RESUMO
BACKGROUND: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk. METHODS: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors. RESULTS: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10-2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47-1.02; Ptrend, 0.18). CONCLUSION: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist. IMPACT: Further studies are warranted to better clarify these preliminary observations.
Assuntos
Neoplasias Colorretais/etiologia , Endotoxinas/sangue , Flagelina/sangue , Biomarcadores/sangue , Estudos de Coortes , Neoplasias Colorretais/sangue , Europa (Continente) , Feminino , Humanos , Masculino , Avaliação Nutricional , Estudos Prospectivos , Fatores de RiscoRESUMO
Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding. Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats. F344 rats were provided with diets that contained putative risk factors for CRC: low calcium and low vitamin D, high iron, high fructose, and decreased light (UV) exposure or a control diet for 14 wk. The rats were then assessed with biochemical measures and by topological examination for evidence of colon abnormalities. Circulating ionized calcium was decreased from 2.85 to 1.69 mmol/L, and ACF were increased from 0.7 to 13.6 lesions/colon (both P < 0.001). Rats exposed to the multiple environmental conditions associated with colon cancer, developed ACF similar to the heterogeneous or ill-defined ACF in the human colon. Heterogeneous ACF are the most frequently seen in humans and are also seen in rats shortly after exposure to the non-genotoxic colon carcinogen, dextransulfate sodium. The rodent model could be used to assess the pathways from diet and environment to colon cancer and to provide guidance for clinical studies.
Assuntos
Focos de Criptas Aberrantes/etiologia , Neoplasias Colorretais/etiologia , Animais , Cálcio/sangue , Colo/patologia , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Endogâmicos F344 , Fatores de RiscoRESUMO
BACKGROUND: A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer. METHODS: A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status. RESULTS: Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.57-1.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14). CONCLUSIONS: In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer. IMPACT: Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development.
Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/epidemiologia , Produtos Finais de Glicação Avançada/sangue , Gliceraldeído/sangue , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
We observed an unexpectedly strong association of three different endogenous aldehydes and noted that the association could be explained by multiple reactions in which oxidative stress increased the formation of endogenous aldehydes and endogenous aldehydes increased oxidative stress. These interactions make it reasonable to assess multiple exposures to endogenous oxidative and aldehyde stress with less specific measures such as advanced glycation end-products or protein carbonyls.
Assuntos
Aldeídos/metabolismo , Estresse OxidativoRESUMO
Thermolysis of proteins produces xenobiotic amino-acids such as the potentially toxic lysinoalanine, and the alkylating agent, dehydroalanine, which have been considered possible health hazards. We observed that thermolyzed casein promoted aberrant crypt foci (ACF) and colon cancer growth in rats initiated with azoxymethane and speculated that promotion might be due to the formation of these compounds. To test this notion we first measured the concentration of the modified amino acids as a function of thermolysis time. The concentration of dehydroalanine in the casein paralleled the degree of promotion, that of lysinoalanine did not. We then tested diets containing foods with high levels of dehydroalanine (thermolyzed sodium-caseinate, cooked Swiss cheese) for their effect on ACF promotion. They decreased the number and/or size of ACF significantly, indicating that dehydroalanine did not promote, but protected rats against colon carcinogenesis. These results do not support the notion that lysinoalanine or dehydroalanine are a hazard with respect to colon carcinogenicity.
Assuntos
Alanina/análogos & derivados , Caseínas/química , Neoplasias do Colo/induzido quimicamente , Lisinoalanina/toxicidade , Alanina/análise , Alanina/metabolismo , Alanina/toxicidade , Animais , Azoximetano/toxicidade , Testes de Carcinogenicidade , Caseínas/toxicidade , Queijo/análise , Neoplasias do Colo/patologia , Dieta , Fezes/química , Feminino , Temperatura Alta , Mucosa Intestinal/patologia , Lisinoalanina/análise , Lisinoalanina/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
A thermolyzed diet has the potential of providing exogenous oxidative stress in the form of advanced glycation end-products (AGE) and decreased thiamin. There is then a possibility that it could result in intracellular exposure to alpha-oxoaldehydes (glyoxal and methylglyoxal (MG)) with metabolic and genetic consequences. Two groups of Fischer 344 rats were fed the following diets: group A was given an AIN93G diet (control diet), while group B was given a thermolyzed AIN93G diet for 77 days. At the end of 77 days TK activity in red blood cells; glyoxal/MG levels in the plasma; glyoxal/MG HI protein adducts and dicarbonyls in the plasma, liver and colon tissues; glutathione levels of whole blood; and oxidative stress/inflammatory markers in the colon were measured. The thermolyzed diet resulted in: decreased thiamin status, increased plasma levels of glyoxal/MG and their adducts, increased protein dicarbonyls in the liver and plasma, lowered blood glutathione levels, increased infiltration of macrophages and increased colon nitrotyrosine levels. The thermolyzed diet increased the body burden of AGEs and decreased the thiamin status of the rats. This increased endogenous alpha-oxoaldehydes and oxidative stress has the potential to injure tissues that have low levels of antioxidant defenses such as the colon.
Assuntos
Aldeídos/sangue , Colite/metabolismo , Dieta , Estresse Oxidativo , Animais , Biomarcadores/metabolismo , Peso Corporal , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Glutationa/metabolismo , Imuno-Histoquímica , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed.
Assuntos
Ácido Fólico/metabolismo , Mitocôndrias/metabolismo , Piridoxal/metabolismo , Vitamina B 12/metabolismo , Complexo Vitamínico B/metabolismo , Animais , Humanos , Deficiência de Vitaminas do Complexo B/metabolismoRESUMO
The B vitamins are water-soluble vitamins required as coenzymes for enzymes essential for cell function. This review focuses on their essential role in maintaining mitochondrial function and on how mitochondria are compromised by a deficiency of any B vitamin. Thiamin (B1) is essential for the oxidative decarboxylation of the multienzyme branched-chain ketoacid dehydrogenase complexes of the citric acid cycle. Riboflavin (B2) is required for the flavoenzymes of the respiratory chain, while NADH is synthesized from niacin (B3) and is required to supply protons for oxidative phosphorylation. Pantothenic acid (B5) is required for coenzyme A formation and is also essential for alpha-ketoglutarate and pyruvate dehydrogenase complexes as well as fatty acid oxidation. Biotin (B7) is the coenzyme of decarboxylases required for gluconeogenesis and fatty acid oxidation. Pyridoxal (B6), folate and cobalamin (B12) properties are reviewed elsewhere in this issue. The experimental animal and clinical evidence that vitamin B therapy alleviates B deficiency symptoms and prevents mitochondrial toxicity is also reviewed. The effectiveness of B vitamins as antioxidants preventing oxidative stress toxicity is also reviewed.
Assuntos
Mitocôndrias/metabolismo , Complexo Vitamínico B/metabolismo , Animais , Biotina/administração & dosagem , Biotina/metabolismo , Metabolismo Energético/fisiologia , Humanos , Mitocôndrias/efeitos dos fármacos , Niacina/administração & dosagem , Niacina/metabolismo , Estresse Oxidativo/fisiologia , Ácido Pantotênico/administração & dosagem , Ácido Pantotênico/metabolismo , Riboflavina/administração & dosagem , Riboflavina/metabolismo , Tiamina/administração & dosagem , Tiamina/metabolismo , Complexo Vitamínico B/administração & dosagem , Deficiência de Vitaminas do Complexo B/metabolismoRESUMO
The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.
Assuntos
Colo/patologia , Neoplasias Colorretais/etiologia , Hiperinsulinismo/patologia , Resistência à Insulina , Reto/patologia , Animais , Peso Corporal , Proliferação de Células , Emulsões Gordurosas Intravenosas/farmacologia , Hiperinsulinismo/complicações , Fator de Crescimento Insulin-Like I/análise , Mucosa Intestinal/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Análise de RegressãoRESUMO
We hypothesized that in marginal thiamin deficiency intracellular alpha-oxoaldehydes form macromolecular adducts that could possibly be genotoxic in colon cells; and that in the presence of oxidative stress these effects are augmented because of decreased detoxification of these aldehydes. We have demonstrated that reduced dietary thiamin in F344 rats decreased transketolase activity and increased alpha-oxoaldehyde adduct levels. The methylglyoxal protein adduct level was not affected by oral glyoxal or methylglyoxal in the animals receiving thiamin at the control levels but was markedly increased in the animals on a thiamin-reduced diet. These observations are consistent with our suggestion that the induction of aberrant crypt foci with marginally thiamin-deficient diets may be a consequence of the formation of methylglyoxal adducts.
Assuntos
Aldeídos/sangue , Proteínas Sanguíneas/análise , Estresse Oxidativo , Deficiência de Tiamina/enzimologia , Transcetolase/metabolismo , Aldeídos/química , Animais , Proteínas Sanguíneas/química , Proteínas Sanguíneas/efeitos dos fármacos , Regulação para Baixo , Glioxal/sangue , Glioxal/farmacologia , Masculino , Aldeído Pirúvico/sangue , Aldeído Pirúvico/farmacologia , Ratos , Ratos Endogâmicos F344 , Tiamina/farmacologiaRESUMO
Polyethylene glycol 8000 inhibits the formation of tumors and of aberrant crypt foci (ACF) in carcinogen-initiated rats. We asked: is the inhibition associated with a reduction of colonic inflammation and an increase in colonic cell permeability? Twenty-eight, male F 344 rats were divided into two groups, 10 control animals and 18 animals initiated with azoxymethane. Nine of the rats in the carcinogen-initiated group were given a diet with 5% PEG 8000 in an AIN-93 based, high fat diet. The other nine, and the control group received the diet without the addition of PEG. Nine weeks later, the rats receiving the diet containing PEG had a 43% reduction in ACF (P<0.001) compared with the carcinogen-initiated rats on the control diet, a result confirming earlier observations that PEG inhibits colon carcinogenesis. The animals receiving the diet containing PEG also had a 10-fold reduction in fecal granulocyte marker protein (GMP) (P<0.001) compared with both the carcinogen-treated and the control animals. PEG reduced inflammation below the levels of carcinogen-treated and of untreated animals. Fecal water from the rats receiving PEG did not reduce transepithelial resistance of, or manitol flux through, human Caco-cells grown as monolayers in vitro. PEG may reduce colon carcinogenesis through a mechanism involving colonic inflammation.
Assuntos
Neoplasias do Colo/prevenção & controle , Inflamação , Polietilenoglicóis/farmacologia , Lesões Pré-Cancerosas/prevenção & controle , Solventes/farmacologia , Administração Oral , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Células CACO-2 , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/veterinária , Humanos , Masculino , Permeabilidade , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos Endogâmicos F344RESUMO
Thiamin deficiency leads to the endogenous formation of genotoxic alpha-oxoaldehydes (glyoxals). To evaluate whether marginal deficiency poses a carcinogenesis risk we fed rats AIN-76A sucrose-based diets containing thiamin at 4.9 (control), 1.6 or 1.0 mg/kg diet and examined their colons after 160 days. Reduced thiamin increased aberrant crypt foci (ACF) from 1.14+/-0.46 to 3.70+/-1.17 and 2.60+/-1.02 ACF/colon in the absence of exogenous carcinogen or of symptoms of beriberi. Since typical Western diets can provide marginal levels of thiamin with high levels of simple sugars, individuals could be exposed to an increased risk of colon and perhaps other cancers.
Assuntos
Colo/patologia , Dieta , Deficiência de Tiamina/patologia , Animais , Peso Corporal , Neoplasias do Colo/etiologia , Masculino , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Endogâmicos F344RESUMO
Corpet and Pierre (D. E. Corpet and F. Pierre, Cancer Epidemiol. Biomark. Prev., 12: 391-400, 2003) have reviewed the prevention studies made with the azoxymethane rat and Min mouse colon cancer models, and have shown that many agents reduce the numbers of these experimental tumors. They suggest that agents with preventive activity with little or no toxicity should be evaluated in clinical intervention studies without delay. I think that the decision to proceed to a clinical trial is more complex, and involves an understanding of the safety of the agent and of the strength and consistency of the preclinical data. However, I am also impressed by the wide range of agents that have been found to affect the development of colon cancer in animals. This suggests that human colon cancer may be the consequence of many different dietary and lifestyle deficiencies, a view supported by the observation that normal mice develop colon cancer when fed diets deficient in several food components known to prevent tumors with the azoxymethane rat model [Newmark, H. L. et al., Carcinogenesis (Lond.), 22: 1871-1875, 2001]. There is a clear need to evaluate the preventive effects of additional combinations of these agents, identified perhaps from the Corpet and Pierre review (D. E. Corpet and F. Pierre, Cancer Epidemiol. Biomark. Prev., 12: 391-400, 2003), or from actual human high-risk diets. With diets that increase the risk of "spontaneous cancer" in hand, the stage would be set for assessing the most effective ways to reduce colon cancer risk, again first with animal studies, then clinical trials, and then perhaps population studies.
Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias do Colo/prevenção & controle , Dieta , Modelos Animais de Doenças , Lesões Pré-Cancerosas/prevenção & controle , Animais , Azoximetano , Quimioprevenção , Neoplasias do Colo/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Camundongos Mutantes , Lesões Pré-Cancerosas/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , RatosRESUMO
The similarity in lifestyle risk factors for the development of colorectal cancer (CRC) and type 2 diabetes suggests that there are common underlying pathogenic mechanisms. High-risk lifestyle factors may lead to insulin resistance that, through increased circulating levels of energy substrates, insulin, and insulin-like growth factor-1, may promote the development of CRC. The objective was to determine the extent to which direct and surrogate measures of insulin resistance correlate with multiplicity of aberrant crypt foci, which are putative precursors of CRC. Rats were initiated with the carcinogen azoxymethane, then fed low, intermediate, or high saturated fat diets. Metabolic parameters were assessed at 50 days and ACF at 100 days after initiation. Results indicate that CRC promotion was most strongly correlated with direct measures of insulin sensitivity as assessed with the hyperinsulinemic-euglycemic clamp (r = -0.52, P < 0.009). Practical surrogate measures of insulin resistance such as insulin levels at 180 min after an oral glucose load were strongly correlated with direct measures of insulin sensitivity (r = -0.61, P < 0.001) and with CRC promotion (r = 0.42, P = 0.044) in this animal model. Fasting levels of glucose, insulin, total insulin-like growth factor-1, nonesterified fatty acids, and triglyceride, as well as body weight and insulin sensitivity indices (such as fasting insulin resistance index, quantitative insulin sensitivity check index, homeostasis model assessment formula, insulin sensitivity index of glycemia, oral glucose insulin sensitivity, and composite insulin sensitivity index for the hepatic and peripheral tissues) were all less strongly correlated with direct measures of insulin sensitivity and all poorly correlated with CRC promotion in this animal model. These correlations do not prove causality, however, they suggest possible mechanisms linking diet, insulin resistance with its related parameters, and promotion of CRC.