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author:("Raskin, hlya")
1.  Development and Phytochemical Characterization of High Polyphenol Red Lettuce with Anti-Diabetic Properties 
PLoS ONE  2014;9(3):e91571.
Polyphenol-rich Rutgers Scarlet Lettuce (RSL) (Lactuca sativa L.) was developed through somaclonal variation and selection in tissue culture. RSL may contain among the highest reported contents of polyphenols and antioxidants in the category of common fruits and vegetables (95.6 mg/g dry weight and 8.7 mg/g fresh weight gallic acid equivalents and 2721 µmol/g dry weight and 223 µmol/g fresh weight Trolox equivalents). Three main compounds accumulate at particularly high levels in RSL: chlorogenic acid, up to 27.6 mg/g dry weight, cyanidin malonyl-glucoside, up to 20.5 mg/g dry weight, and quercetin malonyl-glucoside, up to 35.7 mg/g dry weight. Major polyphenolic constituents of RSL have been associated with health promotion as well as anti-diabetic and/or anti-inflammatory activities. Daily oral administration of RSL (100 or 300 mg/kg) for up to eight days acutely reduced hyperglycemia and improved insulin sensitivity in high fat diet-induced obese hyperglycemic mice compared to vehicle (water) control. Data presented here support possible use of RSL as a functional food for the dietary management of diabetes.
doi:10.1371/journal.pone.0091571
PMCID: PMC3956610  PMID: 24637790
2.  Effects of Pregnane Glycosides on Food Intake Depend on Stimulation of the Melanocortin Pathway and BDNF in an Animal Model 
Pregnane glycosides appear to modulate food intake by possibly affecting the hypothalamic feeding circuits; however, the mechanisms of the appetite-regulating effect of pregnane glycosides remain obscure. Here, we show that pregnane glycoside-enriched extracts from swamp milkweed Asclepias incarnata at 25–100 mg/kg daily attenuated food intake (up to 47.1 ± 8.5% less than controls) and body weight gain in rats (10% for males and 9% for females, respectively) by activating melanocortin signaling and inhibiting gastric emptying. The major milkweed pregnane glycoside, ikemagenin, exerted its appetite-regulating effect by decreasing levels of agouti-related protein (0.6-fold) but not NPY satiety peptides. Ikemagenin treatment also increased secretion of brain-derived neurotropic factor (BDNF) downstream of melanocortin receptors in the hypothalamus (1.4-fold) and in the C6 rat glioma cell culture in vitro (up to 6-fold). These results support the multimodal effects of pregnane glycosides on feeding regulation, which depends on the activity of the melanocortin signaling pathway and BDNF.
doi:10.1021/jf3033649
PMCID: PMC3805381  PMID: 23308358
appetite; satiety; body weight; milkweed; Asclepias
3.  Blueberry polyphenol-enriched soybean flour reduces hyperglycemia, body weight gain and serum cholesterol in mice 
Defatted soybean flour (DSF) can sorb and concentrate blueberry anthocyanins and other polyphenols, but not sugars. In this study blueberry polyphenol-enriched DSF (BB-DSF) or DSF were incorporated into very high fat diet (VHFD) formulations and provided ad libitum to obese and hyperglycemic C57BL/6 mice for 13 weeks to investigate anti-diabetic effects. Compared to the VHFD containing DSF, the diet supplemented with BB-DSF reduced weight gain by 5.6%, improved glucose tolerance, and lowered fasting blood glucose levels in mice within 7 weeks of intervention. Serum cholesterol of mice consuming the BB-DSF-supplemented diet was 13.2% lower than mice on the diet containing DSF. Compounds were eluted from DSF and BB-DSF for in vitro assays of glucose production and uptake. Compared to untreated control, doses of BB-DSF eluate containing 0.05 – 10 μg/μL of blueberry anthocyanins significantly reduced glucose production by 24% - 74% in H4IIE rat hepatocytes, but did not increase glucose uptake in L6 myotubes. The results indicate that delivery of blueberry polyphenols stabilized in a high-protein food matrix may be useful for the dietary management of pre-diabetes and/or diabetes.
doi:10.1016/j.phrs.2012.11.008
PMCID: PMC3833590  PMID: 23220243
metabolic syndrome; diabetes; blueberry; soybean; anthocyanins; polyphenols
4.  Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae) 
Phytochemistry  2007;68(6):10.1016/j.phytochem.2006.11.029.
Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook. f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-γ). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components.
doi:10.1016/j.phytochem.2006.11.029
PMCID: PMC3867260  PMID: 17250858
Tripterygium; Celastraceae; Thunder god vine; Terpenoids; Triptolide; Inflammation; Antiinflammatory drugs; Immunosuppression
5.  In vivo and in vitro antidiabetic effects of aqueous cinnamon extract and cinnamon polyphenol-enhanced food matrix 
Food chemistry  2012;135(4):2994-3002.
Cinnamon has a long history of medicinal use and continues to be valued for its therapeutic potential for improving metabolic disorders such as type 2 diabetes. In this study, a phytochemically-enhanced functional food ingredient that captures water soluble polyphenols from aqueous cinnamon extract (CE) onto a protein rich matrix was developed. CE and cinnamon polyphenol-enriched defatted soy flour (CDSF) were effective in acutely lowering fasting blood glucose levels in diet-induced obese hyperglycemic mice at 300 and 600 mg/kg, respectively. To determine mechanisms of action, rat hepatoma cells were treated with CE and eluates of CDSF at a range of 1–25 µg/ml. CE and eluates of CDSF demonstrated dose-dependent inhibition of hepatic glucose production with significant levels of inhibition at 25 µg/ml. Furthermore, CE decreased the gene expression of two major regulators of hepatic gluconeogenesis, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. The hypoglycemic and insulin-like effects of CE and CDSF may help to ameliorate type 2 diabetes conditions.
doi:10.1016/j.foodchem.2012.06.117
PMCID: PMC3444749  PMID: 22980902
Cinnamomum burmannii; cinnamon; diabetes; fasting blood glucose; glucose production
6.  Toxicological evaluation of a chicory root extract 
An Ames test and a 28-day sub-chronic toxicity study in male and female Sprague–Dawley rats were conducted to evaluate the safety of a chicory root extract being investigated as a therapeutic for inflammation. Chicory extract had no mutagenic activity in the Ames test although it was cytotoxic to certain strains of Salmonella at higher doses with and without metabolic activation. For the 28-day rat study, measurements included clinical observations, body weights, food consumption, clinical pathology, gross necropsy and histology. There were no treatment-related toxic effects from chicory extract administered orally at 70, 350, or 1000 mg/kg/day. Since there were no observed adverse effects of chicory extract in these studies, the NOAEL for the extract is 1000 mg/kg/g administered orally for 28 days.
doi:10.1016/j.fct.2006.12.019
PMCID: PMC3836359  PMID: 17306431
Chicorium intybus; Sesquiterpene lactone; Ames; Dietary supplement; Inflammation; Toxicity
7.  Ecdysteroids Elicit a Rapid Ca2+ Flux Leading to Akt Activation and Increased Protein Synthesis in Skeletal Muscle Cells 
Steroids  2010;75(10):10.1016/j.steroids.2010.03.008.
Phytoecdysteroids, structurally similar to insect molting hormones, produce a range of effects in mammals, including increasing growth and physical performance. In skeletal muscle cells, phytoecdysteroids increase protein synthesis. In this study we show that in a mouse skeletal muscle cell line, C2C12, 20-hydroxyecdysone (20HE), a common phytoecdysteroid in both insects and plants, elicited a rapid elevation in intracellular calcium, followed by sustained Akt activation and increased protein synthesis. The effect was inhibited by a G-protein Coupled Receptor (GPCR) inhibitor, a phospholipase C (PLC) inhibitor, and a phosphoinositide kinase-3 (PI3K) inhibitor.
doi:10.1016/j.steroids.2010.03.008
PMCID: PMC3815456  PMID: 20363237
ecdysteroid; skeletal muscle; Akt; GPCR; calcium; C2C12
8.  Toxicological evaluation of Grains of Paradise (Aframomum melegueta) [Roscoe] K. Schum 
Journal of ethnopharmacology  2009;127(2):10.1016/j.jep.2009.10.031.
Ethnopharmacological relevance
Grains of Paradise (Aframomum melegueta [Roscoe] K. Schum.) seeds are used in West Africa as a remedy for variety of ailments such as stomachache, snakebite, diarrhea and they have reported anti-inflammatory properties. Additionally, the seeds contain gingerols and related compounds that may be useful against cardiovascular disease, diabetes, and inflammation.
Aim of study
A 28-day sub-chronic toxicity study in male and female Sprague Dawley rats was conducted to evaluate the safety of a Grains of Paradise extract.
Materials and methods
An ethanolic extract of the seeds was evaluated for toxicological effect on rats.
Results
A dose-related increase in absolute and relative liver weights was observed in males and females dosed with 450 and 1500 mg/kg. There was a corresponding increase in alkaline phosphatase with no signs of steatosis or cirrhosis. At the same doses, there was a significant decrease in blood glucose in male rats.
Conclusions
This study shows that Grains of Paradise extract may be useful as a treatment for diabetes, however liver toxicity should be considered.
doi:10.1016/j.jep.2009.10.031
PMCID: PMC3815460  PMID: 19883745
Aframomum melegueta; gingerols; liver toxicity; alkaline phosphatase; dietary supplement
9.  Phytochemical Characterization of an Adaptogenic Preparation from Rhodiola heterodonta 
Natural product communications  2009;4(8):1053-1058.
The phytochemical constituents of a biologically active, standardized, 80% ethanol extract of Rhodiola heterodonta were characterized. The extract was fractionated over a Sephadex LH-20 column to afford two main fractions representing two classes of secondary metabolites: phenylethanoids and proanthocyanidins. This fractionation facilitated the identification and quantification of individual compounds in the fractions and sub-fractions using HPLC, and LC-MS. The major compounds in the phenylethanoid fraction were heterodontoside, tyrosol methyl ether, salidroside, viridoside, mongrhoside, tyrosol, and the cyanogenic glucoside rhodiocyanoside A. These seven compounds comprised 17.4% of the EtOH extract. Proanthocyanidins ranged from oligomers to polymers based on epigallocatechin and gallate units. The main identified oligomeric compounds in the proanthocyanidin fraction were epigallocatechin gallate, epigallocatechin-epigallocatechin-3-O-gallate and 3-O-galloylepigallocatechin-epigallocatechin-3-O-gallate, which constituted 1.75% of the ethanol extract. Tyrosol methyl ether, mongrhoside, and the two proanthocyanidin dimers were reported for the first time from this species in this study. Intraperitoneal injection of the 80% ethanol extract increased survival time of mice under hypoxia by 192%, as an indication of adaptogenic activity.
PMCID: PMC3815471  PMID: 19768982
Rhodiola heterodonta; HPLC-ESI/MS; phenylethanoid; proanthocyanidin; adaptogenic activity; anti-hypoxia
10.  Plant-derived therapeutics for the treatment of metabolic syndrome 
Metabolic syndrome is defined as a set of coexisting metabolic disorders that increase an individual’s likelihood of developing type 2 diabetes, cardiovascular disease and stroke. Medicinal plants, some of which have been used for thousands of years, serve as an excellent source of bioactive compounds for the treatment of metabolic syndrome because they contain a wide range of phytochemicals with diverse metabolic effects. In order for botanicals to be effectively used against metabolic syndrome, however, botanical preparations must be characterized and standardized through the identification of their active compounds and respective modes of action, followed by validation in controlled clinical trials with clearly defined endpoints. This review assesses examples of commonly known and partially characterized botanicals to describe specific considerations for the phytochemical, preclinical and clinical characterization of botanicals associated with metabolic syndrome.
PMCID: PMC3755736  PMID: 20872313
Botanical; cardiovascular disease; diabetes; hypertension; insulin resistance; phytochemical; obesity
11.  Efficient sorption of polyphenols to soybean flour enables natural fortification of foods 
Food chemistry  2012;131(4):1193-1200.
The present study demonstrated that defatted soybean flour (DSF) can sorb polyphenols from blueberry and cranberry juices while separating them from sugars. Depending on DSF concentration and juice dilution, the concentration of blueberry anthocyanins and total polyphenols sorbed to DSF ranged from 2 – 22 mg/g and 10 – 95 mg/g, respectively while the concentration of anthocyanins and proanthocyanidins in cranberry polyphenol-enriched DSF ranged from 2.5 – 17 mg/g and 21 – 101 mg/g, respectively. Blueberry polyphenols present in one serving of fresh blueberries (73g) were delivered in just 1.4 g of blueberry polyphenol-enriched DSF. Similarly, one gram of cranberry polyphenol-enriched DSF delivered the amount of proanthocyanidins available in three 240 ml servings of cranberry juice cocktail. The concentration of blueberry anthocyanins and total polyphenols eluted from DSF remained constant after 22 weeks of incubation at 37°C, demonstrating the high stability of the polyphenol-DSF matrix. LC-MS analysis of eluates confirmed DSF retained major cranberry and blueberry polyphenols remained intact. Blueberry polyphenol-enriched DSF exhibited significant hypoglycemic activities in C57bl/6J mice, and cranberry polyphenol-enriched DSF showed anti-microbial and anti-UTI activities in vitro, confirming its efficacy. The described sorption process provides a means to create protein-rich food ingredients containing concentrated plant bioactives without excess sugars, fats and water that can be incorporated in a variety of scientifically validated functional foods and dietary supplements.
doi:10.1016/j.foodchem.2011.09.103
PMCID: PMC3742044  PMID: 23950619
polyphenols; anthocyanins; proanthocyanidins; soybean flour; nutrition; diabetes; antibacterial
12.  Complementary approaches to gauge the bioavailability and distribution of ingested berry polyphenolics 
Two different strategies for investigating the likely fate, after ingestion, of natural, bioactive berry constituents (anthocyanins and other non-nutritive flavonoids) are compared. A model of the human gastrointestinal tract (TIM-1) which mimicked the biological environment from the point of swallowing and ingestion through the duodenum, jejunum, and ileum (but not the colon) was used to monitor the stability and bioaccessibility of anthocyanins from both maqui berry and wild blueberry. TIM-1 revealed that most anthocyanins were bioaccessible between the second and third hour after intake. Alternatively, biolabeled anthocyanins and other flavonoids generated in vitro from berry and grape cell cultures were administered to in vivo (rodent) models, allowing measurement and tracking of the absorption and transport of berry constituents and clearance through the urinary tract and colon. The advantages and limitations of the alternative strategies are considered.
doi:10.1021/jf203526h
PMCID: PMC3310271  PMID: 22111523
bioavailability; bioaccessibility; radiolabeling; artificial gastrointestinal tract
13.  Tools for the identification of bioactives impacting the metabolic syndrome: Screening of a botanical extract library using subcutaneous and visceral human adipose-derived stem cell based assays 
Plant extracts continue to represent an untapped source of renewable therapeutic compounds for the treatment and prevention of illnesses including chronic metabolic disorders. With the increase in worldwide obesity and its related morbidities, the need for identifying safe and effective treatments is also rising. As such, use of primary human adipose-derived stem cells represents a physiologically relevant cell system to screen for bioactive agents in the prevention and treatment of obesity and its related complications. By using these cells in a primary screen, the risk and cost of identifying artifacts due to interspecies variation and immortalized cell lines is eliminated. We demonstrate that these cells can be formatted into 384-well high throughput screens to rapidly identify botanical extracts that affect lipogenesis and lipolysis. Additionally, counterscreening with human primary stem cells from distinct adipose depots can be routinely performed to identify tissue specific responses. In our study, over 500 botanical extracts were screened and 16 (2.7%) were found to affect lipogenesis and 4 (0.7%) affected lipolysis.
doi:10.1016/j.jnutbio.2011.02.005
PMCID: PMC3154462  PMID: 21543201
Adipogenesis; Adipose-derived Stem Cells; Botanical Extracts; Lipogenesis; Lipolysis; Subcutaneous; Visceral
14.  Qualitative variation of anti-diabetic compounds in different tarragon (Artemisia dracunculus L.) cytotypes 
Fitoterapia  2011;82(7):1062-1074.
Ethanolic extracts of diploid Artemisia dracunculus L. (wild tarragon) from populations in the U.S., and polyploid tarragon from a variety of sources, were screened for the anti-diabetic compounds davidigenin; sakuranetin; 2′,4′-dihydroxy-4-methoxydihydrochalcone; 4,5-di-O-caffeoylquinic acid; 5-O-caffeoylquinic acid and 6-demethoxycapillarisin using LC-MS. Only decaploid plants contained all six target compounds and were the only plants that contained davidigenin and 2,4-dihydroxy-4-methoxydihydrochalcone. These results exhibit the importance of germplasm selection and provenance when studying plants for medicinal activity. Relying only on the “right species” for consistent medicinal activities may not be sufficient, as intraspecific variation may be highly significant.
doi:10.1016/j.fitote.2011.07.003
PMCID: PMC3164315  PMID: 21798321
Artemisia dracunculus; wild tarragon; polyploidy; germplasm; diabetes; sakuranetin
15.  Biochemical Analysis and in Vivo Hypoglycemic Activity of a Grape Polyphenol–Soybean Flour Complex 
Defatted soybean flour (DSF) can efficiently sorb, concentrate, and stabilize polyphenols, but not sugars, from Concord grape juice, to yield grape polyphenol-enriched DSF. Sorption of grape polyphenols to DSF particles was dependent on the ratio of DSF and grape juice concentrate used, but not time of mixing or pH. Depending on ratios of starting materials, 1 g of grape polyphenol-enriched DSF contained 1.6–10.4 mg of anthocyanins, 7.5–93.1 mg of proanthocyanidins, and 20.5–144.5 mg of total polyphenols. LC-MS analysis of grape juice samples before and after addition and removal of DSF and eluate from grape polyphenol-enriched DSF confirmed that a broad range of grape compounds were sorbed to the DSF matrix. Finally, grape polyphenol-enriched DSF was able to significantly lower blood glucose levels in hyperglycemic C57BL/6J mice. The data indicate that grape polyphenol-enriched DSF can provide a high-protein, low-sugar ingredient for delivery of concentrated grape polyphenolics.
doi:10.1021/jf300232h
PMCID: PMC3419343  PMID: 22462390
Concord grape juice; defatted soy flour; anthocyanins; proanthocyanidins; polyphenols; hypoglycemic; diabetes
16.  Akt-dependent anabolic activity of natural and synthetic brassinosteroids in rat skeletal muscle cells 
Journal of medicinal chemistry  2011;54(12):4057-4066.
Brassinosteroids are plant-derived polyhydroxylated derivatives of 5α-cholestane, structurally similar to cholesterol-derived animal steroid hormones and insect ecdysteroids. In this study, we synthesized a set of brassinosteroid analogues of a natural brassinosteroid (22S,23S)-homobrassinolide (HB, 1) including (22S,23S)-homocastasterone (2), (22S,23S)-3α-fluoro-homobrasinolide (3), (22S,23S)-3α-fluoro-homocastasterone (4), (22S,23S)-7v-aza-homobrassinolide (5), (22S,23S)-6-aza-homobrassinolide (6), and studied their anabolic efficacy in the L6 rat skeletal muscle cells in comparison to other synthetic and naturally occurring brassinosteroids (22R,23R)-homobrassinolide (7), (22S,23S)-epibrassinolide (8), and (22R,23R)-epibrassinolide (9). Presence of the 6-keto group in the B ring and stereochemistry of 22α,23α-vicinal hydroxyl groups in the side chain were critical for the anabolic activity, possibly due to higher cytotoxicity of the 22β, 23β-hydroxylated brassinosteroids. All anabolic brassinosteroids tested in this study selectively activated PI3K/Akt signaling pathway as evident by increased Akt phosphorylation in vitro. Plant brassinosteroids and their synthetic derivatives may offer a novel therapeutic strategy for promoting growth, repair, and maintenance of skeletal muscles.
doi:10.1021/jm200028h
PMCID: PMC3128125  PMID: 21491949
brassinosteroid; protein synthesis; protein degradation; anabolic steroids; muscle mass; muscle loss
17.  Antiplasmodial Activity of Aporphine Alkaloids and Sesquiterpene Lactones from Liriodendron tulipifera L 
Journal of ethnopharmacology  2010;133(1):26-30.
Aim of the study
The objective of this study was to isolate and characterize the active constituents of the traditionally used antimalarial plant Liriodendron tulipifera by antiplasmodial-assay guided fractionation.
Materials and methods
Bark and leaves were extracted with solvents of increasing polarity. Fractions were generated using flash chromatography, counter current chromatography and preparative HPLC and subjected to in vitro antiplasmodial and cytotoxicity assays. Active fractions were subjected to further fractionation until pure compounds were isolated, for which the IC50 values were calculated.
Results and discussion
Six known aporphine alkaloids, asimilobine (1), norushinsunine (2), norglaucine (3), liriodenine (4), anonaine (5) and oxoglaucine (6) were found to be responsible for the antiplasmodial activity of the bark. Leaves yielded two known sesquiterpene lactones, peroxyferolide (7) and lipiferolide (8) with antiplasmodial activity. The antiplasmodial activity of (2) (IC50 = 29.6 μg/ml), (3) (IC50 = 22.0 μg/ml), (6) (IC50= 9.1 μg/mL), (7) (IC50 = 6.2 μg/ml) and (8) (IC50 = 1.8 μg/ml) are reported for the first time.
Conclusion
This work supports the historical use of Liriodendron tulipifera as an antimalarial remedy of the United States and characterizes its antiplasmodial constituents.
doi:10.1016/j.jep.2010.08.059
PMCID: PMC3010440  PMID: 20826204
Antimalarial; Aporphine alkaloids; Sesquiterpene lactones; Liriodendron tulipifera L.; Magnoliaceae; Cytotoxicity
18.  Potato protease inhibitors inhibit food intake and increase circulating cholecystokinin levels by a trypsin-dependent mechanism 
Objective
To investigate the mechanisms underlying the satiety-promoting effects of a novel protease inhibitors concentrate derived from potato (PPIC).
Methods
Acute and prolonged effects of oral PPIC administration (100 mg/kg per day) on food intake, body weight, and gastric emptying were evaluated in healthy rats. Parameters of body weight, food intake, plasma glucose, insulin, and cholecystokinin (CCK) were measured. Duodenal proteolytic activity and CCK expression were determined in tissue extracts. Intestinal STC-1 cell culture model was used to investigate the direct effect of PPIC on CCK transcript level and secretion.
Results
Acute oral administration of PPIC reduced immediate food intake during the first two hours following the treatment, delayed gastric emptying, and decreased proteolytic activity in the duodenum. Repeated oral ingestion of PPIC reduced weight gain in male rats and significantly elevated the plasma CCK levels. Although duodenal mucosal CCK mRNA levels increased in response to PPIC administration, the concentrate failed to elevate CCK expression or release in STC-1 cells. The 14-day ascending dose range study (33 to 266 mg/kg PPIC per day) showed no adverse side effects associated with PPIC administration.
Conclusion
These findings provided evidence that PPIC is effective in reducing food intake and body weight gain in healthy rats when administered orally by increasing circulating CCK levels through a trypsin-dependent mechanism.
doi:10.1038/ijo.2010.192
PMCID: PMC3033477  PMID: 20820171
satiety; body weight; cholecystokinin; protease inhibitors; potato
19.  Improved absorption and bioactivity of active compounds from an anti-diabetic extract of Artemisia dracunculus L 
An ethanolic extract of Artemisia dracunculus L. (PMI-5011) was shown to be hypoglycemic in animal models for Type 2 diabetes and contain at least 6 bioactive compounds responsible for its anti-diabetic properties. To evaluate the bioavailability of the active compounds, high fat dietary induced obese C57BL/6J male mice were gavaged with PMI-5011 at 500 mg/kg body weight, after 4 h of food restriction. Blood plasma samples (200 uL) were obtained after ingestion, and the concentrations of the active compound in the blood sera were measured by electrospray LC-MS and determined to be maximal 4–6 h after gavage. Formulations of the extract with bioenhancers/solubilizers were evaluated in vivo for hypoglycemic activity and their effect on the abundance of active compounds in blood sera. At doses of 50–500 mg/kg/day, the hypoglycemic activity of the extract was enhanced 3–5 fold with the bioenhancer Labrasol, making it comparable to the activity of the anti-diabetic drug metformin. When combined with Labrasol, one of the active compounds, 2′, 4′-dihydroxy-4-methoxydihydrochalcone, was at least as effective as metformin at doses of 200–300 mg/kg/day. Therefore, bioenhancing agents like Labrasol can be used with multi-component botanical therapeutics such as PMI-5011 to increase their efficacy and/or to reduce the effective dose.
doi:10.1016/j.ijpharm.2008.11.012
PMCID: PMC3130197  PMID: 19084584
20.  Alaskan Wild Berry Resources and Human Health Under the Cloud of Climate Change 
Wild berries are integral dietary components for Alaska Native tribes and a rich source of polyphenolic metabolites that can ameliorate metabolic disorders such as obesity and diabetes. In this study, five species of wild Alaskan berries (Vaccinium ovalifolium, V. uliginosum, Rubus chamaemorus, R. spectabilis, and Empetrum nigrum) were screened for bioactivity through a community-participatory research method involving three geographically-distinct tribal communities. Compositional analysis by HPLC and LC-MS2 revealed substantial site-specific variation in anthocyanins (0.01-4.39 mg/g-FW) and proanthocyanidins (0.74-6.25 mg/g-FW), and identified A-type proanthocyanidin polymers. R. spectabilis increased expression levels of preadipocyte-factor-1 (182%), and proanthocyanidin-enriched fractions from other species reduced lipid accumulation in 3T3-L1 adipocytes. Selected extracts reduced serum glucose levels in C57bl/6j mice by up to 45%. Local observations provided robust insights into effects of climatic fluctuations on berry abundance and quality, and preliminary site-specific compositional and bioactivity differences were noted, suggesting the need to monitor this Alaska Native resource as climate shifts impact the region.
doi:10.1021/jf902693r
PMCID: PMC2850959  PMID: 20025229
Anthocyanins; proanthocyanidins; Vaccinium ovalifolium; Vaccinium uliginosum; Rubus spectabilis; Rubus chamaemorus; Empetrum nigrum; Traditional Ecological Knowledge; pref-1; adipocytes; diabetes; obesity; metabolic syndrome
21.  Merging Traditional Chinese Medicine with Modern Drug Discovery Technologies to Find Novel Drugs and Functional Foods 
Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements.
PMCID: PMC3017680  PMID: 20156139
Artemisia annua; artemisinin; Camellia sinensis; (−)-epigallocatechin-3-gallate (EGCG); functional foods; nutraceuticals; traditional Chinese medicine (TCM); tripdiolide; Tripterygium wilfordii; triptolide
22.  A natural history of botanical therapeutics 
Metabolism: clinical and experimental  2008;57(7 Suppl 1):S3-S9.
Plants have been used as a source of medicine throughout history and continue to serve as the basis for many pharmaceuticals used today. Although the modern pharmaceutical industry was born from botanical medicine, synthetic approaches to drug discovery have become standard. However, this modern approach has led to a decline in new drug development in recent years and a growing market for botanical therapeutics that are currently available as dietary supplements, drugs, or botanical drugs. Most botanical therapeutics are derived from medicinal plants that have been cultivated for increased yields of bioactive components. The phytochemical composition of many plants has changed over time, with domestication of agricultural crops resulting in the enhanced content of some bioactive compounds and diminished content of others. Plants continue to serve as a valuable source of therapeutic compounds because of their vast biosynthetic capacity. A primary advantage of botanicals is their complex composition consisting of collections of related compounds having multiple activities that interact for a greater total activity.
doi:10.1016/j.metabol.2008.03.001
PMCID: PMC2981029  PMID: 18555851
23.  Bioactives of Artemisia dracunculus L enhance cellular insulin signaling in primary human skeletal muscle culture 
Metabolism: clinical and experimental  2008;57(7 Suppl 1):S58-S64.
An alcoholic extract of Artemisia dracunculus L (PMI 5011) has been shown to decrease glucose and improve insulin levels in animal models, suggesting an ability to enhance insulin sensitivity. We sought to assess the cellular mechanism by which this botanical affects carbohydrate metabolism in primary human skeletal muscle culture. We measured basal and insulin-stimulated glucose uptake, glycogen accumulation, phosphoinositide 3 (PI-3) kinase activity, and Akt phosphorylation in primary skeletal muscle culture from subjects with type 2 diabetes mellitus incubated with or without various concentrations of PMI 5011. We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. Glucose uptake was significantly increased in the presence of increasing concentrations of PMI 5011. In addition, glycogen accumulation, observed to be decreased with increasing free fatty acid levels, was partially restored with PMI 5011. PMI 5011 treatment did not appear to significantly affect protein abundance for IRS-1, IRS-2, PI-3 kinase, Akt, insulin receptor, or Glut-4. However, PMI 5011 significantly decreased levels of a specific protein tyrosine phosphatase, that is, PTP1B. Time course studies confirmed that protein abundance of PTP1B decreases in the presence of PMI 5011. The cellular mechanism of action to explain the effects by which an alcoholic extract of A dracunculus L improves carbohydrate metabolism on a clinical level may be secondary to enhancing insulin receptor signaling and modulating levels of a specific protein tyrosine phosphatase, that is, PTP1B.
doi:10.1016/j.metabol.2008.04.003
PMCID: PMC2981033  PMID: 18555856
24.  Hypoglycemic activity of a novel Anthocyanin-rich formulation from Lowbush Blueberry, Vaccinium angustifolium Aiton 
Blueberry fruits are known as a rich source of anthocyanin components. In this study we demonstrate that anthocyanins from blueberry have the potency to alleviate symptoms of hyperglycemia in diabetic C57b1/6J mice. The anti-diabetic activity of different anthocyanin-related extracts was evaluated using the pharmaceutically acceptable self-microemulsifying drug delivery system; Labrasol. Treatment by gavage (500 mg/kg body wt) with a phenolic-rich extract and an anthocyanin-enriched fraction formulated with Labrasol lowered elevated blood glucose levels by 33 and 51%, respectively. The hypoglycemic activities of these formulae were comparable to that of the known anti-diabetic drug metformin (Baily and Day, 2004; 27% at 300 mg/kg). The extracts were not significantly hypoglycemic when administered without Labrasol, demonstrating its bio-enhancing effect, most likely due to increasing the bioavailability of the administered preparations. The phenolic-rich extract contained 287.0 ± 9.7 mg/g anthocyanins, while the anthocyanin-enriched fraction contained 595 ± 20.0 mg/g (cyanidin-3-glucoside equivalents), as measured by HPLC and pH differential analysis methods. The greater hypoglycemic activity of the anthocyanin-enriched fraction compared to the initial phenolic-rich extract suggested that the activity was due to the anthocyanin components. Treatment by gavage (300 mg/kg) with the pure anthocyanins, delphinidin-3-O-glucoside and malvidin-3-O- glucoside, formulated with Labrasol, showed that malvidin-3-O- glucoside was significantly hypoglycemic while delphinidin-3-O-glucoside was not.
doi:10.1016/j.phymed.2009.02.018
PMCID: PMC2718544  PMID: 19303751
Blueberry; Vaccinium angustifolium; Anthocyanins; Malvidin; Diabetes; Hyperglycemia; Hypoglycemia; Labrasol
25.  Dietary phenethylisothiocyanate attenuates bowel inflammation in mice 
BMC Chemical Biology  2010;10:4.
Background
Phenethylisothiocyanate (PEITC) is produced by Brassica food plants. PEO is a PEITC Essential Oil containing >95% natural PEITC. PEITC is known to produce various health benefits but its effect in alleviation of ulcerative colitis signs is unknown.
Results
In two efficacy studies (acute and chronic) oral administration of PEO was effective at remitting acute and chronic signs of ulcerative colitis (UC) in mice. Disease activity, histology and biochemical characteristics were measured in the treated animals and were compared with appropriate controls. PEO treatment significantly improved body weights and stool consistency as well as decreased intestinal bleeding. PEO treatment also reduced mucosal inflammation, depletion of goblet cells and infiltration of inflammatory cells. Attenuation of proinflammatory interleukin1β production was observed in the colons of PEO-treated animals. Expression analyses were also carried out for immune function related genes, transcription factors and cytokines in lipopolysaccharide-activated mouse macrophage cells. PEO likely affects an intricate network of immune signaling genes including a novel concentration dependent reduction of total cellular Signal Transducer and Activator of Transcription 1 (STAT1) as well as nuclear phosphorylated-STAT1 (activated form of STAT1). A PEO-concentration dependent decrease of mRNA of C-X-C motif ligand 10 (a STAT1 responsive chemokine) and Interleukin 6 were also observed.
Conclusions
PEO might be a promising candidate to develop as a treatment for ulcerative colitis patients. The disease attenuation by PEO is likely associated with suppression of activation of STAT1 transcription and inhibition of pro-inflammatory cytokines.
doi:10.1186/1472-6769-10-4
PMCID: PMC2881005  PMID: 20423518

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