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1.  Clinical investigation of the acute effects of pomegranate juice on blood pressure and endothelial function in hypertensive individuals 
ARYA Atherosclerosis  2013;9(6):326-331.
BACKGROUND
Pomegranate juice (PJ) is rich in bioactive phytochemicals with antioxidant, and anti-inflammatory and cardioprotective functions. The present trial investigated the acute effects of PJ consumption on blood pressure and markers of endothelial function.
METHODS
In this single-arm study, thirteen hypertensive men aged 39-68 years were recruited. Included subjects were assigned to natural PJ (150 ml/day) following a 12 hour fast. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and flow-mediated dilation (FMD), along with serum concentrations of C-reactive protein (CRP), intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and interleukin-6 (IL-6) were measured at baseline and 4-6 hours after PJ consumption.
RESULTS
Comparison of pre- vs. post-trial values revealed a significant reduction in both SBP (7%; P = 0.013) and DBP (6%; P < 0.010). However, changes in FMD (20%) as well as circulating levels of CRP, ICAM-1, VCAM-1, E-selectin, and IL-6 did not reach statistical significance (P = 0.172).
CONCLUSION
PJ has promising acute hypotensive properties. Consumption of PJ could be considered in the context of both dietary and pharmacological interventions for hypertension.
PMCID: PMC3933059  PMID: 24575134
Punica Granatum L.; Cardiovascular Disease; Hypertension; Inflammation; Endothelium-Dependent Dilation
2.  Cellular Adhesion Molecules in Healthy Subjects: Short Term Variations and Relations to Flow Mediated Dilation 
Biomarker Insights  2008;3:57-62.
The objective was primarily to describe short term intra-individual variation in serum levels of soluble adhesion molecules (sCAMs: E-selectin, P-selectin, intercellular adhesion molecule-1(sICAM-1) and vascular cellular adhesion molecule-1(sVCAM-1)) in healthy subjects. Secondly, sCAMs were correlated to brachial artery flow mediated vasodilation (FMD).
Forty healthy subjects aged 24–66 years had sCAMs measured twice with 4 week intervals and short-term intra-individual variation was estimated as variation in the paired measurements after correcting for the analytical precision of the used method. At baseline, brachial FMD was measured.
No difference was observed in mean sCAMs in the whole study group. Estimated intra-subject variations in sCAMs were 7.6–11.3%. In a regression analysis, significant negative association was found between sE-selectin and FMD after controlling for possible confounders (p < 0.04) while no significant correlation could be demonstrated between the other sCAMs and FMD.
In conclusion, short term intra-individual variations in sCAMs were 7.6–11.3% in healthy subjects. We also found a significant negative association between sE-selectin and FMD, indicating an possible association between inflammation and dysfunction of the vascular endothelium; however further studies are required to confirm this preliminary finding.
PMCID: PMC2688346  PMID: 19578494
variation; healthy subjects; cellular adhesion molecules; flow mediated dilation
3.  Metabolic Abnormalities and Viral Replication is Associated with Biomarkers of Vascular Dysfunction in HIV-Infected Children 
HIV Medicine  2011;13(5):264-275.
Objectives
Human immunodeficiency virus (HIV)-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction among HIV-infected children with and without hyperlipidemia to HIV-exposed, uninfected children (HEU) enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers.
Design
Prospective cohort study
Methods
Biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP1)); coagulant dysfunction (fibrinogen and P-selectin); endothelial dysfunction (soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), and E-selectin); and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded.
Results
The median ages were 12.3 y (HIV-infected) and 10.1 y (HEU). Body mass index (BMI) Z-scores, waist and hip circumference, and percent body fat were lower among HIV-infected. Total and non-HDL cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children had higher MCP-1, fibrinogen, sICAM, and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavorable lipid profiles were positively associated with IL6, MCP1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP1 and CRP) and endothelial dysfunction (sICAM and sVCAM).
Conclusions
HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavorable lipid levels and active HIV replication.
doi:10.1111/j.1468-1293.2011.00970.x
PMCID: PMC3297698  PMID: 22136114
Children; HIV/AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers
4.  Biomarkers of Vascular Dysfunction in Children Infected with Human Immunodeficiency Virus-1 
Background
We compared biomarkers of vascular dysfunction among HIV-infected children to a demographically-similar group of uninfected children and determined factors associated with these biomarkers.
Methods and Results
We measured several biomarkers of vascular dysfunction: C-Reactive Protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein -1 (MCP1) [inflammation]; fibrinogen and P-selectin [coagulant dysfunction]; soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), and E-selectin [endothelial dysfunction]; and leptin [metabolic dysfunction]. Anthropometry, body composition, CD4%, HIV viral load, and antiretroviral therapy were recorded. Mean age was 14.8y [106 HIV-infected children] and 12.3y [55 control children]. Sex and body mass index Z-scores were similar. Infected children had higher sICAM, sVCAM, MCP1, IL-6, and fibrinogen levels. E-selectin (p=0.07), and CRP (p=0.08) trended to be greater in the HIV group, yet leptin, and P-selectin were similar. In multivariable analyses in the HIV-infected children alone, each 1-standard-deviation increase in waist:hip ratio was associated with increases in sICAM (17%), MCP1 (19%), IL6 (18%), and CRP (59%). CD4% was inversely associated with sVCAM, MCP1, IL6, fibrinogen, and CRP.
Conclusion
HIV-infected children have higher levels of biomarkers of vascular dysfunction than healthy children. Risk factors associated with these biomarkers include higher waist:hip ratios and HIV disease severity.
doi:10.1097/QAI.0b013e3181e222c9
PMCID: PMC2943965  PMID: 20531209
Children; HIV/AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers
5.  Protective effects of pomegranate (Punica granatum) juice on testes against carbon tetrachloride intoxication in rats 
Background
Pomegranate fruit has been extensively used as a natural medicine in many cultures. The present study was aimed at evaluating the protective effects of pomegranate (Punica granatum) juice against carbon tetrachloride (CCl4)-induced oxidative stress and testes injury in adult Wistar rats.
Methods
Twenty eight Wistar albino male rats were divided equally into 4 groups for the assessment of protective potential of pomegranate juice. Rats of group I (control) received only vehicles and had free access to food and water. Rats of groups II and IV were treated with CCl4 (2 ml/kg bwt) via the intraperitoneal route once a week for ten weeks. The pomegranate juice was supplemented via drinking water 2 weeks before and concurrent with CCl4 treatment to group IV. Group III was supplemented with pomegranate juice for twelve weeks. The protective effects of pomegranate on serum sex hormones, oxidative markers, activities of antioxidant enzymes and histopathology of testes were determined in CCl4-induced reproductive toxicity in rats.
Results
Pomegranate juice showed significant elevation in testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) those depleted by the injection of CCl4. Activity levels of endogenous testesticular antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) and glutathione (GSH) contents were increased while lipid peroxidation (LPO) and nitric oxide (NO) were decreased with pomegranate juice. Moreover, degeneration of germ and Leydig cells along with deformities in spermatogenesis induced after CCl4 injections were restored with the treatment of pomegranate juice.
Conclusion
The results clearly demonstrated that pomegranate juice augments the antioxidant defense mechanism against carbon tetrachloride-induced reproductive toxicity and provides evidence that it may have a therapeutic role in free radical mediated diseases.
doi:10.1186/1472-6882-14-164
PMCID: PMC4041339  PMID: 24884677
Punica granatum; Carbon tetrachloride; Oxidative stress; Testes; Rats
6.  Relations of Dietary Magnesium Intake to Biomarkers of Inflammation and Endothelial Dysfunction in an Ethnically Diverse Cohort of Postmenopausal Women 
Diabetes Care  2009;33(2):304-310.
OBJECTIVE
Although magnesium may favorably affect metabolic outcomes, few studies have investigated the role of magnesium intake in systemic inflammation and endothelial dysfunction in humans.
RESEARCH DESIGN AND METHODS
Among 3,713 postmenopausal women aged 50–79 years in the Women's Health Initiative Observational Study and free of cardiovascular disease, cancer, and diabetes at baseline, we measured plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), turnor necrosis factor-α receptor 2 (TNF-α-R2), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin. Magnesium intake was assessed using a semiquantitative food frequency questionnaire.
RESULTS
After adjustment for age, ethnicity, clinical center, time of blood draw, smoking, alcohol, physical activity, energy intake, BMI, and diabetes status, magnesium intake was inversely associated with hs-CRP (P for linear trend = 0.003), IL-6 (P < 0.0001), TNF-α-R2 (P = 0.0006), and sVCAM-1 (P = 0.06). Similar findings remained after further adjustment for dietary fiber, fruit, vegetables, folate, and saturated and trans fat intake. Multivariable-adjusted geometric means across increasing quintiles of magnesium intake were 3.08, 2.63, 2.31, 2.53, and 2.16 mg/l for hs-CRP (P = 0.005); 2.91, 2.63, 2.45, 2.27, and 2.26 pg/ml for IL-6 (P = 0.0005); and 707, 681, 673, 671, and 656 ng/ml for sVCAM-1 (P = 0.04). An increase of 100 mg/day magnesium was inversely associated with hs-CRP (−0.23 mg/l ± 0.07; P = 0.002), IL-6 (−0.14 ± 0.05 pg/ml; P = 0.004), TNF-α-R2 (−0.04 ± 0.02 pg/ml; P = 0.06), and sVCAM-1 (−0.04 ± 0.02 ng/ml; P = 0.07). No significant ethnic differences were observed.
CONCLUSIONS
High magnesium intake is associated with lower concentrations of certain markers of systemic inflammation and endothelial dysfunction in postmenopausal women.
doi:10.2337/dc09-1402
PMCID: PMC2809271  PMID: 19903755
7.  Maternal Serum Levels of VCAM-1, ICAM-1 and E-selectin in Preeclampsia 
Journal of Korean Medical Science  2004;19(5):688-692.
Endothelial dysfunction is thought to be a central pathogenic feature in preeclampsia on the basis of elevated adhesion molecules. The aim of the present study was to compare the levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1) and E-selectin (sE-selectin) in sera of normal and preeclamptic pregnancies. We studied the serum levels of sVCAM-1, sICAM-1 and sE-selectin in normal pregnant women (n=63), mild preeclampsia (n=33) and severe preeclampsia (n=82). Concentrations of soluble adhesion molecules were determined with enzyme-linked immunoassay (ELISA). Serum concentrations of sVCAM-1 were significantly higher in both mild (p=0.004) and severe preeclampsia (p=0.000) than normal pregnancy. There were also significant differences in sVCAM-1 levels between mild and severe preeclampsia (p=0.002). sICAM-1 levels of severe preeclampsia were statistically different from those of normal pregnancy (p=0.038). Levels of sE-selectin were elevated in both mild (p=0.011) and severe preeclampsia (p=0.000) compared to normal pregnancy, but no statistical difference between the mild and severe preeclampsia (p=0.345). These results suggest that all three soluble adhesion molecules are increased in severe preeclampsia, and sVCAM-1 among them may be useful in predicting the severity of preeclampsia.
doi:10.3346/jkms.2004.19.5.688
PMCID: PMC2816332  PMID: 15483345
Pre-Eclampsia; Cell Adhesion Molecules; Vasurlar Cell Adhesion Molecule-1, Intercellular Adhesion Molecule-1, E-Selectin
8.  Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model 
Carcinogenesis  2011;33(3):644-651.
We earlier provided evidence that oral consumption of pomegranate fruit extract (PFE) inhibits prostate cancer (PCa) cell growth in nude mice. To ascertain convincing evidence of chemopreventive effects of PFE against PCa, its efficacy requires to be evaluated in animal models that closely emulate human disease. Here, we provide evidence of remarkable tumor growth inhibitory effects of PFE using the TRAMP model. Mice received 0.1 and 0.2% PFE, equivalent to 250 and 500 ml of pomegranate juice, in drinking water, starting at 6 weeks and examined at 12, 20 and 34 weeks of age. In water-fed group, 100% mice developed palpable tumors by 20 weeks compared with only 30 and 20% in the 0.1 and 0.2% PFE-supplemented groups, respectively. At 34 weeks, palpable tumors were observed in 70 of 0.1% and only 50 of 0.2% PFE-supplemented mice. Compared with median survival of 43 weeks in water-fed mice, 0.1 and 0.2% PFE-supplemented mice exhibited median life expectancy of 73 and 92 weeks, respectively. Compared with respective water-fed groups, none of the mice in PFE-supplemented groups exhibited metastases to any of the distant organs at 20 weeks and only 20% mice exhibited metastasis at 34 weeks of age. Many of the PFE-supplemented animals had multiple foci of well-differentiated carcinoma but no evidence of poorly differentiated carcinoma. PFE supplementation resulted in simultaneous and significant inhibition of IGF-I/Akt/mTOR pathways in the prostate tissues and tumors. We suggest that pomegranate juice be evaluated in clinical trials in patients at high risk for developing PCa.
doi:10.1093/carcin/bgr308
PMCID: PMC3291862  PMID: 22198212
9.  Effects of Antioxidant Supplementation on Insulin Sensitivity, Endothelial Adhesion Molecules and Oxidative Stress in Normal Weight and Overweight Young Adults 
Metabolism  2009;58(2):254-262.
Objective
To determine whether short-term antioxidant supplementation affects insulin sensitivity, endothelial adhesion molecule levels, and oxidative stress in overweight young adults.
Methods and Procedures
A randomized, double-blind, controlled study tested the effects of antioxidants (AOX) on measures of insulin sensitivity (homeostasis model assessment, HOMA and QUICKI), endothelial adhesion molecules (sICAM-1, sVCAM-1, sE-selectin), adiponectin and oxidative stress (lipid hydroperoxides, PEROX) in overweight and normal weight individuals (N=48, 18-30 years). Participants received either AOX (vitamin E 800IU, vitamin C 500mg, β-carotene 10mg) or placebo (PLC) for 8 weeks.
Results
HOMA values were initially higher in the overweight subjects and were lowered with AOX by week 8 (15% reduction, p=0.02). Adiponectin increased in both AOX groups. sICAM-1 and sE-selectin decreased in overweight AOX treated groups by 6% and 13%, respectively (p<0.05). Plasma PEROX were reduced by 0.31 and 0.70 nmol/ml in the normal weight and overweight AOX treated groups, respectively, by week 8 (p<0.05).
Discussion
AOX supplementation moderately lowers HOMA and endothelial adhesion molecule levels in overweight young adults. A potential mechanism to explain this finding is the reduction in oxidative stress by AOX. Long term studies are needed to determine whether AOX are effective in suppressing diabetes or vascular activation over time.
doi:10.1016/j.metabol.2008.09.022
PMCID: PMC3325609  PMID: 19154960
obesity; antioxidant; inflammation; adiponectin
10.  Long-term orange juice consumption is associated with low LDL-cholesterol and apolipoprotein B in normal and moderately hypercholesterolemic subjects 
Background
This study investigated the hypothesis that long-term orange juice consumption (≥ 12 months) was associated with low risk factors for cardiovascular disease in adult men and women with normal and moderately high cholesterol blood levels.
Methods
The sample consisted of 103 men (18–66 y) and 26 women (18–65 y); all were employees of an orange juice factory with daily access to free orange juice. The results showed that 41% of the individuals consumed 2 cups (480 mL) of orange juice per day for at least twelve months, while 59% of the volunteers are non-consumers of orange juice.
Results
Orange juice consumers with normal serum lipid levels had significantly lower total cholesterol (−11%, p <0.001), LDL-cholesterol (−18%, p < 0.001), apolipoprotein B (apo B) (−12%, p < 0.01) and LDL/HDL ratio (−12%, p < 0.04) in comparison to non-consumers, as did the consumers with moderate hypercholesterolemia: lower total cholesterol (−5%, p <0.02), LDL-cholesterol (−12%, p <0.03), apolipoprotein B (−12%, p <0.01) and LDL/HDL ratio (−16%, p <0.05) in comparison the non-consumers counterparts. Serum levels of homocysteine, HDL- cholesterol and apolipoprotein A-1, body composition and the dietary intake of food energy and macronutrients did not differ among orange juice consumers and non-consumers, but vitamin C and folate intake was higher in orange juice consumers.
Conclusion
Long-term orange juice consumers had lower levels of total cholesterol, LDL-cholesterol, apo B and LDL/HDL ratio and an improvement of folate and vitamin C in their diet.
doi:10.1186/1476-511X-12-119
PMCID: PMC3750609  PMID: 23919812
Orange juice; LDL-cholesterol; Apo B; Homocysteine; Humans; Suco de laranja LDL-colesterol; Apo B; Homocisteína; Humanos
11.  The association of ventricular tachycardia and endothelial dysfunction in the setting of acute myocardial infarction with ST elevation 
Background
Ventricular tachycardia (VT) is frequently seen in ischemic settings like acute myocardial infarction with ST segment elevation (STEMI). Endothelial dysfunction (ED) represents inflammation and the loss of all protective features of the endothelium. We aimed to examine the association between VT and ED in patients with STEMI.
Material/Methods
The study included 90 subjects (30 with VT and acute STEMI, 30 with STEMI without VT, and 30 controls). Sera of all subjects were tested on ED markers by enzyme immunoassay: sICAM-1 (intracellular adhesive molecule-1), sVCAM-1 (vascular adhesive molecule-1), P- and E-selectins, and VEGF (vascular endothelial growth factor). In addition, CRP (C-reactive protein) was detected.
Results
Significantly increased values of low-density lipoprotein, triglycerides, leukocytes, creatinine, and the number of cigarettes smoked were observed among patients with VT+STEMI in comparison to controls. The levels of E-selectin were significantly lower in the VT+STEMI group than in the other groups, while the levels of VCAM-1 were significantly higher in the groups with STEMI and VT+STEMI compared to the controls. Lower levels of VEGF were recorded in STEMI and VT+STEMI groups compared to the control group. A significant correlation between CRP and VCAM-1 in patients with VT +STEMI was demonstrated.
Conclusions
We showed that ED may have a role in the immunopathogenesis of VT in patients with STEMI. The role of sE-selectin and correlation of sVCAM-1 with CRP as possible ED predictive markers in patients with VT+STEMI should be further investigated in a large cohort of patients.
doi:10.12659/MSM.884026
PMCID: PMC3852622  PMID: 24253420
ventricular tachycardia; acute myocardial infarction with ST segment elevation; endothelial dysfunction; adhesion molecules
12.  Effect of Fresh Orange Juice Intake on Physiological Characteristics in Healthy Volunteers 
ISRN Nutrition  2014;2014:405867.
Background. Impaired endothelial function is a predictor of cardiovascular events. Orange juice (OJ) is rich in dietary flavonoids and could inhibit oxidative stress and inflammatory responses. We examined the effects of commercial (COJ) and fresh orange juice (FOJ) on endothelial function and physiological characteristics in healthy humans. Materials and Methods. Twenty-two healthy volunteers years were enrolled in a single blind randomized crossover controlled trial. The two groups consumed either COJ for the first 4 weeks and then FOJ (CFOJ, 4 weeks), or FOJ for the first 4 weeks and then COJ (FCOJ, 4 weeks). We assessed endothelial function by measuring flow-mediated dilation, serum concentrations of lipids, apolipoproteins A and B (apo A-1 and apo B), and inflammatory markers such as vascular endothelial adhesion molecule 1 (VCAM-1), E-selectin, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6. Results. Consumption of both juices decreased VCAM, hs-CRP, and E-selectin but increased apo A-1. A decline in LDL occurred in the FOJ group. There were no differences between the characteristics of two groups, with the exception of apo A-1 levels that were increased with both forms of OJ. The largest variations occurred with hs-CRP, VCAM in both groups. Conclusion. Consumption of COJ and FOJ produced beneficial effects on the physiological characteristics of healthy volunteers. Although these results could encourage the consumption of OJ, intervention studies are needed to determine the long-term effects of these types of OJ on metabolic and cardiovascular endpoints.
doi:10.1155/2014/405867
PMCID: PMC4045306  PMID: 24967267
13.  Association of inflammation and endothelial dysfunction with metabolic syndrome, prediabetes and diabetes in adults from Inner Mongolia, China 
Background
We examined the association of biomarkers of inflammation and endothelial dysfunction with diabetes and metabolic syndrome (MetS) in persons from Inner Mongolia.
Methods
A cross-sectional study was conducted among 2,536 people aged 20 years and older from Inner Mongolia, China. Overnight fasting blood samples were obtained to measure plasma concentrations of high sensitivity C-reactive protein (hsCRP), soluble inter-cellular adhesion molecule-1 (sICAM-1), sE-selectin, angiotensin II, high density lipoprotein cholesterol, triglycerides, and blood glucose. Waist circumference and blood pressure were measured by trained staff. MetS was defined according to the modified ATP III definition for Asians. Elevated level of the biomarker was defined as values in the upper tertile of the distribution. Participants were categorized into one of four groups based on the presence or absence of metabolic and glycemic abnormalities: 1) free of prediabetes, diabetes and MetS (reference group), 2) prediabetes or diabetes only, 3) MetS without prediabetes or diabetes, and 4) MetS plus prediabetes or diabetes. The multivariable models are adjusted for age, gender, smoking, drinking, family history of hypertension, and body mass index.
Results
Among study participants, 18.5% had prediabetes, 3.6% had diabetes, and 27.4% of the entire study population had 3 or more components of the MetS. Elevated hsCRP was associated with an increased odds of prediabetes or diabetes only, MetS without prediabetes or diabetes, and MetS plus prediabetes or diabetes with multivariable adjusted odds ratios (95% confidence intervals) of 2.3 (1.7-3.1), 3.0 (2.4-3.8), and 5.8 (4.5-7.5), respectively. Elevated sICAM-1 was associated with increased odds (95% CI) of prediabetes or diabetes only (2.1, 1.6-2.9) and MetS plus prediabetes or diabetes (4.2, 3.2-5.3) but was not associated with MetS alone. Elevated sE-selectin was associated with a modestly increased risk of MetS (OR 1.7, 95% CI 1.4-2.2). Elevated levels of Angiotensin II were not associated with the MetS plus prediabetes or diabetes in this study.
Conclusions
Diabetes and the MetS are common in the Inner Mongolia population. The biomarkers of inflammation and endothelial dysfunction are associated with increased risk for diabetes and MetS in this population. These results are consistent with results from other populations.
doi:10.1186/1472-6823-11-16
PMCID: PMC3204247  PMID: 21989115
metabolic syndrome; diabetes; inflammation; endothelial dysfunction; C-reactive protein; intercellular adhesion molecule-1; E-selectin
14.  Association of Endothelial and Oxidative Stress with Metabolic Syndrome and Subclinical Atherosclerosis: Multi-Ethnic Study of Atherosclerosis 
Objectives
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
Methods
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
Results
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
Conclusions
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
doi:10.1038/ejcn.2011.47
PMCID: PMC3130805  PMID: 21505504
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
15.  A randomized trial of exercise for blood pressure reduction in type 2 diabetes: effect on flow-mediated dilation and circulating biomarkers of endothelial function 
Atherosclerosis  2012;224(2):446-453.
Objective
To investigate the effect of an exercise intervention on flow-mediated dilation (FMD) and circulating endothelial biomarkers in adults with type 2 diabetes (T2DM)
Methods
Sedentary adults (n=140), aged 40–65, with T2DM and untreated pre- or Stage I hypertension or treated hypertension were randomized to a 6-month, supervised, exercise program (3×week) or a sedentary control. Assessments included BMI, body and visceral fat, blood pressure, lipids, HbA1c, insulin sensitivity (QUICKI), fitness, FMD, E-selectin, P-selectin, intracellular and vascular cellular adhesion molecules (ICAM, VCAM), and tissue plasminogen activator (tPA). Intervention effects were compared by t-tests. Pearson’s correlations were calculated between changes in cardiovascular risk factors and endothelial outcomes.
Results
Exercisers significantly improved BMI (−0.6 kg/m2), body fat % (−1.4%), HbA1c (−0.5%), and fitness (2.9 mL/kg·min) vs. controls (p<0.05). However, there were no differences between groups in changes in FMD, E-selectin, P-selectin, ICAM, VCAM, or tPA. Among exercisers, changes in cardiovascular risk factors correlated with several biomarkers. Decreased P-selectin correlated with decreased BMI (r=0.29, p=0.04) and increased HDL cholesterol (r=−0.36, p=0.01). Decreased ICAM correlated with decreased triglycerides and HbA1c (r=0.30, p=0.04; r=0.31, p=0.03) and increased QUICKI (r=−0.28, p=0.05). Decreased tPA correlated with decreased total body and visceral fat (r=0.28, p=0.05; r=0.38, p=0.008) and increased QUICKI (r=−0.38, p=0.007).
Conclusions
While exercise resulted in improved fitness, body composition, and glycemic control, there were no changes in FMD or circulating endothelial biomarkers. The associations of changes in cardiovascular risk factors and endothelial biomarkers suggest that improvement in risk factors could mediate the exercise-induced improvements in endothelial function seen in prior studies.
doi:10.1016/j.atherosclerosis.2012.07.035
PMCID: PMC3459298  PMID: 22889573
Endothelial function; adhesion molecules; exercise; type 2 diabetes; vasodilation
16.  Evaluation of endothelial function and subclinical atherosclerosis in association with hepatitis C virus in HIV-infected patients: a cross-sectional study 
BMC Infectious Diseases  2011;11:265.
Background
Relationship of hepatitis C virus (HCV) infection with an increased risk of cardiovascular disease (CVD) in HIV-infected patients remains controversial. We evaluated endothelial function and subclinical atherosclerosis in HIV-infected patients with and without HCV.
Methods
Flow-mediated dilatation (FMD) of the brachial artery and circulating levels of cell adhesion molecules (CAM) were measured in HCV/HIV-coinfected and HIV-monoinfected patients. Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT).
Results
63 (31%) HCV/HIV-coinfected and 138 (69%) HIV-monoinfected patients were included. Median soluble vascular CAM-1 (sVCAM-1) and intercellular CAM-1 (sICAM-1) levels were significantly higher in HIV/HCV-coinfected patients (P < 0.001 for both cases). Median (interquartile range) FMD was 6.21% (2.86-9.62) in HCV/HIV-coinfected and 5.54% (2.13-9.13) in HIV-monoinfected patients (P = 0.37). Adjustment for variables associated with HCV and FMD disclosed similar results. FMD correlated inversely with cIMT and age. Carotid IMT did not differ between HCV/HIV-coinfected and HIV-monoinfected patients in unadjusted (0.61 [0.55-0.65] mm vs 0.60 [0.53-0.72] mm; P = 0.39) or adjusted analyses.
Conclusion
HCV infection was associated with higher levels of sICAM-1 and sVCAM-1, but no evidence of increased subclinical atherosclerosis was found when endothelial function was evaluated through FMD, or when assessing the cIMT.
doi:10.1186/1471-2334-11-265
PMCID: PMC3198698  PMID: 21967471
17.  Levels of Soluble Adhesion Molecules PECAM-1 and P-Selectin are Decreased in Children with Autism Spectrum Disorder 
Biological psychiatry  2012;72(12):1020-1025.
Background
Although the etiopathology of Autism Spectrum Disorder (ASD) is not clear there is increasing evidence that dysfunction in the immune system affects many children with ASD. Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines and microglial activity in brain tissue and CSF, as well as abnormal peripheral immune cell function.
Methods
Adhesion molecules, such as platelet endothelial adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), P-Selectin, and L-Selectin, function to facilitate leukocyte transendothelial migration. We assessed concentrations of soluble adhesion molecules, sPECAM-1, sICAM-1, sVCAM-1, sP-Selectin, and sL-Selectin in the plasma of 49 participants with ASD, and 31 typically developing controls of the same age, all of whom were enrolled as part of the Autism Phenome Project (APP). Behavioral assessment, the levels of soluble adhesion molecules, head circumference and MRI measurements of brain volume were compared in the same subjects.
Results
Levels of sPECAM-1 and sP-Selectin were significantly reduced in the ASD group compared to typically developing controls (p < 0.02). Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p=0.03).
Conclusions
As adhesion molecules modulate the permeability and signaling at the blood brain barrier as well as leukocyte infiltration into the CNS, current data suggests a role for these molecules in the complex pathophysiology of ASD.
doi:10.1016/j.biopsych.2012.05.004
PMCID: PMC3496806  PMID: 22717029
Autism; PECAM-1; P-Selectin; CD31; CD62-P; Adhesion
18.  Persistent Inflammation and Endothelial Activation in HIV-1 Infected Patients after 12 Years of Antiretroviral Therapy 
PLoS ONE  2013;8(6):e65182.
Objective
The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART).
Methods
Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, β2-microglobulin, interleukin (IL) 8, tumor necrosis factor α (TNFα), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE-Selectin, and sP-Selectin.
Results
HIV infected patients had higher levels of β2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls.
Conclusion
Discrete signs of systemic and vascular inflammation persist even after very long term cART.
doi:10.1371/journal.pone.0065182
PMCID: PMC3670840  PMID: 23755191
19.  Maternal Biomarkers of Endothelial Dysfunction and Preterm Delivery 
PLoS ONE  2014;9(1):e85716.
Background
Endothelial dysfunction is key to the development of atherosclerosis. Preterm delivery foreshadows later maternal cardiovascular disease (CVD), but it is not known if endothelial dysfunction also occurs. We prospectively measured circulating biomarkers of endothelial dysfunction in pregnant women with preterm or term delivery.
Methods
We conducted a case-control study nested within a large prospective epidemiological study of young, generally healthy pregnant women. Women who delivered preterm (<37 completed weeks gestation, n = 240) and controls who delivered at term (n = 439) were included. Pregnancies complicated by preeclampsia were analyzed separately. Circulating endothelial dysfunction biomarkers included soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin).
Results
Elevated levels of sICAM-1 and sVCAM-1 were positively associated with preterm delivery independent of usual risk factors. At entry (∼16 wks), the adjusted odds ratio (AOR) was 1.73 (95% confidence interval (CI) 1.09–2.74) for the highest quartile of sICAM-1 versus the lowest quartile and for sVCAM-1 the AOR was 2.17 (95% CI 1.36–3.46). When analysis was limited to cases with a spontaneous preterm delivery, the results were unchanged. Similar results were obtained for the 3rd trimester (∼30 wks). Elevated sE-selectin was increased only in preterm delivery complicated by preeclampsia; risk was increased at entry (AOR 2.32, 95% CI 1.22–4.40) and in the 3rd trimester (AOR 3.37, 95% CI 1.78–6.39).
Conclusions
Impaired endothelial function as indicated by increased levels of soluble molecules commonly secreted by endothelial cells is a pathogenic precursor to CVD that is also present in women with preterm delivery. Our findings underscore the need for follow-up studies to determine if improving endothelial function prevents later CVD risk in women.
doi:10.1371/journal.pone.0085716
PMCID: PMC3899071  PMID: 24465662
20.  Expression of ICAM1 and VCAM1 Serum Levels in Rheumatoid Arthritis Clinical Activity. Association with Genetic Polymorphisms 
Disease markers  2009;26(3):119-126.
To investigate the association of sICAM-1 and sVCAM-1 with ICAM1 721G>A and VCAM1 1238G>C polymorphisms and rheumatoid arthritis (RA) clinical activity, sixty RA patients and 60 healthy non-related subjects (HS) matched for age and sex were recruited. Soluble adhesion molecules were determined by ELISA technique. Rheumatoid factor (RF), C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured by routine methods. Disability and clinical activity was measured with Spanish-HAQ-DI and DAS28 scores, respectively. The ICAM1 and VCAM1 polymorphism were identified using the PCR-RFLP procedure. Inter-group comparison showed increased levels of sICAM-1 and sVCAM-1 in RA patients (284 and 481 ng/mL) versus HS (132 and 280 ng/mL); in the RA group, significant correlations between sVCAM-1 and RF (r = 0.402), ESR (r = 0.426), Spanish-HAQ-DI (r = 0.276), and DAS28 (r = 0.342) were found, whereas sICAM-1 only correlated with RF (r = 0.445). In RA patients, a significant association with the 721A allele of ICAM1 polymorphism (p = 0.04), was found. In addition, the allele impact (G/A + A/A) of this polymorphism was confirmed, (p = 0.038, OR = 2.3, C.I. 1.1–5.0). sVCAM-1 and sICAM-1 serum levels reflected the clinical status in RA, independently of the ICAM1 and VCAM1 polymorphism. However, the ICAM1 721A allele could be a genetic marker to RA susceptibility.
doi:10.3233/DMA-2009-0621
PMCID: PMC3833410  PMID: 19597294
Rheumatoid arthritis; polymorphism; soluble adhesion molecules; ICAM-1; VCAM-1
21.  Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer - Results of a Phase IIb Randomized Controlled Trial 
Journal of Cancer  2013;4(7):597-605.
Pomegranate has been shown to prolong PSA doubling time in early prostate cancer, but no data from a placebo controlled trial has been published yet. The objective of this study was to prospectively evaluate the impact of pomegranate juice in patients with prostate cancer.
We conducted a phase IIb, double blinded, randomized placebo controlled trial in patients with histologically confirmed prostate cancer. Only patients with a PSA value ≥ 5ng/ml were included. The subjects consumed 500 ml of pomegranate juice or 500 ml of placebo beverage every day for a 4 week period. Thereafter, all patients received 250 ml of the pomegranate juice daily for another 4 weeks. PSA values were taken at baseline, day 14, 28 and on day 56. The primary endpoint was the detection of a significant difference in PSA serum levels between the groups after one month of treatment. Pain scores and adherence to intervention were recorded using patient diaries.
102 patients were enrolled. The majority of patients had castration resistant prostate cancer (68%). 98 received either pomegranate juice or placebo between October 2008 and May 2011. Adherence to protocol was good, with 94 patients (96%) completing the first period and 87 patients (89%) completing both periods. No grade 3 or higher toxicities occurred within the study. No differences were detected between the two groups with regard to PSA kinetics and pain scores.
Consumption of pomegranate juice as an adjunct intervention in men with advanced prostate cancer does not result in significant PSA declines compared to placebo.
doi:10.7150/jca.7123
PMCID: PMC3781990  PMID: 24069070
Pomegranate juice; PSA; prostate cancer; nutraceutical; ellagig acids; polyphenols.
22.  Inflammation Markers are Associated with Cardiovascular Diseases Risk in Adolescents: The Young Hearts Project 2000 
The Journal of Adolescent Health  2010;47(4):346-351.
Purpose
The traditional approach for identifying subjects at risk from cardiovascular diseases (CVD) is to determine the extent of clustering of biological risk factors adjusted for lifestyle. Recently, markers of endothelial dysfunction and low grade inflammation, including high sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecules (sICAM), and soluble vascular adhesion molecules (sVCAM), have been included in the detection for high risk individuals. However, the relationship of these novel biomarkers with CVD risk in adolescents remains unclear. The purpose of this study, therefore, was to establish the association of hsCRP, sICAM, and sVCAM with CVD risk in an adolescent population.
Methods
Data from the Young Hearts 2000 cross-sectional cohort study, carried out in 1999–2001, were used. From a total of 2,017 male and female participants, 95 obese subjects were identified and matched according to age, sex, and cigarette smoking, with 95 overweight and 95 normal-weight adolescents. Clustered CVD risk was computed using a sum of Z-scores of biological risk factors. The relationship was described using multiple linear regression analyses.
Results
hsCRP, sICAM, and sVCAM showed significant associations with CVD risk. hsCRP and sICAM had a positive relation with CVD risk, whereas sVCAM showed an inverse relationship. In this study, lifestyle factors showed no relation with CVD risk.
Conclusion
The results fit the hypothesized role of low grade inflammation and endothelial dysfunction in CVD risk in asymptomatic adolescents. The inverse relationship of VCAM, however, is hard to explain and indicates the complex mechanisms underlying CVD. Further research is needed to draw firm conclusions on the biomarkers used.
doi:10.1016/j.jadohealth.2010.04.008
PMCID: PMC2958312  PMID: 20864003
Cardiovascular diseases; Adolescence; hsCRP; sICAM; sVCAM
23.  Controlled, double-blind, randomized clinical trial to evaluate the impact of fruit juice consumption on the evolution of infants with acute diarrhea 
Nutrition Journal  2005;4:23.
In order to assess the effects of juice feedings during acute diarrhea a double-blind, randomized study was performed in 90 children, mean age of 10 ± 4.28 months. Thirty patients with acute diarrhea were fed twice-daily 15 ml/kg of Apple Juice (AJ), 30 received White Grape Juice (WGJ), and 30 were given colored and flavored water (WA) as part of their age appropriate dietary intake. The duration and severity of diarrhea were the main endpoint variables of the study performed in a metabolic unit. The patients were similar among the 3 groups, had diarrhea for 50–64 hours prior to admission, and were dehydrated when admitted to the unit for study. Half of the patients in each group were well nourished and the others had mild to moderate degrees of malnutrition. Rotavirus infection was the agent causing the illness in 63% of the patients. The infants fed juice ingested 14–17% more calories than those given WA, (those receiving AJ and WGJ ingested 95 and 98 Calories/Kg/d respectively) whereas those receiving WA consumed 81 cal/kg/d). The increased energy intake was not at the expense of other foods or milk formula. The mean body weight gain was greater among patients receiving WGJ (+ 50.7 gm) as compared with the patients in the AJ group (+ 18.3 gm) or the patients fed WA (- 0.7 gm) (p = 0.08). The duration of the illness was longer in the infants fed juice as compared with those given WA (p = 0.006), the mean +/- SD duration in hours was 49.4 ± 32.6, 47.5 ± 38.9 and 26.5 ± 27.4 in patients fed AJ, WGJ and WA respectively. All patients improved while ingesting juice and none of them developed persistent diarrhea; most recovered within 50 hours of the beginning of treatment and less than one fourth had diarrhea longer than 96 hours in the unit. The fecal losses were also increased among the juice fed patients (p = 0.001); the mean ± SD fecal excretion in g/kg/h was 3.94 ± 2.35, 3.59 ± 2.35, and 2.19 ± 1.63 in AJ, WGJ and WA respectively. The stool output was highest during the first day of treatment among all the patients, though those fed AJ had the highest volume of fecal losses and those who received WA had the lowest stool excretion. After the first day of treatment the differences in fecal excretion were not significant. The ability to tolerate carbohydrates during the illness and immediately after recovery was similar among the 3 groups of patients. Intake of juices with different fructose/glucose ratios and osmolarities resulted in more fecal losses and more prolonged diarrhea as compared with water feedings, but the patients given juice ingested more calories and gained more weight, particularly among those being fed the juice with equimolar concentrations of fructose and glucose.
doi:10.1186/1475-2891-4-23
PMCID: PMC1216327  PMID: 16091146
24.  Grape Consumption Increases Anti-Inflammatory Markers and Upregulates Peripheral Nitric Oxide Synthase in the Absence of Dyslipidemias in Men with Metabolic Syndrome 
Nutrients  2012;4(12):1945-1957.
We evaluated the effects of grape consumption on inflammation and oxidation in the presence or absence of dyslipidemias in metabolic syndrome (MetS). Men with MetS (n = 24), 11 with high triglycerides and low HDL and 13 with no dyslipidemia were recruited and randomly allocated to consume daily either 46 g of lyophilized grape powder (GRAPE), equivalent to 252 g fresh grapes, or placebo with an identical macronutrient composition and caloric value as GRAPE for four weeks. After a three-week washout, participants followed the alternate treatment. We measured changes between placebo and GRAPE periods in inflammatory and oxidative stress markers both in circulation and in gene expression. Changes in plasma adiponectin (p < 0.05), interleukin (IL)-10 (p < 0.005) and in mRNA expression of the inducible isoform of nitric oxide synthase (iNOS) (p < 0.25) were increased in the GRAPE compared to the placebo period only in those individuals without dyslipidemia. Additionally, plasma IL-10 was negatively correlated with NOX2 expression, a marker of oxidative stress (r = −0.55, p < 0.01), while iNOS expression was positively correlated with the expression of superoxide dismutase 2 (r = 0.642, p < 0.01), a key anti-oxidative enzyme. Grape consumption displayed anti-oxidative and increased anti-inflammatory markers in the absence of the inflammatory milieu associated with dyslipidemias.
doi:10.3390/nu4121945
PMCID: PMC3546615  PMID: 23222963
metabolic syndrome; dyslipidemia; grape polyphenols; IL-10; iNOS
25.  Elevated pretreatment serum levels of soluble vascular cell adhesion molecule 1 and lactate dehydrogenase as predictors of survival in cutaneous metastatic malignant melanoma. 
British Journal of Cancer  1998;78(1):40-45.
Very rapid progression of disease with a median survival of 6-9 months is a common feature of metastatic cutaneous malignant melanoma. Nevertheless, substantial variability of survival suggests that metastatic cutaneous malignant melanoma can be divided into several biological subgroups. Pretreatment serum levels of soluble adhesion molecules and various clinical parameters in cutaneous metastatic malignant melanoma were evaluated to determine their prognostic value. In this study pretreatment serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular cell adhesion molecule 1 (sICAM-1), soluble endothelial leukocyte adhesion molecule 1 (sE-selectin) and multiple clinical factors were assessed in relation to overall survival of 97 consecutive patients with metastatic cutaneous malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, both univariate and multivariate Cox proportional-hazards models were used. Elevated pretreatment serum levels of sVCAM-1 (P < 0.005) and of lactate dehydrogenase (P < 0.002) were rendered statistically independent and were significantly associated with unfavourable outcome. Patients were assigned to one of three risk categories (low, intermediate and high) according to a cumulative risk score defined as the function of the sum of these two variables. There were significant differences in overall survival (P < 0.0001) between low- (n = 53, 5-year survival probability of 23.3%), intermediate- (n = 29, 5-year survival probability of 9.9%) and high-risk (n = 15) patients. Elevated pretreatment serum levels of sVCAM-1 and of lactate dehydrogenase correlate with poor outcome in metastatic cutaneous malignant melanoma. These data support risk stratification for future therapeutic trials and identify factors that need to be validated in prospective studies and may potentially influence decision-making in palliative management of patients with disseminated cutaneous malignant melanoma.
PMCID: PMC2062938  PMID: 9662248

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