BLUEBERIN (from Blueberry Leaf)


Effect of Blueberin on fasting glucose, C-reactive protein and plasma aminotransferases, in female volunteers with diabetes type 2: double-blind, placebo controlled clinical study.
Georgian Med News. 2006 Dec;(141):66-72.
Abidov M, Ramazanov A, Jimenez Del Rio M, Chkhikvishvili I.
Institute of Immunopathology, Center of Modern Medicine, Russian Academy of Natural Sciences, Moscow, Russia

In a 4-week randomised placebo-controlled clinical trial we investigated the effect of 300 mg Blueberin, a phytomedicine containing 250 mg Blueberry leaves (Vaccinium arctostaphylos L, Ericaceae) extract providing minimum 50 mg 3,4-caffeoylquinic (chlorogenic) acid, and 50 mg myricetin, on fasting plasma glucose, alanine aminotransferases (ALT), aspartate aminotransferases (AST), glutamyltransferase (GGT) enzymes levels, and serum inflammatory C-Reactive proteins (CRP) in forty-two volunteer subjects (46+/-15 year of age, BMI 25+/-3 kgs/(m2)) diagnosed with Type 2 diabetes. During the 4-week trial, the Blueberin supplement was administered three times per day, 15-30 minutes prior to a meal along with 100 ml of water. Results of this trial revealed that the supplementation of Blueberin reduced fasting plasma glucose from 143+/-5,2mg/L to 104+/-5,7 mg/L (p<0,001), whereas there was no statistically significant changes in the Placebo group from 138+/-4,8 mg/L to 126+/-5,1mg/L (p>0,05). The reduction of fasting glucose was correlated with the reduction of serum CRP and in the Blueberin group from 5,18+/-1,4 mg/l to 2,14+/-1,8 mg/L (p<0,05), whereas in the Placebo group CRP levels were not significantly reduced from 5,11+/-1,7 mg/l to 4,94+/-1,1mg/L (p>0,05). Furthermore, the Blueberin also significantly reduced the levels of plasma enzymes ALT, AST and GGT, indicating that, in addition to anti-diabetes effects, the Blueberin also possess pharmacologically relevant anti-inflammatory properties.

Blueberries and Metabolic Syndrome

Metabolic syndrome is a cluster of metabolic disorders that is associated with an increased risk of cardiovascular events (Daskalopoulou et al., 2006). Type 2 diabetes, hypertension and dyslipidemia are among the metabolic disorders included in the syndrome. In 2007, 76 million Americans were diagnosed with metabolic syndrome (American Heart Association, 2009). Because metabolic syndrome is tightly correlated with obesity, this number is more likely to increase due to the growing number of obese persons that is escalating to epidemic levels, which the Western society faces today. The U.S.
National Cholesterol Education Program Adult Treatment Panel III has set diagnostic criteria for metabolic syndrome, defined as an individual having at least three of the five clinical parameters listed in CHART1.

Chart 1: Parameters for the detection of the metabolic syndrome
· (Waist circumference ≥ 40 inches for men or 35 inches for women
· (Triglycerides ≥ 150mg/dL
· (HDL cholesterol ≥ 40mg/dL for men or ≥ 50mg/dL for women
· (Blood pressure ≥ 130/85 mm Hg
· (Fasting glucose ≥ 110 mg/dL

In spite of efforts from academia and private companies, there is no magic pill that could collectively treat all the disorders encompassed under metabolic syndrome. Currently, the disorders are treated individually and the approaches are limited to drugs used for the treatment of obesity and type 2 diabetes (Flordellis et al., 2005). This approach has several disadvantages including non-specificity and cost. In one study, the effect of sibutramine, a weight loss drug, on some of the symptoms associated with the metabolic syndrome was evaluated (James et al., 2000). Sibutramine decreased the triglyceride and VLDL-cholesterol levels, and increased the HDLcholesterol levels. These effects contributed positively in the treatment of lipid imbalance in patients with metabolic syndrome. However, sibutramine does not treat other cardiovascular risks such as hypertension. Hypertension, a condition defined as having blood pressure of 140/90 mm Hg or higher, is a major risk factor for stroke and myocardial infarction. Coronary heart disease and stroke make up the largest percentage of cardiovascular diseases and are leading causes of death in the US (Lloyd-Jones et al., 2009).
High costs of medications combined with complex diseases inadequately treated leave a place for the use of alternative therapies such as nutraceuticals and functional foods. Numerous epidemiological studies (e.g., Agudo et al., 2007; Benetou et al., 2008; Ellingsen et al., 2008) have provided results that emphasize the importance of fruits and vegetables as being part of the daily diet for better health, and for the prevention of degenerative diseases including cancer and neurological disorders (Ames et al., 1993). Most of the phytonutrients found in fruits and vegetables are antioxidants. Therefore, the protective effects of fruit- and vegetable-rich diets could be attributed to the antioxidant compounds. A large clinical study conducted for 7.5 years that included 5220 adults provided results in support of recommendations to consume antioxidant-rich foods to reduce the risk of metabolic syndrome (Czernichow et al., 2009). This study also found that antioxidant supplements were effective in reducing the risk of metabolic syndrome. Apart from their positive effects on metabolic disorders, dietary antioxidants also provide other health benefits such as prevention of cancer (Ohigashi and Murakami, 2004; Khan et al., 2008). Antioxidants inhibit the initiation or propagation of oxidizing chain reactions that cause oxidative damage to lipids, proteins and nucleic acids (Yu, 1994). In addition to the well known antioxidants vitamins C and E, the flavonoids, which are ubiquitous in fruits and vegetables, have also been demonstrated to be effective antioxidants and to modulate various biological pathways (Benavente- Garcia et al., 2008; Soory, 2009). These polyphenols reduce oxidative stress by directly scavenging free radical species, chelating transition metals, quenching singlet oxygen, or inhibiting oxidative enzymes (Cos et al., 2000).
Among twenty-four fruits investigated, blueberries were found to have the highest total antioxidant capacity (TAC) in an oxygen radical absorbance capacity assay (13427 TAC/serving; Wu et al., 2004). In a cell-based assay, wild blueberries also showed the highest cellular antioxidant activity (Wolfe et al., 2008). Wild blueberries (Vaccinium angustifolium) are originally from North America and Canada. Maine is the largest producer in the world with blueberries being cultivated on over 60,000 acres (Yarborough, 2009). There are over 400 species of blueberries. Highbush blueberry, Vaccinium corymbosum, is the most commercialized species growing on over 100,000 acres in the US and Canada (Nesom, 2001). Highbush blueberry is cultivated predominantly in the northern states while in the southern states rabbiteye blueberry (Vaccinium ashei) is the species mostly produced. In Europe, bilberry (Vaccinium myrtillus) is the most common species.

In view of their strong antioxidant activity and in relation to recent reports that antioxidant-rich foods reduce the risk of metabolic syndrome, various studies on blueberries that could have applications for the treatment of the disorders encompassing metabolic syndrome are reviewed here.

Cassia S. Mizuno and Agnes M. Rimando*
United States Department of Agriculture, Agricultural Research Service,
Natural Products Utilization Research Unit
University, MS 38677-8048

Phenolic Compounds from Blueberries Can Inhibit Colon Cancer Cell Proliferation and Induce Apoptosis
Research has shown that diets rich in phenolic compounds may be associated with lower risks of several chronic diseases including cancer. This study systematically evaluated the bioactivities of phenolic compounds in rabbiteye blueberries and assessed their potential antiproliferation and apoptosis induction effects using two colon cancer cell lines, HT-29 and Caco-2. Polyphenols in three blueberry cultivars, Briteblue, Tifblue, and Powderblue, were extracted and freeze-dried. The extracts were further separated into phenolic acids, tannins, flavonols, and anthocyanins using an HLB cartridge and LH20 column. Some individual phenolic acids and flavonoids were identified by HPLC with >90% purity in anthocyanin fractions. The dried extracts and fractions were added to the cell culture medium to test for antiproliferation activities and induction of apoptosis. Flavonol and tannin fractions resulted in 50% inhibition of cell proliferation at concentrations of 70−100 and 50−100 μg/mL in HT-29 and Caco-2 cells, respectively. The phenolic acid fraction showed relatively lower bioactivities with 50% inhibition at 1000 μg/mL. The greatest antiproliferation effect among all four fractions was from the anthocyanin fractions. Both HT-29 and Caco-2 cell growth was significantly inhibited by >50% by the anthocyanin fractions at concentrations of 15−50 μg/mL. Anthocyanin fractions also resulted in 2−7 times increases in DNA fragmentation, indicating the induction of apoptosis. The effective dosage levels are close to the reported range of anthocyanin concentrations in rat plasma. These findings suggest that blueberry intake may reduce colon cancer risk.
Yi W, Fischer J, Krewer G, & CC. Akoh C. J. Agric. Food Chem., 2005, 53 (18), pp 7320–7329. DOI: 10.1021/jf051333o

Differential effects of blueberry proanthocyanidins on androgen sensitive and insensitive human prostate cancer cell lines
Blueberries are rich in health-promoting polyphenolic compounds including proanthocyanidins. The purpose of this study was to determine if proanthocyanidin-rich fractions from both wild and cultivated blueberry fruit have the same inhibitory effects on the proliferation of LNCaP, an androgen-sensitive prostate cancer cell line, and DU145, a more aggressive androgen insensitive prostate cancer cell line. When 20μg/ml of a wild blueberry proanthocyanidin fraction (fraction 5) was added to LNCaP media, growth was inhibited to 11% of control with an IC50 of 13.3μg/ml. Two similar proanthocyanidin-rich fractions from cultivated blueberries (fractions 4 and 5) at the same concentration inhibited LNCaP growth to 57 and 26% of control with an IC50 of 22.7 and 5.8μg/ml, respectively. In DU145 cells, the only fraction that significantly reduced growth compared to control was fraction 4 from cultivated blueberries with an IC50 value of 74.4μg/ml, indicating only minor inhibitory activity. Differences in cell growth inhibition of LNCaP and DU145 cell lines by blueberry fractions rich in proanthocyanidins indicate that blueberry proanthocyanidins have an effect primarily on androgen-dependant growth of prostate cancer cells. Possible molecular mechanisms for growth inhibition are reviewed.
Schmidt BM, Erdman Jr JW, & Lila MA. Cancer Letters. Volume 231, Issue 2, Pages 240-246 (18 January 2006)

Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events
Regulation of the matrix metalloproteinases (MMPs) is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis. This study investigated the mechanism(s) by which three flavonoid-enriched fractions from lowbush blueberry (Vaccinium angustifolium) down-regulate MMP activity in DU145 human prostate cancer cells. Metalloproteinase activity was evaluated from cells exposed to &#147;crude,&#148; anthocyanin-enriched (AN) and proanthocyanidin-enriched (PAC) fractions. Differential down-regulation of MMPs was observed. The activity of the endogenous tissue inhibitors of metalloproteinases (TIMPs) from these cells was also evaluated. Increases in TIMP-1 and TIMP-2 activity were observed in response to these fractions. The possible involvement of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase pathways in the flavonoid-mediated decreases in MMP activity was observed. These findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells.
Matchett MD, MacKinnon, L, Sweeney MI, Gottschall-Pass KT, & Hurta, RAR. NRC Institute. DOI: 10.1016/j.jnutbio.2005.05.014. http://www.sciencedirect.com/science

Anticarcinogenic Activity of Strawberry, Blueberry, and Raspberry Extracts to Breast and Cervical Cancer Cells
Freeze-dried fruits of two strawberry cultivars, Sweet Charlie and Carlsbad, and two blueberry cultivars, Tifblue and Premier were sequentially extracted with hexane, 50% hexane/ethyl acetate, ethyl acetate, ethanol, and 70% acetone/water at ambient temperature. Each extract was tested separately for in vitro anticancer activity on cervical and breast cancer cell lines. Ethanol extracts from all four fruits strongly inhibited CaSki and SiHa cervical cancer cell lines and MCF-7 and T47-D breast cancer cell lines. An unfractionated aqueous extract of raspberry and the ethanol extract of Premier blueberry significantly inhibited mutagenesis by both direct-acting and metabolically activated carcinogens.
Wedge DE, Meepagala KM, Magee JB, Smith SH, Huang G, & Larcom LL. Journal of Medicinal Food. March 2001, 4(1): 49-51. doi:10.1089/10966200152053703.

Inhibition of Cancer Cell Proliferation and Suppression of TNF-induced Activation of NFκB by Edible Berry Juice
Berries contain several phytochemicals, such as phenolic acids, proanthocyanidins, anthocyanins and other flavonoids. There has been growing interest in a variety of potential chemopreventive activities of edible berries. The potential chemopreventive activity of a variety of small berries cultivated or collected in the province of Québec, Canada were evaluated here. Materials and Methods: Strawberry, raspberry, black currant, red currant, white currant, gooseberry, high-bush blueberry, low-bush blueberry, velvet leaf blueberry, serviceberry, blackberry, black chokeberry, sea buckthorn and cranberry were evaluated for antioxidant capacity, anti-proliferative activity, anti-inflammatory activity, induction of apoptosis and cell cycle arrest. Results: The growth of various cancer cell lines, including those of stomach, prostate, intestine and breast, was strongly inhibited by raspberry, black currant, white currant, gooseberry, velvet leaf blueberry, low-bush blueberry, sea buckthorn and cranberry juice, but not (or only slightly) by strawberry, high-bush blueberry, serviceberry, red currant, or blackberry juice. No correlation was found between the anti-proliferative activity of berry juices and their antioxidant capacity (p>0.05). The inhibition of cancer cell proliferation by berry juices did not involve caspase-dependent apoptosis, but appeared to involve cell-cycle arrest, as evidenced by down-regulation of the expression of cdk4, cdk6, cyclin D1 and cyclin D3. Of the 13 berries tested, juice of 6 significantly inhibited the TNF-induced activation of COX-2 expression and activation of the nuclear transcription factor NFκB.
Boivin D, Blanchette M, Barrette S, et al. Anticancer Research. March-April 2007 vol. 27 no. 2 937-48

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