BERRIES

In colorectal cancer suppression, black raspberry extracts have shown re-activation of tumor suppressor genes when consumed at sufficient levels for at least a month (see Highlights). Here, the absorption of anthocyanins is indicated as the mechanism meaning the effects are local to the digestive tract.

Berries active compounds include the their pigments anthocyanins, and stilbenes resveratrol and pterostilbene (see Supplements Library). Evidence from studies varies, but can show anti-inflammatory. metabolic and microbiome health effects. Wild berries have much higher concentrations of key compounds, but still modest amounts overall, clincial trials use powdered extracts or supplement classes.

Overall research studies tend to show at moderate effects on cholesterol with delphinol containing dark berries such as blackberry, blueberry, bilberry and chokeberry having tendencies to improve glucose related markers. As tends to be the case with functional food and diet, the anti-inflammatory effects are mostly seen in patient groups with some systemic inflammatory condition. In these groups, improvements in markers of inflammation can be quite substantial with sufficient doses.

There is good evidence that at sufficient concentration, anthocyanins reduce markers of vascular inflammation that are strongly linked to metastatic spread. Platelet aggregation is upregulated to evade immune response in curculation. 320mg supplements of wild bilberry for instance are reported to reduce aggregation by 29% and also 14% reduction in some adhesion molecule levels. As with most compounds, the benefits are not found in all research, and here it seems most clear in patients with some type of systemic inflammatory condition

Patented natural supplements such as Delphinol (maqui berries) and MEDOX are also emerging

ANTI-METASTATIC ACTIONS ->

EXAMPLES OF IMPROVED OUTCOMES

PRE-DIAGNOSIS OR PREVENTION

Highlighted Studies

..our results suggest that BRBs [black raspberries] protectively modulate both genetic and epigenetic biomarkers in tissues from colorectal cancer patients. The berries appeared to demethylate tumor suppressor genes (SFRP2 and WIF1) upstream, and protectively modulate the expression of genes (β-catenin, E-cadherin) downstream. . Colon and rectal tissues showed differential responses to berry treatment.. suggests that longer term treatment of colorectal cancer patients wit...

24 CRC [colorectal cancer] patients who had not received prior therapy and drank a slurry of black raspberry powder (20 g in 100 ml drinking water) 3 times a day for 1 to 9 wk. Plasma concentrations of GM-CSF and IL-8 changed in patients receiving berries for more than 10 days. These changes were correlated with beneficial changes in markers of proliferation and apoptosis observed in colorectal tissue taken within the same week… Little is known about the effect of raspberries on GM-CSF ...

13 RCTs [clinical trials] were analyzed ..with a duration longer than 4 weeks.. Our findings indicate that a median dose of 320 mg/day anthocyanins, either from fruit extracts or pure supplements, for a median intervention length of 8 weeks significantly reduced HbA_1c [glycated hemoglobin], FBG [Fasting Blood Glucose], 2-h postprandial glucose, TG [total cholesterol], and LDL

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TABLE OF REFERENCES

URL	Rating	Category	Highlight	Highlight 2
https://aacrjournals.org/clincancerres/article/17/3/598/76734/Modulation-of-Genetic-and-Epigenetic-Biomarkers-of	3	Human study	These data provide evidence of the ability of BRBs to demethylate tumor suppressor genes and to modulate other biomarkers of tumor development in the human colon and rectum. While demethylation of genes did not occur in colorectal tissues from all treated patients, the positive results with the secondary endpoints suggest that additional studies of BRBs for the prevention of colorectal cancer in humans now appear warranted.	The methylation of three Wnt inhibitors, SFRP2, SFRP5, and WIF1, upstream genes in Wnt pathway, and PAX6a, a developmental regulator, was modulated in a protective direction by BRBs in normal tissues and in colorectal tumors only in patients who received BRB treatment for an average of 4 weeks, but not in all 20 patients with 1–9 weeks of BRB treatment. This was associated with decreased expression of DNMT1. BRBs modulated expression of genes associated with Wnt pathway, proliferation, apoptosis, and angiogenesis in a protective direction.
https://pubmed.ncbi.nlm.nih.gov/28901892/	2.5	Human study	Biomarkers of thrombogenesis and platelet activation induced by ADP; platelet aggregation induced by ADP, collagen and arachidonic acid; biochemical, lipid, inflammatory and coagulation profile were evaluated before and after supplementation. ACN supplementation reduced monocyte-platelet aggregate formation by 39 %; inhibited platelet endothelial cell adhesion molecule-1 expression by 14 %; reduced platelet activation-dependant conformational change and degranulation by reducing procaspase activating compound-1 (PAC-1) (↓10 %) and P-selectin expression (↓14 %), respectively; and reduced ADP-induced whole blood platelet aggregation by 29 %	Due to its ability to mediate leucocyte infiltration, PECAM-1 when highly expressed on leucocyte population has been linked with atherosclerotic involvement( Reference Veach, Hosking and Thompson 29 ). The decreased expression of PECAM-1 in this study by 14 % (P<0·05) demonstrates ACN ability to reduce leucocyte migration and aggregate formation in the damaged endothelium that would typically occur during atherogenesis( Reference Chong, Macdonald and Lovegrove 16 ). In an ex vivo study evaluating the anti-thrombogenic properties of a phenolic metabolite, shikimic acid (SA), a reduced expression of PECAM-1 was observed post-treatment with 1 mm of SA, also demonstrating the ability of polyphenols in minimising thrombus growth
https://pmc.ncbi.nlm.nih.gov/articles/PMC3427773/	2.5	Human study	Decreased plasma IL-8 concentrations were associated with increased apoptosis of adenocarcinoma (rΔIL-8, ΔTUNEL carcinoma = −0.50; P = 0.04) and increased apoptosis of adenocarcinoma versus adjacent normal appearing tissue (rΔIL-8, ΔTUNEL carcinoma - normal = −0.52; P = 0.03; Table 3). IL-8 is a pro-inflammatory chemokine, primarily involved in trafficking of white blood cells(20), that may promote carcinogenesis by decreasing apoptosis of endothelial and cancer cells(21). Elevated expression of IL-8 in the human tumor microenvironment is one of the strongest predictors of tumor progression, metastasis, invasion, and recurrence(22). Regardless whether IL-8 result in the above mentioned changes or vice versa(20), our results suggest that changes in plasma concentrations of GM-CSF and IL-8 are associated with changes in colorectal tissue markers in response to berry treatment.	We observed that the berry treatment increased plasma concentrations of GM-CSF (+0.12 ± 0.04 pg/mL; P = 0.01) in patients receiving berries for more than 10 days (Table 2). Little is known about the effect of raspberries on GM-CSF except that quercetin, a raspberry component, stimulates GM-CSF secretion and recruitment of dendritic cells to human prostate cancer cells(14). Patients receiving berries for more than 10 days also had decreased plasma concentrations of IL-8 (−1.61 ± 0.71 pg/mL; P = 0.04; Table 2). Consistent with our results, raspberries attenuated IL-8 secretion in cell culture(15). Furthermore, supplementation of quercetin, a component of raspberries, in humans attenuated liposaccharide-induced IL-8 secretion(16). Thus, changes in circulating GM-CSF and IL-8 may indicate a treatment response in CRC patients consuming berries.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804301/	2.5	Human study	The pooled result showed that berries consumption significantly lowered the low density lipoprotein (LDL)-cholesterol..systolic blood pressure, fasting glucose , body mass index , Hemoglobin A1c (HbA1c) and tumor necrosis factor-α (TNF-α) However, no significant changes were seen in other markers. The current evidence suggests that berries consumption might be utilized as a possible new effective and safe supplementary option to better prevent and control CVD [cardiovascular disease] in humans.	The effects of berries on LDL-cholesterol reduction were found in several subgroups of individuals (i.e., longer-term intervention duration, and parallel study design). Similarly, subgroup analyses showed that significant reductions in the level of SBP were observed in subjects with shorter-term intervention duration (≤8 weeks), age ≥50 y, cranberry consumption group and parallel study design group. In addition, finding from subgroup analyzes also clearly show that berries products consumption significantly decreased the levels of serum TC, LDL-cholesterol and SBP in subjects with cardiovascular risk factors
https://pubs.rsc.org/en/content/articlehtml/2024/fo/d3fo04579j	2.5	Meta-analysis	VCAM was also measured in two studies; one study by Wang et al. observed a decrease in VCAM-1 after a 6-month intervention with black rice pigment fraction in individuals with CHD.180 VCAM plays a role in the adhesion and transmigration of leukocytes as part of the inflammatory process.124 Reducing such levels could lower the inflammatory process, atherosclerosis progression, and CVD. Xie et al.85 observed contrasting results and investigated the effects of daily consumption of Aronia berry ANT (500 mg) in 49 healthy adult former smokers over 12 weeks. Individuals with heart diseases such as CHD possess higher soluble vascular cell adhesion molecule-1 (sVCAM) levels.	hus, this systematic review focused on determining the effects of anthocyanin-containing foods and nutraceuticals on biomarkers associated with CVDs using animal studies and human interventions supported by in vitro mechanistic insights. Overall, the results showed that the regular consumption of anthocyanin-containing foods and nutraceuticals improved vascular function, lipid profile, and antioxidant and anti-inflammatory effects. The daily dosage, the participants’ health status, and the duration of the intervention also significantly influenced the results.
https://www.sciencedirect.com/science/article/pii/S0022316622086849?via%3Dihub#	2.5	Human study	We extended our findings to diabetic patients and found that berry food derived anthocyanin intervention resulted in a dual beneficial effect in diabetic patients by increasing HDL-cholesterol and lowering LDL-cholesterol concentrations, resulting in a significant improvement of lipid profiles. Changes in these risk factors, which are of the same magnitude as those observed in this study, are clinically relevant. To put this into perspective, it was reported that the rate of cardiovascular disease events is reduced by nearly 1% for each 1% reduction in LDL cholesterol and by ≥1% for each 1% increase in HDL cholesterol (35). Therefore, the 7.9% decrease in LDL cholesterol and the 19.4% increase in HDL cholesterol observed in the present study would result in a nearly 27.3% reduction in coronary artery disease risk.	Our data also point toward favorable effects on glucose homeostasis after 24 wk of anthocyanin supplementation in diabetic subjects. Indeed, HOMA-IR was improved after anthocyanin supplementation, suggesting favorable effects on insulin sensitivity. These beneficial effects of anthocyanin on metabolism are in concordance with animal studies. Because consumption of anthocyanin supplements has increased, interest in their possible interactions with drug-metabolizing enzymes has increased. In this regard, anthocyanin supplementation may affect the clearance of medications with lipid-lowering and/or glucose-lowering activities in our study patients. However, a recent study reported that anthocyanin-rich food caused only mild changes in some activities of drug-metabolizing enzymes in rat liver, whereas those in the small intestine were not affected. Thus, the consumption of anthocyanin-rich food in reasonable amounts seems to be safe, and serious supplement-drug interactions do not seem probable
https://pmc.ncbi.nlm.nih.gov/articles/PMC8714924/	2.5	Meta-analysis	Pooled analysis of RCTs showed that purified anthocyanin supplementation could significantly reduce blood LDL cholesterol (weighted mean difference (WMD): −5.43 mg/dL) and triglyceride (WMD: −6.18 mg/dL) while increase HDL cholesterol (WMD: 11.49 mg/dL) concentrations. Purified anthocyanins also markedly decreased circulating tumor necrosis factor alpha (WMD: −1.62 pg/mL) and C-reactive protein (WMD: −0.028 mg/dL). Besides, administration of anthocyanin-rich berries could significantly lower blood total cholesterol (WMD: −4.48 mg/dL) and C-reactive protein (WMD: −0.046 mg/dL)	In the present meta-analysis of RCTs and prospective cohort studies, we demonstrated that administration of purified anthocyanins effectively improved blood lipid profiles and reduced circulating CRP and TNF-α, biomarkers of chronic low-grade inflammation, while not affecting adiposity, blood pressure, or FMD. Supplementation of anthocyanin-rich berries could also moderately decrease blood concentrations of TC and CRP, albeit the ameliorative effects were less remarkable than those of purified anthocyanins. We also found that high dietary intake of anthocyanins was associated with lower CHD risk and also total CVD incidence and mortality in the pooled analysis of prospective cohort studies.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527938/	2	Human study	Of these 34 and 6 metabolites were significantly changed by BRBs in urine and plasma, respectively. Increased levels of 4-methylcatechol sulfate in both post-BRB urine and post-BRB plasma were significantly correlated with a higher level of apoptotic marker (TUNEL) in post-BRB tumors. One tricarboxylic acid (TCA) cycle metabolites, Cis-aconitate, was increased in post-BRB urine. Furthermore, BRB-derived polyphenols were absorbed and metabolized to various benzoate species, which were significantly increased in post-BRB specimens. Increased benzoate levels were positively correlated with enhanced levels of amino acid metabolites. These results suggest that BRBs induce significant metabolic changes and affect energy generating pathways. This study supports the hypothesis that BRBs might be beneficial to colorectal cancer patients through the regulation of multiple metabolites.	Numerous studies have consistently confirmed accumulation of lactate and reduced levels of TCA cycle intermediates in many cancer types, including colorectal cancer (11–13, 15, 22–24, 30, 31). This change is commonly referred to as the “Warburg effect” (32). Consistent with our previous studies which demonstrated anti-proliferative effects of BRBs in colorectal cancer patients (19), current metabolomics identified one TCA cycle intermediates, cis-aconitate, that was up-regulated by BRBs in urine (Figure 2 B). No significant changes were observed in lactate levels or lactate/pyruvate ratio in plasma specimens. However, nucleotide sugars, i.e. xylose and xylitol, were increased in post-BRB plasma/urine, which might suggest more glucose was processed through pentose phosphate pathways. Accumulation of TCA cycle intermediates suggests a higher TCA cycle turnover rate and further leads to an enhanced rate of mitochondrial oxidative respiration.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10556752/	2	Human study, Meta-analysis	13 RCTs [clinical trials] were analyzed ..with a duration longer than 4 weeks.. Our findings indicate that a median dose of 320 mg/day anthocyanins, either from fruit extracts or pure supplements, for a median intervention length of 8 weeks significantly reduced HbA1c [glycated hemoglobin], FBG [Fasting Blood Glucose], 2-h postprandial glucose, TG [total cholesterol], and LDL...However, the effects of anthocyanins on fasting insulin, HOMA-IR, TC, HDL cholesterol, systolic blood pressure, and diastolic blood pressure in patients with T2DM were not statistically significant.	The significant improvements in glycemic parameters and lipid profile, suggest the benefits of anthocyanins, especially from fruit extract or powder, in the management of T2DM, and their ability to delay the onset of lipid disorder-related diseases such as cardiovascular disease associated with T2DM. The mechanism behind this reduction in glycemic markers could be attributed to the antioxidant and anti-inflammatory activity of anthocyanins. Further research with well-designed RCTs is required to determine the optimal dosage of anthocyanins for the treatment of T2DM
https://www.sciencedirect.com/science/article/pii/S0531556524002158	2	Human study	People with higher levels of inflammation demonstrated significantly better cognitive function after anthocyanin treatment compared to placebo at 24 weeks. Additionally, these individuals had higher BMI, a greater prevalence of diabetes, increased medication usage, and lower HDL cholesterol levels compared to those with lower inflammatory profiles. The anti-inflammatory and antioxidant properties of anthocyanins suggest they could be a promising intervention, warranting future prospective trials in individuals with elevated inflammation levels.	Cluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels.
https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2021.747884/full	2	Meta-analysis	Circulating CRP and TNF-α are two commonly used biomarkers of chronic low-grade inflammation. We found reduced blood concentrations of TNF-α due to supplementation of purified anthocyanins (WMD: −1.62 pg/mL, 95% CI: −2.76, −0.48 pg/mL; pdifference = 0.005; I2 = 0.0%; nine comparisons; 481 subjects; Supplementary Table 14) but not of anthocyanin-rich berries (WMD: 0.10 pg/mL, 95% CI: −0.15, 0.35 pg/mL; pdifference = 0.436; I2 = 0.0%; 10 comparisons; 460 subjects). In addition, treatment of either purified anthocyanins (WMD: −0.028 mg/dL, 95% CI: −0.050, −0.005 mg/dL; pdifference = 0.014; I2 = 26.0%; eight comparisons; 579 subjects) or anthocyanin-rich berries (WMD: −0.046 mg/dL, 95% CI: −0.070, −0.022 mg/dL; pdifference < 0.001; I2 = 0.0%; 13 comparisons; 655 subjects) significantly lowered circulating CRP as shown	The effects of purified anthocyanins and anthocyanin-rich berries on blood lipids were inconsistent. We found considerable reductions in blood LDL-C concentrations after regular intake of purified anthocyanins (WMD: −5.43 mg/dL, 95% CI: −8.96, −1.90 mg/dL; pdifference = 0.003; I2 = 31.3%; 14 comparisons; 891 subjects; Figure 1 and Table 1) but not of anthocyanin-rich berries (WMD: −3.34 mg/dL, 95% CI: −7.39, 0.71 mg/dL; pdifference = 0.106; I2 = 81.8%; 14 comparisons; 620 subjects). Additionally, the reductions in LDL-C were more obvious in subjects taking ≥200 mg/day purified anthocyanins
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00326-1/fulltext	2	Human study	ompared to placebo group, anthocyanins at 80 mg/day for 12 weeks reduced collagen-induced platelet aggregation (-3.39±2.36%) and activated GPⅡbⅢa (-8.25±2.45%) (P < 0.05). Moreover, compared to placebo group, anthocyanins at 320 mg/day inhibited collagen-induced platelet aggregation (-7.05±2.38%), ADP-induced platelet aggregation (-7.14±2.00%), platelet ROS levels (-14.55±1.86%), and mitochondrial membrane potential (7.40±1.56%) (P < 0.05). There were dose-response relationships between anthocyanins and the attenuation of platelet aggregation, mitochondrial membrane potential and ROS levels (P for trend <0.05). Furthermore, significantly positive correlations were observed between changes in collagen-induced (r = 0.473) or ADP-induced (r = 0.551) platelet aggregation and ROS levels in subjects with dyslipidemia after the 12-week intervention (	Anthocyanins at 320 mg/day for 12 weeks also increased serum HDL-C and ApoA-1 levels, and this was consistent with our previous studies [21]. In addition, 6 weeks of anthocyanin supplementation did not significantly improve platelet activation, aggregation, oxidative stress or lipid levels. These findings suggested that anthocyanins could inhibit platelet activation, aggregation and oxidative stress in a dose-response manner and that receiving 80 mg or more of anthocyanins per day could help attenuate platelet function in individuals with dyslipidemia.
https://www.mdpi.com/2072-6643/13/6/2003	2	Meta-analysis	The tendency of delphinidin-based anthocyanins to improve TC and glucose levels were also observed. In contrast, the trials involving cyanidin-based anthocyanins only showed improvement in TC and glucose, and malvidin-based anthocyanins only showed improvement in HDL-C. The MD of TC was −0.30, −0.24, and 0.15 for delphinidin-, cyanidin-, and malvidin-based anthocyanins, respectively, and a significant difference was observed among the three groups. The result for LDL-C was similar. Sensitivity analyses indicated that, except for the effects of cyanidin-based anthocyanins on glucose and of malvidin-based anthocyanins on HDL-C, the robustness of the effects of anthocyanins or main anthocyanin in the test foods on glucose and lipid metabolism remains consistent. From these results, the effectiveness of anthocyanins in improving lipid metabolism seemed to be in the following order: delphinidin- > cyanidin- > and malvidin-based	n this meta-analysis, it was suggested that foods which contain delphinidin-, cyanidin-, and malvidin-based anthocyanins may be effective for the improvement of lipid metabolism in humans in that order, due to their chemical structure. The differences in the effects of the three main anthocyanins were particularly noticeable for TC and HDL-C. While the effects on the glucose metabolism parameters were not remarkable, they seemed to be more favorable for glucose, insulin, and HOMA-IR in trials using delphinidin-based anthocyanins compared with trials using cyanidin-based anthocyanins. Additionally, it was also suggested that the optimal conditions for achieving the effects of each compound easily, such as the types of anthocyanin source and target population, may differ. The possibility that these findings will contribute to the elucidation of anthocyanin intake to prevent lifestyle-related diseases and atherosclerosis more effectively was indicated.
https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2023.1199815/full	2	Meta-analysis	The significant improvements in glycemic parameters and lipid profile, suggest the benefits of anthocyanins, especially from fruit extract or powder, in the management of T2DM, and their ability to delay the onset of lipid disorder-related diseases such as cardiovascular disease associated with T2DM. The mechanism behind this reduction in glycemic markers could be attributed to the antioxidant and anti-inflammatory activity of anthocyanins. Further research with well-designed RCTs is required to determine the optimal dosage of anthocyanins for the treatment of T2DM and to comprehend the consequences.	Our findings indicate that a median dose of 320 mg/day anthocyanins, either from fruit extracts or pure supplements, for a median intervention length of 8 weeks significantly reduced HbA1c [Weighted Mean Difference (WMD) −0.31, p = 0.00], FBG (WMD −0.63, p = 0.00), 2-h postprandial glucose (WMD −1.60, p = 0.00), TG (WMD −0.45, p = 0.01), and LDL (WMD −0.26 p = 0.02). However, the effects of anthocyanins on fasting insulin, HOMA-IR, TC, HDL cholesterol, systolic blood pressure, and diastolic blood pressure in patients with T2DM were not statistically significant. Anthocyanins from fruit extracts or powder exhibited a higher reduction of HbA1c compared to pure anthocyanin supplements.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054926/	1	Lab study	Biological experiments showed that Gardenblue anthocyanins (L1) had antiproliferative effect on cervical cancer cells (Hela, 51.98 μg/mL), liver cancer cells (HepG2, 23.57 μg/mL), breast cancer cells (MCF-7, 113.39 μg/mL), and lung cancer cells (A549, 76.10 μg/mL), and no apparent toxic effects were indicated by methyl thiazolyl tetrazolium (MTT) assay, especially against HepG2 cells both in vitro and in vivo. After combining it with DDP (cisplatin) and DOX (doxorubicin), the antiproliferative effects were enhanced, especially when combined with DOX against HepG2 cells; the IC50 value was 0.02 μg/mL	Blueberry anthocyanins may be recommended for the treatment of HepG2 cells. Besides anthocyanins, ellagitannins, and their gut microbiota-derived metabolites, other important bioactive molecules found in blueberries were shown to trigger autophagy in human colorectal cancer cells and to induce apoptosis by increasing the expression of proapoptotic proteins p21 and p53 and decreasing the anti-apoptotic protein expression of B-cell lymphoma-2 (Bcl-2). Moreover, the proapoptotic effect was achieved through downregulation of the phosphatidylinositol 3-kinase/amino threonine protein kinase (PI3K/AKT) signaling pathway [44]. With the rise in consumer awareness regarding the need for healthy eating habits, researchers have been striving to find alternative natural sources of additives that, while being completely safe, may also have health benefits. Gardenblue contains five anthocyanins (delphinidin, peonidin, petunidin, cyanidin, and malvidin) and can inhibit the growth of cancer cells and induced apoptosis, which suggests that it may be a potential healthy food or drug.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174855/	1	Absorption and dosage, Lab study	This study demonstrates that the oral intake of whole BB powder effectively decreased MDA-MB-231–derived triple negative breast tumor growth and metastasis in mice. Taken together with our previous data, we conclude that BB ingestion affects tumor growth and metastasis through the mediation of key processes such as inflammation, cell signaling, survival, and migration through modulation of signaling pathways such as PI3K, AKT, NF-κB and β-catenin. Importantly, the dosage used in these studies was nontoxic and may be considered physiologic, because the human equivalent dose of the 5% BB diet (based on body surface area) (59) is 300 g (10.6 oz.) of fresh BB (~ 2 cups/d). Future clinical trials using whole BB powder are planned that will aid in the determination of a suitable human dose. It is our hope that the knowledge gained from this study may aid in the design of future dietary strategies for the prevention of TNBC.	In this study, tumor volume was 75% lower in mice fed the 5% BB diet and 60% lower in mice fed the 10% BB diet than in control mice (P ≤ 0.05). Tumor cell proliferation (Ki-67) was lower in the 5 and 10% BB-fed mice and cell death (Caspase 3) was greater in the 10% BB-fed mice compared to control mice....A second study tested the ability of the 5% BB diet to inhibit MDA-MB-231-luc-D3H2LN metastasis in vivo. In this study, 5% BB-fed mice developed 70% fewer liver metastases (P = 0.04) and 25% fewer lymph node metastases (P = 0.09) compared to control mice. This study demonstrates the oral antitumor and metastasis activity of whole BB powder against TNBC in mice.
https://content.iospress.com/articles/journal-of-berry-research/jbr120#jbr-6-jbr120-g004	1	Lab study	In Summary, our results show that the berries and their polyphenolics demonstrate a great degree of therapeutic effects. Results also demonstrate that the anthocyanidins show a higher degree of efficacy than the anthocyanins against lung cancer cells and that the combination of BB [Blueberry] and BRB [Black Raspberry] rendered a greater degree of lung tumor growth inhibition than individual entities. It is suggested that the BB diet be tested in a chemically-induced lung cancer model to fully recognize chemopreventive effects of BB constituents and combinations of the berry bioactives be further investigated for mechanistic studies.	It is becoming increasingly clear that the modulation of multiple pathways would be an effective approach for the prevention and treatment of human cancers, including lung cancer. The use of natural and chemotherapeutic agents acting on different deregulated gene products may represent a potentially better strategy than targeting one specific oncogene target to treat or prevent cancer and disease recurrence [24, 25]. We have reported that the mixture of anthocyanidins from BB affected distinct and overlapping molecular targets in lung cancer leading to enhanced anti-cancer effects [14]. Our current findings indicate BB anthocyanidins in combination with other polyphenolics including EA from BRB resulted in an enhanced anti-tumor effect, corroborating with the presumption of synergism when used together.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862148/	1	Lab study, Absorption and dosage	In vivo, the efficacy of blueberry to inhibit triple negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry treated mice, where apoptosis (caspase-3 expression) was increased compared to controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFκB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFκB pathway.	herefore, the results of our proliferation studies are likely a consequence of the effects of the phytochemicals in blueberries, not the production of H2O2 in the cell medium. The dose of blueberry in our in vivo study is equal to a fresh blueberry intake of 25 grams/kg. With a conversion to human dose (based on surface area) (49), this is equal to 2.03 g/kg human or 122 grams (4.3 oz) of fresh blueberries/day for a 60 kg person. A single serving of fresh blueberries is 6 oz. which is an attainable intake for the average person. Therefore, blueberry intake could be an important part of dietary cancer prevention strategies.
https://www.spandidos-publications.com/10.3892/ol.2017.6094	1	Lab study	Therefore, the present study ..revealed a significant result with respect to the use of blueberry juice for the treatment of OC [Ovarian Cancer] in the mouse model.. the present study firstly reported the molecular mechanisms for the inhibition of OC by blueberry, revealing that a suitable dosage of blueberry juice decreases the expression of COX-1 and COX-2, which are 2 biomarkers for the development of OC. .. blueberry juice decreases the levels of COX-1 and COX-2, and inhibits the progression of OC. Furthermore, detecting the levels of COX-1 and COX-2 aid in the prediction of patients at risk for OC, as reported in previous studies. Blueberry juice therapy may therefore provide a non-pharmaceutical treatment for patients with OC.	Prior to the blueberry treatment, the volumes of the OC tumors were similar between groups. Subsequent to the blueberry treatment, the volumes of OC in the 500 mg group significantly decreased by 40% compared with the group that received no blueberry treatment (P=0.0008). The high-efficiency inhibitory concentrations of blueberry were between 8 and 16 mg. The weights of the OC tumors were 4.82±0.41, 4.25±0.35, 3.16±0.23 and 2.47±0.26 g in blank, 0, 100, 200 and 400 mg blueberry groups, respectively, yielding growth inhibitions of 12.5, 35.4, and 49.4%. From the aforementioned results, the 400 mg blueberry group showed significant inhibitory results for OC (P=0.014).
https://www.mdpi.com/2076-3921/10/8/1319	1	Lab study	This is the first study to demonstrate that whole bilberry powder exhibits anticarcinogenic activity on human oral squamous carcinoma cells in vitro and in vivo. Bilberry powder inhibited the fundamental behaviors of oral cancer cells, including viability, proliferation, migration, and invasion. These inhibitory effects were more pronounced with higher bilberry powder concentrations as well as in malignant cells compared with benign cells. Moreover, compared with cetuximab, bilberry powder was observed to have comparable effects, and even more potent effects in a dose-dependent manner. The in vivo tumor-inhibiting activity of bilberry powder was confirmed in the zebrafish xenograft	The effects of 0, 1, 10, and 25 mg/mL of whole bilberry powder on the viability, proliferation, migration, and invasion of OSCC (HSC-3) cells were examined and compared with 0.01 mg/mL of cetuximab. Two oral keratinocyte cell lines served as controls. Tumor area was analyzed in zebrafish microinjected with HSC-3 cells and treated with 2.5, 10, or 25 µg/mL of bilberry powder. Metastases in the head or tail areas were counted. Bilberry powder inhibited the viability, proliferation, migration, and invasion of HSC-3 cells (p < 0.05), which was more pronounced with higher concentrations.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0770-7#Sec14	1	Lab study	The results of the present study demonstrate that polyphenol-enriched blueberry preparation potently reduced the tumor growth and metastasis in mice. We have demonstrated that repression of breast Cancer Stem Cells (CSCs) by fermented blueberry supports a diet-mediated targeting of CSCs. We have provided evidence that PEBP selectively inhibits the inflammatory signature in CSCs through signaling pathways linked to the maintenance stemness and metastasis. The mechanisms of action involve, at least in part, alterations in the MAPKs cascade and inhibition of the STAT3 signaling pathway, involved in inflammatory pathways. The results convincingly demonstrated that PEBP, indeed, holds great promise as a chemopreventive agent and may represent a novel complementary therapy against breast cancer and metastasis	Chronic administration of PEBP via incorporation in drinking water significantly reduced tumor volume and breast cancer stem cell development derived from the tumor. This diminution supports the low count of metastasis in lungs of PEBP-treated animals. Especially, PEBP anticancer and antimetastatic effects were observed at a therapeutic dose as low as 12.5 %, which, according to dose translation from animal to human using body surface area, corresponds to 1.2 cups of juice per day for humans..In addition, the biotransformation process [PEBP Polyphenol Enriched Blueberry Preparation - fermented] has probably broken down long polyphenol chains, which are poorly absorbed into gastro-intestinal tracts, increasing their bioavailability, and rendering PEBP highly functional
https://www.spandidos-publications.com/10.3892/br.2016.774	1	Lab study	The apoptosis rate in the three groups was significantly higher than that in the control group, and the apoptosis rate in the high dosage group was significantly higher than that in the low dosage group at 48 and 72 h (P<0.05). Thus, blueberries may facilitate the clinical treatment of HCC [Liver cancer], providing a novel therapeutic and prevention strategy for HCC as an anticancer therapeutic agent.	The results indicated that the blueberry juice exerted significant antitumor and therapeutic effects on HEPG2 cells. The different concentrations of blueberry juice and varying treatment times resulted in distinct influences on the invasion, migration, proliferation, cell cycle and apoptosis in the HEPG2 cells. Following co-culture with serum obtained from blueberry-fed rats, the inhibition rates of HEPG2 cells in the low-, moderate- and high-dosage groups were significantly lower than in the control group, at 48 and 72 h
https://www.nature.com/articles/srep30917#Sec2	1	Lab study	Gene expression analysis revealed the modulation of 12 genes playing different roles in the cellular migration, adhesion and invasion processes. Finally, in vivo experiments showed the growth inhibition of A17 cells orthotopically transplanted into FVB syngeneic mice fed with PRSE. Overall, we demonstrated that PRSE exerts important biological activities against a highly invasive breast cancer cell line both in vitro and in vivo suggesting the strawberry extracts as preventive/curative food strategy	..our results suggest an anti-invasive potential of “Alba” PRSE [ strawberry extracts] against breast cancer cells both in vitro and in vivo. Further studies will be necessary to unravel the pathways involved in the biological effects of PRSE [strawberry extracts] and to elucidate the molecular basis of strawberry extract action, as well as to shed light on the possible introduction in the diet of [strawberry extracts]...and strawberries as a useful nutrient to limit (or prevent) tumor formation.
https://www.mdpi.com/1422-0067/24/4/3677	1	Lab study	In conclusion, our findings show the chemoprevention potential of a PCA-based polyphenolic mixture works, at least partly, by decreasing the number of tumor-initiating cells and preventing metastasis through the upregulation of miR-145. Our data might suggest this polyphenolic mixture could act as a potent chemo-preventive agent. Finally, nutritional approaches enriched with bioactive polyphenol compounds may be a viable strategy for preventing cancer.	Studies have revealed the significant role of naturally occurring polyphenolic compounds derived from fermented blueberry fruits in cancer chemoprevention by modulation of cancer stem cell development through the epigenetic mechanism and regulation of cellular signaling pathways. In this study, we first investigated the phytochemical changes during the blueberry fermentation process..our results show that phenolic compounds found in fermented blueberry delay the formation of tumor-initiating cells in vitro and in vivo and reduce the spread of metastatic cells