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Dietary polyunsaturated fatty acids and heme iron induce oxidative stress biomarkers and a cancer promoting environment in the colon of rats

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Abstract

The end products of polyunsaturated fatty acid (PUFA) peroxidation, such as malondialdehyde (MDA), 4-hydroxynonenal (HNE), and isoprostanes (8-iso-PGF2α), are widely used as systemic lipid oxidation/oxidative stress biomarkers. However, some of these compounds have also a dietary origin. Thus, replacing dietary saturated fat by PUFAs would improve health but could also increase the formation of such compounds, especially in the case of a pro-oxidant/antioxidant imbalanced diet. Hence, the possible impact of dietary fatty acids and pro-oxidant compounds was studied in rats given diets allowing comparison of the effects of heme iron vs. ferric citrate and of ω-6- vs. ω-3-rich oil on the level of lipid peroxidation/oxidative stress biomarkers. Rats given a heme iron-rich diet without PUFA were used as controls. The results obtained have shown that MDA and the major urinary metabolite of HNE (the mercapturic acid of dihydroxynonane, DHN-MA) were highly dependent on the dietary factors tested, while 8-iso-PGF2α was modestly but significantly affected. Intestinal inflammation and tissue fatty acid composition were checked in parallel and could only explain the differences we observed to a limited extent. Thus, the differences in biomarkers were attributed to the formation of lipid oxidation compounds in food or during digestion, their intestinal absorption, and their excretion into urine. Moreover, fecal extracts from the rats fed the heme iron or fish oil diets were highly toxic for immortalized mouse colon cells. Such toxicity can eventually lead to promotion of colorectal carcinogenesis, supporting the epidemiological findings between red meat intake and colorectal cancer risk.

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... Heme iron has also been linked to the onset of diabetes [7]. We have previously shown that dietary heme iron, but not ferric citrate given as the same iron molar concentration, could induce a cancer-promoting environment in the colon, through the luminal over-generation of cyto-and geno-toxic alkenals, among which 4-hydroxynonenal (HNE) seems to be the most important [8]. Recently, some authors reported the formation of HNE following heme-induced lipid peroxidation of oil-in-water emulsion, under in vitro gastric digestion conditions [9]. ...
... They were given tap water and commercial rat show ad libitum during this period. The quantities of hemin and safflower oil represented the amount given for a day in our previous experiments on hemin promotive effects on colorectal cancer [5,8], namely 18.8 mg of hemin in 1 g of safflower oil, corresponding to the quantities present in 20 g of a diet containing 5% safflower oil and 0.094% hemin. Two hemin treated rats and one control rat were sacrificed by progressive CO 2 inhalation at the different time points of the experiment: 1, 4, 8 and 24 h after the gavage. ...
... On the other hand, HHE that is formed upon omega-3 fatty acid peroxidation, was not found in the digestive tract and only in very limited amounts in the fecal waters of hemin treated rats ( Figure 2C), with a mean concentration of 25 ng/mL. This could be associated to an inflammatory process associated to heme iron and polyunsaturated fatty acid consumption [8,26] as peroxidation of dietary fatty acids could not be invoked, due to the absence of omega-3 fatty acid in safflower oil. ...
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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.
... In vivo models of red meat exposure and colon cancer promotion are summarized in Table 3. Many of the in vivo models evaluating an association among red meat exposure, potential for increased lipid peroxidation and neoplastic promotion utilized analysis of the composition of fecal water from heme fed rats (Sesink et al., 1999;Mirvish et al., 2008;Chenni et al., 2013;Guéraud et al., 2015;. It is important to remember that these studies did not evaluate exposure conditions that are representative of realistic human exposures to red meat; instead, the rats were given hemin or hemoglobin at levels that corresponded to 11-360,724 times the DGAC recommended total intake of meat. ...
... The authors noted a direct correlation between the cytotoxicity of the fecal water and the production of TBARS. Guéraud et al. (2015) fed rats experimental diet contained hemin at levels that exaggerated recommended meat intake by 54-fold along with various sources of lipid. End products of polyunsaturated fatty acid (PUFA) peroxidation such as MDA, HNE, and isoprostanes (8-iso-PGF2α), which are widely used as systemic lipid oxidation/oxidative stress biomarkers, were measured in urine. ...
... Many of the in vivo models evaluating an association between increased lipid peroxidation due to heme exposure and neoplastic promotion utilized analysis of the composition of fecal water from heme fed rats (Sesink et al., 1999;Mirvish et al., 2008;Chenni et al., 2013;Guéraud et al., 2015;. It is important to remember that these studies did not evaluate exposure conditions that are representative of realistic human exposures to red meat; instead, the rats were given hemin or hemoglobin at levels that correspond to 11-360,724 times the DGAC recommended total intake of meat. ...
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On October 26, 2015, IARC published a summary of their findings regarding the association of cancer with consumption of red meat or processed meat (IARC 2015a; The Lancet Oncology 2015). The Working Group concluded that there is limited evidence in human beings for carcinogenicity from the consumption of red meat and inadequate evidence in experimental animals for the carcinogenicity of consumption of red meat. Nevertheless, the working group concluded that there is strong mechanistic evidence by which ingestion of red meat can be linked to human colorectal cancer and assigned red meat to Group 2A "probably carcinogenic to humans". The Working Group cited supporting mechanistic evidence for multiple meat components, including those formed from meat processing, such as N-nitroso compounds (NOC) and heterocyclic aromatic amines, and the endogenous compound, heme iron. The mechanism of action with colorectal cancer for each of these components is different and so it is critical to evaluate the evidence for each component separately. Consequently, this review critically examined studies that investigated mechanistic evidence associated with heme iron to assess the weight of the evidence associating exposure to red meat with colorectal cancer. The evidence from in vitro studies utilized conditions that are not necessarily relevant for a normal dietary intake and thus do not provide sufficient evidence that heme exposure from typical red meat consumption would increase the risk of colon cancer. Animal studies utilized models that tested promotion of preneoplastic conditions utilizing diets low in calcium, high in fat combined with exaggerations of heme exposure that in many instances represented intakes that were orders of magnitude above normal dietary consumption of red meat. Finally, clinical evidence suggests that the type of NOC found after ingestion of red meat in humans consists mainly of nitrosyl iron and nitrosothiols, products that have profoundly different chemistries from certain N-nitroso species which have been shown to be tumorigenic through the formation of DNA adducts. In conclusion, the methodologies employed in current mechanistic studies of heme and colorectal cancer have not provided sufficient documentation that the mechanisms studied would contribute to an increased risk of promotion of preneoplasia or colon cancer at usual dietary intakes of red meat in the context of a normal diet.
... However, when beef was digested in combination with n-3 PUFA rich fish oil [6], or lard [5,7], a large increase in oxidative reactions was observed. In fact, most animal feeding studies demonstrating pro-oxidant effects of heme-Fe, blood sausage, or beef simultaneously included n-6 PUFA rich vegetable oils in their diet, such as 2-5% safflower oil [8][9][10][11], 4% corn oil [12] or 13.7-15% sunflower oil [13,14], whereas rats consuming heme-Fe with saturated coconut oil did not demonstrate increased oxidation in their intestines [9]. Likewise, when sunflower oil (13.7%) was added to a diet containing red meat (17.1%), rats had increased plasma levels of n-6 PUFA oxidation products and ox-LDL, along with a worsened endothelial dysfunction and atherosclerosis compared to rats on the experimental meat diet without added sunflower oil [14]. ...
... However, when beef was digested in combination with n-3 PUFA rich fish oil [6], or lard [5,7], a large increase in oxidative reactions was observed. In fact, most animal feeding studies demonstrating pro-oxidant effects of heme-Fe, blood sausage, or beef simultaneously included n-6 PUFA rich vegetable oils in their diet, such as 2-5% safflower oil [8][9][10][11], 4% corn oil [12] or 13.7-15% sunflower oil [13,14], whereas rats consuming heme-Fe with saturated coconut oil did not demonstrate increased oxidation in their intestines [9]. Likewise, when sunflower oil (13.7%) was added to a diet containing red meat (17.1%), rats had increased plasma levels of n-6 PUFA oxidation products and ox-LDL, along with a worsened endothelial dysfunction and atherosclerosis compared to rats on the experimental meat diet without added sunflower oil [14]. ...
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Oxidative reactions during cooking and gastrointestinal digestion of meat and fish lead to the formation of various lipid- and protein oxidation products, some of which are toxic. In the present study, it was investigated how the addition of 3% butter or oils affect lipid- and protein oxidation during cooking and in vitro digestion of meat (chicken thigh, chicken breast, beef) and fish (mackerel, cod). These muscle foods were selected based on their differences in heme-Fe and PUFA contents, and n-6/n-3 PUFA ratio, and therefore varying potential to form oxidation products during digestion. Without additional fat, mackerel digests displayed the highest n-3 PUFA oxidation (4-hydroxy-2-hexenal, propanal, thiobarbituric reactive acid substances), and chicken digests the highest n-6 PUFA oxidation (4-hydroxy-2-nonenal, hexanal), whereas both lipid- and protein oxidation (protein carbonyl compounds) were low in cod and beef digests. Lipid oxidative reactions were generally not altered by the addition of butter to any muscle matrix, whereas the addition of fish oil and safflower oil in different ratios (3:0, 2:1, 1:2, 0:3) as n-3 PUFA and n-6 PUFA source respectively, stimulated oxidative reactions, especially during digestion of beef. Since beef was considered the muscle matrix with the highest potential to stimulate oxidation in the added fat substrate, in a second experiment, beef was cooked and digested with 3% butter or seven commercial vegetable oils (sunflower-, maize-, peanut-, rapeseed-, olive-, rice bran- or coconut oil), all labeled ‘suitable for heating’. No relevant oxidative reactions were however observed during digestion of beef with any of these commercial vegetable oils.
... However, n-3 PUFAs are easily oxidized due to the presence of 6 double bonds, which makes these compounds susceptible to oxygen free radical attack (156). As a result, n-3 PUFAs are converted into malondialdehyde (MDA) and 4-oxo-2-nonenal (4-OHE) (156,157). Thus, MDA is a biomarker reflecting the oxidation of n-3 PUFAs in vivo, and urinary MDA concentration is commonly tested after the intake of n-3 PUFAs (157). Recently, GC-MS was applied to quantify the concentrations of n-3 PUFAs in blood samples (158). ...
... Importantly, 4-OHE was determined to induce gene mutations by forming 4-OHE-DNA adducts (160). A recent study found that fecal extracts from rats fed n-3 PUFAs plus dietary oxidants exhibited higher intestinal toxicities than those supplemented with dietary oxidants alone (157). Hence, diet should be controlled in cancer patients receiving n-3 PUFAs. ...
Article
Chemotherapy- or radiotherapy-related intestinal microbial dysbiosis is one of the main causes of intestinal mucositis. Cases of bacterial translocation into peripheral blood and subsequent sepsis occur as a result of dysfunction in the intestinal barrier. Evidence from recent studies depicts the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis, which creates an imbalance between beneficial and harmful bacteria in the gut. Decreases in beneficial bacteria can lead to a weakening of the resistance of the gut to harmful bacteria, resulting in robust activation of proinflammatory signaling pathways. For example, lipopolysaccharide (LPS)-producing bacteria activate the nuclear transcription factor-κB signaling pathway through binding with Toll-like receptor 4 on stressed epithelial cells, subsequently leading to secretion of proinflammatory cytokines. Nevertheless, various studies have found that the omega-3 (n-3) polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid and eicosapentaenoic acid can reverse intestinal microbial dysbiosis by increasing beneficial bacteria species, including Lactobacillus, Bifidobacterium, and butyrate-producing bacteria, such as Roseburia and Coprococcus. In addition, the n-3 PUFAs decrease the proportions of LPS-producing and mucolytic bacteria in the gut, and they can reduce inflammation as well as oxidative stress. Importantly, the n-3 PUFAs also exert anticancer effects in colorectal cancers. In this review, we summarize the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis and introduce the contributions of dysbiosis to the pathogenesis of intestinal mucositis. Next, we discuss how n-3 PUFAs could alleviate chemotherapy- or radiotherapy-related intestinal microbial dysbiosis. This review provides new insights into the clinical administration of n-3 PUFAs for the management of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis.
... An additional study also indicated a potential reduction in endoplasmic reticulum stress and metabolic stress in the liver by the plant polyphenols [62]. Another effect of plant antioxidants is that they help prevent lipid oxidation, especially for polyunsaturated fatty acids (PUFA) that are particularly susceptible to oxidative damage, resulting in lipid peroxidation of membrane phospholipids that can affect normal cellular functions [63][64][65][66]. The PBC with an antioxidant potential can be supplied through silage feeding, and studies usually show far higher concentrations in herbaceous species than in corn [67], with variations according to the botanical families, seasons, and production systems [68]. ...
... It was also shown that feeding lambs with silages containing sainfoin and red clover can improve the oxidative stability of the meat, as evidenced when meat was subjected to strong oxidative challenge, such as cooking and incubation with pro-oxidant catalysts [98]. This is particularly beneficial as meat with high PUFA and poor oxidative stability results in deterioration of its flavor, odor and color [64], and lipid oxidation end-products may facility carcinogenic processes in the colon [65]. ...
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Plant bioactive compounds (PBC) are widespread in the plant kingdom, including in forage species, but their impact on silage fermentation and ruminant use of PBC-containing silage has been under-researched. The beneficial effects of PBC include plant-protein protection against excessive degradation by tannins or polyphenol oxidase leading to reduced soluble nitrogen (N) and better N use efficiency by animals, reduced emissions of pollutants such as enteric methane (CH4), improved animal health through antimicrobial, anthelmintic or antioxidant activities, and positive effects on animal product quality—especially greater increased polyunsaturated fatty acid (PUFA) content. However, there are still gaps in the research that require an interdisciplinary effort to ensure a balanced approach that co-addresses the economic, environmental and health pillars of sustainability. Here we review the potential offered by PBC to improve silage quality, nutrient use efficiency, performances and health of ruminants, and product quality. In addition, we use an example of cross-fertilization between disciplines to show that incorporating PBC-containing legume species in grass silage can provide multiple and additive effects from silage fermentation to product quality.
... However as we recently reviewed (Tullberg & Undeland, 2021), the cytotoxicity and reactivity of the lipid oxidation markers followed in this study have been reported both in cell-and animal studies. For example, Guéraud et al. (2015) investigated the impact of a "peroxidable" diet on oxidative stress biomarkers in rats by giving them two edible oils (fish oil versus safflower oil) combined with heme iron or ferric citrate. Results showed that heme iron plus fish oil gave 5-fold as high MDA-levels compared to ferric citrate alone in the GI tract of the rats. ...
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The degradation of trout and bovine hemoglobin (Hb) and their pro-oxidant activities in washed cod muscle mince (WCM) were studied using simple pH-shifts to simulate gastrointestinal (GI) conditions (pH 7→6→3→7), as well as full static in vitro GI digestion. Following gastric acidification to pH 6, metHb formation increased, especially for trout Hb. Subsequent acidification to pH 3 promoted Hb unfolding and partial or complete heme group-loss. During full GI digestion, polypeptide/peptide analyses revealed more extensive Hb-degradation in the gastric than duodenal phase, without any species-differences. When digesting WCM +/-Hb, both Hbs strongly promoted malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE), and 4-hydroxy-2-nonenal (HNE) formation, peaking at the end of the gastric phase. Trout-Hb stimulated MDA and HHE more than bovine Hb in gastric phase 1. Altogether, partially degraded Hb, and/or free hemin -both mammal and fish-derived- stimulated oxidation of PUFA-rich lipids under GI-conditions, especially gastric ones.
... and glutathione peroxidase (GSH-Px) (10)(11) . Lipid oxidation products and metabolites such as malondialdehyde (MDA) can serve as markers of endogenous lipid peroxidation in tissues (12)(13) . ...
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The regulation of lipogenesis and lipolysis mechanisms related to consumption of lipid has not been studied in swimming crab. The aims of present study were to evaluate the effects of dietary lipid levels on growth, enzymes activities, and expression of genes of lipid metabolism in hepatopancreas of juvenile swimming crab. Three isonitrogenous diets were formulated to contain crude lipid levels at 5.8 %, 9.9 % and 15.1 %, respectively. Crabs fed the diet containing 15.1 % lipid had significantly lower weight gain, specific growth rate and survival, and higher feed conversion ratio than those fed the 5.8 % and 9.9 % lipid diets. Crabs fed 5.8 % lipid had lower malondialdehyde concentrations in the hemolymph and hepatopancreas than those fed the other diets. Highest glutathione peroxidase in hemolymph and superoxide dismutase in hepatopancreas were observed in crabs fed 5.8 % lipid. The lowest fatty acid synthase and glucose 6-phosphate dehydrogenase activities in hepatopancreas were observed in crabs fed 15.1 % lipid, whereas crabs fed 5.8 % lipid had lower carnitine palmitoyltransferase-1 activity than those fed the other diets. Crabs fed 15.1 % lipid showed lower hepatopancreas expression of genes involved in LC-PUFA biosynthesis, lipoprotein clearance, fatty acid uptake, fatty acid oxidation, lipid anabolism and lipid catabolism than those fed the other diets, whereas expression of some genes of lipoprotein assembly and fatty acid oxidation were up-regulated compared with crabs fed 5.8 % lipid. Overall, high dietary lipid level can inhibit growth, reduce feed utilization and reduce antioxidant enzyme activities. Moreover, dietary lipid influenced enzyme activities and gene expression involved in lipid metabolism of juvenile swimming crab.
... Several potential mechanisms likely account for the association between dietary heme iron intake and risk of CVD mortality. Increased dietary heme iron intake can induce oxidative stress biomarkers and lipid peroxidation 34,35 and has been found be associated with makers of inflammation. 36 All of these pathways can contribute to atherosclerosis development. ...
Article
Background and objectives: Many studies have investigated the association between dietary iron intake and death due to cardiovascular disease (CVD), but the results were inconsistent. We performed a dose-response meta- analysis to quantitatively assess the risk of CVD mortality with dietary intake of iron (total iron, heme iron, and non-heme iron). Methods and study design: PubMed and Embase databases were searched for articles published up to February 21, 2019. Prospective cohort studies were included if reporting relative risks (RRs) and 95% confidence intervals (CIs) for risk of CVD mortality associated with dietary iron intake. Restricted cubic splines were used to model the dose-response association. Results: We included eight articles (19 studies including 720,427 participants [46,045 deaths due to CVD]) in the meta-analysis. When comparing the highest versus lowest level of dietary heme iron intake, the pooled RR for CVD mortality was 1.19 (95% CI, 1.01-1.39). With a 1-mg/day increase in dietary heme iron intake, the pooled RR for death due to CVD, stroke, coronary heart disease, and myocardial infarction were 1.25 (95% CI, 1.17-1.33), 1.17 (1.04-1.32), 1.25 (0.70-2.22), and 1.17 (0.55-2.50) respectively. The association between dietary iron intake and CVD mortality was linear (pnonlinearity> 0.05). Conclusions: Higher dietary intake of heme iron was associated with a greater risk of CVD mortality. Reducing consumption of heme iron may help to prevent premature death due to CVD.
... Consequently, individualised predictive approach is essential to make the primary prevention targeted and costeffective [201,202]. One of the most ubiquitous stress factors is an imbalanced and/or unhealthy diet increasing the general predisposition to colon cancer [203]. Specifically, so-called Western Diet Pattern is characterised by high intake of processed meat, red meat, or high-fat dairy products [204] being associated with an increased risk of colon cancer [167,168]. ...
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Severe durable changes may occur to the DNA structure caused by exogenous and endogenous risk factors initiating the process of carcinogenesis. By evidence, a large portion of malignancies have been demonstrated as being preventable. Moreover, the targeted prevention of cancer onset is possible, due to unique properties of plant bioactive compounds. Although genoprotective effects of phytochemicals have been well documented, there is an evident lack of articles which would systematically present the spectrum of anticancer effects by phytochemicals, plant extracts, and plant-derived diet applicable to stratified patient groups at the level of targeted primary (cancer development) and secondary (cancer progression and metastatic disease) prevention. Consequently, clinical implementation of knowledge accumulated in the area is still highly restricted. To stimulate coherent co-development of the dedicated plant bioactive compound investigation on one hand and comprehensive cancer preventive strategies on the other hand, the current paper highlights and deeply analyses relevant evidence available in the area. Key molecular mechanisms are presented to detail genoprotective and anticancer activities of plants and phytochemicals. Clinical implementation is discussed. Based on the presented evidence, advanced chemopreventive strategies in the context of 3P medicine are considered.
... The suppression of colonic aberrant crypt foci formation has been established as a short-term assay to screen candidate compounds for chemo-preventive activity in colon carcinogenesis studies in rats. 25 MNU is a direct alkylating agent that does not require metabolic activation and is therefore an effective local carcinogen. 26,27 MNUinduced rat colorectal cancer models are widely used to elucidate researches involved in colorectal cancer carcinogenesis (initiation and progression) and chemo-preventive mechanisms. ...
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Background: Omega 3 polyunsaturated fatty acid (Omega-3PUFA) is one of the essential nutrients for human body involved in intracellular metabolic regulation and cell signaling. Previous studies have shown that Omega-3PUFA is involved in the pathogenesis of digestive system tumors, including colorectal cancer (CRC), however, the effects of Omega-3PUFA on CRC has not been fully elucidated. In the current study, we evaluated whether Omega-3PUFA can alleviate N-methyl-N-nitrosourea(MNU) induced CRC in a rat model and illustrated the potential mechanism. Methods: The effects of Omga-3PUFA on MNU-induced colorectal cancer in rats were analyzed by in vivo experiments. The viability, apoptosis, colony formation and invasion of CRC cells treated with Omga-3PUFA were detected by CCK8, flow cytometry, clone formation assay and transwell invasion assay. The expression of apoptosis-related proteins in CRC cells treated with Omga-3PUFA was detected by Western blotting. Finally, after adding PI3K activator, the viability, apoptosis and protein expression of CRC cells treated with Omga-3PUFA were detected by CCK8, flow cytometry and Western blotting. Results: Our results showed that Omega-3PUFA attenuated MNU-induced CRC in rats and inhibited AKT/Bcl-2 signaling in rats. In addition, Omega-3PUFA inhibited CRC cell proliferation and induces CRC cell apoptosis. Moreover, Omega-3PUFA inhibited CRC cell colony formation and invasion, and inhibited PI3K/AKT/Bcl-2 signaling in CRC cells. Furthermore, The effects of Omega-3PUFA on cell proliferation and apoptosis were inhibited by blocking PI3K/AKT signaling. Conclusion: Omega-3PUFA can attenuate MNU-induced colorectal cancer in rats by blocking PI3K/AKT/Bcl-2 signaling, which suggests that Omega-3PUFA may be a potent agent for CRC treatment.
... Markers of global peroxidation of fecal water (thiobarbituric acid reactive substances [TBARs]) and specific peroxidation of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) in fecal water changes from baseline [18,19]. The level of global and specific peroxidation will be explored with the assay of respectively free 4-hydroxy hexenal (4-HHE) and free 4hydroxy-2-nonenal (4-HNE). ...
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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.
... PPARδ promotes lipid accumulation in macrophages [45], and this may explain the high concentration of PUFAs and constant upregulation of PPARβ/δ in tumour-associated macrophages (TAMs) in ovarian cancer ascites [43], which play a pro-tumorigenic role in tumour microenvironment. This kind of fatty acid accumulated in TAM is now recognized as tumour promotor [46,47]. ...
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Accumulating evidence highlights the importance of interactions between tumour cells and stromal cells for tumour initiation, progression, and metastasis. In tumours that contain adipocyte in their stroma, adipocytes contribute to modification of tumour microenvironment and affect metabolism of tumour and tumour progression by production of cytokines and adipokines from the lipids. The omentum and bone marrow (BM) are highly adipocyte-rich and are also common metastatic and primary tumour developmental sites. Omental adipocytes exhibit metabolic cross-talk, immune modulation, and angiogenesis. BM adipocytes secrete adipokines, and participate in solid tumour metastasis through regulation of the CCL2/CCR2 axis and metabolic interactions. BM adipocytes also contribute to the progression of hematopoietic neoplasms. Here, we here provide an overview of research progress on the cross-talks between omental/BM adipocytes and tumour cells, which may be pivotal modulators of tumour biology, thus highlighting novel therapeutic targets. Abbreviations: MCP-1, monocyte chemoattractant protein 1IL, interleukinSTAT3, signal transducer and activator of transcription 3FABP4, fatty acid binding protein 4PI3K/AKT, phosphoinositide 3-kinase/protein kinase BPPAR, peroxisome proliferator-activated receptorPUFA, polyunsaturated fatty acidTAM, tumour-associated macrophagesVEGF, vascular endothelial growth factorVEGFR, vascular endothelial growth factor receptorBM, bone marrowBMA, bone marrow adipocytesrBMA, regulated BMAcBMA, constitutive BMAUCP-1, uncoupling protein-1TNF-α, tumour necrosis factor-alphaRANKL, receptor activator of nuclear factor kappa-Β ligandVCAM-1, vascular cell adhesion molecule 1JAK2, Janus kinase 2CXCL (C–X–C motif) ligandPGE2, prostaglandin E2COX-2, cyclooxygenase-2CCL2, C-C motif chemokine ligand 2NF-κB, nuclear factor-kappa BMM, multiple myelomaALL, acute lymphoblastic leukemiaAML, acute myeloid leukemiaGDF15, growth differentiation factor 15AMPK, AMP-activated protein kinaseMAPK, mitogen-activated protein kinaseAPL, acute promyelocytic leukemiaCCR2, C-C motif chemokine receptor 2SDF-1α, stromal cell-derived factor-1 alphaFFA, free fatty acidsLPrA, leptin peptide receptor antagonistMCD, malonyl-CoA decarboxylase.
... Certain animal model studies described the associations between red meat consumption and increase risk of colon cancer which systematically analyzed by Turner and Lloyd [30]. They expressed the causes of cancer in association to heme iron and nitroso-compounds [31][32][33][34] or cooking effects [35]. However, we could not find such association between the type of consumed meat, oil, and cooking method with colon cancer, which may be due to low sample size of this study. ...
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Colon cancer is the most commonly diagnosed gastrointestinal cancers in developed countries with varied incidence and the onset age of disease worldwide. Overall, 161 participants who were under patronage of a local relief foundation and referred to the endoscopy ward of Razi Hospital affiliated to the Guilan University of Medical Sciences. These patients have been aged more than 50 or more than 40 years with history of colorectal cancer in their first-degree family were enrolled from March 2016-March 2017. Demographic information were collected. Colonoscopy was performed and histopathological evaluation of observed lesions and polyps was done. Most of participants were female (113 individuals, 70.2%) and aged 50-60 years (83 individuals, 51.6%). Seventy-four (46%) had certain lesions. Most of colonoscopy findings were observed in the ascending colon in which depressed polyps and diverticulum were most frequent. However, rectum showed the most histological findings. All polyps of descending and ascending colons were neoplastic, while most of rectal polyps were non-neoplastic. Male patients, who were aged more than 60 years and smokers had significant higher percentage of both lesions and polyps in their colon (p<0.05). Moreover, significant positive association was detected between exposure to harmful industries and having polyps (p=0.01). We found male gender, higher age, smoking, and exposure to harmful industries as important risk factors for having colorectal lesions, which must be confirmed in further studies.
... In the same way, the generation of OS will produce peroxidation of polyunsaturated fatty acids giving as final products MDA and 4-HNE. At the same time, it will worsen free radical chain reactions, alter the integrity of the intestinal mucosa barrier, and activate inflammatory mediators [105,106]. This was evident in the quantification of MDA concentration and % 4-HNE expression, as both are lipoperoxidation markers. ...
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Chickpea has been classified as a nutraceutical food due to its phytochemical compounds, showing antioxidant, anti-inflammatory, and anticancer activity. To investigate this, we evaluated the effect of cooking on the nutritional and non-nutritional composition and the in vitro and in vivo antioxidant activity of chickpea seed. The latter was determined by the variation in the concentration of nitric oxide (NO), oxidized carbonyl groups (CO), malondialdehyde (MDA), and the expression of 4-hydroxy-2-nonenal (4-HNE) in the colon of male BALB/c mice fed with a standard diet with 10 and 20% cooked chickpea (CC). We induced colon cancer in mice by administering azoxymethane/dextran sulfate sodium (AOM/DSS); for the evaluation, these were sacrificed 1, 7, and 14 weeks after the induction. Results show that cooking does not significantly modify (p < 0.05) nutritional compounds; however, it decreases the concentration of non-nutritional ones and, consequently, in vitro antioxidant activity. The in vivo evaluation showed that animals administered with AOM/DSS presented higher concentrations of NO, CO, MDA, and 4-HNE than those in animals without AOM/DSS administration. However, in the three evaluated times, these markers were significantly reduced (p < 0.05) with CC consumption. The best effect on the oxidation markers was with the 20% CC diet, demonstrating the antioxidant potential of CC.
... 36 The importance of fat content and fatty acid profile was also previously demonstrated upon digestion of meat or heme iron supplemented with different types of oils or by adding different proportions of lard to meat. 10,37,38 The chicken meat in the present study consisted of a mixture of breasts, thighs, and added chicken skin, which led to a considerable proportion of n-6 PUFA. In contrast, in their in vitro digestions, Van Hecke et al. normalized the fatty acid composition of chicken, pork, and beef meat by adding lard, which might offer a possible explanation for the different results obtained. ...
Article
Human diets contain a complex mixture of antioxidants and pro-oxidants that contribute to the body’s oxidative status. In this study, 32 pigs were fed chicken versus red & processed meat in the context of a prudent or Western dietary pattern for four weeks, to investigate their oxidative status. Lipid oxidation products (malondialdehyde, 4-hydroxy-2-nonenal and hexanal) were higher in the chicken versus red & processed meat diets (1.7- to 8.3-fold) and subsequent in vitro (1.3- to 1.9-fold) and in vivo (1.4 to 3-fold) digests (P < 0.001), which was presumably related to the higher polyunsaturated fatty acid content in chicken meat and/or the added antioxidants in processed meat. However, diet only had a marginal or no effect on the systemic oxidative status as determined by plasma oxygen radical absorbance capacity, malondialdehyde, glutathione and glutathione peroxidase activity in blood and organs, except for α-tocopherol, which was higher after the consumption of the chicken-Western diet. In conclusion, in contrast to the hypothesis, the consumption of chicken compared to red & processed meat resulted in higher concentrations of lipid oxidation products in the pig intestinal contents, however, this was not reflected in the body’s oxidative status.
... Meat intake has repeatedly been shown to exert adverse effects on colon health by increasing the risk of colon cancer [77,78]. Factors associated with cellular stress and proliferation control were suggested to be responsible for the adverse effects of meat on the gut [79,80]. In the current study, we did not detect any difference in the relative mRNA expression of genes associated with cellular stress and proliferation between the three groups of pigs. ...
Article
Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome.
... (5,6) It has been suggested that hemoprotein-induced lipid peroxidation is involved in the etiology of colon carcinogenesis based on the consumption of red and processed meat. (7,8) Angeli et al. (9) indicated the combination of lipid hydroperoxides, primary lipid peroxidation products, and hemoglobin enhanced lipid peroxidation as well as DNA damage in a colon cancer cell line. ...
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To determine the preventive effect of dietary rutin on oxidative damages occurring in the digestive tract, 13-hydroperoxyoctadecadienoic acid and hemoglobin were exposed to Caco-2 intestinal cells after the pretreatment with colonic rutin metabolites. Among four catechol-type metabolites, quercetin and 3,4-dihydroxytoluene exerted significant protection on 13-hydroperoxyoctadecadienoic and hemoglobin-dependent lipid peroxidation of this epithelial cell. Compared with quercetin, a much lower concentration allowed 3,4-dihydroxytoluene to maximize the protective effect, though it needed a longer pre-incubation period. Neither quercetin nor 3,4-dihydroxytoluene affected the expression of peroxiredoxin-6 protein, which comprises the cellular antioxidant defense system. It is concluded that 3,4-dihydroxytoluene is a plausible rutin colonic metabolite that can suppress oxidative damages of intestinal epithelial cells by directly inhibiting lipid peroxidation. This result may illuminate the preventive role of dietary rutin against colorectal cancer incidence in relation to the consumption of red and processed meat.
... The iron molecule present in heme reacts with nitrogen, sulphur and oxygen of amino acids and peptides. This coordinated heme and free heme are hypothesised to catalyse lipid peroxidation of polyunsaturated fatty acids (PUFA) in the cellular membranes of intestinal cells (Baron and Andersen, 2002;Gueraud et al., 2015). Heme-initiated lipid peroxidation on the cell membrane leads to inactivation of membrane-bound enzymes and receptors, leading to the decreased fluidity of the membrane and increased nonspecific permeability to ions such as calcium (Kanner, 2007). ...
Article
Abstract Emerging evidence that heme iron in red meat is a risk factor for colorectal carcinogenesis is a topic that has received recent scrutiny. This review aims to summarise the mechanism of colorectal carcinogenesis by heme contained in red and processed meat. Heme iron can induce cytotoxicity by ‘cytotoxic heme factor’ and promote surface epithelial cell apoptosis and compensatory epithelial hyperplasia. Heme, induces peroxidation of lipids, leading to free radical formation and generation of DNA adducts in colorectal epithelial cells. In addition, heme catalyses the formation of N-nitroso-compounds, which in turn results in the initiation of colorectal carcinogenesis. Emerging data suggest that intestinal dysbiosis can promote carcinogenic properties of heme. Heme induces multiple genetic alterations by regulating WNT signalling pathway and causing mutations in major colon cancer genes such as APC, TP53 and KRAS. However, a balanced diet containing green vegetables, olive oil and calcium may reduce the carcinogenic effects of heme. Keywords Colorectal cancer; Carcinogenesis; Heme; Red meat; Processed meat; Cytotoxicity; Gene mutation; WNT
... Indeed, the observed HHE/HNE ratios were 81%/19% and 73%/27% for fish and linseed oils, respectively whereas the published mean compositions of these oils display n−3/n−6 fatty acid ratios of respectively 90%/10% and 66%/34% for fish and linseed oils. The measured HHE/HNE ratios in faecal waters were in the same range as their precursors in the dietary oils, with only a slight increase in HNE content in the fish oil group, possibly due to an inflammatory effect as previously reported [40]. Indeed, this inflammation could induce an endogenous production of hydroxy-alkenals, particularly HNE, from the cell membrane fatty acids of the rat intestine. ...
Article
Red or processed meat rich diets have been shown to be associated with an elevated risk of colorectal cancer (CRC). One major hypothesis involves dietary heme iron which induces lipid peroxidation. The quantification of the resulting reactive aldehydes (e.g. HNE and HHE) in the colon lumen is therefore of great concern since these compounds are known for their cytotoxic and genotoxic properties. UHPLC-ESI-MS/MS method has been developed and validated for HNE and HHE quantification in rat faeces. Samples were derivatised using a brominated reagent (BBHA) in presence of pre-synthesized deuterated internal standards (HNE-d11/HHE-d5), extracted by solid phase extraction, and then analysed by LC-positive ESI-MS/MS (MRM) on a TSQ Vantage mass spectrometer. The use of BBHA allowed the efficient stabilisation of the unstable and reactive hydroxy-alkenals HNE and HHE. The MRM method allowed selective detection of HNE and HHE on the basis of characteristic transitions monitored from both the 79 and 81 bromine isotopic peaks. This method was validated according to the European Medicines Agency (EMEA) guidelines, by determining selectivity, sensitivity, linearity, carry-over effect, recovery, matrix effect, repeatability, trueness and intermediate precision. The performance of the method enabled the quantification of HNE and HHE in concentrations 0.10–0.15 μM in faecal water. Results are presented on the application to the quantification of HNE and HHE in different faecal waters obtained from faeces of rats fed diets with various fatty acid compositions thus corresponding to different pro-oxidative features.
... Current evidence indicates that iron is an important factor in the formation of oxidized compounds through the Fenton reaction, as summarized by Van Hecke et al. [8]. However, if we put on a scale the heme iron implication or the food lipid composition, it would be the availability of oxidizable substrates, such as lipids, that would clearly determine the meat oxidation levels [47][48][49]. Thus, we insist on the urgent need to perform ample controlled studies considering meat major factors (e.g., level of PUFA, heme iron and different meat protein with antioxidant/prooxidant properties) to find out a sort of ponderate oxidation score that allows us to classified meat accurately ...
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High meat and meat-products consumption has been related to degenerative diseases. In addition to their saturated fatty acids and cholesterol contents, oxidation products generated during their production, storage, digestion, and metabolization have been largely implicated. This review begins by summarizing the concept of meat and meat-products by the main international regulatory agencies while highlighting the nutritional importance of their consumption. The review also dials in the controversy of white/red meat classification and insists in the need of more accurate classification based on adequate scores. Since one of the negative arguments that meat receives comes from the association of its consumption with the increase in oxidative stress, main oxidation compounds (malondialdehyde, thermaloxidized compounds, 4-hydroxy-nonenal, oxysterols, or protein carbonyls) generated during its production, storage, and metabolization, are included as a central aspect of the work. The review includes future remarks addressed to study the effects meat consumption in the frame of diet-gene interactions, stressing the importance of knowing the genetic variables that make individuals more susceptible to a possible oxidative stress imbalance or antioxidant protection. The importance of consumed meat/meat-products in the frame of a personalized nutrition reach in plant-food is finally highlighted considering the importance of iron and plant biophenols on the microbiota abundance and plurality, which in turn affect several aspects of our physiology and metabolism.
... Indeed, ROS production can be modulated by fatty acids [51]. Dietary fatty acids have been associated with oxidative stress and carcinogenesis in a rat model [52]. Obese patients with dyslipidemia may present a loss of antioxidant capacity caused by low activity of the antioxidant enzyme SOD [53]. ...
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Background: Colorectal cancer (CRC) progression and related mortality are highly associated with metabolic disorders. However, the molecular mechanism involved in the regulation of hyperlipidemia-associated CRC metastasis remains unclear. This study aimed to investigate the effects of angiopoietin-like 4 (ANGPTL4) on NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) production, which might provide new targets for improving outcomes in patients with hyperlipidemia-associated CRC metastasis. Methods: The clinical relevance of relationship between NOX4 expression and ANGPTL4 was examined in CRC patients by the Oncomine and TCGA data set. Expressions of NOX4, epithelial-mesenchymal transition (EMT) markers, and gene regulation of NOX4 in free fatty acids (FFAs)-treated CRC cells were determined. The FFAs-triggered metastatic ability of CRC cells under treatments of antioxidants or knockdown of NOX4, ANGPTL4, and MMPs was evaluated in vitro and in vivo. In addition, effects of antioxidants and depletion of metastasis-associated molecules on the correlation between ROS production and FFAs-promoted CRC metastasis were also clarified. Results: In this study, we found that the induction of NOX4, followed by the increased ROS was essential for oleic acid (OA)-promoted CRC cell metastasis. The depletion of ANGPTL4 significantly inhibited c-Jun-mediated transactivation of NOX4 expression, accompanied with reduced levels of ROS, MMP-1, and MMP-9, resulting in the disruption of OA-promoted CRC cell metastasis. Moreover, knockdown of ANGPTL4, NOX4, MMP-1, and MMP-9 or the treatment of antioxidants dramatically inhibited circulating OA-enhanced tumor cell extravasation and metastatic seeding of tumor cells in lungs, indicating that the ANGPTL4/NOX4 axis was critical for dyslipidemia-associated tumor metastasis. Conclusion: The coincident expression of NOX4 and ANGPTL4 in CRC tumor specimens provides the insight into the potential therapeutic targets for the treatment of dyslipidemia-associated CRC metastasis.
... The intestinal epithelium is also exposed to toxins present in the diet (either in foods or generated in the lumen by interactions among dietary components), and to toxins, known as endotoxins, locally produced by the microbiota. As an example of the former, consumption by rats of polyunsaturated fatty acids in conjunction with heme iron has been demonstrated to lead to the generation of lipid oxidation products, e.g., malondialdehyde and 4hydroxynonenal, which can exert negative effects within the colon or be absorbed where they can have systemic pro-oxidant effects (Gueraud et al., 2015). Sterol oxidation products constitute other major absorbable food toxins and these compounds can also potentially exert local adverse effects, e.g., meat consumption and potential promotion of GI cancers (Biasi et al., 2008), or after absorption, lead to systemic adverse effects. ...
Article
The gastrointestinal (GI) tract plays a central role in the absorption, distribution, metabolism, and excretion of flavonoids, which ultimately define the health effects of these bioactives. These aspects are modulated by the interactions of flavonoids with other dietary components, environmental factors, the host, and the GI microbiota. Flavonoid can target molecules in the luminal content, the different GI tract cell types, and the microbiota. Importantly, flavonoid actions at the GI tract can have an impact systemically, e.g. on glucose homeostasis, lipid and energy metabolism, or cardiovascular risk factors. The beneficial actions of flavonoids at the GI include their capacity to: i) protect the intestinal epithelium against pharmacological insults and food toxins; ii) modulate the activity of enzymes involved in lipid and carbohydrate absorption; iii) maintain the intestinal barrier integrity; iv) modulate the secretion of gut hormones; v) modulate the GI tract immune system; vi) exert potential anti-colorectal cancer activity; and vii) shape microbiota composition and function. Further understanding of the mechanisms mediating the effects of flavonoids on the intestine (and its microbiota) is of critical importance given the relevance of the GI tract on sustaining overall health and of the widespread recommendations of increasing the intake of plant bioactives.
... ω-3 PUFAs are highly unstable and are easily oxidized. Oxidized ω-3 PUFAs release lipid peroxidation/oxidative products, which are cytotoxic and genotoxic to colonic cells [78,79]. Moreover, persistent organic pollutants (POPs) and foreign contaminations in fish oil supplements could exacerbate the colon carcinogenesis by stimulating aberrant crypt foci formation in rats [80]. ...
Article
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Substantial human and animal studies support the beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) on colonic inflammation and colorectal cancer (CRC). However, there are inconsistent results, which have shown that ω-3 PUFAs have no effect or even detrimental effects, making it difficult to effectively implement ω-3 PUFAs for disease prevention. A better understanding of the molecular mechanisms for the anti-inflammatory and anticancer effects of ω-3 PUFAs will help to clarify their potential health-promoting effects, provide a scientific base for cautions for their use, and establish dietary recommendations. In this review, we summarize recent studies of ω-3 PUFAs on colonic inflammation and CRC and discuss the potential roles of ω-3 PUFA-metabolizing enzymes, notably the cytochrome P450 monooxygenases, in mediating the actions of ω-3 PUFAs.
... 67 Makanan yang mengandung tinggi akan zat besi heme dapat menyebabkan oksidatif stres dan peroksidasi lipid. 68 Hal tersebut berkaitan erat dengan metabolisme nitrat atau nitrit dan pembentukan senyawa N-nitroso. 69 Produksi senyawa N-nitroso endogen dirangsang oleh zat besi heme, bukan oleh residu protein. ...
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Latar belakang: Asupan zat besi dan protein berperan penting untuk pertumbuhan pada masa remaja. Asupan zat gizi yang tidak seimbang dapat mengakibatkan masalah gizi seperti status gizi kurang atau lebih pada remaja.Tujuan: Penelitian ini bertujuan untuk meneliti hubungan asupan protein, zat besi, dan status gizi pada remaja putriMetode: Penelitian ini dilaksanakan pada bulan November 2020-Januari 2021 dengan desain penelitian cross-sectional. Sampel yang digunakan adalah 88 siswi berusia 15-18 tahun di SMAN 1 Kendal yang dipilih secara simple random sampling. Pengumpulan data dilakukan melalui pengukuran berat badan dengan menggunakan timbangan injak digital dan tinggi badan menggunakan microtoise. Asupan protein dan zat besi diperoleh dengan metode SQ-FFQ dan Food Record 224 jam, kemudian dihitung dengan menggunakan software nutrisurvey. Analisis data penelitian menggunakan analisis bivariat dengan uji korelasi Spearman.Hasil: Hasil uji korelasi Spearman menunjukkan asupan protein dengan status gizi (p=0,848 dan r=0,021) dan asupan zat besi dengan status gizi (p=0,685, r=0,044). Sebagian besar siswi memiliki status gizi normal (84,09%), tingkat kecukupan Simpulan: Tidak terdapat hubungan antara asupan protein dengan status gizi dan asupan zat besi dengan status gizi.
... However, they suggested that high transferrin saturation could reflect the organism's iron overload, while a low concentration of total thiol groups (-S-H) of serum proteins may reflect systemic redox imbalance in obese patients. This could, at least partially, explain the associations of iron overload and obesity with colorectal adenoma, supporting the previously described association of iron accumulation and lipid peroxidation in colon carcinogenesis [6,7]. On the other hand, iron might be also considered a potentially beneficial anticancer pro-oxidant that triggers the peroxidation of PUFAs, thus generating cytotoxic and growth-regulating aldehydes, especially 4-hydroxynonenal (HNE) [8]. ...
Article
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The current concepts of biomedicine consider oxidative stress to be one of crucial pathophysiological processes behind major stress- and age-associated diseases, including cancer [...]
... Iron as the most widespread transition metal in animal, can gain and lose electrons easily, and has multiple oxidation state, electron configuration, and reduction potential (Amaral, Silva, and Lannes 2018). When meat is processed, some iron-porphyrin falls off the porphyrin ring and becomes free iron, and then takes part in the oxidation of fat as the catalyst (Gueraud et al. 2015;Huang et al. 2011). Hemoglobin can combine with oxygen to form oxyhemoglobin during the storage of meat. ...
Article
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Iron-porphyrin is a very important substance in organisms, especially in animals. It is not only the source of iron in human body, but is also the catalytic center of many reactions. Previous studies suggested that adequate intake of iron was important for the health of human, especially for children and pregnant women. However, associated diseases caused by iron over-intake and excessive meat consumption suggested its potential harmfulness for human health. During meat processing, Iron-porphyrin will cause the oxidation of proteins and fatty acids. In the gastrointestinal tract, iron-porphyrin can induce the production of malondialdehyde, fats oxidation, and indirectly cause oxidation of amino acids and nitrates etc. Iron-porphyrin enters the intestinal tract and disturbs the balance of intestinal flora. Finally, some common measures for inhibiting its activity are introduced, including the use of chelating agent, antioxidants, competitive inhibitor, etc., as well as give the hypothesis that sodium chloride increases the catalytic activity of iron-porphyrin. The purpose of this review is to present an overview of current knowledge about the changes of iron-porphyrin in the whole technico- and gastrointesto- processing axis and to provide ideas for further research in meat nutrition.
... Among the ω-oxo carboxylic acids, and as far as they can be considered to behave similarly towards electrospray ionization, 5-OPA and 9-ONA were the most abundantly detected (see Supplementary Table S1); although present in less abundance in the hydrogenated coconut oil diet, they were both detected in all samples. 9-ONA is known to be one of the main peroxidation products of ω-6 fatty acids [36], and its presence in all of the samples could be tentatively explained by basal lipid peroxidation of intestinal cells [37]. Finally, 8-OOA was the ω-oxo carboxylic acid displaying the highest fold change between the two diets. ...
Article
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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.
... As anticipated, stomach contents of rats on the beef diets contained higher levels of MDA, 4-HNE and HEX compared to rats on the chicken diets, however the levels reached were 3-to 7-fold lower as reported in our previous rat study (Van Hecke et al., 2019a). This may be explained by the relatively lower contribution of safflower oil to the diet in present study (0.5% vs. 2%), which serves as an important substrate for n-6 PUFA oxidation (Guéraud et al, 2015). Surprisingly, stomach contents of rats on nitritecured meat diets contained equal amounts of lipid oxidation products and even elevated PCC compared to the fresh meat diets, which was in contrast with the in vitro antioxidant effects. ...
Article
Mechanisms explaining epidemiological associations between red (processed) meat consumption and chronic disease risk are not yet elucidated, but may involve oxidative reactions, microbial composition alterations, inflammation and/or the formation of toxic bacterial metabolites. First, in vitro gastrointestinal digestion of 23 cooked beef-lard minces, to which varying doses of nitrite salt (range 0-40 g/kg) and sodium ascorbate (range 0-2 g/kg) were added, showed that nitrite salt decreased protein carbonylation up to 3-fold, and inhibited lipid oxidation, demonstrated by up to 4-fold lower levels of ‘thiobarbituric acid reactive substances’, 32-fold lower 4-hydroxynonenal, and 21-fold lower hexanal values. The use of ascorbate increased the antioxidant effect of low nitrite salt levels, whereas it slightly increased protein carbonylation at higher doses of nitrite salt. The addition of a low dose of ascorbate without nitrite salt slightly promoted oxidation during digestion, whereas higher doses had varying antioxidant effects. Second, 40 rats were fed a diet of cooked chicken- or beef-lard minces, either or not cured, for three weeks. Beef, compared to chicken, consumption increased lipid oxidation (2- to 4-fold) during digestion, and gut protein fermentation (cecal iso-butyrate, (iso-)valerate, and fecal indole, cresol), but oxidative stress and inflammation were generally not affected. Cured, compared to fresh, meat consumption significantly increased stomach protein carbonylation (+16%), colonic Ruminococcaceae (2.1-fold) and cecal propionate (+18%), whereas it decreased cecal butyrate (-25%), fecal phenol (-69%) and dimethyl disulfide (-61%) levels. Fecal acetaldehyde and diacetyl levels were increased in beef-fed rats by 2.8-fold and 5.9-fold respectively, and fecal carbon disulfide was 4-fold higher in rats consuming cured beef vs. fresh chicken. Given their known toxicity, the role of acetaldehyde and carbon disulfide in the relation between meat consumption and health should be investigated in future studies.
... The aging process is caused by deleterious effects of reactive oxygen species (ROS) generated spontaneously from normal cellular metabolism [19]. In beef production, cull cows had higher myoglobin or heme-Fe contents [20], which accelerates the oxidation process [21]. Previous study elaborated that inclusion of forage in the diet of beef cattle during the finishing phase altered antioxidant status [22]. ...
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The objectives of this study were to investigate the effects of age and dietary straw levels on growth performance, carcass and meat traits, as well as tissue antioxidant status of Yiling cull cows. Twenty-four Yiling cull cows were arranged in a 2 × 2 factorial design: two age classes consisting of younger cull cows (YCC; appearing with three or four pairs of permanent teeth) and older cull cows (OCC; worn out teeth); two dietary treatments consisting of lower and higher rice straw levels (LRS and HRS; providing 0.7 kg/d and 1.2 kg/d rice straw per head based on air-dry basis, respectively). Cows were fed twice a day. Straw was offered at half of the predetermined weight each meal; concentrate was separately supplied ad libitum. After 300 d of feeding, final body weight (BW), total BW gain, average daily gain and gain:feed intake were higher (p < 0.01) in the YCC group than in the OCC group. Total dry matter intake was higher (p = 0.03) in the HRS group than in the LRS group, but neutral detergent fiber apparent digestibility was negatively affected (p = 0.01) by increased straw levels. Decreased C15:0, C17:0, C20:5n3c, and saturated fatty acids (SFAs) proportion as well as increased C18:1n9c and monounsaturated fatty acids (MUFAs) proportion in meat from YCC with HRS diet were observed as compared to that in meat from YCC with LRS diet (p < 0.05). Meat from HRS group had higher (p = 0.04) C18:3n3c proportion than meat from LRS group. No significant differences (p > 0.05) were found for meat quality attributes except for cooking loss, which was higher (p = 0.02) in the HRS group than in the LRS group. Both YCC group and HRS group had higher (p < 0.05) cold carcass weight compared to OCC group and LRS group. Moreover, catalase activity of liver tissue was higher (p = 0.045) in YCC than in OCC, while superoxide dismutase activity of muscle tissue was higher (p = 0.01) in LRS than in HRS. Based on results, we concluded that younger age and feeding high-level straw can improve the finishing performance of Yiling cull cows.
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Fat-related diseases and chemical hazards produced during the frying process pose a major threat to human health. Coatings have been used as a practical method to reduce the amount of oil and chemical hazards associated with fried foods. Methyl cellulose (MC) and soy protein isolate were used as coating materials to pretreat Chinese fried dough cake (CFDC) before frying. The 1.5% MC concentration was the best choice for coating to simultaneously lower oil and chemical hazards in CFDC. The CFDC prepared using 1.5% MC had 11.3% oil, 73.70 μg/kg acrylamide, 0.15 mg KOH/100 kg acid, 8.54 mmol/kg peroxide, p-anisidine value of 6.36, 0.36 μg/g malondialdehyde, 0.13 μg/g 4-hydroxy-2-(E)-hexenal (HHE), 0.51 μg/g 4-hydroxy-2-(E)-nonenal (HNE), and 4,272 μg/kg glycidyl ester. In contrast, the uncoated CFDC had 19.2% oil, 117.55 μg/kg acrylamide, 0.25 mg KOH/100 kg acid, 14.40 mmol/kg peroxide, p-anisidine value of 9.76, 0.63 μg/g malondialdehyde, 0.23 μg/g HHE, 0.86 μg/g HNE, and 5,758 μg/kg glycidyl ester. MC and soy protein isolate enhanced the oil barrier of the coating film, which effectively reduced the heat transfer coefficients, oil transfer, oil oxidation, and chemical hazards in the CFDC. Our work on this edible coating contributes to methods for control of oil and chemical hazards in fried foods. HIGHLIGHTS
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Metabolic diseases are becoming more common and more severe in populations adhering to western lifestyle. Since metabolic conditions are highly diet and lifestyle dependent, it is suggested that certain diets are the cause for a wide range of metabolic dysfunctions. Oxidative stress, excess calcium excretion, inflammation, and metabolic acidosis are common features in the origins of most metabolic disease. These primary manifestations of “metabolic syndrome” can lead to insulin resistance, diabetes, obesity, and hypertension. Further complications of the conditions involve kidney disease, cardiovascular disease, osteoporosis, and cancers. Dietary analysis shows that a modern “Western-style” diet may facilitate a disruption in pH homeostasis and drive disease progression through high consumption of exogenous acids. Because so many physiological and cellular functions rely on acid-base reactions and pH equilibrium, prolonged exposure of the body to more acids than can effectively be buffered, by chronic adherence to poor diet, may result in metabolic stress followed by disease. This review addresses relevant molecular pathways in mammalian cells discovered to be sensitive to acid - base equilibria, their cellular effects, and how they can cascade into an organism-level manifestation of Metabolic Syndromes. We will also discuss potential ways to help mitigate this digestive disruption of pH and metabolic homeostasis through dietary change.
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Scope High consumption of red meat and sucrose increases the epidemiological risk for chronic diseases. Mechanistic hypotheses include alterations in oxidative status, gut microbial composition, fat deposition and low‐grade inflammation. Methods and results For two weeks, 40 rats consumed a diet high in white or red meat (chicken‐based or beef‐based cooked mince respectively), and containing corn starch or sucrose in a 2 × 2 factorial design. Lard was mixed with lean chicken or beef to obtain comparable dietary fatty acid profiles. Beef (vs. chicken)‐fed rats had higher lipid oxidation products (malondialdehyde, 4‐hydroxy‐2‐nonenal and hexanal) in stomach content and blood, and lower blood glutathione. Sucrose (vs. corn starch)‐fed rats showed increased blood lipid oxidation products and glutathione peroxidase activity, higher liver weight and malondialdehyde concentrations, and mesenterial and retroperitoneal fat accumulation. Beef‐sucrose‐fed rats had increased cardiac weight, suggesting pathophysiological effects on the cardiovascular system. The colonic microbiome of beef‐sucrose‐fed rats showed an outgrowth of the sulfate‐reducing family of the Desulfovibrionaceae, partly in expense of the Lactobacillus genus, indicating intestinal dysbiosis. Blood C‐reactive protein, a marker for inflammation, was not different among groups. Conclusions Consumption of a cooked beef‐based meat product with sucrose increased oxidative stress parameters and promoted cardiac hypertrophy and intestinal dysbiosis. This article is protected by copyright. All rights reserved
Chapter
This chapter focuses on the oxidative stability of n-3 polyunsaturated fatty acids (n-3 PUFAs) delivery systems and n-3 PUFAs fortified foods during digestion, with specific attention given to the long-chain n-3 PUFAs. The topic is of importance since the formation of reactive lipid oxidation products in the gastrointestinal tract (GIT) can lead to unwanted reactions e.g., with proteins, phospholipids, and DNA of the intestinal epithelial layer as well as decrease the amount of n-3 PUFAs being bioavailable in the GIT. Initially, the use of in vitro digestion models to study lipid oxidation is reviewed, after which available literature about the susceptibility of different n-3 PUFA delivery systems—neat oils, emulsions, capsules, and n-3 PUFA-rich foods—to oxidation in the GIT is summarized. In the next part of the chapter, the link between digestion-induced oxidation and initial oxidative status of the n-3 PUFA system, the degree of lipolysis as well as the presence of different pro- and antioxidants is discussed. Based on available findings, some future directions in the current research area are finally given.
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About 20 years ago, the research group of Sheila Anne Bingham in Cambridge, UK, showed for the first time that volunteers consuming large amounts of red meat excrete high amounts of nitroso compounds via feces. In the meantime, it has been demonstrated that heme leads to the enhanced formation of nitroso compounds in the gastrointestinal tract and that the main nitroso compounds formed in the gastrointestinal tract are S-nitrosothiols and the nitrosyl heme. Moreover, it has been postulated that these endogenously formed nitroso compounds may alkylate guanine at the O6-position, resulting in the formation of the promutagenic DNA lesions O6-methylguanine and O6-carboxymethylguanine, which, if not repaired (in time), could lead to gene mutations and, subsequently to the development of colorectal cancer. Alternatively, it has been postulated that heme iron could contribute to colorectal carcinogenesis by inducing lipid peroxidation. In the present review, the evidence supporting the above-mentioned hypotheses will be presented.
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Red and processed meat consumption has been strongly related to increase the risk of colorectal cancer (CRC), although its impact is largely unknown. Hemin, an iron-containing porphyrin, is acknowledged as a putative factor of red and processed meat pro-carcinogenic effects. The aim of this study was to investigate the effects of high dietary hemin on the promotion/progression stages of 1,2-dimethylhydrazine (1,2-DMH)-induced colon carcinogenesis. Twenty-four Wistar male rats were given four subcutaneous 1,2-DMH injections and received either balanced diet or balanced diet supplemented with hemin 0.5 mmol/kg for 23 weeks. Colon specimens were analyzed for aberrant crypt foci (ACF) and tumor development. Dietary hemin significantly increased ACF number and fecal water cytotoxicity/genotoxicity in Caco-2 cells when compared to 1,2-DMH control group. However, tumor incidence, multiplicity and cell proliferation did not differ between 1,2-DMH + hemin and 1,2-DMH control group. Gene expression analysis of 91 target-genes revealed that only three genes (Figf, Pik3r5 and Tgfbr2) were down-regulated in the tumors from hemin-fed rats compared to those from 1,2-DMH control group. Therefore, the findings of this study show that high hemin intake promotes mainly DNA damage and ACF development and but does not change the number nor incidence of colon tumors induced by 1,2-DMH in male rats.
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Coating has been used as a practical method to ensure the physiochemical properties and reduce the chemical hazard of fried foods. Methyl cellulose (MC) was used as a coating material to pretreat Chinese fried dough cake (CFDC) before frying. The results showed that the water content, hardness, and L* value of the 1% MC coated sample was 31.67%, 848.54 g and 51.62, respectively at the seventh day at 25 °C. Coating contents 1% MC could reduce the oil content, hardness, and extent of browning and improve the physiochemical properties of CFDC on 7 days of storage. Coating contents 1% MC also reduced the acid value, peroxide value, p‐anisidine value, malondialdehyde content, 4‐hydroxy‐2‐(E)‐hexenal content, 4‐hydroxy‐2‐(E)‐nonenal content, acrylamide content and glycidyl ester content in CFDC on 7 days of storage. Our work contributes to the control of the oil content and chemical hazards for fried food during storage by applying an edible coating.
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An early mechanism for the health benefits of dietary plant phenols is their antioxidant activity in the upper digestive tract. Indeed, these non-essential micronutrients abundant in fruits and vegetables can efficiently fight the iron-induced peroxidation of dietary lipids in the gastric compartment, a recognized form of postprandial oxidative stress. In this work, this phenomenon is investigated through a simple model based on nano-emulsions of trilinoleylglycerol, which permits a direct spectroscopic monitoring and mechanistic insights sustained by extensive kinetic analysis. Polyphenols belonging to the main dietary classes are tested, in particular, flavonols, anthocyanins, flavanols and oligomeric procyanidins. Overall, the common polyphenols tested are good inhibitors of lipid peroxidation induced by metmyoglobin (heme iron) in the early stage of digestion (pH 5–6). For instance, under our peroxidation conditions (2 μM heme, 0.7 mM linoleic acid equivalent, 4.5 mM Brij®35), IC50 concentrations in the range 0.4–1.9 μM were estimated for the set of polyphenols, with oligomeric procyanidins being less inhibitory than the flavanol monomers. However, the polyphenols are ineffective at lower pH (pH 4) when the hematin cofactor is dissociated from its protein (globin). On the other hand, a moderate protection against lipid peroxidation induced by free iron (e.g., released by the oxidative degradation of hematin) persists. This protocol, which combines simplicity and nutritional relevance, could provide a basis for standard tests aimed at assessing the antioxidant capacity of foods and food additives.
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Background & aims Although disorders of iron metabolism are among the most common diseases and dietary intakes of vitamin A, B2, B6, C, E, and folic acid are known to affect the absorption or oxidation of iron, limited data are available on the association of dietary iron and these vitamins with mortality in the same population. Specifically, the holistic dietary vitamins intake and its combined effect with iron on mortality are unclear. The purpose of this study was to evaluate the association of dietary iron, holistic dietary vitamins, and their interactive effect with total and cause-specific mortality. Methods We evaluated the effects of dietary total/heme/non-heme iron, vitamins, and their interaction on all-cause/cardiovascular disease (CVD)/cancer mortality among 14,826 US adults in the National Health and Nutrition Examination Survey (NHANES), a population-based nationally representative study. We developed a vitamin score to represent the holistic dietary intakes of vitamin A, B2, B6, C, E, and folic acid. Results A total of 2154 deaths occurred during a median follow-up of 9.3 years. Results from multivariate Cox proportional hazards models showed that higher vitamin score was associated lower risk of all-cause mortality (P-trend = 0.027). Negative interactions between dietary heme iron and vitamin score were observed on all-cause/CVD mortality. Dietary higher vitamins combined with lower heme iron was associated with lower risk of all-cause and CVD mortality (HR (95% confidence intervals (CIs)): 0.80 (0.64–0.98) and 0.55 (0.31–0.98), respectively). Higher dietary vitamins combined with higher total/non-heme iron was associated with lower risk of CVD mortality (HR (95%CIs): 0.69 (0.48–0.99) and 0.70 (0.48–0.99), respectively). These results remained significant even excluding participants with iron supplementation. Conclusion Our findings suggested that interactive effect of holistic dietary vitamins and iron play a protective role in decreasing all-cause and CVD mortality. Future studies, including cohort studies and clinical trials, are necessary to confirm these findings.
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PUFAs are known to regulate cholesterol synthesis and cellular uptake by multiple mechanisms that do not involve SFAs. Polymorphisms in any of the numerous proteins involved in cholesterol homeostasis, as a result of genetic variation, could lead to higher or lower serum cholesterol. PUFAs are susceptible to lipid peroxidation, which can lead to oxidative stress, inflammation, atherosclerosis, cancer, and disorders associated with inflammation, such as insulin resistance, arthritis, and numerous inflammatory syndromes. Eicosanoids from arachidonic acid are among the most powerful mediators that initiate an immune response, and a wide range of PUFA metabolites regulate numerous physiological processes. There is a misconception that dietary SFAs can cause inflammation, although endogenous palmitic acid is converted to ceramides and other cell constituents involved in an inflammatory response after it is initiated by lipid mediators derived from PUFAs. This article will discuss the many misconceptions regarding how dietary lipids regulate serum cholesterol, the fact that all-cause death rate is higher in humans with low compared with normal or moderately elevated serum total cholesterol, the numerous adverse effects of increasing dietary PUFAs or carbohydrate relative to SFAs, as well as metabolic conversion of PUFAs to SFAs and MUFAs as a protective mechanism. Consequently, dietary saturated fats seem to be less harmful than the proposed alternatives.
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Normand cull-cows received a diet enriched in n-3 polyunsaturated fatty acids (PUFA), known to enhance nutritional quality, but to decrease beef lipid stability. Half of the cows received a supplementation of vitamin E and plant extracts rich in polyphenols during the finishing period. Half of each feeding group was slaughtered under limited, the others under added stress conditions. Longissimus thoracis (LT) and Semitendinosus (ST) were evaluated after storage under air, or 70% O2/30% CO2 or vacuum conditions. Irrespectively of diet, pre-slaughter stress i) increased post-mortem malondialdehyde (MDA) formation except in vacuum-stored meat, ii) decreased vitamin A levels in the LT, iii) decreased vitamin E levels in meat stored in 70% O2/30% CO2 and total anti-oxidant status in vacuum stored meat. Effects were global; dietary supplementation with vitamin E and plant extracts was associated with lower MDA levels and MetMb percentage and higher levels of vitamin A and E.
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Ethyl Carbamate (EC), as a carcinogen widely found in fermented foods, was verified that its cytotoxicity was associated with oxidative stress. Polysaccharides from natural sources due to their antioxidative capacity have attracted great attention in the past time. In this study, purified polysaccharide from Tetrastigma hemsleyanum vines (TVP) with 64.89 kDA was extracted and conducted multiple analysis to identify its structural information. It could be discovered that TVP was composed of mannose, rhamnose, glucuronic acid, glucose, galactose, and arabinose. In vitro, TVP could inhibit cytotoxicity and genotoxicity, attenuate oxidative damage and mitochondrial dysfunction induced by EC in Caco-2 cells. Meanwhile, TVP could suppress apoptosis by mTOR and Bcl-2 signaling pathways, ameliorate oxidative via Sirt1-FoxO1 and Nrf2-Keap1 signaling pathways. In vivo, EC as well triggered the decline of survival and athletic ability in Caenorhabditis elegans (C. elegans) and TVP could reverse the decline. In the meantime, TVP could ameliorate oxidative damage in N2 and daf-2 (-) mutant but fail in daf-16 (-) mutant, which suggested that DAF-16 (FOXO) might affect the antioxidative protection of TVP in C. elegans. In brief, our results manifested that TVP could attenuate EC-induced cytotoxicity both in vitro and in vivo.
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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 towards nucleophilic sites present in bio-macromolecules. 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 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.
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Cold chain (-20 °C) is one of the main transportation methods for storage of Tan sheep products. Lipids (66) in seven subclasses involved in sphingolipid, glycerophospholipid and fatty acid degradation metabolism were quantified in Tan sheep under cold chain storage, including fatty acyl carnitines, phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), ceramides, sphingomyelin (SM) and lysophosphatidylethanolamine (LPE). Lipid transformation and molecular mechanism analyzed using fragmentation mechanisms and UHPLC-Q-Orbitrap MS/MS combined with lipidomics approaches determined transient increases of certain PC, PE and fatty acyl carnitine during the first 12 days of cold storage, subsequent declines of SM, PC, PE and fatty acyl carnitine, as well as increases of ceramide, LPC and LPE (24 days). These results offered insights into lipid transformation and quality of Tan sheep during cold chain storage.
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Red meat is classified as probably carcinogenic to humans by International Agency for Research on Cancer (IARC) based on evidence on how it may affect the development of colorectal cancer, the third most common cancer worldwide. A plethora of scientific experiments prevailing to establish a positive association between red meat and colorectal cancer suggested different mechanistic hypotheses in order to explain such a phenomenon. This paper aims to discuss major hypotheses related to how red meat consumption may lead to colorectal cancer. Such hypotheses involve the role of natural compounds present in red meat (such as lipid, protein, N-glycolylneuraminic acid and heme iron) and neoformed substances during meat processing (such as heterocyclic amines, polyaromatic hydrocarbons and N-nitroso compounds).
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The impact of six culinary practices – oven/microwave combined with/without seasoning with oregano/beer – on lipid and protein oxidation of chicken burgers after cooking and after in vitro digestion was assessed. Five oxidation markers - malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), hexanal (HEX), carbonyls, and Schiff bases – as well as free amino acids and total fatty acids content were measured. Oregano prevented MDA, HEX, and HNE formation during cooking, while beer seems not to influence their formation. After in vitro digestion, MDA, carbonyls, and Schiff bases increased, regardless of the culinary practice, while HNE and HEX values were reduced. Globally, cooking with oregano exhibited the lowest losses of PUFAs and formation of all oxidation markers, thus it should be used as a mitigation strategy to avoid the formation of oxidation products during cooking, as well as to prevent their formation during in vitro digestion.
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Oxidative stress occurs when there exists an imbalance between the generation and elimination of reactive oxygen species (ROS). As inevitable exposure to foreign substances and microbial pathogens, intestine is a key resource of ROS. Disproportionate generation and long-term exposure to ROS lead to various intestinal diseases, such as inflammatory bowel diseases (IBD), enteric infections, ischemic intestinal injury and colorectal cancers. Natural nutrients including vitamins, proteins, fats, minerals and phytochemicals provide numerous evidences that they can protect the health of intestine and alleviate the damage caused by oxidative stress, which can be developed as novel functional foods. This review summarized the recent research progress on the insights of the causes, mechanisms of intestinal oxidative stress and the health intervention effects of nutrients. This review has also given the prospects that the new discovered nutrients with health benefits might be developed as novel functional foods or possible nutraceutical agents.
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Although Corni Fructus (CF) is a fruit with great economic value and development potential in medicine and food, too much reliance on personal experience for quality evaluation seriously limits the trading and circulation of CF. In the present study, through the research on the correlation between the chemical composition and the appearance color, a standard colorimetric card related to CF quality was established, which simplified the quality evaluation process and improved the accuracy of the visual evaluation of CF. Firstly, a total of 29 batches of CF from different places were collected. Then, "imread" in the MATLAB software was used to convert the color of all samples into RGB values, and HPLC-DVD was used to measure the content of the main chemical components in CF. Thereafter, the correlation between the content and color was studied by using MLR, BP-ANNs and SVM chemometric tools to screen the Q-marker of CF, which was further confirmed by in vivo and in vitro experiments. Finally, the Q-marker standard colorimetric card with the best fitting degree is established according to the prediction model. Thus, this study provides an auxiliary reference for the color evaluation of CF and a reference for the standardization and quantification of the macro characteristics of traditional Chinese medicine and food.
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Résumé Les composés réducteurs d’origine végétale sont abondants dans l’alimentation, notamment les composés phénoliques (polyphénols). Ils sont trop souvent qualifiés d’antioxydants alors que cette notion reste floue et ouverte aux abus. Certes, les polyphénols et autres micronutriments réducteurs peuvent contribuer à la protection des acides gras polyinsaturés (AGPI) contre l’oxydation, non seulement dans les aliments (y compris en tant qu’additifs) mais aussi dans le tractus digestif. Cette aptitude peut être sommairement évaluée par la capacité antioxydante totale (TAC) mais doit être confirmée dans des tests plus élaborés mettant en jeu les AGPI. Par contre, les créditer d’une activité antioxydante dans les tissus (au-delà du tractus digestif) sur la seule base d’une valeur TAC élevée est abusif, d’une part, parce que la lutte contre le stress oxydant chronique via une alimentation riche en produits végétaux implique une grande variété de mécanismes et reste indissociable d’actions anti-inflammatoires, d’autre part, parce que les polyphénols subissent en général un fort catabolisme par le microbiote intestinal et sont distribués aux tissus sous la forme de métabolites de structures très différentes de celles des formes initialement présentes dans l’aliment.
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Epidemiology shows that red and processed meat intake is associated with an increased risk of colorectal cancer. Heme iron, heterocyclic amines and endogenous N-nitroso compounds (NOC) are proposed to explain this effect, but their relative contribution is unknown. Our study aimed at determining, at nutritional doses, which is the main factor involved and proposing a mechanism of cancer promotion by red meat. The relative part of heme iron (1% in diet), heterocyclic amines (PhIP+MeIQx, 50+25 µg/kg in diet) and NOC (induced by NaNO2+NaNO3 0.17+0.23 g/l of drinking water) was determined by a factorial design and preneoplastic endpoints in chemically-induced rats and validated on tumors in Min mice. The molecular mechanisms (genotoxicity, cytotoxicity) were analyzed in vitro in normal and Apc-deficient cell lines and confirmed on colon mucosa. Heme iron increased the number of preneoplastic lesions but dietary heterocyclic amines and NOC had no effect on carcinogenesis in rats. Dietary hemoglobin increased tumor load in Min mice (control diet: 67±39 mm2; 2,5% hemoglobin diet: 114±47 mm2, p=0.004). In vitro, fecal water from rats given hemoglobin was rich in aldehydes and was cytotoxic to normal cells, but not to premalignant cells. The aldehydes 4-hydroxynonenal and 4-hydroxyhexenal were more toxic to normal versus mutated cells and were only genotoxic to normal cells. Genotoxicity was also observed in colon mucosa of mice given hemoglobin. These results highlight the role of heme iron in the promotion of colon cancer by red meat and suggest that heme iron could initiate carcinogenesis through lipid peroxidation. Copyright © 2015, American Association for Cancer Research.
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ω -3 Polyunsaturated fatty acids (PUFAs), mainly present in fish oil, are part of the human diet. Among PUFAs, docosahexaenoic acid (DHA) has received particular attention for its anti-inflammatory, antiproliferative, proapoptotic, antiangiogenetic, anti-invasion, and antimetastatic properties. These data suggest that DHA can exert antitumor activity potentially representing an effective adjuvant in cancer chemotherapy. This review is focused on current knowledge supporting the potential use of DHA for the enhancement of the efficacy of anticancer treatments in relation to its ability to enhance the uptake of anticancer drugs, regulate the oxidative status of tumor cells, and inhibit tumor cell invasion and metastasis.
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Colon cancer is a major cause of cancer deaths in Western countries and is associated with diets high in red meat. Heme, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents which injures surface cells leading to compensatory hyperproliferation of crypt cells. This hyperproliferation results in epithelial hyperplasia which increases the risk of colon cancer. In humans, a high red-meat diet increases Bacteroides spp in feces. Therefore, we simultaneously investigated the effects of dietary heme on colonic microbiota and on the host mucosa of mice. Whole genome microarrays showed that heme injured the colonic surface epithelium and induced hyperproliferation by changing the surface to crypt signaling. Using 16S rRNA phylogenetic microarrays, we investigated whether bacteria play a role in this changed signaling. Heme increased Bacteroidetes and decreased Firmicutes in colonic contents. This shift was most likely caused by a selective susceptibility of Gram-positive bacteria to heme cytotoxic fecal water, which is not observed for Gram-negative bacteria, allowing expansion of the Gram-negative community. The increased amount of Gram-negative bacteria most probably increased LPS exposure to colonocytes, however, there is no appreciable immune response detected in the heme-fed mice. There was no functional change in the sensing of the bacteria by the mucosa, as changes in inflammation pathways and Toll- like receptor signaling were not detected. This unaltered host-microbe cross-talk indicates that the changes in microbiota did not play a causal role in the observed hyperproliferation and hyperplasia.
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Experimental models showed consistently a modulation of carcinogenesis by omega 3 polyunsaturated fatty acids (ω3 PUFA). Fish intake is often described as part of a beneficial dietary pattern. However, observational epidemiological studies on the relationship between ω3 PUFA reported conflicting results. The objective of this systematic review is to determine whether there exists any progress in the evaluation of the causal relationship between dietary ω3 PUFA and cancers since the previous FAO/OMS expert consultation and whether it is possible to propose preventive and/or adjuvant therapeutic recommendations. Prospective and case-control observational studies published since 2007 and meeting validity criteria were considered together with RCT. Experimental studies are mentioned to provide for biological plausibility. When evaluating the level of evidence, a portfolio approach was used, weighted by a hierarchy giving higher importance to prospective studies followed by RCT if any. There is a probable level of evidence that ALA per se is neither a risk factor nor a beneficial factor with regards to cancers. Observational studies on colorectal, prostate and breast cancers only provided limited evidence suggesting a possible role of LC-ω3PUFA in cancer prevention because insufficient homogeneity of the observations. Explanation for heterogeneity might be the inherent difficulties associated with epidemiology (confounding and dietary pattern context, measurement error, level of intake, genetic polymorphism). The role of LC-ω3PUFA as adjuvant, might be considered of possible use, in view of the latest RCT on lung cancers even if RCT on other cancers still need to be undertaken.
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Dietary intake of long-chain n-3 PUFA is now widely advised for public health and in medical practice. However, PUFA are highly prone to oxidation, producing potentially deleterious 4-hydroxy-2-alkenals. Even so, the impact of consuming oxidized n-3 PUFA on metabolic oxidative stress and inflammation is poorly described. We therefore studied such effects and hypothesized the involvement of the intestinal absorption of 4-hydroxy-2-hexenal (4-HHE), an oxidized n-3 PUFA end-product. In vivo, four groups of mice were fed for 8 weeks high-fat diets containing moderately oxidized or unoxidized n-3 PUFA. Other mice were orally administered 4-HHE and euthanized postprandially versus baseline mice. In vitro, human intestinal Caco-2/TC7 cells were incubated with 4-hydroxy-2-alkenals. Oxidized diets increased 4-HHE plasma levels in mice (up to 5-fold, P < 0.01) compared with unoxidized diets. Oxidized diets enhanced plasma inflammatory markers and activation of nuclear factor kappaB (NF-κB) in the small intestine along with decreasing Paneth cell number (up to -19% in the duodenum). Both in vivo and in vitro, intestinal absorption of 4-HHE was associated with formation of 4-HHE-protein adducts and increased expression of glutathione peroxidase 2 (GPx2) and glucose-regulated protein 78 (GRP78). Consumption of oxidized n-3 PUFA results in 4-HHE accumulation in blood after its intestinal absorption and triggers oxidative stress and inflammation in the upper intestine.
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The gastric tract may be the first site where food is exposed to postprandial oxidative stress and antioxidant activity by plant micronutrients. After food intake, dietary iron, dioxygen, and emulsified lipids come into close contact and lipid oxidation may take place. This study investigated lipid oxidation and its inhibition by dietary polyphenols in gastric-like conditions. Lipid oxidation induced by heme and nonheme iron was studied in acidic sunflower oil-in-water emulsions. The emulsifier type (bovine serum albumin, phospholipids), pH, and iron form were found to be factors governing the oxidation rates. Quercetin, rutin, and chlorogenic acid highly inhibited the metmyoglobin-initiated lipid oxidation in both emulsified systems at pH 5.8. Additionally, quercetin inhibited nonheme iron-initiated processes, while it was inefficient with hematin as an initiator. The presence of human gastric juice did not influence lipid oxidation, although it diminished the antioxidant activity of phenolics. Model emulsions may thus be valuable tools to study the gastric stability of polyunsaturated lipids.
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The aim of this study was to investigate whether the effects of aging on oxidative stress markers and expression of major oxidant and antioxidant enzymes associate with impairment of renal function and increases in blood pressure. To explore this, we determined age-associated changes in lipid peroxidation (urinary malondialdehyde), plasma and urinary hydrogen peroxide (H(2)O(2)) levels, as well as renal H(2)O(2) production, and the expression of oxidant and antioxidant enzymes in young (13 weeks) and old (52 weeks) male Wistar Kyoto (WKY) rats. Urinary lipid peroxidation levels and H(2)O(2) production by the renal cortex and medulla of old rats were higher than their young counterparts. This was accompanied by overexpression of NADPH oxidase components Nox4 and p22(phox) in the renal cortex of old rats. Similarly, expression of superoxide dismutase (SOD) isoforms 2 and 3 and catalase were increased in the renal cortex from old rats. Renal function parameters (creatinine clearance and fractional excretion of sodium), diastolic blood pressure and heart rate were not affected by aging, although slight increases in systolic blood pressure were observed during this 52-week period. It is concluded that overexpression of renal Nox4 and p22(phox) and the increases in renal H(2)O(2) levels in aged WKY does not associate with renal functional impairment or marked increases in blood pressure. It is hypothesized that lack of oxidative stress-associated effects in aged WKY rats may result from increases in antioxidant defenses that counteract the damaging effects of H(2)O(2).
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Air pollution is known to contribute to respiratory and cardiovascular mortality and morbidity. Oxidative stress has been suggested as one of the main mechanisms for these effects on health. The aim of this study was to analyze the effects of exposure to particulate matter (PM) with aerodynamic diameters < or = 10 microm (PM10) and < or = 2.5 microm (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) on urinary malondialdehyde (MDA) levels in schoolchildren. The study population consisted of 120 schoolchildren. The survey and measurements were conducted in four cities--two in China (Ala Shan and Beijing) and two in Korea (Jeju and Seoul)--between 4 and 9 June 2007. We measured daily ambient levels of PM and their metal components at the selected schools during the study period. We also measured urinary 1-hydroxypyrene (1-OHP) and 2-naphthol, to assess PAH exposure, and MDA, to assess oxidative stress. Measurements were conducted once a day for 5 consecutive days. We constructed a linear mixed model after adjusting for individual variables to estimate the effects of PM and PAH on oxidative stress. We found statistically significant increases in urinary MDA levels with ambient PM concentrations from the current day to the 2 previous days (p < 0.0001). Urinary 1-OHP level also showed a positive association with urinary MDA level, which was statistically significant with or without PM in the model (p < 0.05). Outdoor PM and urinary 1-OHP were synergistically associated with urinary MDA levels. Some metals bound to PM10 (aluminum, iron, strontium, magnesium, silicon, arsenic, barium, zinc, copper, and cadmium) and PM2.5 (magnesium, iron, strontium, arsenic, cadmium, zinc, aluminum, mercury, barium, and copper) also had significant associations with urinary MDA level. Exposure to PM air pollution and PAHs was associated with oxidative stress in schoolchildren.
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Lipid peroxidation is highly associated with chronic degenerative diseases such as cancer. 4-hydroxy-2-nonenal is one of the major products of lipid peroxidation. 4-hydroxy-2-nonenal can interact with biomolecules, changing their conformation and activity. This study presents 4-hydroxy-2-nonenal-protein adducts formation in the first stages of Long-Evans Cinnamon rat hepatitis, a well recognized model for oxidative stress-associated hepatocarcinogenesis. 4-hydroxy-2-nonenal-protein adducts appeared in hepatocyte cytoplasm before the beginning of hepatitis and their presence was very strong during hepatitis, while a transient perinuclear expression of 4-hydroxy-2-nonenal-protein adducts was shown mainly at early hepatitis stages. 4-hydroxy-2-nonenal-protein adducts formation correlated to the expression of the tumour marker glutathione S-transferase P-form. These results show that lipid peroxidation modification of proteins might be implicated in the first stages of hepatocyte cancer initiation in Long-Evans Cinnamon rats.
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Consumption of red meat is associated with increased colon cancer risk. Our previous work indicated that this association might be due to the heme content of red meat. In rat studies, dietary heme increased colonic cytotoxicity and epithelial cell turnover, carcinogenesis biomarkers. Here we apply DNA microarray technology to examine effects of heme on colonic gene expression. A rat colon-specific microarray was constructed and hybridized in duplicate to RNA extracts from colon scrapings of rats fed diets with or without heme (n=6-7). We were able to reproducibly identify changes in colonic mRNA abundance in response to heme. Most striking was a >10-fold down-regulation of a single rat gene, an unprecedented gene-modulating effect of a dietary component. Based on homology, the novel gene encodes a pentraxin, the first identified in colon. Pentraxins are postulated to be involved in dealing with dying cells. Quantitative PCR confirmed the strong heme-induced down-regulation of this gene, which we named mucosal pentraxin (Mptx). Overall, our data support the efficacy of cDNA array expression profiling to investigate effects of specific nutrients in an in vivo system and may provide an approach to establishing markers for diet-induced stress of mammalian colonic mucosa.
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Red meat intake is associated with colon cancer risk. Puzzlingly, meat does not promote carcinogenesis in rat studies. However, we demonstrated previously that dietary heme promotes aberrant crypt foci (ACF) formation in rats given a low-calcium diet. Here, we tested the hypothesis that heme-rich meats promote colon carcinogenesis in rats treated with azoxymethane and fed low-calcium diets (0.8 g/kg). Three meat-based diets were formulated to contain varying concentrations of heme by the addition of raw chicken (low heme), beef (medium heme), or black pudding (blood sausage; high heme). The no-heme control diet was supplemented with ferric citrate and the heme control diet with hemoglobin to match iron and heme concentrations in the beef diet, respectively. After 100 d, colons were scored for ACF and mucin-depleted foci (MDF). Fecal water was assayed for lipoperoxides and cytotoxicity. Only diets with heme promoted the formation of MDF, but all meat diets promoted ACF formation. The number of MDF/colon was 0.55 +/- 0.68 in controls, but 1.2 +/- 0.6 (P = 0.13), 1.9 +/- 1.4 (P < 0.01), and 3.0 +/- 1.2 (P < 0.001) in chicken-, beef-, and black pudding-fed rats. MDF promotion by the high-heme black pudding diet was greater than that by the medium-heme beef diet. The number of ACF/colon was 72 +/- 16 in controls, but 91 +/- 18, 100 +/- 13, and 103 +/- 14 in chicken-, beef-, and black pudding-fed rats (all P < 0.001). ACF and MDF did not differ between rats fed the beef diet and those fed the heme control diet. MDF promotion was correlated with high fecal water lipoperoxides and cytotoxicity (r = 0.65, P < 0.01). This is the first study to show the promotion of experimental carcinogenesis by dietary meat and the association with heme intake.
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