Access to this full-text is provided by Frontiers.
Content available from Frontiers in Nutrition
This content is subject to copyright.
NUTRITION
REVIEW ARTICLE
published: 01 September 2014
doi: 10.3389/fnut.2014.00014
Zinc is an antioxidant and anti-inflammatory agent: its role
in human health
Ananda S. Prasad*
Department of Oncology and Barbara Ann Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI, USA
Edited by:
Hasan Mukhtar, University of
Wisconsin-Madison, USA
Reviewed by:
Luigi Iuliano, Sapienza University of
Rome, Italy
Hasan Mukhtar, University of
Wisconsin-Madison, USA
*Correspondence:
Ananda S. Prasad, Department of
Oncology,Wayne State University
School of Medicine, 421 East
Canfield, Detroit, MI 48201, USA
e-mail: prasada@karmanos.org
Zinc supplementation trials in the elderly showed that the incidence of infections was
decreased by approximately 66% in the zinc group. Zinc supplementation also decreased
oxidative stress biomarkers and decreased inflammatory cytokines in the elderly. In our
studies in the experimental model of zinc deficiency in humans, we showed that zinc
deficiency per se increased the generation of IL-1βand its mRNA in human mononuclear
cells following LPS stimulation. Zinc supplementation upregulated A20, a zinc transcrip-
tion factor, which inhibited the activation of NF-κB, resulting in decreased generation of
inflammatory cytokines. Oxidative stress and chronic inflammation are important contribut-
ing factors for several chronic diseases attributed to aging, such as atherosclerosis and
related cardiac disorders, cancer, neurodegeneration, immunologic disorders and the aging
process itself. Zinc is very effective in decreasing reactive oxygen species (ROS). In this
review, the mechanism of zinc actions on oxidative stress and generation of inflammatory
cytokines and its impact on health in humans will be presented.
Keywords: zinc, anti-inflammatory agent, antioxidant agent, oxidative stress, inflammatory cytokines
INTRODUCTION
Essentiality of zinc for human health was recognized only 50 years
ago (1,2). Currently, World Health Organization (WHO) esti-
mates that nearly two billion subjects in the developing world may
be zinc deficient. The clinical manifestations of zinc deficiency
include growth retardation, testicular hypofunction, immune dys-
functions, increased oxidative stress, and increased generation of
inflammatory cytokines (3–8). If severe zinc deficiency, as seen in
patients with acrodermatitis enteropathica (AE), is not recognized
and treated promptly with zinc administration, it may become
fatal (9).
Zinc has now been used to treat and prevent diarrhea in infants
and children throughout the world resulting in saving millions
of lives (10,11). Zinc is an effective therapeutic agent for the
treatment of Wilson’s disease (12).
The severity and duration of common cold may be decreased
significantly with the proper use of zinc lozenges (13,14). The pro-
gression of age-related macular degeneration (AMD) and its com-
plications and blindness in the elderly has been shown to be effec-
tively managed by the use of the therapeutic zinc supplementation
(15–18).
The studies of age-related eye diseases study group (AREDS)
in AMD subjects has shown that during 10 years of follow-up, the
mortality due to cardiovascular events in the elderly was signifi-
cantly decreased in the zinc group (18). These clinical effects of
zinc supplementation in humans are very impressive and have a
high impact on human health.
The study of the roles of zinc in basic biochemical and mol-
ecular biology fields has also advanced tremendously during the
past half a century. We now know that over 300 enzymes require
zinc for their activation or stability of structures and there are over
2000 transcription factors that are involved in gene expression of
proteins that are zinc-dependent (7). We have now learned that
zinc is a molecular signal for immune cells and that homeostasis
of intracellular Zn++ levels are maintained by 14 ZIP (SLC 39A)
and 10 ZNT (SLC 30A) transporters.
In this review article, I will briefly describe the history of dis-
covery of zinc as an essential element for humans and discuss the
clinical manifestation of zinc deficiency and the role of zinc in cell-
mediated immunity and as an antioxidant and anti-inflammatory
agent in humans.
DISCOVERY OF HUMAN ZINC DEFICIENCY
Zinc was known to be essential for the growth of plants and ani-
mals but its role in human health was not known until 1963
(2). The story of zinc in human health began when an Iranian
physician presented to me a 21years-old male patient who was
severely anemic at the Medial Center grand round at Saadi Hos-
pital, University of Shiraz Medical School. In the fall of 1958,
following my training under Dr. C. J. Watson at the University
of Minnesota Medical School as a clinical investigator, I went
to Shiraz, Iran to teach the medical students in Shiraz Medical
School. The patient was severely retarded in growth. Although
he was 21-years-old chronologically, he looked like a 10-years-
old male. He had infantile genitalia, rough and dry skin, mental
lethargy, hepatosplenomegaly, and geophagia. He ate only bread
made of whole wheat flour and the intake of animal protein was
negligible. He also ate 1 pound of clay daily. This habit of clay eat-
ing (geophagia) was common in the villages around Shiraz, Iran
(1). The anemia was severe. The hemoglobin was 5 g% and we
determined that the patient was severely iron deficient. Although
he was iron deficient, we found no evidence of blood loss (See
Figure 1). Later, I discovered that this syndrome of iron defi-
ciency, anemia, hepatosplenomegaly, hypogonadism, dwarfism,
www.frontiersin.org September 2014 | Volume 1 | Article 14 | 1
Prasad Zinc: antioxidant and anti-inflammatory agent
FIGURE 1 | A picture of four dwarfs from Iran. From left to right (i) Age
21 years, height 4 ft, 11 (1/200); (ii) age 18 years, height 4ft 900 ; (iii) age
18 years, height 4 ft 700; (iv) age 21 years, height 4ft 700 Staff physician at left
is 6 ft in height (1).
and geophagia was common in the villages near Shiraz, Iran (1).
The extreme growth retardation affected approximately 10% of
the villagers.
This interesting case presented two major clinical dilemmas
for me. One was that how did this patient become severely iron
deficient when there was no blood loss? The second problem was
that I could not explain growth retardation and hypogonadism on
the basis of iron deficiency, inasmuch as growth retardation and
testicular atrophy are not observed in iron-deficient animals and
humans. An examination of the Periodic Table suggested to me
that deficiency of zinc may have been also present accounting
for the growth failure and testicular hypofunction. We, there-
fore, hypothesized that a high phosphate content of their diet and
geophagia may have caused malabsorption of both iron and zinc,
resulting in the deficiency of both elements (1). In Shiraz, we had
no facility to assay zinc in the plasma.
I subsequently moved to Cairo, Egypt and studied this syn-
drome extensively at the US Naval Medical Research Unit No. 3.
My research was supported by the Vanderbilt University, School
of Medicine, Department of Biochemistry and Medicine, and US
Navy and NIH.
We observed that zinc concentrations in plasma, red blood cells,
hair, and total zinc in 24-h urine were decreased in the Egyptian
dwarfs. Zn65 studies showed that the plasma zinc turn-over rate
was increased and the 24-h exchangeable pool was decreased in
the dwarfs in comparison to the controls (2). We also showed
that the zinc supplementation to these dwarfs resulted in 12.7–
15.2 cm of longitudinal growth in 1 year and the genitalia size
became normal within 3–6 months of zinc supplementation. Thus,
our studies showed for the first time that zinc was essential for
humans and that its deficiency occurred in the Middle East (3).
The details of the circumstances leading to the discovery of human
zinc deficiency have been recently published (19).
For nearly one decade, the suggestion that zinc deficiency
occurred in humans remained very controversial. In 1974,
however, National Research Council of the National Academy
of Sciences declared zinc as an essential element for humans
and established a recommended dietary allowance (RDA) (20).
In 1978, FDA made it mandatory to include zinc in the total
parenteral nutritional fluids (21).
It has been now estimated by WHO that nearly two billion sub-
jects may be zinc deficient in the developing countries. This is due
to the fact that most of these populations consume mainly bread
made of whole wheat flour, which is high in phosphate compound
that decreases the absorption of both iron and zinc. The phytate
to zinc molar ratio >20 in a diet is unfavorable for zinc absorption
and this may lead to zinc deficiency.
In the developed countries, zinc deficiency is also prevalent in
the elderly population (approximately 30% may be zinc deficient).
25–30% of the Black-Americans and Mexican-Americans are also
zinc deficient and approximately 25% of the pre-menopausal
women of the child bearing ages are vulnerable to zinc deficiency
(7,22).
Conditioned deficiency of zinc in patient with alcoholic cir-
rhosis of the liver, chronic alcoholism with hyperzincuria, chronic
renal disease, patients with malabsorption syndrome, and patients
with sickle cell disease (SCD) who exhibit hyperzincuria due to
persistent hemolysis are some of the examples of conditioned
deficiency of zinc commonly seen in the world (7). Patients with
chronic diseases including malignancies have poor appetite, and
therefore, they are vulnerable to zinc deficiency. It is, thus, clear
that zinc deficiency is fairly common in clinical practice but sadly
the clinicians do not recognize this problem.
CLINICAL MANIFESTATIONS OF ZINC DEFICIENCY
There is a spectrum of clinical deficiency of zinc in humans. The
symptoms may be very severe and even fatal if not recognized
and treated promptly by zinc such as seen in patients with AE. AE
is a genetic disorder mainly affecting infants of Italian, Armen-
ian, or Iranian lineage (7,9). The manifestations include bullous
pustular dermatitis, particularly around the orifices. Opthalmic
signs include blepharitis, conjunctivitis, photophobia, and corneal
opacities. Neuropsychiatric signs include irritability, emotional
instability, tremors and cerebellar ataxia, weight loss, growth fail-
ure, and male hypodonadism are prominent features. Congenital
malformation of fetuses and infants born of pregnant women with
AE has been reported frequently (23).
Acrodermatitis enteropathica patients are very susceptible to
infections. Thymic hypolasia and plasmacytosis in the spleen are
commonly seen in experiment animals. T cell-mediated immune
disorders are corrected by zinc supplementation. Without zinc
supplementation, the clinical course is downhill with failure
to thrive and complicated by intercurrent bacterial, viral, fun-
gal, and opportunistic infections. Gastrointestinal manifestations
include diarrhea, malabsorption, steatorrhea, and lactose intol-
erance. Zinc supplementation in therapeutic doses (in excess of
50 mg elemental zinc daily) results in complete recovery.
Acrodermatitis enteropathica gene has been localized to a
~3.5 cm region on 8q 24 chromosome. The gene encodes for ZIP-4
known as one of the zinc transporter. In AE, mutations of this gene
have been documented (24). Because of this mutation, intestinal
absorption of zinc is affected adversely.
Frontiers in Nutrition | Clinical Nutrition September 2014 | Volume 1 | Article 14 | 2
Prasad Zinc: antioxidant and anti-inflammatory agent
Severe deficiency of zinc has been observed in patients who
receive total parenteral nutrition without zinc for prolonged
period (25). Zinc is now routinely included in parenteral fluids
to prevent this complication. Severe deficiency of zinc has also
been observed in a patient with Wilson’s disease, who received
penicillamine, which reduces the copper burden (26).
In moderate deficiency of zinc, the clinical manifestations
include growth retardation, testicular failure, rough skin, poor
appetite, mental lethargy,delayed wound healing, T cell-mediated
immune dysfunction, and neurosensory disorders (7). Females are
equally susceptible to zinc deficiency and their ovarian functions
are also affected adversely due to zinc deficiency (7). Moderate
deficiency of zinc is commonly seen in patients with nutritional
deficiency of zinc throughout the world and many patients who
develop conditioned deficiency of zinc.
The recognition of mild deficiency of zinc is difficult. In order
to characterize this, we developed a human model of experimental
mild zinc deficiency state in human volunteers. This was accom-
plished by the use of a semi-purified experimental diet, which
supplied 3.0–5.0 mg of zinc daily (27). All other essential nutri-
ents were adequate meeting RDA (RDA). The details of these
experiments have been published earlier (27).
In this model, as a result of zinc deficiency, we observed
decreased serum testosterone level, oligospermia, decreased NK
cell (natural kill cell) lytic activity, decreased IL-2 activity of
T helper cells, decreased serum thymulin activity (thymulin is
a thymic hormone essential for the development and matura-
tion of T cells), hyperammonemia, hypogeusia, decreased dark
adaptation, and decreased lean body mass (27–29). It is clear
from this study that even a mild deficiency of zinc in humans
may affect clinical, biochemical, and immunological functions
adversely.
Currently, the most widely used test for diagnosing zinc defi-
ciency in humans is the determination of plasma zinc level. In our
laboratory, normal levels of plasma zinc in adults and children
are 100 ±10 µg/dl. Values below 80 µg/dl will be considered to
be in the deficient range. Measurement of plasma zinc by flame-
less atomic absorption specifically is useful provided the sample
is not hemolyzed or contaminated. In patients with acute stress
or infection, zinc from the plasma pool may redistribute to other
compartments, thus making the diagnosis of zinc deficiency diffi-
cult. Intravascular hemolysis would also increase the plasma zinc
level, inasmuch as the zinc in the red cells is much higher than in
the plasma (7). Plasma zinc level of <50 µg/dl would be indicative
of severe deficiency of zinc.
In our experience, determination of zinc in the lymphocytes,
plasma somatomedin activity, and measurement of IL-2 mRNA in
PHA stimulated mononuclear cells by reverse transcriptase (RT)-
polymerase chain reaction (PCR) are the most sensitive tests for
diagnosing zinc deficiency in humans (7). Zinc supplementation
to humans corrects the plasma zinc levels and all other parameters
mentioned above.
Recommended daily dietary allowances (RDA) for infants up
to 1 year is 3–5 mg, for children from 1 to 10 years is 10 mg, and for
adults (both males and females) it is 15 mg. For pregnant women,
RDA is 20 mg and for lactating women RDA is 25 mg.
OXIDATIVE STRESS AND CHRONIC INFLAMMATION IN THE
ELDERLY
Oxidative stress is an important contributing factor for several
chronic diseases attributed to aging, such as atherosclerosis and
related cardiac disorders, cancer, neurodegeneration, immuno-
logic disorders, and the aging process itself (5,6). Together, ·O−
2,
H2O2, and ·OH are known as reactive oxygen species (ROS) and
they are continuously being produced in vivo under aerobic con-
ditions. In eukaryotic cells, the mitochondrial respiratory chain,
microsomal cytochrome P450 enzymes, flavoprotein oxidases,
and peroxisomal fatty acid metabolism are the most significant
intracellular sources of ROS (6). The nicotinamide adenine din-
ucleotide phosphate (NADPH) oxidases are a group of plasma
membrane-associated enzymes, which catalyze the production of
·O−
2, from oxygen by using NADPH as the electron donor (6,7).
Zinc is an inhibitor of NADPH oxidase,which results in decreased
generation of ROS. Zinc is also a co-factor of super oxide dismu-
tase (SOD) an enzyme that catalyzes the dismutation of ·O−
2, to
H2O2. Zinc also induces the generation of metallothionein, which
is very rich in cysteine and is an excellent scavenger of ·OH.
Although the role of zinc as an antioxidant in cell cultures and
animal models have been observed earlier,our studies showed for
the first time the role of zinc as an antioxidant in the elderly.
We observed that zinc supplementation to healthy human
subjects aged 20–50 years decreased the concentration of MDA
(malondialdehyde), 4 hydroxy alkenals (HAE), and 8-hydroxy
deoxyguanine in the plasma (30). This demonstrated that the
oxidative stress markers were decreased by zinc supplementa-
tion in young adult human subjects (30). We also observed that
the ex vivo induction of TNF-αand IL-1βmRNA in mononu-
clear cells were inhibited in zinc supplemented subjects and this
resulted in decreased TNF-αinduced nuclear factor-κB (NF-κB)
activation in isolated MNCs (mononuclear cells) (30). We also
reported that the gene expression of A20 and the binding of A20
transactivating factor to DNA were increased,resulting in the inhi-
bition of NF-κB activation (30). NF-κB is involved in the gene
expression of TNF-αand IL-1βin monocytes and macrophages
in humans and HL-60 cells (human promyelocytic leukemia cell
line, which differentiates to the monocyte and macrophage phe-
notype in response to PMA). This effect of zinc, inhibition of
the gene expression of TNF-αand IL-1βin these cells is cell
specific (30).
In order to understand the mechanism of zinc effect on cell-
mediated immunity, we utilized RT-PCR analysis to determine
PHA (phytohemagglutinins) induced expression of IL-2 mRNA in
isolated MNCs in elderly subjects before and after zinc supplemen-
tation. Since zinc supplementation to younger subjects decreased
the generation of inflammatory cytokines and decreased oxidative
stress markers (30), we hypothesized that zinc supplementation
would not only increase the generation of IL-2 in MNCs but also
decrease the generation of inflammatory cytokines and decrease
oxidative stress in the elderly.
We recruited 50 healthy elderly subjects of both sexes (aged
55–87 years) and all ethnic groups from a senior citizen center
in Detroit, MI, USA to participate in a randomized, placebo-
controlled trial of the efficacy of zinc with respect to the incidence
www.frontiersin.org September 2014 | Volume 1 | Article 14 | 3
Prasad Zinc: antioxidant and anti-inflammatory agent
Table 1 | A comparison of selected variables in young adults
(18–54 years old) and in older subjects (>55 years old).
VariablesaYoung adults Older subjects pValuec
Plasma zinc (µg/dl) 101.4 ±10.0a(31)b94.3 ±11.4 (49)0.046
Plasma ICAM-1 (ng/ml) 538 ±112.7 (25)652.6 ±169.8 (47)0.001
Plasma
VCAM-1 (ng/ml)
1766 ±480.4 (25)2209 ±890.5 (46)0.008
Plasma E-selectin
(ng/ml)
32.2 ±13.1 (19)6±47.6 (69)0.001
Plasma NO (µM) 42.7 ±10.9 (24)55.6±14.7 (36)0.001
Plasma MDA (µM) 0.36 ±0.10 (16)0.49 ±0.15 (34) <0.001
IL-1 β(% cells) 0.5 ±9.2 (28)0.4 ±23.5 (48)0.023
IL-1 βgenerated (pg/ml) 0.5 ±110.9 (31)0.3 ±423.3 (28)0.004
TNF-α(% cells) 10.18 ±10.86 (22)18.25±20.5 (48)0.035
TNF-αgenerated
(pg/ml)
1522 ±390 (26)1882±722.6 (24)0.036
Ref (5).
aValues represent mean±SD; bnumber of subjects; ct-test.
Table 2 | Effect of zinc and placebo supplementation on clinical
variables.
Variables Percentage of subjects
affected in 1year
Zinc
group
(n=24)
Placebo
group
(n=25)
Chi square
Fishers exact
test, p
Infection 29 88 <0.001
Upper respiratory
Tract infection 12 24 0.136
Tonsillitis 0 8 0.255
Common cold 16 40 0.067
Cold sores 0 12 0.124
Flu 0 12 0.124
Fever 0 20 0.027
One infection each/year 29% 52%
Two infections each/year 0 24%
Three infections each/year 0 8%
Four infections each/year 0 4%
Received antibiotics 8% 48%
Ref (5).
Each person could appear in more than one sub-category of infection.
of infections and the effect on ex vivo generated inflammatory
cytokines and plasma oxidative stress markers (5).
Exclusion criteria included life expectancy of <8 months, pro-
gressive neoplastic disease, severe cardiac dysfunction, significant
Table 3 | Effect of zinc and placebo supplementation on plasma
oxidative stress markers.
Baseline 6 months p=(time ×groupa)
MDA +HAE (µmol/l)
Zinc suppl.b1.66 ±0.34c1.35 ±0.18 0.0002
Placebo suppl.c1.70 ±0.30 1.71 ±0.35
8-OHdG (ng/ml)
Zinc suppl. 0.63 ±0.16 0.50 ±0.14 0.030
Placebo suppl. 0.66 ±0.13 0.68 ±0.13
Nitric oxide (µmol/l)
Zinc suppl. 87.34 ±8.08 79.01 ±10.96 0.180
Placebo suppl. 89.43 ±11.72 86.74 ±9.28
Ref (5).
ap Value for change in groups over time. Multivariate repeated measures analy-
ses were used to examine measures over time. bZinc (n =13) or placebo (n=11)
supplemented subjects. cValues represent mean ±SD. There were no signifi-
cant differences (t-test) in oxidative stress markers between the two groups at
baseline.
Table 4 | Effect of zinc and placebo supplementation on interleukin
(IL)2 mRNA and plasma zinc concentration in zinc-deficient elderly
subjects.
Baseline 6 months p=(time ×groupa)
IL-2 mRNAb
Zinc suppl.c0.38 ±0.07d0.63 ±0.03 <0.001
Placebo suppl.d0.40 ±0.05 0.39 ±0.04
Plasma Zne
Zinc suppl. 84.0 ±3.03 97.6 ±5.98 <0.0088
Placebo suppl. 0.8 ±2.04 89.2 ±3.06
Ref (5).
ap Value for change in groups over time. Multivariate repeated measures analy-
ses were used to examine measures over time. bRelative expression of IL-2
mRNA/18S. cZinc supplemented (n=6) or placebo supplemented (n =6) zinc-
deficient elderly subjects. dValues represent mean ±SD. There was no significant
difference (t-test) in IL-2 mRNA between the two groups at baseline. In spite of
the random assignment of zinc-deficient subjects into zinc and placebo group,
the plasma zinc level was lower in the zinc group in comparison to the placebo
group (p =0.016). ePlasma zinc levels (microgram per deciliter).
kidney, and liver disease. We also excluded those who were self-
supplementing with zinc, who were not mentally competent, and
who could not provide informed consent. The zinc supplemented
group received 45mg elemental zinc as gluconate daily.
A comparison of baseline data between the younger subjects
and the elderly subjects is shown in Table 1. Plasma zinc was lower
and the percentage of cells producing IL-1βand TNF-αand the
generated levels of these cytokines were significantly higher in the
elderly subjects. Generated IL-10 was also significantly higher in
the elderly. This cytokine is known to produce a negative effect on
IL-2 generation by Th1 cells. The plasma oxidative stress markers
also were significantly higher in the elderly in comparison to the
younger adults.
Frontiers in Nutrition | Clinical Nutrition September 2014 | Volume 1 | Article 14 | 4
Prasad Zinc: antioxidant and anti-inflammatory agent
FIGURE 2 | Zinc is an integral part of a thymic hormone molecule,
thymulin.Thymulin is required for maturation ofT cells. Zinc
deficiency-induced decrease in thymulin activity is associated with
decreased maturation of T cells and Th1 production of IL-2 and INF-γ.
Decreased IL-2 leads to decreased NK and T cytolytic cell activities.
Macrophages–monocytes produce IL-12 (a zinc-dependent cytokine), which
along with INF-γkills parasites, viruses, and bacteria. Th2 cytokines, in
general are not affected by zinc deficiency except IL-10, which may be
increased in zinc-deficient elderly individuals. Increased IL-10 from Th2 cells
further affectsTh1 functions adversely.Thus, in zinc deficiency there is a
shift fromTh1 to Th2 functions and cell-mediated immune functions are
impaired. Zinc deficiency also leads to stress and activation of
macrophages–monocytes, resulting in increased generation of
inflammatory cytokines, IL-1β, IL-6, IL-8, and TNF-α. Solid lines indicate
pathways leading to generation of selected cytokines and dotted lines
represent pathways, which lead to inhibition of cytokine generation. NK
represent natural-killer cells; Th1 represent activated Th1 type T cells and
secreted cytokines (small triangles); Th2 represents activated Th2 type T
cells and secreted cytokines (small rounds); B-cell represents B-cell
lineages and associated immunoglobulins (triangles). (Prasad, AS. Zinc: role
in immunity, oxidative stress and chronic inflammation. Current Opinion in
Clin Nutr and Metab Care, 12:646–652, 2009)
Table 2 shows the effect of zinc supplementation on clinical
variables. The mean incidence of infections in 12 months was sig-
nificantly lower (p<0.01) in the zinc supplemented group than
in the placebo group. In the zinc supplemented group, the total
incidence of infections in 12 months was 7, whereas in the placebo
group it was 35.
The changes in plasma markers of oxidative stress
(MDA +HAE and 8-OHdG) between baseline and at the end of
6 months of zinc supplementation showed a greater significant
decrease compared to the placebo group (6) (Table 3).
With time (12 months of zinc supplementation), the plasma
zinc in the zinc group increased significantly. Whereas in the
placebo group, it tended to remain lower. Also with time, the ex
vivo generation of TNF-αdecreased significantly in the zinc group
and increased significantly in the placebo group. The reduction
in TNF-αconcentration was maximal at the end of 6 months. Ex
vivo generation of IL-10 decreased non-significantly in the zinc
group. Tables 4 and 5show the changes in the plasma zinc levels
following supplementation.
In MNCs isolated from zinc-deficient elderly, zinc supple-
mentation increased the ex vivo PHA-induced IL-2 mRNA and
plasma zinc concentration, whereas placebo treated zinc-deficient
subjects showed no such changes (5,6) (Table 4). Our study
in the elderly showed that zinc supplementation decreased the
incidence of infections significantly (5). Zinc deficiency not only
affects adversely the thymulin (a thymic hormone) activity but
also decreases the generation of IL-2 and IFN-γfrom Th1 cells.
Zinc deficiency also decreases IL-12 generation from macrophages.
IL-12 and IFN-γare required for optimal phagocytic activity of
macrophages against parasites, viruses, and bacteria.
In our experimental human zinc deficiency model, even a mild
deficiency increased ex vivo generation of IL-1βby monocytes,
suggesting that zinc deficiency per se may activate monocytes and
macrophages to generate inflammatory cytokines and increase
oxidative stress (28). Our study showed that zinc supplementation
improved Th1 cells cytokines production, decreased generation of
inflammatory cytokines, and decreased oxidative stress. Figure 2
summarizes our concept of the role of zinc in cell-mediated
immunity.
EFFECT OF ZINC SUPPLEMENTATION ON OXIDATIVE STRESS
AND INFLAMMATORY CYTOKINES IN THE ELDERLY
Oxidative stress and inflammatory cytokines have been implicated
in many chronic diseases in the elderly including atherosclero-
sis. It is a slowly progressive chronic inflammatory condition
characterized by focal arterial lesions that ultimately occlude the
blood vessels and may lead to angina, myocardial infarction,
stroke, and sudden death. Classical risk factors for atherosclerosis
www.frontiersin.org September 2014 | Volume 1 | Article 14 | 5
Prasad Zinc: antioxidant and anti-inflammatory agent
Table 5 | Changes in plasma zinc, oxidative stress makers, and inflammatory cytokines/molecules in zinc supplemented (Zn supp) elderly
subjectsa(6).
Group nPre Post PbChangec∆Pd
Zinc (µM)
Placebo 20 92.0 ±3.8e,f 90.8 ±5.0 0.134 −1.17 ±4.59 <0.0001
Zn supp 20 91.9 ±7.4e101.5 ±9.2 0.00006 9.52 ±8.88
MDA +HAE (µM)
Placebo 14 1.66 ±0.37e1.68±0.35 0.357 0.019 ±0.186 0.002
Zn supp 14 1.59 ±0.40e1.29 ±0.26 0.0011 −0.30 ±0.30
Antioxidant power (U/mL)
Placebo 20 6.6 ±2.2e6.5 ±1.7 0.417 −0.11 ±2.32 0.0258
Zn supp 20 6.0±1.6e7.6 ±1.9 0.0001 1.56 ±2.23
hsCRP (µg/L)
Placebo 20 2.14 ±1.71e2.49 ±1.94 0.149 0.36 ±1.45 0.0298
Zn supp 20 2.46 ±1.91e1.90±1.51 0.015 −0.55 ±1.05
IL-6 (pg/mL)
Placebo 20 5.42 ±3.47e7.15 ±4.56 0.026 1.74 ±3.76 0.0031
Zn supp 20 8.34 ±7.13e5.44 ±4.85 0.013 −2.94 ±5.46
MCP-1 (pg/mL)
Placebo 20 496.5 ±154.0e570.4 ±205.4 0.011 74.1 ±133.3 0.0113
Zn supp 20 531.5 ±142.7e506.8 ±131.0 0.136 −24.25 ±97.2
sPLA (U/mL)
Placebo 20 76.0 ±25.8e100.6 ±28.8 0.001 24.6 ±30.9 0.006
Zn supp 20 73.3 ±34.6e70.0 ±32.2 0.314 −3.23 ±29.5
sVCAM-1 (ng/mL)
Placebo 20 2102.9 ±415.1e2297.6 ±358.2 0.0 024 194.7 ±273.1 <0.0001
Zn supp 20 2208.0 ±345.6e2035.0 ±267.8 0.001 −171.5 ±218.5
sICAM-1 (ng/mL)
Placebo 20 321.1 ±89.1e302.7 ±105.6 0.307 −18.40 ±160.4 0.830
Zn supp 20 301.3 ±68.9e292.4 ±75.6 0.365 −8.90 ±113.6
sE-selectin (ng/mL)
Placebo 20 54.7 ±8.3e57.5 ±7.3 0.023 2.73 ±5.70 0.0068
Zn supp 20 57.2 ±9.7e51.6 ±8.6 0.023 −5.65±11.7
aPre, baseline; Post, after 6 months; MDA +HAE, malondialdehyde and hydroxyalkenals; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; MCP-1,
macrophage chemoattractant protein 1; sPLA, secretory phospholipase A2; sVCAM-1, soluble vascular cell adhesion molecule 1; sICAM-1, soluble intercellular
adhesion molecule 1; sE-selectin, soluble E-selectin. bPre compared with Post values (paired f-test). cPost minus Pre values. dP for differences (Pre compared
with Post) between placebo and zinc groups (t-test). eThere was no significance of plasma zinc and all biomarkers between placebo and Zn supp groups before
supplementation (Pre). fMean ±SD (all such values).
include advanced age, smoking, hypertension, diabetes, and obe-
sity. Recently chronic inflammation has been implicated in the
development of atherosclerosis.
Nutritional deficiency of zinc is common not only in devel-
oping countries but also in certain groups of populations in the
developed countries. We have reported that nearly 30% of the
healthy elderly subjects may be zinc deficient (5,6).
In healthy elderly zinc-deficient subjects, we showed increased
concentrations of plasma lipid peroxidation by-products and
endothelial cell adhesion molecules compared with those in
younger adults (5,6). We proposed that zinc may have an
atheroprotective function because of its anti-inflammatory and
antioxidant properties (6).
We supplemented 20 elderly subjects, ages >65 years with
45 mg elemental zinc as gluconate daily for 6months. Twenty
elderly subjects’ ages >65 years received placebo. This was a dou-
ble blind placebo-controlled trial. In the zinc group, plasma
zinc increased, plasma antioxidant power increased, and plasma
oxidative stress marker decreased in comparison to the placebo
group (6).
Zinc supplementation resulted in significant decreases in
hsCRP, plasma IL-6 concentration, MCP-1, sPLA (secretory phos-
pholipase A), SE-selectin (soluble E-selection), and sVCAM-1 after
6 months of supplementation compared with the placebo group
(6). Our analysis also showed that the plasma zinc concentrations
were inversely correlated with the changes in concentrations of
Frontiers in Nutrition | Clinical Nutrition September 2014 | Volume 1 | Article 14 | 6
Prasad Zinc: antioxidant and anti-inflammatory agent
Table 6 | Effect of zinc on tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), vascular cell adhesion molecule 1 (VCAM-1), and
malondialdehyde and hydroxyalkenals (MDA +HAE) in HL-60 and THP-1 cells and human aortic endothelial cells (HAECs)a(6).
No stimulation ox-LDL stimulation
Zn−Zn+PbZn−Zn+Pb
HL-60 cells
TNF-α(pg/mL) 26.5 ±25.4 12.1 ±12.1 0.21 317.2 ±119.7 152.7 ±96.4 0.007
IL-1β(pg/mL) 1.4 ±1.2 0.8 ±0.7 0.52 3.9 ±1.4 1.3 ±0.5 0.042
VCAM-1 (pg/mL) 18.3 ±4.7 14.2 ±1.7 0.073 69.9 ±2.8 32.1 ±4.3 0.006
MDA +HAE (µM) THP-1 cells 2.6 ±0.7 1.5 ±0.6 0.001 5.6 ±1.4 2.3 ±0.5 0.046
THP-1 cells
TNF-α(pg/mL) 32.2 ±15.1 23.8 ±12.0 0.022 181.2 ±13.9 121.0 ±17.9 0.027
IL-β(pg/mL) 1.5 ±0.1 0.9 ±0.4 0.027 4.4 ±0.7 1.7 ±0.9 0.004
MDA +HAE (µM) 1.4 ±0.6 1.0±0.5 0.013 4.5 ±0.6 2.0 ±0.7 0.004
HAECs
TNF-α(pg/mL) 8.0 ±6.6 4.2 ±5.0 0.06 22.6 ±2.3 13.6 ±2.1 0.034
IL-lβ(pg/mL) 5.8 ±5.7 2.8 ±2.7 0.11 13.1 ±4.8 6.2±1.8 0.028
VCAM-1 (ng/mL) 3.5 ±1.5 4.5 ±2.1 0.247 23.8 ±4.7 13.8 ±2.1 0.016
MDA +HAE (µm) 1.16 ±0.36 1.02 ±0.20 0.18 3.33 ±1.02 1.45 ±0.77 0.028
aAll values are means±SDs. Zn−, zinc deficient; Zn+, zinc sufficient.
bFor differences between Zn−(1 µM Zn) and Zn+(15 µM. Zn) cell groups (Student’s t-test; n =3).
plasma hsCRP, MCP-1,MDA +HAE, and VCAM-1 after 6 months
of zinc supplementation (Tables 5 and 6).
C-reactive protein is widely used as a biomarker of chronic
inflammation and prognosis in patients with cardiovascular
disease (6). Ours is the first observation that zinc supplementation
downregulates hsCRP in humans.
The increased generation of ROS and the activation of redox-
dependent signaling cascades are involved in atherosclerosis (6).
ROS itself can upregulate NF-κB-mediated transcriptional acti-
vation of inflammatory genes (6), thereby potentially acting as
independent triggers of atherosclerosis. Zinc supplementation
decreased oxidative stress in cell culture models, animal mod-
els, and humans (6). Thus decreased oxidative stress by zinc in
the elderly may decrease LDL oxidation and exhibit atheropro-
tecitve effect. Results of our studies in the elderly support this
hypothesis.
ZINC AND AGE-RELATED MACULAR DEGENERATION
Age-related macular degeneration affects nearly 25% of individu-
als older than 65 years of age, and late-stage disease accounts for
nearly 50% of legal blindness in Europe and North-America (15–
18). Newsome et al. (15) reported that zinc levels are decreased n
human eyes with signs of AMD and suggested that zinc deficiency
may lead to oxidative stress and retinal damage.
Age-related eye diseases study group supported by NIH, con-
ducted an 11-center double blind clinical trial in patients with
dry-type AMD (16,17). Three thousand six hundred forty partic-
ipants of age 55–80 years were enrolled for trial and their follow-
up period was 6.3 years. Participants were randomly assigned to
receive daily orally one of the following: (1) antioxidants (Vitamin
C 500 mg, Vitamin E 400 IU, and β-Carotene 15 mg; (2) zinc 80 mg
as zinc oxide and copper 2mg as copper oxide to prevent copper
deficiency induced by therapeutic level of zinc; (3) antioxidants
plus zinc, or (4) placebo.
In the group taking zinc supplements, advanced AMD was
decreased by ~21% and loss of vision was prevented in 11%.
In the group taking the vitamins alone, advanced AMD was
decreased by 17% and vision loss was decreased by 10%. In the
group taking both zinc and the vitamins, the advanced AMD
decreased by 25% and the vision loss was decreased by 19%
(16,17). No significant side effects were noted in subjects who
received therapeutic levels of zinc (16,17). In the group taking
both zinc and the vitamins, the advanced AMD decreased by 25%
and the vision loss was decreased by 19% (16,17). Interestingly,
only the zinc supplemented group showed increased longevity
(17). The risk of mortality was reduced by 27% in the AREDs
studies in subjects who received only therapeutic levels of zinc
daily. Most importantly, a later follow-up study showed that the
reduction in mortality was due to a decrease in death caused by
cardiovascular diseases, suggesting a beneficial effect of zinc on
atherosclerosis (18).
MECHANISM OF ZINC ACTION AS ANTI-INFLAMMATORY
AGENT: STUDIES IN CELL CULTURE MODELS
We studied the effect of zinc on inflammatory cytokines and oxida-
tive stress markers in HL-60 (human promyelocytic leukemia cell
line), THP-1 (human monocytic leukemia cell line), and HAEC
(human aortic endothelial cells) (6,30). The generation of TNF-α
(tumor necrosis factor-α), IL-1β, VCAM-1, and MDA +HAE in
HL-60, THP-1 cells, and HAECs after incubation with ox-LDL for
24 h were significantly decreased in zinc sufficient cells in compari-
son to the zinc-deficient cells. Zinc increased A20 and PPAR-αgen-
eration in ox-LDL stimulated THP-1 and HAEC cells compared
with zinc-deficient cells. After 24 h of ox-LDL stimulation, zinc
www.frontiersin.org September 2014 | Volume 1 | Article 14 | 7
Prasad Zinc: antioxidant and anti-inflammatory agent
FIGURE 3 | Signaling pathway for zinc prevention of atherosclerosis
in monocytes/macrophages and vascular endothelial cells: a
proposed hypothesis. Reactive oxygen species (ROS) induced by many
stimuli modifies LDL into oxidized LDL (ox-LDL) in macrophages and
vascular endothelial cells. ox-LDL or ROS can activate the apoptotic
pathway via activation of proapoptotic enzymes and the nuclear
transcription factor κB (NF-κB) pathway via NF-κB inducible kinase (NIK)
activation, which eventually results in the development and progression of
atherosclerosis. Zinc might have an atheroprotective function by the
following mechanisms: (1) inhibition of ROS generation via metallothionein
(MT), superoxide dismutase (SOD), and NADPH, and (2) down-regulation
of atherosclerotic cytokines/molecules such as inflammatory cytokines,
adhesion molecules, inducible nitric oxide synthase (iNOS),
cyclooxygenase 2 (COX2), fibrinogen, and tissue factor (TF) through
inhibition of NF-κB activation by A20-mediating tumor necrosis factor
(TNF)-receptor associated factor (TRAF) signaling and peroxisome
proliferator-activated receptor a (PPAR-a)-mediating crosstalk signaling.The
black arrows indicate up-regulation; arrows with a broken line indicate
down-regulation or the inhibitory pathway. IKK, I-κB kinase; IL, interleukin;
MCP-1, macrophage chemoattractant protein 1; CRP, C-reactive protein;
ICAM-1, intercell adhesion molecule 1; VCAM-1, vascular cell adhesion
molecule 1 (14).
sufficient THP-1 and HAEC cells showed a significant decrease in
NF-κB activation compared to zinc-deficient cells (6).
NF-κB is one of the major immune response transcription fac-
tors involved in molecular signaling. Zinc plays an important role
in activation of NF-κB. The regulation of NF-κB activation by zinc
is, however, cell specific (30). We have reported earlier that zinc is
required for NF-κB DNA binding in purified or recombinant NF-
κB p50 protein in T helper cell lines (31). We reported that normal
healthy volunteers who were supplemented with 45 mg elemental
zinc daily had a significant decrease in TNF-αand IL-1βmessenger
RNAs and TNF-αinduced NF-κB DNA binding in isolated periph-
eral blood mononuclear cells in comparison to placebo treated
subjects (30). Additionally, zinc upregulated the expression of A20
in HL-60 cells. Our study showed that zinc decreased ox-LDL-
induced generation of TNF-α, IL-1β, and VCAM-1,oxidative stress
markers in the plasma and activation of NF-κB, and increased A20
and PPAR-αprotein in human monocytic and vascular endothe-
lial cells (6). We proposed that zinc inhibited NF-κB activation
via A20, a zinc finger transactivating factor that plays an impor-
tant role in down regulating IL-1βand TNF-αinduced NF-κB
activation (6). A20 was originally thought to protect cells from
TNF-α-induced cytotoxicity by inhibiting the activation of NF-κB
resulting in decreased IL-1βand TNF-αsignaling in endothelial
cells (6). It was reported that A20 inhibits NF-κB signaling by
TNF-αand IL-1βvia TNF-receptor-associated factor pathways in
endothelial cells (6).
The PPAR-αand -γof nuclear receptors, the mediators of
lipoprotein metabolism, inflammation, and glucose homeosta-
sis were shown to play a protective role in the development and
progression of atherosclerosis. The mechanism by which zinc
may exhibit atheroprotective role is most likely due to its anti-
inflammatory effect. We showed that zinc-sufficient HAEC cells
had an increase in PPAR-αconcentration compared with zinc-
deficient HAEC cells, which suggested that zinc increases the
expression of PPAR-αprotein, which may contribute to down-
regulation of inflammatory cytokines and adhesion molecules.
We conclude that down-regulation of NF-κB activation by zinc
via A20-PPAR-αsignaling pathways results in decreased gener-
ation of inflammatory cytokines, which protects the endothelial
cells from atherosclerosis.
Frontiers in Nutrition | Clinical Nutrition September 2014 | Volume 1 | Article 14 | 8
Prasad Zinc: antioxidant and anti-inflammatory agent
PROPOSED CONCEPT OF MECHANISM OF ZINC ACTION AS
AN ANTIOXIDANT AND ANTI-INFLAMMATORY AGENT
Our concept of the mechanism of zinc action as an antioxidant
and anti-inflammatory agent is shown in Figure 3. Inflamma-
tion generates oxidative stress by increasing ROS, which results in
oxidation of LDL. Oxidized LDL activates the NF-κB inducible
kinase/IK-βkinase/NF-κB signaling pathway and upregulates its
downstream target genes such as inflammatory cytokines, CRP,
adhesion molecules, inducible nitric oxide synthase, cyclooxyge-
nase 2, fibrinogen, and tissue factor. These cytokines and mole-
cules attract neutrophils, monocytes, macrophages, and platelets,
induce coagulation, and initiate development of atherosclerosis.
Our study showed that zinc supplementation increased plasma
antioxidant power, decreased plasma inflammatory cytokines, and
oxidative stress biomarkers in the elderly subjects.
Zinc decreased NF-κB activation and its target genes such
as TNF-α, IL-1β, and VCAM and increased the gene expression
of A20 and PPAR-α, the two zinc finger proteins with anti-
inflammatory properties in HL-60 and THP-1 cells and HAECs
after ox-LDL stimulation. Thus, zinc decreased the expression of
these cytokines and molecules by inhibition of NF-κB activation
via A20 and PPAR-αpathways.
MECHANISM OF ZINC ACTION AS AN ANTIOXIDANT
Zinc functions as an antioxidant by different mechanisms. Firstly,
zinc competes with iron (Fe) and copper (cu) ions for binding to
cell membranes and proteins, displacing these redox active metals,
which catalyze the production of ·OH from H2O2. Secondly, zinc
binds to (SH) sulfhydryl groups of bio-molecules protecting them
from oxidation. Thirdly, zinc increases the activation of antioxi-
dant proteins, molecules,and enzymes such as glutathione (GSH),
catalase, and SOD and also reduces the activities of oxidant-
promoting enzymes such as inducible nitric acid synthase (iNOS)
and NADPH oxidase and inhibits the generation of lipid perox-
idation products (32). Fourthly, zinc induces the expression of a
metal-binding protein metallothionein (MT), which is very rich
in cysteine and is an excellent excavanger of ·OH ions (32).
Nuclear factor erythroid 2-related factor 2 (Nrf2), a family
member of cap’n’collas/basic leucine zipper (CNC-bZIP) proteins
is a critical transcription factor that regulates the gene expression
of antioxidant proteins and enzymes such as GSH and SOD, as
well as detoxifying enzymes such as glutathione-S-transferase-1
(GSTA1) and hemeoxygenase-1 (HO-1), by binding to an antioxi-
dant responsive element (ARE) in the promoterregion of the target
gene (32). Several studies have shown that zinc may have a regu-
latory role in Nrf2. Zinc upregulates Nrf2 activity and decreases
oxidative stress (32).
CONCLUSION
Deficiency of zinc in humans was first reported nearly 50 years ago.
The current estimate of the WHO is that nearly two billion subjects
worldwide may have nutritional deficiency of zinc. This is because
populations subsisting on high cereal protein diets havehigh intake
of phytate, an organic phosphate compound, which complexes
zinc and makes it unavailable for absorption. Major effects of zinc
deficiency are growth retardation, hypogonadism, cell-mediated
immune dysfunctions, increased oxidative stress, and increased
generation of inflammatory cytokines. Zinc is a molecular signal
for immune cells. Zinc is required for differentiation and genera-
tion of T helper cells. Generation of mRNA s of IL-2 and IFN-γ
by Th1 cells are zinc-dependent and zinc-dependent transcrip-
tion factors are involved in this process. Zinc supplementation
to elderly subjects resulted in decreased incidences of infections,
decreased plasma oxidative stress markers, and decreased genera-
tion of inflammatory cytokines and increased plasma zinc levels.
Inasmuch as chronic inflammation and oxidative stress are impli-
cated in many chronic diseases of the elderly, we hypothesize that
zinc supplementation to the elderly may be very beneficial.
ACKNOWLEDGMENTS
I acknowledge the support of Labcatal, Paris, France, for our
studies in the elderly subjects.
REFERENCES
1. Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia,
hepatosplenomegaly, hypogonadism, dwarfism, and geophagia. Am J Med
(1961) 31:532–46. doi:10.1016/0002-9343(61)90137-1
2. Prasad AS, Miale A, Farid Z, Schulert A, Sandstead HH. Zinc metabolism
in patients with the syndrome of iron deficiency anemia, hypogonadism and
dwarfism. J Lab Clin Med (1963) 61:537–49.
3. Sandstead HH, Prasad AS, Schulert AR, Farid Z, Miale A Jr, Bassily S, et al.
Human zinc deficiency, endocrine manifestations and response to treatment.
Am J Clin Nutr (1967) 20:422–42.
4. Prasad AS, Miale A, Farid Z, Sandstead HH, Schulert AR, Darby WJ. Biochem-
ical studies on dwarfism, hypogonadism, and anemia. Arch Intern Med (1963)
111:407–428.
5. Prasad AS, Beck FWJ, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, et al. Zinc
supplementation decreases incidence of infections in the elderly: effect of zinc
on generation of cytokines and oxidative stress. Am J Clin Nutr (2007) 85:
837–44.
6. Bao B, Prasad AS, Beck FWJ, Fitzgerald JT, Snell D,Bao GW,e t al. Zinc decreases
C-Reactive protein, lipid peroxidation, and implication of zinc as an atheropro-
tective agent. Am J Clin Nutr (2010) 91:1634–41. doi:10.3945/ajcn.2009.28836
7. Prasad AS. Biochemistry of Zinc. New York: Plenum Press (1993).
8. Sandstead HH, Penland JG, Alcock NW,Dayal HH, Chen XC, Li JS, et al. Effec ts
of repletion with zinc and other micronutrients on neuropsychologic perfor-
mance and growth of Chinese children. Am J Clin Nutr (1998) 68:470S–5S.
9. Barnes PM, Moynahan EJ. Zinc deficiency in acrodermatitis enteropathica. Proc
R Soc Med (1973) 66:327–9.
10. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplemen-
tation in young children with acute diarrhea in India. N Engl J Med (1995)
333:839–44. doi:10.1056/NEJM199509283331304
11. Fisher Walker CL,Lamberti L, Roth D, Black RE. Zinc and infectious diseases. In:
Rink L, editor. Zinc in Human Health. Amsterdam: IOS Press (2011). p. 234–53.
12. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (1992) 71:139–64.
doi:10.1097/00005792-199205000- 00004
13. Prasad AS, Fitzgerald JT, Bao B, Beck WJ, Chandrasekar PH. Duration of symp-
toms and plasma cytokine levels in patients with the common cold treated with
zinc acetate. Ann Intern Med (2000) 133:245–52. doi:10.7326/0003-4819- 133-
4-200008150- 00006
14. Prasad AS, Beck FWJ, Bao B, Snell D, Fitzgerald T. Duration and severity
of symptoms and levels of plasma interleukin-1 receptor antagonist, solu-
ble tumor necrosis factor receptor, and adhesion molecule in patients with
common cold treated with zinc acetate. J Infect Dis (2008) 197:795–802.
doi:10.1086/528803
15. Newsome DA, Miceli MV, Tats DJ, Alcock NW, Oliver PD. Zinc content of
human retinal pigment epithelium decreases with age and macular degenera-
tion but superoxide dismutase activity increases. J Trace Elements Expert Med
(1996) 8:193–9. doi:10.1002/(SICI)1520-670X(199605)8:4<193::AID-JTRA1>
3.3.CO;2-2
16. Age-Related Eye Disease Study Research group (AREDS Report No. 8). A ran-
domized, placebo controlled, clinical trial of high-dose supplemented with
www.frontiersin.org September 2014 | Volume 1 | Article 14 | 9
Prasad Zinc: antioxidant and anti-inflammatory agent
vitamins C and E, beta-carotene, for age-related macular degeneration and
vision loss. Arch Ophthalmol (2001) 119:1417–36. doi:10.1001/archopht.119.
10.1417
17. AREDS Report No.13. Association of mortality with ocular disorders and an
intervention of high dose antioxidants and zinc in the age-related eye disease
study. Arch Ophthalmol (2004) 122:716–26. doi:10.1001/archopht.122.5.716
18. Chew EY, Clemons TE, Agron E, Sperduto RD, Sangiovanni JP, Kurinij N, et al.
Age-related Eye Disease Study Research Group Long-term effects of vitamins
C and E, β-carotene, and zinc on age-related macular degeneration: AREDS
report no. 35. Ophthalmology (2013) 120(8):1604.e–11.e. doi:10.1016/j.ophtha.
2013.01.021
19. Sandstead HH. Human zinc deficiency: discovery to initial translation. Adv Nutr
(2013) 4:76–81. doi:10.3945/an.112.003186
20. Recommended Dietary Allowance. National Academy of Sciences Trace Elements
Zinc, 8th Revised Edition. WashingtonDC: National Academy of Sciences (1974).
p. 99–101.
21. Guidelines for Essential Trace Element Preparation for Parenteral Use. A state-
ment by an expert panel. AMA Department of Foods and Nutrition. Expert
panel: Shils, M.E., Burke, A.W., Greene, H.L., Jeejeebhoy,K.N., Prasad, A.S., and
Sandstead, H.H. JAMA (1979) 241(19):2051–4.
22. Sandstead HH, Prasad AS, Penland JG, Beck FWJ, Kaplan J, Egger NG, et al. Zinc
deficiency in Mexican American children: influence of zinc and other micronu-
trients on T cells, cytokines, and anti-inflammatory plasma proteins. Am J Clin
Nutr (2008) 88:1067–73.
23. Cavdar AO, Babacan E, Arcasoy A, Ertein U. Effect of nutrition on serum zinc
concentration during pregnancy in Turkish women. Am J Clin Nutr (1980)
33:542–4.
24. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel member of a zinc
transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet
(2002) 71:66–73. doi:10.1086/341125
25. Kay RG, Tasman-Jones C. Zinc deficiency and intravenous feeding. Lancet
(1975) 2:605–6. doi:10.1016/S0140-6736(75)90194-4
26. Klingberg WG, Prasad AS, Oberleas D. Zinc deficiency following penicillamine
therapy. In: Prasad AS, editor.Trace Elements in Human Health and Disease. New
York, NY:Academic Press (1976). p. 51–65.
27. Prasad AS, Rabbani P, Abbasi A, Bowersox E, Spivey-FoxMR. Experimental zinc
deficiency in humans. Ann Intern Med (1978) 89:483–490.
28. Beck FWJ, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ. Changes in cytokine
production and T cell subpopulations in experimentally induced zinc deficient
humans. Am J Physiol Endocrinol Metab (1977) 272:1002–7.
29. Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF, et al.
Serum thymulin in human zinc deficiency. J Clin Invest (1988) 82:
1202–1210.
30. Prasad AS, Bao B, Beck FWJ, Kucuk O, Sarkar FH. Antioxidant effect of zinc in
humans. Free Rad Biol Med (2004) 37:1182–90. doi:10.1016/j.freeradbiomed.
2004.07.007
31. Prasad AS, Bao B, Beck FW, Sarkar FH. Zinc activates NF-κB in HUT-78 cells. J
Lab Clin Med (2001) 138:250–5. doi:10.1067/mlc.2001.118108
32. Bao B, Ahmad A, Azmi A, Li Y, Prasad AS, Sarkar FH. The biological signif-
icance of zinc in inflammation and aging. In: Rahman I, Bagchi D, editors.
Inflammation, Advancing and Nutrition. New York, NY: Elsevier Inc (2013).
p. 15–27.
Conflict of Interest Statement: The author declares that the researchwas conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 15 May 2014; paper pending published: 09 June 2014; accepted: 31 July 2014;
published online: 01 September 2014.
Citation: Prasad AS (2014) Zinc is an antioxidant and anti-inflammatory agent: its
role in human health. Front. Nutr. 1:14. doi: 10.3389/fnut.2014.00014
This article was submitted to Clinical Nutrition, a section of the journal Frontiers in
Nutrition.
Copyright © 2014 Prasad. This is an open-access article distributed under the terms
of the Creative Commons Attribution License (CC BY). The use, distribution or repro-
duction in other forums is permitted, provided the original author(s) or licensor are
credited and that the original publication in this journal is cited, in accordance with
accepted academic practice. No use, distribution or reproduction is permitted which
does not comply with these terms.
Frontiers in Nutrition | Clinical Nutrition September 2014 | Volume 1 | Article 14 | 10
Available via license: CC BY 3.0
Content may be subject to copyright.
