = 0.03), particularly of distal colon and rectal cancer (trend p = 0.02), and high intake of non-rice cereals tended to be related to an increased risk of colon cancer (trend p = 0.07). There was no association between vegetable consumption and colorectal cancer, whereas individuals with the lowest intake of fruits tended to have an increased risk of colorectal cancer. CONCLUSIONS: The present study did not corroborate a protective association between dietary fiber and colorectal cancer, but suggested a decreased risk of distal colorectal cancer associated with rice consumption.
Asunto(s)
Neoplasias Colorrectales/prevención & control , Fibras de la Dieta/administración & dosificación , Oryza , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Femenino , Humanos , Incidencia , Hallazgos Incidentales , Japón/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Medición de Riesgo , Encuestas y CuestionariosRESUMEN
Cytochrome P450 2E1 (CYP2E1) is involved in the metabolic activation of a wide variety of potential carcinogens, and functional polymorphisms in the CYP2E1 gene have been investigated in relation to colorectal cancer. We examined the relation of the CYP2E1 RsaI and 96-bp insertion polymorphisms to colorectal cancer risk and the interaction between these polymorphisms and some lifestyle risk factors. Subjects were 685 incident cases of colorectal cancer and 778 community controls. Statistical adjustment was made for alcohol use, body mass index, physical activity, and other factors. The RsaI c2 allele was associated with a decreased risk of rectal cancer [adjusted odds ratio for at least one c2 allele, 0.71; 95% confidence interval (95% CI), 0.53-0.95], and an increased risk of rectal cancer was observed among individuals having one or two 96-bp insertion alleles (adjusted odds ratio, 1.40; 95% CI, 1.06-1.85). Individuals with two 96-bp insertion alleles showed a 2.28-fold increase in colon cancer risk (95% CI, 1.29-4.01). The two polymorphisms were in almost complete linkage disequilibrium (D' = 0.94). A positive association between alcohol intake and colorectal cancer was observed only in individuals without RsaI c2 allele (P(trend) = 0.03) or in those without 96-bp insertion allele (P(trend) = 0.009). Colon cancer risk was increased in relation to red meat intake only in individuals having one or two 96-bp insertion alleles (P(interaction) = 0.03). The present study suggests that variation in activity and inducibility of CYP2E1, in relation to alcohol or red meat intake, contributes to the development of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/genética , Citocromo P-450 CYP2E1/genética , Polimorfismo Genético , Consumo de Bebidas Alcohólicas/efectos adversos , Alelos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Neoplasias Colorrectales/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Entrevistas como Asunto , Japón/epidemiología , Estilo de Vida , Modelos Logísticos , Masculino , Carne/efectos adversos , Persona de Mediana Edad , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
Epidemiologic evidence supporting a protective role of calcium and vitamin D in colorectal carcinogenesis has been accumulating in Western populations, but it is limited in Asian populations, whose intake of calcium is relatively low. We investigated the association of intakes of these nutrients with colorectal cancer risk in Japanese. Study subjects were participants of a large-scale case-control study in Fukuoka, Japan. Diet was assessed through interview regarding 148 dietary items by showing typical foods or dishes on the display of a personal computer. In a multivariate analysis adjusting for potential confounding variables, calcium intake was significantly, inversely associated with colorectal cancer risk (P for trend=0.01); the odds ratio for the highest versus lowest quintile of calcium intake was 0.64 (95% confidence interval, 0.45-0.93). Higher levels of dietary vitamin D were significantly associated with decreased risk of colorectal cancer among those who had fewer chances of sunlight exposure at work or in leisure (P for trend=0.02). A decreased risk of colorectal cancer associated with high calcium intake was observed among those who had higher levels of vitamin D intake or among those who had a greater chance of daily sunlight exposure, but not among those with medium or lower intake of vitamin D or among those with potentially decreased sunlight exposure. These results add to support for a joint action of calcium and vitamin D in the prevention of colorectal carcinogenesis.