Obesity during pregnancy alters maternal oxidant balance and micronutrient status.

OBJECTIVE: Little is known about the effect of obesity on inflammatory status in pregnant women. The objective of this study was to determine the effect of obesity on markers of inflammation, oxidative stress and micronutrient status in obese pregnant women and their infants compared with lean controls (Lc). STUDY DESIGN: This was a prospective case-control study. A total of 15 obese (Ob; body mass index (BMI) >30 kg m(-2)) and 15 lean (BMI 18-25 kg m(-2)) women were recruited based on prepregnancy BMI. Vitamins A, B6, C, E and 25-hydroxyvitamin D (25(OH)D), zinc, red blood cell (RBC) folate, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α and oxidized and reduced glutathione were measured from maternal blood between 24 and 28 weeks of gestation. Vitamins A, B6, C and E, 25(OH)D, zinc, red blood cell folate, CRP and IL-6 were measured from cord blood at delivery. RESULT: Ob pregnant women have statistically significantly lower levels of vitamin B6, vitamin C, vitamin E, RBC folate, higher CRP and IL-6 levels and higher ratio of oxidized to reduced glutathione compared with Lc pregnant women. Infants born to Ob mothers did not have statistically significantly higher measures of inflammation or oxidative stress. There were no differences in micronutrient concentrations between Lc and Ob infants, but folate, vitamin B6 and zinc levels correlated strongly between mother and infant. There was no statistically significant difference in any parameter between Ob and Lc cord blood. CONCLUSION: Ob pregnant women have increased inflammation and oxidative stress, and lower levels of nutritional antioxidant defenses compared with Lc pregnant women. We speculate that lower antioxidant defenses combined with increased oxidative stress and inflammation may contribute to the adverse outcomes associated with pregnancy in Ob women.

Micronutrient supplementation and T cell-mediated immune responses in patients with tuberculosis in Tanzania.

Limited studies exist regarding whether incorporating micronutrient supplements during tuberculosis (TB) treatment may improve cell-mediated immune response. We examined the effect of micronutrient supplementation on lymphocyte proliferation response to mycobacteria or T-cell mitogens in a randomized trial conducted on 423 patients with pulmonary TB. Eligible participants were randomly assigned to receive a daily dose of micronutrients (vitamins A, B-complex, C, E, and selenium) or placebo at the time of initiation of TB treatment. We found no overall effect of micronutrient supplements on lymphocyte proliferative responses to phytohaemagglutinin or purified protein derivatives in HIV-negative and HIV-positive TB patients. Of HIV-negative TB patients, the micronutrient group tended to show higher proliferative responses to concanavalin A than the placebo group, although the clinical relevance of this finding is not readily notable. The role of nutritional intervention in this vulnerable population remains an important area of future research.

Obesity during pregnancy and fetal iron status: is Hepcidin the link?

OBJECTIVE: To ascertain the effect of obesity-related inflammation on maternal and fetal iron status. We hypothesized that obese (Ob) pregnant women would have increased inflammation, hepcidin levels, and that their infants would have impaired iron status compared with lean (Lc) controls. STUDY DESIGN: Fifteen Ob and fifteen Lc women were recruited in their second trimester of pregnancy. Markers of iron status, inflammation and hepcidin were measured in maternal and cord blood. Student's t-test was used to compare Ob and Lc groups, and Pearson's correlation coefficients were determined between maternal and cord blood values. RESULT: Maternal C-reactive protein (P<0.01) and hepcidin (P<0.01) were higher, and cord blood iron (P<0.01) was lower in the Ob group. Maternal body mass index (P<0.01) and hepcidin (P<0.05) were negatively correlated with cord blood iron status. CONCLUSION: Maternal obesity is associated with impaired maternal-fetal iron transfer, potentially through hepcidin upregulation.

Vitamin E-enhanced IL-2 production in old mice: naive but not memory T cells show increased cell division cycling and IL-2-producing capacity.

Aging is associated with reduced T cell function, as demonstrated by decreased T cell proliferation and IL-2 production. These changes respond to supplemental vitamin E both in animals and humans, in part by the reduction of T cell suppressive PGE(2), the production of which by macrophages is increased with age. To evaluate whether vitamin E has a direct PGE(2)-independent effect on T cell responses, T cells purified from the spleens of young and old mice were preincubated with vitamin E or vehicle control. Activation-induced cell division of T cells from old mice was lower than that by young, and the production of IL-2 following 48-h activation was less by T cells from old mice. There was an age-related decline in both the number of IL-2+ T cells and the amount of IL-2 produced per cell. Despite decreased IL-2 protein at 48 h, the expression of IL-2 mRNA at 6 h and IL-2 protein production at 6 and 16 h was greater by T cells from old mice compared with that of young. Age-related decline in cell division and IL-2 production at 48 h was only observed within the naive T cell subpopulation. Vitamin E increased both cell-dividing and IL-2-producing capacity of naive T cells from old mice, with no effect on memory T cells. These data indicate that naive T cells exhibit the greatest age-related defect and show for the first time that supplemental vitamin E has direct immunoenhancing effect on naive T cells from old mice.

Metabolic, psychological, and health correlates of dietary restraint in healthy postmenopausal women.

BACKGROUND: Dietary restraint, a term used to describe the intentional control of food intake to prevent weight gain or promote weight loss, is commonly practiced by older adults, but little is known about its effects on physiology and metabolism. METHODS: We therefore compared a wide range of parameters between groups of healthy non-obese postmenopausal women classified psychometrically as unrestrained eaters (body mass index [BMI] 23.8 +/- 0.6 [SEM] kg/m(2), n = 28) or restrained eaters (BMI 24.5 +/- 0.5, n = 39). Measurements were made of reported micronutrient intakes, cardiopulmonary function, hematology, body temperature, skin thickness, bone mass, and immune function; in addition, self-perceived health, mood, and some dimensions of eating behavior were assessed by questionnaire. RESULTS: Macronutrient and micronutrient intakes were not significantly different between restrained and unrestrained eaters reporting energy intake to within 30% of predicted total energy expenditure. Restrained eaters had significantly lower hemoglobin (12.9 +/- 0.1 [SEM] vs 13.2 +/- 0.1 g/dl; p <.05), but values were within the normal range in both groups. In addition, restrained eaters scored significantly higher on the Eating Attitudes Test (p <.01) and drive-for-thinness (p <.001) and maturity fears (p <.05) subscores of the Eating Disorders Inventory, but values were again within the normal range. No other parameter differed significantly between groups. CONCLUSIONS: In this normal-weight population, restrained eating was not associated with detrimental effects in a wide range of physiological, metabolic, and health characteristics. Further work is needed to determine the relevance of these results to the general population.

Vitamin E and genome stability.

Free radicals and reactive oxygen species (ROS) which are generated continuously cause mutagenic alterations resulting in cancer, aging and abnormalities in the nervous system. Accumulating evidence indicates that Vitamin E, the most potent lipid peroxyl radical scavenger, may reduce free radical induced chromosomal damages through inhibition of free radical formation, and activation of endonuclease that can be triggered by intracellular oxidative stress, and by increasing the rate of removal of damaged DNA. Although some studies suggest a potential usefulness of Vitamin E in the prevention of mutagenic effects caused by genotoxic free radicals, other studies report no effects. Thus the data are not conclusive enough to be used as a basis to change the current recommended dietary allowances (RDA). Future research should address molecular mechanisms underlying the protective effects of Vitamin E and develop appropriate biologically relevant biomarkers of DNA damage to further help in determining the dietary levels of Vitamin E needed to protect the genetic pool from internally and externally induced DNA damages.

Interleukin-6 production does not increase with age.

Investigators have reported an increase, decrease, or no effect of age on interleukin-6 (IL-6) production. Differences in experimental conditions and the health status of subjects may explain these contradicting results. Because the subjects used in most of the previous studies were not carefully screened for health, we investigated the effect of age on IL-6 production in healthy young and elderly subjects. Twenty young (aged 20-30 years) and 26 elderly (>65 years) men completed the study. Each subject was screened for good health, undergoing physical examinations and laboratory tests. Circulating IL-6 levels were not significantly different between young and elderly subjects. A subgroup of subjects representing both young and elderly volunteers had high (>1000 pg/ml) circulating levels of IL-6. However, circulating IL-6 levels were low (<100 pg/ml) in the majority of subjects in both age groups. Peripheral blood mononuclear cells (PBMC) were cultured for IL-6 production in the presence or absence of phytohemagglutinin (PHA) or concanavalin (Con)A for 48 hours. Unstimulated secretion of IL-6 by PBMC cultured in autologous plasma (AP) or fetal bovine serum (FBS) was detectable in the majority of cultures. Age did not influence this spontaneous secretion of IL-6. PBMC stimulation with PHA or ConA significantly increased IL-6 production, but age did not affect the ability of PBMC to secrete IL-6 after stimulation when cultured in FBS. IL-6 production by PBMC cultured in AP and stimulated with PHA was not affected by age. However, when stimulated with ConA, PBMC from the elderly subjects produced less IL-6 than PBMC from the young subjects. Because IL-6 has been suggested to contribute to the age-related increase in prostaglandin (PG)E2 and nitric oxide (NO) production, we investigated the effect of age on the production of IL-6 by murine peritoneal macrophages (Mphi) as well as the effect of IL-6 on the production of other Mphi inflammatory products. Similar to the findings in humans, mouse age did not influence the level of IL-6 produced by Mphi. These data suggest that in healthy subjects, increased production of IL-6 is not a normal consequence of aging. Previously reported higher IL-6 levels in elderly subjects might reflect an underlying, undiagnosed disease state. PGE2 and NO production were not affected by the addition of IL-6 to Mphi from young mice or anti-IL-6 antibody to Mphi from old mice. Thus, IL-6 does not appear to influence the Mphi production of selected inflammatory molecules.

Effect of long-term dietary antioxidant supplementation on influenza virus infection.

This study compared the effect of vitamin E on the course of influenza infection with that of other antioxidants. (In a previous study we showed that short-term vitamin E supplementation significantly decreased pulmonary viral titer in influenza-infected old mice). Eighteen-month-old C57BL/6NCrlBR mice were fed one of the following semisynthetic diets for 6 months: control, vitamin E supplemented, glutathione supplemented, vitamin E and glutathione supplemented, melatonin supplemented, or strawberry extract supplemented. After influenza virus challenge, mice fed vitamin E-supplemented diet had significantly lower pulmonary viral titers compared to those fed the control diet (10(2.6) vs 10(4.0), p < .05) and were able to maintain their body weight after infection (1.8+/-0.9 g weight loss/5 days postinfection in vitamin E group vs 6.8+/-1.4 g weight loss/5 days postinfection in control group, p < .05). Other antioxidants did not have a significant effect on viral titer or weight loss. There was a significant inverse correlation of weight loss with food intake (r = -.96, p < .01), indicating that the observed weight changes were mainly due to decreased food intake. Pulmonary interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha levels increased significantly postinfection. The vitamin E group had lower lung IL-6 and TNF-alpha levels following infection compared to the control group. In addition, there was a significant positive correlation between weight loss and lung IL-6 (r = .77, p < .01) and TNF-alpha (r = .68, p < .01) levels. Because IL-6 and TNF-alpha have been shown to contribute to the anorexic effect of infectious agents, the prevention of weight loss by vitamin E might be due to its reduced production of IL-6 and TNF-alpha following infection. Thus, among the antioxidants tested, only vitamin E was effective in reducing pulmonary viral titers and preventing an influenza-mediated decrease in food intake and weight loss. Other dietary antioxidant supplementations that reduced one or more measures of oxidative stress (4-hydroxynonenal, malondialdehyde, and hydrogen peroxide) did not have an effect on viral titer, which suggests that, in addition to its antioxidant activity, other mechanisms might be involved in vitamin E's beneficial effect on lowering viral titer and preventing weight loss.

Antioxidants, cytokines, and influenza infection in aged mice and elderly humans.

The age-associated dysregulation of the immune response contributes to higher incidences of infectious diseases in the aged. Of note, there is dysregulation of cytokines, including a change in T helper (Th) 1/Th2 cytokine balance and an increase in production of proinflammatory cytokines. Synthesis of many cytokines is influenced by changes in the cellular oxidant/antioxidant balance. Because vitamin E supplementation reduces oxidative stress and improves the immune response in the aged, a series of experiments was conducted to determine the effect of supplementation with vitamin E and other antioxidants on resistance to influenza infection in aged mice and the role of cytokines in vitamin E-induced increase in resistance to influenza infection. The results of these studies plus findings by other investigators on the effects of age and antioxidants on production of cytokines in human and animal models are reviewed.

Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus.

Compared with young mice, old mice infected with influenza virus have significantly higher pulmonary viral titres, although these can be reduced significantly with dietary vitamin E supplementation. T helper 1 (Th1) cytokines, especially interferon-gamma (IFN-gamma), play an important role in defending against influenza infection. However, there is an age-associated loss of Th1 cytokine production. Prostaglandin E2 (PGE2) production, which increases with age, can modulate the T helper cell function by suppressing Th1 cytokine production. To investigate the mechanism of vitamin E supplementation on reduction of influenza severity in old mice, we studied the cytokine production by splenocytes, and PGE2 production by macrophages (Mphi), in young and old C57BL mice fed semipurified diets containing 30 (control) or 500 parts per million (ppm) (supplemented) vitamin E for 8 weeks, and then infected with influenza A/PC/1/73 (H3N2). Old mice fed the control diet had significantly higher viral titres than young mice; old mice fed the vitamin E-supplemented diet had significantly lower pulmonary viral titres than those fed the control diet (P = 0.02 and 0.001 for overall age and diet effect, respectively). Following influenza infection, interleukin (IL)-2 and IFN-gamma production was significantly lower in old mice than in young mice. Vitamin E supplementation increased production of IL-2 and IFN-gamma in old mice; higher IFN-gamma production was associated with lower pulmonary viral titre. Old mice fed the control diet showed significantly higher lipopolysaccharide (LPS)-stimulated Mphi PGE2 production than old mice fed the vitamin E diet or young mice fed either diet. There was no significant age difference in IL-6, IL-1beta, or tumour necrosis factor-alpha (TNF-alpha) production by splenocytes. Young mice fed the vitamin E-supplemented diet had significantly lower IL-1beta (day 7) and TNF-alpha production (day 5) compared with those fed the control diet. Old mice fed the vitamin E-supplemented diet had significantly lower TNF-alpha production (day 2) than those fed the control diet. Our results indicate that the vitamin E-induced decrease in influenza viral titre is mediated through enhancement of Th1 cytokines, which may be the result of reduced PGE2 production caused by vitamin E.

Immunologic effects of yogurt.

Many investigators have studied the therapeutic and preventive effects of yogurt and lactic acid bacteria, which are commonly used in yogurt production, on diseases such as cancer, infection, gastrointestinal disorders, and asthma. Because the immune system is an important contributor to all of these diseases, an immunostimulatory effect of yogurt has been proposed and investigated by using mainly animal models and, occasionally, human subjects. Although the results of these studies, in general, support the notion that yogurt has immunostimulatory effects, problems with study design, lack of appropriate controls, inappropriate route of administration, sole use of in vitro indicators of the immune response, and short duration of most of the studies limit the interpretation of the results and the conclusions drawn from them. Nevertheless, these studies in toto provide a strong rationale for the hypothesis that increased yogurt consumption, particularly in immunocompromised populations such as the elderly, may enhance the immune response, which would in turn increase resistance to immune-related diseases. This hypothesis, however, needs to be substantiated by well-designed randomized, double-blind, placebo-controlled human studies of an adequate duration in which several in vivo and in vitro indexes of peripheral and gut-associated immune response are tested.

In vitro supplementation with different tocopherol homologues can affect the function of immune cells in old mice.

Alpha-tocophorel (T) is the most common form of vitamin E inplasma and tissues. Alpha-T is also believed to be superior to its homologues beta-T, gamma-T, and delta-T in antioxidant activity. Biological activity of alpha-T has been intensively studied in a number of bodily systems. In contrast, the other homologues have received little attention beyond the evaluation of their relative antioxidant activity. We as well as others have previously shown that alpha-T can enhance cell- mediated immune function of aged animals and humans. Gamma-T is a principal form of vitamin E in the American diet and some cooking oils contain substantial amount of beta-T and delta-T. Thus it is of public health interest to compare their biological effects with than of alpha-t in various systems. In this study, we used an in vitro supplementation protocol to determine immunologic effects of these T homologues on murine splenocytes. The results showed that all four T homologues enhance both spontaneous and mitogen-stimulated lymphocyte proliferation (LP) and the maximal enhancement produced by them was of the same magnitude. The dose range to produce maximal enhancement varied with different homologues. The efficiency was in the order of beta-T approximately delta-T > alpha-T. Interestingly, at 50 (optimal for alpha-T) and 150 micromol/L, while alpha-T enhanced LP, all the other homologues inhibited LP. This inhibition was found to be due to their cytotoxicity at these levels. T homologues had a differential effect on interleukin (IL)-2 and prostaglandin (PG)E(2) production. IL-2 production by mouse splenocytes was not affected by alpha-T or beta-T, but was increased by gamma-T and delta-T. All T homologues, except for beta-T, inhibited PGE(2) alpha-T. Thus, all the T homologues enhance LP. However, the dose required to reach maximal enhancement varies among the homologues. On the other hand, they have a differential effect on IL-2 and PGE(2) production. The difference in nature and magnitude of the effect on immune function does not correlate with their reported relative antioxidant activity and might be due to minor differences in their structure important to their other biological activities.

Vitamin E and infectious diseases in the aged.

The incidence of infectious diseases, particularly respiratory diseases, increases with age. Age-associated decline in immune function contributes to the increased susceptibility of the aged to infections. Vitamin E supplementation has been shown to improve some aspects of immune function in aged animals and human subjects. The protective effect of vitamin E against viral or bacterial infections in experimentally-challenged young animals has been reported. We investigated the effects of supplementation with vitamin E and other antioxidants on resistance to influenza infection in young and old animals. While vitamin E-supplemented young mice showed only a modest reduction in lung viral titre, vitamin E-supplemented old mice exhibited a highly significant (P < 0.05) reduction in viral lung titre. In subsequent studies, we focused on the mechanism of vitamin E-induced reduction of influenza viral titre. The results of these studies as well as those reported by other investigators on the relationship between vitamin E and infectious diseases will be reviewed.

Biomarkers as early predictors of long-term health status and human immune function.

A central issue that must be addressed by phytonutrient research is how to assess the effects of phytonutrients on long-term health. Proper assessment of these effects requires the measurement of biomarkers of long-term health in people consuming any particular phytonutrient. This is a brief review of what is known about biomarkers of cancer risk, immune function, and aging. Relatively few biomarkers of long-term health have been even partially validated in experimental animals or people.

Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects.

BACKGROUND: We have shown that the age-associated increase in prostaglandin E(2) production contributes to the decline in T cell-mediated function with age. Black currant seed oil (BCSO), rich in both gamma-linolenic (18:3n-6) and alpha-linolenic (18:3n-3) acids, has been shown to modulate membrane lipid composition and eicosanoid production. OBJECTIVE: Our objectives were to 1) test whether dietary supplementation with BCSO can improve the immune response of healthy elderly subjects, and 2) determine whether the altered immune response is mediated by a change in the factors closely associated with T cell activation. DESIGN: A randomized, double-blind, placebo-controlled (soybean oil) study was conducted to examine the effect of 2 mo of BCSO supplementation on the immune response of 40 healthy subjects aged >/=65 y. In vivo immune function was determined by delayed-type hypersensitivity skin response. Peripheral blood mononuclear cells (PBMCs) were tested for in vitro immune response. RESULTS: In subjects supplemented with BCSO, the total diameter of induration at 24 h and individual responses to tetanus toxoid and Trichophyton mentagrophytes were significantly higher than their baseline values. The change in response to tetanus toxoid was significantly different from that of the placebo group. The BCSO group showed a significant increase in proliferative response of PBMCs to the T cell mitogen phytohemagglutinin that was not significantly different from that observed in the placebo group. BCSO had no effect on concanavalin A-induced mitogenic response, interleukin 2 and -1beta production, and PBMC membrane fluidity. Prostaglandin E(2) production was significantly reduced in the BCSO-supplemented group, and this change was significantly different from that of the placebo group. CONCLUSION: BCSO has a moderate immune-enhancing effect attributable to its ability to reduce prostaglandin E(2) production.

Dietary conjugated linoleic acid influences the immune response of young and old C57BL/6NCrlBR mice.

Aging is associated with a decline in the immune response in mammals. Conjugated linoleic acid (CLA) has been suggested to have immunoenhancing properties. We examined the influence of dietary CLA on the immune response of young and old mice. Forty young (4 mo) and 40 old (22 mo) mice consumed ad libitum diets containing 0 or 1 g CLA /100 g for 8 wk. Splenocytes from half of the mice were isolated to evaluate proliferation to concanavalin A (Con A) (0.5, 1.5, 5.0 mg/L) and phytohemagglutinin A (PHA) (5, 20, 40 mg/L) and lipopolysaccharide (LPS) (5, 15, 30 mg/L), natural killer cell (NK) activity and prostaglandin (PG)E2 and interleukin (IL)-2 production. The remaining mice were used to evaluate in vivo delayed-type hypersensitivity (DTH) skin response. There was a significant decline due to age in response to all three mitogens tested (P < 0. 05). CLA supplementation significantly increased all CLA isomers measured in hepatic neutral lipids and phospholipids (P < 0.05). Young mice fed 1% CLA had greater splenocyte proliferation in response to Con A (0.5 and 5.0 mg/L) and PHA (40 mg/L) (P < 0.05) than young mice fed control diet. Old mice fed 1 g CLA/100 g had significantly higher proliferative response to optimal concentrations of Con A (1.5 mg/L) (P < 0.001) than the mice fed the control diet. Old mice fed the control diet had significantly lower splenocyte IL-2 production than the young mice (P < 0.005). CLA-supplemented young mice had significantly higher splenocyte IL-2 production than those fed the control diet (P < 0.05). CLA had no effect on NK cell activity, PGE2 production or DTH in young or old mice. Further studies are needed to determine the mechanism of CLA-induced enhancement of IL-2 production and T cell proliferation.