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The glycation (glycosylation)
theory of aging was first introduced by A. Cerami,
(1985) and Monnier (1989). The glycation hypothesis
of aging suggests that modification of proteins
by glucose and associated browning or Maillard reactions
leads to the gradual cross-linking, polymerization,
development of brown-color products. All these processes
ultimately result in the formation of "advanced
glycosylation end-products" (AGEs). These changes
are postulated to lead ultimately to the deterioration
in structure and function of tissue protein, in
a manner similar to the mechanism by which the same
reactions are considered to contribute to the pathophysiology
of the complications resulting from diabetes.
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2005
Department of Biochemistry,
Jawaharlal Institute of Postgraduate Medical
Education and Research, Pondicherry - 605
006.
Several studies have indicated
the presence of increased oxidative stress
as a critical feature in the pathogenesis
of chronic obstructive pulmonary disease
(COPD). Another biochemical complication
leading to pathogenesis is protein glycation.
The nexus between oxidative stress and protein
glycation in various pathological conditions
is being unraveled. Increased oxidative
stress can lead to enhanced protein glycation
by a process of auto-oxidative glycation.
No information is available in the literature
regarding protein glycation among COPD patients.
Eleven non-diabetic COPD patients were included
in the study and equal number of age and
sex-matched healthy individuals were enrolled
as controls. The whole-blood reduced glutathione
was found to be less among the patients
while lipid peroxides and fructosamine were
elevated in comparison to control. The present
study confirmed oxidative stress and enhanced
protein glycation among the COPD patients.
Antioxidant therapy may be considered as
part of the treatment regimen for COPD patients.
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Department of Biochemical
Sciences Charles University in Prague Faculty
of Pharmacy, Hradec Kralove Czech Republic.
drsata@faf.cuni.cz.
Non-enzymatic glycation
as the chain reaction between reducing sugars
and free amino groups of proteins has been
shown to correlate with physiological ageing
and severity of diabetes. The process involves
oxidative steps (glycoxidation). In this
paper, the effect of D-fructose as a reactive
sugar on aspartate aminotransferase (AST)
as a model protein was monitored by measurements
of the enzyme activity and formation of
fluorescent advanced glycation end products
(AGEs). Change in the AST activity was considered
as a measure of the overall protein damage
caused by glycation, and total AGEs and
pentosidine represent, at least partly,
the formation of glycoxidation products.
Catalytic activity of AST in an incubation
mixture containing D-fructose (50 mmol L(-1)),
decreased compared to control values to
42% (p < 0.05) and to 11% (p < 0.05)
on the 5th and on 21st day of incubation,
respectively. In the presence of fructose,
total fluorescent AGEs concentration was
significantly higher since 5th day of incubation
(110%, p < 0.05) and the fluorescent
pentosidine concentration from 15th day
of incubation (117%, p < 0.05) compared
to control values, respectively. Catalytic
activity of AST clearly and quantitatively
demonstrated functional changes in the enzyme
molecule caused by structural modifications
initiated by fructose, while the evaluation
of AGE formation and especially that of
pentosidine by fluorescence measurement
was less reliable.
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| 2001
The Kenneth S Warren,
Laboratories, Tarrytown, New York 10591, USA.
Biological amines react
with reducing sugars to form a complex family
of rearranged and dehydrated covalent adducts
that are often yellow-brown and/or fluorescent
and include many cross-linked structures.
Food chemists have long studied this process
as a source of flavor, color, and texture
changes in cooked, processed, and stored
foods. During the 1970s and 1980s, it was
realized that this process, called the Maillard
reaction or advanced glycation, also occurs
slowly in vivo. Advanced glycation endproducts
(AGEs) that form are implicated, causing
the complications of diabetes and aging,
primarily via adventitious and crosslinking
of proteins. Long-lived proteins such as
structural collagen and lens crystallins
particularly are implicated as pathogenic
targets of AGE processes. AGE formation
in vascular wall collagen appears to be
an especially deleterious event, causing
crosslinking of collagen molecules to each
other and to circulating proteins. This
leads to plaque formation, basement membrane
thickening, and loss of vascular elasticity.
The chemistry of these later-stage, glycation-derived
crosslinks is still incompletely understood
but, based on the hypothesis that AGE formation
involves reactive carbonyl groups, the authors
introduced the carbonyl reagent aminoguanidine
hydrochloride as an inhibitor of AGE formation
in vivo in the mid 1980s. Subsequent studies
by many researchers have shown the effectiveness
of aminoguanidine in slowing or preventing
a wide range of complications of diabetes
and aging in animals and, recently, in humans.
Since, the authors have developed a new
class of agents, exemplified by 4,5-dimethyl-3-phenacylthiazolium
chloride (DPTC), which can chemically break
already-formed AGE protein-protein crosslinks.
These agents are based on a new theory of
AGE crosslinking that postulates that alpha-dicarbonyl
structures are present in AGE protein-protein
crosslinks. In studies in aged animals,
DPTC has been shown to be capable of reverting
indices of vascular compliance to levels
seen in younger animals. Human clinical
trials are underway.
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2000
University of Medicine
and Dentistry of New Jersey-New Jersey Medical
School, Newark, NJ 07103, USA.
Decreased elasticity of
the cardiovascular system is one of the
hallmarks of the normal aging process of
mammals. A potential explanation for this
decreased elasticity is that glucose can
react nonenzymatically with long-lived proteins,
such as collagen and lens crystallin, and
link them together, producing advanced glycation
endproducts (AGEs). Previous studies have
shown that aminoguanidine, an AGE inhibitor,
can prevent glucose cross-linking of proteins
and the loss of elasticity associated with
aging and diabetes. Recently, an AGE cross-link
breaker (ALT-711) has been described, which
we have evaluated in aged dogs. After 1
month of administration of ALT-711, a significant
reduction ( approximately 40%) in age-related
left ventricular stiffness was observed
[(57.1 +/- 6.8 mmHg x m(2)/ml pretreatment
and 33.1 +/- 4.6 mmHg x m(2)/ml posttreatment
(1 mmHg = 133 Pa)]. This decrease was accompanied
by improvement in cardiac function.
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1995
Department of Internal
Medicine, Bowman Gray School of Medicine,
Winston-Salem, North Carolina, USA.
Nonenzymatic glycation
of body proteins and subsequent advanced
glycation reactions have been implicated
in the aging process, while caloric restriction
(CR) in rodents results in an increase in
both mean and maximum life span. We have
evaluated the effect of chronic (25 months)
CR on glycation of blood proteins and accumulation
of advanced glycation and oxidation (glycoxidation)
products, N epsilon-(carboxymethyl)lysine
(CML), and pentosidine, in skin collagen.
Brown-Norway rats, fed ad libitum (AL) from
birth, were divided into two equal groups
at 4 months of age and placed on AL or CR
diets (CR = 60% of AL diet). Cohorts of
animals were sacrificed at 7, 13, and 25
months after the initiation of CR. At necropsy
glycated hemoglobin was measured by affinity
HPLC and glycated plasma protein by the
fructosamine assay; extracts of skin collagen
were analyzed by gas chromatography-mass
spectrometry for CML and by reversed-phase
HPLC for pentosidine. Glycation of hemoglobin,
plasma proteins, and skin collagen was decreased
significantly (18-33%) by CR. Concentrations
of CML and pentosidine increased significantly
with age in skin collagen in both AL and
CR animals; however, CR significantly reduced
levels of CML (25%), pentosidine (50%),
and fluorescence (15%) in collagen in the
oldest rats. We conclude that CR reduces
the extent of glycation of blood and tissue
proteins and the age-related accumulation
of glycoxidation products in skin collagen.
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