Life Extension Magazine®

Issue: Apr 2015

Blueberry

Blueberry, Olive Oil, Liver Disease, and CoQ10

By Life Extension.

Blueberry extract prolongs life span of Drosophila melanogaster.

Blueberry possesses greater antioxidant capacity than most other fruits and vegetables. The present study investigated the life span-prolonging activity of blueberry extracts in fruit flies and explored its underlying mechanism. Results revealed that blueberry extracts at 5 mg/mL in diet could significantly extend the mean lifespan of fruit flies by 10%, accompanied by up-regulating gene expression of superoxide dismutase (SOD), catalase (CAT) and Rpn11 and down-regulating Methuselah (MTH) gene. Intensive H(2)O(2) and Paraquat challenge tests showed that life span was only extended in Oregon-R wild type flies but not in SOD(n108) or Cat(n1) mutant strains. Chronic Paraquat exposure shortened the maximum survival time from 73 to 35 days and decreased the climbing ability by 60% while blueberry extracts at 5mg/mL in diet could significantly increase the survival rate and partially restore the climbing ability with up-regulating SOD, CAT, and Rpn11. Furthermore, gustatory assay demonstrated that those changes were not due to the variation of food intake between the control and the experimental diet containing 5 mg/ml blueberry extracts. It was therefore concluded that the life span-prolonging activity of blueberry extracts was at least partially associated with its interactions with MTH, Rpn11, and endogenous antioxidant enzymes SOD and CAT.

Exp Gerontol. 2012 Feb;47(2):170-8

Antioxidant capacities of flavones and benefits in oxidative-stress related diseases.

Flavonoids, a group of secondary metabolites widely distributed in the plant kingdom, have been acknowledged for their interesting medicinal properties. Among them, natural flavones, as well as some of their synthetic derivatives, have been shown to exhibit several biological activities, including antioxidant, anti-inflammatory, antitumor, anti-allergic, neuroprotective, cardioprotective and antimicrobial. The antioxidant properties of flavones allow them to demonstrate potential application as preventive and attenuating agents in oxidative stress, i.e., a biological condition that is closely associated to aging processes and to several diseases. Some flavones interfere in distinct oxidative-stress related events by directly reducing the levels of intracellular free radicals (hydroxyl, superoxide and nitric oxide) and/or of reactive species (e.g. hydrogen peroxide, peroxynitrite and hypochlorous acid) thus preventing their amplification and the consequent damage of other biomolecules such as lipids, proteins and DNA. Flavones can also hinder the activity of central free radical-producing enzymes, such as xanthine oxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) or inducible nitric oxide synthase (iNOS) and can even modulate the intracellular levels of oxidant and/or antioxidant enzymes. The evaluation of flavones antioxidant ability has been extensively determined in chemical or biological in vitro models, but in vivo therapy with individual flavones or with flavones-enriched extracts has also been reported. The present manuscript revises relevant studies focusing the preventive effects of flavones on stress-related diseases, namely the neurological and cardiovascular diseases and diabetes and its associated complications.

Curr Top Med Chem. 2014 Dec 9

Biotransformed blueberry juice protects neurons from hydrogen peroxide-induced oxidative stress and mitogen-activated protein kinase pathway alterations.

A growing body of evidence supports the therapeutic effects of blueberry in neurodegenerative disorders. Biotransformation of blueberry juice by Serratia vaccinii bacteria increases its phenolic content and antioxidant activity. In neuronal cell culture, biotransformed blueberry juice (BJ) significantly increased the activity of antioxidant enzymes, namely catalase and superoxide dismutase. Moreover, BJ protected neurons against H2O2-induced cell death in a dose-dependent manner. This associated with the upregulation of mitogen-activated protein kinase (MAPK) family enzymes p38 and c-Jun N-terminal kinase (JNK) activation, as well as with the protection of extracellular signal-regulated kinase (ERK1/2) and MAPK/ERK kinase (MEK1/2) activity loss induced by H2O2. The present studies demonstrate that BJ can protect neurons against oxidative stress possibly by increasing antioxidant enzyme activities and activating p38- and JNK-dependent survival pathways while blocking MEK1/2- and ERK1/2-mediated cell death. Thus, BJ may represent a novel approach to prevent and to treat neurodegenerative disorders, and it may represent a source of novel therapeutic agents against these diseases.

Br J Nutr. 2010 Sep;104(5):656-63

Dietary blueberries attenuate atherosclerosis in apolipoprotein E-deficient mice by upregulating antioxidant enzyme expression.

Protective effects of blueberries (BB) against atherosclerosis and potential underlying mechanisms in reducing oxidative stress were examined in apoE-deficient (apoE(-/-)) mice. ApoE(-/-) mice were fed an AIN-93G diet (CD) or CD formulated to contain 1% freeze-dried whole BB for 20 wk. The mean lesion area for apoE(-/-) mice fed BB was reduced by 39% (P < 0.001) in the aorta sinus and 58% (P < 0.001) in the descending aorta compared with CD-fed mice. These atheroprotective effects were independent of the serum lipid profile or total antioxidant capacity (as measured by oxygen radical absorbance capacity). The concentration of a biomarker of lipid peroxidation, F(2)-isoprostane, was lower in liver of BB-fed mice (P < 0.05). Genes analyzed by RT-PCR array showed that 4 major antioxidant enzymes in aorta [superoxide dismutase (SOD) 1, SOD2, glutathione reductase (GSR), and thioredoxin reductase 1] were upregulated in BB-fed mice. Enzyme activities of SOD and GSR were greater (P < 0.05) in liver and/or serum of BB-fed mice than those of CD-fed mice. In addition, serum paraoxonase 1 activity in serum of BB-fed mice was also greater than that of CD-fed mice (P < 0.05) at the end of the study. These results suggest a protective effectiveness of BB against atherosclerosis in this apoE(-/-) mouse model. The potential mechanisms may involve reduction in oxidative stress by both inhibition of lipid peroxidation and enhancement of antioxidant defense.

J Nutr. 2010 Sep;140(9):1628-32

Blueberry polyphenols increase life span and thermotolerance in Caenorhabditis elegans.

The beneficial effects of polyphenol compounds in fruits and vegetables are mainly extrapolated from in vitro studies or short-term dietary supplementation studies. Due to cost and duration, relatively little is known about whether dietary polyphenols are beneficial in whole animals, particularly with respect to aging. To address this question, we examined the effects of blueberry polyphenols on life span and aging of the nematode, Caenorhabditis elegans, a useful organism for such a study. We report that a complex mixture of blueberry polyphenols increased life span and slowed aging-related declines in C. elegans. We also found that these benefits did not just reflect antioxidant activity in these compounds. For instance, blueberry treatment increased survival during acute heat stress, but was not protective against acute oxidative stress. The blueberry extract consists of three major fractions that all contain antioxidant activity. However, only one fraction, enriched in proanthocyanidin compounds, increased C. elegans life span and thermotolerance. To further determine how polyphenols prolonged C. elegans life span, we analyzed the genetic requirements for these effects. Prolonged life span from this treatment required the presence of a CaMKII pathway that mediates osmotic stress resistance, though not other pathways that affect stress resistance and longevity. In conclusion, polyphenolic compounds in blueberries had robust and reproducible benefits during aging that were separable from antioxidant effects.

Aging Cell. 2006 Feb;5(1):59-68

Protective roles of Gadd45 and MDM2 in blueberry anthocyanins mediated DNA repair of fragmented and non-fragmented DNA damage in UV-irradiated HepG2 cells.

Growth Arrest and DNA Damage-inducible 45 (Gadd45) and MDM2 proteins, together with p21 and p53, play important roles in cell cycle checkpoints, DNA repair, and genome integrity maintenance. Gadd45 and MDM2 were activated and transcribed instantly by UV irradiation, whereas blueberry anthocyanins (BA) decreased the gene and protein expression levels in HepG2 cells for up to 24 h, and gradually restored the UV-induced fragmented and non-fragmented DNA damage of the nucleus at a time point of 12 h. Nevertheless, UV-irradiated HepG2 cell arrests occurred mainly in the G1 phase, which indicated G1 as a checkpoint. The proteins, p21 and p53, retain cellular integrity, suppressing the oncogenic transformation by interruption of the G1 phase of the cellular cycle, giving time for repairing the damage to DNA, or apoptosis induction if the damage is too severe to be repaired, while MDM2 and Gadd45 concomitantly ensure the presence of p53 and p21. Thus, we conclude that repair, together with Gadd45 and MDM2 genes, were involved in light and dark reaction mechanisms, however, BA could interfere and assist the repair through restoration, although further studies of the complex of the gene cascades triggered and responded to in BA-assisted DNA repair are needed.

Int J Mol Sci. 2013 Oct 30;14(11):21447-62

Effect of a wild blueberry (Vaccinium angustifolium) drink intervention on markers of oxidative stress, inflammation and endothelial function in humans with cardiovascular risk factors.

PURPOSE: Wild blueberries (WB) (Vaccinium angustifolium) are rich sources of polyphenols, such as flavonols, phenolic acids and anthocyanins (ACNs), reported to decrease the risk of cardiovascular and degenerative diseases. This study investigated the effect of regular consumption of a WB or a placebo (PL) drink on markers of oxidative stress, inflammation and endothelial function in subjects with risk factors for cardiovascular disease. METHODS: Eighteen male volunteers (ages 47.8 ± 9.7 years; body mass index 24.8 ± 2.6 kg/m²) received according to a cross-over design, a WB (25 g freeze-dried powder, providing 375 mg of ACNs) or a PL drink for 6 weeks, spaced by a 6-week wash-out. Endogenous and oxidatively induced DNA damage in blood mononuclear cells, serum interleukin levels, reactive hyperemia index, nitric oxide, soluble vascular adhesion molecule concentration and other variables were analyzed. RESULTS: Wild blueberry drink intake significantly reduced the levels of endogenously oxidized DNA bases (from 12.5 ± 5.6 % to 9.6 ± 3.5 %, p ≤ 0.01) and the levels of H₂O₂-induced DNA damage (from 45.8 ± 7.9 % to 37.2 ± 9.1 %, p ≤ 0.01), while no effect was found after the PL drink. No significant differences were detected for markers of endothelial function and the other variables under study. CONCLUSIONS: In conclusion, the consumption of the WB drink for 6 weeks significantly reduced the levels of oxidized DNA bases and increased the resistance to oxidatively induced DNA damage. Future studies should address in greater detail the role of WB in endothelial function.

Eur J Nutr. 2013 Apr;52(3):949-61

Effect of anthocyanin fractions from selected cultivars of Georgia-grown blueberries on apoptosis and phase II enzymes.

In recent years, considerable attention has been paid to anthocyanins due to their abilities to inhibit oxidative stress and cell proliferation. The regulations of apoptosis and the phase II enzymes glutathione-S-transferase (GST) and quinone reductase (QR) are other potential mechanisms through which flavonoids such as anthocyanins may prevent cancer. Our study confirmed that anthocyanin fractions from high bush blueberry cultivars increased apoptosis using two different methods: DNA fragmentation and caspase-3 activity. The effect of anthocyanins on the activity of the detoxifying enzymes GST and QR was also determined. Major anthocyanins identified were delphinidin, cyanidin, peonidin, petunidin, and malvidin. In Tifblue and Powderblue cultivars, DNA fragmentation increased at anthocyanin concentrations from 50 to 150 microg/mL, but cells treated with the anthocyanin fraction of Brightblue and Brightwell showed a prominent ladder at 50-100 microg/mL when compared to cells treated with 150 microg/mL. There was a significant difference in the caspase-3 activity (P < 0.05) between the control cells and the cells treated with anthocyanins from all of the cultivars. The response correlated positively with dose. The QR activity was lower in all cells treated with an anthocyanin fraction from Tifblue, Powderblue, Brightblue, and Brightwell cultivars than in control cells (P < 0.05). The activity decreased gradually when treated with increased concentrations of anthocyanin fractions (50-150 microg/mL) in the Tifblue and Powderblue cultivars. The GST activity was lower (P < 0.05) in cells treated with anthocyanin fractions from all of the cultivars and at all concentrations. These results indicated that apoptosis was confirmed in HT-29 cells when treated with anthocyanins from blueberry cultivars at 50-150 microg/mL concentrations, but these same concentrations decrease QR and GST activities rather than induce them.

J Agric Food Chem. 2007 Apr 18;55(8):3180-5

Effects of blueberry (Vaccinium ashei) on DNA damage, lipid peroxidation, and phase II enzyme activities in rats.

Blueberry extracts have high antioxidant potential and increase phase II enzyme activities in vitro. This study tested the hypothesis that blueberries would reduce DNA damage and lipid peroxidation and increase phase II enzyme activities in vivo. Young, healthy male Sprague-Dawley rats (n = 8 per group) were fed control AIN-93 diets or AIN-93 diets supplemented with blueberries or blueberry extracts for 3 weeks. Diets were supplemented with 10% freeze-dried whole blueberries, blueberry polyphenol extract and sugars to match the 10% blueberry diet, or 1 and 0.2% blueberry flavonoids, which were primarily anthocyanins. Liver and colon mucosa glutathione-S-transferase (GST), quinone reductase, and UDP-glucuronosyltransferase activities in colon mucosa and liver were not significantly increased by freeze-dried whole blueberries or blueberry fractions. Liver GST activity, however, was approximately 25% higher than controls for the freeze-dried whole blueberry, blueberry polyphenol, and 1% flavonoid groups. DNA damage was significantly lower than control only in the liver of animals fed the 1% flavonoid diet. The level of urinary F(2)-isoprostanes, a measure of lipid peroxidation, was unaffected. In summary, in healthy rats, short-term supplementation with freeze-dried whole blueberries, blueberry polyphenols, or blueberry flavonoids did not significantly increase phase II enzyme activities. However, supplementation with 1% blueberry flavonoids did decrease oxidative DNA damage in the liver.

J Agric Food Chem. 2008 Dec 24;56(24): 11700-6

Antioxidative dietary compounds modulate gene expression associated with apoptosis, DNA repair, inhibition of cell proliferation and migration.

Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair.

Int J Mol Sci. 2014 Sep 15;15(9):16226-45

Monounsaturated fatty acids, olive oil and health status: a systematic review and meta-analysis of cohort studies.

BACKGROUND: The aim of the present meta-analysis of cohort studies was to focus on monounsaturated fat (MUFA) and cardiovascular disease, cardiovascular mortality as well as all-cause mortality, and to distinguish between the different dietary sources of MUFA. METHODS: Literature search was performed using the electronic databases PUBMED, and EMBASE until June 2nd, 2014. Study specific risk ratios and hazard ratios were pooled using a inverse variance random effect model. RESULTS: Thirty-two cohort studies (42 reports) including 841,211 subjects met the objectives and were included. The comparison of the top versus bottom third of the distribution of a combination of MUFA (of both plant and animal origin), olive oil, oleic acid, and MUFA:SFA ratio in each study resulted in a significant risk reduction for: all-cause mortality (RR: 0.89, 95% CI 0.83, 0.96, p = 0.001; I2 = 64%), cardiovascular mortality (RR: 0.88, 95% CI 0.80, 0.96, p = 0.004; I2 = 50%), cardiovascular events (RR: 0.91, 95% CI 0.86, 0.96, p = 0.001; I2 = 58%), and stroke (RR: 0.83, 95% CI 0.71, 0.97, p = 0.02; I2 = 70%). Following subgroup analyses, significant associations could only be found between higher intakes of olive oil and reduced risk of all-cause mortality, cardiovascular events, and stroke, respectively. The MUFA subgroup analyses did not reveal any significant risk reduction. CONCLUSION: The results indicate an overall risk reduction of all-cause mortality (11%), cardiovascular mortality (12%), cardiovascular events (9%), and stroke (17%) when comparing the top versus bottom third of MUFA, olive oil, oleic acid, and MUFA:SFA ratio. MUFA of mixed animal and vegetable sources per se did not yield any significant effects on these outcome parameters. However, only olive oil seems to be associated with reduced risk. Further research is necessary to evaluate specific sources of MUFA (i.e. plant vs. animal) and cardiovascular risk.

Lipids Health Dis. 2014 Oct 1;13:154

Fruit, vegetables, and olive oil and risk of coronary heart disease in Italian women: the EPICOR Study.

BACKGROUND: Many observational studies support the recommendation to eat sufficient amounts of fruit and vegetables as part of a healthy diet. OBJECTIVE: The present study aimed to investigate the association between consumption of fruit, vegetables, and olive oil and the incidence of coronary heart disease (CHD) in 29,689 women enrolled between 1993 and 1998 in 5 European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts in northern (Turin and Varese), central (Florence), and southern (Naples and Ragusa) Italy. DESIGN: Baseline dietary, anthropometric, and lifestyle characteristics were collected. Major events of CHD (fatal and nonfatal myocardial infarction and coronary revascularization) were identified through a review of clinical records. Analyses were stratified by center and adjusted for hypertension, smoking, education, menopause, physical activity, anthropometric measures, nonalcohol energy, alcohol, total meat, vegetables in analyses for fruit, and fruit in analyses for vegetables. RESULTS: During a mean follow-up of 7.85 y, 144 major CHD events were identified. A strong reduction in CHD risk among women in the highest quartile of consumption of leafy vegetables (hazard ratio: 0.54; 95% CI: 0.33, 0.90; P for trend = 0.03) and olive oil (hazard ratio: 0.56; 95% CI: 0.31, 0.99; P for trend = 0.04) was found. In contrast, no association emerged between fruit consumption and CHD risk. CONCLUSION: An inverse association between increasing consumption of leafy vegetables and olive oil and CHD risk emerged in this large cohort of Italian women.

Am J Clin Nutr. 2011 Feb;93(2):275-83

Olive oil intake and mortality within the Spanish population (EPIC-Spain).

BACKGROUND: Olive oil consumption is associated with a decreased risk of several chronic diseases, in particular cardiovascular disease (CVD). However, data on the effects of olive oil on overall mortality are scarce. OBJECTIVE: We evaluated the association between olive oil and overall and cause-specific mortality in the Spanish population in the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). DESIGN: A total of 40,622 participants (62% female) aged 29-69 y were recruited from 5 Spanish regions in 1992-1996. The association between olive oil (analyzed as a categorical and continuous variable) and overall and cause-specific mortality (CVD, cancer, and other causes) was analyzed by using Cox proportional hazards regression models adjusted for potential confounders. RESULTS: A total of 1,915 deaths were reported during 13.4 y of follow-up: 416 CVD deaths, 956 cancer deaths, and 417 deaths from other causes (for 126 deaths the cause was not available). In comparison with nonconsumers, the highest quartile of olive oil consumption was associated with a 26% (95% CI: 13%, 36%) reduction in risk of overall mortality and a 44% (95% CI: 21%, 60%) reduction in CVD mortality. For each increase in olive oil of 10 g · 2,000 kcal⁻¹ · d⁻¹, there was a 7% (95% CI: 3%, 10%) decreased risk of overall mortality and a 13% (95% CI: 6%, 20%) decreased risk of CVD mortality. No significant association was observed between olive oil and cancer mortality. CONCLUSIONS: Olive oil was associated with a decreased risk of overall mortality and an important reduction in CVD mortality in this large Mediterranean cohort. This provides further evidence on the beneficial effects of one of the key Mediterranean dietary components.

Am J Clin Nutr. 2012 Jul;96(1):142-9

Olive oil and the cardiovascular system.

Olive oil is the primary source of fat in the Mediterranean diet which is associated with a low mortality for cardiovascular disease. In spite of this, data concerning olive oil consumption and primary end points for cardiovascular disease are scarce. However, a large body of knowledge exists providing evidence of the benefits of olive oil consumption on secondary end points for cardiovascular disease. The benefits of olive oil consumption are beyond a mere reduction of the low density lipoprotein cholesterol. Here, we review the state of the art concerning the knowledge of the most important biological and clinical effects related to the intake of olive oil rich diets on lipoprotein metabolism, oxidative damage, inflammation, endothelial dysfunction, blood pressure, thrombosis, and carbohydrate metabolism. The extent to which we possess evidence of the health benefits of olive oil minor components is also assessed. The wide range of anti-atherogenic effects associated with olive oil consumption could contribute to explain the low rate of cardiovascular mortality found in Southern European Mediterranean countries, in comparison with other western countries, despite a high prevalence of coronary heart disease risk factors.

Pharmacol Res. 2007 Mar;55(3):175-86

Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases.

The overall health beneficial action of olive oil phenolic components is well established. Recent studies have elucidated the biological effects of two isolated compounds, namely oleuropein and hydroxytyrosol, with particular attention on their antioxidant activity. Thus, a protective action has been demonstrated in preclinical studies against several diseases, especially cardiovascular and metabolic disorders. The present review will describe the biological effects of oleuropein and hydroxytyrosol, with particular attention on the molecular mechanism underlying the protective action on cardiovascular and metabolic alterations, as demonstrated by in vitro and in vivo experimental studies performed with the isolated compounds.

J Transl Med. 2014 Aug 3;12:219

Active components and clinical applications of olive oil.

The olive tree, Olea europaea, is native to the Mediterranean basin and parts of Asia Minor. The fruit and compression-extracted oil have a wide range of therapeutic and culinary applications. Olive oil also constitutes a major component of the “Mediterranean diet.” The chief active components of olive oil include oleic acid, phenolic constituents, and squalene. The main phenolics include hydroxytyrosol, tyrosol, and oleuropein, which occur in highest levels in virgin olive oil and have demonstrated antioxidant activity. Antioxidants are believed to be responsible for a number of olive oil’s biological activities. Oleic acid, a monounsaturated fatty acid, has shown activity in cancer prevention, while squalene has also been identified as having anticancer effects. Olive oil consumption has benefit for colon and breast cancer prevention. The oil has been widely studied for its effects on coronary heart disease (CHD), specifically for its ability to reduce blood pressure and low-density lipoprotein (LDL) cholesterol. Antimicrobial activity of hydroxytyrosol, tyrosol, and oleuropein has been demonstrated against several strains of bacteria implicated in intestinal and respiratory infections. Although the majority of research has been conducted on the oil, consumption of whole olives might also confer health benefits.

Altern Med Rev. 2007 Dec;12(4):331-42

Valuable nutrients and functional bioactives in different parts of olive (Olea europaea L.)-a review.

The Olive tree (Olea europaea L.), a native of the Mediterranean basin and parts of Asia, is now widely cultivated in many other parts of the world for production of olive oil and table olives. Olive is a rich source of valuable nutrients and bioactives of medicinal and therapeutic interest. Olive fruit contains appreciable concentration, 1-3% of fresh pulp weight, of hydrophilic (phenolic acids, phenolic alchohols, flavonoids and secoiridoids) and lipophilic (cresols) phenolic compounds that are known to possess multiple biological activities such as antioxidant, anticarcinogenic, antiinflammatory, antimicrobial, antihypertensive, antidyslipidemic, cardiotonic, laxative, and antiplatelet. Other important compounds present in olive fruit are pectin, organic acids, and pigments. Virgin olive oil (VOO), extracted mechanically from the fruit, is also very popular for its nutritive and health-promoting potential, especially against cardiovascular disorders due to the presence of high levels of monounsaturates and other valuable minor components such as phenolics, phytosterols, tocopherols, carotenoids, chlorophyll and squalene. The cultivar, area of production, harvest time, and the processing techniques employed are some of the factors shown to influence the composition of olive fruit and olive oil. This review focuses comprehensively on the nutrients and high-value bioactives profile as well as medicinal and functional aspects of different parts of olives and its byproducts. Various factors affecting the composition of this food commodity of medicinal value are also discussed.

Int J Mol Sci. 2012;13(3):3291-340

The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial.

BACKGROUND: Virgin olive oils are richer in phenolic content than refined olive oil. Small, randomized, crossover, controlled trials on the antioxidant effect of phenolic compounds from real-life daily doses of olive oil in humans have yielded conflicting results. Little information is available on the effect of the phenolic compounds of olive oil on plasma lipid levels. No international study with a large sample size has been done. OBJECTIVE: To evaluate whether the phenolic content of olive oil further benefits plasma lipid levels and lipid oxidative damage compared with monounsaturated acid content. DESIGN: Randomized, crossover, controlled trial. SETTING: 6 research centers from 5 European countries. PARTICIPANTS: 200 healthy male volunteers. MEASUREMENTS: Glucose levels, plasma lipid levels, oxidative damage to lipid levels, and endogenous and exogenous antioxidants at baseline and before and after each intervention. INTERVENTION: In a crossover study, participants were randomly assigned to 3 sequences of daily administration of 25 mL of 3 olive oils. Olive oils had low (2.7 mg/kg of olive oil), medium (164 mg/kg), or high (366 mg/kg) phenolic content but were otherwise similar. Intervention periods were 3 weeks preceded by 2-week washout periods. RESULTS: A linear increase in high-density lipoprotein (HDL) cholesterol levels was observed for low-, medium-, and high-polyphenol olive oil: mean change, 0.025 mmol/L (95% CI, 0.003 to 0.05 mmol/L), 0.032 mmol/L (CI, 0.005 to 0.05 mmol/L), and 0.045 mmol/L (CI, 0.02 to 0.06 mmol/L), respectively. Total cholesterol-HDL cholesterol ratio decreased linearly with the phenolic content of the olive oil. Triglyceride levels decreased by an average of 0.05 mmol/L for all olive oils. Oxidative stress markers decreased linearly with increasing phenolic content. Mean changes for oxidized low-density lipoprotein levels were 1.21 U/L (CI, -0.8 to 3.6 U/L), -1.48 U/L (-3.6 to 0.6 U/L), and -3.21 U/L (-5.1 to -0.8 U/L) for the low-, medium-, and high-polyphenol olive oil, respectively. LIMITATIONS: The olive oil may have interacted with other dietary components, participants’ dietary intake was self-reported, and the intervention periods were short. CONCLUSIONS: Olive oil is more than a monounsaturated fat. Its phenolic content can also provide benefits for plasma lipid levels and oxidative damage.

Ann Intern Med. 2006 Sep 5;145(5):333-41

Beneficial effects of polyphenol-rich olive oil in patients with early atherosclerosis.

PURPOSE: Diets rich in plant-derived polyphenols such as olive oil (OO) and/or catechins such as epigallocatechin 3-gallate (EGCG) have been shown to reduce the incidence of cardiovascular diseases, potentially by improving endothelial function, an important surrogate for atherosclerosis. The possible augmentation of endothelial function with the combined efforts of OO and EGCG is intriguing, yet unknown. METHODS: Eighty-two patients with early atherosclerosis (presence of endothelial dysfunction) were enrolled in this double-blind, randomized trial with 52 completing the study. The aim of the study was to compare the effect of a daily intake of 30 mL simple OO, with 30 ml of EGCG-supplemented OO, on endothelial function as well as on inflammation and oxidative stress after a period of 4 months. Endothelial function was assessed noninvasively via peripheral arterial tonometry (Endo-PAT ®). RESULTS: After 4 months, when OO and EGCG-supplemented OO groups were combined, OO significantly improved endothelial function (RHI, 1.59 ± 0.25-1.75 ± 0.45; p < 0.05). However, there were no significant differences in results between the two olive oil groups. Interestingly, with OO supplementation there was a significant reduction in inflammatory parameters: sICAM (196 to 183 ng/mL, p = < 0.001); white blood cells (WBCs) (6.0 × 10⁹/L-5.8 × 10⁹/L, p < 0.05); monocytes (0.48 × 10⁹/L to 0.44 × 10⁹/L, p = 0.05); lymphocytes (1.85 × 10⁹/L to 1.6 × 10⁹/L, p = 0.01); and platelets (242-229 × 10⁹/L, p = 0.047). CONCLUSIONS: Improvement in endothelial dysfunction in patients with early atherosclerosis in association with significant reduction in leukocytes may suggest an important role of early cellular inflammatory mediators on endothelial function. The current study supports one potential mechanism for the role of olive oil, independent of EGCG, modestly supplemented to a healthy cardiovascular diet.

Eur J Nutr. 2013 Apr;52(3):1223-31

Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.

OBJECTIVES: We investigated the value of reactive hyperemia peripheral arterial tonometry (RH-PAT) as a noninvasive tool to identify individuals with coronary microvascular endothelial dysfunction. BACKGROUND: Coronary endothelial dysfunction, a systemic disorder, represents an early stage of atherosclerosis; RH-PAT is a technique to assess peripheral microvascular endothelial function. METHODS: Using RH-PAT, digital pulse volume changes during reactive hyperemia were assessed in 94 patients without obstructive coronary artery disease and either normal (n = 39) or abnormal (n = 55) coronary microvascular endothelial function; RH-PAT index, a measure of reactive hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia divided by that at baseline. RESULTS: Average RH-PAT index was lower in patients with coronary endothelial dysfunction compared with those with normal coronary endothelial function (1.27 +/- 0.05 vs. 1.78 +/- 0.08: p < 0.001). An RH-PAT index <1.35 was found to have a sensitivity of 80% and a specificity of 85% to identify patients with coronary endothelial dysfunction. CONCLUSIONS: Digital hyperemic response, as measured by RH-PAT, is attenuated in patients with coronary microvascular endothelial dysfunction, suggesting a role for RH-PAT as a noninvasive test to identify patients with this disorder.

J Am Coll Cardiol. 2004 Dec 7;44(11):2137-41

Olive oil polyphenols enhance high-density lipoprotein function in humans: a randomized controlled trial.

OBJECTIVE: Olive oil polyphenols have shown beneficial properties against cardiovascular risk factors. Their consumption has been associated with higher cholesterol content in high-density lipoproteins (HDL). However, data on polyphenol effects on HDL quality are scarce. We, therefore, assessed whether polyphenol-rich olive oil consumption could enhance the HDL main function, its cholesterol efflux capacity, and some of its quality-related properties, such HDL polyphenol content, size, and composition. APPROACH AND RESULTS: A randomized, crossover, controlled trial with 47 healthy European male volunteers was performed. Participants ingested 25 mL/d of polyphenol-poor (2.7 mg/kg) or polyphenol-rich (366 mg/kg) raw olive oil in 3-week intervention periods, preceded by 2-week washout periods. HDL cholesterol efflux capacity significantly improved after polyphenol-rich intervention versus the polyphenol-poor one (+3.05% and -2.34%, respectively; P=0.042). Incorporation of olive oil polyphenol biological metabolites to HDL, as well as large HDL (HDL2) levels, was higher after the polyphenol-rich olive oil intervention, compared with the polyphenol-poor one. Small HDL (HDL3) levels decreased, the HDL core became triglyceride-poor, and HDL fluidity increased after the polyphenol-rich intervention. CONCLUSIONS: Olive oil polyphenols promote the main HDL antiatherogenic function, its cholesterol efflux capacity. These polyphenols increased HDL size, promoted a greater HDL stability reflected as a triglyceride-poor core, and enhanced the HDL oxidative status, through an increase in the olive oil polyphenol metabolites content in the lipoprotein. Our results provide for the first time a first-level evidence of an enhancement in HDL function by polyphenol-rich olive oil.

Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2115-9

Nonalcoholic fatty liver disease, obesity and the metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. This article details the pathogenesis of NAFLD along with the current state of its diagnosis and treatment.

Best Pract Res Clin Gastroenterol. 2014 Aug;28(4):637-53

Nonalcoholic fatty liver disease and metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic entity increasingly recognized as a major health burden in developed countries. It includes a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and rarely, progression to cirrhosis. Recent studies emphasize the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction in the development and progression of NAFLD. Furthermore, accumulating evidence supports an association between NAFLD and metabolic syndrome. Although the data are mainly epidemiological, the pathogenesis of NAFLD and metabolic syndrome seems to have common pathophysiological mechanisms, with focus on insulin resistance as a key factor. This review summarizes the current knowledge on the epidemiology, pathophysiology and diagnosis of both NAFLD and metabolic syndrome and the findings that strongly support the association of nonalcoholic fatty liver disease as a possible component in the cluster of metabolic syndrome.

Hippokratia. 2009 Jan;13(1):9-19

Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010.

OBJECTIVE: To assess recent trends in nonalcoholic fatty liver disease (NAFLD) prevalence among US adolescents. STUDY DESIGN: Cross-sectional data from 12,714 12-19 year olds (exclusions: chronic hepatitis, hepatotoxic medications) in the National Health and Examination Survey between 1988-1994 and 2007-2010 were used to estimate trends in suspected NAFLD, defined as overweight (body mass index ≥85th percentile) plus elevated alanine aminotransferase levels (boys >25.8 U/L; girls >22.1 U/L). Linear trends in prevalence and the independent effect of demographic indicators and adiposity on NAFLD risk were tested using regression models. Complex sampling methods and P values of <.05 were used to assess statistical significance. RESULTS: Suspected NAFLD prevalence (SE) rose from 3.9% (0.5) in 1988-1994 to 10.7% (0.9) in 2007-2010 (P < .0001), with increases among all race/ethnic subgroups, males and females, and those obese (P trend ≤.0006 for all). Among those obese, the multivariate adjusted odds of suspected NAFLD were higher with increased age, body mass index, Mexican American race, and male sex; the adjusted odds in 2007-2010 were 2.0 times those in 1988-1994. In 2007-2010, 48.1% (3.7) of all obese males and 56.0% (3.5) of obese Mexican American males had suspected NAFLD. CONCLUSION: Prevalence of suspected NAFLD has more than doubled over the past 20 years and currently affects nearly 11% of adolescents and one-half of obese males. The rapid increase among those obese, independent of body mass index, suggests that other modifiable risk factors have influenced this trend.

J Pediatr. 2013 Mar;162(3):496-500

Gender and racial differences in nonalcoholic fatty liver disease.

Due to the worldwide epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of elevated liver enzymes. NAFLD represents a spectrum of liver injury ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may progress to advanced fibrosis and cirrhosis. Individuals with NAFLD, especially those with metabolic syndrome, have higher overall mortality, cardiovascular mortality, and liver-related mortality compared with the general population. According to the population-based studies, NAFLD and NASH are more prevalent in males and in Hispanics. Both the gender and racial ethnic differences in NAFLD and NASH are likely attributed to interaction between environmental, behavioral, and genetic factors. Using genome-wide association studies, several genetic variants have been identified to be associated with NAFLD/NASH. However, these variants account for only a small amount of variation in hepatic steatosis among ethnic groups and may serve as modifiers of the natural history of NAFLD. Alternatively, these variants may not be the causative variants but simply markers representing a larger body of genetic variations. In this article, we provide a concise review of the gender and racial differences in the prevalence of NAFLD and NASH in adults. We also discuss the possible mechanisms for these disparities.

World J Hepatol. 2014 May 27;6(5):274-83

Nonalcoholic fatty liver disease in children: recent practice guidelines, where do they take us?

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States. It is strongly associated with childhood obesity, insulin resistance and metabolic syndrome. Although some children with NAFLD may remain asymptomatic, progression to nonalcoholic steatohepatitis (NASH), and to advanced stages of fibrosis and cirrhosis is well recognized. Unfortunately, despite the increase in awareness of this disease, there are still no reliable non-invasive diagnostic tests and liver biopsy remains the gold standard for the diagnosis of NASH and staging of fibrosis. In addition, there are no approved pharmacological treatments currently. Lifestyle modification remains the cornerstone of treatment. Team based multidisciplinary approach involving hepatologists, endocrinologists, exercise physiologist, dieticians, and cardiologists may lead to better outcomes. Recently, the American Association for the Study of Liver Diseases (AASLD) and European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) committees have made recommendations for the diagnosis and management of NAFLD in pediatric patients. This review focuses on current literature on epidemiology, natural history, pathogenesis along with summarizing the recent guidelines on diagnosis and treatment of pediatric NAFLD.

Curr Pediatr Rev. 2014;10(2):151-61

Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.

Fatty liver disease that develops in the absence of alcohol abuse is recognized increasingly as a major health burden. This report summarizes the presentations and discussions at a Single Topic Conference held September 20-22, 2002, and sponsored by the American Association for the Study of Liver Diseases. The conference focused on fatty liver disorders. Estimates based on imaging and autopsy studies suggest that about 20% to 30% of adults in the United States and other Western countries have excess fat accumulation in the liver. About 10% of these individuals, or fully 2% to 3% of adults, are estimated to meet current diagnostic criteria for nonalcoholic steatohepatitis (NASH). Sustained liver injury leads to progressive fibrosis and cirrhosis in a fraction, possibly up to one third, of those with NASH, and NASH may be a cause of cryptogenic cirrhosis. NASH is now a significant health issue for obese children as well, leading to cirrhosis in some. The diagnostic criteria for NASH continue to evolve and rely on the histologic findings of steatosis, hepatocellular injury (ballooning, Mallory bodies), and the pattern of fibrosis. Generally recognized indications for biopsy include establishing the diagnosis and staging of the injury, but strict guidelines do not exist. Liver enzymes are insensitive and cannot be used reliably to confirm the diagnosis or stage the extent of fibrosis. Older age, obesity, and diabetes are predictive of fibrosis. The pathogenesis of NASH is multifactorial. Insulin resistance may be an important factor in the accumulation of hepatocellular fat, whereas excess intracellular fatty acids, oxidant stress, adenosine triphosphate (ATP) depletion, and mitochondrial dysfunction may be important causes of hepatocellular injury in the steatotic liver. Efforts are underway to refine the role of insulin resistance in NASH and determine whether improving insulin sensitivity pharmacologically is an effective treatment. An altered lifestyle may be a more effective means of improving insulin sensitivity. The research agenda for the future includes establishing the role of insulin resistance and abnormal lipoprotein metabolism in NASH, determining the pathogenesis of cellular injury, defining predisposing genetic abnormalities, identifying better noninvasive predictors of disease, and defining effective therapy.

Hepatology. 2003 May;37(5):1202-19

Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994.

Previous estimates of the prevalence of nonalcoholic fatty liver disease (NAFLD) in the US population relied on measures of liver enzymes, potentially underestimating the burden of this disease. We used ultrasonography data from 12,454 adults who participated in the Third National Health and Nutrition Examination Survey, conducted in the United States from 1988 to 1994. We defined NAFLD as the presence of hepatic steatosis on ultrasonography in the absence of elevated alcohol consumption. In the US population, the rates of prevalence of hepatic steatosis and NAFLD were 21.4% and 19.0%, respectively, corresponding to estimates of 32.5 (95% confidence interval: 29.9, 35.0) million adults with hepatic steatosis and 28.8 (95% confidence interval: 26.6, 31.2) million adults with NAFLD nationwide. After adjustment for age, income, education, body mass index (weight (kg)/height (m)²), and diabetes status, NAFLD was more common in Mexican Americans (24.1%) compared with non-Hispanic whites (17.8%) and non-Hispanic blacks (13.5%) (P = 0.001) and in men (20.2%) compared with women (15.8%) (P < 0.001). Hepatic steatosis and NAFLD were also independently associated with diabetes, with insulin resistance among people without diabetes, with dyslipidemia, and with obesity. Our results extend previous national estimates of the prevalence of NAFLD in the US population and highlight the burden of this disease. Men, Mexican Americans, and people with diabetes and obesity are the most affected groups.

Am J Epidemiol. 2013 Jul 1;178(1):38-45

Ethnicity and the diagnosis gap in liver disease: a population-based study.

BACKGROUND: Liver disease is a major cause of morbidity and mortality worldwide. Large numbers of liver function tests (LFTs) are performed in primary care, with abnormal liver biochemistry a common finding. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. Metabolic syndrome, common in people from South Asia, is an important risk factor for NAFLD. AIM: It is hypothesised that a large gap exists between numbers of patients with abnormal LFTs and those with recorded liver diagnoses, and that NAFLD is more common among adults of South Asian ethnic groups. DESIGN AND SETTING: A cross-sectional study of 690,683 adults in coterminous general practices in a region with high ethnic diversity. METHOD: Data were extracted on LFTs, liver disease, and process of care measures from computerised primary care medical records. RESULTS: LFTs were performed on 218,032 patients, of whom 31,627 had elevated serum transaminases. The prevalence of abnormal LFTs was highest among individuals of Bangladeshi ethnicity. Of the patients with abnormal LFTs, 88.4% did not have a coded liver diagnosis. NAFLD was the most frequently recorded liver disease and was most common among Bangladeshi patients. In a multivariate analysis, independent risk factors for NAFLD included Bangladeshi ethnicity, diabetes, raised BMI, hypertension, and hypercholesterolaemia. CONCLUSION: Abnormal LFTs are common in the population, but are underinvestigated and often remain undiagnosed. Bangladeshi ethnicity is an important independent risk factor for NAFLD.

Br J Gen Pract. 2014 Nov;64(628):e694-702

Oxidative stress-related parameters in the liver of nonalcoholic fatty liver disease patients.

Oxidative stress is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In the present study, hepatic and plasma oxidative stress-related parameters were measured and correlated with clinical and histological findings in 31 NAFLD patients showing increased body mass index. Liver protein carbonyl content was enhanced by 403% in patients with steatosis (n=15) compared with control values (n=12), whereas glutathione content, superoxide dismutase (SOD) activity and the ferric reducing ability of plasma (FRAP) were decreased by 57%, 48% and 21% (P<0.05) respectively. No changes in microsomal p-nitrophenol hydroxylation and the total content of cytochrome P450 (CYP) or CYP2E1 were observed. Patients with steatohepatitis (n=16) exhibited protein carbonyl content comparable with that of controls, whereas glutathione content, SOD and catalase activities were decreased by 27%, 64% and 48% (P<0.05). In addition, FRAP values in patients with steatohepatitis were reduced by 33% and 15% (P<0.05) when compared with controls and patients with steatosis respectively, whereas p-nitrophenol hydroxylation (52%) and CYP2E1 content (142%) were significantly increased (P<0.05) compared with controls. It is concluded that oxidative stress is developed in the liver of NAFLD patients with steatosis and is exacerbated further in patients with steatohepatitis, which is associated with CYP2E1 induction. Substantial protein oxidation is followed by proteolysis of the modified proteins, which may explain the co-existence of a diminished antioxidant capacity and protein oxidation in the liver of patients with steatohepatitis.

Clin Sci (Lond). 2004 Mar;106(3):261-8

Effect of silymarin on kidneys of rats suffering from alloxan-induced diabetes mellitus.

Oxidative stress contributes to the pathogenesis of diabetes mellitus and its sequelae nephropathy. The kidneys are especially prone to damage by free radicals. We therefore tested the effect of the flavonoid mixture silymarin, a free radical scavenger, on the activity and gene expression of superoxide dismutase, glutathione peroxidase and catalase, as well as on renal tissue morphology in rats with alloxan-induced diabetes mellitus. Alloxan-intoxicated rats were treated with silymarin 20 days after alloxan administration for 9 weeks. Alloxan-induced tissue damage and decreased the activity of the three enzymes, SOD (U/mg prot.): 14.4±1.75 vs 112±6.45 control, p<0.05, n=6; GSHPx (µM NADPH/min/mg prot.): 0.02±0.002 vs 0.121±0.01 control, p<0.05, n=6; CAT (k/seg/mg prot.): 0.022±0.003 vs 0.044±0.002 control, p<0.05, n=6. Silymarin treatment prevented tissue damage and restored the activity (SOD: 110.7±12.9U/mg prot.; GSHPx: 0.329±0.031 µM NADPH/min/mg prot.; CAT: 0.054±0.002 k/seg/mg prot., n=6) and gene expression of the three antioxidant enzymes after 20 days of alloxan administration (SOD: 12.00±0.57 control, 9.00±0.1 diabetic p<0.05, 11.00±0.20 silymarin treated; GSHPx: 6.01±0.78 control, 9.03±0.3 diabetic p<0.05, 7.02±0.07 silymarin treated; CAT: 9.03±1.07 control, 12.02±0.60 diabetic p<0.05, 8.06±0.31 silymarin treated, n=6). It is suggested in this study that recuperative effect of silymarin on the renal tissue damage induced by alloxan may be related to an increase in the activity and recovery of gene expression of antioxidant enzymes which in addition to the glutathione system constitute some of the most important defense mechanisms against free radicals damage. As these results show, silymarin may be considered potentially in the treatment of diabetic nephropathy.

Phytomedicine. 2010 Dec 1;17(14):1090-4

Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction.

In a randomized, double-blind, controlled trial, the effects of oral treatment with coenzyme Q10 (CoQ10, 120 mg/day), a bioenergetic and antioxidant cytoprotective agent, were compared for 1 year, on the risk factors of atherosclerosis, in 73 (CoQ, group A) and 71 (B vitamin group B) patients after acute myocardial infarction (AMI). After 1 year, total cardiac events (24.6 vs. 45.0%, p < 0.02) including non-fatal infarction (13.7 vs. 25.3%, p < 0.05) and cardiac deaths were significantly lower in the intervention group compared to control group. The extent of cardiac disease, elevation in cardiac enzymes, left ventricular enlargement, previous coronary artery disease and elapsed time from symptom onset to infarction at entry to study showed no significant differences between the two groups. Plasma level of vitamin E (32.4 +/- 4.3 vs. 22.1 +/- 3.6 umol/L) and high density lipoprotein cholesterol (1.26 +/- 0.43 vs. 1.12 +/- 0.32 mmol/L) showed significant (p < 0.05) increase whereas thiobarbituric acid reactive substances, malondialdehyde (1.9 + 0.31 vs. 3.1 + 0.32 pmol/L) and diene conjugates showed significant reduction respectively in the CoQ group compared to control group. Approximately half of the patients in each group (n = 36 vs. 31) were receiving lovastatin (10 mg/day) and both groups had a significant reduction in total and low density lipoprotein cholesterol compared to baseline levels. It is possible that treatment with CoQ10 in patients with recent MI may be beneficial in patients with high risk of atherothrombosis, despite optimal lipid lowering therapy during a follow-up of 1 year. Adverse effect of treatments showed that fatigue (40.8 vs. 6.8%, p < 0.01) was more common in the control group than CoQ group.

Mol Cell Biochem. 2003 Apr;246(1-2):75-82

Effects of coenzyme Q10 on vascular endothelial function in humans: a meta-analysis of randomized controlled trials.

OBJECTIVE: The purpose of this study was to quantify the effect of coenzyme Q10 on arterial endothelial function in patients with and without established cardiovascular disease. BACKGROUND: Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. METHODS AND RESULTS: The search included MEDLINE, Cochrane Library, Scopus, and EMBASE to identify studies up to 1 July 2011. Eligible studies were randomized controlled trials on the effects of coenzyme Q10 compared with placebo on endothelial function. Two reviewers extracted data on study characteristics, methods, and outcomes. Five eligible trials enrolled a total of 194 patients. Meta-analysis using random-effects model showed treatment with coenzyme Q10 significantly improvement in endothelial function assessed peripherally by flow-mediated dilatation (SMD 1.70, 95% CI: 1.00-2.4, p<0.0001). However, the endothelial function assessed peripherally by nitrate-mediated arterial dilatation was not significantly improved by using fix-effects model (SMD -0.19, 95% CI: -1.75 to 1.38, p = 0.81). CONCLUSION: Coenzyme Q10 supplementation is associated with significant improvement in endothelial function. The current study supports a role for CoQ10 supplementation in patients with endothelial dysfunction.

Atherosclerosis. 2012 Apr;221(2):311-6

Prevention of coronary atherosclerosis by the use of combination therapy with antioxidant coenzyme Q10 and statins.

The goal of the present research was to assess the efficacy of combination treatment with antioxidant coenzyme Q10 and simvastatin as well as coenzyme Q10 without statin therapy in order to prevent coronary atherosclerosis. 42 outpatients were divided into 2 groups: receiving coenzyme Q10 (Hasco-Lek, Poland) 60 mg daily and its combination with simvastatin (zocor, vasilip) 10 mg daily for an 8-week period. The treatment with coenzyme Q10 demonstrated its potential independent role in positive modification of oxidative stress, antiatherogenic fraction of lipid profile, atherogenic ratio, platelet aggregability. Taking into consideration the obtained results the study supports the use of coenzyme Q10 in combination with statins. Suggested attractive approach may result in complete correction of dislipidemia, reverse of endothelial dysfunction, reduce degree of oxidative stress and platelet aggregability. Consequently such a combination may be beneficial in preventing of further development of atherosclerosis in native coronary arteries as well as in bypass grafts in all coronary heart disease patients with or without myocardial revascularization.

Georgian Med News. 2005 Jan;(118):20-5

Aged garlic extract and coenzyme Q10 have favorable effect on inflammatory markers and coronary atherosclerosis progression: A randomized clinical trial.

BACKGROUND: Aged garlic extract (AGE) and coenzyme Q10 (CoQ10) have been shown to affect multiple cardiovascular risk factors. The current study evaluates the effect of AGE combined with CoQ10 on inflammatory markers and progression of coronary atherosclerosis compared with placebo. METHODS AND RESULTS: In this placebo-controlled, double-blind, randomized trial, 65 intermediate risk firefighters (age 55 ± 6 years) were treated with a placebo capsule or a capsule containing AGE and CoQ10 (AGE+CoQ10, 1,200 and 120 mg, respectively) daily for 1 year. All participants underwent coronary artery calcium (CAC) scanning and C-reactive protein (CRP) at baseline and at 12 months. At 1 year, mean CAC progression was significantly lower in AGE+CoQ10 (32 ± 6 vs. 58 ± 8, P = 0.01) than placebo. Similarly, CRP were significantly decreased in AGE+CoQ10 compared with placebo (-0.12 ± 0.24 vs. 0.91 ± 0.56 mg/L, P < 0.05). After adjustment for age, gender, conventional cardiac risk factors, and statin therapy, AGE+CoQ10 was associated with 3.99 fold (95% 1.3-12.2, P = 0.01) lack of CAC progression compared with the placebo. CONCLUSION: AGE+CoQ10 are associated with beneficial effects on inflammatory markers and reduced progression of coronary atherosclerosis.

J Cardiovasc Dis Res. 2012 Jul;3(3):185-90

Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction.

The effects of oral treatment with coenzyme Q10 (120 mg/d) were compared for 28 days in 73 (intervention group A) and 71 (placebo group B) patients with acute myocardial infarction (AMI). After treatment, angina pectoris (9.5 vs. 28.1), total arrhythmias (9.5% vs. 25.3%), and poor left ventricular function (8.2% vs. 22.5%) were significantly (P < 0.05) reduced in the coenzyme Q group than placebo group. Total cardiac events, including cardiac deaths and nonfatal infarction, were also significantly reduced in the coenzyme Q10 group compared with the placebo group (15.0% vs. 30.9%, P < 0.02). The extent of cardiac disease, elevation in cardiac enzymes, and oxidative stress at entry to the study were comparable between the two groups. Lipid peroxides, diene conjugates, and malondialdehyde, which are indicators of oxidative stress, showed a greater reduction in the treatment group than in the placebo group. The antioxidants vitamin A, E, and C and beta-carotene, which were lower initially after AMI, increased more in the coenzyme Q10 group than in the placebo group. These findings suggest that coenzyme Q10 can provide rapid protective effects in patients with AMI if administered within 3 days of the onset of symptoms. More studies in a larger number of patients and long-term follow-up are needed to confirm our results.

Cardiovasc Drugs Ther. 1998 Sep;12(4):347-53

Influence of coenzyme Q(10) and cerivastatin on the flow-mediated vasodilation of the brachial artery: results of the ENDOTACT study.

AIM: Endothelial dysfunction (ED) is the functional prestep in atherosclerosis. Aim of the present study was to evaluate the effects of a potent antioxidant (coenzyme Q(10), CoQ(10)) and of cerivastatin on ED of the brachial artery. METHODS AND RESULTS: Twenty-five male patients with manifest ED (flow-mediated vasodilation [FMD%]<4.5%) were included in this prospective, randomized, cross-over study. ED of the brachial artery was assessed by the use of high-resolution ultrasound. Each patient had to pass through three treatment phases ((1) single therapy with cerivastatin (C), (2) single therapy with CoQ(10), (3) combination therapy). FMD% significantly improved throughout all treatment phases ((1) 3.50+/-4.05% vs. 8.80+/-6.39%, p=0.009; (2) -0.25+/-4.0% vs. 7.06%+/-4.39%, p=0.004; (3) 3.14+/-3.54% vs. 8.82+/-5.78%, p=0.011). C led to a significant decrease of CoQ(10) plasma levels (1.23+/-0.34 vs. 0.87+/-0.39 microg/ml, p=0.004). CONCLUSION: Our results indicate a positive influence of CoQ(10) supplementation on human ED, which appears to be independent of lipid lowering. Although large-scale studies evaluating other antioxidants failed to demonstrate a positive prognostic effect, Q(10) has never been evaluated in larger trials. Experimental as well as clinical results indicate that CoQ(10) warrants further attention in atherosclerosis research.

Int J Cardiol. 2005 Feb 28;98(3):413-9

Coenzyme Q10 and exercise training in chronic heart failure.

AIMS: There is evidence that plasma coenzyme Q(10) (CoQ(10)) levels decrease in patients with advanced chronic heart failure (CHF). However, it is not known whether oral CoQ(10) supplementation may improve cardiocirculatory efficiency and endothelial function in patients with CHF. METHODS AND RESULTS: We studied 23 patients in NYHA class II and III (20 men, three women, mean age 59+/-9 years) with stable CHF secondary to ischaemic heart disease [ejection fraction 37+/-7%], using a double-blind, placebo-controlled cross-over design. Patients were assigned to each of the following treatments: oral CoQ(10) (100 mg tid), CoQ(10) plus supervised exercise training (ET) (60% of peak VO(2), five times a week), placebo, and placebo plus ET. Each phase lasted 4 weeks. Both peak VO(2) and endothelium-dependent dilation of the brachial artery (EDDBA) improved significantly after CoQ(10) and after ET as compared with placebo. CoQ(10) main effect was: peak VO(2)+9%, EDDBA +38%, systolic wall thickening score index (SWTI) -12%; ET produced comparable effects. CoQ(10) supplementation resulted in a four-fold increase in plasma CoQ(10) level, whereas the combination with ET further increased it. No side effects were reported with CoQ(10). CONCLUSIONS: Oral CoQ(10) improves functional capacity, endothelial function, and LV contractility in CHF without any side effects. The combination of CoQ(10) and ET resulted in higher plasma CoQ(10) levels and more pronounced effects on all the abovementioned parameters. However, significant synergistic effect of CoQ(10) with ET was observed only for peak SWTI suggesting that ET amplifies the already described effect of CoQ(10) on contractility of dysfunctional myocardium.

Eur Heart J. 2006 Nov;27(22):2675-81

Supplemental ubiquinol in patients with advanced congestive heart failure.

Patients with CHF, NYHA class IV, often fail to achieve adequate plasma CoQ10 levels on supplemental ubiquinone at dosages up to 900 mg/day. These patients often have plasma total CoQ10 levels of less than 2.5 microg/mL and have limited clinical improvement. It is postulated that the intestinal edema in these critically ill patients may impair CoQ10 absorption. We identified seven patients with advanced CHF (mean EF 22%) with sub-therapeutic plasma CoQ10 levels with mean level of 1.6 microg/mL on an average dose of 450 mg of ubiquinone daily (150-600 mg/day). All seven of these patients were changed to an average of 580 mg/day of ubiquinol (450-900 mg/day) with follow-up plasma CoQ10 levels, clinical status, and EF measurements by echocardiography. Mean plasma CoQ10 levels increased from 1.6 microg/mL (0.9-2.0 microg/mL) up to 6.5 microg/ml (2.6-9.3 microg/mL). Mean EF improved from 22% (10-35%) up to 39% (10-60%) and clinical improvement has been remarkable with NYHA class improving from a mean of IV to a mean of II (I to III). Ubiquinol has dramatically improved absorption in patients with severe heart failure and the improvement in plasma CoQ10 levels is correlated with both clinical improvement and improvement in measurement of left ventricular function.

Biofactors. 2008;32(1-4):119-28

Overview of the use of CoQ10 in cardiovascular disease.

The clinical experience in cardiology with CoQ10 includes studies on congestive heart failure, ischemic heart disease, hypertensive heart disease, diastolic dysfunction of the left ventricle, and reperfusion injury as it relates to coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA reductase inhibitors and the potential adverse consequences are of growing concern. Supplemental CoQ10 alters the natural history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (> 3.5 micrograms/ml) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement. In this communication, 34 controlled trials and several open-label and long-term studies on the clinical effects of CoQ10 in cardiovascular diseases are reviewed.

Biofactors. 1999;9(2-4):273-84

Coenzyme Q10 improves contractility of dysfunctional myocardium in chronic heart failure.

BACKGROUND: There is evidence that plasma CoQ(10) levels decrease in patients with advanced chronic heart failure (CHF). OBJECTIVE: To investigate whether oral CoQ(10) supplementation could improve cardiocirculatory efficiency in patients with CHF. METHODS: We studied 21 patients in NYHA class II and III (18M, 3W, mean age 59 +/- 9 years) with stable CHF secondary to ischemic heart disease (ejection fraction 37 +/- 7%), using a double-blind, placebo-controlled cross-over design. Patients were assigned to oral CoQ(10) (100 mg tid) and to placebo for 4 weeks, respectively. RESULTS: CoQ(10) supplementation resulted in a threefold increase in plasma CoQ(10) level (P < 0.0001 vs placebo). Systolic wall thickening score index (SWTI) was improved both at rest and peak dobutamine stress echo after CoQ(10) supplementation (+12.1 and 15.6%, respectively, P < 0.05 vs placebo). Left ventricular ejection fraction improved significantly also at peak dobutamine (15% from study entry P < 0.0001) in relation to a decrease in LV end-systolic volume index (from 57 +/- 7 mL/m(2) to 45 mL/m(2), P < 0.001). Improvement in the contractile response was more evident among initially akinetic (+33%) and hypokinetic (+25%) segments than dyskinetic ones (+6%). Improvement in SWTI was correlated with changes in plasma CoQ(10) levels (r = -0.52, P < 0.005). Peak VO(2) was also improved after CoQ(10) as compared with placebo (+13%, <0.005). No side effects were reported with CoQ(10). CONCLUSIONS: Oral CoQ(10) improves LV contractility in CHF without any side effects. This improvement is associated with an enhanced functional capacity.

Biofactors. 2005;25(1-4):137-45