Resveratrol inhibits migration and invasion of human breast‐cancer cells

Metastasis is the primary cause of death from breast cancer. Cell migration and invasion play important roles in neoplastic metastasis. The insulin‐like growth factor (IGF‐1) stimulates cell migration through activation of PI‐3K/Akt signaling pathway. IGF‐1 induces the tumorigenicity of many types of cancer cells and is critical for metastatic cell spread in estrogen receptor (ER)‐negative breast‐cancer cells. Matrix metalloproteinase‐2 (MMP‐2) is a key enzyme in the degradation of extracellular matrices and its expression has been dysregulated in breast cancer invasion and metastasis. Resveratrol exhibited potential anticarcinogenic activities in several studies. However, the inhibitory effects of resveratrol on the expression of MMP‐2, migration and invasion of breast‐cancer cell have not been demonstrated yet. In the present study, we investigated the anti‐invasive mechanism of resveratrol in human breast cancer MDA‐MB 435cells. Here, we showed that IGF‐1 is a potent stimulant of the migration of ER‐negative human breast‐cancer cells. Resveratrol could inhibit IGF‐1‐mediated cell migration of MDA‐MB 435 in vitro. The inhibitory effect of resveratrol was mediated in part through the suppression of the activation of PI‐3K/Akt signaling pathway. Furthermore, IGF‐1‐mediated expression of MMP‐2 was significantly inhibited by resveratrol in concomitance with alteration of cell invasion.     

Dietary Amino Acids and the Gut‐Microbiome‐Immune Axis: Physiological Metabolism and Therapeutic Prospects

Dietary amino acids (AAs) are not only absorbed and metabolized by enterocytes but also available to the microbiota in the gut in mammals. In addition to serving as the materials for protein synthesis, AAs can act as precursors for numerous metabolic end products in reactions involving the intestinal mucosa and microbiota. After penetrating the epithelial barrier, microbial metabolites can enter and accumulate in the host circulatory system, where they are sensed by immune cells and then elicit a wide range of biological functions via different receptors and mechanisms. Some intestinal bacteria can also synthesize certain AAs, implying that the exchange of AAs between hosts and microorganisms is bidirectional. Changes in AA composition and abundance can affect AA‐metabolizing bacterial communities and modulate macrophages and dendritic cells via toll‐like receptors (TLRs), autoinducer‐2 (AI‐2), and NOD‐like receptors (NLRs), and also regulate the gut‐microbiome‐immune axis via aryl hydrocarbon receptor (AhR), serotonin/5‐hydroxytryptamine (5‐HT), and other signaling pathways, all of which play critical roles in regulating the intestinal mucosal immunity and microbiota directly or indirectly, contributing to intestinal homeostasis. Therefore, the current findings of the effects of certain functional AAs on the gut‐microbiome‐immune axis are reviewed, illustrating signaling pathways of tryptophan (Trp), glutamine (Gln), methionine (Met), and branched‐chain AAs (BCAAs) in the intestinal barrier and regarding immunity via crosstalk with their receptors or ligands. These findings have shed light on the clinical applications of dietary AAs in improving gut microbiota and mucosal immunity, therefore benefiting the gut as well as local and systemic health.     

Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice

Scope : In this study, we evaluated the efficacy of lycopene against the growth of prostate cancer in vivo. Methods and results : Athymic nude mice were implanted subcutaneously with human androgen‐independent prostate carcinoma PC‐3 cells. They were supplemented with a low or a high dose of lycopene (4 and 16 mg/kg) and a single dose of β‐carotene (16 mg/kg) twice a week for 7 wk. At the end of the experiment, both lycopene and β‐carotene strongly inhibited the tumor growth, as evidenced by the decrease in tumor volume and tumor weight. High‐dosage lycopene and β‐carotene significantly decreased the expression of proliferating cell nuclear antigen in tumor tissues and increased the levels of insulin‐like growth factor‐binding protein‐3 in plasma. In addition, high‐dosage lycopene supplementation significantly decreased the vascular endothelial growth factor (VEGF) levels in plasma. In contrast, β‐carotene supplementation significantly increased the VEGF levels, as compared with tumor control group. Conclusion : Lycopene and β‐carotene supplementation suppressed the growth of prostate tumor cells, and the effects are likely associated with reduction of proliferation (attenuation of proliferating cell nuclear antigen expression) and with interference of the insulin‐like growth factor 1 signaling (increased plasma insulin‐like growth factor‐binding protein‐3 levels). Furthermore, the inhibition of VEGF by lycopene suggests that the antitumor mechanisms of lycopene also involve anti‐angiogenesis.     

Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway

The aberrant regulation of the phosphoinositide 3-kinase/Akt survival signaling pathway in cancer has prompted significant interest in suppression of this pathway to treat cancer. Previous studies identified an important role for phosphoinositide 3-kinase/Akt in colon cancer progression. Lycopene, a major component in tomato, exhibited potential anti-carcinogenic activity. Consumption of tomato has been associated with reduced risk of several types of human cancer. However, the inhibitory mechanisms of lycopene on the proliferation of human colon cancer have not been studied well yet. Thus we investigated the inhibitory effects of lycopene on the Akt signaling pathway in human colon cancer HT-29 cells. Lycopene inhibited cell proliferation in human colon cancer HT-29 cells with a IC(50) value of 10 microM. Lycopene treatment suppressed Akt activation and non-phosphorylated beta-catenin protein level in human colon cancer cells. Immunocytochemical results indicated that lycopene increased the phosphorylated form of beta-catenin proteins. These effects were also associated with reduced promoter activity and protein expression of cyclin D1. Furthermore, lycopene significantly increased nuclear cyclin-dependent kinase inhibitor p27(kip)abundance and inhibited phosphorylation of the retinoblastoma tumor suppressor protein in human colon cancer cells. In conclusion, lycopene inhibited cell proliferation of human colon cancer cells via suppression of the Akt signaling pathway and downstream targeted molecules.     

Egg White Ovotransferrin‐Derived ACE Inhibitory Peptide Ameliorates Angiotensin II‐Stimulated Insulin Resistance in Skeletal Muscle Cells

1 Scope

The renin‐angiotensin system (RAS) is a major contributor to the development of insulin resistance and its related complications. Egg white ovotransferrin‐derived tripeptides, IRW (Ile‐Arg‐Trp), IQW (Ile‐Gln‐Trp), or LKP (Leu‐Lys‐Pro) are previously identified as the inhibitors of angiotensin‐converting enzyme (ACE), a key enzyme in the RAS. This study aims at determining whether these peptides are effective in improving insulin resistance, and their mechanisms of action, in a rat derived skeletal muscle cell line (L6 cells).

2 Methods and results

Insulin resistance is induced by treating L6 cells with 1 μm angiotensin II (Ang II) for 24 h. Effects of peptides on glucose uptake are determined using glucose uptake assay, glucose transporter 4 (GLUT4) translocation by immunofluorescence, reactive oxygen species (ROS) by dihydroethidium (DHE) staining, while insulin signaling pathway, Ang II receptor (AT1R or AT2R) levels, and NADPH oxidase activation are measured using Western Blot. Only IRW treatment significantly improves insulin resistance in L6 cells via stimulation of insulin signaling. IRW decreases Ang II‐stimulated AT1R expression, ROS formation, and NADPH oxidase activation.

3 Conclusions

Of three ACE inhibitory peptides studied, only IRW improves insulin resistance in L6 cells, at least partially via reduced AT1R expression and its anti‐oxidative activity.     

Optimisation of biological and physical parameters for lycopene supercritical CO2 extraction from ordinary and high‐pigment tomato cultivars

BACKGROUND: Lycopene is used for several industrial applications. Supercritical CO₂ (SC‐CO₂) extraction from red‐ripe tomato fruits is an excellent technique to replace the use of harmful solvents. In this study, starting from red‐ripe tomatoes of ordinary and high‐lycopene cultivars, the effect of different agronomical and technical aspects on lycopene content, stability and yield was evaluated throughout the production process from fresh tomatoes to the final SC‐CO₂‐extracted oleoresin containing lycopene. RESULTS: Red‐ripe tomato cultivars differed in their lycopene content. Irrigation excess or deficit caused an increase in the amount of lycopene in the fruits. Fresh tomatoes were processed into a lyophilised matrix suitable for SC‐CO₂ extraction, which could be stored for more than 6 months at ? 20 °C without lycopene loss. Under the optimal extraction conditions, efficiencies of up to 80% were achieved, but the recovery of lycopene in the extracted oleoresin was very low (～24%). Co‐extraction of the tomato matrix mixed with a lipid co‐matrix allowed the recovery of ～90% of lycopene in the oleoresin. Using the high‐lycopene cultivars, the yield of total extracted lycopene increased by ～60% with respect to the ordinary cultivars. Lipids and other biologically active molecules were present in the oleoresin. CONCLUSION: A method for extracting, from a tomato matrix, a natural and solvent‐free oleoresin containing lycopene dissolved in a highly unsaturated vegetable oil has been described. The oleoresin represents an excellent product for testing on cancer and cardiovascular disease prevention. Copyright © 2010 Society of Chemical Industry     

Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF‐7 tumor growth through estrogen receptor‐ and growth factor‐signaling pathways

This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF‐7) at low circulating estrogen levels, and potential mechanisms of action. In a 2×2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER‐mediated (ER‐α, ER‐β, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor‐mediated (epidermal growth factor receptor, human epidermal growth factor receptor‐2, insulin‐like growth factor receptor‐1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM‐treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER‐ and growth factor‐mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM‐treated tumors but FO was more effective. The mechanisms involve both the ER‐ and growth factor‐signaling pathways.     

Preparation,Bioavailability, and Mechanism of Emerging Activities of Ile‐Pro‐Pro and Val‐Pro‐Pro

Ile‐Pro‐Pro and Val‐Pro‐Pro are two most well‐known food‐derived bioactive peptides, initially identified as inhibitors of angiotensin I‐converting enzyme (ACE) from a sample of sour milk. These two peptides were identified in fermented and enzymatic hydrolyzed cow and non‐cow (that is, goat, sheep, buffalo, yak, camel, mare, and donkey) milk, as well as sourdough prepared from wheat, rye, and malt. Similar to other bioactive peptides, bioavailability of these peptides is low (about 0.1%), reaching picomolar concentration in human plasma; they showed blood pressure lowering activity in animals and in human, via improved endothelial function, activation of ACE2, and anti‐inflammatory property. Emerging bioactivities of these two peptides toward against metabolic syndrome and bone‐protection received limited attention, but may open up new applications of these peptides as functional food ingredients. Further studies are warranted to determine the best source as well as to identify novel enzymes (particularly from traditional fermented milk products) to improve the efficiency of production, to characterize possible peptide receptors using a combination of omics technology with molecular methods to understand if these two peptides act as signal‐like molecules, to improve their bioavailability, and to explore new applications based on emerging bioactivities.     

Tomato powder impedes the development of azoxymethane‐induced colorectal cancer in rats through suppression of COX‐2 expression via NF‐κB and regulating Nrf2/HO‐1 pathway

Cancer is one of the leading causes of death worldwide. Since dietary factors have been connected to a reduced risk of a diversity of human cancers, in this study we investigated the effects of tomato powder (TP) on the development of azoxymethane (AOM)‐induced colorectal cancer in Wistar rats, and possible mechanism(s) by which TP shows its chemopreventive activity. Here we show that TP added to feed at 5% rate decreases the rate of aberrant crypt foci (ACF) and reduces the development of adenocarcinoma and growth of AOM‐induced colorectal cancer in rats. In addition, we demonstrate that TP supplementation shows its chemopreventive activities through inhibition of cyclooxygenase‐2 (COX‐2) expression via NF‐κB pathway and promotion of apoptosis, as well as regulating Nrf2/HO‐1 signaling pathway in colorectal tissue of AOM‐treated rats. Our findings identify an intimate connection between dietary supplementation of TP and the decreased risk of colorectal cancer in rats, and suggest that consumption of TP would be a natural candidate for the prevention of colorectal cancer in men.     

Bioactivity of Flavonoids on Insulin‐Secreting Cells

ABSTRACT: Flavonoids are usually found in fruits and other plant organs and therefore widely consumed. They are antioxidants, anti‐inflammatory, anticarcinogenic, and protective against coronary disease and metabolic disorders. These beneficial effects make them good candidates for the development of new functional foods with potential protective/preventive properties against several diseases. We must consider that this fact could lead to a higher intake of some of these flavonoids. Most of the studies concerning their beneficial effects showed peripheral activity of these molecules, but there is no clear information about their central effects on a key organ on metabolic control: the endocrine pancreas. The pancreas has an endocrine function of major importance to regulate nutrient metabolism, such as control of glucose homeostasis via insulin and glucagon secretion. Its importance in whole body nutrient equilibrium is highlighted by the fact that several pathologies, such as type 1 and/or 2 diabetes, are related at some point to a pancreatic cell deregulation. In this review, we compile the most relevant results concerning the effects of flavonoids on several aspects of pancreatic functionality. Studies using animals with drug‐induced diabetes support the hypothesis that flavonoids can ameliorate this pathogenesis. The great diversity of flavonoid structures makes it difficult to establish common effects in the pancreas. Published data suggest that there might be direct effects of flavonoids on insulin secretion, as well as on prevention of beta‐cell apoptosis, and they could even act via modulation of proliferation. The mechanisms of action involve mainly their antioxidant properties, but other pathways might also take place.     

Regulatory Roles of Flavonoids on Inflammasome Activation during Inflammatory Responses

Inflammation is an innate immune response to noxious stimuli to protect the body from pathogens. Inflammatory responses consist of two main steps: priming and triggering. In priming, inflammatory cells increase expressions of inflammatory molecules, while in triggering, inflammasomes are activated, resulting in cell death and pro‐inflammatory cytokine secretion. Inflammasomes are protein complexes comprising intracellular pattern recognition receptors (PRRs) (e.g., nucleotide‐binding oligomerization domain‐like receptors (NLRs), absent in melanoma 2 (AIM2), and caspases‐4/5/11) and pro‐caspase‐1 with or without a bipartite adaptor molecule ASC. Inflammasome activation induces pyroptosis, inflammatory cell death, and stimulates caspase‐1‐mediated secretion of interleukin (IL)‐1b and IL‐18. Flavonoids are secondary metabolites found in various plants and are considered as critical ingredients promoting health and ameliorating various disease symptoms. Anti‐inflammatory activity of flavonoids and underlying mechanisms have been widely studied. This review introduces current knowledge on different types of inflammasomes and their activation during inflammatory responses and discusses recent studies regarding anti‐inflammatory roles of flavonoids as suppressors of inflammasomes in inflammatory conditions. Understanding the regulatory effects of flavonoids on inflammasome activation will increase our knowledge of flavonoid‐mediated anti‐inflammatory activity and provide new insights into the development of flavonoid preparations to prevent and treat human inflammatory diseases.     

Protective Effects of Anthocyanins in Obesity‐Associated Inflammation and Changes in Gut Microbiome

Obesity is a complex disease and a major public health epidemic. Chronic, low‐grade inflammation is a common underlying feature of obesity and associated metabolic diseases; adipose tissue is a major contributor to this systemic inflammation. Evidence shows that obesity‐associated inflammation may originate from gut dysfunction, including changes in intestinal bacteria or microbiome profiles. Increasingly, food and plant bioactive compounds with antioxidant and anti‐inflammatory properties are proposed to ameliorate obesity‐associated inflammation. Among these, the health‐promoting effects of anthocyanin‐rich foods are of interest here. Specifically, this review summarizes the reported benefits of anthocyanins in obesity‐associated inflammation and underlying molecular mechanisms, including the role of gut microbiome and cell signaling pathways regulated by anthocyanins both in vivo and in vitro.     

Effects of genotype and cultivation environment on lycopene content in red‐ripe tomatoes

Lycopene, a natural red pigment found in tomato, is correlated with reduced incidence of some cancers. Forty tomato varieties, including cluster F₁ hybrid tomatoes, round breeding line tomatoes (Lycopersicon esculentum Mill) and cherry tomato types (L esculentum var cerasiforme), grown under greenhouse and field conditions were evaluated for their lycopene content using high‐performance liquid chromatography (HPLC) and spectrophotometry. Lycopene content varied significantly among the tomato varieties, with cherry tomato types having the highest lycopene content. Greenhouse‐grown cluster and round tomatoes contained more lycopene (mean = 30.3 mg kg^?1) than field‐grown tomatoes (mean = 25.2 mg kg^?1), whereas cherry tomato types had a higher lycopene content in field‐grown (mean = 91.9 mg kg^?1) than in greenhouse‐grown (mean = 56.1 mg kg^?1) fruits. HPLC analysis of lycopene isomeric forms revealed a higher content of all‐trans isomers in all tomato genotypes examined. However, the cis isomeric form was exceptionally higher in the field‐ and greenhouse‐grown cherry tomato L esculentum var cerasiforme cv Gardener's Delight, which contained ～9.3 and 9.9 mg kg^?1 cis isomers respectively. Results indicate that genetics and choice of cultivation environment may have a strong influence on tomato lycopene content. Copyright © 2005 Society of Chemical Industry     

Quercetin‐induced apoptotic cascade in cancer cells: Antioxidant versus estrogen receptor α‐dependent mechanisms

The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti‐proliferative effects in many cancer cell lines. Antioxidant or pro‐oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin‐induced anti‐proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor α (ERα; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H₂O₂‐induced ROS production both in the presence and in the absence of ERα. However, this flavonoid induces the activation of p38/MAPK, leading to the pro‐apoptotic caspase‐3 activation and to the poly(ADP‐ribose) polymerase cleavage only in the presence of ERα. Notably, no down‐regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings suggest that quercetin results in HeLa cell death through an ERα‐dependent mechanism involving caspase‐ and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.     

Induction of apoptosis by tomato using space mutation breeding in human colon cancer SW480 and HT‐29 cells

BACKGROUND: As far as we know, there have been no reports concerning the functional characteristics of tomatoes using space mutation breeding. The aim of this study was to evaluate the anti‐colon cancer effect of tomatoes M1 and M2 using space mutation breeding. RESULTS: In the present study, obvious anti‐cancer activity was shown with tomato juice of M1 and M2 and their parent CK treatment in colon cancer cell lines SW480 and HT‐29 in cell growth inhibition. In addition, SW480 cells were more sensitive to M1 and M2 than HT‐29 cells in cell apoptosis. Furthermore, M1 and M2 induced cell cycle arrest both in G0–G1 and G2/M phases. CONCLUSION: These data suggest that consumption of tomato using space mutation breeding may provide benefits to inhibit growth of colon cancer cells. Therefore, tomato production using space mutation breeding may be a good candidate for development as a dietary supplement in drug therapy for colon cancer. Copyright © 2010 Society of Chemical Industry