Literature Review - December 2012
Carotenoids, Lutein, Zeaxanthin
Nutrition, Volume 29, Issue 1, January 2013, Pages 195-202
Assessment of phytochemical content in human milk during different stages of lactation
Song, B.J., Jouni, Z.E., Ferruzzi, M.G.
Objective: The present study reports the presence of several carotenoidsand flavonoids in human milk samples.
Methods: Samples were collected from 17 women who delivered healthy term babies (≥37 wk of gestation) at
1-, 4-, and 13-wk postpartum intervals.
Results: Epicatechin (63.7-828.5 nmol/L), epicatechin gallate (55.7-645.6 nmol/L), epigallocatechin gallate
(215.1-2364.7 nmol/L), naringenin (64.1-722.0 nmol/L), kaempferol (7.8-71.4 nmol/L), hesperetin (74.8-1603.1
nmol/L), and quercetin (32.5-108.6 nmol/L) were present in human milk samples with high inter-
/intraindividual variability. With the exception of kaempferol, the mean flavonoid content in human milk
was not statistically different among lactation stages. In contrast, carotenoidsα-carotene (59.0-23.2 nmol/L),
β-carotene (164.3-88.0 nmol/L), α-cryptoxanthin (30.6-13.5 nmol/L), β-cryptoxanthin (57.4-24.8 nmol/L),
zeaxanthin (46.3-21.4 nmol/L), lutein (121.2-56.4 nmol/L), and lycopene (119.9-49.5 nmol/L) significantly
decreased from weeks 1 to 13 of lactation.
Conclusion: The observed differences in the relative concentrations of the two phytochemical classes in human
milk may be a result of several factors, including dietary exposure, stability in the milk matrix, efficiency of
absorption/metabolism, and transfer from plasma to human milk. These data support the notion that
flavonoids, as with carotenoids, are dietary phytochemicals present in human milk and potentially
available to breast-fed infants. © 2013 Elsevier Inc.
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European Journal of Epidemiology, 2012, Pages 1-9 Article in Press
Low levels of plasma carotenoids are associated with an increased risk of atrial fibrillation
Karppi, J., Kurl, S., Mäkikallio, T.H., Ronkainen, K., Laukkanen, J.A.
Systemic inflammation, oxidative stress, and atrial fibrosis are identified as the main mechanisms for atrial
fibrillation (AF). Antioxidant micronutrients may have antiarrhythmic benefit in humans. We studied whether
plasma carotenoids are related to the risk of AF in elderly subjects. The study population consisted of 1,847
Finnish subjects (620 women and 1,227 men) aged 61-82 years from the Kuopio Ischaemic Heart Disease
Risk Factor study cohort. Plasma concentrations of carotenoids were measured by high-performance liquid
chromatography. The multivariable-adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) of plasma
carotenoidswere analyzed using the Cox proportional hazard's model. During a median follow-up of 2.8 years a
total of 105 subjects developed incident AF. The HRs of AF among subjects with levels in the highest
through the lowest tertile after adjustment for age, examination year, gender, systolic blood pressure,
smoking, alcohol consumption, education, diabetes, use of antihypertensive medication, congestive heart
failure, recurrent AF, prevalent coronary heart disease and baseline prevalence of myocardial infarction were
1.70 (95 % CI: 1.01-2.86, p = 0.047) for lutein, 1.99 (95 % CI: 1.14-3.48, p = 0.016) for zeaxanthin. Risk of
AF was borderline significant for β-carotene (HR = 1.69, 95 % CI: 1.00-2.87, p = 0.050). Results remained
unchanged, when season was added to the multivariable model. Lycopene, β-cryptoxanthin, α-carotene and total
carotenoidswere not associated with the risk of AF. Results of the present study suggest that low plasma
concentrations of lutein and zeaxanthin were associated with an increased risk of AF in elderly
L:\Tech Services & Quality\Papers\Lutein\Cardiovascular health
Journal of Hypertension, 11 December 2012, Article in Press
Tomato extract and the carotenoidslycopene and lutein improve endothelial function and attenuate
inflammatory NF-κB signaling in endothelial cells
Armoza, A., Haim, Y., Basiri, A., Wolak, T., Paran, E.
December 27, 2012
OBJECTIVES: In our previous research the antihypertensive properties of lycopene-containing tomato
oleoresin have been revealed. The present study was aimed to assess if oleoresin interferes in the inflammatory
signalling in endothelial cells, imitating reduction of inflammatory processes in the vessel wall and in this way
to propose the mechanism for the reduction of blood pressure by oleoresin.
METHODS AND RESULTS: A wide number of functional and inflammatory markers were investigated in
two cultured endothelial cell models [EA.hy926 and human umbilical vein endothelial cell (HUVEC)],
exposed to oleoresin and carotenoids lycopene and lutein. All the carotenoids significantly improved basic
endothelial function as measured by increased nitric oxide and decreased endothelin (ET-1) release. They
were effective in attenuation of inflammatory nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB) signalling: decrease of tumour necrosis factor-alpha (TNF-α)-induced leukocytes adhesion,
expression of adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion
molecule 1 (VCAM-1), and nuclear translocation of NF-κB components as well as some revert of
inhibitor of kappa B (IκB) ubiquitination. In addition, the carotenoidswere able to inhibit NF-κB
activation in transfected endothelial cells. When combined with lutein, oleoresin exerted synergistic effect
on preclusion of leukocytes adhesion. CONCLUSIONS: Prevention of over-expression of adhesion
molecules through inhibition of NF-κB signalling may be one of the main mechanisms driving carotenoids to
attenuate inflammatory leukocyte adhesion to endothelium. This is the first profound study on the mechanisms
involved in the positive action of natural tomato products in endothelial cells.
Nutrients, Volume 4, Issue 12, December 2012, Pages 1812-1827
Retinal spectral domain optical coherence tomography in early atrophic age-related macular
degeneration (amd) and a new metric for objective evaluation of the efficacy of ocular nutrition
Richer, S., Cho, J.. Stiles, W., Levin, M., Wrobel, J.S., Sinai, M., Thomas, C.
Purpose: A challenge in ocular preventive medicine is identification of patients with early pathological retinal
damage that might benefit from nutritional intervention. The purpose of this study is to evaluate retinal thinning
(RT) in early atrophic age-related macular degeneration (AMD) against visual function data from the
Zeaxanthin and Visual Function (ZVF) randomized double masked placebo controlled clinical trial (FDA IND
Methods: Retrospective, observational case series of medical center veterans with minimal visible AMD
retinopathy (AREDS Report #18 simplified grading 1.4/4.0 bilateral retinopathy). Foveal and extra-foveal
four quadrant SDOCT RT measurements were evaluated in n = 54 clinical and ZVF AMD patients. RT
by age was determined and compared to the OptoVue SD OCT normative database. RT by quadrant in a subset
of n = 29 ZVF patients was correlated with contrast sensitivity and parafoveal blue cone increment thresholds.
Results: Foveal RT in AMD patients and non-AMD patients was preserved with age. Extrafoveal regions,
however, showed significant slope differences between AMD patients and non-AMD patients, with the
superior and nasal quadrants most vulnerable to retinal thinning (sup quad: -5.5 µm/decade thinning vs.
Non-AMD: -1.1 µm/decade, P < 0.02; nasal quad: -5.0 µm/decade thinning vs. Non-AMD: -1.0 µm/decade, P <
0.04). Two measures of extrafoveal visual deterioration were correlated: A significant inverse correlation
between % RT and contrast sensitivity (r = -0.33, P = 0.01, 2 Tailed Paired T) and an elevated extrafoveal
increment blue cone threshold (r = +0.34, P = 0.01, 2 Tailed T). Additional SD OCT RT data for the non-
AMD oldest age group (ages 82-91) is needed to fully substantiate the model.
Conclusion: A simple new SD OCT clinical metric called "% extra-foveal RT" correlates well with functional
visual loss in early AMD patients having minimal visible retinopathy. This metric can be used to follow the
effect of repleting ocular nutrients, such as zinc, antioxidants, carotenoids, n-3 essential fats, resveratrol and
L:\Tech Services & Quality\Papers\AMD
IFMBE Proceedings, Volume 38 IFMBE, 2013, Pages 51-54
December 27, 2012
International Symposium on Biomedical Engineering and Medical Physics, ISBEMP 2012;Riga;10 October
2012through12 October 2012;Code94250
LED based dual wavelength heterochromatic flicker method for separate evaluation of lutein and
zeaxanthin in retina ( Conference Paper )
Ozolinsh, M., Paulins, P.
The decrease of density and consequentially optical density of macular pigment serves as a diagnostic mean for
a number of ophthalmological pathologies, particularly as a risk factor for age related macular degeneration.
Macular pigment absorbs light in short wavelength blue spectral range. Thus the optical density of macular
pigment can be detected by various optical - both objective and subjective psychophysical techniques. Latter
techniques use eye and brain visual pathways as spectral sensitive optical detector and decision maker,
and exploit perception facility to process information flow in a unique manner to create various
perception illusions. The psychophysical methods of detection of optical density of macular pigment include
heterochromatic flicker photometry and minimum illusory motion photometry. We develop and employ a
heterochromatic flicker photometry method where LEDs are used as visual stimuli. LED emission
maximum wavelengths in blue spectrum region are chosen in range 445-460 nm, that corresponds to spectrally
resolved maxima of light absorption for two types of macula pigments - lutein and zeaxanthin or in spectral
range 500-510 nm, where luteinand zeaxanthin absorption have decay, that for both type of pigments have a
detectable shift. Statistical dispersion of the results allows to use the difference between results of
psychophysical measurements obtained for different LEDs to estimate the concentration of lutein and
zeaxanthin in human retina. © 2013 IFMBE.
Journal of Nutrition, Health and Aging, 2012, Pages 1-5 Article in Press
Low vitamin and carotenoid levels are related to cerebral white matter lesions
Ohshima, Y., Mizuno, T., Yamada, K., Matsumoto, S., Nagakane, Y., Kondo, M., Kuriyama, N., Miyazaki,
T., Takeda, K., Nishimura, T., Nakagawa, M., Ozasa, K., Watanabe, Y.
Objectives: Purpose: To determine the effects of vitamins and carotenoids on brain white matter lesions
(WMLs), we examined the associations between WMLs with vitamin and carotenoid levels in Japanese middle-
aged and elderly subjects.
Subjects and methods: Four-hundred and sixty-nine healthy participants (male = 317; female = 152) that
underwent medical examinations were examined. Deep white matter lesions (DWLs) were detected via
magnetic resonance imaging (MRI) in 39 subjects. We evaluated the effects of vitamin and carotenoid levels on
DWLs via logistic regression analysis.
Results: Lower gamma-tocopherol levels were significantly associated with DWLs in all subjects. While lower
gamma-tocopherol and vitamin C levels were significantly associated with DWLs in males, lower delta-
tocopherol levels were associated with DWLs in females. The associations between DWLs and lower gamma-
and delta-tocopherol and vitamin C levels were independent of age, hypertension, or smoking. However, the
associations between DWLs and lower alfatocopherol were not significant following adjustments for smoking.
Conclusion: Lower carotenoid and vitamin levels were independently associated with cerebral DWLs in
J Ophthalmic Vis Res. 2012 Jul;7(3):261-7.
Autofluorescence Imaging for Diagnosis and Follow-up of Cystoid Macular Edema.
Ebrahimiadib N, Riazi-Esfahani M.
Lipofuscin results from digestion of photoreceptor outer segments by the retinal pigment epithelium (RPE) and
is the principal compound that causes RPE fluorescence during autofluorescence imaging. Absorption of the
488-nanometer blue light by macular pigments, especially by the carotenoids lutein and zeaxanthin, causes
normal macular hypo-autofluorescence. Fundus autofluorescence imaging is being increasingly employed in
ophthalmic practice to diagnose and monitor patients with a variety of retinal disorders. In macular edema
for example, areas of hyper-autofluorescence are usually present which are postulated to be due to
December 27, 2012
dispersion of macular pigments by pockets of intraretinal fluid. For this reason, the masking effect of
macular pigments is reduced and the natural autofluorescence of lipofuscin can be observed without
interference. In cystic types of macular edema, e.g. cystoid macular edema due to retinal vein occlusion,
diabetic macular edema and post cataract surgery, hyper-autofluorescent regions corresponding to cystic spaces
of fluid accumulation can be identified. In addition, the amount of hyper-autofluorescence seems to correspond
to the severity of edema. Hence, autofluorescence imaging, as a noninvasive technique, can provide
valuable information on cystoid macular edema in terms of diagnosis, follow-up and efficacy of
J Sci Food Agric. 2012 Nov 16. [Epub ahead of print]
Plasma carotenoid concentrations of infants are increased by feeding a milk-based infant formula
supplemented with carotenoids.
Mackey AD, Albrecht D, Oliver J, Williams T, Long AC, Price PT.
BACKGROUND: Human milk is the gold standard of infant nutrition and is a source of important substances,
including carotenoids. Infant formulas are designed to mimic the composition and/or performance of human
milk, although currently carotenoids are not routinely added to US infant formulas. The aim of this study was to
assess plasma concentrations of β-carotene, lutein and lycopene 56 days after feeding infants milk-based infant
formula without (CTRL) or with different concentrations of added carotenoids (L1 and L2).
RESULTS: Plasma carotenoid concentrations increased in infants fed carotenoid-supplemented formulas
as compared with the control formula with no added carotenoids. At study day 56, infants fed the
supplemented formulas (L1 and L2) had mean plasma lutein, β-carotene and lycopene concentrations
that were within the range of a concurrent group of human milk-fed infants (HM). Anthropometric
measurements were comparable among all study groups.
CONCLUSION: Plasma carotenoid concentrations of infants fed the supplemented formulas were within the
range of the HM group and are consistent with reported plasma carotenoid ranges in human milk-fed infants.
The experimental formulas were well tolerated and anthropometric measurements were comparable among
all study groups.
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J Pediatr Gastroenterol Nutr. 2012 Dec 18. [Epub ahead of print]
Resonance Raman Spectroscopy and the Preterm Infant Carotenoid Status.
Chan GM, Chan MM, Gellermann W, Ermakov I, Ermakova M, Bhosale P, Bernstein P, Rau C.
OBJECTIVE: To validate the noninvasive resonance Raman spectroscopy method in infants in comparison
with the high performance liquid chromatography (HPLC) method, and to evaluate the carotenoid status in
preterm infants fed mother's milk or formula
STUDY DESIGN: In the first phase of this study, resonance Raman measurements were made on male
term infants' skin and correlated with tissue harvested at the time of circumcision. Each baby's foreskin
was weighed, enzymatically digested, and the total carotenoids were extracted and quantitated by the HPLC.
Next, to evaluate the carotenoid status of preterm infants (BW <1500 g), the skin and serum carotenoids in
infants fed either human milk or preterm formula were studied from the start of feedings and every two weeks
until hospital discharge. Skin carotenoids were measured by resonance Raman spectroscopy and the serum total
carotenoids by HPLC.
RESULTS: Foreskin carotenoid levels measured by resonance Raman spectroscopy correlated with HPLC
measurements of total serum carotenoids (R=0.52, P<0.01, n=16). Forty preterm infants were studied for their
carotenoid status. Thirty-two infants were fed mother's milk while 8 were fed a preterm infant formula that was
not enriched with carotenoids. The gestation and birth weight of the two feeding groups were similar. The
infants fed human milk had a higher serum total carotenoid concentration and skin Raman counts than formula
December 27, 2012
fed infants. The skin Raman counts and total serum carotenoid correlated, (R=0.44, P=0.01). The human milk
fed infants' serum total carotenoid concentrations and Raman values did not change during the study period;
however, the formula fed group's total serum and skin carotenoid decreased significantly during the study.
CONCLUSION: Resonance Raman spectroscopy of infant's skin reliably assesses total carotenoid status
noninvasively. Human milk fed preterm infants have higher serum and skin carotenoids than formula
fed infants suggesting that formula fed infants might benefit from carotenoid supplementation.
Bull Exp Biol Med. 2012 Jul;153(3):375-7.
Systemic markers of age-related changes in the lens.
Kudryavtseva YV, Chuprov AD, Ivanova IP, Tsapok PI, Tsibel' VB, Bojko ER.
A dependency was found between total protein content and cataract maturity (P=-0.91, p<0.01). LPO intensity
sharply increased and remained stably high after appearance of lens opacity. A strict negative correlation was
found between the content of polyunsaturated fatty acids in earwax and lens nucleus (P=-0.7, p<0.01). The
content of conjugated dienes, crotonic aldehyde, and Schiff bases decreased during cataract development. The
content of vitamins B(2), A, and E decreased with increasing brown coloration of lens nucleus. Studying the
parameters of lipid metabolism in wax-producing glands of the external ear canal we can evaluate the
disturbances in lipid metabolism in the lens, which was confirmed by the correlation between fatty acid
composition of the earwax and lens nucleus. These data do not demonstrate the dependence of the lens state
on earwax, but suggest general features of the process in organs and tissues during aging. Some markers in the
blood of patients with cataract change during progress of lens opacity and intensification of brown coloration of
lens nucleus, but these changes are inspecific and reflect general activation of peroxidation processes and
Eur J Pharm Biopharm. 2012 Dec 13. [Epub ahead of print]
Influence of dietary carotenoids on radical scavenging capacity of the skin and skin lipids.
Meinke MC, Friedrich A, Tscherch K, Haag SF, Darvin ME, Vollert H, Groth N, Lademann J, Rohn S.
Nutrition rich in carotenoids is well known to prevent cell damage, premature skin aging, and skin cancer.
Cutaneous carotenoids can be enriched in the skin by nutrition and topically applied antioxidants have shown an
increase in radical protection after VIS/NIR irradiation. In this paper, it was investigated whether orally
administered carotenoids increase the radical scavenging activity and the radical protection of the skin using in
vivo electron paramagnetic resonance spectroscopy and the skin lipid profile was investigated applying HPTLC
on skin lipid extracts. Furthermore, in vivo Raman resonance spectroscopy was used to measure the cutaneous
carotenoid concentration. A double blind placebo controlled clinical study was performed with 24 healthy
volunteers, who have shown a slow but significant and effective increase in cutaneous carotenoids in the verum
group. The enhancement in carotenoids increases the radical scavenging activity of the skin and provides
a significant protection against stress induced radical formation. Furthermore, the skin lipids in the
verum group increased compared to the placebo group but only significantly for ceramide [NS]. These
results indicate that a supplementation with dietary products containing carotenoids in physiological
concentrations can protect the skin against reactive oxygen species and could avoid premature skin aging
and other radical associated skin diseases.
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British Journal of Nutrition, Volume 108, Issue 11, 14 December 2012, Pages 2054-2065
Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects
Farges, M.-C., Minet-Quinard, R., Walrand, S., Thivat, E., Ribalta, J., Winklhofer-Roob, B., Rock, E., Vasson,
December 27, 2012
Prospective studies have indicated an age-related impairment of the immune response. Carotenoids have been
hypothesised to enhance immune cell function. The aim of the present study was to describe the age-related
effects and the impact of in vivo dietary carotenoid depletion and repletion on specific and non-specific
immunity. A total of ninety-eight healthy male subjects (aged 20-75 years) received a carotenoid-depleted
diet for 3 weeks and were then supplemented daily for 5 weeks with 30mg β-carotene, 15mg lycopene and
9mg lutein. Blood samples were collected at study entry, after depletion and supplementation, and biomarkers
of immune status were determined. We found that serum IgA levels were positively correlated with ageing.
Lymphocyte phenotyping indicated an increase with age in the memory T-helper cell subpopulation
(CD4+CD45RO+) concomitantly with a decrease in naive T-helper cells (CD4+CD45RA+). A significant
increase in the natural killer cells subpopulation and a small decrease in B lymphocytes were also observed,
especially for the oldest volunteers. From ex vivo cell function exploration, a positive correlation was observed
between age and IL-2 production of phytohaemagglutinin-stimulated lymphocytes. Neutrophils' bactericidal
activity was significantly impaired with age (from 50 years) and was modulated by carotenoid status. An
age effect was found on neutrophils' spontaneous migration but not on directed migration. Immune
response in healthy human subjects is mostly affected by age rather than by dietary carotenoid depletion
and repletion. Even in carefully selected healthy volunteers, some age-related immune changes occur
predominantly from 50 years onwards. This immunosenescence could generate a loss in the immune
system adjustment capacity.
Cancer Prev Res (Phila). 2012 Dec 28. [Epub ahead of print]
β-Cryptoxanthin Restores Nicotine-Reduced Lung SIRT1 to Normal Levels and Inhibits Nicotine-
Promoted Lung Tumorigenesis and Emphysema in A/J Mice.
Iskandar AR, Liu C, Smith DE, Hu KQ, Choi SW, Ausman LM, Wang XD.
Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data
supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced
emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-
butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was
accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has
been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of
AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid
receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-
cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several
cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX
supplementation at two different doses was associated with reductions of the nicotine-promoted lung
tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine.
Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and
RAR-β to that of the control group, increased survival probability; and decreased the levels of lung il-6
mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against
emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant
animal lung cancer model for studying tumor growth within emphysematous microenvironments.