E. Mitchell Seymour

Altered Hyperlipidemia, Hepatic Steatosis, and Hepatic Peroxisome Proliferator-Activated Receptors in Rats with Intake of Tart Cherry

Elevated plasma lipids, glucose, insulin, and fatty liver are among components of metabolic syndrome, a phenotypic pattern that typically precedes the development of Type 2 diabetes. Animal studies show that intake of anthocyanins reduces hyperlipidemia, obesity, and atherosclerosis and that anthocyanin-rich extracts may exert these effects in association with altered activity of tissue peroxisome proliferator-activated receptors (PPARs). However, studies are lacking to test this correlation using physiologically relevant, whole food sources of anthocyanins. Tart cherries are a rich source of anthocyanins, and whole cherry fruit intake may also affect hyperlipidemia and/or affect tissue PPARs. This hypothesis was tested in the Dahl Salt-Sensitive rat having insulin resistance and hyperlipidemia. For 90 days, Dahl rats were pair-fed AIN-76a-based diets supplemented with either 1% (wt:wt) freeze-dried whole tart cherry or with 0.85% additional carbohydrate to match macronutrient and calorie provision. After 90 days, the cherry-enriched diet was associated with reduced fasting blood glucose, hyperlipidemia, hyperinsulinemia, and reduced fatty liver. The cherry diet was also associated with significantly enhanced hepatic PPAR-alpha mRNA, enhanced hepatic PPAR-alpha target acyl-coenzyme A oxidase mRNA and activity, and increased plasma antioxidant capacity. In conclusion, physiologically relevant tart cherry consumption reduced several phenotypic risk factors that are associated with risk for metabolic syndrome and Type 2 diabetes. Tart cherries may represent a whole food research model of the health effects of anthocyanin-rich foods and may possess nutraceutical value against risk factors for metabolic syndrome and its clinical sequelae.

Low-Sodium Dietary Approaches to Stop Hypertension Diet Reduces Blood Pressure, Arterial Stiffness, and Oxidative Stress in Hypertensive Heart Failure With Preserved Ejection Fraction

Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In ‘salt-sensitive’ HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155 to 138 mmHg, p=.02) and diastolic BP (79 to 72 mmHg, p=.04), 24-hour ambulatory systolic (130 to 123 mmHg, p=.02) and diastolic BP (67 to 62 mmHg, p=.02), and carotid-femoral pulse wave velocity (12.4 to 11.0 m/s, p=.03). Urinary F2-isoprostanes decreased by 31% (209 to 144 pmol/mmol Cr, p=.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of ‘salt-sensitive’ hypertension, a phenotype present in many HFPEF animal models, and suggest shared pathophysiological mechanisms linking these two conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In salt-sensitive HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155–138 mm Hg; P=0.02) and diastolic blood pressure (79–72 mm Hg; P=0.04), 24-hour ambulatory systolic (130–123 mm Hg; P=0.02) and diastolic blood pressure (67–62 mm Hg; P=0.02), and carotid-femoral pulse wave velocity (12.4–11.0 m/s; P=0.03). Urinary F2-isoprostanes decreased by 31% (209–144 pmol/mmol Cr; P=0.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of salt-sensitive hypertension, a phenotype present in many HFPEF animal models and suggest shared pathophysiological mechanisms linking these 2 conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.

Low-Sodium DASH Diet Improves Diastolic Function and Ventricular–Arterial Coupling in Hypertensive Heart Failure With Preserved Ejection Fraction

Background—Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted dietary approaches to stop hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular–arterial coupling in hypertensive HFPEF. Methods and Results—Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium, 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central blood pressure (via radial arterial tonometry) and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the parametrized diastolic filling formalism that yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through the analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees) and ventricular–arterial coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs signed-rank tests were used for pre–post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155±35 to 138±30 and 130±16 to 123±18 mm Hg; both P=0.02), and central end-systolic pressure trended lower (116±18 to 111±16 mm Hg; P=0.12). In conjunction, diastolic function improved (c=24.3±5.3 to 22.7±8.1 g/s; P=0.03; k=252±115 to 170±37 g/s2; P=0.03), Ea decreased (2.0±0.4 to 1.7±0.4 mm Hg/mL; P=0.007), and ventricular–arterial coupling improved (Ees:Ea=1.5±0.3 to 1.7±0.4; P=0.04). Conclusions—In patients with hypertensive HFPEF, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and ventricular–arterial coupling. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00939640.

Blueberry intake alters skeletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in obese rats.

Metabolic syndrome can precede the development of type 2 diabetes and cardiovascular disease and includes phenotypes such as obesity, systemic inflammation, insulin resistance, and hyperlipidemia. A recent epidemiological study indicated that blueberry intake reduced cardiovascular mortality in humans, but the possible genetic mechanisms of this effect are unknown. Blueberries are a rich source of anthocyanins, and anthocyanins can alter the activity of peroxisome proliferator-activated receptors (PPARs), which affect energy substrate metabolism. The effect of blueberry intake was assessed in obesity-prone rats. Zucker Fatty and Zucker Lean rats were fed a higher-fat diet (45% of kcal) or a lower-fat diet (10% of kcal) containing 2% (wt/wt) freeze-dried whole highbush blueberry powder or added sugars to match macronutrient and calorie content. In Zucker Fatty rats fed a high-fat diet, the addition of blueberry reduced triglycerides, fasting insulin, homeostasis model index of insulin resistance, and glucose area under the curve. Blueberry intake also reduced abdominal fat mass, increased adipose and skeletal muscle PPAR activity, and affected PPAR transcripts involved in fat oxidation and glucose uptake/oxidation. In Zucker Fatty rats fed a low-fat diet, the addition of blueberry also significantly reduced liver weight, body weight, and total fat mass. Finally, Zucker Lean rats fed blueberry had higher body weight and reduced triglycerides, but all other measures were unaffected. In conclusion, whole blueberry intake reduced phenotypes of metabolic syndrome in obesity-prone rats and affected PPAR gene transcripts in adipose and muscle tissue involved in fat and glucose metabolism.

Whole Grape Intake Impacts Cardiac Peroxisome Proliferator-Activated Receptor and Nuclear Factor κB Activity and Cytokine Expression in Rats With Diastolic Dysfunction

Prolonged hypertension is the leading cause of heart failure. Failing hearts show reduced peroxisome proliferator-activating receptor (PPAR) activity and enhanced nuclear factor &kgr;B (NF-&kgr;B) activity, which together modify cardiac inflammation and fibrosis. In vitro studies suggest that phytochemicals alter PPAR and NF-&kgr;B activity, but the capabilities of a phytochemical-rich diet are less understood. Grapes contain an array of commonly consumed dietary phytochemicals. In Dahl salt-sensitive hypertensive rats, we showed previously that dietary provision of whole table grape powder (3% weight:weight) for 18 weeks reduced blood pressure, cardiac hypertrophy, and diastolic dysfunction. The hypothesis tested here is that, in this model, phytochemical provision from whole grape powder impacts cardiac PPAR and NF-&kgr;B activity and their related gene transcripts. Grape-fed rats had enhanced PPAR-&agr; and PPAR-&ggr; DNA binding activity but reduced NF-&kgr;B DNA binding activity. RT-PCR revealed that grape-fed rats showed upregulated mRNA for PPAR-&agr;, PPAR-&ggr; coactivator-1&agr;, PPAR-&ggr;, and the cytosolic NF-&kgr;B inhibitor, inhibitor-&kgr;B&agr;. By contrast, grape-fed rats showed downregulated mRNA for tumor necrosis factor-&agr; and transforming growth factor-&bgr;1. Finally, grape-fed rats showed significantly reduced cardiac tumor necrosis factor-&agr; and transforming growth factor-&bgr; protein expression, increased inhibitor-&kgr;B&agr; expression, and reduced cardiac fibrosis. In the Dahl salt-sensitive rat, chronic intake of grapes altered cardiac transcripts related to PPAR and NF-&kgr;B that may be significant to the observed diet-associated cardioprotection.

Processed Tart Cherry Products—Comparative Phytochemical Content, in vitro Antioxidant Capacity and in vitro Anti-inflammatory Activity

Processing of fruits and vegetables affects their phytochemical and nutrient content. Tart cherries are commercially promoted to possess antioxidant and anti-inflammatory activity. However, processing affects their phytochemical content and may affect their related health benefits. The current study compares the in vitro antioxidant capacity and anti-inflammatory cyclooxygenase activity of processed tart cherry (Prunus cerasus) products-cherry juice concentrate, individually quick-frozen cherries, canned cherries, and dried cherries. Cherry products were analyzed for total anthocyanin and proanthocyanidin content and profile. On a per serving basis, total anthocyanins were highest in frozen cherries and total proanthocyanidins were highest in juice concentrate. Total phenolics were highest in juice concentrate. Juice concentrate had the highest oxygen radical absorbance capacity (ORAC) and peroxynitrite radical averting capacity (NORAC). Dried cherries had the highest hydroxyl radical averting capacity (HORAC) and superoxide radical averting capacity (SORAC). Processed tart cherry products compared very favorably to the U.S. Dept. of Agriculture-reported ORAC of other fresh and processed fruits. Inhibition of in vitro inflammatory COX-1 activity was greatest in juice concentrate. In summary, all processed tart cherry products possessed antioxidant and anti-inflammatory activity, but processing differentially affected phytochemical content and in vitro bioactivity. On a per serving basis, juice concentrate was superior to other tart cherry products.

Diet-relevant phytochemical intake affects the cardiac AhR and nrf2 transcriptome and reduces heart failure in hypertensive rats.

Intake of phytochemical-rich diets is inversely related to hypertension. Phytochemicals alter in vitro aryl hydrocarbon receptor (AhR) and NF-E2 related factor (nrf2) transcription factor activity and related genes pertinent to antioxidant defense. However, it is unknown if these molecular effects occur in the heart with dietary intake of physiologically relevant phytochemicals and if this correlates with reduced hypertension-associated heart failure. This extended feeding study used whole grapes as a model of a phytochemical-rich food and hypertensive heart failure-prone rats to assess mechanisms of effect. Grape intake reduced cardiac hypertrophy and fibrosis and improved diastolic function. At the development of diastolic dysfunction, hypertensive rats show reduced AhR activity, reduced expression of AhR-regulated genes, reduced glutathione and reduced activity of glutathione-regulating proteins. However, grape intake significantly increased cardiac AhR and nrf2 activity, Phase I/II gene transcripts and protein activity related to antioxidant defense. Heart failure is the leading cause of morbidity and mortality in the aged and the intake of phytochemicals from fruits and vegetables decreases with age. Concentrated antioxidant nutrient trials have failed to affect heart failure. However, this study demonstrates that diet-relevant intake of non-nutrient phytochemicals significantly reduces heart failure progression. Therefore, this study suggests that higher intake of phytochemical-containing foods may achieve cardiac benefits that isolated antioxidant supplements may not. In summary, intake of diet-relevant phytochemicals altered the cardiac antioxidant transcriptome, antioxidant defense, oxidative damage and fibrosis. Regular phytochemical intake may therefore increase cardiac resistance to cardiac pathology instigated by prolonged hypertension.

Tissue bioavailability of anthocyanins from whole tart cherry in healthy rats

Our aim was to confirm and identify the presence of tart cherry anthocyanins in several target tissues of healthy rats. Liquid chromatography-mass spectrometry analysis was employed for detection and characterisation of anthocyanin metabolites. It was shown that four native anthocyanins, namely cyanidin 3-glucosylrutinoside, cyanidin 3-rutinoside, cyanidin 3-rutinoside 5-β-D-glucoside, and peonidin 3-rutinoside were differentially distributed among targeted tissues of rats. Bladder and kidney contained more total anthocyanins than all other tissues analysed. It was also revealed that the bioavailability pattern of these native anthocyanins among tissues is varied. The highest concentration of individual anthocyanin cyanidin 3-glucosylrutinoside (2339 picograms/gram of tissue) was detected in bladder, followed by cyanidin 3-rutinoside 5-β-d-glucoside (916 picograms/gram) in the liver of rats. Although the diverse distribution of tart cherry anthocyanins in different rat tissues still requires further explanation, it may provide an evidentiary link between tissue bioavailability and health-enhancing properties of anthocyanins at target sites.

The Use of Selected Medicinal Herbs for Chemoprevention and Treatment of Cancer, Parkinson’s Disease, Heart Disease, and Depression

In this chapter, we present recent advances on the use of several different kinds of medicinal herbs to treat cancer, Parkinson’s disease (PD), heart disease, and depression. These include recent studies on the use of Vaccinium spp. (blueberries and relatives) for cancer treatment and prevention; blueberries in the diet to improve motor skills and cognitive ability in patients with PD; digitalis (foxglove) to treat patients with heart disease; and St. John’s wort that is used to treat patients with mild-to-moderate depression. The basic conclusion from these studies is that rigorous, well-designed clinical trials are needed to validate the safe use of these and other medicinal herbs for treatment of these and other diseases.

The inhibitory potential of Montmorency tart cherry on key enzymes relevant to type 2 diabetes and cardiovascular disease

The inhibitory potential of Montmorency tart cherry on glycemia regulation and other enzymes relevant to inflammation were evaluated. Tart cherry has superior inhibitory potential against key enzymes associated with carbohydrate digestion linked to hypertension. In particular, α-amylase activity was significantly inhibited (IC50 = 3.46 ± 0.06 mg/ml), whereas we observed mild inhibition of α-glucosidase (IC50 = 11.64 ± 0.65 mg/ml). Angiotensin I-converting enzyme inhibition was also strong by about 89%. Tart cherry extract showed strong to moderate inhibitions of cyclooxygenase-1 (65%), lipoxygenase (64%), cyclooxygenase-2 (38%) and xanthine oxidase (26%), respectively. Anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, were strong inhibitors of α-amylase and α-glucosidase. Kaempferol showed relatively potent inhibition on COX and XO. It was revealed that some pairs of metabolites manifest positive or negative interactions against XO enzyme inhibition. Inhibition of all these enzymes provides a strong biochemical basis for management of type 2 diabetes and cardiovascular disease by controlling glucose absorption, reducing associated hypertension and inflammation.