Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 ...isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.
Tumor acidosis promotes disease progression through a stimulation of fatty acid (FA) metabolism in cancer cells. Instead of blocking the use of FAs by acidic cancer cells, we examined whether excess ...uptake of specific FAs could lead to antitumor effects. We found that n-3 but also remarkably n-6 polyunsaturated FA (PUFA) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding buffering capacity of triglyceride storage into lipid droplets, n-3 and n-6 PUFA peroxidation led to cytotoxic effects in proportion to the number of double bonds and even more so in the presence of diacylglycerol acyltransferase inhibitors (DGATi). Finally, an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers. These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.
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•n-3 and n-6 PUFAs preferentially accumulate in lipid droplets of acidic cancer cells•Excess LC-PUFAs undergo peroxidation and induce ferroptosis in acidic cancer cells•DGAT inhibitors prevent the formation of lipid droplets and promote ferroptosis•DGATi enhance the tumor growth inhibitory effects of dietary n-3 LC-PUFAs in mice
Tumor acidosis is associated with the metabolic use of fatty acids. Dierge et al. describe that in acidic cancer cells, n-3 and n-6 LC-PUFAs that exceed lipid droplet storage capacity undergo peroxidation and induce ferroptosis. Antitumor effects of dietary n-3 LC-PUFAs are further increased upon administration of DGAT inhibitors.
•Different phytochemicals were evaluated in 16 cultivars of Sacha inchi (SI) seeds.•High variability in the content of the evaluated compounds was found.•No correlation was found between the ...different antioxidants and the oxidative stability of the oil.•High α linoleic acid (ω3) and linolenic (ω6) were found.•The ratio ω6/ω3 is close to one.
Fatty acids (FA), phytosterols, tocopherols, phenolic compounds, total carotenoids and hydrophilic and lipophilic ORAC antioxidant capacities were evaluated in 16 cultivars of Sacha inchi (SI) seeds with the aim to valorise them and offer more information on the functional properties of SI seeds. A high α linolenic (α-Ln) fatty acid content was found in all cultivars (ω3, 12.8–16.0g/100g seed), followed by linoleic (L) fatty acid (ω6, 12.4–14.1g/100g seed). The ratio ω6/ω3 was within the 0.83–1.09 range. γ- and δ-tocopherols were the most important tocopherols, whereas the most representative phytosterols were β-sitosterol and stigmasterol. Contents of total phenolics, total carotenoids and hydrophilic and lipophilic antioxidant capacities ranged from 64.6 to 80mg of gallic acid equivalent/100g seed; from 0.07 to 0.09mg of β-carotene equivalent/100g of seed; from 4.3 to 7.3 and, from 1.0 to 2.8μmol of Trolox equivalent/g of seed, respectively, among the evaluated SI cultivars. Results showed significant differences (p<0.05) among the evaluated SI cultivars in the contents of ω3, ω6, antioxidant capacities and other evaluated phytochemicals. SI seeds should be considered as an important dietary source of health promoting phytochemicals.
Alterations in the composition of gut microbiota--known as dysbiosis--has been proposed to contribute to the development of obesity, thereby supporting the potential interest of nutrients targeting ...the gut with beneficial effect for host adiposity. We test the ability of a specific concentrate of water-extractable high molecular weight arabinoxylans (AX) from wheat to modulate both the gut microbiota and lipid metabolism in high-fat (HF) diet-induced obese mice.
Mice were fed either a control diet (CT) or a HF diet, or a HF diet supplemented with AX (10% w/w) during 4 weeks. AX supplementation restored the number of bacteria that were decreased upon HF feeding, i.e. Bacteroides-Prevotella spp. and Roseburia spp. Importantly, AX treatment markedly increased caecal bifidobacteria content, in particular Bifidobacterium animalis lactis. This effect was accompanied by improvement of gut barrier function and by a lower circulating inflammatory marker. Interestingly, rumenic acid (C18:2 c9,t11) was increased in white adipose tissue due to AX treatment, suggesting the influence of gut bacterial metabolism on host tissue. In parallel, AX treatment decreased adipocyte size and HF diet-induced expression of genes mediating differentiation, fatty acid uptake, fatty acid oxidation and inflammation, and decreased a key lipogenic enzyme activity in the subcutaneous adipose tissue. Furthermore, AX treatment significantly decreased HF-induced adiposity, body weight gain, serum and hepatic cholesterol accumulation and insulin resistance. Correlation analysis reveals that Roseburia spp. and Bacteroides/Prevotella levels inversely correlate with these host metabolic parameters.
Supplementation of a concentrate of water-extractable high molecular weight AX in the diet counteracted HF-induced gut dysbiosis together with an improvement of obesity and lipid-lowering effects. We postulate that hypocholesterolemic, anti-inflammatory and anti-obesity effects are related to changes in gut microbiota. These data support a role for wheat AX as interesting nutrients with prebiotic properties related to obesity prevention.
•Whey protein isolate modulates β-carotene bioaccessibility depending on digestive conditions.•Reduced β-carotene bioaccessibility was pronounced with impaired lipid digestion.•Strong positive ...influence of simulated peristalsis on β-carotene bioaccessibility.
Carotenoids are lipophilic phytochemicals; their intake has been associated with reduced chronic diseases. However, their absorption depends on emulsification during digestion and incorporation into mixed micelles, requiring digestive enzymes, gastric peristalsis, bile, and dietary lipids. In this study, we investigated whether whey-protein-isolate (WPI), a commonly consumed protein source, can modulate β-carotene bioaccessibility in vitro, especially under incomplete digestive conditions, i.e. under low digestive enzyme concentrations. Thus, amounts of pepsin, pancreatin, bile, co-digested lipids and kinetic energy and gastric digestion time were modified, and WPI at concentrations equivalent to 0/25/50% of the protein recommended dietary allowance (approx. 60 g/d) were added to β-carotene dissolved in oil. WPI enhanced bioaccessibility by up to 20% (p < 0.001), especially under higher simulated peristalsis or reduced amount of dietary lipids. Conversely, they impaired bioaccessibility to one third (p < 0.001) under incomplete digestive conditions. WPI modulated β-carotene bioaccessibility depending on digestive conditions.
Pentacyclic triterpenes are naturally found in a great variety of fruits, vegetables and medicinal plants and are therefore part of the human diet. The beneficial health effects of edible and ...medicinal plants have partly been associated with their triterpene content, but the in vivo efficacy in humans depends on many factors, including absorption and metabolism. This review presents an overview of in vitro and in vivo studies that were carried out to determine the bioavailability of pentacyclic triterpenes and highlights the efforts that have been performed to improve the dissolution properties and absorption of these compounds. As plant matrices play a critical role in triterpene bioaccessibility, this review covers literature data on the bioavailability of pentacyclic triterpenes ingested either from foods and medicinal plants or in their free form.
•A detailed nutritional composition of Rhodomyrtus tomentosa fruit (sim fruit) was determined for the first time.•Dietary fibres contributed up to 67% of the dry weight of sim fruit.•Total phenolics ...and antioxidant capacity of sim fruits were particularly high and similar to those of berries.
In this study, detailed chemical properties of sim (Rhodomyrtus tomentosa (Ait.) Hassk.) fruit including nutritional composition, phenolic content and antioxidant capacity were determined for the first time. A 150g serving of sim fruit contained high levels of dietary fibre (69.94–87.43% of Recommended Daily Intake (RDI)), α-tocopherol (38.90–51.87% RDI), manganese (>100% RDI), and copper (44.44% RDI) but low levels of protein (2.63% RDI), lipid (1.59–3.5% RDI), and sugars (5.65% RDI). The predominant fatty acid in the sim fruit sample was linoleic acid (75.36% of total fatty acids). Interestingly, total phenolics (49.21±0.35mg gallic acid equivalent (GAE)/g dry weight (DW)) were particularly high and resulted in a high antioxidant capacity (431.17±14.56μmol Trolox equivalent (TE)/g DW). These results, together with our recent discovery of high amount of piceatannol, a stilbene with potent biological activities, highlight the potential of sim, an under-utilised plant species from South–East Asia, as a new source of health-promoting compounds including dietary fibres, essential fatty acids, and phenolic compounds.
Optimal conditions for the extraction of phenolic compounds, anthocyanins, flavanols and ORAC antioxidant activity for two mashua genotypes were determined using the conventional liquid–solid method. ...Phenolic contents and antioxidant activity were affected by the type of solvent, pH level, solvent–water ratio and extraction time. In general, no significant differences in total phenolic recovery and ORAC values were observed when 90% methanol or methanol/acetone/water (45/45/10), both with 0.1% HCl, were used. By contrast, the 90% methanol solution with 0.1% HCl extracted the highest level of anthocyanins, whereas the solvent mixture extracted the highest level of flavanols. The purified extracts from the mashua genotypes presented total phenolics and ORAC contents within the ranges 14.4–18.7
mg gallic acid equivalents/g mashua dry matter (DM) and 221–359
μmol of trolox equivalents/g mashua DM, respectively. The HPLC-DAD phenolic profiles obtained for the purified phenolic extracts for both mashua genotypes showed differences in proportions (% total area at 280 and 520
nm) depending on the solvents selected in this study. The high content of phenolic compounds and antioxidant activity found in the purified extracts for both mashua genotypes indicated that mashua extracts might be considered as a potential source of nutraceuticals in the future.
Cancer research has benefited immensely from the use of animal models. Several genetic tools accessible in rodent models have provided valuable insight into cellular and molecular mechanisms linked ...to cancer development or metastasis and various lines are available. However, at the same time, it is important to accompany these findings with those from alternative or non-model animals to offer new perspectives into the understanding of tumor development, prevention, and treatment. In this review, we first discuss animals characterized by little or no tumor development. Cancer incidence in small animals, such as the naked mole rat, blind mole rat and bats have been reported as almost negligible and tumor development may be inhibited by increased defense and repair mechanisms, altered cell cycle signaling and reduced rates of cell migration to avoid tumor microenvironments. On the other end of the size spectrum, large animals such as elephants and whales also appear to have low overall cancer rates, possibly due to gene replicates that are involved in apoptosis and therefore can inhibit uncontrolled cell cycle progression. While it is important to determine the mechanisms that lead to cancer protection in these animals, we can also take advantage of other animals that are highly susceptible to cancer, especially those which develop tumors similar to humans, such as carnivores or poultry. The use of such animals does not require the transplantation of malignant cancer cells or use of oncogenic substances as they spontaneously develop tumors of similar presentation and pathophysiology to those found in humans. For example, some tumor suppressor genes are highly conserved between humans and domestic species, and various tumors develop in similar ways or because of a common environment. These animals are therefore of great interest for broadening perspectives and techniques and for gathering information on the tumor mechanisms of certain types of cancer. Here we present a detailed review of alternative and/or non-model vertebrates, that can be used at different levels of cancer research to open new perspectives and fields of action.
Deoxynivalenol (DON), one of the most common mycotoxin contaminants of raw and processed cereal food, adversely affects the gastrointestinal tract. Since DON acts as a protein synthesis inhibitor, ...the constantly renewing intestinal epithelium could be particularly sensitive to DON. We analyzed the toxicological effects of DON on intestinal epithelial protein synthesis and barrier integrity. Differentiated Caco-2 cells, as a widely used model of the human intestinal barrier, were exposed to realistic intestinal concentrations of DON (50, 500 and 5000
ng/ml) during 24
h. DON caused a concentration-dependent decrease in total protein content associated with a reduction in the incorporation of
3H-leucine, demonstrating its inhibitory effect on protein synthesis. DON simultaneously increased the paracellular permeability of the monolayer as reflected through a decreased transepithelial electrical resistance associated with an increased paracellular flux of the tracer
3H-mannitol. A concentration-dependent reduction in the expression level of the tight junction constituent claudin-4 was demonstrated by Western blot, which was not due to diminished transcription, increased degradation, or NF-κB, ERK or JNK activation, and was also observed for a tight junction independent protein, i.e. intestinal alkaline phosphatase. These results demonstrate a dual toxicological effect of DON on differentiated Caco-2 cells consisting in an inhibition of protein synthesis as well as an increase in monolayer permeability, and moreover suggest a possible link between them through diminished synthesis of the tight junction constituent claudin-4.
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