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Advanced Glycation and Lipoxidation End Products–Amplifiers of Inflammation: The Role of Food
Stig Bengmark, MD, PhD, FRACS (hon), FRCPS (hon)
From UCL Institute of Hepatology, University College, London Medical
School, London, United Kingdom
Correspondence: Stig Bengmark, MD, PhD, FRACS (hon), FRCPS (hon), 185 Barrier
Point Road, Royal Docks, London, E16 2SE, United Kingdom. Electronic mail may
be sent to
s.bengmark{at}ucl.ac.uk.
Background: High levels of glycated and lipoxidated proteins and
peptides in the body are repeatedly associated with chronic diseases. These
molecules are strongly associated with activation of a specific receptor
called RAGE and a long-lasting exaggerated level of inflammation in the body.
Methods: PubMed reports over 5000 papers plus >13,500 articles
about the related HbA1c, most of them published in the past 5
years. Most of the available abstracts have been read and approximately 800
full papers have been studied. Results: RAGE, a member of the
immunoglobulin superfamily of cell surface molecules and receptor for advanced
glycation end products, known since 1992, functions as a master switch,
induces sustained activation of nuclear factor  B (NFB),
suppresses a series of endogenous autoregulatory functions, and converts
long-lasting proinflammatory signals into sustained cellular dysfunction and
disease. Its activation is associated with high levels of dysfunctioning
proteins in body fluids and tissues, and is strongly associated with a series
of diseases from allergy and Alzheimers to rheumatoid arthritis and urogenital
disorders. Heat treatment, irradiation, and ionization of foods increase the
content of dysfunctioning molecules. Conclusions: More than half of
the studies are performed in diabetes and chronic renal diseases; there are
few studies in other diseases. Most of our knowledge is based on animal
studies and in vitro studies. These effects are worth further
exploration both experimentally and clinically. An avoidance of foods rich in
deranged proteins and peptides, and the consumption of antioxidants,
especially polyphenols, seem to counteract such a development.
It has been almost 100 years since
Malliard1 described
the nonenzymatic pathway for glycation of proteins and suggested that such
chemically modified proteins could play a role in the pathogenesis of chronic
diseases (ChDs), particularly diabetes (DM). However, it is only during the
last 2 decades, and especially the last 5 years, that this concept has
received wider attention among scientists. Still, most practicing physicians
and nutrition experts are still unaware of the concept and its eventual
implications on health. Contributory to the recent increase in interest is the
observation that glycated hemoglobin,
HbA1c,2,3
is deeply involved in DM and in various age-associated diseases and, probably
more important, the identification of several receptors in the body, which are
involved in these processes, of which RAGEs are the most well known and
studied.4,5
More than 5000 papers about the biology of advanced glycation products, plus
over 13,500 articles about HbA1c, are presently available on
PubMed.
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RAGE: A Master Switch
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Metabolic syndrome, with all its clinical manifestations, is strongly
associated with the development of ChDs. A discrete, often long-lasting,
increased inflammation plays an important role in the development of and
maintenance of this
syndrome,6 and in
the pathogenesis of ChDs. Common to ChDs are, in addition to the increased
inflammatory state, a significant elevated oxidant stress (OS) and OS-induced
gene
expression.6–9
RAGE, a member of the immunoglobulin superfamily of cell surface molecules and
receptor for advanced glycation end products (AGEs), functions as a master
switch, converting long-lasting proinflammatory signals into sustained
cellular dysfunction and disease (Table
I).10,11
This receptor and various other receptors for AGEs and lipoxidation end
products (ALEs) play important roles in both oxidative stress and
inflammation. RAGE induces a sustained activation of proinflammatory
transcription factor NFB and suppresses a series of endogenous
autoregulatory
functions.12
Experimental studies suggest that increased deposition of AGEs/ALEs in tissues
is strongly associated with down-regulation of leptin expression in adipocytes
and metabolic
syndrome.13
Reducing the inflammatory environment through reduction of tissue accumulation
of AGE and ALE ligands has also been shown to reduce sustained exaggerated
inflammation and cellular dysfunction, and to improve outcome of
disease.10,14
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Tissue Accumulation of AGEs and ALEs
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As described by
Vlassara,14
industrial processes aimed to make food safer, flavorful, and colorful, such
as heating, irradiation, and ionization, do this but in combination with gross
overnutrition, and also contribute significantly to production of, exposure
to, and accumulation of AGEs/ALEs in the body. Vlassara and her
group15,16
have demonstrated in human studies significant correlation between ingested
AGEs, circulating AGEs, and induction of markers of inflammation. In animal
studies, dietary restriction of AGEs has shown "protective"
effects against impaired immune function in induced ChDs and in complications
to ChDs: DM-induced
vasculopathy,17
nephropathy,18 and
impaired wound
healing.19
Furthermore, it was concluded that the animals remained nearly free of
pathology despite the remaining presence of the underlying
disease.14 Dietary
AGE restriction in animals seemed to be as effective in extending lifespan as
caloric restriction
(CR).20 Similar
observations have been made in human studies, in DM, vascular disease, and
kidney disease: patients who were supplied a low-AGE diet responded with a
considerable reduction in inflammatory markers and vascular
dysfunction.15,21
AGEs constitute a complex and heterogenous group of compounds formed by
nonenzymatic reactions of reducing sugars with amino acids, nucleic acids,
peptides, and proteins. The first compounds produced, generally called Amadori
products, will slowly undergo complex changes, cyclization, dehydration,
oxidation, condensation, cross-linking, and polymerization, to finally form
more irreversible chemical products, referred to as AGEs/ALEs. These processes
are also called Maillard reactions and the products, Maillard products. Some
highly reactive carbonyls such as glyoxal and methylglyoxal have been found to
rapidly modify reactive side chains of proteins. The  -amino group of
lysine and the guanido group of arginine are identified as the most
preferential targets for the highly reactive dicarbonyls, which makes lysine-
and arginine-rich tissues and foods special targets for such processes. High
intracellular and extracellular concentrations of reactive carbohydrates such
as glucose, and especially the highly reactive fructose, are important
triggers for increased glycation and formation of glyoxal, methylglyoxal, and
3-deoxyglucosan, which glycate proteins, which accumulate both intra- and
extracellularly. Significantly elevated visceral AGE formation, serum AGE
levels, caspase-3 activation, and cytoplasmic DNA fragmentation are observed
in organs such as heart, liver, and kidneys in animals with dyslipidemia due
to high-fat diet (32–42%
fat),22 findings
well in line with >50-year-old observations that a high-fat diet
contributes to manifestations of diseases: thrombus formation, renal infarcts,
and myocardial
infarctions.23
Glyoxal and methylglyoxal formation constitutes an intermediate stage in
the Maillard reaction, whereas pentoside, an often-studied glyco-oxidation
product and fluorescent cross-link, is formed in the late stage of the
reaction, where it becomes more stable and irreversible. Many AGE/ALE
compounds have been identified in tissues, and new previously unknown
substances are identified at a rate of 2–3 per year. Most studies thus
far have focused only on a handful of these substances, apart from
HbA1c, mainly pentoside, N-(carboxymethyl)lysine
(CML) and N-(carboxyethyl) lysine (CEL). Recent and
increasing evidence suggests that lipids are as important contributors as
carbohydrates to chemical modification of proteins, accumulation in tissues of
Maillard products, and pathogenesis of
diseases.24 As
diary products and meat are the dominating sources of fats and are usually
exposed to higher temperature, it is these foods that are the largest
contributor of ALEs to the body. Some Maillard products are formed from both
carbohydrate and lipid sources; one such example is
CML.25 Products
derived only from carbohydrate sources, AGEs, are pentoside, crosslines,
vesperlysines, and 3DG-imidozolones. Malondialdehyde (MDA), acrolein adducts
of lysine, histidine, and cysteine are specific
AGEs.24
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AGEs/ALEs and Disease
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The levels of AGEs/ALEs in individuals with incipient or manifest ChDs are,
when compared with healthy individuals, dramatically and significantly
increased. There is, however, great variation in pattern of AGEs/ALEs in the
tissues and in the circulation between various patients and groups of patients
with ChDs. Both AGEs and ALEs will, when accumulated in tissues, significantly
increase the level of inflammation in the
body,26,27
reduce antioxidant
defense,28 weaken
the immune
system,29 impair
DNA repair
mechanisms,30 and
increase accumulation of toxins within the
tissues26 and
increase the rate of
infection.26,27
The differences are great; glycated proteins are suggested to produce almost
50 times more free radicals than nonglycated
proteins,31 and the
plasma concentrations of free CML are reported to be increased about 8-fold
with CEL reported at 22-fold in hemodialysis
patients.32
Accumulation of modified insoluble, indigestible, and dysfunctional
proteins (AGEs/ALEs) occurs predominantly in long-lived tissues such as
collagen, neural myelins, and lenses. It leads to decreased elasticity of
collagen-rich tissues, which seems to explain the agedependent (and
ChD-dependent) increase in stiffness of lenses, joints, skeletal muscles,
vascular walls, and an increase in systolic and decrease in diastolic
pressure.33
AGEs/ALEs exert strong effects also on shortlived cells such as endothelial
cells and pericytes, stimulate growth, interact with cell-surface receptor
RAGE, and activate the NFB pathway, induce vascular endothelium growth
factor (VEGF), inhibit prostacycline production, and stimulate plasminogen
activator inhibitor-1 (PAI-1) synthesis by endothelial and other cells.
Table 1 summarizes documented
cellular events and changes associated with AGE and RAGE activation.
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Hormones Potentiate AGE/ALE-Induced Inflammation
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The process of inflammation is, in addition to being dependent on the
status of oxidation/antioxidation, also enhanced by hormones, especially
growth and sex hormones, and low levels of vitamins, particularly
vitaminD.17β-Estradiol, for example, has been shown to significantly
up-regulate RAGE mRNA in human microvascular endothelial
cells34 and
VEGF-dependent
angiogenesis.35
This could explain a common observation, exacerbation of diabetic vasculopathy
and retinopathy during pregnancy. This assumption is further supported by the
finding that RAGE mRNA activation on endothelial cells induced by
7β-estradiol is abolished when an antiestrogen such as 4-OH tamoxifen is
supplemented.35
These observations might also explain why commercial bovine milk, rich in not
only AGEs/ALEs but also in estrogens (eg, 17β-estradiol) have been
associated with ChDs such as
allergy,36 coronary
heart
disease,37,38
DM,39–41
Parkinson disease
(PD),42 and various
cancers such as
breast,43,44
prostatic,45,46
testicular,46 and
to some extent
ovarian47,48
malignancies. It might not be a coincidence that ChDs and rate of
complications to ChDs are significantly higher, especially during the winter,
at higher altitudes (northern Europe, northern North America), where also
secondary hyperparathyroidism, due to poor supply of vitamin D, is more often
found.49,50
Parathyroid hormone is known to induce IL-6 and is claimed to significantly
increase IL-6 both in hyperthyroid patients (16-fold) and in overweight
patients.49
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The Role of AGE/ALE Tissue Deposition in Common ChDs
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The deposition of dysfunctioning proteins in tissues will, when pronounced,
result in accumulation of histologic changes referred to as amyloid, a common
feature in various ChDs. These deposits of AGEs/ALEs produce a significant
fluorescence, and the degree of ALE/AGE in tissues and body fluids can easy
and reliably be measured in organs such as the skin, blood, and lenses through
estimation of their
fluorescence.51
There is with aging a continuous but slow increase in content of AGEs/ALEs
also in healthy individuals, but the increase is significantly more pronounced
in individuals who are developing or have acquired ChDs. Pronounced increase
in levels of AGEs/ALEs in tissues is reported to be strongly associated to
metabolic
syndrome4,52
and to down-regulation of leptin expression in
adipocytes.53
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Clinical Relevance of AGEs/ALEs in Specific Groups of Diseases
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Accumulation of AGEs/ALEs in tissues and changes suggested to be induced by
AGEs/ALEs have been reported in the following ChDs.
Allergy and autoimmune diseases. Thermal processing, curing, and
roasting of foods introduce major changes in allergenicity of foods and will
often introduce neoantigens and increase allergenicity. Further studies are
needed, however, as reduced allergenicity has sometimes been
reported.54,55
Heated foods like milk, roasted peanuts and soy are reported to induce
significant increases in AGE levels and affect the IgE-binding
capacity.56,57
Significantly elevated urinary levels of the AGE pentosine are observed in
allergic children with clinical signs of exacerbation of atopic
dermatitis.58
Alzheimers disease (AD) and other neurodegenerative diseases.
Similarities between AD and type 2 diabetes (T2DM) exist to the extent that AD
has been called "the diabetes of the brain." The incidence of AD
is also reported to be 2- to 5-fold increased in
T2DM.59 A common
feature of both diseases is accumulation of amyloid deposits, a process that
progresses during the course of disease. Increased levels of AGEs/ALEs have
repeatedly been demonstrated with immunohistochemical methods in senile
plaques, tau proteins, amyloid β proteins, and in neurofibrillary
tangles.60,61
A 3-fold increase in content of AGE is also reported in the brains of AD
patients compared with age-matched
controls.62
Increased levels of AGEs and signs of oxidative damage are also observed in
olfactory bulbs, known to be early targets of
AD.62 A strong
association between severity of disease, RAGE-expression in microglia, and
increases in RAGE protein has been
reported.63 Signs
of amyloidosis, pertubation of neuronal properties and functions,
amplification of glial inflammatory response, increased oxidative stress,
increased vascular dysfunction, increased Aβ in the blood-brain barrier,
and induction of autoantibodies were also
reported.63
Involvement of AGEs/ALEs in the pathogenesis of other neurodegenerative
diseases is also reported:
PD,64,65
amyotrophic lateral sclerosis
(ALS),65–68
Huntington
disease,69
stroke,70 familial
amyloidotic
polyneuropathy,71
and Creutzfeldt-Jakob
disease.72 Early
accumulation of AGEs is also observed in Down syndrome and early antiglycation
treatment suggested to reduce cognitive
impairments.73 It
was recently suggested that bovine spongiform encephalopathy (BSE), a disease
with its significant similarities to AD, might also be associated with
increased glycation and
lipoxidation.74
AGEs, amyloid fibrils, and prions seem all to have the same target, RAGE, and
all activate the NFB pathway. Involvement in BSE of glycation products
and activation of prion proteins are also suggested by other
authors.75,76
Atherosclerosis and cardiovascular diseases. Oxidative stress
(lipid peroxidation) and protein glycation have repeatedly been associated
with extensive arteriosclerosis. A recent study reports significant increases
in both chemical AGEs (carboxymethyl lysine) and fluorescent AGEs
(spectrofluorimetry) in 42 patients with atherosclerosis when compared with 21
healthy controls (p <
.001).77 Increased
levels of MDA, lipid peroxides, and pentosidine in a study of 225 hemodialysis
patients were recently shown to be significantly and positively correlated to
coronary artery calcification score
(CACS).78 Increased
development of atherosclerosis and deposition of AGEs/ALEs in the arterial
walls, in parallel to a significant increase in lipid oxidation, were observed
when rabbits were fed a diet containing 1% cholesterol or 1% cholesterol +10%
fructose in drinking water, and especially so in the fructose-complemented
group.79
High-density lipoproteins (HDL) will, when subject to structural modifications
by lipoxidation, glycation, homocysteinylation, or enzymatic degradation, lose
their antiinflammatory and cytoprotective
properties,80
suggested as important in the pathogenesis of arteriosclerosis but also in
neuro-degenerative diseases, DM, and other autoimmune
diseases.81
Dendritic cells (DCs) are known to play an important role in the pathogenesis
of arteriosclerosis. A recent experimental study demonstrated that
supplementation of AGE-modified serum albumin increased levels of cytokine
secretions, increased maturation of DCs, and augmented capacity to stimulate
T-cell
proliferation.82
Cancers. The influence of AGEs/ALEs on the pathogenesis of
malignant tumors and their ability to grow is not extensively studied.
However, it is reported that the sRAGE receptor, highly expressed in healthy
lung tissues and especially at the site of alveolar epithelium, is
significantly down-regulated in lung
carcinomas,83 and
the RAGE expression is reported to be elevated in human pancreatic cells with
high metastatic ability and decreased in tumor cells with low metastatic
ability.84 High
RAGE expression is also reported in
colonic85 and
prostatic86
cancers. Little information is available about other types of cancers,
including breast cancer, but it has recently been suggested that inhibition of
AGE-RAGE interaction might have a potential as a molecular target for both
cancer prevention and
therapy.84,86
Cataract and other eye disorders. AGEs/ALEs accumulate with age in
all ocular tissues, including lacrimal glands, and trigger pathogenic events,
especially in diabetic patients, in all parts of the
eye.87
DM. More than 2000 publications listed in PubMed (ie, almost half
of all DM papers listed) deal with AGEs/AGEs and their role in DM. Several
excellent reviews have recently been
published.88–90
Overconsumption of fat and carbohydrates, not only of glucose but also other
carbohydrates such as lactose and fructose, contribute especially in diabetic
patients to a significant accumulation of AGEs/ALEs in the tissues.
Consumption of high-fructose corn syrup in the United States exceeds that of
sucrose and is suggested to be the major contributor not only to obesity and
hepatic steatosis but especially to T2DM and to severe complications of both
types 1 and 2 DM.91
The feeding of dairy cows have in recent years, similar to human foods,
undergone significant changes from mainly forage-based feeds to significant
amounts of starch-rich and fast-absorbed carbohydrates: corn, maize grains,
barley, molasses, and dextrose, feeds that induce insulin resistance in cows
and, if the cows are allowed to live long enough, will lead to manifest DM.
Insulin resistance is also observed in calves when intensively fed milk and
lactose.92
Endocrine disorders. Many if not most of the signs and symptoms of
aging, as well as age-associated diseases, are identical to manifestations
seen in hormone deficiencies and in premature aging, which is strongly
associated with multiple hormone deficiencies. Most consequences of aging such
as excessive free radical formation, imbalanced apoptosis system, tissue
accumulation of waste products, failure of repair systems, deficient immune
system, poor gene polymorphisms, and premature telomere shortening are also
associated, if not caused, by hormone
deficiencies.93
Up-regulation of putative pathologic pathways, accumulation of AGEs,
activation of the renin-angiotensin system, oxidative stress, and increased
expression of growth factors and cytokines are all associated with aging.
However, little information either in health or disease, is available about
content of AGEs/ALEs in endocrine organs: the pituitary gland, thyroids,
parathyroids, adrenals, ovaries, and testes. Increased serum AGE levels and
activation of RAGE are reported in women with polycystic ovary
syndrome.94
Activation of the renin-angiotensin system, known to have a pivotal role in
ChDs such as DM and chronic renal disease, contributes to enhanced pathogenic
mechanisms: increased oxidative stress, increased general inflammation,
increased serum levels of free fatty acids, increased glycotoxicity and
lipotoxicity, and advanced glycation and
lipoxidation.95–97
Gastrointestinal disorders. It is likely that digestive tract
disorders such as liver cirrhosis and liver steatosis, as well as inflammatory
bowel disorders, are associated with elevated AGEs/ALEs. A recent study
reports a 14- to 16-fold increase of glyoxal-derived adducts in portal and
hepatic venous plasma of cirrhotic patients compared with healthy
controls.98 Plasma
AGE levels were also measured in 51 patients with liver cirrhosis, 5 patients
after liver transplantation, and 19 healthy
controls.99
Patients with liver cirrhosis demonstrated significantly increased AGE levels,
almost to the same extent as seen in patients with end-stage renal disease. A
dramatic improvement was observed in patients after liver transplantation,
although the AGE levels did not return to those seen in healthy controls, and
the preoperative decrease in renal function did persist. One hundred ten
patients with chronic liver disease (CLD) were recently studied and compared
with 124 healthy controls. Serum levels of AGE (CML) were significantly
affected by the stage of liver cirrhosis and closely associated with liver
function capacity, and AGE (CML) level was reported to positively correlate
with levels of hyaluronic acid (HA; r = 0.639; p <
.0001).100 A
recent animal study suggests that blockage of RAGE is highly protective
against hepatocellular death and necrosis following ischemia and reperfusion,
and increases significantly the rate of
survival.101
Similar observations were also made in acetaminophen-induced hepatotoxicity in
mice.102 In
addition to increased survival, decreased hepatic necrosis, and significant
increase in glutathione, also significant increases in proregenerative
cytokines TNF- and IL-6 were observed.
Pulmonary disorders. Lack of homeostasis in oxidant/antioxidant
balance is obvious in a variety of airway diseases, including asthma, chronic
obstructive pulmonary disease (COPD), cystic fibrosis, and idiopathic
pulmonary fibrosis. Interaction of AGEs/ALEs and RAGE plays a large role, if
not a dominating one, in the pathogenesis of these pulmonary diseases, and
depletion of antioxidants, particularly GSH, in lung epithelial lining is
suggested to play a key role in these
disorders.103–105
Rheumatoid arthritis and other skeletomuscular disorders. A very
strong expression of RAGE, and some of the highest levels of AGEs in the body
are found in tissues with slow turnover, such as tendons, bone, cartilage,
skin, and amyloid plaques. Changes, frequently associated with change in color
from white to yellow-brown, include increased fluorescence, increased
expression of proinflammatory cytokines, matrix metalloproteinases (MMP),
especially MMP-1 and -9. These manifestations are likely responsible for the
observed increased tissue stiffness and brittleness in structures such as
intervertebral discs, bones tendons, cartilages, synovial membranes, and
skeletal muscles and will most likely constitute a major pathogenic factor in
diseases such as
osteoarthritis,106,107
rupture of intervertebral
discs,108 Achilles
tendons109 and
eventually menisci, and are involved also in rheumatoid
diseases110–112
such as rheumatoid arthritis (RA) and fibromyalgia. A significant increase in
glycation of myosin occurs with
age,113 which most
likely contributes to age-associated muscular disorders. Observations in
subjects with osteoporosis of significantly elevated levels of pentosidine and
CML in serum114
and significantly increased pentosidine in cortical
bone115 are of
considerable interest. It has also been observed that the remodeling of
senescent bone is impaired by AGEs both through stimulation of bone-resorbing
cytokines and enhancement of bone resorption by
osteoclasts.116
The role of bovine milk in prevention of osteoporosis could be found to
discredit what has been claimed for decades, should future studies verify that
osteoporosis is more due to interactions of RAGE and AGEs/ALEs than to lack of
minerals.
Skin and oral cavity. Skin has a high density of AGE receptors.
AGEs/ALEs are known to accumulate in dermal elastin and in collagens also, and
are known to interact with dermal fibroblasts, inhibiting their proliferation
capacity. A 10-times reduction in proliferation rate is described as normal in
humans between the second and seventh
decade,117 which
might well explain the reduced healing capacity of age-related wounds and
especially chronic wounds such as those in the extremities of people with DM.
It has also been observed that accumulation of AGEs/ALEs in the skin reflects
the AGE/ALE deposition in the rest of the body to such a degree that skin
autofluorescence has been suggested as a measure of cumulative metabolic
stress and AGEs in the
body.118 Skin
autofluorescence is suggested to be so exact that it is able to predict
progression of retinopathy and nephropathy in DM, as well as mortality in
hemodialysis
patients.118 RAGE
and AGE/ALE-induced apoptosis and enhanced loss of fibroblasts and osteoblasts
are also regarded as major pathogenic factors in periodontal pathology,
especially in chronic
periodontitis.119
A 50% increase in RAGE mRNA is observed in gingiva of diabetic patients
compared with controls (p <
.05).120
Urogenital disorders. Nephropathy is common in the modern world
and its incidence is fast increasing, much in parallel to the increase in DM.
Diabetic nephropathy alone affects today 15%–25% of patients with type 1
DM and as many as 30%–40% of patients with T2DM. Furthermore, it is the
single most important cause of end-stage renal failure in the western
world.121 The
kidney appears as both culprit and target of AGEs/ALEs, and it is well
documented that RAGE is significantly activated and levels of AGEs/ALEs are
markedly elevated in patients with renal failure. More than 500 papers on
PubMed deal with RAGE and AGEs/ALEs in renal diseases. A decrease in renal
function and reduced renal clearance are observed much in parallel to
increases in circulating AGEs. AGEs are also involved in the structural
changes observed in progressing nephropathies such as glomerulosclerosis,
interstitial fibrosis, and tubular
atrophy122; more
detailed information has been published in recent excellent
reviews.122–127
Patients with mild chronic uremic renal failure are reported to have plasma
glycation free adduct concentrations increased up to 5-fold; patients with
end-stage renal disease, as much as 18-fold when receiving peritoneal dialysis
and up to 40-fold when receiving
hemodialysis.128
Kidney transplantation is reported to improve but does not fully correct the
increased levels of AGE/ALE in patients who have been previously
dialyzed.129
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Dietary Measures to Reduce AGEs/ALEs
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The greatest of contributors by far of AGEs/ALEs by food
(Table II) seem to be dairy
products130
(Figure 1), bread, and meat,
not only because they are rich in these substances but also as these foods
constitute the bulk of modern food, especially in the western world. Also,
plants contribute to accumulation of AGEs/ALEs in the body, especially fruits,
which contain larger amounts of fructose, which is highly reactive with
proteins. However, consumption of carbohydrates seem mainly, or only, to be of
considerable risk when consumed as industrially concentrated products, refined
sugar, and high-fructose corn
syrup.91
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FIGURE 1. Relative furosine content in various milk-based products. A, Milk powder
kept for 2 years in room temperature. B, Milk powder kept for 1 year at room
temperature. C, DIF with whey plus casein. D, DIF with hydrolyzed whey. E,
Milk powder kept for 1 year at 4°C. F, Fresh milk powder. G, Raw (whole)
bovine milk. Reprinted from Baptista JAB, Carvalho RCB. Indirect determination
of Amadori compounds in milk-based products by HPLC/ELSD/UV as an index of
protein deterioration. Food Res Int. 2004;37:739–747, with permission
from Elsevier. DIF, dietetic infant formulas; UHT, ultraheat treatment.
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Consuming a vegan diet, known to be low in AGEs/ALEs, seems to result in
statistically lower systolic and diastolic blood pressure, lower serum total
cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting blood
glucose, fewer weight problems, and less incidence of ChDs, especially DM and
its complications. However, there are also problems with a vegetarian
(lactovegetarian and vegan) lifestyle which need to be corrected, among them
risk of shortage in vitamin B12 and poor taurine
status,132 and for
lactovegetarians, higher serum levels of homocysteine. The serum levels of
AGEs/ALEs are reported as higher in longtime healthy lactovegetarians than in
healthy omnivorous
people.133 One
explanation could be, as suggested by the authors, a higher intake of
fructose, especially because this carbohydrate is significantly more reactive
with proteins than sucrose. Another explanation could be a higher consumption
of various milk products, especially cheese and milk powder, known to be rich
in AGEs/ALEs, meant to substitute meat and fish in the diet.
Several measures have been demonstrated to significantly decrease serum and
tissue concentrations of AGEs/ALEs, among which are the following.
Calorie restriction. Evidence from animal studies suggests that
restriction in food intake is an effective means to extending median lifespan
and preventing
ChDs.15 Few studies
are, unfortunately, available in primates and almost no studies in humans.
Significant benefits of long-term (2–11 years) CL compared with normal
western diet were recently reported in a study in healthy humans: blood
pressure 102 ± 10/61 ± 7 vs 131 ± 11/83 ±
6 mm Hg, c-reactive protein (CRP) 0.3 ± 0.3 vs 1.9 ±
2.8 mg/L, tumor necrosis factor (TNF)- 0.8 ± 0.5 vs 1.5
± 1.0 pg/mL, transforming growth factor (TGF)-β 29.4 ± 6.9
ng/mL vs 35.4 ± 7.1 ng/mL
respectively.134
Patients with RA receiving a low-energy diet for 54 days demonstrated a
significant reduction in both urinary pentosidine level and RA disease
activity.135
However, studies on the effects of CL on AGEs/ALEs are thus far lacking in
other groups of ChDs.
Vitamins and antioxidants. Glutathione ( -glutamyl-cysteinyl
glycine [GSH]) is regarded as an important factor for optimal cellular
function and defense against oxidative stress. Dietary supply of GSH has been
shown to reduce glycation and prevents diabetic complications such as diabetic
nephropathy and
neuropathy.136
Rich supply of vitamins A, C, E, and particularly B6,
B12, and folic acid (Figure
2) is often emphasized in the
literature.137
Vitamin D should most likely also be supplemented, especially at higher
latitudes.49
Several thousands of plant-derived chemopreventive agents, polyphenols, and
many others, most often yet unexplored, have the potential to reduce the speed
of aging and prevent degenerative malfunctions of organs, among them,
isothiocyanates in cruciferous vegetables, anthocyanins and hydroxycinnamic
acids in cherries, epigallocatechin-3-gallate (EGCG) in green tea, chlorogenic
acid and caffeic acid in coffee beans and also tobacco leaves, capsaicin in
hot chili peppers, chalcones in apples, eugenol in cloves, gallic acid in
rhubarb, hisperitin in citrus fruits, naringenin in citrus fruits, kaempferol
in white cabbage, myricetin in berries, rutin and quercetin in apples and
onions, resveratrol and other procyanidin dimers in red wine and virgin
peanuts, various curcumenoids, the main yellow pigments in turmeric curry
foods,138 and
daidzein and genistein from the soybean. These compounds have all slightly
different functions and seem to complement each other well. Several, most
likely the majority, of these substances have a great capacity to inhibit the
second phase of the glycation process, eg, the conversion of the Amadori
products to AGEs. A significant number of animal studies support health
benefits of these antioxidants and AGE/ALE
scavengers.139,140
Again, human studies are largely lacking.
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FIGURE 2. Involvement of homocysteine, folic acid, and vitamins B6 and
B12 influences metabolism and possible mechanisms whereby elevated
homocysteine contributes to increased risks of chronic diseases. Reprinted
from Mattson MP. Will caloric restriction and folate protect against AD and
PD? Neurology. 2003;60:690–695, with permission from Lippincott Williams
&
Wilkins.137
|
|
Taurine, carnitine, carnosine, histidine. Taurine, a sulfonic acid
compound, is normally found in high concentrations intracellularly in most
animal tissues, and especially in blood cells, retina, and nervous tissues.
The highest concentrations are found in neutrophils, where it is suggested to
reduce
inflammation.141
The richest sources of taurine are seafood, fish, and poultry. Moderate
amounts are also found in meat, whereas plants, with the only known exception
of some algae, and consequently also vegan diets, are devoid of this amino
acid.142 Taurine
has strong hypoglycemic effects, observed already in the
1930s.143 It
reduces production of AGEs/ALEs and prevents high-fructose-diet-induced
collagen abnormalities in
animals.144,145
In vitro and animal studies suggest that similar effects are obtained
also from supplementing amino acids such as histidine or peptides such as
carnitine and carnosine. Again, no human studies have been undertaken.
Pre- and pro-biotics. Plant-derived antioxidants and AGE/ALE
scavengers need to be released from the plant fibers during passage through
the digestive tract. This process is mainly dependent on microbial enzymes,
provided by the flora in the lower gastrointestinal tract. This flora is
reported to be severely impaired in about 75% of omnivorous Americans and
one-third of vegetarian
Americans.146
Lactic acid bacteria (LAB) are also in their own capacity strong oxidation
scavengers and effective inhibitors of inflammation. LAB might also have the
capacity, before the food is absorbed to eliminate AGE/ALE protein and
peptides, as was earlier demonstrated for
gluten147 and
carcinogens.148
Support for such an assumption derives from an in vitro study, where
fructose lysine, the main modified molecule in heated
milk,126 is
eliminated (deaminated) when incubated with live
flora.149
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Future Directions
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|---|
In the past, most studies on lifestyle-associated disease have focused
mainly on coronary heart disease, T2DM, and chronic renal disease. Increasing
evidence suggests that an "unhealthy" lifestyle is negatively
associated with most, if not all, ChDs. Common to the ChDs is a permanent,
often silent, exaggerated inflammation, strongly associated with metabolic
syndrome and increased deposits in tissues of AGEs/ALEs. ChD patients,
including those with obscure etiology and those with inherent genetic
disorders (Down
syndrome,73,150
cystic
fibrosis,151,152
schizophrenia,153,154
and mental
depression155–157)
might well benefit from reduced AGE/ALE intake. However, more studies are
needed. Studies performed in the United States have reported that the
incidence of a number of chronic diseases would be greatly reduced if people
would follow a "healthy lifestyle." These estimates suggest that
the incidence of coronary artery disease could be reduced by 83%, diabetes
mellitus in women could be reduced by 91%, and colon cancer in men by
71%.160 It is
likely that controlled intake and cellular production of AGEs/ALEs constitute
important contributions to such a healthy lifestyle.
Exaggerated inflammation is also observed in patients who have
complications to acute diseases: sepsis, trauma, and advanced surgical and
medical treatments such as transplantations. Complications and sequelae to
these events are significantly more common in elderly people and in those with
ChDs. Clearly, lifestyle of the individual and inflammation before the trauma
will significantly influence
outcome.161
Presence of metabolic syndrome has been shown to have a strong negative
influence on outcome in acute morbidities and in ICU patients. Future attempts
to minimize accumulation of such substances in the body might provide
significant benefits in both acute and chronic morbidities. It is important to
stress that research in this field is in its infancy, and many more studies
are needed, particularly in humans. I wish such studies will be given the
highest priority.
Received for publication March 27, 2006.
Accepted for publication February 23, 2007.
- Maillard LC. Action des acids amine sur des sucres: formation des
melanoides per voie methodique. C R Acad Sci.1912; 154:66
–68.
- Rahbar S. An abnormal hemoglobin in red cells of diabetics.Clin Chem Acta.
1968;22:296
–298.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Rahbar S. The discovery of glycated haemoglobin: a major event in
the study of nonenzymatic chemistry in biological systems. Ann N Y Acad
Sci. 2005;1043:9
–19.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Chavakis T, Bierhaus A, Nawroth PP. RAGE (receptor for advanced
glycation end products): a central player in the inflammatory response.Microbes Infect.
2004;6:1219
–1225.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM.
Advanced glycation end products and RAGE: a common thread in aging, diabetes,
neurodegeneration, and inflammation. Glycobiology.2005; 15:16R
–28R.[Abstract/Free Full Text]
- Das UN. Metabolic syndrome X: an inflammatory condition?Curr Hypertens Rep.
2004;6:66
–73.[Web of Science][Medline]
[Order article via Infotrieve]
- Black PH. The inflammatory response is an integral part of stress
response: implications for atherosclerosis, insulin resistance, type II
diabetes and metabolic syndrome X. Brain Behav Immun.2003; 17:350
–364.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Pickup JC. Inflammation and activated innate immunity in the
pathogenesis of type 2 diabetes. Diabetes Care.2004; 27:813
–823.[Abstract/Free Full Text]
- Libby P. Inflammation in atherosclerosis. Nature.2003; 420:868
–874.
- Bierhaus A, Humpert PM, Stern DM, Arnold B, Nawroth PP. Advanced
glycation end product receptor-mediated cellular dysfunction. Ann N Y
Acad Sci. 2005;1043:676
–680.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE
is a progression factor amplifying immune and inflammatory responses. J
Clin Invest. 2001;108:949
–955.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bierhaus A, Schiekofer S, Schwaninger M, et al. Diabetes-associated
sustained activation of the transcription factor nuclear factor-B.Diabetes.
2001;50:2792
–2808.[Abstract/Free Full Text]
- Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous
secretory RAGE is associated with components of the metabolic syndrome and
atherosclerosis. Arterioscler Thromb Vasc Biol.2005; 25:2587
–2593.[Abstract/Free Full Text]
- Vlassara H. Advanced glycation in health and disease: role of the
modern environment. Ann N Y Acad Sci.2005; 1043:452
–460.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Vlassara H, Cai J, Crandall J, et al. Inflammatory mediators are
induced by dietary glycotoxins, a major risk factor for diabetic angiopathy.Proc Natl Acad SciUSA.2002; 99:15596
–15601. Erratum 2002;763.[Abstract/Free Full Text]
- Peppa M, Uribarri J, Cai W, Lu M, Vlassara H. Glycoxidation and
inflammation in renal failure patients. Am J Kidney Dis.2004; 43:690
–695.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Lin RY, Choudhury W, Cai W, et al. Dietary glycotoxins promote
diabetic atherosclerosis in apolipoprotein E-deficient mice.Atherosclerosis.
2003;168:213
–220.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zheng F, He C, Cai W, Hattori M, Steffes M, Vlassara H. Prevention
of nephropathy in mice by a diet low in glycoxidation products.Diabetes Metab Res Rev.2002; 18:224
–237.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Peppa M, Brem H, Ehrlich P, et al. Adverse effects of glycotoxins
on wound healing in genetically diabetic mice. Diabetes.2003; 52:2805
–2813.[Abstract/Free Full Text]
- Cai W, He JC, Lu M, et al. Amelioration of insulin resistance,
weight gain and markers of oxidant stressing aging mice by dietary glycotoxin
restriction: a therapeutic alternative to caloric restriction.Diabetes.
2004;(suppl 2):A343
.
- Uribarri J, Peppa M, Cai W, et al. Restriction of dietary
glycotoxins markedly reduces AGE toxins in renal failure patients. J Am
Soc Nephrol. 2003;14:728
–731.[Abstract/Free Full Text]
- Li SY, Liu Y, Sigmin VK, McCort A, Ren J. High fat diet enhances
visceral advanced glycation end products, nuclear O-Glc-Nac
modification, p38 mitogen-activated protein kinase activation and apoptosis.Diabetes Obes Metab.2005; 7:448
–454.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hartroft WS, Thomas WA. Pathological lesions related to
disturbances of fat and cholesterol metabolism in man. JAMA.1957; 164:1899
–1905.[Abstract/Free Full Text]
- Thorpe SR, Baynes JW. Maillard reaction products in tissue
proteins: new products and new perspectives. Amino Acids.2003; 25:275
–281.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Baynes JW, Thorpe SR. Glycoxidation and lipoxidation in
atherosclerosis. Free Radic Biol Med.2000; 28:1708
–1716.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Vamvakas S, Bahner U, Heidland A. Cancer in end-stage renal
disease: potential factors involved. Am J Nephrol.1998; 18:89
–95.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced
glycation end products is mediated by oxidative stress. J Neural
Transm. 1998;105:1005
–1015.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Morena M, Cristol JP, Senecal L, Leray-MoraguesH, Krieter D, Canaud
B. Oxidative stress in hemodialysis patients: is NADPH oxidase complex the
culprit? Kidney Int.2002; 80(suppl):109
–114.
- Descamps-Latscha B, Jungers P, Witko-Sarsat V. Immune system
dysregulation in uremia: the role of oxidative stress. Blood
Purif. 2002;20:481
–484.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zevin D, Malachi T, Gafter U, Friedman J, Levi J. Impaired DNA
repair in patients with end-stage renal disease and its improvement with
hemodialysis. Miner Electrolyte Metab.1991; 17:303
–306.[Web of Science][Medline]
[Order article via Infotrieve]
- Mullarkey CJ, Edelstein D, Brownlee M. Free radical generation by
early glycation products: a mechanism for accelerated athero-genesis in
diabetes. Biochem Biophys Res Commun.1990; 173:932
–939.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Agalou S, Ahmed N, Dawnay A, Thornalley PJ. Removal of advanced
glycation products in clinical renal failure by peritoneal dialysis and
haemodialysis. Biochem Soc Trans.2003; 31:1394
–1396.[Web of Science][Medline]
[Order article via Infotrieve]
- Aronson D. Cross-linking of glycated collagen in the pathogenesis
of arterial and myocardial stiffening of aging and diabetes. J
Hypertens. 2003;21:3
–12.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Yamagishi S, Fujimori H, Yonekura H, Yamamoto Y, Yamamoto H.
Advanced glycation end products inhibit prostacyclin production and induce
plasminogen activator inhibitor-1 in human microvascular endothelial cells.Diabetologia.
1998;41:1435
–1441.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Suzuma K, Mandai M, Takagi H, et al. 17-Beta-estradiol increases
VEGF receptor-2 and promotes DNA synthesis in retinal microvascular
endothelial cells. Invest Ophthalmol Vis Sci.1999; 40:2122
–2129.[Abstract/Free Full Text]
- Rautava S, Isolauri E. Cow's milk allergy in infants with atopic
eczema is associated with aberrant production of interleukin-4 during oral
cow's milk challenge. J Pediatr Gastroenterol Nutr.2004; 39:529
–535.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Artaud-Wild SM, Connor SL, Sexton G, Connor WE. Differences in
coronary mortality can be explained by differences in cholesterol and
saturated fat intakes in 40 countries but not in France and Finland: a
paradox. Circulation.1993; 88:2771
–2779.[Abstract/Free Full Text]
- Moss M, Freed DL. Survival trends, coronary event rates, and the
MONICA project: monitoring trends and determinants in cardiovascular disease.Lancet.
1999;354:862
–865.[Web of Science][Medline]
[Order article via Infotrieve]
- Dahl-Jorgensen K, Joner G, Hanssen KF. Relationship between cows'
milk consumption and incidence of IDDM in childhood. Diabetes
Care. 1991;14:1081
–1083.[Abstract]
- Gimeno SG, de Souza JM. IDDM and milk consumption: a case-control
study in Sao Paulo, Brazil. Diabetes Care.1997; 20:1256
–1260.[Abstract]
- Virtanen SM, Hypponen E, Laara E, et al. Cow's milk consumption,
disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up
study in siblings of diabetic children: Childhood Diabetes in Finland Study
Group. Diabet Med. 1998;15:730
–738.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Park M, Ross GW, Petrovitch H, et al. Consumption of milk and
calcium in midlife and the future risk of Parkinson disease.Neurology.
2005;64:1047
–1051.[Abstract/Free Full Text]
- Outwater JL, Nicholson A, Barnard N. Dairy products and breast
cancer: the IGF-I, estrogen, and bGH hypothesis. Med
Hypotheses. 1997;48:453
–461.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hjartaker A, Laake P, Lund E. Childhood and adult milk consumption
and risk of premenopausal breast cancer in a cohort of 48,844 women: the
Norwegian Women and Cancer Study. Int J Cancer.2001; 93:888
–893.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ganmaa D, Li XM, Wang J, Qin LQ, Wang PY, Sato A. Incidence and
mortality of testicular and prostatic cancers in relation to world dietary
practices. Int J Cancer.2002; 98:262
–267.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ganmaa D, Li XM, Qin LQ, Wang PY, Takeda M, Sato A. The experience
of Japan as a clue to the etiology of testicular and prostatic cancers.Med Hypotheses.
2003;60:724
–730.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Larsson SC, Bergkvist L, Wolk A. Milk and lactose intakes and
ovarian cancer risk in the Swedish Mammography Cohort. Am J Clin
Nutr. 2004;80:1353
–1357.[Abstract/Free Full Text]
- Genkinger JM, Hunter DJ, Spiegelman D, et al. Dairy products and
ovarian cancer: a pooled analysis of 12 cohort studies. Cancer
Epidemiol Biomarkers Prev.2006; 15:364
–372.[Abstract/Free Full Text]
- Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular
disease and vitamin D insufficiency into perspective. Br J
Nutr. 2005;94:483
–492.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- McCarty MF. Secondary hyperparathyroidism promotes the acute phase
response: a rational for supplementing vitamin D in prevention of vascular
events in elderly. Med Hypotheses.2005; 64:1022
–1026.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Meerwaldt R, Links T, Graaff R, et al. Simple noninvasive
measurement of skin autofluorescence. Ann N Y Acad Sci.2005; 1043:290
–298.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Soldatos G, Cooper ME, Jandeleit-Dahm KA. Advanced-glycation end
products in insulin-resistant states. Curr Hypertens Rep.2005; 7:96
–102.[Web of Science][Medline]
[Order article via Infotrieve]
- Unno Y, Sakai M, Sakamoto Y, et al. Advanced glycation end
products-modified proteins and oxidized LDL mediate down-regulation of leptin
in mouse adipocytes via CD36. Biochem Biophys Res Commun.2004; 325:151
–156.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Davis PJ, Smales CM, James DC. How can thermal processing modify
the antigenicity of proteins? Allergy.2001; 56(suppl 67):56
–60.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sancho AI, Rigby NM, Zuidmeer L, et al. The effect of thermal
processing on the IgE reactivity of the non-specific lipid transfer protein
from apple, Mal d 3. Allergy.2005; 60:1262
–1268.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Chung SY, Champagne ET. Association of end-product adducts with
increased IgE binding of roasted peanuts. J Agric Food Chem.2001; 49:3911
–3916.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Franck P, Moneret Vautrin DA, Dousset B, et al. The allergenicity
of soybean-based products is modified by food technologies. Int Arch
Allergy Immunol. 2002;128:212
–219.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tsukahara H, Shibata R, Ohta N, et al. High levels of urinary
pentosidine, an advanced glycation end product, in children with acute
exacerbation of atopic dermatitis: relationship with oxidative stress.Metabolism.
2003;52:1601
–1605.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Nicolls MR. The clinical and biological relationship between type
II diabetes mellitus and Alzheimer's disease. Curr Alzheimer
Res. 2004;1:47
–54.[CrossRef][Medline]
[Order article via Infotrieve]
- Smith MA, Taneda S, Richey PL, et al. Advanced Maillard reaction
end products are associated with Alzheimer pathology. Proc Natl Acad
SciUSA. 1994;91:5710
–5714.[Abstract/Free Full Text]
- Vitek MP, Bhattacharya K, Gendening JM, et al. Advanced glycation
end products contribute to amyloidosis in Alzheimer disease. Proc Natl
Acad SciUSA. 1994;91:4766
–4770.[Abstract/Free Full Text]
- Moreira PI, Smith MA, Zhu X, Nunomora A, Castellani RJ, Perry G.
Oxidative stress and neurodegeneration. Ann N Y Acad Sci.2005; 1043:543
–552.
- Lue L-F, Yan SD, Stern DM, Walker DG. Preventing activation of
receptor for advance glycation end products in Alzheimer's disease.Curr Drug Targets CNS Neurol Disord.2005; 4:249
–266.[CrossRef][Medline]
[Order article via Infotrieve]
- Castellani R, Smith MA, Richey PL, Perry G. Glycoxidation and
oxidative stress in Parkinson disease and diffuse Lewy body disease.Brain Res.
1996;737:195
–200.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Dalfo E, Portero-Otin M, Ayala V, Martinez A, Pamplona R, Ferrer I.
Evidence of oxidative stress in the neocortex in incidental Lewy body disease.J Neuropathol Exp Neurol.2005; 64:816
–830.[Web of Science][Medline]
[Order article via Infotrieve]
- Kikuchi S, Shinpo K, Ogata A, et al. Detection of
N-(carboxymethyl)lysine (CML) and non-CML advanced glycation end products in
the anterior horn of amyotrophic lateral sclerosis spinal cord.Amyotroph Lateral Scler Other Motor Neuron Disord.2002; 3:63
–68.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Chou SM, Wang HS, Taniguchi A, Bucala R. Advanced glycation end
products in neurofilament conglomeration of motoneurons in familial and
sporadic amyotrophic lateral sclerosis. Mol Med.1998; 4:324
–332.[Web of Science][Medline]
[Order article via Infotrieve]
- Kaufmann E, Boehm BO, Sussmuth SD, et al. The advanced glycation
end-product N epsilon-(carboxymethyl)lysine level is elevated in cerebrospinal
fluid of patients with amyotrophic lateral sclerosis. Neurosci
Lett. 2004;371:226
–229.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ma L, Nicholson LF. Expression of the receptor for advanced
glycation end products in Huntington's disease caudate nucleus. Brain
Res. 2004;1018:10
–17.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zimmerman GA, Meistrell M, Bloom O, et al. Neurotoxicity of
advanced glycation endproducts during focal stroke and neuro-protective
effects of aminoguanidine. Proc Natl Acad SciUSA.1995; 92:3744
–3748.[Abstract/Free Full Text]
- Gomes R, Sousa Silva M, Quintas A, et al. Argpyrimidine, a
methylglyoxal-derived advanced glycation end-product in familial amyloidotic
polyneuropathy. Biochem J.2005; 385:339
–345.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sasaki N, Takeuchi M, Chowei H, et al. Advanced glycation end
products (AGE) and their receptor (RAGE) in the brain of patients with
Creutzfeldt-Jacob disease with prion plaques. Neurosci Lett.2002; 326:117
–120.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Thiel R, Fowkes SW. Can cognitive deterioration associated with
Down syndrome be reduced? Med Hypotheses.2005; 64:524
–532.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Frey J. Bovine spongiform encephalopathy: are the cows mad or full
of carbohydrate? Clin Chem Lab Med.2002; 40:101
–103.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Boratynski J, Gorski A. BSE: a consequence of cattle feeding with
glycated molecules host-unknown? Med Hypotheses.2002; 58:276
–278.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Choi YG, Kim JI, Jeon YC, et al. Nonenzymatic glycation at the N
terminus of pathogenic prion protein in transmissible spongiform
encephalopathies. J Biol Chem.2004; 279:30402
–30409.[Abstract/Free Full Text]
- Kalousova M, Zak A, Soukupova J, Stipek S, Malbohan IM, Zima T.
Advanced glycation and oxidation products in patients with atherosclerosis [in
Czech]. Cas Lek Cesk.2005; 144:385
–390.[Medline]
[Order article via Infotrieve]
- Taki K, Takayama F, Tsuruta Y, Niwa T. Oxidative stress, advanced
glycation end product, and coronary artery calcification in hemodialysis
patients. Kidney Int.2006; 70:218
–224.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tokita Y, Hirayama Y, Sekikawa A, et al. Fructose ingestion
enhances atherosclerosis and deposition of advanced glycated end-products in
cholesterol-fed rabbits. J Atheroscler Thromb.2005; 12:260
–267.[Web of Science][Medline]
[Order article via Infotrieve]
- Ferretti G, Bacchetti T, Negre-Salvayre A, Salvayre R, Doussett N,
Curatola G. Structural modifications of HDL and functional consequences.Atherosclerosis.
2006;184:1
–7.[Medline]
[Order article via Infotrieve]
- de Leeuw K, Kallenberg C, Bijl M. Accelerated atherosclerosis in
patients with systemic autoimmune diseases. Ann N Y Acad Sci.2005; 1051:362
–371.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ge J, Jia Q, Liang C, et al. Advanced glycosylation end products
might promote atherosclerosis through inducing the immune maturation of
dendritic cells. Arterioscler Thromb Vasc Biol.2005; 25:2157
–2163.[Abstract/Free Full Text]
- Bartling B, Hofmann HS, Weigle B, Silber RE, Simm A.
Down-regulation of the receptor for advanced glycation end-products (RAGE)
supports non-small cell lung carcinoma. Carcinogenesis.2005; 26:293
–301.[Abstract/Free Full Text]
- Takada M, Hirata K, Ajiki T, Suzuki Y, Kuroda Y. Expression of
receptor for advanced glycation end products (RAGE) and MMP-9 in human
pancreatic cancer cells. Hepatogastroenterology.2004; 51:928
–930.[Medline]
[Order article via Infotrieve]
- Yamagishi S, Nakamura K, Inoue H, Kikuchi S, Takeuchi M. Possible
participation of advanced glycation end products in the pathogenesis of
colorectal cancer in diabetic patients. Med Hypotheses.2005; 64:1208
–1210.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ishiguro H, Nakaigawa N, Miyoshi Y, Fujinama K, Kubota Y, Uemura H.
Receptor for advanced glycation end products (RAGE) and its ligand, amphoterin
are overexpressed and associated with prostate cancer development.Prostate.
2005;64:92
–100.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Stitt AW. The Maillard reaction in eye diseases. Ann N Y
Acad Sci. 2005;1043:582
–597.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Wada R, Yagihashi S. Role of advanced glycation end products and
their receptors in development of diabetic neuropathy. Ann N Y Acad
Sci. 2005;1043:598
–604.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Monnier VM, Sell DR, Genuth S. Glycation products as markers and
predictors of the progression of diabetic complications. Ann N Y Acad
Sci. 2005;1043:567
–581.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Yamagishi S, Imaizumi T. Diabetic vascular complications:
pathophysiology, biochemical basis and potential therapeutic strategy.Curr Pharm Des.
2005;11:2279
–2299.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Gaby AR. Adverse effects of dietary fructose. Altern Med
Rev. 2005;10:294
–306.[Web of Science][Medline]
[Order article via Infotrieve]
- Hostettler-Allen RL, Tappy L, Blum JW. Insulin resistance,
hyperglycemia, and glucosuria in intensively milk-fed calves. J Anim
Sci. 1994;72:160
–173.[Abstract]
- Hertoghe T. The "multiple hormone deficiency" theory of
aging: is human senescence caused mainly by multiple hormone deficiencies?Ann N Y Acad Sci.2005; 1057:448
–465.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Diamanti-Kandarakis E, Piperi C, Kalofoutis A, Creatsas G.
Increased levels of serum advanced glycation end-products in women with
polycystic ovary syndrome. Clin Endocrinol.2005; 62:37
–43.[CrossRef][Medline]
[Order article via Infotrieve]
- Flyvbjerg A, Khatir DS, Jensen LJ, Dagnaesh-Hansen F, Gronbaek H,
Rasch R. The involvement of growth hormone (GH), insulin-like growth factors
(IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney
disease. Curr Pharm Des.2004; 10:3385
–3394.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Allen TJ, Jandeleit-Dahm KA. Preventing atherosclerosis with
angiotensin-converting enzyme inhibitors: emphasis on diabetic
atherosclerosis. Curr Drug Targets Cardiovasc Haematol Disord.2005; 5:503
–512.[CrossRef][Medline]
[Order article via Infotrieve]
- Tikellis C, Cooper ME, Thomas MC. Role of the renin-angiotensin
system in the endocrine pancreas: implications for the development of
diabetes. Int J Biochem Cell Biol.2005; 38:737
–751.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ahmed N, Lüthen R, Häussinger D, et al. Increased protein
glycation in cirrhosis and therapeutic strategies to prevent it. Ann N
Y Acad Sci. 2005;1043:718
–724.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sebekova K, Kupcova V, Schinzel R, Heidland A. Markedly elevated
levels of plasma advanced glycation end products in patients with liver
cirrhosis: amelioration by liver transplantation. J Hepatol.2002; 36:66
–71.[Medline]
[Order article via Infotrieve]
- Yagmur E, Tacke F, Weiss C, et al. Elevation of
Nepsilon-(carboxymethyl)lysine-modified advanced glycation end products in
chronic liver disease is an indicator of liver cirrhosis. Clin
Biochem. 2006;39:39
–45.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zeng S, Feirt N, Goldstein M, et al. Blockade of receptor for
advanced glycation end product (RAGE) attenuates ischemia and reperfusion
injury to the liver in mice. Hepatology.2004; 39:422
–432.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ekong U, Zeng S, Dun H, et al. Blockade of the receptor for
advanced glycation end products attenuates acetaminophen-induced
hepatotoxicity in mice. J Gastroenterol Hepatol.2006; 21:682
–688.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Nadeem A, Raj HG, Chhabra SK. Increased oxidative stress and
altered levels of antioxidants in chronic obstructive pulmonary disease.Inflammation.
2005;29:23
–32.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hartl D, Starosta V, Maier K, et al. Inhaled glutathione decreases
PGE2 and increases lymphocytes in cystic fibrosis lungs. Free Radic
Biol Med. 2005;39:463
–472.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Rahman I, Biswas SK, Kode A. Oxidant and antioxidant balance in the
airways and airway diseases. Eur J Pharmacol.2006; 533:222
–239.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- DeGroot J. The AGE of the matrix: chemistry, consequence and cure.Curr Opin Pharmacol.2004; 4:301
–305.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Steenvoorden MM, Huizinga TW, Verzijl N, et al. Activation of
receptor for advanced glycation end products in osteoarthritis leads to
increased stimulation of chondrocytes and synoviocytes. Arthritis
Rheum. 2006;54:253
–263.[CrossRef][Medline]
[Order article via Infotrieve]
- Hormel SE, Eyre DR. Collagen in the ageing human intervertebral
disc: an increase in covalently bound fluorophores and chromophores.Biochim Biophys Acta.1991; 1078:243
–250.[CrossRef][Medline]
[Order article via Infotrieve]
- Reddy GK. Cross-linking in collagen by nonenzymatic glycation
increases the matrix stiffness in rabbit Achilles tendon. Exp Diabet
Res. 2004;5:143
–153.[CrossRef]
- Hofmann MA, Drury S, Hudson BI, et al. RAGE and arthritis: the G82S
polymorphism amplifies the inflammatory response. Genes Immun.2002; 3:117
–118.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hein GE, Kohler M, Oelzner P, Stein G, Franke S. The advanced
glycation end product pentosidine correlates to IL-6 and other relevant
inflammatory markers in rheumatoid arthritis. Rheumatol Int.2005; 26:137
–141.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Makino
H. Increased expression of receptor for advanced glycation end products by
synovial tissue macro-phages in rheumatoid arthritis. Arthritis
Rheum. 2006;54:97
–104.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ramamurthy B, Hook P, Jones AD, Larsson L. Changes in myosin
structure and function in response to glycation. FASEB J.2001; 15:2415
–2422.[Abstract/Free Full Text]
- Hein G, Wiegand R, Lehmann G, Stein G, Franke S. Advanced glycation
end-products pentosidine and N epsilon-carboxy-methyllysine are elevated in
serum of patients with osteoporosis. Rheumatology.2003; 42:1242
–1246.[Abstract/Free Full Text]
- Odetti P, Rossi S, Monacelli F, et al. Advanced glycation end
products and bone loss during aging. Ann N Y Acad Sci.2005; 1043:710
–717.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Miyata T, Kawai R, Taketomi S, Sprague SM. Possible involvement of
advanced glycation end-products in bone resorption. Nephrol Dial
Transplant. 1996;11(suppl
5): 54–57.[Free Full Text]
- Stamatas GN, Estanislao RB, Suero M, et al. Facial skin
fluorescence as a marker of the skin's response to chronic environmental
insults and its dependence on age. Br J Dermatol.2006; 154:125
–132.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Meerwaldt R, Hartog JW, Graaff R, et al. Skin autofluorescence, a
measure of cumulative metabolic stress and advanced glycation end products,
predicts mortality in hemodialysis patients. J Am Soc Nephrol.2005; 16:3687
–3693.[Abstract/Free Full Text]
- Holla LI, Kankova K, Fassmann A, et al. Distribution of the
receptor for advanced glycation end products gene polymorphisms in patients
with chronic periodontitis: a preliminary study. J Periodontol.2001; 72:1742
–1746.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Katz J, Bhattacharyya I, Farkhondeh-Kish F, Perez FM, Caudle RM,
Heft MW. Expression of the receptor of advanced glycation end products in
gingival tissues of type 2 diabetes patients with chronic periodontal disease:
a study utilizing immunohistochemistry and RT-PCR. J Clin
Periodontol. 2005;32:40
–44.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ostergaard J, Hansen TK, Thiel S, Flyvbjerg A. Complement
activation and diabetic vascular complications. Clin Chim Acta.2005; 361:10
–19.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bohlender JM, Franke S, Stein G, Wolf G. Advanced glycation end
products and the kidney. Am J Physiol Renal Physiol.2005; 289:F645
–F659.[Abstract/Free Full Text]
- Khan ZA, Farhangkhoee H, Chakrabarti S. Towards newer molecular
targets for chronic diabetic complications. Curr Vasc
Pharmacol. 2006;4:45
–57.[CrossRef][Medline]
[Order article via Infotrieve]
- Thomas MC, Forbes JM, Cooper ME. Advanced glycation end products
and diabetic nephropathy. Am J Ther.2005; 12:562
–572.[CrossRef][Medline]
[Order article via Infotrieve]
- Kalousova M, Zima T, Tesar V, et al. Advanced glycoxidation end
products in chronic diseases-clinical chemistry and genetic background.Mutat Res.
2005;579:37
–46.[Web of Science][Medline]
[Order article via Infotrieve]
- Saito A, Takeda T, Sato K, et al. Significance of proximal tubular
metabolism of advanced glycation end products in kidney diseases. Ann N
Y Acad Sci. 2005;1043:637
–643.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Jensen LJ, Ostergaard J, Flyvbjerg A. AGE-RAGE and AGE cross-link
interaction: important players in the pathogenesis of diabetic kidney disease.Horm Metab Res.2005; 37(suppl 1):26
–34.[Web of Science][Medline]
[Order article via Infotrieve]
- Agalou S, Ahmed N, Babaei-Jadidi, Dawnay A, Thornalley PJ. Profound
mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol.
2005;16:1471
–1485.[Abstract/Free Full Text]
- Hartog JW, de Vries AP, Lutgers HL, et al. Accumulation of advanced
glycation end products, measured as skin autofluorescence, in renal disease.Ann N Y Acad Sci.2005; 1043:299
–307.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Baptista JAB, Carvalho RCB. Indirect determination of Amadori
compounds in milk-based products by HPLC/ELSD/UV as an index of protein
deterioration. Food Res Int.2004; 37:739
–747.[CrossRef]
- Goldberg T, Cai W, Peppa M, et al. Advanced glycoxidation end
products in commonly consumed foods. J Am Diet Assoc.2004; 104:1287
–1291.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- McCarty MF. The low-AGE content of low fat vegan diets could
benefit diabetics, though concurrent taurine supplementation may be needed to
minimize endogenous AGE production. Med Hypotheses.2005; 64:394
–398.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sebekova K, Krajcoviova-Kudlackova M, Schinzel R, Faist V, Klvanova
J, Heidland A. Plasma levels of advanced glycation end products in healthy,
long-term vegetarians and subjects on a western mixed diet. Eur J
Nutr. 2001;40:275
–281.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Meyer TE, Kovács SJ, Ehsani AA, Klein S, Holloszy JO,
Fontant L. Long-term caloric restriction ameliorates the decline in diastolic
function in humans. J Am Coll Cardiol.2006; 47:398
–402.[Abstract/Free Full Text]
- Iwashige K, Kouda K, Kouda M, et al. Calorie restricted diet and
urinary pentosidine in patients with rheumatoid arthritis. J Physiol
Anthropol Appl Hum Sci. 2004;23:19
–24.[CrossRef][Medline]
[Order article via Infotrieve]
- Osawa T, Kato Y. Protective role of antioxidative food factors in
oxidative stress caused by hyperglycemia. Ann N Y Acad Sci.2005; 1043:440
–451.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mattson MP. Will caloric restriction and folate protect against AD
and PD? Neurology. 2003;60:690
–695.[Abstract/Free Full Text]
- Bengmark S. Curcumin: an atoxic antioxidant and natural NFB,
COX-2, LOX and iNOS inhibitor: a shield against acute and chronic diseases.JPEN J Parenter Enteral Nutr.2006; 30:45
–51.[Abstract/Free Full Text]
- McCarty MF. Nutraceutical resources for diabetes prevention: an
update. Med Hypotheses.2005; 64:151
–158.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- McCarty MF. Potential utility of natural polyphenols for reversing
fat-induced insulin resistance. Med Hypotheses.2005; 64:628
–635.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- McCarty MF. The reported clinical utility of taurine of ischemic
disorders may reflect a down-regulation of neutrophil activation and adhesion.Med Hypotheses.
1999;53:290
–299.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Laidlaw S, Grosvenor M, Kopple JD. The taurine content of common
foodstuffs. JPEN J Parenter Enteral Nutr.1990; 14:183
–188.[Abstract]
- Hansen SH. The role of taurine in diabetes and the development of
diabetic complications. Diabetes Metab Res Rev.2001; 17:330
–346.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Nandhini AT, Thirunavukkarasu V, Anuradha CV. Stimulation of
glucose utilization and inhibition of protein glycation and AGE products by
taurine. Acta Physiol Scand.2004; 181:297
–303.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Nandhini AT, Thirunavukkarasu V, Anuradha CV. Taurine prevents
collagen abnormalities in high fructose-fed rats. Indian J Med
Res. 2005;122:171
–177.[Web of Science][Medline]
[Order article via Infotrieve]
- Finegold SM, Sutter VL, Mathisen GE. Normal indigenous intestinal
flora. In: Hentges DJ, ed. Human Intestinal Microflora in Health and
Disease. London: Academic Press; 1983:3
–31.
- di Cagno R, de Angelis M, Alfonsi G, et al. Pasta made from durum
wheat semolina fermented with selected lactobacilli as a tool for a potential
decrease of the gluten intolerance. J Agric Food Chem.2005; 53:4393
–4402.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tavan E, Cayuela C, Antoine JM, Cassand P. Antimutagenic activities
of various lactic acid bacteria against food mutagens: heterocyclic amines.J Dairy Res.
2002;69:335
–341.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Erbersdobler H, Gunsser I, Weber G. Abbau von Fructoselysine durch
die Darmflora. Zentralbl Veterinarmed A.1970; A17:573
–575.[Medline]
[Order article via Infotrieve]
- Odetti P, Angelini G, Dapino D, et al. Early glycoxidation damage
in brains from Down's syndrome. Biochem Biophys Res Commun.1998; 243:849
–851.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hudson VM. New insights into the pathogenesis of cystic fibrosis:
pivotal role of glutathione system dysfunction and implications for therapy.Treat Respir Med.
2004;3:353
–363.[CrossRef][Medline]
[Order article via Infotrieve]
- Foell D, Seeliger S, Vogl T, et al. Expression of S100A12 (ENRAGE)
in cystic fibrosis. Thorax.2003; 58:613
–617.[Abstract/Free Full Text]
- Altamura AC, Boin F, Maes M. HPA axis and cytokines dys-regulation
in schizophrenia: potential implications for the anti-psychotic treatment.Eur Neuropsychopharmacol.1999; 10:1
–4.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Muller N, Riedel M, Schwarz MJ. Psychotropic effects of COX-2
inhibitors: a possible new approach for the treatment of psychiatric
disorders. Pharmacopsychiatry.2004; 37:266
–269.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Raison CL, Capuron L, Miller AH. Cytokines sing the blues:
inflammation and the pathogenesis of depression. Trends
Immunol. 2006;27:24
–31.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Gundersen Y, Opstad PK, Reistad T, Thrane I, Vaagenes P. Seven
days' around the clock exhaustive physical exertion combined with energy
depletion and sleep deprivation primes circulating leukocytes. Eur J
Appl Physiol. 2006;97:151
–157.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Muller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2
inhibitor celecoxib has therapeutic effects in major depression: results of a
double-blind, randomized, placebo controlled, add-on pilot study to
reboxetine. Mol Psychiatry.2006; 11:680
–684.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary
prevention of coronary heart disease in women through diet and lifestyle.N Engl J Med.
2000;343:16
–22.[Abstract/Free Full Text]
- Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle and the risk
of type 2 diabetes mellitus in women. N Engl J Med.2001; 345:790
–797.[Abstract/Free Full Text]
- Platz EA, Willett WC, Colditz GA, Rimm EB, Spiegelman D,
Giovannucci E. Proportion of colon cancer risk that might be preventable in a
cohort of middle-aged US men. Cancer Causes Control.2000; 11:579
–588.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bengmark S. Bioecologic control of inflammation and infection in
critical illness. Anaesthesiol Clin.2006; 24:299
–323.[CrossRef]
Journal of Parenteral and Enteral Nutrition, Vol. 31, No. 5,
430-440 (2007)
DOI: 10.1177/0148607107031005430
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RAGE: A Master Switch
Tissue Accumulation of AGEs...