ArticlePDF AvailableLiterature Review


It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.
Aluminium and Iron in Humans:
Bioaccumulation, Pathology, and Removal
Maximus V. Peto
It is well known that exposure to various elements has a noticeable effect on human health. The effect of an
element is determined by several characteristics, including its similarity to elements of biological necessity,
metabolism, and degree of interaction with physiological processes. This review investigates the scientific lit-
erature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in
humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships
with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is
reviewed because of its prevalence in daily life, observed interference with several biological processes, con-
troversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these
metals has long been investigated for a possible relationship with various pathological states, a substantial
volume of research is available regarding the effects of iron and aluminium in biological systems. For both
aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility
of bioaccumulation, and (3) exploring methods of managing their accumulation.
To determine the potential for aluminium (Al) to ac-
cumulate and cause pathology in humans, a search of
the relevant scientific literature was performed. Not all arti-
cles found in this search are included in this review. Instead,
the results of these searches were analyzed for evidence re-
lated to the focus of this review.
Evidence of Al toxicity
Alzheimer disease. Al has been investigated as a con-
tributor to the development and progression of Alzheimer
disease (AD) for decades,
and the possible role of Al in AD
continues to be discussed in the literature. For example, one
found Al in human pyramidal neurons, which con-
tained Al either in the cell nucleus or cytoplasm, the latter
being relatively high in Al and containing neurofibrillary
tangles (NFT). Other studies have suggested Al has at least a
secondary role in the development of AD.
However, evi-
dence for a primary, causative role of Al in AD induction is
so further investigation into this question
Oxidative stress. More generally, Al is also considered
to be a mediator of oxidative stress,
and efforts have
been made to understand the underlying mechanisms of
Al-catalyzed oxidative stress.
For example, one study
found that Al
ions augment iron-induced lipid peroxidation
in rat liver microsomes at pH 7.4. This study also found Al
that accelerates the peroxidation of erythrocytes by hydrogen
peroxide (H
). Another study found similar results.
Interference with iron metabolism. It is also been postu-
lated that oral Al interferes with iron (Fe) absorption, use, or
both, and contributes to some cases of anemia.
tested the possibility of Fe binding to transferrin
being disrupted by Al in Wistar rats by administration of Al
via Camellia sinensis (green tea) decoction. It was found that
serum Al increased in a tea dose-dependant manner. It was
also observed that the Fe content of all organs tested was
reduced compared to controls. This suggests that the Al
present in green tea may affect Fe metabolism (discussed
below). However, it is known that green tea contains both Al
and polyphenols. Polyphenols are known to chelate Fe and
perhaps contribute to iron-deficiency anemia.
It may be
the presence of polyphenols, or Al jointly with polyphenols,
that affects Fe metabolism, and not Al alone. Furthermore,
asserts that Al from heavy drinking of tea infusions
can be a greater contributor to serum Al than from all other
dietary sources. Other studies have suggested similar hy-
potheses related to the possibility of green tea being a sig-
nificant source of Al.
It is important to consider the
Toledo, Ohio.
Volume 13, Number 5, 2010
ªMary Ann Liebert, Inc.
DOI: 10.1089/rej.2009.0995
possibility that infusions of the plant C. sinensis may con-
tribute to ill health, especially given the increasing interest in
green tea consumption due to its possible health benefits.
Osteomalacia. Al has also been implicated in the de-
velopment of osteomalacia (bone softening),
in hemodialysis patients who experience high Al exposure
from the Al-contaminated dialysate used in dialysis proce-
Bone disease is also observed in patients un-
dergoing long-term administration of total parenteral
nutrition (TPN).
It has been postulated that this increased
incidence of bone disease in TPN is related to Al contami-
nation of nutrition solutions.
However, note that both of
these observations occur in the uncommon circumstances of
acute (dialysates) or nongastrointestinal (TPN) Al exposure.
Parathyroid hormone. Further considering Al toxicity, Al
is known to disrupt parathyroid hormone (PTH) secretion by
interfering with calcium metabolism, which in turn disrupts
osteoclast activity.
However, PTH is not considered by
Jeffrey et al.
to be the primary way by which Al disrupts
bone metabolism. Instead, these authors suggest that Al
disruption of PTH may contribute to the development of
bone disease, aggravate an existing disease, or interact with
some other condition, thus precipitating disease.
Kidney damage. Related to the observation that most Al
is excreted via urine, it is known that kidneys are affected by
Al exposure.
In Al accumulation in the kidney, renal tu-
bular cells are damaged. In rats with normal kidney function,
intraperitoneal Al administration was found to cause swell-
ing, hemorrhaging, and fibrosis in the glomeruli, proximal
tubuli, and the Bowman capsules.
It has been hypothesized
that this damage is caused by Al-induced increases in reac-
tive oxygen species (ROS).
Other studies in rats found Al
accumulation in the normal kidney, accompanied by kidney
Breast cancer. Finally, a few studies have suggested that
Al present in underarm antiperspirants containing Al salts
may increase the risk of breast cancer.
Further con-
founding this question is the possibility that underarm
shaving habits may disrupt the dermal barrier that may
otherwise restrict Al absorption. On the other hand, a few
studies have asserted that the possibility of an increased risk
of breast cancer due to these Al salts is either nonexistent
based on available research
or needs further investiga-
The question regarding the role of Al in the devel-
opment of breast cancer is still being investigated, and it
seems premature to draw a conclusion at this time.
Evidence of Al accumulation
There is considerable evidence to support the hypothesis
that Al accumulates in humans. It has been observed that
tissue Al levels are positively correlated with age in hu-
Furthermore, at least one study
has found tissue
Al concentration to increase exponentially with age. This
suggests two possibilities. First, common daily exposure is
higher than the body’s removal capacity, resulting in accu-
mulation. Second, the exponential age-related increase in Al
burden may be due to general age-related kidney decline,
which would result in an ever-decreasing ability to remove
Al with age. Thus, it may be increasingly important to manage
Al exposure with advancing age or otherwise declining
kidney function.
Although a relatively small proportion of Al is deposited
in tissues, Al turnover is important to consider. While Al
turnover is difficult to quantify, it has been estimated that Al
in the human brain has half-life of 7 years.
This slow turn-
over is, again, suggestive of the accumulation potential of Al.
Oral availability. Oral bioavailability of Al is low to mod-
erate in humans (0.001–24%) depending on dose, and a larger
dose may have lower bioavailability.
However, this range
includes a wide range of observed absorption rates. Rates in
the middle of this range are more commonly observed. For
example, one study
indicates that 4% of total Al intake will
be retained by humans with normal renal function. Further-
more, it may be that there is no dose-dependency for oral
Al bioavailability, as has been observed in some animal
Bodily Al distribution. Once uptake occurs, Al distribu-
tion is widespread,
with Al being present in most tissues
with few exceptions, such as the lens of the eye (in fish).
rats given a single intravenous injection of trace amounts of
Al-26, the largest proportion of injected Al was found in
bone (0.9%) and kidney (0.2%).
The lowest proportion was
found in brain and muscle (0.02% each). Sahin et al.
vestigated Al deposition in mice administered aluminium
hydroxide orally for 105 days. In the treatment group, they
observed Al content of liver, kidney, and brain that was 30%,
60%, and 340% higher, respectively, than the control group.
In humans, aluminium is estimated to have a distribution of
approximately 60, 25, 10, 3, 1, and <1% in skeleton, lung,
muscle, liver, brain, and blood, respectively.
Al accumulation in bone. One primary site of Al accu-
mulation is in bone,
where it contributes to the develop-
ment of osteomalacia,
especially in chronic hemodialysis
patients. Jeffrey et al.
postulated that the half-life of Al in
bone may depend on which type of bone it is incorporated
into (i.e., cortical vs. trabecular). Jeffrey et al. also suggested
that a toxicity threshold for Al exposure would be helpful in
preventing Al-related bone disorders.
Al from drinking water. Drinking water, a possible source
of chronic Al intake leading to accumulation, can contain Al
both by natural as well as water treatment processes. Al
bioavailability from this source is estimated to be approxi-
mately 0.3%.
Several epidemiological studies have found
correlations between AD and high Al concentrations in
drinking water. One such study warned that limiting resid-
ual Al in drinking water deserves ‘‘serious attention.’
should be noted that epidemiological studies have their
limitations, including this one, which were discussed by
Al restriction and removal
Substantial evidence exists supporting the hypothesis that
Al is toxic. Furthermore, the evidence on the half-life of Al in
tissues, as well as on Al distribution, indicates that Al
590 PETO
accumulates in humans. Thus, a discussion of Al restriction
and removal is appropriate.
Al restriction and complexation chemistry. When at-
tempting to understand ways by which to avoid gastroin-
testinal absorption of Al, it is important to consider the
complexation chemistry of Al. Al complexation chemistry
has received substantial attention from researchers. Two as-
pects of Al complexation are important to discuss: Dissolu-
tion for absorption and complexation in the physiological
environment. Each of these processes may occur quite dif-
ferently and thus should be considered separately.
In water at neutral pH, Al is poorly soluble. As pH de-
creases from 7.0 to 5.0, Al forms hydrate complexes in so-
lution. This phenomenon lends support for the common
advice against cooking acidic foods in Al cookware, because
Al dissolves more easily in acidic environments. As pH is
subsequently increased, successive deprotonations result in
the formation of a tetrahedral aluminate at pH >6.2, in-
cluding the physiological pH.
Modulators of gastrointestinal Al absorption. Because the
physiological pH is close to neutral, researchers have inves-
tigated which physiological Al complexes may facilitate Al
transport in the body. Several researchers
have suggested
that the complex Al–maltolate may be one such candidate.
Maltol is present in the diet as a flavor enhancer added to
foods. Al–maltolate is stable over the pH range of 3.0–10.0.
Partly due to this chemical behavior of the Al–maltolate
complex, it has been suggested as a complex to administer in a
rabbit model in the study of AD development and patholo-
Other dietary ligands have been suggested as playing a
role in enhancing Al absorption and retention, including
ascorbate, lactate, succinate, malate, oxalate, gluconate, citrate,
fluoride, glutamate, gallate, chlorogenate, caffeate, proto-
chatechuate, tartrate,
and possibly polyphenols.
and silica
appear to reduce absorption.
Dietary intake of Al
Dietary Al intake has been estimated to be 4–9mg/day.
Because Al is abundant in the Earth’s crust, most food plants
are grown in this medium. Food animals are fed plants raised
in soil, so it follows that much of the human food chain may
be a source of low, chronic Al exposure. Foods known to be
high in Al include corn, yellow cheese, salt, herbs, spices, and
tea, as well as foods incorporating Al-containing leavening
agents such as sodium aluminium phosphate (SALP), often
used in baking powders.
Restriction of these foods may be
helpful in reducing chronic Al burden. Al is also used in
drinking water purification. Another source of Al exposure
includes Al containers and cookware.
Al in tea. Al content of teas varies widely. Street et al.
found tea infusions to vary between 0.2 mg L
to 9.3 mg L
after a 5-min infusion. To put this in perspective, the World
Health Organization (WHO) recommends a maximum Al
concentration in drinking water (for ‘‘aesthetic’’ consider-
ations, not health) to be 0.2 mg L
This makes the Al
concentration in many tea infusions investigated
up to 46
times greater than the WHO ‘‘aesthetic’’ standard. This evi-
dence, combined with the possibility that Al from green tea
is as well absorbed as Al from other dietary sources due to
polyphenolic hydroxyl groups that provide multiple com-
plexation sites,
causes one to consider that green tea may
contribute to the accumulation of toxic levels of Al. One re-
asserted that heavy green tea drinking may dou-
ble one’s Al intake (further considering that 95% of Al intake
is normally from food, and only 1–2% from drinking
Green tea has been investigated for its potential
therapeutic and preventative applications, so it would be ill-
advised to cease green tea consumption altogether. Whether
tea contributes substantially to Al-related toxicity requires
further investigation.
Furthermore, consuming green tea without acidic com-
ponents such as lemon juice, which is sometimes practiced,
might be reconsidered. Several studies found acidic compo-
nents, such as citrate present in citrus juices, facilitated
greater gastrointestinal absorption of Al.
For exam-
ple, one study
in rats found that 1 h after oral Al admin-
istration, the extent of aluminium accumulation was
increased by a factor of 2 to 5 in the presence of citrate,
depending on tissue and other factors.
Nongastrointestinal absorption of Al
Gastrointestinal absorption is not the only route of Al
uptake. Other intake routes have been investigated including
nasal, dermal, and respiratory.
A preliminary study
found approximately 4 mg of Al to be absorbed transdermally
by a single administration of an Al-containing antiperspirant.
Another study found, in a single patient, plasma and urine
Al to decrease after discontinuing antiperspirant use.
question of transdermal Al absorption is a concern and is still
being investigated. For most individuals, oral Al intake is a
much greater source of Al exposure.
Al removal
Al restriction is important in preventing and slowing the
accumulation of Al. However, some people may currently have
a substantial accumulation of Al (i.e., in advanced age
Assuming that Al accumulation, left to itself, will eventually
result in pathology, it is beneficial to address this accumula-
tion before pathology arises. Of course, this is the case only if
methods of Al measurement and removal are not more harmful
than the presence of nonpathological Al levels. Moreover, some
populations may be subjected to Al exposure due to health
conditions requiring treatments that can be contaminated with
Al (i.e., hemodialysis patients). Further complicating the issue is
the possibility that Al in some tissues may have a fairly long
half-life. Thus, dietary Al restriction is helpful, but will not
be effective in alleviating Al burden in some circumstances or
Al, apo-transferrin, and serum albumin. One important
characteristic of Al is that it is found bound to apo-
and serum albumin.
This characteristic of Al
binding to serum is important when considering Al reduc-
tion therapies, such as chelation and phlebotomy. One
investigating competitive binding constants of Al
and citrate, human serum albumin (HSA), and human serum
transferrin (HSTF) concluded that in hemodialysis patients
*34% of serum Al is bound to HSA, *60% is bound to
HSTF, and the remainder bound to citrate. This substantial
binding to HSA
was in contrast to several other studies
(referred to in ref. 66), which estimated a much lower bind-
ing to HSA and a much higher binding rate to HSTF.
Al and chelation therapy. Desferroxamine and other
chelators used in the treatment of iron (Fe) overload have
been frequently discussed in the literature as a chelator of
One study
found desferroxamine therapy to
result in a reduction of surface Al on bone from 44% to 13%
in hemodialysis patients.
Evaluating the appropriateness of such chelation therapy
might be done with the so-called ‘‘chelator challenge,’’
whereby a patient is given a single dose of chelator and uri-
nary excretion of the metal (in this case, Al) is compared be-
fore and after the treatment. This would assist doctor and
patient in evaluating the extent of Al accumulation in the
Side effects of chelators. Desferroxamine and other
clinical chelators are known to have serious side effects, such
as mucormycosis
(also referred to as zygomycosis), ‘‘ocular
and auditory anomalies, sensorimotor neurotoxicity, changes
in renal function, and pulmonary toxicity,’’
as well as
stunted height in developing children.
Thus, alternative
methods of Al removal are desired.
Kruck and colleagues
investigated the effectiveness of 10
chelators, alone or in combination, in the removal of nuclear-
bound Al. They found a combination of ascorbic acid and
Feralex-G, a recently described chelator intended for oral use,
to be an effective combination. This combination removed
between 29% and 35% of nuclear-bound Al(III), dependent on
ascorbic acid concentration. The mechanism used to explain
the effectiveness of this combination was called ‘‘molecular
shuttle chelation,’’ whereby a smaller molecule (ascorbate)
penetrates the nucleus, chelates Al, diffuses to regions with
the larger chelator (Feralex-G), and relinquishes the Al to that
chelator. They further suggest that chelators with cis-hydroxy
ketone groups (such as Feralex-G) are particularly useful in
chelating nuclear bound Al. Chelators found to be relatively
ineffective included fluoride, hydroxyurea, dihydroxyacetone,
maltol, citrate, EDTA, and salicylate.
Inositol hexaphosphate (IP6, also known as phytic acid)
has been investigated as a chelator for a number of other
elements, including Fe (discussed later) and uranium.
However, a search of PubMed using phrases that included
various terms related to IP6 and chelation returned no results
related to Al removal or chelation. IP6 might be investigated
as a potential, safe, oral, Al-chelating agent and needs further
Flora and colleagues
investigated the effectiveness of
citric acid (CA) and N-(2-hydroxyethyl)ethylenediamin-
etriacetic acid (HEDTA), alone or in combination, on Al
burden in blood and brain compartments in Wistar rats.
They found that CA and HEDTA reduced blood and Al
burden, alone and in combination, but did not have a syn-
ergistic effect on these compartments.
The chelator EDTA, used to treat lead poisoning, was not
found to cause improvement for AD patients.
EDTA was found to prevent Zn(II) and Cu(II) from binding
to amyloid-beta (Ab) sites, so EDTA may still be useful in
The element iron (Fe) is a critical component of aerobic
metabolism of many organisms, including humans. As an
oxygen-carrier, Fe
or Fe
is bound in the porphyrin heme,
four of which are included in the hemoprotein hemoglobin.
It is well known that inadequate Fe can be detrimental and
even fatal. However, recent research has illuminated several
relationships between ‘‘excess’’ Fe status and pathology.
Unfortunately, quantitative values for what constitutes ‘‘ex-
cess’’ Fe status have been difficult to determine, partly due to
the lack of immediate manifestation of pathology related to
excess Fe. These types of pathology that are related to excess
Fe take time to manifest, and because of this time lag, it is
often difficult to implicate Fe status in these pathologies.
Evidence of Fe toxicity
Fe and AD. Fe (as well as copper and zinc) have been
increasingly considered to play a critical role in AD pathol-
Mechanisms by which Fe is thought to play a role in
AD include Fe-induced oxidative stress
and/or induction
of aggregation of hyperphosphorylated tau
or Ab.
Fe has
also been found to be elevated in Abdeposits.
Fe and cancer incidence, outcome, and survival. The
relationship between cancer and Fe stores has been inves-
tigated. Observations have been mixed, and relationships
between body Fe and cancer seem to exist for some cancer
types, whereas no relationship exists for others. One
found that reduction of Fe by phlebotomy in pa-
tients with peripheral arterial disease resulted in a lower
incidence of visceral cancer and all-cause mortality. An-
other study
found no correlation between serum ferritin
and stomach or lung cancer incidence. Yet another study
found an increased risk of liver cancer in patients with
hereditary hemochromatosis (a disease characterized by Fe
accumulation) compared to a control group with non–Fe-
related chronic liver disease. Although it seems to have
proven difficult to discover the exact mechanisms by which
Fe influences cancer risk, outcome, and mortality, the
currently available evidence indicates a relationship be-
tween Fe and cancer may exist and is yet to be fully
Glucose disposal. Blood sugar control is important for
sustaining excellent long-term health, especially for diabetics.
Chronic high blood sugar, most commonly presented in di-
abetics, has been implicated in a number of conditions, in-
cluding vision loss, nerve damage, and an increase in the risk
of heart disease and stroke.
Furthermore, chronic high
blood sugar is implicated in the development of type 2 dia-
betes in those individuals with no previous blood sugar
abnormalities. Thus, to prevent possible onset of diabetes, as
well as manage complications of the condition, it is impor-
tant to manage one’s blood sugar and insulin sensitivity.
One study
found lacto-ovo vegetarians to be more glu-
cose tolerant than meat eaters. Fe status of the two groups,
measured as micrograms of ferritin/L (ng/mL), was found
to be 35 and 72, respectively. Insulin sensitivity of the two
groups, measured by steady-state plasma glucose (mmol/L),
was found to be 4.1 vs. 6.9 in the vegetarian and meat-eater
groups, respectively. Moreover, the Fe stores of the meat-
592 PETO
eating group were lowered by phlebotomy to levels similar
to the vegetarian group. Postphlebotomy tests measured an
approximate 40% increase in insulin-mediated glucose dis-
posal in the meat-eating group after phlebotomy. This sug-
gests that Fe status is somehow related to glucose disposal,
because it is well known that a meat diet often contains more
bioavailable Fe (heme) than does a vegetarian diet. It should
be noted that other factors in a high-meat diet, such as fat
intake and displacement of fruit and vegetable intake, may
account for a small part of the difference in insulin sensitivity
between these groups.
A different study
found no difference in insulin sensi-
tivity between groups of high-frequency versus low-
frequency blood donators. The average serum ferritin of each
group was 23 and 36 ng/mL, respectively. This, combined
with the above study, suggests that improvements in insulin
sensitivity might be realized by reduction in serum ferritin,
but the maximum benefit in insulin sensitivity derived from
serum ferritin reduction may be at a serum ferritin level of
approximately 35 ng/mL. It has also been suggested that Fe
may impede insulin extraction in the liver, impair insulin
secretion by the pancreas, and/or interfere with insulin
action of, and glucose uptake by, adipocytes.
Fe and lipid peroxidation. Another way in which Fe ex-
erts harmful effects in the body is catalysis of lipid perox-
which can damage cell membranes and other
lipids. There are numerous studies that indicate a relation-
ship between body Fe and lipid peroxidation. In one study,
it was found that Fe miners, as well as office workers of that
mine, had higher serum Fe and markers of lipid peroxidation
than controls. A different study
investigated Fe status and
markers of lipid peroxidation in a group of young women
receiving Fe supplementation for low Fe stores (defined as
plasma ferritin of 20 ng/mL). Fe supplementation was
98 mg/day of ferrous sulfate. In this low-Fe group (n¼12), it
was found that after 6 weeks of supplementation, serum
ferritin almost doubled and markers of lipid peroxidation
increased by >40%. While it was apparent that the young
women in this study could benefit from increased Fe stores,
lipid peroxidation had increased considerably. Several ways
to reduce this side-effect are theoretically possible, including
the use of a different form of Fe, taking a lower dose over a
longer period of time, or dividing a dose into several smaller
doses to be administered throughout the day. These need
further investigation.
Beta-thalassemia major (thalassemia), a disease charac-
terized by the improper formation of blood cells, is often
treated by blood transfusions to improve blood cell param-
eters in these patients. These repeated blood transfusions
have the negative side effect of causing Fe accumulation in
thalassemia patients. Because of this relationship between
thalassemia patients and Fe overload, these patients have
been the subject of numerous studies investigating the rela-
tionship between Fe and various pathologies.
In one study,
thalassemia patients were found to have
plasma markers of lipid peroxidation more than two-fold
higher than controls. In this study, it was also found that
serum ferritin was positively correlated with conjugated di-
ene lipid hydroperoxides (CD, a marker of lipid peroxida-
tion). In this study, mean CD was found to be three-fold
higher than controls.
Lipid peroxidation,
and specifically Fe,
have also
been thoroughly investigated as possibly contributing to the
development of cardiovascular disease. Research in this area
is inconclusive.
Other associations between Fe and disease. A number
of other diseases have been associated with excess Fe, in-
cluding Parkinson disease, Huntington chorea, human im-
munodeficiency virus (HIV) encephalopathy, basal ganglia
disease, pantothenate kinase-associated neurodegeneration
(PKAN), and Friedreich ataxia (the latter being associated
with mitochondrial Fe accumulation).
These conditions
have not all been shown to be caused by excess Fe. Rather,
each has been found to have some relationship to elevated
Fe levels.
Evidence of Fe accumulation. Human glial cells,
stantia nigra, and globus pallidus have been found to ac-
cumulate Fe with age.
Fe deposits have also been
observed in cerebral cortices, cerebellar nuclei, hippocam-
pus, and subcortical astrocytes.
After considerable re-
search of the literature, no studies were found that either
supported or denied a general, whole-body accumulation of
Fe with age in humans. This specific question seems to be a
neglected area of research, and it would be helpful to de-
termine whether this occurs. To answer this question, it is
important to determine the most reliable means by which to
evaluate body Fe stores. Evidence has been accumulated
suggesting serum ferritin to be a useful indicator, and this is
the indicator often used by medical practitioners. However,
other indicators have been discussed, such as serum trans-
ferrin, tissue ferritin, free Fe, transferrin saturation (TSat),
and hemosiderin (the latter especially in liver). These other
Fe compartments may need to be considered during the
course of designing a thorough and effective Fe quantifi-
cation protocol.
A considerable amount of evidence exists showing the
accumulation of Fe with age in rodents. Fe has been ob-
served to be positively correlated with age in kidney, brain,
liver, muscle,
and retinal pigment epithelium
in rats.
One interesting study in rats
found Fe to accumulate with
age, and this accumulation was markedly attenuated with
40% caloric restriction (CR). Conversely, Borten et al.
found 40% CR to not attenuate age-related accumulation of
peroxidase-positive astrocyte granules in the dorsal hippo-
campus of rats. Note that CR did not reduce this Fe accu-
mulation even though these particular rats were not
supplemented with Fe to make up for reduced Fe intake
associated with CR.
Management of Fe status
Diagnostic measurements of Fe status. Serum ferritin is
one of the most common end points used to determine Fe
status, partly due to its usefulness in determining Fe defi-
A commonly cited reference range for serum
ferritin is 12–300 ng/mL for males and 12–150 ng/mL for
Considering this seemingly wide range, one
sought to test the hypothesis of an ‘‘optimal’’ level of
serum ferritin, and suggested that it may be approximately
25 ng/mL, a level similar to that found in children and pre-
menopausal women.
One study
used phlebotomy as an Fe reduction protocol
for patients with peripheral vascular disease. Using serum
ferritin as the primary indicator of Fe status, the protocol set a
target to lower serum ferritin via phlebotomy to approxima-
tely 25 ng/mL. They found that after the 5-year study duration,
the treatment group had a 30% reduction of patient mortality
versus the control group. When tracking 3.5 years of patient
accrual, a 20% reduction was found in the ferritin-reduction
group, compared to anticipated values. Thus, if a reduction of
Fe bound to serum ferritin was the cause of improved out-
comes in the phlebotomy group, serum ferritin may be an
appropriate measure for other Fe reduction protocols.
There are several methods other than serum ferritin by
which to characterize Fe stores. One study
investigated the
effectiveness of Fe-dependent bodily regulation of dietary Fe
absorption. It is well known that dietary Fe absorption in-
creases during Fe deficiency in healthy humans.
refers to references of pooled data concluding that
only *50% of the variation in serum ferritin was related to
variations in amounts of stored Fe, indicating that serum
ferritin may not be representative of total Fe stores. Hallberg
et al.
found that there was a strong relationship between
Fe absorption and Fe status. Using Fe absorption as the in-
dicator of Fe status (instead of ferritin), they suggested that
serum ferritin may not be a good measure of Fe stores in Fe-
replete men if their serum ferritin is >70 ng/mL. Further-
more, they suggest that high ferritin may instead represent
some other pathological condition affecting ferritin metabo-
lism that is unrelated to Fe stores. This assertion was sup-
ported by references to several studies that failed to raise
body Fe in Fe-replete, normal subjects using ascorbic acid
fortification combined with oral Fe supplements. If this is
true, then it may be high ferritin, and not high Fe stores, that
must be addressed to reduce the incidence of excess ferritin-
related pathology discussed above.
Determination of Fe accumulation in humans seems to be
a convoluted problem. For example, a recent review of fer-
asserted that ferritin is a useful indicator of Fe over-
load, at least in pathological conditions related directly to Fe
overload or accumulation, such as hemochromatosis and
thalassemia. However, this same review noted that organs
can accumulate Fe independently of one another, and that
the Fe in a single organ is not representative of whole-body
Fe. For example, patients can accumulate cardiac Fe while
having seemingly normal hepatic Fe, even though the latter
(via biopsy) is considered the gold standard for determina-
tion of Fe overload.
Regarding this ‘‘compartmentaliza-
tion’’ of Fe overload, superconducting quantum interference
devices (SQUID) and magnetic resonance imaging (MRI)
may be useful diagnostic tools that can help determine Fe in
various tissues.
As for Fe accumulation in humans, it may be important
first to recognize the compartments that can accumulate Fe
(i.e., hemosiderin in liver, heart, pituitary, kidney, and other
tissues, and ferritin in blood) and determine the most reliable
diagnostic methods of determining such accumulation. Once
this is known, these accumulations might be treated as dis-
tinct medical issues, rather than classify all of them under the
category of ‘‘high Fe stores.’’ Doing the latter may result in
Fe reduction strategies that fail to achieve reduction in the
specific compartments that have accumulated Fe to a
harmful level.
Reducing Fe intake and exposure
Diet. Fe reduction through dietary modification can be
effective, but is relatively slow.
Fe excretion is limited due
to the body’s excellent Fe recycling mechanisms
the lack of a physiological mechanism by which the body
may quickly excrete excess Fe.
However, daily Fe loss is
estimated to be 1–2 mg/day.
Studies in hepatitis C pa-
and mice
indicate that limiting dietary Fe intake
can reduce markers of Fe storage.
Because heme Fe is absorbed more efficiently than non-
heme (inorganic) Fe,
a distinction must be made between
heme and non-heme Fe. Heme Fe is found in meat products,
including beef, pork, chicken, and fish.
Sources high in
inorganic Fe (greater than 2.5 mg/serving) include some
fortified cereals, soybeans, pumpkin seeds, some beans,
blackstrap molasses, and lentils.
If meat-intake is reduced,
the comprehensive dietary effects of such an adjustment
should be addressed, such as ensuring adequate protein and
vitamin intake from other sources to offset those displaced
by this dietary modification.
Other dietary factors to take into consideration are inhib-
itors and enhancers of Fe absorption.
Inhibitors of Fe
absorption might be increased in an Fe-depletion diet. In-
hibitors include polyphenols,
phytates (discussed later),
and calcium. Consuming Fe absorption enhancers with
meals high in Fe may also be avoided. Fe absorption is en-
hanced by vitamin C,
so its consumption should be
avoided at meals that include high Fe components if one
wishes to lower Fe stores.
IP6, also known as phytate, is known to inhibit Fe ab-
sorption in the gastrointestinal tract (GI) tract.
IP6 is
found in the bran and seeds of plants
and is also available
as a low-cost dietary supplement; it may be an effective
adjuvant to other dietary interventions directed to reduce Fe
stores (and perhaps other metals). Other dietary compounds
useful in reducing Fe absorption in the GI tract may include
hemicellulose and lignin.
Most Fe is obtained via oral consumption, but other routes
of exposure exist. Environmental exposure, such as in a
workplace, can increase levels of body Fe.
Other sources of
Fe intake must be considered, including cookware and food
utensils. One study
reviewed the use of Fe cooking pots
and their effect on reducing the incidence of Fe deficiency in
the populations of developing countries. The study concluded
that the use of Fe cooking pots may be an innovative method
of reducing Fe deficiency in Fe-deficient populations, thus
supporting cookware as a substantial source of dietary Fe.
Reducing Fe stores
Chelation therapy. Chelation treatment is used for Fe
accumulation caused by repeated blood transfusions re-
quired to treat thalassemia, a blood disease characterized by
the faulty synthesis of hemoglobin.
Three compounds
commonly used in Fe chelation therapy include deferox-
amine, deferiprone, and deferasirox. A good discussion of
these three compounds and their comparative attributes can
be found in a study published in the journal Blood.
useful, a number of Fe chelation compounds have harmful or
otherwise unpleasant side effects (noted earlier), which must
be weighed against the seriousness of Fe accumulation pre-
sented by each patient.
594 PETO
Phlebotomy/blood donation. Phlebotomy or blood do-
nation has been found to be an effective method of reducing
body Fe stores as measured by serum ferritin concentra-
Phlebotomy is used in the treatment of Fe
overload in hemochromatosis
and thalassemia. Theoreti-
cally, phlebotomy might be considered an extreme measure
of Fe removal, because all components of blood are lost
during whole-blood phlebotomy/donation, including those
components that are critical to optimal health (immune cells,
vitamins, minerals, etc.). Whereas phlebotomy has been
shown to be effective in reducing serum ferritin, the com-
prehensive health effects of such an intervention should be
evaluated before it is recommended as a routine method of
reducing moderate Fe stores.
Al and Fe are both apparently related to a number of
disease states, particularly those relating to oxidative stress, a
phenomenon that results in a type of damage that can ac-
cumulate with age. Both metals also appear to accumulate
with age, although the sites of accumulation in humans and
the resulting implications are not perfectly clear. Develop-
ment of reliable and accurate measurement techniques for
whole-body Fe and Al burden would be useful.
Al and Fe seem to have substantially different accumula-
tion sites, and it would be beneficial if these were further
elucidated. Al seems to be cleared via the renal system and
accumulates primarily (as measured by Al mass) on bone.
Alternatively, a considerable amount of Fe accumulates in
liver and in serum ferritin. While it seems that substantial
removal of accumulated Al occurs via the renal system in
healthy people, the body appears to lack a high Fe regulatory
mechanism, besides the well-known decrease in GI absorp-
tion. Chelation therapy may help remove both metals, and
phlebotomy has been shown to reduce serum ferritin.
However, chelation therapies are not without their negative
side effects, many of which may outweigh the benefit of re-
ducing body metal burden in nonpathological states. Che-
lation therapy also has the risk of removing other metals,
some of which are biologically necessary, and it may be that
prolonged chelation therapy would contribute to mineral
deficiencies. Phlebotomy is effective in reducing serum fer-
ritin, but caution must be used before recommending this
treatment because many required blood components are lost
in the procedure. Further development of measurement
methods and treatments to optimize body Al burden and Fe
stores may contribute positively to health span by mini-
mizing negative and accumulating biological effects to which
high levels of these metals seem to contribute.
Several, constructive, scientific comments were given to
this author by John Schloendorn and Mark Hamalainen and
implemented into this manuscript. Furthermore, contribu-
tions to the formatting of references were made by Alicia L.
Author Disclosure Statement
No conflicts of interest are considered by this author to
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Address correspondence to:
Maximus V. Peto
1428 Lawnview Avenue
Toledo, OH 43607
Received: November 18, 2009
Accepted: April 21, 2010
598 PETO
... This tendency was already observed in a previous study with lettuce in Brazil (Stertz et al., 2005) but differs from a study with conventional and organic carrots in the Czech Republic, which found higher levels in organic cultivation (Krejčová et al., 2016). Al has no known physiological function in human beings and is known to be neurotoxic, generate oxidative stress, and cause damage to the kidneys (Klotz et al., 2017;Peto, 2010). However, acute effects due to dietary exposure are not known (Klotz et al., 2017). ...
... The excess of Fe promotes oxidative stress, which can damage the lipids and, consequently, cell membranes. Additionally, elevated Fe levels have been related to Alzheimer's and Parkinson's diseases, cirrhosis and fibrosis in the liver, and diabetes (Peto, 2010;Wessling-Resnick, 2017). ...
Full-text available
Trace and potentially toxic elements represent one class of food contaminants that has stimulated research. In markets, two main methods of growing vegetables are generally available: conventional and organic. Conventional farming has been the target of some concerns about the use of agrochemicals, especially the excessive use of pesticides, whereas organic agriculture minimizes the use of agrochemicals. As the main route for potentially toxic elements’ absorption by humans is by food intake, it is important to evaluate if the method of cultivation influences their concentrations. This study evaluated the levels of potentially toxic elements and nutrients on four leafy vegetables: curly lettuce, collard greens, escarole, and rocket, cultivated by conventional and organic farming. We found that Al, Ba, Fe, and Sr levels were higher in conventional samples, whereas K, Pb, and Zn were higher in organic. Amongst the elements analysed, values of Fe, Al, and K were around 0.2, 0.3, and 70 g kg−1, respectively, except in collard greens, in which the values were lower. On the other hand, Ba, Sr, and Mn presented higher concentration in collard greens compared to the other vegetables in conventional cultivation (~ 35, 80, and 120 mg kg−1, respectively). The principal component analysis result shows that the samples were grouped according to the type of vegetable, regardless of the type of cultivation. Despite this, the evaluation of the cultivation by different types of farming is important in order to choose the healthiest option.
... In time, this can cause a contamination of water with aluminium and cause many medical disorders in living organisms. 7,8 Harmfulness of aluminium can be attributed to its accumulation in bone and central nervous system, especially in people who have kidney failure. In high doses (>110 μg L −1 ), 9 aluminium can cause neurotoxicity being associated with Parkinson dementia, and Alzheimer's disease. ...
... The Freundlich isotherm is an empirical model that is not limited to monolayer adsorption, but also to the description of multilayer adsorption. The mathematical expression of the linearized form is: 43 (8) where q e is amount of Al (III) adsorbed at equilibrium (mg/g), C e is concentration of Al(III) in aqueous solution at equilibrium (mg/L); K F and n are Freundlich constants that include factors that affect adsorption capacity and adsorption intensity, respectively. Graphical representation of log q e as function of logC e (Figure 8b) gives a linear graph with slope 1/n and intercept log K F from which Freundlich constants were estimated (Table 3). ...
In this work we have presented the results obtained in the adsorption behavior of hydroxyapatite with different treatment towards aluminium ions from synthetic wastewaters. Experiments were performed in batch technique at different pH values, temperatures, sorbent dosage, contact time and initial aluminium concentration. The thermodynamic studies on the adsorption process of aluminium onto hydroxyapatite indicated that the process is spontaneous and endothermic. The Langmuir, Freundlich, Flory-Huggins, Dubinin-Radushkevich and Temkin equilibrium models were applied to the description of experimental data. The adsorption of aluminium follows the Langmuir adsorption isotherm. The kinetics of adsorption was evaluated using the pseudo-first order, pseudo-second order and intraparticle diffusion kinetic models. The rate of aluminium adsorption was successfully described by a pseudo-second-order kinetic model. The obtained results indicated that hydroxyapatite treated with Pluronic P123 surfactant has a higher sorption capacity toward aluminium ions (117.65 mg g−1) than hydroxyapatite treated with Pluronic F127 surfactant (109.89 mg g−1) while untreated hydroxyapatite exhibited the lowest one (104.17 mg g−1).
... Their presence, and estimated amount, in the swabs certainly warrants a discussion in terms of their potential impact to human health, particularly given the high number of tests that many people are undergoing, which could potentially lead to bioaccumulation of these elements in the body from repeated exposure. The bioaccumulation of aluminium, 28,29 and fluoride 30 are well recognized phenomena, although accumulation is highly dose-dependent. 31,32 Less studied is the bioaccumulation of transition metals in humans. ...
... The reason is that kidney and liver are the gateway for heavy metals detoxification in the body and the gill is an important site for heavy metal entry that provokes lesions and gill demage (Bols et al. 2001;Lock and Overbeeke 1981). Iron is an essential element of biological function, but when the iron content exceeds the recommended level, it will cause heart disease, cancer and insulin sensitivity decline (Peto 2010). The presence of large amounts of heavy metals in various parts of the body will definitely cause changes in biochemical metabolism and other stresses. ...
... The reason is that kidney and liver are the gateway for heavy metals detoxification in the body and the gill is an important site for heavy metal entry that provokes lesions and gill demage (Bols et al. 2001;Lock and Overbeeke 1981). Iron is an essential element of biological function, but when the iron content exceeds the recommended level, it will cause heart disease, cancer and insulin sensitivity decline (Peto 2010). The presence of large amounts of heavy metals in various parts of the body will definitely cause changes in biochemical metabolism and other stresses. ...
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Fish contamination with heavy metal (loid)s could be a serious threat to human health. In this study, the concentrations of twelve heavy metal (loid)s in the liver, kidney, gills, muscles, skin and bones were determined in five different fishes, collected from the Hainan Island, China. Results indicated that the average concentrations of Fe, Cu, Zn, Cr, Mn, Se, Ni, As, Hg, Cd, Pb and Co in the fish tissues were 75.56, 6.935, 4.76, 4.05, 3.298, 0.981, 0.732, 0.643, 0.585, 0.263, 0.232, and 0.08 mg/kg respectively. Therefore, the hierarchical order of the metal concentrations in fishes observed was Fe > Cu > Zn > Cr > Mn > Se > Ni > As > Hg > Cd > Pb > Co. Findings of our study revealed that the average maximum concentrations of biologically essential heavy metals were found higher than those of biologically non-essential heavy metals. An average maximum Fe content was present in the kidneys of all fish, followed by liver, then gills. However, skin, muscles and bones which are not metabolically active sites for bioaccumulation contained low concentration. Significant positive and negative correlations were observed among the metal pairs. The THQ values for Cr, Cd, and As above 1 indicated a non-carcinogenic risk to human health. Integration of 12 heavy metal concentrations followed the order: metals in benthic fish > metals in demersal fish > metals in pelagic fish. Regular monitoring of the water and fish for heavy metals (loid)s should be done regularly to protect aquatic ecosystem and human health through targeted response measures.
... However, the same situation is observed for the stable protein complex from milk, in which the aluminum content is very high (124 µg/g), 3 times higher than in milk [18]. Aluminum participates in the formation of phosphate and protein complexes; the processes of the formation of the skeleton, cartilage, regeneration of bone, connective, and epithelial tissues; has inhibiting or activating effects on digestive enzymes, depending on the concentration; and is able to affect the function of the parathyroid glands [55,56]. ...
Full-text available
Metal ions and other elements play many different critical roles in all biological processes. They can be especially important in high concentrations for the functioning of organisms living in seawater. It is important to understand how much the concentrations of different trace elements in such organisms can be higher than in seawater. Some marine organisms capable of rapid recovery after different injuries are fascinating in this regard. Sea cucumbers Eupentacta fraudatrix can completely restore all organs and the whole body within several weeks after their division into two parts. Here, for the first time, a comparison of the content of different elements in seawater, sea cucumber, and its very stable multiprotein complex (2000 kDa) was performed using two-jet plasma atomic emission spectrometry. Among the 18 elements we found in sea cucumbers, seawater contained only six elements in detectable amounts, and their content decreased in the following order: Mg > Ca > B > Sr ≈ Si > Cr (0.13–930 µg/g of seawater). The content of these elements in sea cucumbers was higher compared with seawater (-fold): Ca (714) > Sr (459) > Cr (75) > Si (42)> B (12) > Mg (6.9). Only four of them had a higher concentration in the protein complex than in seawater (-fold): Si (120.0) > Cr (31.5) > Ca (9.1) > Sr (8.8). The contents of Mg and B were lower in the protein complex than in seawater. The content of elements additionally found in sea cucumbers decreased in the order (µg/g of powder) of P (1100) > Fe (47) > Mn (26) > Ba (15) > Zn (13) > Al (9.3) > Mo (2.8) > Cu (1.4) > Cd (0.3), and in the protein complex, in the order of P (290) > Zn (51) > Fe (23) > Al (14) ≈ Ni (13) > Cu (7.5) > Ba (2.5) ≈ Co (2.0) ≈ Mn (1.6) > Cd (0.7) >Ag (0.2). Thus, sea cucumbers accumulate various elements, including those contained in very low concentrations in seawater. The possible biological roles of these elements are discussed here.
... Aluminum and iron are two precipitants popularly used in the nutrient recovery from the wastewater (Peto 2010). Besides, the coagulant selection depends on the pH in the treatment plant and in general, a pH range of 6-8 is preferred for facilitating efficient functioning of the treatment plant (Kurniawan et al. 2020). ...
Sewage and sludge constitute liquid and solid fractions of the city sewerage system. The raw sewage usually consists of water carrying various solids partly in solution and partly in suspension. Sewage is a rich source of plant nutrients and in addition, contains suspended solids in the form of solid organic matter. Sewage has been used in agriculture from the beginning of civilization but due to less industrialization in the past, the contamination of sewage with heavy metals and other toxic materials is limited. But rapid industrialization resulted in building up of toxic substances like heavy metals and pathogens in sewage and further accompanied with population expansion made its disposal to be a major global concern. Direct landfilling of sludge along with heavy metal pollutes the soil and water consequently. Hence, adoption of right nutrient recovery technology based on feasibility after analysing the pros and cons of the technology is need of the hour for safe management of sewage and subsequent usage in agriculture. The chapter mentioned different nutrient recovery technologies available in a systematic manner characterizing the technologies under three steps of nutrient recovery and thus provided a complete overview of processes involved their advantages and limitations; thereby widening the scope of nutrient recovery from sewage and sludge for future research and adoption.
... Iron and aluminum were chosen for this study since iron is considered vital for humans' life whereas having apparent relationships with numerous diseases such as heart disease, cancer, and insulin sensitivity. Concurrently, aluminum is being widely used daily whilst it interferes with several biological processes including its controversial role in Alzheimer's disease (Peto, 2010). ...
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Tailoring highly efficient adsorbents for environmental remediation is a great challenge key. This paper reports the synthesis of nanostructured pure hydroxylapatite and hydroxyapatite coupled with copper ferrite CuFe2O4@HAp by simple routes for utilizing in the capture of some heavy metal ions like Fe(II) and Al(III) ions. The prepared CuFe2O4@HAp has the advantage of the feasible removal of the adsorbent materials after the treatment process by just exposing them to an external magnetic field. The obtained adsorbent has been characterized by several techniques; XRD patterns showed the high purity of the materials. Moreover, the morphological study by TEM revealed the size of the nanoparticles with a needlelike shape that had a length of 21.9 to 44.04 nm and a cross-sectional dimension of 7.15 to 7.83 nm. Factors like contact time, pH, and the initial concentration have been investigated. Furthermore, different isothermic and kinetic models have been also simulated to study the adsorption performance of CuFe2O4@HAp. The obtained results revealed that this adsorbent could be a promising, safe, and sustainable inexpensive material for the wastewater treatment processes.
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The chemical composition of COVID test swabs has not been examined beyond the manufacturers’ datasheets. Given the unprecedented demand for swabs to conduct rapid lateral flow tests and nucleic acid amplification tests, which led to mass production, including 3-D printing platforms, it is plausible that manufacturing impurities could be present in the swabs and, if so, could pose a risk for human health. We used scanning electron microscopy and energy dispersive X-ray (EDX) spectroscopy to examine the ultrastructure of five assorted brands of COVID test swabs, and to identify and quantify their chemical elements. We detected unexpected elements, including transition metals, such as titanium and zirconium, as well as aluminium, silicon, and fluorine. The amount of some of the detected elements is close to reported toxicological thresholds for inhalation routes. Experimental studies have shown that detrimental effects of the unexpected chemical elements include moderate to severe inflammatory states in the exposed epithelium as well as proliferative changes. Given the massive testing still being used in the context of the COVID pandemic, often as requisites for travelling, attending universities, or as mandatory work policies, we urge caution in continuing to recommend repeated and frequent testing, particularly of healthy, non-symptomatic, individuals.
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Citation: Fule, R.; Kaleem, M.; Asar, T.O.; Rashid, M.A.; Shaik, R.A.; Eid, B.G.; Nasrullah, M.Z.; Ahmad, A.; Kazmi, I. Formulation, Optimization Abstract: Innovative drug delivery systems based on iron oxide nanoparticles (INPs) has generated a lot of interest worldwide and have prime biomedical benefits in anticancer therapy. There are still issues reported regarding the stability, absorption, and toxicity of iron oxide nanoparticles (INPs) when administered due to its rapid surface oxidation and agglomeration with blood proteins. To solve this problem, we have synthesized trehalose-coated stabilized iron oxide nanoparticles (TINPs) by a co-precipitation technique. The surface coating of INPs with trehalose helps to improve the stability, prevents protein binding, and increase absorption uptake inside the body. Developed TINPs was then loaded with anticancer drug cytarabine by chemical crosslinking encapsulation method using suitable solvent. Engineered cytarabine-loaded trehalose-coated stabilized iron oxide nanoparticles (CY-TINPs) were optimized for particle size, zeta potential (−13.03 mV), and solid-state characterization such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and transmission electron microscope (TEM) studies. The particle size of 50 nm was achieved for developed CY-TINPs. The developed CY-TINPs was further evaluated for in vitro cell line investigations which confirmed potential cytotoxic activity. Developed CY-TINPs show remarkable enhancement in in vivo pharmacokinetic parameters C max as 425.26 ± 2.11 and AUC 0-72 as 11,546.64 ± 139.82 as compared to pure drug. Compared to traditional drug delivery, the CY-TINPs formulation can effectively delay release, improve bioavailability, and boost cytotoxic activity against tumors.
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Iron accumulates in aging mammalian neural tissues and, to a greater extent, in Alzheimer's disease, Parkinson's disease, and other central nervous system disorders. By engaging in Fenton and other redox reactions, transition metals generate reactive chemical species implicated in the development of numerous neurological conditions. Oxidative stress, mitochondrial insufficiency, and abnormal transition metal mobilization may represent a core, mutually reinforcing neuropathological 'lesion' that provides a critical link between normal brain aging and neurodegeneration. Moreover, sustained upregulation of the heme-degrading enzyme, heme oxygenase-1, within the astrocytic compartment may be necessary and sufficient for the development of this pivotal tripartite lesion.
We investigated the oxidative state of low-density lipoprotein (LDL) in patients with β-thalassemia to determine whether there was an association with atherogenesis. Conjugated diene lipid hydroperoxides (CD) and the level of major lipid antioxidants in LDL, as well as modified LDL protein, were evaluated in 35 β-thalassemia intermedia patients, aged 10 to 60, and compared with age-matched healthy controls. Vitamin E and β-carotene levels in LDL from patients were 45% and 24% of that observed in healthy controls, respectively. In contrast, the mean amount of LDL-CD was threefold higher and lysil residues of apo B-100 were decreased by 17%. LDL-CD in thalassemia patients showed a strong inverse correlation with LDL vitamin E (r = −0.784; P < .0001), while a negative trend was observed with LDL-β–carotene (r = −0.443; P = .149). In the plasma of thalassemia patients, malondialdehyde (MDA), a byproduct of lipid peroxidation, was increased by about twofold, while vitamin E showed a 52% decrease versus healthy controls. LDL-CD were inversely correlated with plasma vitamin E (r = −0.659; P < .0001) and correlated positively with plasma MDA (r = 0.621; P < .0001). Plasma ferritin was positively correlated with LDL-CD (r = 0.583; P =.0002). No correlation was found between the age of the patients and plasma MDA or LDL-CD. The LDL from thalassemia patients was cytotoxic to cultured human fibroblasts and cytotoxicity increased with the content of lipid peroxidation products. Clinical evidence of mild to severe vascular complications in nine of the patients was then matched with levels of LDL-CD, which were 36% to 118% higher than the mean levels of the patients. Our results could account for the incidence of atherogenic vascular diseases often reported in β-thalassemia patients. We suggest that the level of plasma MDA in β-thalassemia patients may represent a sensitive index of the oxidative status of LDL in vivo and of its potential atherogenicity.
Using stored serum samples collected during from 1970 to 1972 and/or 1977 to 1979 from a fixed population in Hiroshima and Nagasaki, Japan, serum ferritin, transferrin, and ceruloplasmin levels were determined immunologically for persons in whom stomach (233 cases) or lung cancer (84 cases) subsequently developed as well as for their controls. An elevated stomach cancer risk was associated with low antecedent serum ferritin levels, with more than a threefold excess among those in the lowest compared with the highest ferritin quintile. The risk did not vary with the time between blood collection and stomach cancer onset, remaining high among those with low ferritin levels 5 or more years before cancer diagnosis. Achlorhydria, diagnosed in a sample of the population about 10 years before the 1970-to-1972 blood collection and up to 25 years before cancer, was an independent marker of stomach cancer risk. In combination, low serum ferritin and achlorhydria were associated with a tenfold increase in the subsequent risk. No effect of transferrin or ceruloplasmin, independent of ferritin, was observed in the gastric cancer risk, and the risk of lung cancer was not related to these three serum proteins. These prospective findings indicate that biologic markers of an increased risk of stomach cancer can be detected long before cancer onset.
Iron as well as aluminum is reported to accumulate in neurons with neurofibrillary tangles (NFTs) of Alzheimer's disease (AD) brain. Previously we demonstrated that aluminum (III) shows phosphate-dependent binding with hyperphosphorylated tau (PHFtau), the major constituent of NFTs, thereby inducing aggregation of PHFtau. Herein we report that iron (III) can also induce aggregation of soluble PHFtau. Importantly, for the aggregation of PHFtau to occur, iron in the oxidized state (III) is essential since iron in the reduced state (II) lacks such ability. Furthermore, iron (III)-induced aggregation is reversed by reducing iron (III) to iron (II). Thus the iron-participating aggregation is mediated not only by tau phosphorylation but also by the transition of iron between reduced (II) and oxidized (III) states. Further incubation of insoluble PHFtau aggregates isolated from AD brain with reducing agents produced liberation of solubilized PHFtau and iron (II), indicating that PHFtau in association with iron (III) constitutes the insoluble pool of PHFtau. These results indicate that iron might play a role in the aggregation of PHFtau leading to the formation of NFTs in AD brain.
The effects of different polyphenol-containing beverages on Fe absorption from a bread meal were estimated in adult human subjects from the erythrocyte incorporation of radio-Fe. The test beverages contained different polyphenol structures and were rich in either phenolic acids (chlorogenic acid in coffee), monomeric flavonoids (herb teas, camomile (Matricaria recutita L.), vervain (Verbena officinalis L.), lime flower (Tilia cordata Mill.), pennyroyal (Mentha pulegium L.) and peppermint (Mentha piperita L.), or complex polyphenol polymerization products (black tea and cocoa). All beverages were potent inhibitors of Fe absorption and reduced absorption in a dose-dependent fashion depending on the content of total polyphenols. Compared with a water control meal, beverages containing 20-50 mg total polyphenols/serving reduced Fe absorption from the bread meal by 50-70%, whereas beverages containing 100-400 mg total polyphenols/serving reduced Fe absorption by 60-90%. Inhibition by black tea was 79-94%, peppermint tea 84%, pennyroyal 73%, cocoa 71%, vervain 59%, lime flower 52% and camomile 47%. At an identical concentration of total polyphenols, black tea was more inhibitory than cocoa, and more inhibitory than herb teas camomile, vervain, lime flower and pennyroyal, but was of equal inhibition to peppermint tea. Adding milk to coffee and tea had little or no influence on their inhibitory nature. Our findings demonstrate that herb teas, as well as black tea, coffee and cocoa can be potent inhibitors of Fe absorption. This property should be considered when giving dietary advice in relation to Fe nutrition.