Effects of Flavonoid-Rich Beverages on Prostacyclin Synthesis in Humans and Human Aortic Endothelial Cells: Association with Ex Vivo Platelet Function

Carl L. Keen,John A. Polagruto,Derek D. Schramm,Janice F. Wang-Polagruto,Luke Lee 한국식품영양과학회 2003 Journal of medicinal food Vol.6 No.4

Diets rich in flavonoids have been associated with reduced risk for cardiovascular disease. This may be due,in part, to flavonoid-induced alterations in eicosanoid synthesis. Our objective was to identify plant-derived beverages that al-ter synthesis of prostacyclin in cultured human aortic endothelial cells (HAEC), and to determine if these beverages could al-ter in vivo6-keto-prostaglandin F 1a (a stable metabolite of prostacyclin) synthesis and platelet function. HAEC were treatedwith nine commonly consumed beverages to determine their effects on prostacyclin synthesis under acute and chronic treat-ment regimens. Orange, purple grape, and pomegranate juices and coffee (6 9 mL/kg) were then provided to 28 fasted, healthyadult subjects (eight men and 20 women) on five separate days. Plasma samples were collected immediately following juiceconsumption (baseline), and at 2 and 6 hours post-consumption. On an acute basis, administration of HAEC with pomegran-ate juice increased media prostacyclin. Chronic exposure to purple grape and pomegranate juice increased aortic endothelialcell prostacyclin synthesis (38% and 61%, respectively; P, .05). The consumption of purple grape, pomegranate, and orangejuice prolonged epinephrine/collagen-induced clotting time (P, .05). Purple grape juice increased plasma 6-keto-prostaglandinF1a (20%; P, .05) at 2 hours; pomegranate and orange juice did not significantly influence plasma prostacyclin concentra-tions. Consistent with the in vitrodata, coffee consumption did not influence clotting time or plasma prostacyclin concentra-tions. These results indicate that the HAEC model system can provide a qualitative means to screen food and food-derivedproducts for biologic activity related to cardiovascular health.

Nitric Oxide Donor 첨가가 구리 결핍 배아의 발달과 Nitric Oxide 하위 신호전달체계에 미치는 영향

양수진(Yang Soo Jin),Keen Carl L,Uriu-Adams,Janet Y 韓國營養學會 2008 Journal of Nutrition and Health Vol.41 No.8

본 연구는 착상 후 단계의 쥐 배아와 난황낭을 대상으로 구리 결핍이 NO 하부 신호전달체계에 영향을 주는지를 알아보기 위한 것으로, 연구 결과는 다음과 같이 요약할 수 있다. 첫째, 구리 결핍은 정상적인 배아 및 난황낭 발달을 억제하고, NO의 생물학적 이용도와 아세틸콜린에 대한 NO dose-response를 낮추었다. 둘째, 구리 결핍은 NO의 하부 신호전달 물질인 cGMP 수준을 감소시켰으나, NO/cGMP하부 신호전달체계 표적 중 하나인 P-VASP에는 영향을 미치지 않았다. 셋째, 구리 결핍 배양액에 NO donor를 첨가하는 것은 구리 결핍 배아와 난황낭의 기형 발생 빈도를 구리 정상군과 비슷한 수준으로 개선시켰다. 넷째, NO donor 첨가는 구리 결핍군에서 감소되었던 cGMP의 농도를 유의적으로 증가시켰지만, P-VASP에는 영향을 미치지 않았다. 상기 연구 결과들은 구리 결핍으로 인한 NO의 생물학적 이용도의 감소가 기형발생의 주요 발생 기전이라는 것을 뒷받침하고 있다. 또한, 임상적으로 임신 기간 중 적절한 구리 섭취의 중요성을 강조한다. One suggested mechanism underlying copper (Cu) deficiency teratogenicity is a low availability of nitric oxide (NO), a signaling molecule which is essential in developmental processes. Increased superoxide anions secondary to decreased activities of Cu-zinc superoxide dismutase (Cu-Zn SOD) in Cu deficiency can interact with NO to form peroxynitrite, which can nitrate proteins at tyrosine residues. In addition, peroxynitrite formation can limit NO bioavailability. We previously reported low NO availability and increased protein nitration in Cu deficient (Cu-) embryos. In the current study, we tested whether Cu deficiency alters downstream signaling of NO by assessing cyclic GMP (cGMP) and phosphorylated vasodilator-stimulating phosphoprotein (VASP) levels, and whether NO supplementation can affect these targets as well as protein nitration. Gestation day 8.5 embryos from Cu adequate (Cu+) or Cu- dams were collected and cultured in either Cu+ or Cu- media for 48 hr. A subset of embryos was cultured in Cu- media supplemented with a NO donor (DETA/NONOate; 20 μM) and/or Cu-Zn SOD. Cu-/Cu- embryos showed a higher incidence of embryonic and yolk sac abnormalities, low NO availability, blunted dose-response in NO concentrations to increasing doses of acetylcholine, low mRNA expression of endothelial nitric oxide synthase (eNOS), increased levels of 3-nitrotyrosine (3-NT) compared to Cu+/Cu+ controls. cGMP concentrations tended to be low in Cu-/Cu- embryos, and they were significantly lower in Cu-/Cu- yolk sacs than in controls. Levels of phosphorylated VASP at serine 239 (P-VASP) were similar in all groups. NO donor supplementation to the Cu- media ameliorated embryonic and yolk sac abnormalities, and resulted in increased levels of cGMP without altering levels of P-VASP and 3-NT. Taken together, these data support the concept that Cu deficiency limits NO availability and alters NO/cGMP-dependent signaling in Cu- embryos and yolk sacs, which contributes to Cu deficiency-induced abnormal development.

Effects of a Flavonol-Rich Diet on Select Cardiovascular Parameters in a Golden Syrian Hamster Model

Swati Kalgaonkar,Heidrun B. Gross,Wallace Yokoyama,Carl L. Keen 한국식품영양과학회 2010 Journal of medicinal food Vol.13 No.1

The concept that the consumption of a diet rich in flavonoids can be associated with a reduced risk for cardiovascular disease is becoming increasingly accepted. In the present study we investigated the effects of the following four diets on blood pressure and cholesterol ester levels in hypercholesterolemic Golden Syrian hamsters: a high-fat, high-cholesterol diet (HFHC); a HFHC with 2% cranberry concentrate powder (HFHC+CE); a HFHC with 0.1% rutin (HFHC+Rutin); and a HFHC with 30mg/kg vitamin E (HFHC+Vit.E). Diets were fed for either 12 or 20 weeks. Over the experimental period, heart rate and blood pressure measurements increased in the animals fed HFHC and HFHC+Vit.E; in contrast, these measurements were not increased in the animals fed HFHC+CE and HFHC+Rutin. Mesenteric and total abdominal fat were significantly lower in the animals fed HFHC+Rutin than in animals fed the other three diets. Ratios of plasma high-density lipoprotein cholesterol (HDL-C) to very-low-density lipoprotein cholesterol and of plasma HDL-C to low-density lipoprotein cholesterol were significantly higher in animals consuming HFHC+Vit.E than in animals fed the other three diets. Aortic cholesteryl ester levels were significantly lower in animals fed HFHC+CE, HFHC+Rutin, and HFHC+Vit.E at 20 weeks than in the animals fed HFHC. Fasting blood glucose concentrations were significantly lower in animals fed HFHC+Rutin and HFHC+Vit.E, and glucose clearance rates improved in animals fed HFHC+Rutin compared to animals fed the other three diets. Results obtained from this study support the concept that the chronic consumption of a flavonoid-rich diet can be beneficial with respect to cardiovascular health.

Use of Vitamins, Minerals, and Other Dietary Supplements by 17- and 18-Year-Old Students in Korea

김선효,Ji H. Han,Qin Yan Zhu,Carl L. Keen 한국식품영양과학회 2003 Journal of medicinal food Vol.6 No.1

Various types of dietary suplements (DS) are popularly taken by young individuals. We sur-veyed 1,190 Korean senior high school third grade students for their DS use, motivational fac-tors for this use, and potential dietary consequences of vitamin/mineral suplement (VMS)use. The use prevalence of DS including VMS, tonic medicines, manufactured health foodsuplements, cordial food suplements, and drink rehabilitators was 54%. VMS were takenmost frequently, followed by tonic medicines and manufactured health food suplements.VMS use was highest in individuals who had a significant concern for their overall healthand in those from families with a high socioeconomic level and with parental use of DS. To-tal daily study time of DS users was only slightly longer than that of nonusers. The VMSmost frequently used were vitamin C and multivitamins. More than 46% of other DS users,and 58% of VMS users, had increased their intake of suplements during third grade rela-tive to the previous year. VMS users had a more positive view of the potential health bene-fit of VMS than did nonusers. Vitamin and mineral intakes from VMS occurred over a widerange, with mean intakes typically exceeding the Korean and Canadian-U.S. RecommendedDietary Allowances. For a significant number of individuals, intakes of vitamin A, niacin,folic acid, vitamin C, calcium, iron, and zinc exceeded the Tolerable Uper Intake Levels.Given the widespread use of DS by older tenagers, the contribution of these suplementsto their overall health and well-being is a subject that clearly merits aditional study.27

Non-Alcoholic Fatty Liver Disease: The New Epidemic and the Need for Novel Nutritional Approaches

Carlo Selmi,Christopher L. Bowlus,Carl L. Keen,M. Eric Gershwin 한국식품영양과학회 2007 Journal of medicinal food Vol.10 No.4

The epidemic of non-alcoholic fatty liver disease (NAFLD) in the United States is staggering, and there is anenormous void in our understanding of the clinical epidemiology other than the common themes of obesity and insulin re-and appropriate nutritional supplements. There is, however, a wealth of basic science that helps to set the stage for definingthe mechanisms leading to liver pathology. In this article we will attempt to put these concepts in perspective to highlight theneed for future research including the use of medicinal food.

Cocoa Flavanols and Procyanidins Can Modulate the Lipopolysaccharide Activation of Polymorphonuclear Cells In Vitro

Thomas P. Kenny,Shang-an Shu,Yuki Moritoki,Carl L. Keen,M. Eric Gershwin 한국식품영양과학회 2009 Journal of medicinal food Vol.12 No.1

Flavanols and procyanidins isolated from cocoa have been reported to possess multiple activities potentially relevant to oxidant defenses, vascular function, and immune function. In a combination of in vivo and in vitro studies, we and others have observed that cocoa can be an anti-inflammatory modulator and that compounds in cocoa are capable of modulating eicosanoid production, platelet aggregation, and the pool size of nitric oxide. The present study extends these findings by examining the in vitro effects of cocoa procyanidins on polymorphonuclear cells (PMNs). PMNs, part of the innate arm of the immune system, represent 50–60% of the total peripheral white blood cells and are the first cells to be recruited to the sites of inflammation or injury secondary to bacterial infections. Herein, we demonstrate that certain flavanols and procyanidins isolated from cocoa can moderate a subset of signaling pathways derived from lipopolysaccharide (LPS) stimulation of PMNs, mainly, PMN oxidative bursts and activation markers, and they can influence select apoptosis mechanisms. We hypothesize that flavanols and procyanidins can decrease the impact of LPS on the N-formyl-Met-Leu-Phe-primed PMN ability to generate reactive oxygen species by partially interfering in activation of the mitogen-activated protein kinase pathway.

Effects of Short-Term Dried Plum (Prune) Intake on Markers of Bone Resorption and Vascular Function in Healthy Postmenopausal Women: A Randomized Crossover Trial

Yousef A. Al-Dashti,Roberta R. Holt,John G. Carson,Carl L. Keen,Robert M. Hackman 한국식품영양과학회 2019 Journal of medicinal food Vol.22 No.10

Osteoporosis and cardiovascular disease are global health burdens, with postmenopausal women being at great risk. Dried plums/prunes (DPs) have been reported to provide bone health benefits in animal models, which is consistent with in vitro models. Data from human studies suggest that DP intake can enhance lipid metabolism, anti-inflammatory, and oxidant defense systems, which can impact cardiovascular health. We tested the hypothesis that short-term consumption of low and reasonable levels of DPs augments bone resorption and vascular function. Twenty-seven healthy, postmenopausal women were randomly assigned to consume six DPs (∼42 g) or two DPs (∼14 g) per day for 2 weeks, then a 2-week washout period and then crossed over. Serum C-telopeptide, beta-crosslinked (CTX) was used as a measure of bone resorption. Peripheral artery tonometry (PAT) was used to assess microvascular function. The pattern of changes in CTX in the second 2-week period (no change or decline) differed significantly from the pattern in the first 2 weeks (increases in both groups; F = 9.26, P = .006), suggesting a trend in CTX reduction (i.e., a decrease in bone resorption) in those consuming six DPs per day in the second phase. No effects on vascular function were noted. A significant interaction was observed for the augmentation index, a measure of arterial stiffness, between treatment and years after menopause (P = .045). The results suggest a potentially favorable impact of DPs on bone health when assessed with a short-term, crossover study design in postmenopausal women. Given the novel assessments used in this study, follow-up studies are warranted.

Cocoa Flavanols and Procyanidins Can Modulate the Lipopolysaccharide Activation of Polymorphonuclear Cells In Vitro

Kenny, Thomas P.,Shu, Shang-An,Moritoki, Yuki,Keen, Carl L.,Gershwin, M. Eric The Korean Society of Food Science and Nutrition 2009 Journal of medicinal food Vol.12 No.1

Flavanols and procyanidins isolated from cocoa have been reported to possess multiple activities potentially relevant to oxidant defenses, vascular function, and immune function. In a combination of in vivo and in vitro studies, we and others have observed that cocoa can be an anti-inflammatory modulator and that compounds in cocoa are capable of modulating eicosanoid production, platelet aggregation, and the pool size of nitric oxide. The present study extends these findings by examining the in vitro effects of cocoa procyanidins on polymorphonuclear cells (PMNs). PMNs, part of the innate arm of the immune system, represent 50-60% of the total peripheral white blood cells and are the first cells to be recruited to the sites of inflammation or injury secondary to bacterial infections. Herein, we demonstrate that certain flavanols and procyanidins isolated from cocoa can moderate a subset of signaling pathways derived from lipopolysaccharide (LPS) stimulation of PMNs, mainly, PMN oxidative bursts and activation markers, and they can influence select apoptosis mechanisms. We hypothesize that flavanols and procyanidins can decrease the impact of LPS on the N-formyl-Met-Leu-Phe-primed PMN ability to generate reactive oxygen species by partially interfering in activation of the mitogen-activated protein kinase pathway.

Platelet Reactivity in Male Smokers Following the Acute Consumption of a Flavanol-Rich Grapeseed Extract

Robert M. Hackman,John A. Polagruto,Heidrun B. Gross,Faranak Kamangar,Ken-Ichi Kosuna,Buxiang Sun,Hajime Fujii,Carl L. Keen 한국식품영양과학회 2007 Journal of medicinal food Vol.10 No.4

Epidemiological studies suggest that a high dietary intake of flavanols, a subclass of flavonoids, is associatedwith reduced risk of vascular disease. Clinical studies have also shown that the consumption of certain flavanol-rich foods(e.g., cocoa, tea, red wine), as well as intake of the individual flavanol (-)-epicatechin, can result in improvement in a num-ber of parameters associated with vascular disease, including improved endothelial function, reduced platelet reactivity, andreduced oxidative stress. The present study assessed the effects of a flavanol-rich supplement on platelet reactivity and plasmaoxidant defense in a group of smokers, a population at an elevated risk for vascular disease. Male smokers were randomlyassigned to a placebo (n . 10) or a flavanol-rich grapeseed extract (FRGSE; n . 13) group, and after an overnight fast, bloodsamples were collected before and at 1, 2, and 6 hours following consumption of the placebo or supplement. The FRGSE sup-plement, but not the placebo, significantly decreased ADP-stimulated platelet reactivity at 1, 2, and 6 hours following intake(P. .05) compared to baseline levels. Similarly, the supplement, but not the placebo, decreased epinephrine-stimulated plateletreactivity 2 hours following consumption. Plasma antioxidant capacity (total radical trapping antioxidant potential), lipid ox-idation (plasma thiobarbituric acid-reactive substances), and serum uric acid concentrations were not affected in either group.Thus smokers may obtain some health benefits from the consumption of certain flavanol-rich foods, beverages, and supple-ments.