Life Extension Magazine®

Issue: Mar 2019

Olive Oil, Quercetin, Pain Relief, and Vitamin C

Extra virgin olive oil blunts post-prandial oxidative stress via NOX2 down-regulation.

OBJECTIVE: Olive oil protects against cardiovascular disease but the underlying mechanism is still unclear. We speculated that olive oil could inhibit oxidative stress, which is believed to be implicated in the atherosclerotic process. METHODS AND RESULTS: Post-prandial oxidative stress and endothelial dysfunction were investigated in twenty-five healthy subjects who were randomly allocated in a cross-over design to a Mediterranean diet added with or without extra virgin olive oil (EVOO, 10 g) (first study, n = 25) or Mediterranean diet with EVOO (10 g) or corn oil (10 g) (second study, n = 25). Oxidative stress biomarkers including platelet reactive oxidant species (ROS) and 8-iso-PGF2a-III, activity of NOX2, the catalytic sub-unit of NADPH oxidase, as assessed in platelets and serum, serum vitamin E and endothelial dysfunction, were measured before and 2 h after lunch. In the first study a significant increase of platelet ROS, 8-iso-PGF2a-III, NOX2 activity, sE-selectin, sVCAM1 and a decrease of serum vitamin E were detected in controls but not when EVOO was included in the Mediterranean diet; oxidative stress and endothelial dysfunction increase were also observed in the second study in subjects given corn oil. A significant correlation was found between NOX2 activity and platelet oxidative stress. In vitro study demonstrated that EVOO but not corn oil significantly decreased platelet and PMNs oxidative stress and NOX2 activity. CONCLUSION: The study provides the first evidence that post-prandial oxidative stress may be triggered by NOX2 up-regulation. EVOO but not corn oil, is able to counteract such phenomenon suggesting that addition of EVOO to a Mediterranean diet protects against post-prandial oxidative stress.

Atherosclerosis. 2014 Aug;235(2):649-58.

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

Oleuropein, a component of extra virgin olive oil, lowers postprandial glycaemia in healthy subjects.

AIMS: Extra virgin olive oil lowers postprandial glycaemia. We investigated if oleuropein, a component of extra virgin olive oil, exerts a similar effect on postprandial glycaemia and the underlying mechanism. METHODS: Twenty healthy subjects were randomly allocated in a cross-over design to 20 mg oleuropein or placebo immediately before lunch. Postprandial glycaemia along with blood insulin, dipeptidyl-peptidase-4 (DPP-4) and glucagon-like peptide-1 and oxidative stress, which included soluble NADPH oxidase-derived peptide activity (sNox2-dp), 8-iso-prostaglandin-2a and platelet p47phox phosphorylation, were analysed before and 2 h after meal. RESULTS: After 2 h, subjects who assumed oleuropein had significantly lower blood glucose, DPP-4 activity and higher insulin and glucagon-like peptide-1 compared to placebo. Furthermore, sNox2-dp, 8-iso-PGF2a and platelet p47phox phosphorylation were significantly lower in oleuropein- compared to placebo-treated subjects. DPP-4 significantly correlated with sNox2-dp [Spearman’s rho (Rs) = 0.615; P < 0.001], p47phox phosphorylation (Rs = 0.435; P < 0.05) and 8-iso- prostaglandin-2a (Rs = 0.33; P < 0.05). In vitro study demonstrated that hydroxytyrosol, a metabolite of oleuropein, significantly reduced p47phox phosphorylation and isoprostane formation. CONCLUSIONS: These findings indicate that oleuropein improves postprandial glycaemic profile via hampering Nox2-derived oxidative stress.

Br J Clin Pharmacol. 2018 Jul;84(7):1566-1574.

Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease.

OBJECTIVES: The objective of this study was to evaluate the relation between apolipoprotein A-IV (apoA-IV) plasma concentrations and coronary artery disease (CAD). BACKGROUND: Experimental in vitro and in vivo studies favor apoA-IV to be protective against the development of atherosclerosis. Mice that overexpress either human or mouse apoA-IV demonstrated a significant reduction of aortic atherosclerotic lesions compared with control mice. Data on apoA-IV plasma concentrations and CAD in humans are lacking. METHODS: We determined in two independent case-control studies of a Caucasian and an Asian Indian population whether apoA-IV plasma concentrations are related to the presence of angiographically assessed CAD. RESULTS: Plasma apoA-IV levels were significantly lower in 114 male Caucasian subjects with angiographically defined CAD when compared with 114 age-adjusted male controls (10.2 +/-3.8 mg/dL vs. 15.1 +/- 4.0 mg/dL, p < 0.001). Logistic regression analysis indicated that the association between apoA-IV levels and CAD was independent of the high-density lipoprotein cholesterol and triglyceride concentrations. The inverse relationship between plasma levels of apoA-IV and the presence of CAD was confirmed in an independent sample of 68 male Asian Indians with angiographically documented CAD and 68 age-matched controls. CONCLUSIONS: The results of this cross-sectional study demonstrate for the first time an association between low apoA-IV concentrations and CAD in humans and suggest that apoA-IV may play an antiatherogenic role in humans.

J Am Coll Cardiol. 2000 Sep;36(3):751-7.

Postprandial glucose and NF-κB responses are regulated differently by monounsaturated fatty acid and dietary fiber in impaired fasting glucose subjects.

Recently, much attention has been paid to observational studies that have linked postprandial glycemic response with the risk of cardiovascular disease. In this study, we investigated whether the nutrient composition of dietary formula might affect the postprandial inflammation in impaired fasting glucose (IFG) subjects. Eight subjects underwent three trials in a double-blind, randomized, crossover study with a 1-week washout period. The subjects were given three formulas according to serving size: (1) high-fiber formula (FF); (2) high-monounsaturated fatty acid formula (MF); and (3) control formula (CF). The area under the curves (AUCs) for glucose decreased 0.65- and 0.54-fold in the FF and MF trials, respectively, when compared with CF. A similar pattern was observed for the postprandial insulin response. However, as observed by the phosphorylation of proteolytic degradation product IκB, the AUC for activation of nuclear transcription factor κB (NF-κB) in peripheral blood mononuclear cells was significantly decreased in the FF trial, but not with MF (P=.0114). These findings demonstrated that postprandial glucose and inflammatory responses might be regulated differently by the nutrient composition of dietary formulas in IFG subjects.

J Med Food. 2013 Dec;16(12):1168-71.

The postprandial situation as a pro-inflammatory condition.

Postprandial lipemia has been associated with cardiovascular disease. The current pathophysiological concept is that postprandial remnant lipoproteins migrate into the subendothelial space and that remnants activate circulating leukocytes and endothelial cells. Activated monocytes adhere to endothelial adhesion molecules, facilitating subendothelial migration of monocytes. These cells differentiate into macrophages, with the risk of foam cell formation, due to uptake of remnants and modified lipoproteins. Evidence is emerging that specific interventions may reduce the atherogenic postprandial inflammation. Fruits rich in polyphenols, virgin olive oil, carotenoids and exercise have recently been found to reduce postprandial inflammation. Pharmaceutical interventions with fibrates or statins not only improve the overall lipid profile, but reduce postprandial inflammation as well. This review will deal with the current concept of postprandial inflammation in relation to the development of atherosclerosis and potential interventions to reduce postprandial inflammation.

Clin Investig Arterioscler. 2014 Jul-Aug;26(4):184-92.

High-fat meal induced postprandial inflammation.

Raised levels of circulating inflammatory markers are associated with coronary artery disease, obesity and type II diabetes. It has been proposed that the ingestion of high-fat meals may serve as a stimulus to raise systemic inflammatory tone, although interventional studies have yielded conflicting results. We here review 57 studies of high-fat meal induced acute postprandial inflammation to identify the most frequently reported markers of postprandial inflammation and to compare these results with the highly consistent low-grade endotoxaemia model in man. Most plasma-borne markers of inflammation, such as cytokines and soluble adhesion molecules, were not consistently raised after a high-fat meal. However, pro-inflammatory leukocyte surface markers, mRNA and proteins were elevated in almost all studies in which they were measured. These markers followed kinetics similar to those observed following intravenous injection of low doses of endotoxin in man, were positively associated with likelihood of contamination of test meals with pro-inflammatory bacterial molecules and were reduced in several studies examining parallel meals supplemented with foodstuffs containing anti-inflammatory phytochemicals. Future studies of postprandial inflammation may yield more consistent evidence by focusing on leukocyte, rather than plasma-borne, markers of inflammation and by considering the test meal content of pro- and anti-inflammatory dietary constituents.

Mol Nutr Food Res. 2014 Jan;58(1):136-46.

The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors.

BACKGROUND: Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (~9 AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise. METHODOLOGY/PRINCIPAL FINDINGS: We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6-17% peak-trough amplitudes; p ≤ 0.01). These circadian peaks occurred at a circadian phase corresponding to 8-9 AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3-8 PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors. CONCLUSIONS/SIGNIFICANCE: These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans--independent of the sleep/wake cycle, other behavioral influences and the environment. The 9 AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.

PLoS One. 2011;6(9):e24549.

Accelerated atherosclerosis in apolipoprotein E-deficient mice fed Western diets containing palm oil compared with extra virgin olive oils: a role for small, dense high-density lipoproteins.

To test the hypothesis that extra virgin olive oils from different cultivars added to Western diets might behave differently than palm oil in the development of atherosclerosis, apoE-deficient mice were fed diets containing different cultivars of olive oil for 10 weeks. Female mice were assigned randomly to one of the following five groups: (1-4) fed chow diets supplemented with 0.15% (w/w) cholesterol and 20% (w/w) extra virgin olive oil from the Arbequina, Picual, Cornicabra, or Empeltre cultivars, and (5) fed a chow diet supplemented with 0.15% cholesterol and 20% palm oil. Compared to diets containing palm oil, a Western diet supplemented with one of several varieties of extra virgin olive oil decreased atherosclerosis lesions, reduced plaque size, and decreased macrophage recruitment. Unexpectedly, total plasma paraoxonase activity, apoA-I, plasma triglycerides, and cholesterol played minor roles in the regulation of differential aortic lesion development. Extra virgin olive oil induced a cholesterol-poor, apoA-IV-enriched lipoparticle that has enhanced arylesterase and antioxidant activities, which is closely associated with reductions in atherosclerotic lesions. Given the anti-atherogenic properties of extra virgin olive oil evident in animal models fed a Western diet, clinical trials are needed to establish whether these oils are a safe and effective means of treating atherosclerosis.

Atherosclerosis. 2007 Oct;194(2):372-82.

Dietary mono- and polyunsaturated fatty acids similarly increase plasma apolipoprotein A-IV concentrations in healthy men and women.

We investigated the effect of dietary fatty acid composition on plasma apolipoprotein (apo) A-IV concentrations. Plasma apo A-IV concentrations were measured by ELISA in plasma of 48 healthy men and women in a controlled dietary study. First, all participants consumed a 2-wk baseline diet rich in saturated fatty acids (SFA). Then, they were randomly assigned to one of three dietary treatments, which contained refined olive oil [rich in monounsaturated fatty acids (MUFA), n = 17], rapeseed oil [rich in MUFA and alpha-linolenic acid [18:3(n-3)], n = 13], or sunflower oil [rich in (n-6) PUFA, n = 18] as the principal source of fat for 4 wk. The plasma concentrations of apo A-IV increased when subjects consumed the diets rich in unsaturated fatty acids, by 16% or 13.0 mg/L [F((2,76)) = 12.874, P < 0.001 by repeated-measures ANOVA]. The increase was not affected by diet group affiliation, gender or apo A-IV genotype. In conclusion, diets rich in unsaturated fatty acids, independent of the degree of unsaturation, gender and apo A-IV genotype, increase plasma apo A-IV concentrations compared with a baseline diet rich in SFA in healthy men and women.

J Nutr. 2003 Jun;133(6):1821-5.

A score of low-grade inflammation and risk of mortality: prospective findings from the Moli-sani study.

Low-grade inflammation is associated with an increased risk of chronic degenerative disease, but its relationship with mortality is less well explored. We aimed at evaluating, at a large epidemiological level, the possible association of low-grade inflammation, as measured by a composite score, with overall mortality risk. We conducted a population-based prospective investigation on 20,337 adult subjects free from major hematological disease and acute inflammatory status, randomly recruited from the general population of the Moli-sani study. A low-grade inflammation score was obtained from the sum of 10-tiles of plasmatic (C-reactive protein) and cellular (leukocyte and platelet counts, granulocyte/lymphocyte ratio) biomarkers of low-grade inflammation; higher levels indicated increased low-grade inflammation. Hazard ratios were calculated using multivariable Cox proportional hazard models with 95% confidence intervals. At the end of follow-up (median 7.6 years), 837 all-cause deaths were recorded. As compared to subjects in the lowest quartile of the low-grade inflammation score, those in the highest category had a significantly increased risk in overall mortality (HR=1.44; 1.17-1.77), independently of possible confounders, including the presence of chronic diseases and a number of health-related behaviors. The magnitude of the association of low-grade inflammation with mortality was relatively higher in type 2 diabetic patients (HR=2.90; 1.74-4.84) and in individuals with a history of cardiovascular disease (HR=2.48; 1.50-4.11) as compared to their counterparts who were free from the disease. In conclusion, an elevated degree of low-grade inflammation, as measured by a composite score of inflammatory biomarkers, is an independent risk factor for total mortality in an apparently healthy adult general population.

Haematologica. 2016 Nov;101(11):1434-1441.

DNA damage response and metabolic disease.

Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have suggested that the DNA damage response is involved in regulation of metabolic homeostasis. DNA damage could impair metabolic organ functions by causing cell death or senescence. DNA damage also could induce tissue inflammation that disturbs the homeostasis of systemic metabolism. Various roles of molecules related to DNA repair in cellular metabolism are being uncovered, and such molecules could also have an impact on systemic metabolism. This review explores mechanisms by which the DNA damage response could contribute to metabolic dysfunction.

Cell Metab. 2014 Dec 2;20(6):967-77.

Osteoporosis, inflammation and aging.

Osteoporosis is a condition characterized by low bone mass and increased bone fragility, putting patients at risk of fractures, which are major causes of morbidity substantially in older people. Osteoporosis is currently attributed to various endocrine, metabolic and mechanical factors. However, emerging clinical and molecular evidence suggests that inflammation also exerts significant influence on bone turnover, inducing osteoporosis. Numerous proinflammatory cytokines have been implicated in the regulation of osteoblasts and osteoclasts, and a shift towards an activated immune profile has been hypothesized as important risk factor. Chronic inflammation and the immune system remodelling characteristic of ageing, as well as of other pathological conditions commonly associated with osteoporosis, may be determinant pathogenetic factors. The present article will review the current perspectives on the interaction between bone and immune system in the elderly, providing an interpretation of osteoporosis in the light of inflamm-ageing.

Immun Ageing. 2005 Nov 4;2:14.

Antiobesity efficacy of quercetin-rich Supplement on diet-induced obese rats: effects on body composition, serum lipid profile, and gene expression.

The antiobesity effects of quercetin-rich supplement (QRS), which contain quercetin, lycopene, taurine, and litchi flower extract, on a high-fat diet (HFD)-induced obese rats were investigated. The rats that consume HFD with QRS (185 mg/kg rat) have significantly modulated the final body weights [490 ± 11 (HFD) ® 441 ± 11 (HFD+QRS) g], total body fat [112.9 ± 4.5 (HFD) ® 86.6 ± 5.7 (HFD+QRS) g], liver weights [14.8 ± 0.4 (HFD) ® 12.6 ± 0.4 (HFD+QRS) g/rat], and the serum TG [102.5 ± 7.3 (HFD) ® 90.7 ± 6.5 (HFD+QRS) mg/dL] to a level that resembled the regular diet-consumed rats (p < 0.05). The excretion of lipid in the faeces augmented in QRS groups as compared with the nonsupplemented HFD group [faecal total lipid: 62.43 ± 2.80 (HFD) ® 73.15 ± 0.88 (HFD+QRS) mg/g dried faeces, p < 0.05]. In the histological analysis, quercetin-rich formulation supplemented groups presented a much less lipid accumulation and smaller size of adipocytes. Moreover, a decreased serum thiobarbituric acid reactive substances [1.55 ± 0.17 (HFD) ® 0.78 ± 0.04 (HFD+QRS) nmol MDA eq/mL serum] increased levels of serum Trolox equivalent antioxidant capacity [3.89 ± 0.08 (HFD) ® 6.46 ± 0.20 (HFD+QRS) µmol/mL serum], and more active hepatic antioxidant enzymes were observed in the supplemented groups (p < 0.05). The result of this work is a good demonstration of how a combination of bioactive compounds could work synergistically and become very effective in disease prevention.

J Agric Food Chem. 2018 Jan 10;66(1):70-80.

Adipose tissue and adipokines—energy regulation from the human perspective.

There has been a rapid rise in the incidence of obesity, primarily as a result of changes in lifestyle (diet and activity levels). Obesity has provided considerable impetus for the investigation of the fundamental mechanisms involved in the regulation of energy balance. Important developments include the identification of novel factors involved in the control of appetite, such as ghrelin, orexin A, and the endogenous cannabinoids, and the emergence of the concept of “nonexercise activity thermogenesis” (NEAT) provided new perspectives on energy expenditure. Studies on white adipose tissue have led to the recognition that it is an important endocrine organ, communicating with the brain and peripheral tissues through the secretion of leptin and other adipokines. There is a rapidly expanding list of protein factors released by white adipose tissue, including the key hormone, adiponectin. Of particular note is the range of cytokines, chemokines, and other inflammation-related proteins secreted by white fat as tissue mass rises; indeed, obesity is characterized by chronic mild inflammation. The adipokines provide an extensive network of communication both within adipose tissue and with other organs, and some are implicated directly in the pathologies associated with obesity, particularly the metabolic syndrome. Although the focus remains very much on obesity in humans, the disorder and its sequelae are also a growing concern in companion animals.

J Nutr. 2006 Jul;136(7 Suppl):1935S-1939S.

Circulating soluble IL-6 receptor concentration and visceral adipocyte size are related to insulin resistance in Taiwanese adults with morbid obesity.

BACKGROUND: Morbid obesity is related to chronic inflammation and many metabolic complications. Interleukin (IL)-6 plays a pivotal pathophysiological role in obesity, and IL-6 trans-signaling through the soluble IL-6 receptor (sIL-6R) has a major proinflammatory effect. The aim of this study was to investigate the association between sIL-6R, adipocyte size, and insulin resistance in morbidly obese individuals. METHODS: We measured concentrations of sIL-6R, high-sensitivity C-reactive protein, and lipid parameters and estimated homeostasis model assessment of insulin resistance (HOMA-IR) before the patients underwent bariatric surgery. Mesenteric adipose tissue was collected during surgery, and adipocyte size and concentrations of membrane-bound IL-6 receptor (mIL-6R) were evaluated. In total, 35 adults (20 men and 15 women) were recruited. RESULTS: The subjects with high HOMA-IR (≥2.4) had higher fasting glucose/insulin, triglycerides, sIL-6R, and adipocyte size and lower high-density lipoprotein cholesterol and mIL-6R than those with low HOMA-IR (<2.4). Adipocyte size positively correlated with sIL-6R (r = 0.559, P = 0.001) and HOMA-IR (r = 0.773, P ≤ 0.001) independent of age, gender, body mass index (BMI), waist, and use of diabetic drugs. In addition, every 1 ng/mL increase in sIL-6R concentration corresponded to a 10.2% decrease in the likelihood of maintaining lower insulin resistance. Furthermore, an sIL-6R level of 77.45 ng/mL was a reasonable cutoff level to propose lower insulin resistance in morbidly obese subjects. CONCLUSIONS: Circulating sIL-6R is more closely associated with insulin resistance status than waist-to-hip ratio or BMI in morbidly obese Taiwanese adults. sIL-6R may be a useful biomarker to assess insulin resistance among morbidly obese subjects.

Metab Syndr Relat Disord. 2017 May;15(4):187-193.

Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy.

Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments.

Br J Clin Pharmacol. 2016 Oct;82(4):932-42.

Palmitoylethanolamide, a special food for medical purposes, in the treatment of chronic pain: a pooled data meta-analysis.

BACKGROUND: A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors. OBJECTIVE: The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain. STUDY DESIGN: Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials. METHODS: Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators. RESULTS: Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score = 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain. LIMITATIONS: Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies. CONCLUSION: These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.

Pain Physician. 2016 Feb;19(2):11-24.

Use of palmitoylethanolamide in the entrapment neuropathy of the median in the wrist.

AIM: Carpal tunnel syndrome (CTS) is a medical condition in which the median nerve is compressed, leading to discomfort and pain. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, able to modulate inflammatory cell reactivity and pain. This study deals with the capability of PEA to normalize the electroneurographic alterations associated with moderate CTS. METHODS: Patients displaying moderate CTS were enrolled and daily PEA (600 mg or 1,200 mg/die) was administered for 30 days. Control group received no treatment. RESULTS: PEA treatment significantly improved the CTS-induced reduction of median nerve latency time (P<0.0004); PEA effect was dose-dependent. Tinel’s sign presence and symptoms of discomfort were also reduced. CONCLUSION: Although further studies are needed to better characterize PEA’s effect, the present report represents the first evidence on the improvement of distal motor latency elicited by PEA in patients with moderate CTS. The data support the hypothesis of protection against inflammatory and neuropathic pain by PEA.

Minerva Med. 2011 Apr;102(2):141-7.

Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data.

Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs).Design Systematic review followed by a one stage bayesian individual patient data meta-analysis.Data sources Studies from Canadian and European healthcare databases. Review methods Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. Exposure and outcomes Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction.Results A cohort of 44,6 763 individuals including 6,1 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations.Conclusions: All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.

BMJ. 2017 May 9;357:j1909.

Use of nonsteroidal anti-inflammatory drugs and risk of chronic kidney disease in subjects with hypertension: nationwide longitudinal cohort study.

Limited studies have examined the effects of nonsteroidal anti-inflammatory drug (NSAID) use on the risk of chronic kidney disease (CKD), especially in subjects with hypertension. Using National Health Insurance claims data in Taiwan, we conducted a propensity score-matched cohort study to investigate the relationship between NSAID use and CKD in subjects with hypertension. A total of 3,1976 subjects were included in this study: subjects not taking any NSAIDs in 2007 (n=10,782); subjects taking NSAIDs for 1 to 89 days in 2007 (n=10,605); and subjects taking NSAIDs for ≥90 days in 2007 (n=10589). We performed multivariable proportional hazard models to determine the relationship between NSAID use and CKD. The results showed that NSAID use was associated with a 1.18-fold increased risk of CKD in subjects taking NSAIDs for 1 to 89 days; and a 1.32-fold increased risk of CKD in hypertension subjects taking NSAIDs for ≥90 days, compared with subjects not taking any NSAIDs, after controlling for the confounding factors. In subgroup analyses, subjects taking NSAIDs for ≥90 days, >1 defined daily dose per day or taking NSAIDs >15 cumulative defined daily doses had a greater risk of CKD than subjects not taking any NSAID, but not for congestive heart failure, stroke, cancer, osteoarthritis, or rheumatoid arthritis. These results provide supportive evidence that NSAID use is associated with increased risk of CKD in subjects with hypertension. It is important to closely monitor the effects of NSAID use, particularly in patients with hypertension, a susceptible population for CKD.

Hypertension. 2015 Sep;66(3):524-33. doi

Harnessing the anti-inflammatory potential of palmitoylethanolamide.

Palmitoylethanolamide (PEA) is a peroxisome proliferator-activated receptor alpha (PPAR-a) ligand that exerts anti-inflammatory, analgesic and neuroprotective actions. PEA is synthetized from phospholipids through the sequential actions of N-acyltransferase and N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD), and its actions are terminated by its hydrolysis by two enzymes, fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolysing acid amidase (NAAA). Here, we review the impact of PEA administration in inflammatory and neurodegenerative settings and the differential role of FAAH and NAAA in controlling PEA levels. Recent studies with NAAA inhibitors put forth this enzyme as capable of increasing PEA levels in vivo in inflammatory processes, and identified it as an interesting target for drug discovery research. Thus, PEA hydrolysis inhibitors could constitute potential therapeutic alternatives in chronic inflammatory and neurodegenerative diseases.

Drug Discov Today. 2014 Oct;19(10):1632-9.

Palmitoylethanolamide in CNS health and disease.

The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-a dependent. First, an early molecular control, through Ca(+2)-activated intermediate- and/or big-conductance K(+) channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl(-) currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases.

Pharmacol Res. 2014 Aug;86:32-41.

Effect of palmitoylethanolamide on inflammatory and neuropathic pain in rats.

BACKGROUND: A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, plays an important role in the induction and maintenance of chronic pain. Palmitoylethanolamide (PEA), which is a type of N-acylethanolamide and a lipid, has an anti-inflammatory effect. Relative to the anti-inflammatory effect, little is known about its analgesic effect in chronic pain. This study aimed to determine whether PEA relieves chronic inflammatory and neuropathic pain. METHODS: Male Sprague-Dawley rats were injured by transection of the left L5 and L6 spinal nerves to induce neuropathic pain or were injected with monoiodoacetic acid into the synovial cavity of knee joints to induce inflammatory pain. To assess the degree of pain, two kinds of stimuli - pressing von Frey filaments and wetting with acetone - were applied to the plantar surface of the rat to measure mechanical and cold sensitivity, respectively. Pain was measured by assessing behavioral responses, including paw withdrawal response threshold and paw withdrawal frequency upon stimulation. RESULTS: Neuropathic pain caused by spinal nerve transection (SNT) decreased the mechanical threshold and increased the frequency of response to acetone application. But, cold allodynia caused by SNT did not decrease the withdrawal frequency. Mechanical hyperalgesia caused by chronic inflammation was significantly reduced by both intraperitoneal and intra-articular injections of PEA. CONCLUSIONS: These outcomes revealed that PEA might be effective in relieving inflammatory and neuropathic pain, especially pain induced by mechanical hyperalgesia, but not cold allodynia.

Korean J Anesthesiol. 2017 Oct;70(5):561-566.


Prediagnostic plasma vitamin C and risk of gastric adenocarcinoma and esophageal squamous cell carcinoma in a Chinese population.

BACKGROUND:  China has some of the highest incidence rates for gastric adenocarcinoma (GA) and esophageal squamous cell carcinoma (ESCC) in the world. Prospective studies suggested that vitamin C may reduce risks; however, associations are unclear because of limited sample size. OBJECTIVE: The objective was to examine the relation between prediagnostic plasma vitamin C and the risk of GA and ESCC. DESIGN: A case-cohort study was used to assess the association between prediagnostic plasma vitamin C and incidence of GA (n = 467) and ESCC (n = 618) in the General Population Nutrition Intervention Trial. With the use of multivariate Cox proportional hazards models, we estimated the HRs and 95% CIs. We also conducted a meta-analysis of the literature up to 1 October 2012 on the relation between circulating vitamin C and gastric cancer incidence. Two cohort studies and the current study were included to assess the body of evidence. RESULTS: For GA, each 20-µmol/L increase in plasma vitamin C was associated with a 14% decrease in risk (HR: 0.86; 95% CI: 0.76, 0.96). Compared with individuals with low plasma vitamin C concentrations (≤28 µmol/L), those with normal concentrations (>28 µmol/L) had a 27% reduced risk of GA (HR: 0.73; 95% CI: 0.56, 0.94). No association between vitamin C concentrations and ESCC was seen. Meta-analysis showed that the risk of incident GA among those with the highest concentration of plasma vitamin C was 31% lower (random-effects-pooled-odds ratio 0.69; 95% CI: 0.54, 0.89) than those in the lowest category. CONCLUSION: Our data provide evidence that higher circulating vitamin C was associated with a reduced risk of incident GA, but no association was seen for ESCC.

Am J Clin Nutr. 2013 Nov;98(5):1289-97.

Vitamin C intake and breast cancer mortality in a cohort of Swedish women.

BACKGROUND:  Vitamin C may influence cancer progression through its antioxidant properties. However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, and the safety of vitamin C supplements following breast cancer diagnosis has not been extensively studied. METHODS: Using a food-frequency questionnaire we investigated whether vitamin C intake was associated with survival among 3,405 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. RESULTS: From 1987-2010, there were 1,055 total deaths with 416 deaths from breast cancer. Women in the highest quartile of pre-diagnosis vitamin C intake had an adjusted HR (95% CI) of breast cancer death of 0.75 (0.57-0.99) compared with those in the lowest quartile (Ptrend=0.03). There was a borderline significant association between vitamin C intake and total mortality (HR=0.84; 95% CI=0.71-1.00; Ptrend=0.08). Among 717 breast cancer cases for whom post-diagnosis supplement use was available, there was no association between vitamin C supplement use (≈1,000 mg) and breast cancer-specific mortality (HR=1.06; 95% CI=0.52-2.17). CONCLUSION: Our findings suggest that dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. In addition, post-diagnosis vitamin C supplementation at the level observed in our population was not associated with survival.

Br J Cancer. 2013 Jul 9;109(1):257-64.

Vitamin C and immune function.

The immune system is strongly influenced by the intake of nutrients. For a long time there has been a controversy whether vitamin C can contribute to the prevention and therapy of the common cold. Several cells of the immune system can indeed accumulate vitamin C and need the vitamin to perform their task, especially phagocytes and t-cells. Thus a vitamin C deficiency results in a reduced resistance against certain pathogens whilst a higher supply enhances several immune system parameters. With regard to the common cold different studies including meta-analyses underline that the prophylactic intake of vitamin C may slightly reduce the duration of the illness in healthy persons but does not affect its incidence and severity. Supplementation of vitamin C is most effective in cases of physical strain or insufficient intake of the vitamin. With regard to the therapy of the common cold the application of vitamin C alone is without clinical effects.

Med Monatsschr Pharm. 2009 Feb;32(2):49-54; quiz 55-6.

Micronutrients at the interface between inflammation and infection—ascorbic acid and calciferol: part 1, general overview with a focus on ascorbic acid.

As elements of the antioxidant system, cofactors of enzymes, components of transcription factors, and epigenetic modulators, micronutrients, such as vitamins and trace elements, influence various metabolic processes that are directly associated with immune functions. Specifically, the vitamins C and D have been shown to have significance immune function. Therefore, the objective of this review is to elucidate interactions between micronutrients and the immune system. In the initial section of this review, we present a general overview of interactions between the immune system and micronutrients, with a focus on the immunobiologically relevant functions of vitamin C. Immune competent cells accumulate vitamin C against a concentration gradient, with a close relationship between vitamin C supply and immune cell activity, especially phagocytosis activity and T-cell function. Accordingly, one of the consequences of vitamin C deficiency is impaired resistance to various pathogens, while an enhanced supply increases antibody activity and infection resistance.

Inflamm Allergy Drug Targets. 2011 Feb;10(1):54-63

Neuroendocrine and viral correlates of premature immunosenescence.

Aging continuously remodels the immune system, a process known as immunosenescence. Here, we review evidence of premature immunosenescence in younger individuals under conditions of chronic psychological stress, chronic inflammation, or exposure to certain persistent viral infections. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis and increased cortisol levels. Chronic stress is associated with thymic involution, blunted T cell proliferation, increased serum proinflammatory markers, and shorter telomere lengths. Human cytomegalovirus (CMV) infection has been implicated in accelerating immunosenescence by shrinking the T cell receptor repertoire and causing clonal expansion of senescent CD8(+) CD28(-) T cells with a proinflammatory profile. These factors increase inflammation associated with aging, or “inflammaging,” particularly as it relates to etiology of several age-related diseases and increased mortality. Patients with rheumatoid arthritis have been shown to have several signatures of premature immunosenescence, including expansion of senescent T cells associated with cognitive impairment. We end by speculating that bipolar disorder can be considered as a model of accelerated aging because it has been associated with shortened telomeres, higher CMV IgG titers, and expansion of senescent and regulatory T cells.

Ann N Y Acad Sci. 2015 Sep;1351:11-21.

Antidepressant-like effects of ascorbic acid and ketamine involve modulation of GABAA and GABAB receptors.

BACKGROUND:  It has been suggested that dysregulation of g-aminobutyric acid (GABA)-mediated neurotransmission is involved in the etiology of major depressive disorder and in the action of the fast-acting antidepressant ketamine. Considering that recent evidence has suggested that ascorbic acid may exert an antidepressant-like effect through mechanisms similar to ketamine, this study evaluated the involvement of GABAA and GABAB receptors in the antidepressant-like effect of ascorbic acid, comparing the results with those obtained with ketamine. METHODS: To investigate the involvement of GABAA in the antidepressant-like effect of ascorbic acid and ketamine in the tail suspension test (TST), mice were treated with a sub-effective dose of ascorbic acid (0.1mg/kg, po), ketamine (0.1mg/kg, ip) or vehicle and 30minutes later, a sub-effective dose of muscimol (0.1mg/kg, ip, GABAA receptor agonist) or vehicle was administered. In another set of experiments, mice were treated with ascorbic acid (1mg/kg, po, active dose in the TST) or vehicle and 30minutes later, baclofen (1mg/kg, ip, GABAB receptor agonist) was administered. A similar experimental protocol was performed with ketamine (1mg/kg, ip). RESULTS: The administration of muscimol combined with ascorbic acid or ketamine produced a synergistic antidepressant-like effect in the TST. Moreover, the antidepressant-like effects of ascorbic acid and ketamine were abolished by baclofen. There was no alteration in spontaneous locomotion in any experimental group. CONCLUSIONS: Results indicate that the anti-immobility effect of ascorbic acid and ketamine in TST may involve an activation of GABAA receptors and a possible inhibition of GABAB receptors.

Pharmacol Rep. 2016 Oct;68(5):996-1001.

Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Current antidepressants used to treat pediatric patients have the disadvantage of limited efficacy and potentially serious side effects. The purpose of this study was to assess the efficacy of vitamin C as an adjuvant agent in the treatment of pediatric major depressive disorder in a six-month, double-blind, placebo-controlled pilot trial. METHODS: The study group (n=12) was given fluoxetine (10-20 mg/day) plus vitamin C (1,000 mg/day) and control group (n=12) administered fluoxetine (10-20 mg/day) plus placebo. The data were analyzed by ANOVA and t-test for independent samples. RESULTS: Both groups demonstrated significantly improved scores on the Children’s Depression Rating Scale (CDRS), the Children’s Depression Inventory (CDI), and the Clinical Global Impression (CGI). ANOVA was significantly different on all clinical measurements (group effect, time effect, and interaction), with the exception of group effect and interaction for CGI. Patients treated for six months with fluoxetine and vitamin C showed a significant decrease in depressive symptoms in comparison to the fluoxetine plus placebo group as measured by the CDRS (t=11.36, P<0.0001) and CDI (t=12.27, P<0.0001), but not CGI (t=0.13, P=0.90). No serious adverse effects were observed. CONCLUSIONS: These preliminary results suggest that vitamin C may be an effective adjuvant agent in the treatment of MDD in pediatric patients.

Nutr J. 2013 Mar 9;12:31.

Rapid change of superconductivity and electron-phonon coupling through critical doping in Bi-2212.

Electron-boson coupling plays a key role in superconductivity for many systems. However, in copper-based high-critical temperature (T c) superconductors, its relation to superconductivity remains controversial despite strong spectroscopic fingerprints. In this study, we used angle-resolved photoemission spectroscopy to find a pronounced correlation between the superconducting gap and the bosonic coupling strength near the Brillouin zone boundary in Bi2Sr2CaCu2O8+d The bosonic coupling strength rapidly increases from the overdoped Fermi liquid regime to the optimally doped strange metal, concomitant with the quadrupled superconducting gap and the doubled gap-to-T c ratio across the pseudogap boundary. This synchronized lattice and electronic response suggests that the effects of electronic interaction and the electron-phonon coupling (EPC) reinforce each other in a positive-feedback loop upon entering the strange-metal regime, which in turn drives a stronger superconductivity.

Science. 2018 Oct 5;362(6410):62-65.

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