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1.
NPJ Sci Food ; 8(1): 43, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956092

RESUMO

The haemoglobin content in meat is consistently associated with an increased risk of colorectal cancer, whereas calcium may play a role as a chemopreventive agent. Using rodent models, calcium salts have been shown to prevent the promotion of haem-induced and red meat-induced colorectal carcinogenesis by limiting the bioavailability of the gut luminal haem iron. Therefore, this study aimed to compare impacts of dietary calcium provided as calcium salts or dairy matrix on gut homoeostasis perturbations by high haeminic or non-haeminic iron intakes. A 3-week intervention study was conducted using Fischer 344 rats. Compared to the ferric citrate-enriched diet, the haemoglobin-enriched diet led to increased faecal, mucosal, and urinary lipoperoxidation-related biomarkers, resulting from higher gut luminal haem iron bioavailability. This redox imbalance was associated to a dysbiosis of faecal microbiota. The addition of calcium to haemoglobin-enriched diets limited haem iron bioavailability and counteracted redox imbalance, with improved preventive efficacy when calcium was provided in dairy matrix. Data integration revealed correlations between haem-induced lipoperoxidation products and bacterial communities belonging to Peptococcaceae, Eubacterium coprostanoligenes group, and Bifidobacteriaceae. This integrated approach provides evidence of the benefits of dairy matrix as a dietary calcium vehicle to counteract the deleterious side-effects of meat consumption.

2.
Talanta ; 276: 126230, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38762974

RESUMO

Colorectal cancer (CRC) is the third most common cancer in the world with a higher prevalence in the developed countries, mainly caused by environmental and lifestyle factors such as diet, particularly red meat consumption. The metabolic impact of high red meat consumption on the epithelial part of the colon was investigated using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MSI), to specifically analyze the epithelial substructure. Ten colons from rats fed for 100 days high red or white meat diet were subjected to untargeted MSI analyses using two spatial resolutions (100 µm and 10 µm) to evaluate metabolite changes in the epithelial part and to visualize the distribution of metabolites of interest within the epithelium crypts. Our results suggest a specific effect of red meat diet on the colonic epithelium metabolism, as evidenced by an increase of purine catabolism products or depletion in glutathione pool, reinforcing the hypothesis of increased oxidative stress with red meat diet. This study also highlighted cholesterol sulfate as another up-regulated metabolite, interestingly localized at the top of the crypts. Altogether, this study demonstrates the feasibility and the added value of using MSI to decipher the effect of high red meat diet on the colonic epithelium.


Assuntos
Colo , Metabolômica , Carne Vermelha , Animais , Colo/metabolismo , Carne Vermelha/análise , Ratos , Metabolômica/métodos , Masculino , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Metaboloma , Dieta
3.
Sci Rep ; 14(1): 10905, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740939

RESUMO

Cancer-derived cell lines are useful tools for studying cellular metabolism and xenobiotic toxicity, but they are not suitable for modeling the biological effects of food contaminants or natural biomolecules on healthy colonic epithelial cells in a normal genetic context. The toxicological properties of such compounds may rely on their oxidative properties. Therefore, it appears to be necessary to develop a dual-cell model in a normal genetic context that allows to define the importance of oxidative stress in the observed toxicity. Given that the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is considered to be the master regulator of antioxidant defenses, our aim was to develop a cellular model comparing normal and Nrf2-depleted isogenic cells to qualify oxidative stress-related toxicity. We generated these cells by using the CRISPR/Cas9 technique. Whole-genome sequencing enabled us to confirm that our cell lines were free of cancer-related mutations. We used 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product closely related to oxidative stress, as a model molecule. Here we report significant differences between the two cell lines in glutathione levels, gene regulation, and cell viability after HNE treatment. The results support the ability of our dual-cell model to study the role of oxidative stress in xenobiotic toxicity.


Assuntos
Células Epiteliais , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Animais , Camundongos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Aldeídos/metabolismo , Glutationa/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular , Sistemas CRISPR-Cas , Peroxidação de Lipídeos/efeitos dos fármacos
4.
PLoS One ; 19(4): e0302932, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38669265

RESUMO

INTRODUCTION: Recent studies have shown that epithelial-stromal interactions could play a role in the development of colorectal cancer. Here, we investigated the role of fibroblasts in the transformation of normal colonocytes induced by 4-HNE. METHODS: Normal Co colonocytes and nF fibroblasts from the same mouse colon were exposed, in monoculture (m) or coculture (c), to 4-HNE (5 µM) twice weekly for 3 weeks. Gene expression was then analysed and the ability of Co colonocytes to grow in anchorage-independent conditions was tested in soft agar. Fibroblasts previously treated or not with 4-HNE were also seeded in culture inserts positioned above the agar layers to allow paracrine exchanges with colonocytes. RESULTS: First, 60% of the genes studied were modulated by coculture in Co colonocytes, with notably increased expression of BMP receptors. Furthermore, while 4-HNE increased the ability of monoculture-treated Co colonocytes to form colonies, this effect was not observed in coculture-treated Co colonocytes. Adding a selective BMPR1 inhibitor during the treatment phase abolished the protective effect of coculture. Conversely, addition of a BMP4 agonist to the medium of monoculture-treated Co colonocytes prevented phenotypic transformation by 4-HNE. Second, the presence of nF(m)-HNE fibroblasts during the soft agar assay increased the number and size of Co(m) colonocyte colonies, regardless of whether these cells had been previously treated with 4-HNE in monoculture. For soft agar assays performed with nF(c) and Co(c) cells initially treated in coculture, only the reassociation between Co(c)-HNE and nF(c)-HNE resulted in a small increase in the number of colonies. CONCLUSIONS: During the exposure phase, the epithelial-mesenchymal interaction protected colonocytes from 4-HNE-induced phenotypic transformation via activation of the BMP pathway. This intercellular dialogue also limited the ability of fibroblasts to subsequently promote colonocyte-anchorage-independent growth. In contrast, fibroblasts pre-exposed to 4-HNE in monoculture strongly increased the ability of Co(m) colonocytes to form colonies.


Assuntos
Aldeídos , Proteína Morfogenética Óssea 4 , Técnicas de Cocultura , Colo , Transição Epitelial-Mesenquimal , Fibroblastos , Animais , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Camundongos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Proteína Morfogenética Óssea 4/metabolismo , Aldeídos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fenótipo , Transformação Celular Neoplásica/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/citologia
5.
NPJ Sci Food ; 7(1): 53, 2023 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-37805637

RESUMO

Epidemiological and experimental evidence indicated that processed meat consumption is associated with colorectal cancer risks. Several studies suggest the involvement of nitrite or nitrate additives via N-nitroso-compound formation (NOCs). Compared to the reference level (120 mg/kg of ham), sodium nitrite removal and reduction (90 mg/kg) similarly decreased preneoplastic lesions in F344 rats, but only reduction had an inhibitory effect on Listeria monocytogenes growth comparable to that obtained using the reference nitrite level and an effective lipid peroxidation control. Among the three nitrite salt alternatives tested, none of them led to a significant gain when compared to the reference level: vegetable stock, due to nitrate presence, was very similar to this reference nitrite level, yeast extract induced a strong luminal peroxidation and no decrease in preneoplastic lesions in rats despite the absence of NOCs, and polyphenol rich extract induced the clearest downward trend on preneoplastic lesions in rats but the concomitant presence of nitrosyl iron in feces. Except the vegetable stock, other alternatives were less efficient than sodium nitrite in reducing L. monocytogenes growth.

6.
J Steroid Biochem Mol Biol ; 232: 106346, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37321513

RESUMO

Cholesterol plays important roles in many physiological processes, including cell membrane structure and function, hormone synthesis, and the regulation of cellular homeostasis. The role of cholesterol in breast cancer is complex, and some studies have suggested that elevated cholesterol levels may be associated with an increased risk of developing breast cancer, while others have found no significant association. On the other hand, other studies have shown that, for total cholesterol and plasma HDL-associated cholesterol levels, there was inverse association with breast cancer risk. One possible mechanism by which cholesterol may contribute to breast cancer risk is as a key precursor of estrogen. Other potential mechanisms by which cholesterol may contribute to breast cancer risk include its role in inflammation and oxidative stress, which have been linked to cancer progression. Cholesterol has also been shown to play a role in signaling pathways regulating the growth and proliferation of cancer cells. In addition, recent studies have shown that cholesterol metabolism can generate tumor promoters such as cholesteryl esters, oncosterone, 27-hydroxycholesterol but also tumor suppressor metabolites such as dendrogenin A. This review summarizes some of the most important clinical studies that have evaluated the role of cholesterol or its derivatives in breast cancer. It also addresses the role of cholesterol and its derivatives at the cellular level.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Incidência , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Fatores de Risco
7.
Mol Nutr Food Res ; 67(5): e2200432, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36647294

RESUMO

SCOPE: High red and processed meat consumption is associated with several adverse outcomes such as colorectal cancer and overall global mortality. However, the underlying mechanisms remain debated and need to be elucidated. METHODS AND RESULTS: Urinary untargeted Liquid Chromatography-Mass Spectrometry (LC-MS) metabolomics data from 240 subjects from the French cohort NutriNet-Santé are analyzed. Individuals are matched and divided into three groups according to their consumption of red and processed meat: high red and processed meat consumers, non-red and processed meat consumers, and at random group. Results are supported by a preclinical experiment where rats are fed either a high red meat or a control diet. Microbiota derived metabolites, in particular indoxyl sulfate and cinnamoylglycine, are found impacted by the high red meat diet in both studies, suggesting a modification of microbiota by the high red/processed meat diet. Rat microbiota sequencing analysis strengthens this observation. Although not evidenced in the human study, rat mercapturic acid profile concomitantly reveals an increased lipid peroxidation induced by high red meat diet. CONCLUSION: Novel microbiota metabolites are identified as red meat consumption potential biomarkers, suggesting a deleterious effect, which could partly explain the adverse effects associated with high red and processed meat consumption.


Assuntos
Microbiota , Carne Vermelha , Humanos , Ratos , Animais , Dieta , Carne , Metaboloma
8.
Am J Clin Nutr ; 116(4): 911-919, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36055962

RESUMO

BACKGROUND: Acrylamide is classified as a probable human carcinogen by the International Agency for Research on Cancer but epidemiologic evidence on the carcinogenicity of acrylamide from dietary sources is limited. OBJECTIVES: This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort, accounting for menopausal and hormone receptor status. METHODS: This prospective cohort study included 80,597 French females (mean ± SD age at baseline: 40.8 ± 14 y) during a mean ± SD follow-up of 8.8 ± 2.3 y. Acrylamide intake was evaluated using repeated 24-h dietary records (n ± SD = 5.5 ± 3.0), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal, and postmenopausal) were assessed by Cox hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). RESULTS: The mean ± SD dietary acrylamide intake was 30.1 ± 21.9 µg/d (main contributors: coffee, potato fries and chips, pastries, cakes, bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between dietary acrylamide exposure and breast cancer risk overall (HR for quartile 4 compared with 1: 1.21; 95% CI: 1.00, 1.47) and a positive association was observed with premenopausal cancer (HRQ4vs.Q1: 1.40; 95% CI: 1.04, 1.88). Restricted cubic spline analyses suggested evidence for nonlinearity of these associations, with higher HRs for intermediate (quartile 2) and high (quartile 4) exposures. Receptor-specific analyses revealed positive associations with estrogen receptor-positive breast cancer (total and premenopausal). Acrylamide intake was not associated with postmenopausal breast cancer. CONCLUSIONS: Results from this large prospective cohort study suggest a positive association between dietary acrylamide and breast cancer risk, especially in premenopausal females, and provide new insights that support continued mitigation strategies to reduce the content of acrylamide in food.This trial was registered at clinicaltrials.gov as NCT03335644.


Assuntos
Neoplasias da Mama , Acrilamida/toxicidade , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Carcinógenos , Café , Estudos de Coortes , Dieta , Exposição Dietética , Feminino , Hormônios , Humanos , Estudos Prospectivos , Receptores de Estrogênio , Fatores de Risco
9.
Cell Mol Life Sci ; 79(6): 284, 2022 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-35526196

RESUMO

BACKGROUND AND AIMS: Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of colorectal cancer (CRC). To overcome treatment resistance, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new inhibitor of NCLX. METHODS: We examined whether curcumin and pharmacological compounds induced the inhibition of NCLX-mediated mitochondrial calcium (mtCa2+) extrusion, the role of redox metabolism in this process. We evaluated their anti-tumorigenic activity in vitro and in a xenograft mouse model. We analyzed NCLX expression and associations with survival in The Cancer Genome Atlas (TCGA) dataset and in tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC. RESULTS: In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis. NCLX inhibition with pharmacological and molecular approaches reproduced the effects of curcumin. NCLX inhibitors decreased CRC tumor growth in vivo. Both transcriptomic analysis of TCGA dataset and immunohistochemical analysis of tissue microarrays demonstrated that higher NCLX expression was associated with MSI status, and for the first time, NCLX expression was significantly associated with recurrence-free survival. CONCLUSIONS: Our findings highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic schedule of patients with MSI CRC.


Assuntos
Neoplasias Colorretais , Curcumina , Instabilidade de Microssatélites , Trocador de Sódio e Cálcio , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Curcumina/farmacologia , Humanos , Camundongos , Repetições de Microssatélites , Proteínas Mitocondriais/metabolismo , Trocador de Sódio e Cálcio/antagonistas & inibidores
10.
Antioxidants (Basel) ; 10(8)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439509

RESUMO

Lipid peroxidation and subsequent formation of toxic aldehydes, such as 4-hydroxynonenal, is known to be involved in numerous pathophysiological processes, possibly including the development of colorectal cancer. This work aimed at the development of an untargeted approach using high-performance liquid chromatography coupled with high-resolution mass spectrometry (HPLC-HRMS) for tracking aldehydes in both suspect screening and untargeted methods in fecal water, representing the aqueous environment of colon epithelial cells. This original approach is based on the introduction of a characteristic isotopic labeling by selective derivatization of the carbonyl function using a brominated reagent. Following a metabolomics workflow, the developed methodology was applied to the characterization of aldehyde compounds formed by lipid peroxidation in rats fed two different diets differentially prone to lipoperoxidation. Derivatized aldehydes were first selectively detected on the basis of their isotopic pattern, then annotated and finally identified by tandem mass spectrometry. This original approach allowed us to evidence the occurrence of expected aldehydes according to their fatty acid precursors in the diet, and to characterize other aldehydes differentiating the different diets.

11.
Nutrients ; 13(5)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063614

RESUMO

An economic experiment was conducted in France in 2020 to evaluate consumer attitudes toward two ham products associated with different colorectal cancer risks. We focused specifically on comparing a conventional ham and a new hypothetical antioxidant-enriched ham with a reduced risk of provoking colorectal cancer. Study participants were given descriptions of the two hams before carrying out successive rounds of willingness-to-pay (WTP) assessments. The results show that WTP was higher for the antioxidant-enriched ham than for the conventional ham. WTP estimates were also impacted by providing additional information about the reduction in colorectal cancer risk associated with the antioxidant-enriched ham. Based on the participants' WTP, we came up with ex ante estimates for the social impacts of introducing the antioxidant-enriched ham onto the market, and we suggest that it would be socially optimal to promote the product. Competition arising from pre-existing product labelling and marketing assertions could greatly limit the market potential of antioxidant-enriched ham, which suggests that alternative approaches may be necessary, such as regulations mandating antioxidant enrichment. These results also concern all countries with high levels of meat consumption.


Assuntos
Neoplasias Colorretais/prevenção & controle , Comportamento do Consumidor/economia , Preferências Alimentares/psicologia , Alimentos Fortificados/economia , Carne de Porco/economia , Adulto , Antioxidantes , Comportamento de Escolha , Comércio , Dieta Saudável/economia , Dieta Saudável/psicologia , Feminino , Alimentos Fortificados/análise , França , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Carne de Porco/análise , Adulto Jovem
12.
Metabolomics ; 17(1): 2, 2021 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-33389209

RESUMO

INTRODUCTION: Because of its ease of collection, urine is one of the most commonly used matrices for metabolomics studies. However, unlike other biofluids, urine exhibits tremendous variability that can introduce confounding inconsistency during result interpretation. Despite many existing techniques to normalize urine samples, there is still no consensus on either which method is most appropriate or how to evaluate these methods. OBJECTIVES: To investigate the impact of several methods and combinations of methods conventionally used in urine metabolomics on the statistical discrimination of two groups in a simple metabolomics study. METHODS: We applied 14 different strategies of normalization to forty urine samples analysed by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). To evaluate the impact of these different strategies, we relied on the ability of each method to reduce confounding variability while retaining variability of interest, as well as the predictability of statistical models. RESULTS: Among all tested normalization methods, osmolality-based normalization gave the best results. Moreover, we demonstrated that normalization using a specific dilution prior to the analysis outperformed post-acquisition normalization. We also demonstrated that the combination of various normalization methods does not necessarily improve statistical discrimination. CONCLUSIONS: This study re-emphasized the importance of normalizing urine samples for metabolomics studies. In addition, it appeared that the choice of method had a significant impact on result quality. Consequently, we suggest osmolality-based normalization as the best method for normalizing urine samples. TRIAL REGISTRATION NUMBER: NCT03335644.


Assuntos
Interpretação Estatística de Dados , Metabolômica/métodos , Concentração Osmolar , Urinálise/métodos , Líquidos Corporais/metabolismo , Cromatografia Líquida , Humanos , Biópsia Líquida , Espectrometria de Massas , Metaboloma , Metabolômica/normas , Urinálise/normas
13.
Eur J Nutr ; 60(4): 1887-1896, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32889607

RESUMO

PURPOSE: Red and processed meats are recognized by the International Agency for Research on Cancer as probably carcinogenic and carcinogenic to humans, respectively. Heme iron has been proposed as a central factor responsible for this effect. Furthermore, anxiety affects the intestinal barrier function by increasing intestinal permeability. The objective of this work was to assess how anxiety modifies the association between red and processed meat consumption and cancer risk in the NutriNet-Santé prospective cohort (2009-2019). METHODS: Using multi-adjusted Cox models in a sample of 101,269 subjects, we studied the associations between the consumption of red and processed meat, the amount of heme iron coming from these meats and overall, colorectal, prostate, and breast cancer risks, overall and separately among participants with and without anxiety. RESULTS: An increase in red and processed meat consumption was associated with an increased risk of developing colorectal cancer in the total population (HR for an increase of 50 g/day = 1.18 (1.01-1.37), p = 0.03). After stratification on anxiety, the HR 50 g/day was 1.42 (1.03-1.94, p = 0.03) in anxious participants and 1.12 (0.94-1.33, p = 0.20) in other participants. Similar trends were observed for overall cancer risk. Analyses conducted with heme iron also provided similar results. CONCLUSIONS: Our results strengthen the existing body of evidence supporting that red and processed meat consumption and heme iron intake are associated with an increased risk of overall and more specifically colorectal cancer, and suggest that anxiety modifies these associations, with an increased risk in anxious participants.


Assuntos
Neoplasias da Mama , Produtos da Carne , Carne Vermelha , Ansiedade/epidemiologia , Ansiedade/etiologia , Estudos de Coortes , Dieta/efeitos adversos , Feminino , Humanos , Masculino , Carne , Estudos Prospectivos , Fatores de Risco
14.
Antioxidants (Basel) ; 9(12)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348697

RESUMO

Some epidemiological studies show that heme iron consumption, in red meat, is associated to the development of several chronic diseases, including cancers and cardio-metabolic diseases. As heme iron intestinal absorption is finely regulated, we hypothesized that heme iron may act indirectly, through the peroxidation of dietary lipids, in food or in the intestinal lumen during digestion. This heme-iron-induced lipid peroxidation provokes the generation of toxic lipid oxidation products that could be absorbed, such as 4-hydroxynonenal (HNE). In a first experiment, heme iron given to rats by oral gavage together with the linoleic-acid-rich safflower oil induced the formation of HNE in the intestinal lumen. The HNE major urinary metabolite was elevated in the urine of the treated rats, indicating that this compound has been absorbed. In a second experiment, we showed that stable isotope-labeled HNE given orally to rats was able to reach non-intestinal tissues as a bioactive form and to make protein-adducts in heart, liver and skeletal muscle tissues. The presence of HNE-protein adducts in those tissues suggests a putative biological role of diet-originating HNE in extra-intestinal organs. This finding could have major consequences on the onset/development of chronic diseases associated with red meat over-consumption, and more largely to peroxidation-prone food consumption.

15.
Anal Chem ; 92(2): 1746-1754, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31854978

RESUMO

Among the numerous unknown metabolites representative of our exposure, focusing on toxic compounds should provide more relevant data to link exposure and health. For that purpose, we developed and applied a global method using data independent acquisition (DIA) in mass spectrometry to profile specifically electrophilic compounds originating metabolites. These compounds are most of the time toxic, due to their chemical reactivity toward nucleophilic sites present in biomacromolecules. The main line of cellular defense against these electrophilic molecules is conjugation to glutathione, then metabolization into mercapturic acid conjugates (MACs). Interestingly, MACs display a characteristic neutral loss in MS/MS experiments that makes it possible to detect all the metabolites displaying this characteristic loss, thanks to the DIA mode, and therefore to highlight the corresponding reactive metabolites. As a proof of concept, our workflow was applied to the toxicological issue of the oxidation of dietary polyunsaturated fatty acids, leading in particular to the formation of toxic alkenals, which lead to MACs upon glutathione conjugation and metabolization. By this way, dozens of MACs were detected and identified. Interestingly, multivariate statistical analyses carried out only on extracted HRMS signals of MACs yield a better characterization of the studied groups compared to results obtained from a classic untargeted metabolomics approach.


Assuntos
Acetilcisteína/metabolismo , Aldeídos/metabolismo , Acetilcisteína/análise , Acetilcisteína/urina , Aldeídos/química , Aldeídos/urina , Animais , Masculino , Metabolômica , Estrutura Molecular , Análise Multivariada , Ratos , Ratos Endogâmicos F344 , Espectrometria de Massas em Tandem
16.
Trials ; 20(1): 688, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31815647

RESUMO

BACKGROUND: Convincing evidence suggests that the risk of colorectal cancer (CRC) is increased by the typical Western diet characterized by high consumption of red and processed meat. In addition, some epidemiological studies suggest a reduction in the risk of CRC associated with fish consumption. The role of the gut microbiome in this diet-associated risk is not well understood. METHODS/DESIGN: This is a randomized parallel open clinical trial comprising a total of 150 clinically healthy subjects randomly assigned to three groups: a meat-based diet of which 4 portions per week are red meat (1 portion = 150 g), 3 portions per week are processed meat (1 portion = 50 g), and 1 portion per week is poultry (1 portion = 150 g), for a total amount of 900 g per week of meat and derivatives; a meat-based diet supplemented with alpha-tocopherol; and a pesco-vegetarian diet excluding fresh and processed meat and poultry, but which includes 3 portions per week of fish for a total amount of 450 g per week. Each intervention will last 3 months. The three diets will be isocaloric and of three different sizes according to specific energy requirements. Anthropometric measurements, body composition, and blood and fecal samples will be obtained from each participant at the beginning and end of each intervention phase. The measure of the primary outcome will be the change from baseline in DNA damage induced by fecal water using the comet assay in a cellular model. Secondary outcome measures will be changes in the profile of fecal microbiomes, global fecal and urinary peroxidation markers, and neoplastic biomarkers. DISCUSSION: Although epidemiological data support the promoting role of meat and the possible protective role of fish in colon carcinogenesis, no study has directly compared dietary profiles characterized by the presence of these two food groups and the role of the gut microbiome in these diet-associated CRC risks. This study will test the effect of these dietary profiles on validated CRC risk biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03416777. Registered on 3 May 2018.


Assuntos
Neoplasias Colorretais/etiologia , Dieta Vegetariana , Fezes/microbiologia , Microbioma Gastrointestinal , Carne , Adolescente , Adulto , Neoplasias Colorretais/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Risco , Adulto Jovem
17.
Microbiome ; 7(1): 72, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060614

RESUMO

BACKGROUND: The World Health Organization classified processed and red meat consumption as "carcinogenic" and "probably carcinogenic", respectively, to humans. Haem iron from meat plays a role in the promotion of colorectal cancer in rodent models, in association with enhanced luminal lipoperoxidation and subsequent formation of aldehydes. Here, we investigated the short-term effects of this haem-induced lipoperoxidation on mucosal and luminal gut homeostasis including microbiome in F344 male rats fed with a haem-enriched diet (1.5 µmol/g) 14-21 days. RESULTS: Changes in permeability, inflammation, and genotoxicity observed in the mucosal colonic barrier correlated with luminal haem and lipoperoxidation markers. Trapping of luminal haem-induced aldehydes normalised cellular genotoxicity, permeability, and ROS formation on a colon epithelial cell line. Addition of calcium carbonate (2%) to the haem-enriched diet allowed the luminal haem to be trapped in vivo and counteracted these haem-induced physiological traits. Similar covariations of faecal metabolites and bacterial taxa according to haem-induced lipoperoxidation were identified. CONCLUSIONS: This integrated approach provides an overview of haem-induced modulations of the main actors in the colonic barrier. All alterations were closely linked to haem-induced lipoperoxidation, which is associated with red meat-induced colorectal cancer risk.


Assuntos
Aldeídos/metabolismo , Colo/metabolismo , Heme/administração & dosagem , Mucosa Intestinal/metabolismo , Ferro/metabolismo , Microbiota , Animais , Heme/metabolismo , Homeostase , Inflamação , Peróxidos Lipídicos/metabolismo , Masculino , Testes de Mutagenicidade , Ratos , Ratos Endogâmicos F344
18.
Eur J Nutr ; 58(4): 1515-1527, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29616321

RESUMO

PURPOSE: Lipid intakes such as saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids have been widely studied regarding cardiovascular health, but their relevance to cancer is unclear. Inconsistent epidemiological results may be explained by varied mechanisms involving PUFAs and redox balance, inflammatory status and cell signalling, along with interactions with other dietary components such as antioxidants, dietary fibre and more generally fruits and vegetable intakes. Therefore, this study aimed to investigate the associations between lipid intakes and cancer risk, and their potential modulation by vitamin C, vitamin E, dietary fibre and fruit and vegetable intakes. METHODS: This prospective study included 44,039 participants aged ≥ 45 years from the NutriNet-Santé cohort (2009-2017). Dietary data were collected using repeated 24 h-dietary records. Multivariable Cox models were performed to characterize associations. RESULTS: SFA intake was associated with increased overall [n = 1722 cases, HRQ5vsQ1 = 1.44 (1.10-1.87), p-trend = 0.008] and breast [n = 545 cases, HRQ5vsQ1 = 1.98 (1.24-3.17), p-trend = 0.01] cancer risks. n-6 PUFA [HRQ5vsQ1 = 0.56 (0.32-0.97), p-trend = 0.01] and MUFA (HRQ5vsQ1 = 0.41 [0.18-0.0.95), p-trend = 0.009] intakes were associated with a decreased risk of digestive cancers (n = 190 cases). Associations between n-6 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intakes and digestive cancer risk were modulated by dietary fibre, vitamin C and fruit and vegetable intakes. CONCLUSION: These findings suggested that SFA intake could increase overall and breast cancer risks while some unsaturated fatty acids could decrease digestive cancer risk. However, in line with mechanistic hypotheses, our results suggest that intakes of fruits and vegetables and their constituents (antioxidants, fibre) may interact with PUFAs to modulate these associations.


Assuntos
Dieta/métodos , Gorduras na Dieta/administração & dosagem , Neoplasias/epidemiologia , Ácido Ascórbico/administração & dosagem , Estudos de Coortes , Registros de Dieta , Gorduras Insaturadas na Dieta , Feminino , França/epidemiologia , Frutas , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Verduras , Vitamina E/administração & dosagem , Vitaminas/administração & dosagem
19.
Cancer Prev Res (Phila) ; 11(9): 569-580, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29954759

RESUMO

Red meat is probably carcinogenic to humans (WHO/IARC class 2A), in part through heme iron-induced lipoperoxidation. Here, we investigated whether red meat promotes carcinogenesis in rodents and modulates associated biomarkers in volunteers, speculating that an antioxidant marinade could suppress these effects via limitation of the heme induced lipid peroxidation. We gave marinated or non-marinated beef with various degrees of cooking to azoxymethane-initiated rats, Min mice, and human volunteers (crossover study). Mucin-depleted foci were scored in rats, adenoma in Min mice. Biomarkers of lipoperoxidation were measured in the feces and urine of rats, mice, and volunteers. The organoleptic properties of marinated meat were tested. Fresh beef increased colon carcinogenesis and lipoperoxidation in rats and mice and lipoperoxidation in humans. Without an adverse organoleptic effect on meat, marinade normalized peroxidation biomarkers in rat and mouse feces, reduced peroxidation in human feces and reduced the number of Mucin-depleted foci in rats and adenoma in female Min mice. This could lead to protective strategies to decrease the colorectal cancer burden associated with red meat consumption. Cancer Prev Res; 11(9); 569-80. ©2018 AACR.


Assuntos
Carcinogênese/patologia , Neoplasias do Colo/prevenção & controle , Culinária , Peroxidação de Lipídeos/fisiologia , Carne Vermelha/efeitos adversos , Adulto , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Biomarcadores/análise , Carcinógenos/administração & dosagem , Neoplasias do Colo/etiologia , Estudos Cross-Over , Fezes/química , Feminino , Voluntários Saudáveis , Heme/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/prevenção & controle , Ratos , Ratos Endogâmicos F344
20.
Int J Cancer ; 143(9): 2168-2176, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29752709

RESUMO

Diverse plant products (e.g. fruits, vegetables, legumes) are associated with decreased cancer risk at several locations while red and processed meat were found to increase cancer risk. A pro plant-based dietary score reflecting the relative contribution of consumed plant vs animal products was developed, and was associated with lower overall mortality, type 2 diabetes and cardiovascular disease risk, among omnivorous adults. For the first time, we investigated the prospective associations between this pro plant-based dietary score and cancer risk. This study included 42,544 men and women of the French NutriNet-Santé prospective cohort (2009-2016) aged ≥45 years who completed at least three 24-hr-dietary records during the first year of follow-up. The risk of developing cancer was compared across sex-specific tertiles of pro plant-based dietary score by multivariable Cox models. In total, 1,591 first primary incident cancer cases were diagnosed during follow-up, among which 487 breast, 243 prostate, 198 digestive and 68 lung cancers. A higher pro plant-based dietary score was associated with decreased risks of overall (HRt3vs.t1 =0.85; 95% CI 0.76, 0.97; Ptrend =0.02), digestive (HRt3vs.t1 =0.68; 95% CI 0.47; 0.99; Ptrend = 0.04) and lung (HRt3vs.t1 =0.47; 95% CI 0.25, 0.90; Ptrend =0.02) cancer, though no substantial associations were found for breast or prostate cancers. This large cohort study supports a beneficial role of higher intakes of plant-based products along with lower intakes of animal products, within a balanced omnivorous diet, regarding primary cancer prevention. These results are consistent with mechanistic evidence from experimental studies.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta/efeitos adversos , Frutas , Carne/efeitos adversos , Neoplasias/mortalidade , Verduras , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/dietoterapia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
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