Despite the reported prevalence of micronutrient deficiencies in older adults, it is not yet established whether multivitamin/multimineral (MV/MM) supplements improve blood micronutrient status in individuals over the age of 65. Therefore, a cohort of 35 healthy men (>67 years) was recruited for an MV/MM supplementation trial. The primary endpoint was, as an indicator of micronutrient status, changes in blood micronutrient biomarkers from baseline to at least six months of supplementation with MV/MM or placebo. The secondary endpoint was basal O2 consumption in monocytes as an indicator of cellular metabolism. MV/MM supplementation improved blood concentrations of pyridoxal phosphate, calcifediol, α-tocopherol, and β-carotene concentrations throughout the cohort. By contrast, those in the placebo group generally showed declines in blood vitamin concentrations and an increased prevalence of suboptimal vitamin status during the study period. On the other hand, MV/MM supplementation did not significantly affect blood mineral concentrations, i.e., calcium, copper, iron, magnesium, and zinc. Interestingly, MV/MM supplementation prevented the decline in monocyte O2 consumption rate. Overall, MV/MM use improves or prevents declines in vitamin, but not mineral, status and limits declines in cellular O2 consumption, which may have important implications for metabolism and immune health in healthy older men.

Human blood plasma contains an array of nonenzymatic low-molecular-weight antioxidants. These antioxidants can be classified into two groups: the water-soluble antioxidants present in the aqueous phase of plasma and the lipid-soluble antioxidants associated with lipoproteins. The relative importance of an individual antioxidant in a biological system, such as plasma or low-density lipoprotein (LDL), depends on both the nature of the oxidant stress imposed on the biological system and the type of target molecule to be protected from oxidative damage, for example lipids, proteins, or nucleic acids. This chapter reviews data on the potency of vitamin E relative to the potency of other antioxidants naturally present in human plasma and LDL to prevent peroxidative damage to lipids. An important implication of the oxidative theory of atherosclerosis is that antioxidants which can effectively prevent peroxidative damage to LDL lipids may act an antiatherogens.

Cancer cells often display impaired mitochondrial function, reduced oxidative phosphorylation, and augmented aerobic glycolysis (Warburg effect) to fulfill their bioenergetic and biosynthetic needs. Caveolin-1 (CAV1) is a scaffolding protein that promotes cancer cell migration, invasion, and metastasis in a manner dependent on CAV1 phosphorylation on tyrosine-14 (pY14). Here, we show that CAV1 expression increased glycolysis rates, while mitochondrial respiration was reduced by inhibition of the mitochondrial complex IV. These effects correlated with increased reactive oxygen species (ROS) levels that favored CAV1-induced migration and invasion. Interestingly, pY14-CAV1 promoted the metabolic switch associated with increased migration/invasion and augmented ROS-inhibited PTP1B, a phosphatase that controls pY14 levels. Finally, the glycolysis inhibitor 2-deoxy-D-glucose reduced CAV1-enhanced migration in vitro and metastasis in vivo of murine melanoma cells. In conclusion, CAV1 promotes the Warburg effect and ROS production, which inhibits PTP1B to augment CAV1 phosphorylation on tyrosine-14, thereby increasing the metastatic potential of cancer cells.

Abstract Micronutrients are involved in nearly all cellular processes, inadequacies or deficiencies may accelerate cellular aging and increase risk for chronic diseases later in life.1 Optimizing micronutrient intake may help reduce the risk for developing certain age-related conditions/diseases, including osteopenia/osteoporosis,2 sarcopenia,3 falls,4 mild cognitive impairment,5 immunosenescence,6 impaired resilience,7 hypertension,8 cataracts,9 and age-related macular degeneration.10 The importance of calcium and vitamin D for maintaining bone health has been established,2 but these micronutrients may also be involved with muscle health and reducing the risk for falls and consequent bone fractures in later life.11 Vitamin D may also be involved in stress management and resilience.12 Vitamins C, D, and E, zinc, selenium, and other micronutrients are necessary for healthy immune system function,13,14 and vitamin E is important for cognition,15 immune competence,16 and eye health.10 Although these micronutrients are individually involved with these processes by acting as antioxidants, hormonal regulators of gene expression, or cofactors in enzymatic reactions, there are also important interactions between micronutrients to consider (eg, calcium/vitamin D in musculoskeletal health). Importantly, a significant proportion of the aging population does not meet the recommended intake of many micronutrients.17 Clinical trials on the benefits of micronutrient supplementation have not been conclusive, but adequate intake should be considered an essential component of comprehensive healthcare for older adults. References 1. Ames BN. Proc Natl Acad Sci U S A. 2006;103:17589–94 2. Nieves JW. Am J Clin Nutr. 2005;81:1232s-9s 3. Stockton KA, et al. Osteoporos Int. 2011;22:859–71 4. Shahar D, et al. Ann Nutr Metab. 2009;54:59–66 5. Barnes JL, et al. Nutr Rev. 2014;72:707–19 6. Cabrera AJ. Pathobiol Aging Age Relat Dis. 2015;5:25592 7. Rucklidge JJ, Blampied NM. NZ J Psychol. 2011;40:51–7 8. de Paula TP, et al. Sci Rep. 2017;7:40751 9. Weikel KA, et al. Nutr Rev. 2014;72:30–47 10. Evans JR, Lawrenson JG. Cochrane Database Syst Rev. 2017;7:CD000254 11. Robinson SM, et al. Clin Nutr. 2018;37:1121–32 12. Bracha HS, et al. Am J Geriatr Psychiatry. 2004;12:544–5 13. Puertollano MA, et al. Curr Top Med Chem. 2011;11:1752–66 14. Prietl B, et al. Nutrients. 2013;5:2502–21 15. Parker RS. In: Stipanuk MH, Caudill MA, eds. Biochemical, Physiological, and Molecular Aspects of Human Nutrition. 3rd ed. St. Louis, MO: Elsevier Saunders; 2013:670–82 16. Maijo M, et al. Mech Ageing Dev. 2014;136–137:116–28 17. Bugel S, Frei B. Care Weekly. 2019;3:1–12

Background: alpha-Lipoic acid (LA) is a dietary supplement for maintaining energy balance, but well-controlled clinical trials in otherwise healthy, overweight adults using LA supplementation are lacking. Objectives: The primary objective was to evaluate whether LA supplementation decreases elevated plasma triglycerides in overweight or obese adults. Secondary aims examined if LA promotes weight loss and improves oxidative stress and inflammation. Methods: Overweight adults [n = 81; 57% women; 21-60 y old; BMI (in kg/m(2)) = 25] with elevated plasma triglycerides >= 100 mg/dL were enrolled in a 24-wk, randomized, double-blind, controlled trial, assigned to either (R)-alpha-lipoic acid (R-LA; 600 mg/d) or matching placebo, and advised not to change their diet or physical activity. Linear models were used to evaluate treatment effects from baseline for primary and secondary endpoints. Results: R-LA did not decrease triglyceride concentrations, but individuals on R-LA had a greater reduction in BMI at 24 wk than the placebo group (-0.8; P = 0.04). The effect of R-LA on BMI was correlated to changes in plasma triglycerides (r = +0.50, P = 0.004). Improvement in body weight was greater at 24 wk in R-LA subgroups than in placebo subgroups. Women and obese participants (BMI >= 35) showed greater weight loss (-5.0% and -4.8%, respectively; both P < 0.001) and loss of body fat (-9.4% and -8.6%, respectively; both P < 0.005). Antioxidant gene expression in mononuclear cells at 24 wk was greater in the R-LA group (Heme oxygenase 1 [HMOX1] : +22%; P = 0.02) than in placebo. Less urinary F2-isoprostanes (-25%; P = 0.005), blood leukocytes (-10.1%; P = 0.01), blood thrombocytes (-5.1%; P = 0.03), and ICAM-1 (-7.4%; P = 0.04) at 24 wk were also observed in the R-LA group than in placebo. Conclusions: Long-term LA supplementation results in BMI loss, greater antioxidant enzyme synthesis, and less potential for inflammation in overweight adults. Improved cellular bioenergetics is also evident in some individuals given R-LA.

Micronutrient inadequacies are common in older adults. We sought to assess if multivitamin/multimineral supplement (MVM) use improved micronutrient intake and biomarker status among older adults enrolled in NHANES. The National Cancer Institute Method was used to estimate usual intakes of 18 micronutrients stratified by age and frequency of MVM use. Insufficiency and deficiency prevalence were evaluated using nutrient biomarkers. Compared with food alone, MVM use was associated with higher nutrient intake and lower prevalence of inadequacies of almost all micronutrients exam- ined and improved nutrient biomarker status of folate, iodine, selenium, and vitamins B6, B12, and D. Regular MVM use (!16days/month) decreased the odds of clinical deficiency (defined by biomarker status) of vitamins B6 and D but increased the proportion exceeding the tolerable upper intake level of folic acid. Vitamin B6 deficiency in MVM non-users was common and increased with age. Recommending MVM in the middle-aged and older adult population in the US may help to ensure opti- mal long-term nutritional status and contribute to health maintenance. GSK Consumer Healthcare.

Caveolin-1 (CAV1) enhanced migration, invasion, and metastasis of cancer cells is inhibited by co-expression of the glycoprotein E-cadherin. Although the two proteins form a multiprotein complex that includes β-catenin, it remained unclear how this would contribute to blocking the metastasis promoting function of CAV1. Here, we characterized by mass spectrometry the protein composition of CAV1 immunoprecipitates from B16F10 murine melanoma cells expressing or not E-cadherin. The novel protein tyrosine phosphatase PTPN14 was identified by mass spectrometry analysis exclusively in co-immunoprecipitates of CAV1 with E-cadherin. Interestingly, PTPN14 is implicated in controlling metastasis, but only few known PTPN14 substrates exist. We corroborated by western blotting experiments that PTPN14 and CAV1 co-inmunoprecipitated in the presence of E-cadherin in B16F10 melanoma and other cancer cells. Moreover, the CAV1(Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine-14, as well as suppressed CAV1-enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29(US)] and breast cancer (MDA-MB-231) cell lines. Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo. In summary, we identify here CAV1 as a novel substrate for PTPN14 and show that overexpression of this phosphatase suffices to reduce CAV1-induced metastasis.

Abstract Micronutrient inadequacies are common in older adults and using a multivitamin/multimineral supplement (MVM) may improve their nutritional status. National Health and Nutrition Examination Survey data were analyzed to determine micronutrient intakes based on diet and MVM use in adults aged ≥51 years. Deficiencies were evaluated using nutrient biomarkers. The National Cancer Institute Method was used to estimate usual intakes of 18 micronutrients stratified by age and frequency of MVM use. Compared with food alone, MVM use was associated with higher nutrient intake and lower prevalence of inadequacies of almost all micronutrients examined and improved nutrient biomarker status of folate, iodine, selenium, and vitamins B6, B12, and D. Regular MVM use (≥16 days/month) decreased the odds of clinical deficiency (defined by biomarker status) of vitamins B6 and D but increased the proportion exceeding the tolerable upper intake level of folic acid. Vitamin B6 deficiency in MVM non-users was common and increased with age.

This narrative review describes the distinct nutritional needs of middle-aged and older adults in the European Union.Literature reviews were conducted to identify sources evaluating nutritional status and interventions relevant to these populations.Emphasis was placed on dietary guidelines, systematic reviews, and meta-analyses examining relevant macronutrients and micronutrients and important diseases or conditions related to aging (e.g.cardiovascular disease, infections, osteoporosis, cognition, immunity).Middle-aged and older adults in the European Union frequently do not obtain recommended amounts of key macronutrients and micronutrients necessary for maintaining health.In addition to the nutritional benefits of a healthful diet and contact with professionals to identify nutritional barriers, problem-solving techniques and micronutrient and macronutrient goals can improve the outcomes of dietary interventions in these individuals.Nutrition education programs, particularly those with specific recommendations, are effective for improving the nutritional status of these populations.For those who do not obtain adequate amounts of macronutrients and micronutrients from their diets, adhering to dietary guidelines and, when warranted, supplementation should be considered to improve nutritional status.The findings from randomized, controlled trials suggest that dietary interventions and supplementation can correct nutritional deficiencies and inadequacies that are important to the health of middle-aged and older adults.However, it is important to evaluate nutrient intake from the diet, supplementation, and fortified food to avoid exceeding tolerable upper intake levels of certain nutrients and limit potential adverse outcomes.Medical histories, medication use, dietary patterns, and other risk factors should be considered when recommending dietary improvements and supplements in these populations.

Despite increased consumer interest in organic produce, little is known about how different organic production methods affect both the traditional measures of quality and the naturally occurring health promoting (bioactive) compounds of food. In this study, “Obsidian” and “Triple Crown” blackberries (both Rubus hybrids) were cultivated organically and fertilized with either soy meal, fish emulsion/hydrolysate blend, or processed poultry litter fertilizers at a fixed rate. Fruits were hand-harvested three times during their peak production period and stored at 4°C and 85% RH for up to 12 d. Fertilizer effects on the physicochemical properties were minor, while harvest period had a stronger effect, though that trend varied by year. Antioxidant and sugar profile data revealed an interesting pattern: “Obsidian” had ORAC and lower sugar than “Triple Crown” at harvest and also had greater differentiation due to fertilizer treatments. Fertilizer effects differed based on harvest date and cultivar, with late harvest fruit fertilized with fish emulsion fertilizer showing higher TPC and ORAC than other fertilizer treatments, while the early and middle harvest fruit showed similar or greater responses to soy meal-based fertilizer. Time of harvest and length of storage also affected the antioxidant properties and sugar profiles in different ways depending on fruit cultivar, again with the “Obsidian” fruit showing greater variability in general. This study demonstrated that the two cultivars of organically grown blackberry fruit have different physicochemical and antioxidant properties, thus potentially different shelf lives in the fresh market.

BackgroundInadequate vitamin E and magnesium intakes are of concern for older adults owing to the associated incidence of age-related diseases.ObjectiveThis study was designed to determine the extent to which a 16-wk intervention with hazelnuts alters vitamin E and magnesium status in a group of older men and women, and used a pre-post intervention design without a control group to adjust for temporal changes.MethodsParticipants (n = 32 including 22 women; mean ± SD age: 63 ± 6 y) consumed hazelnuts (∼57 g/d) for 16 wk. Blood and urine samples and anthropomorphic measures were taken at the start and end of the intervention to determine plasma concentrations of α-tocopherol and serum concentrations of magnesium, lipids, glucose, insulin, and high-sensitivity C-reactive protein along with urinary vitamin E metabolites; several other micronutrients were measured by a lymphocyte proliferation assay. There were 3 primary endpoints, calculated as the mean changes in measurements between baseline and the end of the 16-wk intervention for 1) plasma α-tocopherol, 2) urinary α-carboxyethyl hydroxychromanol (α-CEHC; an α-tocopherol metabolite), and 3) serum magnesium.ResultsHazelnut consumption increased concentrations of the urinary α-tocopherol metabolite α-CEHC (mean ± SD: 0.84 ± 0.45 to 1.14 ± 0.50 µmol/g creatinine; P = 0.0006). In addition, hazelnut consumption increased serum concentrations of magnesium (+2.1%, P = 0.05), decreased concentrations of fasting glucose (-3.4%, P = 0.03) and LDL cholesterol (-6.0%, P = 0.02), and decreased total:HDL cholesterol ratios (-4.5%, P = 0.009). No significant changes were observed in blood pressure, lymphocyte proliferation assays, and serum concentrations of insulin, high-sensitivity C-reactive protein, triglyceride, α-tocopherol, or HDL cholesterol.ConclusionsConsuming hazelnuts improves a biomarker of vitamin E status in older adults. Vitamin E is a shortfall micronutrient, as identified by the Dietary Guidelines for Americans 2015-2020, which frequently is consumed at levels less than the Estimated Average Requirement of 12 mg/d; thus, hazelnuts should be considered as part of a healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT03485989.

PurposeEvidence supporting the use of dietary supplements, in particular, multivitamin/multimineral supplements (MVMS), has been mixed, complicating the ability of health care professionals to recommend their use. To clarify the role that MVMS can play in supporting human health, a series of consensus statements was developed based on expert opinion.MethodsA panel of 14 international experts in nutritional science and health care was convened to develop consensus statements related to using MVMS in supporting optimal human health. The modified Delphi process included 2 rounds of remote voting and a final round of voting at a roundtable meeting where evidence summaries were presented and discussed. The level of agreement with each of 9 statements was rated on a 5-point Likert scale: agree strongly; agree with reservation; undecided; disagree; or disagree strongly. Consensus was predefined as ≥80% of the panel agreeing strongly or agreeing with reservation to a given statement.FindingsConsensus was reached for all statements. The panel determined that MVMS can broadly improve micronutrient intakes when they contain at least the micronutrients that are consumed insufficiently or have limited bioavailability within a specified population. MVMS formulations may also be individualized according to age, sex, life cycle, and/or other selected characteristics. There are specific biological processes and health outcomes associated with deficient, inadequate, and adequate micronutrient levels. Adequate intake is necessary for normal biological functioning required for good health; in some instances, higher than recommended micronutrient intakes have the potential to provide additional health benefits. Meeting daily intakes established by dietary reference values should be an explicit public health goal for individuals and populations. Use of MVMS is one approach to ensure that adequate micronutrient needs are met in support of biological functions necessary to maintain health. Long-term use of MVMS not exceeding the upper limit of recommended intakes has been determined to be safe in healthy adults. There is insufficient evidence to indicate that MVMS are effective for the primary prevention of chronic medical conditions, including cardiovascular disease and cancer. However, for certain otherwise healthy subpopulations (eg, pregnant women, older adults) and some individuals with existing medical conditions who experience inadequacies in micronutrient intake, addressing inadequacies by using MVMS can provide health benefits.ImplicationsThis consensus panel has described key issues related to the use of MVMS among individuals at risk of or presenting with inadequacies in micronutrient intake or biomarker status.

Micronutrients are essential to health at every life stage and their deficiencies are associated with increased incidence of various pathophysiological states and poor quality of life. Efficient methods are therefore needed to monitor micronutrient status of individuals and to improve evidenced-based recommendations for populations. This review (i) reports current approaches to assess the vitamin and mineral status in humans, (ii) summarizes current analytical advantages and shortcomings and (iii) provides practical information for both nutrition research and nutritional status diagnostics. Future analytical perspectives are discussed in relation to micronutrient profiling, analytical sensitivity, and miniaturized technologies.

Many Americans have inadequate intakes of several nutrients, and the Dietary Guidelines for Americans 2015–2020 identified vitamins A, C, D, and E, in addition to calcium, magnesium, iron, potassium, choline, and fiber as “underconsumed nutrients”. Based on nationally representative data on 10,698 adults from National Health and Nutrition Examination Surveys (NHANES), 2009–2012, assessments were made of socioeconomic differences, based on the Poverty Income Ratio (PIR), in terms of the association of dietary supplement use on nutrient intake and nutrient inadequacies. Compared to food alone, the use of any dietary supplement plus food was associated with significantly (p < 0.01) higher intakes of 15–16 of 19 nutrients examined in all socioeconomic groups; and significantly reduced rates of inadequacy for 10/17 nutrients in the subgroup PIR > 1.85 (not poor), but only 4–5/17 nutrients (calcium and vitamins A, C, D, E) for the poor and nearly poor subgroups (PIR < 1.35 and PIR 1.35 to ≤1.85, respectively). An increased prevalence of intakes above the Tolerable Upper Intake Level (UL) was seen for 3–9/13 nutrients, but all were less than 5% in the PIR subgroups. In conclusion, dietary supplement use was associated with an increased micronutrient intake, decreased inadequacies, and a slight increase in the prevalence of intakes above the UL, with greater benefits seen in the PIR > 1.85 subgroup.

The U.S. Centers for Disease Control and Prevention has reported that nutritional deficiencies in the U.S. population vary by age, gender, and race/ethnicity, and could be as high as nearly one third of certain population groups. Based on nationally representative data in 10,698 adults from National Health and Nutrition Examination Surveys (NHANES) primarily from 2009–2012, assessments were made of race/ethnic differences in the impact of dietary supplements on nutrient intake and prevalence of inadequacies. Compared to food alone, use of any dietary supplement plus food was associated with significantly higher intakes of 14 to 16 of 19 nutrients examined in all race/ethnic groups; and significantly (p < 0.01) reduced rates of inadequacy for 8/17 nutrients examined in non-Hispanic whites, but only 3–4/17 nutrients (calcium, and vitamins A, D, and E) for other race/ethnic groups. Across race/ethnic groups an increased prevalence of intakes above the Tolerable Upper Intake Level (UL) was seen for 1–9/13 nutrients, but all were less than 5% of the population. In conclusion, use of dietary supplements is associated with increased micronutrient intake, decreased nutrient inadequacies, and slight increases in prevalence above the UL in all race/ethnicities examined, with greater benefits among non-Hispanic whites.

Although >50% of U.S. adults use dietary supplements, little information is available on the impact of supplement use frequency on nutrient intakes and deficiencies. Based on nationally representative data in 10,698 adults from the National Health and Nutrition Examination Surveys (NHANES) 2009 to 2012, assessments were made of intakes from food alone versus food plus multi-vitamin/multi-mineral supplements (MVMS) of 17 nutrients with an Estimated Average Requirement (EAR) and a Tolerable Upper Intake Level (UL), and of the status of five nutrients with recognized biomarkers of deficiency. Compared to food alone, MVMS use at any frequency was associated with a lower prevalence of inadequacy (p < 0.01) for 15/17 nutrients examined and an increased prevalence of intakes >UL for 7 nutrients, but the latter was ≤4% for any nutrient. Except for calcium, magnesium, and vitamin D, most frequent MVMS use (≥21 days/30 days) virtually eliminated inadequacies of the nutrients examined, and was associated with significantly lower odds ratios of deficiency for the examined nutrient biomarkers except for iron. In conclusion, among U.S. adults, MVMS use is associated with decreased micronutrient inadequacies, intakes slightly exceeding the UL for a few nutrients, and a lower risk of nutrient deficiencies.

Many Americans have inadequate intakes of several nutrients. The Dietary Guidelines for Americans 2015–2020 specifically identified vitamins A, C, D and E, calcium, magnesium, iron, potassium, choline and fiber as “underconsumed nutrients”. Based on nationally representative data in 10,698 adults from National Health and Nutrition Examination Surveys (NHANES), 2009–2012, assessments were made of age-group differences in the impact of dietary supplements on nutrient intake and inadequacies. Compared to food alone, use of any dietary supplement plus food was associated with significantly (p < 0.01) higher intakes of 15–16 of 19 nutrients examined in all age groups; and significantly reduced rates of inadequacy for 10/17, 8/17 and 6/17 nutrients examined among individuals age ≥71, 51–70 and 19–50 years, respectively. Compared to the other age groups, older adults (≥71 years) had lower rates of inadequacy for iron and vitamins A, C, D and E, but higher rates for calcium. An increased prevalence of intakes above the Tolerable Upper Intake Level was seen for 8–9 of 13 nutrients, but were mostly less than 5% of the population. In conclusion, dietary supplement use is associated with increased micronutrient intake, decreased inadequacies, and slight increases in prevalence above the UL, with greater benefits seen among older adults.

Endothelial dysfunction due to vascular inflammation and oxidative stress critically contributes to the etiology of atherosclerosis. The intracellular redox environment plays a key role in regulating endothelial cell function and is intimately linked to cellular thiol status, including and foremost glutathione (GSH). In the present study we investigated whether and how the dietary flavonoid, quercetin, affects GSH status of human aortic endothelial cells (HAEC) and their response to oxidative stress. We found that treating cells with buthionine sulfoximine to deplete cellular GSH levels significantly reduced the capacity of quercetin to inhibit lipopolysaccharide (LPS)-induced oxidant production. Furthermore, incubation of HAEC with quercetin caused a transient decrease and then full recovery of cellular GSH concentrations. The initial decline in GSH was not accompanied by a corresponding increase in glutathione disulfide (GSSG). To the contrary, GSSG levels, which were less than 0.5% of GSH levels at baseline (0.26±0.01 vs. 64.7±1.9 nmol/mg protein, respectively), decreased by about 25% during incubation with quercetin. As a result, the GSH: GSSG ratio increased by about 70%, from 253±7 to 372±23. These quercetin-induced changes in GSH and GSSG levels were not affected by treating HAEC with 500 µM ascorbic acid phosphate for 24 h to increase intracellular ascorbate levels. Incubation of HAEC with quercetin also led to the appearance of extracellular quercetin-glutathione conjugates, which was paralleled by upregulation of the multidrug resistance protein 1 (MRP1). Furthermore, quercetin slightly but significantly increased mRNA and protein levels of glutamate-cysteine ligase (GCL) catalytic and modifier subunits. Taken together, our results suggest that quercetin causes loss of GSH in HAEC, not because of oxidation but due to formation and cellular export of quercetin-glutathione conjugates. Induction by quercetin of GCL subsequently restores GSH levels, thereby suppressing LPS-induced oxidant production.