Life Extension Magazine®

Issue: Sep 2012


By Life Extension.

Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial.

BACKGROUND: Evidence suggests that asthma is rooted in the intrauterine environment and that intake of marine n-3 polyunsaturated fatty acids (n-3 PUFAs) in pregnancy may have immunomodulatory effects on the child. OBJECTIVE: Our aim was to examine whether increasing maternal intake of n-3 PUFAs in pregnancy may affect offspring risk of asthma. DESIGN: In 1990, a population-based sample of 533 women with normal pregnancies were randomly assigned 2:1:1 to receive four 1-g gelatin capsules/d with fish oil providing 2.7 g n-3 PUFAs (n = 266); four 1-g, similar-looking capsules/d with olive oil (n = 136); or no oil capsules (n = 131). Women were recruited and randomly assigned around gestation week 30 and asked to take capsules until delivery. Among 531 live-born children, 528 were identified in registries and 523 were still alive by August 2006. Diagnoses from the International Coding of Diseases version 10 were extracted from a mandatory registry that recorded diagnoses reported from hospital contacts. RESULTS: During the 16 y that passed since childbirth, 19 children from the fish oil and olive oil groups had received an asthma-related diagnosis; 10 had received the diagnosis allergic asthma. The hazard rate of asthma was reduced by 63% (95% CI: 8%, 85%; P = 0.03), whereas the hazard rate of allergic asthma was reduced by 87% (95% CI: 40%, 97%; P = 0.01) in the fish oil compared with the olive oil group. CONCLUSION: Under the assumption that intake of olive oil in the dose provided here was inert, our results support that increasing n-3 PUFAs in late pregnancy may carry an important prophylactic potential in relation to offspring asthma.

Am J Clin Nutr. 2008 Jul;88(1):167-75

DHA may prevent age-related dementia.

The risk for dementia, a major contributor to incapacitation and institutionalization, rises rapidly as we age, doubling every 5 y after age 65. Tens of millions of new Alzheimer's disease (AD) and other dementia cases are projected as elderly populations increase around the world, creating a projected dementia epidemic for which most nations are not prepared. Thus, there is an urgent need for prevention approaches that are safe, effective, and affordable. This review addresses the potential of one promising candidate, the (n-3) fatty acid docosahexaenoic acid (DHA), which appears to slow pathogenesis of AD and possibly vascular dementia. DHA is pleiotropic, acting at multiple steps to reduce the production of the beta-amyloid peptide, widely believed to initiate AD. DHA moderates some of the kinases that hyperphosphorylate the tau-protein, a component of the neurofibrillary tangle. DHA may help suppress insulin/neurotrophic factor signaling deficits, neuroinflammation, and oxidative damage that contribute to synaptic loss and neuronal dysfunction in dementia. Finally, DHA increases brain levels of neuroprotective brain-derived neurotrophic factor and reduces the (n-6) fatty acid arachidonate and its prostaglandin metabolites that have been implicated in promoting AD. Clinical trials suggest that DHA or fish oil alone can slow early stages of progression, but these effects may be apolipoprotein E genotype specific, and larger trials with very early stages are required to prove efficacy. We advocate early intervention in a prodromal period with nutrigenomically defined subjects with an appropriately designed nutritional supplement, including DHA and antioxidants.

J Nutr. 2010 Apr;140(4):869-74

Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer.

Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to an increased risk of tumorigenesis and tumor cell invasiveness. Various bioactive lipids, particularly those formed by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, have been well established as therapeutic targets for many epithelial cancers. Emerging studies suggest that there is a role for anti-inflammatory bioactive lipids and their mediators during the resolution phase of inflammation. These proresolving bioactive lipids, including lipoxins (LXs) and resolvins (RVs), have potent anti-inflammatory and anti-carcinogenic properties. The molecular signaling pathways controlling generation and degradation of the proresolving mediators LXs and RVs are now being elucidated, and the component molecules may serve as new targets for regulation of inflammation and inflammation-associated cancers like colon and pancreatic cancers. This review will highlight the recent advances in our understanding of how these bioactive lipids and proresolving mediators may function with various immune cells and cytokines in inhibiting tumor cell proliferation and progression and invasiveness of colon and pancreatic cancers.

Cancer Metastasis Rev. 2011 Dec;30(3-4):507-23

Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer.

BACKGROUND: Palliative chemotherapy is aimed at increasing survival and palliating symptoms. However, the response rate to first-line chemotherapy in patients with nonsmall cell lung cancer (NSCLC) is less than 30%. Experimental studies have shown that supplementation with fish oil (FO) can increase chemotherapy efficacy without negatively affecting nontarget tissue. This study evaluated whether the combination of FO and chemotherapy (carboplatin with vinorelbine or gemcitabine) provided a benefit over standard of care (SOC) on response rate and clinical benefit from chemotherapy in patients with advanced NSCLC. METHODS: Forty-six patients completed the study, n = 31 in the SOC group and n = 15 in the FO group (2.5 g EPA + DHA/day). Response to chemotherapy was determined by clinical examination and imaging. Response rate was defined as the sum of complete response plus partial response, and clinical benefit was defined as the sum of complete response, partial response, and stable disease divided by the number of patients. Toxicities were graded by a nurse before each chemotherapy cycle. Survival was calculated 1 year after study enrollment. RESULTS: Patients in the FO group had an increased response rate and greater clinical benefit compared with the SOC group (60.0% vs 25.8%, P = .008; 80.0% vs 41.9%, P = .02, respectively). The incidence of dose-limiting toxicity did not differ between groups (P = .46). One-year survival tended to be greater in the FO group (60.0% vs 38.7%; P = .15). CONCLUSIONS: Compared with SOC, supplementation with FO results in increased chemotherapy efficacy without affecting the toxicity profile and may contribute to increased survival.

Cancer. 2011 Aug 15;117(16):3774-80

The influence of supplemental lutein and docosahexaenoic acid on serum, lipoproteins, and macular pigmentation.

BACKGROUND: Lutein and docosahexaenoic acid (DHA) may protect against age-related macular degeneration (AMD). Lutein is a component of macular pigment. DHA is in the retina. OBJECTIVE: The objective of this 4-mo study was to determine the effects of lutein (12 mg/d) and DHA (800 mg/d) on their serum concentrations and macular pigment optical density (MPOD). DESIGN: Forty-nine women (60-80 y) were randomly assigned to placebo, DHA, lutein, or lutein + DHA supplement. Serum was analyzed for lutein and DHA (0, 2, and 4 mo). MPOD was determined (0 and 4 mo) at 0.4, 1.5, 3, and 5 degrees temporal retinal eccentricities. Serum was analyzed for lipoproteins (4 mo). RESULTS: There was no interaction between lutein and DHA supplementations for serum lutein and MPOD. The lutein supplementation x DHA supplementation x month interaction was significant for serum DHA response (P < 0.05). In the lutein group, serum lutein increased from baseline at 2 and 4 mo (P < 0.001), and MPOD increased at 3.0 degrees (P < 0.01). In the DHA group, serum DHA increased at 2 and 4 mo (P < 0.0001), and MPOD increased at 0.4 degrees (P < 0.05). In the lutein + DHA group, serum lutein and DHA increased at 2 and 4 mo (P < 0.01), and MPOD increased at 0.4, 1.5, and 3 degrees (P = 0.06, 0.08, and 0.09, respectively). Differences from placebo in lipoprotein subfractions were greatest for the lutein + DHA group (4 mo). CONCLUSIONS: Lutein supplementation increased MPOD eccentrically. DHA resulted in central increases. These results may be due to changes in lipoproteins. Lutein and DHA may aid in prevention of age-related macular degeneration.

Am J Clin Nutr. 2008 May;87(5):1521-9

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.

Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.

Nat Rev Immunol. 2008 May;8(5):349-61

Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity.

The harmony and function of the complex brain circuits and synapses are sustained mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene regulation, and factors, many of which are incompletely understood. A common feature of brain circuit components, such as dendrites, synaptic membranes, and other membranes of the nervous system, is that they are richly endowed in docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family. DHA is avidly retained and concentrated in the nervous system and known to play a role in neuroprotection, memory, and vision. Only recently has it become apparent why the surprisingly rapid increases in free (unesterified) DHA pool size take place at the onset of seizures or brain injury. This phenomenon began to be clarified by the discovery of neuroprotectin D1 (NPD1), the first-uncovered bioactive docosanoid formed from free DHA through 15-lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative stress and neurotrophins. The evolving concept is that DHA-derived docosanoids set in motion endogenous signaling to sustain homeostatic synaptic and circuit integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities, and induces cell survival, which is in contrast to the pro-inflammatory actions of the many of omega-6 fatty acid family members. We highlight here studies relevant to the ability of DHA to sustain neuronal function and protect synapses and circuits in the context of DHA signalolipidomics. DHA signalolipidomics comprises the integration of the cellular/tissue mechanism of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains containing DHA phospholipids, and the precise cellular and molecular events revealed by the uncovering of signaling pathways regulated by docosanoids endowed with prohomeostatic and cell survival bioactivity. Therefore, this approach offers emerging targets for prevention, pharmaceutical intervention, and clinical translation involving DHA-mediated signaling.

Mol Neurobiol. 2011 Oct;44(2):216-22

Health Benefits of n-3 Polyunsaturated Fatty Acids: Eicosapentaenoic Acid and Docosahexaenoic Acid.

Marine-based fish and fish oil are the most popular and well-known sources of n-3 polyunsaturated fatty acids (PUFAs), namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These n-3 PUFAs are known to have variety of health benefits against cardiovascular diseases (CVDs) including well-established hypotriglyceridemic and anti-inflammatory effects. Also, various studies indicate promising antihypertensive, anticancer, antioxidant, antidepression, antiaging, and antiarthritis effects. Moreover, recent studies also indicate anti-inflammatory and insulin-sensitizing effects of these fatty acids in metabolic disorders. Classically, n-3 PUFAs mediate some of these effects by antagonizing n-6 PUFA (arachidonic acid)-induced proinflammatory prostaglandin E(2) (PGE(2)) formation. Another well-known mechanism by which n-3 PUFAs impart their anti-inflammatory effects is via reduction of nuclear factor-κB activation. This transcription factor is a potent inducer of proinflammatory cytokine production, including interleukin 6 and tumor necrosis factor-α, both of which are decreased by EPA and DHA. Other evidence also demonstrates that n-3 PUFAs repress lipogenesis and increase resolvins and protectin generation, ultimately leading to reduced inflammation. Finally, beneficial effects of EPA and DHA in insulin resistance include their ability to increase secretion of adiponectin, an anti-inflammatory adipokine. In summary, n-3 PUFAs have multiple health benefits mediated at least in part by their anti-inflammatory actions; thus their consumption, especially from dietary sources, should be encouraged.

Adv Food Nutr Res. 2012;65:211-22

Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice.

OBJECTIVE: The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators. We aimed to determine whether high-fat (HF) diet-induced n-3 deficiency compromises the resolution capacity of obese mice and thereby contributes to obesity-linked inflammation and insulin resistance. RESEARCH DESIGN AND METHODS: We used transgenic expression of the fat-1 n-3 fatty acid desaturase from C. elegans to endogenously restore n-3 fatty acids in HF-fed mice. After 8 weeks on HF or chow diets, wild-type and fat-1 transgenic mice were subjected to insulin and glucose tolerance tests and a resolution assay was performed. Metabolic tissues were then harvested for biochemical analyses. RESULTS: We report that the n-3 docosanoid resolution mediator protectin D1 is lacking in muscle and adipose tissue of HF-fed wild-type mice. Accordingly, HF-fed wild-type mice have an impaired capacity to resolve an acute inflammatory response and display elevated adipose macrophage accrual and chemokine/cytokine expression. This is associated with insulin resistance and higher activation of iNOS and JNK in muscle and liver. These defects are reversed in HF-fed fat-1 mice, in which the biosynthesis of this important n-3 docosanoid resolution mediator is improved. Importantly, transgenic restoration of n-3 fatty acids prevented obesity-linked inflammation and insulin resistance in HF-fed mice without altering food intake, weight gain, or adiposity. CONCLUSIONS: We conclude that inefficient biosynthesis of n-3 resolution mediators in muscle and adipose tissue contributes to the maintenance of chronic inflammation in obesity and that these novel lipids offer exciting potential for the treatment of insulin resistance and diabetes.

Diabetes. 2010 Dec;59(12):3066-73

Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice.

Type 2 diabetes and obesity have emerged as global public health crises. Adipose tissue expansion in obesity promotes accumulation of classically activated macrophages that perpetuate chronic inflammation and sustain insulin resistance. Acute inflammation normally resolves in an actively orchestrated series of molecular and cellular events that ensures return to homeostasis after an inflammatory insult, a process regulated in part by endogenous lipid mediators such as the resolvins. In this study, we sought to determine whether stimulating resolution with resolvin D1 (RvD1) improves insulin sensitivity by resolving chronic inflammation associated with obesity. In male leptin receptor-deficient (db/db) mice, treatment with RvD1 (2 µg/kg) improved glucose tolerance, decreased fasting blood glucose, and increased insulin-stimulated Akt phosphorylation in adipose tissue relative to vehicle-treated mice. Treatment with RvD1 increased adiponectin production, while expression of IL-6 in adipose tissue was decreased. The formation of crown-like structures rich in inflammatory F4/80(+)CD11c(+) macrophages was reduced by >50% in adipose tissue by RvD1 and was associated with an increased percentage of F4/80(+) cells expressing macrophage galactose-type C-type lectin 1 (MGL-1), a marker of alternatively activated macrophages. These results suggest that stimulating resolution with the endogenous proresolving mediator RvD1 could provide a novel therapeutic strategy for treating obesity-induced diabetes.

Coffee and its consumption: benefits and risks.

Coffee is the leading worldwide beverage after water and its trade exceeds US $10 billion worldwide. Controversies regarding its benefits and risks still exist as reliable evidence is becoming available supporting its health promoting potential; however, some researchers have argued about the association of coffee consumption with cardiovascular complications and cancer insurgence. The health-promoting properties of coffee are often attributed to its rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, hydroxyhydroquinone (HHQ), etc. Many research investigations, epidemiological studies, and meta-analyses regarding coffee consumption revealed its inverse correlation with that of diabetes mellitus, various cancer lines, Parkinsonism, and Alzheimer's disease. Moreover, it ameliorates oxidative stress because of its ability to induce mRNA and protein expression, and mediates Nrf2-ARE pathway stimulation. Furthermore, caffeine and its metabolites help in proper cognitive functionality. Coffee lipid fraction containing cafestol and kahweol act as a safeguard against some malignant cells by modulating the detoxifying enzymes. On the other hand, their higher levels raise serum cholesterol, posing a possible threat to coronary health, for example, myocardial and cerebral infarction, insomnia, and cardiovascular complications. Caffeine also affects adenosine receptors and its withdrawal is accompanied with muscle fatigue and allied problems in those addicted to coffee. An array of evidence showed that pregnant women or those with postmenopausal problems should avoid excessive consumption of coffee because of its interference with oral contraceptives or postmenopausal hormones. This review article is an attempt to disseminate general information, health claims, and obviously the risk factors associated with coffee co3nsumption to scientists, allied stakeholders, and certainly readers.

Crit Rev Food Sci Nutr. 2011 Apr;51(4):363-7

Association of coffee drinking with total and cause-specific mortality.

BACKGROUND: Coffee is one of the most widely consumed beverages, but the association between coffee consumption and the risk of death remains unclear. METHODS: We examined the association of coffee drinking with subsequent total and cause-specific mortality among 229,119 men and 173,141 women in the National Institutes of Health-AARP Diet and Health Study who were 50 to 71 years of age at baseline. Participants with cancer, heart disease, and stroke were excluded. Coffee consumption was assessed once at baseline. RESULTS: During 5,148,760 person-years of follow-up between 1995 and 2008, a total of 33,731 men and 18,784 women died. In age-adjusted models, the risk of death was increased among coffee drinkers. However, coffee drinkers were also more likely to smoke, and, after adjustment for tobacco-smoking status and other potential confounders, there was a significant inverse association between coffee consumption and mortality. Adjusted hazard ratios for death among men who drank coffee as compared with those who did not were as follows: 0.99 (95% confidence interval [CI], 0.95 to 1.04) for drinking less than 1 cup per day, 0.94 (95% CI, 0.90 to 0.99) for 1 cup, 0.90 (95% CI, 0.86 to 0.93) for 2 or 3 cups, 0.88 (95% CI, 0.84 to 0.93) for 4 or 5 cups, and 0.90 (95% CI, 0.85 to 0.96) for 6 or more cups of coffee per day (P<0.001 for trend); the respective hazard ratios among women were 1.01 (95% CI, 0.96 to 1.07), 0.95 (95% CI, 0.90 to 1.01), 0.87 (95% CI, 0.83 to 0.92), 0.84 (95% CI, 0.79 to 0.90), and 0.85 (95% CI, 0.78 to 0.93) (P<0.001 for trend). Inverse associations were observed for deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not for deaths due to cancer. Results were similar in subgroups, including persons who had never smoked and persons who reported very good to excellent health at baseline. CONCLUSIONS: In this large prospective study, coffee consumption was inversely associated with total and cause-specific mortality. Whether this was a causal or associational finding cannot be determined from our data. (Funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.).

N Engl J Med. 2012 May 17;366(20):1891-904

Antioxidant-rich coffee reduces DNA damage, elevates glutathione status and contributes to weight control: results from an intervention study.

Epidemiological and experimental evidence increasingly suggests coffee consumption to be correlated to prevention or delay of degenerative diseases connected with oxidative cellular stress. In an intervention study comprising 33 healthy volunteers, we examined DNA-protective and antioxidative effects exerted in vivo by daily ingestion of 750 mL of freshly brewed coffee rich in both green coffee bean constituents as well as roast products. The study design encompassed an initial 4 wk of wash-out, followed by 4 wk of coffee intake and 4 wk of second wash-out. At the start and after each study phase blood samples were taken to monitor biomarkers of oxidative stress response. In addition, body weight/composition and intake of energy/nutrients were recorded. In the coffee ingestion period, the primary endpoint, oxidative DNA damage as measured by the Comet assay (± FPG), was markedly reduced (p<0.001). Glutathione level (p<0.05) and GSR-activity (p<0.01) were elevated. Body weight (p<0.01)/body fat (p<0.05) and energy (p<0.001)/nutrient (p<0.001-0.05) intake were reduced. Our results allow to conclude that daily consumption of 3-4 cups of brew from a special Arabica coffee exerts health beneficial effects, as evidenced by reduced oxidative damage, body fat mass and energy/nutrient uptake.

Mol Nutr Food Res. 2011 May;55(5):793-7

Instant coffee with high chlorogenic acid levels protects humans against oxidative damage of macromolecules.

SCOPE: Coffee is among the most frequently consumed beverages. Its consumption is inversely associated to the incidence of diseases related to reactive oxygen species; the phenomenon may be due to its antioxidant properties. Our primary objective was to investigate the impact of consumption of a coffee containing high levels of chlorogenic acids on the oxidation of proteins, DNA and membrane lipids; additionally, other redox biomarkers were monitored in an intervention trial. METHODS AND RESULTS: The treatment group (n=36) consumed instant coffee co-extracted from green and roasted beans, whereas the control consumed water (800 mL/P/day, 5 days). A global statistical analysis of four main biomarkers selected as primary outcomes showed that the overall changes are significant. 8-Isoprostaglandin F2α in urine declined by 15.3%, 3-nitrotyrosine was decreased by 16.1%, DNA migration due to oxidized purines and pyrimidines was (not significantly) reduced in lymphocytes by 12.5 and 14.1%. Other markers such as the total antioxidant capacity were moderately increased; e.g. LDL and malondialdehyde were shifted towards a non-significant reduction. CONCLUSION: The oxidation of DNA, lipids and proteins associated with the incidence of various diseases and the protection against their oxidative damage may be indicative for beneficial health effects of coffee.

Mol Nutr Food Res. 2010 Dec;54(12):1722-33

Coffee consumption and risk of cardiovascular events and all-cause mortality among women with type 2 diabetes.

AIMS/HYPOTHESIS: Coffee has been linked to both beneficial and harmful health effects, but data on its relationship with cardiovascular disease and mortality in patients with type 2 diabetes are sparse. METHODS: This was a prospective cohort study including 7,170 women with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Coffee consumption was assessed in 1980 and then every 2-4 years using validated questionnaires. A total of 658 incident cardiovascular events (434 coronary heart disease and 224 stroke) and 734 deaths from all causes were documented between 1980 and 2004. RESULTS: After adjustment for age, smoking and other cardiovascular risk factors, the relative risks were 0.76 (95% CI 0.50-1.14) for cardiovascular diseases (p trend = 0.09) and 0.80 (95% CI 0.55-1.14) for all-cause mortality (p trend = 0.05) for the consumption of >or=4 cups/day of caffeinated coffee compared with non-drinkers. Similarly, multivariable RRs were 0.96 (95% CI 0.66-1.38) for cardiovascular diseases (p trend = 0.84) and 0.76 (95% CI 0.54-1.07) for all-cause mortality (p trend = 0.08) for the consumption of >or=2 cups/day of decaffeinated coffee compared with non-drinkers. Higher decaffeinated coffee consumption was associated with lower concentrations of HbA(1c) (6.2% for >or=2 cups/day versus 6.7% for <1 cup/month; p trend = 0.02). CONCLUSIONS: These data provide evidence that habitual coffee consumption is not associated with increased risk of cardiovascular diseases or premature mortality among diabetic women.

Diabetologia. 2009 May;52(5):810-7

Coffee consumption enhances high-density lipoprotein-mediated cholesterol efflux in macrophages.

RATIONALE: Association of habitual coffee consumption with coronary heart disease morbidity and mortality has not been established. We hypothesized that coffee may enhance reverse cholesterol transport (RCT) as the antiatherogenic properties of high-density lipoprotein (HDL). OBJECTIVE: This study was to investigate whether the phenolic acids of coffee and coffee regulates RCT from macrophages in vitro, ex vivo and in vivo. METHODS AND RESULTS: Caffeic acid and ferulic acid, the major phenolic acids of coffee, enhanced cholesterol efflux from THP-1 macrophages mediated by HDL, but not apoA-I. Furthermore, these phenolic acids increased both the mRNA and protein levels of ATP-binding cassette transporter (ABC)G1 and scavenger receptor class B type I (SR-BI), but not ABCA1. Eight healthy volunteers were recruited for the ex vivo study, and blood samples were taken before and 30 minutes after consumption of coffee or water in a crossover study. The mRNA as well as protein levels of ABCG1, SR-BI, and cholesterol efflux by HDL were increased in the macrophages differentiated under autologous sera obtained after coffee consumption compared to baseline sera. Finally, effects of coffee and phenolic acid on in vivo RCT were assessed by intraperitoneally injecting [(3)H]cholesterol-labeled acetyl low-density lipoprotein-loaded RAW264.7 cells into mice, then monitoring appearance of (3)H tracer in plasma, liver, and feces. Supporting in vitro and ex vivo data, ferulic acid was found to significantly increase the levels of (3)H tracer in feces. CONCLUSIONS: Coffee intake might have an antiatherogenic property by increasing ABCG1 and SR-BI expression and enhancing HDL-mediated cholesterol efflux from the macrophages via its plasma phenolic acids.

Circ Res. 2010 Mar 5;106(4):779-87

Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women's Health Study.

BACKGROUND: Coffee is the major source of dietary antioxidants. The association between coffee consumption and risk of death from diseases associated with inflammatory or oxidative stress has not been studied. OBJECTIVE: We studied the relation of coffee drinking with total mortality and mortality attributed to cardiovascular disease, cancer, and other diseases with a major inflammatory component. DESIGN: A total of 41,836 postmenopausal women aged 55-69 y at baseline were followed for 15 y. After exclusions for cardiovascular disease, cancer, diabetes, colitis, and liver cirrhosis at baseline, 27,312 participants remained, resulting in 410,235 person-years of follow-up and 4265 deaths. The major outcome measure was disease-specific mortality. RESULTS: In the fully adjusted model, similar to the relation of coffee intake to total mortality, the hazard ratio of death attributed to cardiovascular disease was 0.76 (95% CI: 0.64, 0.91) for consumption of 1-3 cups/d, 0.81 (95% CI: 0.66, 0.99) for 4-5 cups/d, and 0.87 (95% CI: 0.69, 1.09) for > or =6 cups/d. The hazard ratio for death from other inflammatory diseases was 0.72 (95% CI: 0.55, 0.93) for consumption of 1-3 cups/d, 0.67 (95% CI: 0.50, 0.90) for 4-5 cups/d, and 0.68 (95% CI: 0.49, 0.94) for > or =6 cups/d. CONCLUSIONS: Consumption of coffee, a major source of dietary antioxidants, may inhibit inflammation and thereby reduce the risk of cardiovascular and other inflammatory diseases in postmenopausal women.

Am J Clin Nutr. 2006 May;83(5):1039-46

Coffee consumption modifies risk of estrogen-receptor negative breast cancer.

INTRODUCTION: Breast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,111 controls), overall, and stratified by ER tumour subtypes. METHODS: Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using the multivariate logistic regression models fitted to examine breast cancer risk in a stratified case-control analysis. Heterogeneity among ER subtypes was evaluated in a case-only analysis, by fitting binary logistic regression models, treating ER status as a dependent variable, with coffee consumption included as a covariate. RESULTS: In the Swedish study, coffee consumption was associated with a modest decrease in overall breast cancer risk in the age-adjusted model (OR> 5 cups/day compared to OR≤ 1 cup/day: 0.80, 95% CI: 0.64, 0.99, P trend = 0.028). In the stratified case-control analyses, a significant reduction in the risk of ER-negative breast cancer was observed in heavy coffee drinkers (OR> 5 cups/day compared to OR≤ 1 cup/day : 0.43, 95% CI: 0.25, 0.72, P trend = 0.0003) in a multivariate-adjusted model. The breast cancer risk reduction associated with higher coffee consumption was significantly higher for ER-negative compared to ER-positive tumours (P heterogeneity (age-adjusted) = 0.004). CONCLUSIONS: A high daily intake of coffee was found to be associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women.

Breast Cancer Res. 2011 May 14;13(3):R49

Coffee consumption and prostate cancer risk and progression in the Health Professionals Follow-up Study.

BACKGROUND: Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer. METHODS: We conducted a prospective analysis of 47,911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests. RESULTS: The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, P(trend) = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, P(trend) = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (≥6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years. CONCLUSIONS: We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.

J Natl Cancer Inst. 2011 Jun 8;103(11):876-84

Antihypertensive effects and mechanisms of chlorogenic acids.

Chlorogenic acids (CGAs) are potent antioxidants found in certain foods and drinks, most notably in coffee. In recent years, basic and clinical investigations have implied that the consumption of chlorogenic acid can have an anti-hypertension effect. Mechanistically, the metabolites of CGAs attenuate oxidative stress (reactive oxygen species), which leads to the benefit of blood-pressure reduction through improved endothelial function and nitric oxide bioavailability in the arterial vasculature. This review article highlights the physiological and biochemical findings on this subject and highlights some remaining issues that merit further scientific and clinical exploration. In the framework of lifestyle modification for the management of cardiovascular risk factors, the dietary consumption of CGAs may hold promise for providing a non-pharmacological approach for the prevention and treatment of high blood pressure.

Hypertens Res. 2012 Apr;35(4):370-4

Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1.

The carotenoid lycopene has been associated with decreased risks of several types of cancer, such as hepatoma. Although lycopene has been shown to inhibit metastasis, its mechanism of action is poorly understood. Here, we used SK-Hep-1 cells (from a human hepatoma) to test whether lycopene exerts its anti-invasion activity via down-regulation of the expression of matrix metalloproteinase (MMP)-9, an important enzyme in the degradation of basement membrane in cancer invasion. The activity and expressions of MMP-9 protein and mRNA were detected by gelatin zymography, Western blotting and RT-PCR, respectively. The binding abilities of nuclear factor-kappa B (NF-kappaB), activator protein-1 and stimulatory protein-1 (Sp1) to the binding sites in the MMP-9 promoter were measured by the electrophoretic mobility shift assay. We showed that lycopene (1-10 microM) significantly inhibited SK-Hep-1 invasion (P<.05) and that this effect correlated with the inhibition of MMP-9 at the levels of enzyme activity (r(2)=.94, P<.001), protein expression (r(2)=.80, P=.007) and mRNA expression (r(2)=.94, P<.001). Lycopene also significantly inhibited the binding abilities of NF-kappaB and Sp1 and decreased, to some extent, the expression of insulin-like growth factor-1 receptor (IGF-1R) and the intracellular level of reactive oxygen species (P<.05). The antioxidant effect of lycopene appeared to play a minor role in its inhibition of MMP-9 and invasion activity of SK-Hep-1 cells because coincubation of cells with lycopene plus hydrogen peroxide abolished the antioxidant effect but did not significantly affect the anti-invasion ability of lycopene. Thus, lycopene decreases the invasive ability of SK-Hep-1 cells by inhibiting MMP-9 expression and suppressing the binding activity of NF-kappaB and Sp1. These effects of lycopene may be related to the down-regulation of IGF-1R, while the antioxidant activity of lycopene appears to play a minor role.

J Nutr Biochem. 2007 Jul;18(7):449-56

Looking older: fibroblast collapse and therapeutic implications.

Skin appearance is a primary indicator of age. During the last decade, substantial progress has been made toward understanding underlying mechanisms of human skin aging. This understanding provides the basis for current use and new development of antiaging treatments. Our objective is to review present state-of-the-art knowledge pertaining to mechanisms involved in skin aging, with specific focus on the dermal collagen matrix. A major feature of aged skin is fragmentation of the dermal collagen matrix. Fragmentation results from actions of specific enzymes (matrix metalloproteinases) and impairs the structural integrity of the dermis. Fibroblasts that produce and organize the collagen matrix cannot attach to fragmented collagen. Loss of attachment prevents fibroblasts from receiving mechanical information from their support, and they collapse. Stretch is critical for normal balanced production of collagen and collagen-degrading enzymes. In aged skin, collapsed fibroblasts produce low levels of collagen and high levels of collagen-degrading enzymes. This imbalance advances the aging process in a self-perpetuating, never-ending deleterious cycle. Clinically proven antiaging treatments such as topical retinoic acid, carbon dioxide laser resurfacing, and intradermal injection of cross-linked hyaluronic acid stimulate production of new, undamaged collagen. Attachment of fibroblasts to this new collagen allows stretch, which in turn balances collagen production and degradation and thereby slows the aging process. Collagen fragmentation is responsible for loss of structural integrity and impairment of fibroblast function in aged human skin. Treatments that stimulate production of new, nonfragmented collagen should provide substantial improvement to the appearance and health of aged skin.

Arch Dermatol. 2008 May;144(5):666-72

Estrogen and skin. An overview.

As the population of postmenopausal women increases, interest in the effects of estrogen grows. The influence of estrogen on several body systems has been well-documented; however, one area that has not been explored is the effects of estrogen on skin. Estrogen appears to aid in the prevention of skin aging in several ways. This reproductive hormone prevents a decrease in skin collagen in postmenopausal women; topical and systemic estrogen therapy can increase the skin collagen content and therefore maintain skin thickness. In addition, estrogen maintains skin moisture by increasing acid mucopolysaccharides and hyaluronic acid in the skin and possibly maintaining stratum corneum barrier function. Sebum levels are higher in postmenopausal women receiving hormone replacement therapy. Skin wrinkling also may benefit from estrogen as a result of the effects of the hormone on the elastic fibers and collagen. Outside of its influence on skin aging, it has been suggested that estrogen increases cutaneous wound healing by regulating the levels of a cytokine. In fact, topical estrogen has been found to accelerate and improve wound healing in elderly men and women. The role of estrogen in scarring is unclear but recent studies indicate that the lack of estrogen or the addition of tamoxifen may improve the quality of scarring. Unlike skin aging, the role of endogenous and exogenous estrogen in melanoma has not been well established.

Am J Clin Dermatol. 2001;2(3):143-50

Chemistry and biotechnology of carotenoids.

Carotenoids are one of the most widespread groups of pigments in nature and more than 600 of these have been identified. Beside provitamin A activity, carotenoids are important as antioxidants and protective agents against various diseases. They are isoprenoids with a long polyene chain containing 3 to 15 conjugated double bonds, which determines their absorption spectrum. Cyclization at one or both ends occurs in hydrocarbon carotene, while xanthophylls are formed by the introduction of oxygen. In addition, modifications involving chain elongation, isomerization, or degradation are also found. The composition of carotenoids in food may vary depending upon production practices, post-harvest handling, processing, and storage. In higher plants they are synthesized in the plastid. Both mevalonate dependent and independent pathway for the formation of isopentenyl diphosphate are known. Isopentenyl diphosphate undergoes a series of addition and condensation reactions to form phytoene, which gets converted to lycopene. Cyclization of lycopene either leads to the formation of β-carotene and its derivative xanthophylls, β-cryptoxanthin, zeaxanthin, antheraxanthin, and violaxanthin or α-carotene and lutein. Even though most of the carotenoid biosynthetic genes have been cloned and identified, some aspects of carotenoid formation and manipulation in higher plants especially remain poorly understood. In order to enhance the carotenoid content of crop plants to a level that will be required for the prevention of diseases, there is a need for research in both the basic and the applied aspects.

Crit Rev Food Sci Nutr. 2010 Sep;50(8):728-60

Carotenoids and human health.

Oxidative stress is an important contributor to the risk of chronic diseases. Dietary guidelines recommend increased consumption of fruits and vegetables to combat the incidence of human diseases such as cancer, cardiovascular disease, osteoporosis and diabetes. Fruits and vegetables are good sources of antioxidant phytochemicals that mitigate the damaging effect of oxidative stress. Carotenoids are a group of phytochemicals that are responsible for different colors of the foods. They are recognized as playing an important role in the prevention of human diseases and maintaining good health. In addition to being potent antioxidants some carotenoids also contribute to dietary vitamin A. There is scientific evidence in support of the beneficial role of phytochemicals in the prevention of several chronic diseases. Although the chemistry of carotenoids has been studied extensively, their bioavailability, metabolism and biological functions are only now beginning to be investigated. Recent interest in carotenoids has focused on the role of lycopene in human health. Unlike some other carotenoids, lycopene does not have pro-vitamin A properties. Because of the unsaturated nature of lycopene it is considered to be a potent antioxidant and a singlet oxygen quencher. This article will review carotenoids in general and lycopene in particular for their role in human health.

Pharmacol Res. 2007 Mar;55(3):207-16

The role of phytonutrients in skin health.

Photodamage is known to occur in skin with exposure to sunlight, specifically ultraviolet (UV) radiation. Such damage includes inflammation, oxidative stress, breakdown of the extracellular matrix, and development of cancer in the skin. Sun exposure is considered to be one of the most important risk factors for both nonmelanoma and melanoma skin cancers. Many phytonutrients have shown promise as photoprotectants in clinical, animal and cell culture studies. In part, the actions of these phytonutrients are thought to be through their actions as antioxidants. In regard to skin health, phytonutrients of interest include vitamin E, certain flavonoids, and the carotenoids, β-carotene, lycopene and lutein.

Nutrients. 2010 Aug;2(8):903-28

Lycopene in tomatoes: chemical and physical properties affected by food processing.

Lycopene is the pigment principally responsible for the characteristic deep-red color of ripe tomato fruits and tomato products. It has attracted attention due to its biological and physicochemical properties, especially related to its effects as a natural antioxidant. Although it has no provitamin A activity, lycopene does exhibit a physical quenching rate constant with singlet oxygen almost twice as high as that of beta-carotene. This makes its presence in the diet of considerable interest. Increasing clinical evidence supports the role of lycopene as a micronutrient with important health benefits, because it appears to provide protection against a broad range of epithelial cancers. Tomatoes and related tomato products are the major source of lycopene compounds, and are also considered an important source of carotenoids in the human diet. Undesirable degradation of lycopene not only affects the sensory quality of the final products, but also the health benefit of tomato-based foods for the human body. Lycopene in fresh tomato fruits occurs essentially in the all-trans configuration. The main causes of tomato lycopene degradation during processing are isomerization and oxidation. Isomerization converts all-trans isomers to cis-isomers due to additional energy input and results in an unstable, energy-rich station. Determination of the degree of lycopene isomerization during processing would provide a measure of the potential health benefits of tomato-based foods. Thermal processing (bleaching, retorting, and freezing processes) generally cause some loss of lycopene in tomato-based foods. Heat induces isomerization of the all-trans to cis forms. The cis-isomers increase with temperature and processing time. In general, dehydrated and powdered tomatoes have poor lycopene stability unless carefully processed and promptly placed in a hermetically sealed and inert atmosphere for storage. A significant increase in the cis-isomers with a simultaneous decrease in the all-trans isomers can be observed in the dehydrated tomato samples using the different dehydration methods. Frozen foods and heat-sterilized foods exhibit excellent lycopene stability throughout their normal temperature storage shelf life. Lycopene bioavailability (absorption) can be influenced by many factors. The bioavailability of cis-isomers in food is higher than that of all-trans isomers. Lycopene bioavailability in processed tomato products is higher than in unprocessed fresh tomatoes. The composition and structure of the food also have an impact on the bioavailability of lycopene and may affect the release of lycopene from the tomato tissue matrix. Food processing may improve lycopene bioavailability by breaking down cell walls, which weakens the bonding forces between lycopene and tissue matrix, thus making lycopene more accessible and enhancing the cis-isomerization. More information on lycopene bioavailability, however, is needed. The pharmacokinetic properties of lycopene remain particularly poorly understood. Further research on the bioavalability, pharmacology, biochemistry, and physiology must be done to reveal the mechanism of lycopene in human diet, and the in vivo metabolism of lycopene. Consumer demand for healthy food products provides an opportunity to develop lycopene-rich food as new functional foods, as well as food-grade and pharmaceutical-grade lycopene as new nutraceutical products. An industrial scale, environmentally friendly lycopene extraction and purification procedure with minimal loss of bioactivities is highly desirable for the foods, feed, cosmetic, and pharmaceutical industries. High-quality lycopene products that meet food safety regulations will offer potential benefits to the food industry.

Crit Rev Food Sci Nutr. 2000 Jan;40(1):1-42

Chemistry, distribution, and metabolism of tomato carotenoids and their impact on human health.

Recent epidemiological studies have suggested that the consumption of tomatoes and tomato-based food products reduce the risk of prostate cancer in humans. This protective effect has been attributed to carotenoids, which are one of the major classes of phytochemicals in this fruit. The most abundant carotenoid in tomato is lycopene, followed by phytoene, phytofluene, zeta-carotene, gamma-carotene, beta-carotene, neurosporene, and lutein. The distribution of lycopene and related carotenoids in tomatoes and tomato-based food products has been determined by extraction and high-performance liquid chromatography-UV/Visible photodiode array detection. Detailed qualitative and quantitative analysis of human serum, milk, and organs, particularly prostate, have revealed the presence of all the aforementioned carotenoids in biologically significant concentrations. Two oxidative metabolites of lycopene, 2,6-cyclolycopene-1,5-diols A and B, which are only present in tomatoes in extremely low concentrations, have been isolated and identified in human serum, milk, organs (liver, lung, breast, liver, prostate, colon) and skin. Carotenoids may also play an important role in the prevention of age-related macular degeneration, cataracts, and other blinding disorders. Among 25 dietary carotenoids and nine metabolites routinely found in human serum, mainly (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, lycopene, and their metabolites were detected in ocular tissues. In this review we identified and quantified the complete spectrum of carotenoids from pooled human retinal pigment epithelium, ciliary body, iris, lens, and in the uveal tract and in other tissues of the human eye to gain a better insight into the metabolic pathways of ocular carotenoids. Although (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, and their metabolites constitute the major carotenoids in human ocular tissues, lycopene and a wide range of dietary carotenoids have been detected in high concentrations in ciliary body and retinal pigment epithelium. The possible role of lycopene and other dietary carotenoids in the prevention of age-related macular degeneration and other eye diseases is discussed.

Exp Biol Med (Maywood). 2002 Nov;227(10):845-51

A simple and rapid method to assess lycopene in multiple layers of skin samples.

Topical application of lycopene is a convenient way to restore antioxidants depleted from the skin by UV radiation and achieve protection against premature aging and cancer. In this study, a simple, rapid and reproducible method to quantify lycopene in different skin layers was developed, validated and employed to assess this compound after skin penetration studies. Lycopene was extracted from the stratum corneum (SC) and viable epidermis and dermis (ED) by vortex homogenization and bath sonication in a mixture of acetonitrile and methanol (52:48, v/v). Lycopene was assayed by HPLC using a C(18) column, and acetonitrile:methanol (52:48, v/v) as mobile phase. The quantification limit of lycopene in samples of SC and ED was 35 ng/mL and the assay was linear from 35 to 2,000 ng/mL. Within-day and between-days assays coefficients of variation and relative errors (indicative of precision and accuracy) were less than 15% (or 20% for the limit of quantification). Lycopene recovery from SC and ED was dependent on the spiked concentration: for 50 ng/mL, recoveries were 88.3 and 90.5%; for 100-1,000 ng/mL, recoveries were 68.6-74.9%. This method has a potential application for lycopene quantification during formulation development and evaluation in the dermatological field.

Biomed Chromatogr. 2010 Feb;24(2):154

Lycopene oxidation product enhances gap junctional communication.

Carotenoids as well as their metabolites and oxidation products stimulate gap junctional communication (GJC) between cells, which is thought to be one of the protective mechanisms related to cancer-preventive activities of these compounds. Increased intake of lycopene by consumption of tomatoes or tomato products has been epidemiologically associated with a diminished risk of prostate cancer. Here, we report a stimulatory effect of a lycopene oxidation product on GJC in rat liver epithelial WB-F344 cells. The active compound was obtained by complete in vitro oxidation of lycopene with hydrogen peroxide/osmium tetroxide. For structural analysis high performance liquid chromatography, gas chromatography coupled with mass spectrometry, ultraviolet/visible-, and infrared spectrophotometry were applied. The biologically active oxidation product was identified as 2,7,11-trimethyl-tetradecahexaene-1,14-dial. The present data indicate a potential role of lycopene degradation products in cell signaling enhancing cell-to-cell communication via gap junctions.

Food Chem Toxicol. 2003 Oct;41(10):1399-407

Quercetin increases oxidative stress resistance and longevity in Saccharomyces cerevisiae.

Quercetin, the major flavonol found in several fruits and vegetables, is a natural antioxidant with potential anticancer and antiaging activities. In this paper, the effect of quercetin in Sacharomyces cerevisiae cells submitted to oxidative stress was studied. Hydrogen peroxide resistance increased in cells pretreated with quercetin. Cellular protection was correlated with a decrease in oxidative stress markers, namely, levels of reactive oxygen species, glutathione oxidation, protein carbonylation, and lipid peroxidation. The acquisition of H2O2 resistance was not associated with the induction of antioxidant defenses or with iron chelation. Oxidative stress is a limiting factor for longevity. In agreement, quercetin also increased 60% chronological life span. These results support the utilization of yeast as a useful model to screen in vivo for natural antioxidants with putative health beneficial effects.

J Agric Food Chem. 2007 Mar 21;55(6):2446-51

Health effects of quercetin: from antioxidant to nutraceutical.

Quercetin, a member of the flavonoids family, is one of the most prominent dietary antioxidants. It is ubiquitously present in foods including vegetables, fruit, tea and wine as well as countless food supplements and is claimed to exert beneficial health effects. This includes protection against various diseases such as osteoporosis, certain forms of cancer, pulmonary and cardiovascular diseases but also against aging. Especially the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical is suggested to be involved in these possible beneficial health effects. Consequently, numerous studies have been performed to gather scientific evidence for these beneficial health claims as well as data regarding the exact mechanism of action and possible toxicological aspects of this flavonoid. The purpose of this review is to evaluate these studies in order to elucidate the possible health-beneficial effects of the antioxidant quercetin. Firstly, the definitions as well as the most important aspects regarding free radicals, antioxidants and oxidative stress will be discussed as background information. Subsequently, the mechanism by which quercetin may operate as an antioxidant (tested in vitro) as well as the potential use of this antioxidant as a nutraceutical (tested both ex vivo and in vivo) will be discussed.

Eur J Pharmacol. 2008 May 13;585(2-3):325-37.

Quercetin-mediated longevity in Caenorhabditis elegans: is DAF-16 involved?

The polyphenol quercetin has recently been found to extend lifespan and increase stress resistance in the nematode Caenorhabditis elegans. The forkhead transcription factor DAF-16 has previously been linked to these effects. However, by using a daf-16(mgDf50) mutant strain, we show that quercetin exposure leads to increased mean lifespans up to 15%. Furthermore, quercetin-treated daf-16(mgDf50) worms show an enhanced resistance to thermal and oxidative stress. Our data reveal that DAF-16 is not obligatorily required for quercetin-mediated longevity and stress resistance.

Mech Ageing Dev. 2008 Oct;129(10):611-3

Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study.

Flavonoids are polyphenolic antioxidants naturally present in vegetables, fruits, and beverages such as tea and wine. In vitro, flavonoids inhibit oxidation of low-density lipoprotein and reduce thrombotic tendency, but their effects on atherosclerotic complications in human beings are unknown. We measured the content in various foods of the flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin. We then assessed the flavonoid intake of 805 men aged 65-84 years in 1985 by a cross-check dietary history; the men were then followed up for 5 years. Mean baseline flavonoid intake was 25.9 mg daily. The major sources of intake were tea (61%), onions (13%), and apples (10%). Between 1985 and 1990, 43 men died of coronary heart disease. Fatal or non-fatal myocardial infarction occurred in 38 of 693 men with no history of myocardial infarction at baseline. Flavonoid intake (analysed in tertiles) was significantly inversely associated with mortality from coronary heart disease (p for trend = 0.015) and showed an inverse relation with incidence of myocardial infarction, which was of borderline significance (p for trend = 0.08). The relative risk of coronary heart disease mortality in the highest versus the lowest tertile of flavonoid intake was 0.42 (95% CI 0.20-0.88). After adjustment for age, body-mass index, smoking, serum total and high-density-lipoprotein cholesterol, blood pressure, physical activity, coffee consumption, and intake of energy, vitamin C, vitamin E, beta-carotene, and dietary fibre, the risk was still significant (0.32 [0.15-0.71]). Intakes of tea, onions, and apples were also inversely related to coronary heart disease mortality, but these associations were weaker. Flavonoids in regularly consumed foods may reduce the risk of death from coronary heart disease in elderly men.

Lancet. 1993 Oct 23;342(8878):1007-11

Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.

Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.

J Nutr. 2012 Jun;142(6):1026-32

Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study.

Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25-65 years with metabolic syndrome traits. Subjects were randomised to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period. Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l (P < 0.001) during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2.6 mmHg (P < 0.01) in the entire study group, by 2.9 mmHg (P < 0.01) in the subgroup of hypertensive subjects and by 3.7 mmHg (P < 0.001) in the subgroup of younger adults aged 25-50 years. Quercetin decreased serum HDL-cholesterol concentrations (P < 0.001), while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL, but did not affect TNF-alpha and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematology and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.

Br J Nutr. 2009 Oct;102(7):1065-74

The effects of quercetin on antioxidant status and tumor markers in the lung and serum of mice treated with benzo(a)pyrene.

Chemoprevention has emerged as a very effective preventive measure against carcinogenesis. Several bioactive compounds present in fruits and vegetables have revealed their cancer curative potential on benzo(a)pyrene (B(a)P) induced carcinogenesis. In the present study, the efficacy of quercetin on the level of lipid peroxides, activities of antioxidant enzymes and tumor marker enzymes in B(a)P induced experimental lung carcinogenesis in Swiss albino mice was assessed. In lung cancer bearing animals there was an increase in lung weight, lipid peroxidation and marker enzymes such as aryl hydrocarbon hydroxylase, gamma glutamyl transpeptidase, 5'-nucleotidase, lactate dehydrogenase and adenosine deaminase with subsequent decrease in body weight and antioxidant enzymes-superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, reduced glutathione, vitamin E and vitamin C. Quercetin supplementation (25 mg/kg body weight) attenuated all these alterations, which indicates the anticancer effect that was further confirmed by histopathological analysis. Overall, the above data shows that the anticancer effect of quercetin is more pronounced when used as an chemopreventive agent rather than as a chemotherapeutic agent against B(a)P induced lung carcinogenesis.

Biol Pharm Bull. 2007 Dec;30(12):2268-73

Dietary quercetin intake and risk of gastric cancer: results from a population-based study in Sweden.

BACKGROUND: To study the impact of the dietary antioxidant quercetin on risk of gastric adenocarcinoma. PATIENTS AND METHODS: Using data from a large Swedish population-based case-control study of gastric cancer (505 cases and 1116 controls), we studied the association between quercetin and risk of anatomic (cardia/noncardia) and histological (intestinal and diffuse) subtypes of gastric cancer. RESULTS: We found strong inverse associations between quercetin and the risk of noncardia gastric adenocarcinoma, with an adjusted odds ratio (OR) of 0.57 (95% confidence interval 0.40-0.83) for the highest quintile (≥11.9 mg) of daily quercetin intake relative to the lowest quintile of intake (<4 mg quercetin/day), supported by a significant decreasing linear trend (P value < 0.001). Similar findings were observed for the intestinal and diffuse subtype. For cardia cancer, we found a less evident and nonsignificant inverse relationship. The protection of quercetin appeared to be stronger among female smokers, with the OR leveled of at values <0.2 in quintiles 3-5 (>6 mg quercetin/day). CONCLUSIONS: High dietary quercetin intake is inversely related to the risk of noncardia gastric adenocarcinoma, and the protection appears to be particularly strong for women exposed to oxidative stress, such as tobacco smoking.

Ann Oncol. 2011 Feb;22(2):438-43

Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans.

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell "stabilizer", is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD(2). Que and cromolyn also inhibit histamine, leukotrienes and PGD(2) from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.

PLoS One. 2012;7(3):e33805

Quercetin inhibits rhinovirus replication in vitro and in vivo.

Rhinovirus (RV), which is responsible for the majority of common colds, also causes exacerbations in patients with asthma and chronic obstructive pulmonary disease. So far, there are no drugs available for treatment of rhinovirus infection. We examined the effect of quercetin, a plant flavanol on RV infection in vitro and in vivo. Pretreatment of airway epithelial cells with quercetin decreased Akt phosphosphorylation, viral endocytosis and IL-8 responses. Addition of quercetin 6h after RV infection (after viral endocytosis) reduced viral load, IL-8 and IFN responses in airway epithelial cells. This was associated with decreased levels of negative and positive strand viral RNA, and RV capsid protein, abrogation of RV-induced eIF4GI cleavage and increased phosphorylation of eIF2α. In mice infected with RV, quercetin treatment decreased viral replication as well as expression of chemokines and cytokines. Quercetin treatment also attenuated RV-induced airway cholinergic hyperresponsiveness. Together, our results suggest that quercetin inhibits RV endocytosis and replication in airway epithelial cells at multiple stages of the RV life cycle. Quercetin also decreases expression of pro-inflammatory cytokines and improves lung function in RV-infected mice. Based on these observations, further studies examining the potential benefits of quercetin in the prevention and treatment of RV infection are warranted.

Antiviral Res. 2012 Mar 23

Role of melatonin in metabolic regulation.

Although the human genome has remained unchanged over the last 10,000 years, our lifestyle has become progressively more divergent from those of our ancient ancestors. This maladaptive change became apparent with the Industrial Revolution and has been accelerating in recent decades. Socially, we are people of the 21st century, but genetically we remain similar to our early ancestors. In conjunction with this discordance between our ancient, genetically-determined biology and the nutritional, cultural and activity patterns in contemporary Western populations, many diseases have emerged. Only a century ago infectious disease was a major cause of mortality, whereas today non-infectious chronic diseases are the greatest cause of death in the world. Epidemics of metabolic diseases (e.g., cardiovascular diseases, type 2 diabetes, obesity, metabolic syndrome and certain cancers) have become major contributors to the burden of poor health and they are presently emerging or accelerating, in most developing countries. One major lifestyle consequence is light at night and subsequent disrupted circadian rhythms commonly referred to as circadian disruption or chronodisruption. Mounting evidence reveals that particularly melatonin rhythmicity has crucial roles in a variety of metabolic functions as an anti-oxidant, anti-inflammatory chronobiotic and possibly as an epigenetic regulator. This paper provides a brief outline about metabolic dysregulation in conjunction with a disrupted melatonin rhythm.

Rev Endocr Metab Disord. 2009 Dec;10(4):261-70

Melatonin combats molecular terrorism at the mitochondrial level.

The intracellular environmental is a hostile one. Free radicals and related oxygen and nitrogen-based oxidizing agents persistently pulverize and damage molecules in the vicinity of where they are formed. The mitochondria especially are subjected to frequent and abundant oxidative abuse. The carnage that is left in the wake of these oxygen and nitrogen-related reactants is referred to as oxidative damage or oxidative stress. When mitochondrial electron transport complex inhibitors are used, e.g., rotenone, 1-methyl-1-phenyl-1,2,3,6-tetrahydropyridine, 3-nitropropionic acid or cyanide, pandemonium breaks loose within mitochondria as electron leakage leads to the generation of massive amounts of free radicals and related toxicants. The resulting oxidative stress initiates a series of events that leads to cellular apoptosis. To alleviate mitochondrial destruction and the associated cellular implosion, the cell has at its disposal a variety of free radical scavengers and antioxidants. Among these are melatonin and its metabolites. While melatonin stimulates several antioxidative enzymes it, as well as its metabolites (cyclic 3-hydroxymelatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine and N(1)-acetyl-5-methoxykynu-ramine), likewise effectively neutralize free radicals. The resulting cascade of reactions greatly magnifies melatonin's efficacy in reducing oxidative stress and apoptosis even in the presence of mitochondrial electron transport inhibitors. The actions of melatonin at the mitochondrial level are a consequence of melatonin and/or any of its metabolites. Thus, the molecular terrorism meted out by reactive oxygen and nitrogen species is held in check by melatonin and its derivatives.

Interdiscip Toxicol. 2008 Sep;1(2):137-49

Therapeutic actions of melatonin in cancer: possible mechanisms.

Melatonin is a phylogenetically well-preserved molecule with diverse physiological functions. In addition to its well-known regulatory control of the sleep/wake cycle, as well as circadian rhythms generally, melatonin is involved in immunomodulation, hematopoiesis, and antioxidative processes. Recent human and animal studies have now shown that melatonin also has important oncostatic properties. Both at physiological and pharmacological doses melatonin exerts growth inhibitory effects on breast cancer cell lines. In hepatomas, through its activation of MT1 and MT2 receptors, melatonin inhibits linoleic acid uptake, thereby preventing the formation of the mitogenic metabolite 1,3-hydroxyoctadecadienoic acid. In animal model studies, melatonin has been shown to have preventative action against nitrosodiethylamine (NDEA)-induced liver cancer. Melatonin also inhibits the growth of prostate tumors via activation of MT1 receptors thereby inducing translocation of the androgen receptor to the cytoplasm and inhibition of the effect of endogenous androgens. There is abundant evidence indicating that melatonin is involved in preventing tumor initiation, promotion, and progression. The anticarcinogenic effect of melatonin on neoplastic cells relies on its antioxidant, immunostimulating, and apoptotic properties. Melatonin's oncostatic actions include the direct augmentation of natural killer (NK) cell activity, which increases immunosurveillance, as well as the stimulation of cytokine production, for example, of interleukin (IL)-2, IL-6, IL-12, and interferon (IFN)-gamma. In addition to its direct oncostatic action, melatonin protects hematopoietic precursors from the toxic effect of anticancer chemotherapeutic drugs. Melatonin secretion is impaired in patients suffering from breast cancer, endometrial cancer, or colorectal cancer. The increased incidence of breast cancer and colorectal cancer seen in nurses and other night shift workers suggests a possible link between diminished secretion of melatonin and increased exposure to light during nighttime. The physiological surge of melatonin at night is thus considered a "natural restraint" on tumor initiation, promotion, and progression.

Integr Cancer Ther. 2008 Sep;7(3):189-203

Anti-angiogenic activity of melatonin in advanced cancer patients.

OBJECTIVES: The anticancer activity of the indole melatonin has been explained to be due to its immunomodulatory, anti-prolferative and anti-oxidant effects, whereas at present no data are available about its possible influence on the angiogenesis, which has been shown to be one of the main biological mechanisms responsible for tumor dissemination. Vascular endothelial growth factor (VEGF) is the most active angiogenic factor, and the evidence of abnormally high blood levels or VEGF has been proven to be associated with poor prognosis in cancer patients. To investigate the influence of melatonin on angiogenesis, in this preliminary study we have evaluated the effects of melatonin therapy on VEGF blood levels in advanced cancer patients. MATERIAL & METHODS: The study included 20 metastatic patients, who progressed on previous conventional antitumor therapies and for whom no other effective treatment was available. Melatonin was given orally at 20 mg/day in the evening for at least 2 months. Serum levels of VEGF were measured by an enzyme immunoassay on venous blood samples collected at 15-day intervals. RESULTS: The clinical response consisted of minor response (MR) in 2, stable disease (SD) in 6 and progressive disease (PD) in the remaining 12 patients. VEGF mean levels decreased on therapy, without, however, statistical differences with respect to the pre-treatment values. In contrast, by evaluating changes in VEGF levels in relation to the clinical response, non-progressing patients (MR + SD) showed a significant decline in VEGF mean concentrations, whereas no effect was achieved in progressing patients. CONCLUSIONS: This study, by showing that melatonin-induced control or the neoplastic growth is associated with a decline in VEGF secretion, would suggest that the pineal hormone may control tumor growth at least in part by acting as a natural anti-angiogenic molecule, with a following opposition or angiogenesis-dependent cancer proliferation.

Neuro Endocrinol Lett. 2001;22(1):45-7

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