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Anthocyanins and Cancer Prevention

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Abstract

Anthocyanins are a class of water-soluble flavonoids, which give the intense color to many fruits and vegetables, such as blueberries and red cabbages. Recent studies have shown that anthocyanins have a range of pharmacological properties, such as prevention of cardiovascular disease, improvement of visual functions, obesity control, and anticancer activity. Their potential anticancer effects are reported to be based on a wide variety of biological activities including anti-oxidative stress; anti-inflammation; anti-mutagenesis; induction of differentiation; inhibition of proliferation; cell cycle arrest and apoptosis; anti-invasion; anti-metastasis; anti-angiogenesis and sensitizing cancer cells to chemotherapy. This chapter summarizes the latest developments on the anticancer activities of anthocyanins and anthocyanin-rich extracts in cell culture models, animal cancer models and some clinical trials. Their chemical structures, molecular mechanisms of action in cancer prevention, and in vivo pharmacokinetics-pharmacodynamics (PK-PD) properties will also be discussed.

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... Comparisons of the antiproliferative effects of anthocyanins on normal as well as cancer cells have surprisingly revealed that they selectively inhibit cancer cell growth while having insignificant effect on normal cell growth (Fakhri et al. 2020;Matsumoto et al. 2001;Zhang et al. 2005). Moreover, anthocyanidins have a greater potential to inhibit cell proliferation than anthocyanins (Zhang et al. 2005;Hudlikar et al. 2020). Key features of anthocyanin mediated anticancer effects are presented in Table 6. ...
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Anthocyanins are naturally occurring water-soluble plant pigments belonging to the flavonoids chemical class. The red, blue and purple colours of leaves, flowers and fruits of plants confirm that they are rich sources of anthocyanins. Many in vivo and in vitro studies reveal that anthocyanins have different health beneficial effects such as antioxidant, antidiabetic, anti-inflammatory, anti-obesity, antihypertensive and anticancer properties. Major benefits of anthocyanin administration are owing to their potent anti-inflammatory and antioxidant activities. Recent investigations have revealed that anti-inflammatory activities of anthocyanins follow the inhibitory pathways of NF-кB-mediated decline of inflammatory cytokines production. Inhibition of the anti-inflammatory pathways also influences the modulation of arteriolar disorders and cardiovascular complications due to anthocyanin administration. Moreover, anthocyanins improve diabetes, obesity and cancer pathology by inhibiting NF-кB-mediated inflammatory pathways. However, considerable variations in activities do exist among structurally diverse anthocyanins. This review appraises the recent literature regarding the health benefits of anthocyanins and their molecular mechanisms in various oxidative stress related pathophysiological conditions.
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Montmorency tart cherries (Prunus cerasus L.) are rich in anthocyanins, compounds capable of augmenting fat oxidation and regulating metabolic dysfunction. The present study examined whether Montmorency tart cherry juice (MTCJ) supplementation could augment fat oxidation rates at rest and during FATMAX exercise, thus improve cardio-metabolic health. Eleven, healthy participants consumed MTCJ or placebo (PLA) twice daily, in a randomised, counterbalanced order for 20 days. Participants cycled at FATMAX for 1-h pre-, mid- (10 days) and post-supplementation whilst substrate oxidation rates were measured. Before exercise anthropometrics and resting metabolic rate were measured. Blood pressure, serum triglycerides, cholesterol, HDL, total antioxidant status (TAS) and glucose were measured immediately before and after exercise. No significant differences between conditions or interactions were observed for any functional and blood-based cardio-metabolic markers or fat oxidation during exercise or rest (P > 0.05). Pre-exercise TAS (P = 0.036) and HDL (P = 0.001) were significantly reduced from mid- to post-supplementation with MTCJ only. Twenty days’ MTCJ supplementation had no effect on fat oxidation; therefore, it is unnecessary for individuals in this participant cohort to consume MTCJ with exercise to improve cardio-metabolic biomarkers.
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Purpose To assess combined data from seventeen randomized controlled trials studying effect of anthocyanin consumption on levels of various lipids and inflammatory markers with meta-analysis approach. Methods Various databases, namely, PubMed, MEDLINE, EMBASE, and Cochrane Trial Register were used to identify randomized controlled trials (RCTs) investigating an association between anthocyanins and lipid profile and inflammatory markers. Heterogeneity was assessed using Q and I² statistics and data was expressed using mean difference with 95% confidence interval. Results Statistically significant reduction in triglyceride [mean difference (MD) = −9.16, 95% CI: −14.02 to −4.31 mg/dL, I² = 33.54%, P = 0.149], low density lipoprotein [MD = −8.86, 95% CI: −11.17 to −20.02 mg/dL, I² = 37.75%, P = 0.098], and apolipoprotein B [MD = −7.13, 95% CI: −8.66 to −5.59 mg/dL, I² = 20.42%, P = 0.287] levels and increase in high-density lipoprotein [MD = 1.67, 95% CI: 0.8 to 2.54 mg/dL, I² = 44.88%, P = 0.053] and apolipoprotein A-1 [MD = 6.1, 95% CI: 4.51 to 7.69 mg/dL, I² = 6.95%, P = 0.358] levels were observed with anthocyanin supplementation. Levels of inflammatory markers were found to reduce [TNF-∞ - MD = −1.98, 95% CI: −2.40 to −1.55 pg/mL, I² = 0%, P = 0.975; IL-6 - MD = 1.17, 95% CI: 0.8 to 1.53 pg/mL, I² = 0%, P = 0.825; hs-CRP - MD = 0.164, 95% CI: −0.06 to 0.39 mg/dL, I² = 0%, P = 0.569]. Though the effect on TC, IL-6, and hs-CRP was positive, it was nonsignificant in nature. Conclusion Anthocyanin supplementation significantly improves lipid profile and inflammatory status. However, future trials with sufficient sample size are recommended to substantiate the findings especially for the parameters showing nonsignificant improvement.
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Freeze-dried black raspberries (BRB), their component anthocyanins (ACs), and a metabolite of BRB ACs, protocatechuic acid (PCA), inhibit the development of esophagus cancer in rats induced by the carcinogen, N-nitrosomethylbenzylamine (NMBA). All three components reduce inflammation in the esophagus and in plasma. The present study determined the relation of changes in inflammatory markers to infiltration of innate immune cells into NMBA-treated esophagus. Rats were injected with NMBA (0.35 mg/kg) for five weeks while on control diet. Following NMBA treatment, rats were fed diets containing 6.1% BRB powder, an AC-rich fraction of BRBs (3.8 µmoles/g diet), or 500 ppm PCA. At weeks 15, 25 and 35, inflammatory biomarker expression in the plasma and esophagus was quantified and infiltration of immune cells in the esophagus was examined. At all three time points, BRB, AC, and PCA similarly affected cytokine production in the esophagus and plasma of NMBA-treated rats, relative to the NMBA-only control. These included decreased expression of the pro-inflammatory cytokine IL1β, and increased the expression of the anti-inflammatory cytokine IL10. Moreover, all three diets also increased the expression of IL12, a cytokine that activates both cytolytic NK and CD8+ T cells. Additionally, the three diets also decreased infiltration of both macrophages and neutrophils into the esophagus. Overall, our results suggest that another mechanism by which BRBs, ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis is by altering cytokine expression and innate immune cell-trafficking into tumor tissues.
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Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results. Objective: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer. Design: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses’ Health Study. Results: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk. Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer.
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Background: exercise-induced muscle damage (EIMD) is a multifactorial phenomenon that induces muscle function loss because of mechanical and immune stressor stimuli. This immunological stress is mostly caused by inflammation and increased oxidative status. Cherries are fruits that contain a phenolic compound known as anthocyanin, which serves as a pigment in natura. However, research suggests this pigment might provide a potent antioxidant and anti-inflammatory strategy when consumed by humans. Objectives: the aim of this study was to critically review the literature on cherry consumption focusing on identifying protective strategies against EIMD conferred by it. Methods: a research was performed in PubMed database. This review presents the results about cherry consumption and EIMD. Results: the articles identified in this review support the notion that tart cherry consumption attenuates EIMD symptoms after intense exercise bouts. This attenuation seems to be related to the antioxidant and anti-inflammatory properties of anthocyanins and other phenolic compounds present in tart cherries. Conclusion: daily consumption of tart cherries may attenuate inflammatory and oxidative responses to EIMD, leading to faster recovery after exercise bouts.
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Objective: Berries are a rich source of anthocyanins, and clinical data suggest that a polyphenol-rich diet may exert health-promoting effects by reducing oxidative stress. The aim of this study was to elucidate the effects of dietary supplementation with Delphinol (trademark owned by MNL Chile) standardized maqui berry (Aristotelia chilensis) extract on products of lipid peroxidation in healthy, overweight, and smoker subjects. Methods: In a double-blind, placebo-controlled design, 42 participants (age 45-65 years) consumed in random order either a standardized extract of maqui berry (162 mg anthocyanins) or a matched placebo, given 3 times daily for 4 weeks. The samples were collected at baseline, after the end of the supplementation, and 40 days after the end of the study. Primary outcome was the measure of oxidized low-density lipoprotein (Ox-LDL) and F2-isoprostanes in plasma and urine, respectively. Secondary outcomes included anthropometric measures, blood pressure, and lipid profile. Results: Delphinol supplementation was associated with reduced levels of Ox-LDL in the anthocyanin group compared to baseline (p < 0.05). There was also a decrease in urinary F2-isoprostanes (8-iso-prostaglandin F2α) at 4 weeks versus baseline in the Delphinol-supplemented group (p < 0.05). However, no differences in primary outcomes were evident at 40 days of follow-up. In the fourth week of the intervention, no significant differences were noted for anthropometric characteristics, ambulatory blood pressure, and lipid profile. Conclusions: Our observations suggest that dietary interventions with maqui berry extract may improve oxidative status (Ox-LDL and F2-isoprostanes) in healthy adults, overweight adults, and adult smokers.
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To develop new and effective chemopreventive agents against bone metastasis, we assessed the effects of muscadine grape skin extract (MSKE), whose main bioactive component is anthocyanin, on bone turnover, using prostate and breast cancer cell models overexpressing Snail transcription factor. MSKE has been shown previously to promote apoptosis in prostate cancer cells without affecting normal prostate epithelial cells. Snail is overexpressed in prostate and breast cancer, and is associated with increased invasion, migration and bone turnover/osteoclastogenesis. CatL is a cysteine cathepsin protease that is overexpressed in cancer and involved in bone turnover. Snail overexpression in prostate (LNCaP, ARCaP-E) and breast (MCF-7) cancer cells led to increased Cathepsin L (CatL) expression/activity and phosphorylated STAT-3 (pSTAT-3), compared to Neo vector controls, while the reverse was observed in C4-2 (the aggressive subline of LNCaP) cells with Snail knockdown. Moreover, CatL expression was higher in prostate and breast tumor tissue compared to normal tissue. MSKE decreased Snail and pSTAT3 expression, and abrogated Snail-mediated CatL activity, migration and invasion. Additionally, Snail overexpression promoted osteoclastogenesis, which was significantly inhibited by the MSKE as effectively as Z-FY-CHO, a CatL-specific inhibitor, or osteoprotegerin, a receptor activator of nuclear factor kappa B ligand (RANKL) antagonist. Overall, these novel findings suggest that Snail regulation of CatL may occur via STAT-3 signaling and can be antagonized by MSKE, leading to decreased cell invasion, migration and bone turnover. Therefore, inhibition using a natural product such as MSKE could potentially be a promising bioactive compound for bone metastatic cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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The gastric absorption of red wine anthocyanins was evaluated using a gastric MKN-28 cell barrier model. Anthocyanin transport was not affected by the presence of 4% ethanol and decreased with the increase of pH. Gastric cells pretreated with anthocyanins were found to increase anthocyanin transport. The presence of D-(+)-glucose was found to decrease anthocyanins uptake suggesting the involvement of glucose transporters. RT-PCR assays revealed that GLUT1, GLUT3 and MCT1 transporters were expressed in MKN-28 cells. Computational studies were performed to provide a structural characterization of the binding site of hGLUT1 to glucose or different anthocyanins under different forms. Docking results demonstrated that anthocyanins can bind to glucose transporters from both intracellular and extracellular sides. Anthocyanins seem to enter into the transporter by two main conformations: B ring or glucose. From MD simulations, hGLUT-1 was found to form complexes with all anthocyanins tested in the different protonation states.
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Anthocyanins are a subgroup of flavonoids responsible for the blue, purple, and red color of many fruits, flowers, and leaves. Consumption of foods rich in anthocyanins has been associated with a reduced risk of cardiovascular disease and cancer. The fate of anthocyanins after oral administration follows a unique pattern rather different from those of other flavonoids. Anthocyanins could be absorbed from the stomach as well as intestines. Active transporters may play a role in the absorption of anthocyanins from the stomach as well as in their transfer within the kidney or liver. Anthocyanins such as cyanidin-3-glucoside and pelargonidin-3-glucoside could be absorbed in their intact form into the gastrointestinal wall; undergo extensive first-pass metabolism; and enter the systemic circulation as metabolites. Phenolic acid metabolites were found in the blood stream in much higher concentrations than their parent compounds. These metabolites could be responsible for the health benefits associated with anthocyanins. Some anthocyanins can reach the large intestine in significant amounts and undergo decomposition catalyzed by microbiota. In turn, these decomposition products may contribute to the health effects associated with anthocyanins in the large intestine. This review comprehensively summarizes the existing knowledge about absorption, distribution, metabolism, and elimination of anthocyanins as well as their decomposition within the gastrointestinal lumen.
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Background: Increasing evidence from animal, epidemiological and clinical investigations suggest that dietary anthocyanins have potential to prevent chronic diseases, including cancers. It is also noteworthy that human epidermal growth factor receptor 2 (ErbB2) protein overexpression or ErbB2 gene amplification has been included as an indicator for metastasis and higher risk of recurrence for breast cancer. Materials and methods: The present experiments investigated the anti-metastasis effects of black rice anthocyanins (BRACs) on ErbB2 positive breast cancer cells in vivo and in vitro. Results: Oral administration of BRACs (150 mg/kg/day) reduced transplanted tumor growth, inhibited pulmonary metastasis, and decreased lung tumor nodules in BALB/c nude mice bearing ErbB2 positive breast cancer cell MDA-MB-453 xenografts. The capacity for migration, adhesion, motility and invasion was also inhibited by BRACs in MDA-MB-453 cells in a concentration dependent manner, accompanied by decreased activity of a transfer promoting factor, urokinase-type plasminogen activator (u-PA). Conclusions: Together, our results indicated that BRACs possess anti-metastasis potential against ErbB2 positive human breast cancer cells in vivo and in vitro through inhibition of metastasis promoting molecules.
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Anthocyanins are phytochemicals with reported vasoactive bioactivity. However, given their instability at neutral pH, they are presumed to undergo significant degradation and subsequent biotransformation. The aim of the present study was to establish the pharmacokinetics of the metabolites of cyanidin-3-glucoside (C3G), a widely consumed dietary phytochemical with potential cardio-protective properties. A 500 mg oral bolus dose of 6,8,10,3',5'-(13) C5 -C3G was fed to eight healthy male participants, followed by a 48 h collection (0, 0.5, 1, 2, 4, 6, 24, 48 h) of blood, urine, and faecal samples. Samples were analysed by HPLC-ESI-MS/MS with elimination kinetics established using non-compartmental pharmacokinetic modelling. 17 (13) C-labelled compounds were identified in serum, including (13) C5 -C3G, its degradation products, protocatechuic acid and phloroglucinaldehyde, 13 metabolites of protocatechuic acid and one metabolite derived from phloroglucinaldehyde. The maximal concentrations of the phenolic metabolites (Cmax ) ranged from 11 ± 3 nM to 1,962 ± 1,389 nM, between 1.8 ± 0.2 h and 30.1 ± 11.4 h (tmax ) post consumption, with half-lives of elimination observed between 0.4 h and 95.6 ± 77.8 h. The major phenolic metabolites identified were hippuric acid (Cmax, 1,962 ± 1,389 nM) and ferulic acid (Cmax, 827 ± 371 nM), which peaked in serum at 15.7 ± 4.1 h and 8.2 ± 4.1 h respectively. Anthocyanins are metabolised to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. Understanding the elimination kinetics of these metabolites is key to the design of future studies examining their utility in dietary interventions or as therapeutics for disease risk reduction.
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Scope Black raspberries (BRB) are a rich source of bioactive phytochemicals, including anthocyanins and ellagitannins. These phytochemicals are poorly absorbed and we hypothesize that upon reaching the colon they may be transformed by gut microbiota into various metabolites that may impact the colonic mucosa or upon absorption have systemic bioactivity. The objective of this study was to define the impact of a BRB‐containing diet on the colon microbiome in mice and quantify the phytochemical metabolites in the colon contents and the circulation. Methods and results Male mice were fed 10% (w/w) freeze‐dried BRB powder for 6 weeks. The colonic microbiota was evaluated by 16S rRNA gene sequencing. Anthocyanin and ellagitannin metabolites, protocatechuic acid and urolithins, were analyzed by HPLC‐MS/MS. The BRB diet impacted colon mucosal microbial composition with a more robust effect observed on the luminal microflora. BRB derived protocatechuic acid and urolithins were quantified in the colon, luminal contents, plasma, liver and prostate with protocatechuic acid present in higher concentrations compared to urolithins. Conclusion This study highlights the complex interactions between dietary phytochemicals, the host microbiome, and metabolism. We demonstrate that microbially‐produced phytochemical metabolites are present in the colon and systemic circulation where they may exert biological activity. This article is protected by copyright. All rights reserved
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Anthocyanin, a natural antioxidant, is reported to have cytotoxicity against cancer cells; however, the mechanism remains unclear. The aim of the present study was to investigate the mechanism by which malvidin-3-galactoside (M3G), the prominent anthocyanin in blueberry, suppresses the development of hepatocellular carcinoma. In vitro, M3G suppressed the proliferation, polarization, migration, and invasion activities of HepG2 cells by regulating the protein expression of cyclin D1, cyclin B, cyclin E, caspase-3, cleaved caspase-3, Bax, p-JNK, and p-P38; activating phosphatase and tensin homolog deleted on chromosome ten (PTEN), accompanied by a decrease in the p-AKT level; and lowering the protein expression levels of MMP-2 and MMP-9. In vivo, M3G promoted the apoptosis of liver tumor cells as determined by immunohistochemistry (cleaved caspase-3, Ki-67, PTEN, and p-AKT), a TUNEL assay, and hematoxylin-eosin staining. Overall, these results suggest that M3G, as an adjuvant ingredient or nutritional supplement, may be beneficial for liver cancer prevention, and the modulatory mechanism seems to be associated with inhibition of proliferation, apoptosis, migration, and invasion-related pathways.
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Subclinical inflammation is frequently noted in chronic diseases such as diabetes, cardiovascular disease (CVD) and obesity. Accumulating epidemiological evidence demonstrates that diets rich in vegetables and fruits, e.g., cherries, may significantly reduce the risk of chronic disease, in part, via antioxidant and anti-inflammatory activities. In this randomized, placebo-controlled crossover study, we recruited 10 at-risk participants (38.1 ± 12.5 y; 8 females, 2 males) with BMI > 25.0 kg/m2 (32.2 ± 4.6 kg/m2; 5 obese, 5 overweight) to consume 240 mL (8 ounces) daily of either 100% tart cherry juice (TCJ) or an alternate placebo beverage, for 4 weeks with a 2-week intervening washout period before switching to the alternate beverage for four weeks. Fasting blood samples were collected at the beginning and end of each arm for measurement of biomarkers of inflammation. The erythrocyte sedimentation rate (ESR), an indicator of chronic inflammation, was significantly (p < 0.05) lower with TCJ than with the placebo beverage, which increased ESR by 19%. Mean baseline hsCRP, an indicator of acute inflammation, was 7.0 ± 5.2 mg /L and consumption of TCJ did not affect hsCRP levels. The chemokine MCP-1 and cytokine TNF-alpha were lower in participants after consuming TCJ compared to those consuming the placebo beverage. Plasma IL-6 and IL-l0 were not different between treatments. Collectively, the data suggest that authentic 100% TCJ may reduce biomarkers of inflammation often noted in chronic disease and may be a preferable dietary selection compared to artificially sweetened beverages.
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Açaí (Euterpe oleracea Mart.) berries, characterized by high polyphenol concentrations (predominantly anthocyanins), have demonstrated anti-inflammatory and anti-diabetic activities. The study objective was to determine the modulation of lipid and glucose-metabolism, as well as oxidative stress and inflammation, by an açaí-beverage (containing 1,139 mg/L gallic acid equivalents of total polyphenolics) in 37 individuals with metabolic syndrome (BMI 33.5 ± 6.7 kg/m²) who were randomized to consume 325 mL twice/d of a placebo control or açaí-beverage for 12 weeks. Anthropometric measurements, dietary intake, and blood and urine samples were collected at baseline and after 12 weeks of consumption. Two functional biomarkers, plasma level of interferon gamma (IFN-γ) and urinary level of 8-isoprostane, were significantly decreased after 12 weeks of açaí consumption compared to the placebo control (p=0.0141 and 0.0099, respectively). No significant modification of biomarkers for lipid- and glucose-metabolism was observed in this study. Findings from this small pilot study provide a weak indication that the selected dose of açaí polyphenols may be beneficial in metabolic syndrome as only two biomarkers for inflammation and oxidative stress were improved over 12 weeks. Follow-up studies should be conducted with higher polyphenol-doses before drawing conclusions regarding the efficacy of açaí polyphenols in metabolic syndrome.
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Tart cherries have been reported to exert potential health benefits attributed to their specific and abundant polyphenol content. However, there is a need to study the impact and fate of tart cherries polyphenols in the gut microbiota. Here, tart cherries, pure polyphenols (and apricots) were submitted to in vitro bacterial fermentation assays and assessed through 16S rRNA gene sequence sequencing and metabolomics. A short-term (5 days, 8 oz. daily) human dietary intervention study was also conducted for microbiota analyses. Tart cherry concentrate juices were found to contain expected abundances of anthocyanins (cyanidin-glycosylrutinoside) and flavonoids (quercetin-rutinoside) and high amounts of chlorogenic and neochlorogenic acids. Targeted metabolomics confirmed that gut microbes were able to degrade those polyphenols mainly to 4-hydroxyphenylpropionic acids and to lower amounts of epicatechin and 4-hydroxybenzoic acids. Tart cherries were found to induce a large increase of Bacteroides in vitro, likely due to the input of polysaccharides, but prebiotic effect was also suggested by Bifidobacterium increase from chlorogenic acid. In the human study, two distinct and inverse responses to tart cherry consumption were associated with initial levels of Bacteroides. High Bacteroides individuals responded with a decrease in Bacteroides and Bifidobacterium, and an increase of Lachnospiraceae, Ruminococcus and Collinsella. Low Bacteroides individuals responded with an increase in Bacteroides or Prevotella and Bifidobacterium, and a decrease of Lachnospiraceae, Ruminococcus and Collinsella. These data confirm that gut microbiota metabolism, in particular the potential existence of different metabotypes, needs to be considered in studies attempting to link tart cherries consumption and health.
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Freeze-dried black raspberry powder is considered as a potential cancer chemopreventive agent. In this study, we fed AOM/DSS treated C57BL/6J mice with diet containing black raspberry anthocyanins for 12 weeks and this led to a reduction in colon carcinogenesis. These animals had consistently lower tumor multiplicity compared to AOM/DSS-treated mice not receiving BRB anthocyanins. In AOM/DSS-treated mice, the number of pathogenic bacteria, including Desulfovibriosp and Enterococcus spp, were increased significantly, whereas probiotics such as Eubacterium rectale, Faecalibacterium prausnitzii and Lactobacillus were dramatically decreased, but BRB anthocyanins supplement could reverse this imbalance in gut microbiota. BRB anthocyanins also caused the demethylation of the SFRP2 gene promoter, resulting in increased expression of SFRP2, both at the mRNA and protein levels. Furthermore, the expression levels of DNMT31 and DNMT3B, as well as of p-STAT3 were down-regulated by BRB anthocyanins in these animals. Taken together, these results suggested that BRB anthocyanins could modulate the composition of gut commensal microbiota and changes in inflammation and the methylation status of the SFRP2 gene may play a central role in the chemoprevention of colorectal cancer.
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Strawberries are a dietary source of anthocyanins, particularly pelargonidin glycosides. Dietary anthocyanins have received increasing attention among researchers and consumers due to their health benefits. The oral bioavailability of anthocyanins is reported to be low and various dietary factors may influence their oral bioavailability further. Milk is suggested to reduce (poly)phenols’ oral bioavailability. However, the effect of milk on anthocyanin oral bioavailability remains uncertain. Likewise, mixed nutrient meals may influence the oral bioavailability of anthocyanins. Therefore, the purpose of this study was to assess the effect of milk on the oral bioavailability and other pharmacokinetic (PK) variables of strawberry anthocyanins consumed with and without a meal. Nine healthy participants consumed a strawberry beverage prepared in milk or water with a standard meal on two occasions. On two additional occasions, the beverages were given to a subset (n = 4) of participants to determine the impact of the meal on anthocyanin PK variables, including oral bioavailability. Independent of the meal, beverages prepared in milk significantly reduced the peak plasma concentrations (Cmax) of pelargonidin-3-O-glucoside (P-3-G), pelargonidin-glucuronide (PG) and pelargonidin-3-O-rutinoside (P-3-R), as well as the PG and P-3-R area under the curve (AUC) (p < 0.05) compared to beverages prepared in water. Milk did not influence the oral relative bioavailability of pelargonidin anthocyanins under meal conditions; however, the oral relative bioavailability of pelargonidin anthocyanins was reduced by ∼50% by milk under without meal conditions (p < 0.05). Consuming strawberry beverages made with milk and consuming those made with water with and without a meal influenced different aspects of strawberry anthocyanin PKs. The significance of this effect on clinical efficacy requires additional research.
Article
The objective was to compare the anti-proliferative effect of anthocyanin-rich plant extracts on human colon cancer cells and determine their mechanism of action. Eleven extracts were tested: red (RG) and purple grape, purple sweet potato, purple carrot, black and purple bean, black lentil (BL), black peanut, sorghum (SH), black rice, and blue wheat. HCT-116 and HT-29 inhibition correlated with total phenolics (r = 0.87 and 0.77, respectively), delphinidin-3-O-glucoside concentration with HT-29 inhibition (r = 0.69). The concentration inhibition fifty (IC50) for BL, SH, RG on HT-29 and HCT-116 cell proliferation ranged 0.9–2.0 mg/mL. Extracts decreased expression of anti-apoptotic proteins (survivin, cIAP-2, XIAP), induced apoptosis, and arrested cells in G1. Anthocyanins exhibited tyrosine kinase inhibitory potential in silico and biochemically; cyanidin-3-O-glucoside had one of the highest binding affinities with all kinases, especially ABL1 (−8.5 kcal/mol). Cyanidin-3-O-glucoside and delphinidin-3-O-glucoside inhibited EGFR (IC50 = 0.10 and 2.37 µM, respectively). Cyanidin-3-O-glucoside was the most potent anthocyanin on kinase inhibition.
Article
Background: Colorectal cancer is the main leading cause of cancer-related deaths worldwide. Present data suggest that plant-derived anthocyanins have anti-inflammatory and chemopreventive properties. This study was aimed at evaluating the effect of an anthocyanin-rich extract from bilberries on colorectal tumour development and growth in the administration of azoxymethan (AOM)/dextran sodium sulfate (DSS) mouse model. Methods: Colonic carcinogenesis was induced by AOM and DSS 3 or 5%, respectively, in 50 female Balb/c mice. Mice received either normal food (controls) or a diet containing either 10 or 1% anthocyanin-rich bilberry extract. Colonoscopy took place at week 4 and 9 after initiation of carcinogenesis. After termination at week 9, colon samples were analysed macroscopically and microscopically. Results: Mice receiving 10% anthocyanins showed significantly (p < 0.004) less reduced colon length (12.1 cm [8.5-14.4 cm]) as compared to controls (11.2 cm [9.8-12.3]) indicating less inflammation. Mice fed with 10% anthocyanin-rich extract revealed significantly less mean tumour numbers (n = 1.2) compared to control (n = 14) and anthocyanin 1% treated mice (n = 10.6, p < 0.001). Conclusion: Anthocyanins prevented the formation and growth of colorectal cancer in AOM/DSS-treated Balb/c mice. Further studies should investigate the mechanisms of how anthocyanins influence the development of colorectal cancer.
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Beneficial properties attributed to the intake of fruit and red wine have been associated with the presence of significant amounts of anthocyanins. However, their low absorption and consequent accumulation in the gut have generated the suspicion that colonic metabolites of anthocyanins are probably involved in their protective effects. Grape pomace and strawberries extracts, rich in malvidin- and pelargonidin-glucoside, respectively, were fermented in-vitro using human feces as microbial inoculum. After 8 h of anaerobic incubation, the anthocyanins were almost completely degraded while their microbial metabolites concentration was highest at 24 h. Syringic acid and tyrosol were the main metabolites of grape and strawberry extracts respectively. Based on the metabolites detected, metabolic pathways of malvidin and pelargonidin glucosides were proposed. Anthocyanin-rich grape and strawberry extracts and their generated metabolites such as hydroxyphenylacetic acid showed apopototic effects in HT-29 colon cancer cells and may suggest their possible contribution as anti-carcinogenic agents.
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Trastuzumab (Herceptin®) is a recombinant humanized monoclonal antibody that is targeted against the human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor. Trastuzumab has been successfully used to treat patients with HER2-positive breast cancer, which accounts for ~25% of invasive breast cancer. However, the majority of patients who initially respond to trastuzumab demonstrate disease progression within 1 year of treatment. Therefore, identifying alternative drugs that overcome trastuzumab resistance and target HER2 may increase the magnitude and duration of response. Through a high‑throughput screening approach, we previously identified numerous anthocyanins that exert activity in HER2‑positive human breast cancer cell lines. The present study aimed to evaluate the anti‑tumor properties of anthocyanins against parental HER2‑positive cells and derivative trastuzumab‑resistant cells in vitro and in vivo. Cell proliferation, western blotting, Annexin V staining, migration and invasion assays were used to determine the effects of anthocyanins in vitro. Cyanidin-3-glucoside and peonidin-3-glucoside were able to inhibit phosphorylation of HER2, induce apoptosis, suppress migration and invasion, and inhibit tumor cell growth. Coupled with the fact that anthocyanins have been used for decades as supplements for the treatment of various types of cancer in Asia, the present study may have established a framework for the development and testing of anthocyanins as a novel treatment paradigm used to overcome classical trastuzumab-resistance and to improve the outcome of this disease.
Article
Lester A Mitscher received his PhD degree in Chemistry in 1958 from Wayne State University, Detroit, USA, where he worked on the structure of coffee oil diterpenes and on optical rotatory dispersion. He continued his work on natural product chemistry at Lederle Laboratories where he rose to group leader in antibiotic discovery until he accepted an assistant professorship in Natural Products Chemistry at Ohio State University (1967), rising soon to the position of Professor. In 1975 he accepted a University Distinguished Professorship and Chairmanship in the Department of Medicinal Chemistry at Kansas University. He returned to the faculty in 1992, and remains there. His academic studies have centered on spectroscopy, synthesis, screening, and structure determination, primarily of naturally occurring antimicrobial and antimutagenic agents. He has published actively in the field of herbal medicines. He consults extensively in the pharmaceutical industry and is a member of the National Institutes of Health Drug Discovery and Antimicrobial Resistance Study Section. His research awards include the Smissman Award in Medicinal Chemistry (American Chemical Society), Volweiler Award (American Association for Pharmaceutical Education), the Research Achievement Award in Natural Products Chemistry (American Pharmaceutical Association), the Award in Medicinal Chemistry, Medicinal Chemistry Division, ACS, and he is an Elected Fellow of the American Association for the Advancement of Science.
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Anthocyanin, a phenolic compound, has been reported to have an anti-inflammatory effect against lipopolysaccharide (LPS) induced changes in immune cells. However, little is known about the molecular mechanisms underlying its anti-inflammatory effects. Few research studies have concerned the anti-inflammation properties of colored rice extract as a functional material. Therefore, the purpose of this study was to examine anti-inflammatory effects of the polar fraction of black rice whole grain extracts (BR-WG-P) that features a high anthocyanin content. Our results showed that BR-WG-P significantly inhibited LPS-induced pro- inflammatory mediators, including production of NO and expression of iNOS and COX-2. In addition, secretion of pro-inflammatory cytokines including TNF-α and IL-6 was also significantly inhibited. Moreover, BR-WG-P and anthocyanin inhibited NF-kB and AP-1 translocation into the nucleus. BR-WG-P also decreased the phosphorylation of ERK, p38 and JNK in a dose dependent manner. These results suggested that BR-WG-P might suppress LPS-induced inflammation via the inhibition of the MAPK signaling pathway leading to decrease of NF-kB and AP-1 translocation. All of these results indicate that BR-WG-P exhibits therapeutic potential associated with the anthocyanin content in the extract for treating inflammatory diseases associated with cancer.
Article
Epidemiological reports as well as experimental studies have demonstrated the significant health benefits provided by regular berry consumption. Berries possess both prophylactic and therapeutic potential against several chronic illnesses, such as cardiovascular, neurodegenerative and neoplastic diseases. Berries owe their health benefits to phytoconstituents, such as polyphenolic anthocyanins, ellagic acid and a diverse array of phytochemicals bestowed with potent antioxidant and anti-inflammatory effects as well as the ability to engage a multitude of signaling pathways. This review highlights the principal chemical constituents present in berries and their primary molecular targets. The article presents and critically analyzes the chemopreventive and therapeutic potential of berry extracts, fractions and bioactive components on various cancers of the gastrointestinal tract (GIT), including esophageal, stomach, intestinal and colorectal cancers as well as cancers of the upper aerodigestive tract, such as oral cancer. The current status of clinical studies evaluating berry products in several aforementioned cancers is presented. Various emerging issues including dose-ranging and dosage forms, the role of synergy and the usage of combination therapy as well as other relevant areas essential for the development of berry phytoconstituents as mainstream chemopreventive and therapeutic agents against aerodigestive and GIT cancers are critically discussed.
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Oxidative stress plays an essential role in the pathogenesis of type 2 diabetes. Anthocyanin, a natural antioxidant, has been reported to reduce oxidative stress and to attenuate insulin resistance and diabetes in animal models; however, the translation of these observations to humans has not been fully tested. This study was designed to investigate the effects of purified anthocyanins on dyslipidemia, oxidative status, and insulin sensitivity in patients with type 2 diabetes. A total of 58 diabetic patients were given 160 mg of anthocyanins twice daily or placebo (n = 29/group) for 24 wk in a randomized, placebo-controlled, double-blind trial. Participants and investigators were masked to treatment allocation. Anthocyanin supplementation significantly decreased serum LDL cholesterol (by 7.9%; P < 0.05), triglycerides (by 23.0%; P < 0.01), apolipoprotein (apo) B-48 (by 16.5%; P < 0.05), and apo C-III (by 11.0%; P < 0.01) and increased HDL cholesterol (by 19.4%; P < 0.05) compared with placebo after the 24-wk intervention. In addition, patients in the anthocyanin group showed higher total radical-trapping antioxidant parameter and ferric ion reducing antioxidant power values than did patients in the placebo group (both P < 0.05). Serum concentrations of 8-iso-prostaglandin F2α, 13-hydroxyoctadecadienoic acid, and carbonylated proteins in patients in the anthocyanin group were significantly less than in patients in the placebo group (23.4%, 25.8%; P < 0.01 and 20%; P = 0.022, respectively). Furthermore, supplementation with anthocyanin lowered fasting plasma glucose (by 8.5%; P < 0.05) and homeostasis model assessment for insulin resistance index (by 13%; P < 0.05), and elevated serum adiponectin (by 23.4%; P < 0.01) and β-hydroxybutyrate (by 42.4%; P = 0.01) concentrations compared with placebo supplementation. These findings demonstrate that anthocyanin supplementation exerts beneficial metabolic effects in subjects with type 2 diabetes by improving dyslipidemia, enhancing antioxidant capacity, and preventing insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT02317211. © 2015 American Society for Nutrition.
Article
Black soybeans (Glycine max (L.) Merr.) are known to be rich in polyphenols, including anthocyanins, and they have been consumed since ancient times for their beneficial effects on health. In addition, it has been reported that black soybean (BS) seed coat may ameliorate obesity and insulin resistance. In the present study, we administered BS extract to type 2 diabetics for 2 months to investigate the effects of BS on glycemic control and lipid metabolism parameters. In addition, we administered BS and antihyperlipidemic agent, fenofibrate, to patients with type 2 diabetes complicated by postprandial hyperlipidemia for 2 months and assessed the combined effects of fenofibrate and BS on serum lipid profile. The results showed that administration of the BS alone had no effect on the blood glucose or lipid levels, but that administration of fenofibrate alone and fenofibrate in combination with the BS significantly lowered their serum triglyceride (TG) level at fasting state, and the percent decrease in the serum TG level after combined administration was significantly higher than in the subjects who received fenofibrate alone. Furthermore, the serum LDL cholesterol concentration, which did not decrease when fenofibrate was administered alone, decreased significantly when the BS and fenofibrate were administered in combination. These results suggest that combined administration of the BS with fenofibrate enhanced the antihyperlipidemic action of fenofibrate, and the results of this study demonstrated the usefulness of the BS in clinical practice.
Article
Anthocyanins (ACN) can exert beneficial health effects not only through their antioxidative potential but also through modulation of inflammatory parameters that play a major role in CVD. A randomised cross-over study was carried out to investigate the effects of ACN-rich beverage ingestion on oxidation- and inflammation-related parameters in thirty healthy female volunteers. The participants consumed 330 ml of beverages (placebo, juice and smoothie with 8·9 (sd 0·3), 983·7 (sd 37) and 840·9 (sd 10) mg/l ACN, respectively) over 14 d. Before and after each intervention, blood and 24 h urine samples were collected. Plasma superoxide dismutase (SOD) and catalase activities increased significantly after ACN-rich beverage ingestion (P< 0·001), whereas after placebo juice ingestion no increase could be observed. Plasma glutathione peroxidase and erythrocyte SOD activities were not affected. An increase in Trolox equivalent antioxidant capacity could also be observed after juice (P< 0·001) and smoothie (P< 0·01) ingestion. The plasma and urinary concentrations of malondialdehyde decreased after ACN-rich beverage ingestion (P< 0·001), whereas those of 8-OH-2-deoxyguanosine as well as inflammation-related parameters (IL-2, -6, -8 and -10, C-reactive peptide, soluble cluster of differentiation 40 ligand, TNF-α, monocyte chemoattractant protein-1 and soluble cell adhesion molecules) were not affected. Thus, ingestion of ACN-rich beverages improves antioxidant enzyme activities and plasma antioxidant capacity, thus protecting the body against oxidative stress, a hallmark of ongoing atherosclerosis.
Article
Human epidermal growth factor receptor 2 (HER2) has been found to be overexpressed in ~25% of invasive breast cancer and is significantly associated with a poor prognosis in breast cancer patients. The anthocyanins cyanidin‑3‑glucoside (C3G) and peonidin‑3‑glucoside have been identified as potential drugs for the therapy of HER2‑positive breast cancer. They have been used as supplements in targeted therapeutics and chemotherapeutics in Asia, however, the underlying mechanism remains to be elucidated. The aim of the present study was to investigate the synergism between C3G and trastuzumab (Trast). To address this question, the response to C3G, Trast and a combination of the two drugs, in three representative HER2‑positive cell lines was evaluated. The combination treatments induced apoptosis, inhibited cell growth and affected HER2 and its downstream signaling pathway in MDA‑MB‑453, BT474 and HCC1569 cells, and the effects were synergistic. The combination of 3CG and Trast inhibited tumor growth in an in vivo xenograft model. The data from the present study suggested that C3G exhibits potent antitumor activity when combined with Trast under the investigated conditions.
Article
Anthocyanins belong to the flavonoid group of polyphenolic compounds, which are responsible for the red and blue colors of plant organs such as fruits, flowers, and leaves. Due to their frequent presence in plants, particularly berry fruits, vegetables, and grapes, they are key components of the human diet. Interest in anthocyanins has increased widely during the past decade. Numerous studies have suggested that anthocyanins have a wide range of health-promoting properties. These compounds are therefore considered to be a functional food factor, which may have important implications in the prevention of chronic diseases. The aim of this body of work is to investigate and review the current literature on anthocyanins, and particularly their pharmacokinetics and any health-promoting properties, in order to summarize existing knowledge and highlight any aspects that require further study and analysis.
Article
Tart cherries are a particularly rich source of anthocyanins. Evidence indicates that dietary intake of anthocyanins is inversely associated with arterial stiffness. We conducted an open-label randomised placebo controlled study to determine whether a tart cherry juice concentrate (Cherry Active®) reduced arterial stiffness, inflammation and risk markers for cardiovascular disease in 47 healthy adults (30-50 years). Participants consumed 30 ml of cherry concentrate diluted to a volume of 250 ml with water or the same volume of an energy matched control drink daily for six weeks. Measurements were taken at baseline and at the end of the intervention. There was no effect of the intervention on arterial stiffness (P = 0.218), c-reactive protein (P = 0.220), systolic blood pressure (P = 0.163), diastolic blood pressure (P = 0.121), total cholesterol (P = 0.342) and high density lipoprotein cholesterol (P = 0.127). At the end of the intervention, plasma antioxidant capacity (measured as the ferric reducing ability of plasma (FRAP)) was significantly higher in the intervention group than the control group (P = 0.012). We conclude that a tart cherry juice concentrate rich in anthocyanins has no effect on arterial stiffness, c-reactive protein and risk markers for cardiovascular disease, but evokes a minor increase in antioxidant status in healthy adults.
Article
Wild lowbush blueberries (Vaccinium angustifolium Ait) are a rich source of anthocyanins and other flavonoids with anti-inflammatory activities, however their individual effects on cellular signaling remain to be elucidated. In this study we determined the capacity of blueberry bioactives to protect murine RAW 264.7 macrophages from lipopolysaccharide-induced inflammation. Fractionation of the crude extract (CE) into polyphenol-rich (PPR), anthocyanin-rich (ANC), proanthocyanidin-rich (PAC), and an ethyl acetate fraction (EA) revealed that PPR, ANC, and PAC components most effectively suppressed mRNA biomarkers of acute inflammation (Cox-2, iNOS, and IL-1). Among major polyphenols found in the wild blueberries, malvidin-3-glucoside was significantly more effective than epicatechin or chlorogenic acid in reducing the expression of pro-inflammatory genes in vitro.