Protein glycation occurs spontaneously when sugars attach to proteins or lipids, forming advanced glycation end products (AGEs) that accumulate over time and contribute to aging and disease pathology. AGEs form through reactions like the Maillard reaction and can crosslink or modify proteins, DNA and lipids. They are implicated in diseases associated with aging like diabetes, where hyperglycemia overwhelms the body's ability to break down AGEs. AGEs bind receptors on macrophages, stimulating inflammation and complications in diabetes such as nephropathy, neuropathy and retinopathy. The accumulation of AGEs over a lifetime may accelerate aging through molecular damage and chronic inflammation.
Aging is a phenomena in which the functions, applicability and
resistance of an organism reduces over time. With the globally aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to a lot of disease and no exception for cardiovascular system. Actually, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. In this review, we discuss about the relationship of oxidative stress with aging and FoxO proteins, which is essential factor for anti-aging of cardiovascular systems.
Aging is a phenomena in which the functions, applicability and
resistance of an organism reduces over time. With the globally aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to a lot of disease and no exception for cardiovascular system. Actually, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. In this review, we discuss about the relationship of oxidative stress with aging and FoxO proteins, which is essential factor for anti-aging of cardiovascular systems.
Neurodegeneration: Factors Involved and Therapeutic Strategiesinventionjournals
Neurodegenerative disorders are disorders of the nervous system which are characterized by a loss of neuronal structure and function. These changes lead to a loss of several abilities that include cognition and movement as observed in Alzheimer’s and Parkinson’s. Several factors like oxidative stress and protein misfolding have been found to play a vital role in the etiology of common neurological disorders. Whether these factors contribute to the progression of the disorders or are a consequence still remains elusive. Inspite of attempts to elucidate the molecular and pathological mechanisms of these pathways, many aspects still remain unclear. However, newer areas of therapeutic interventions like stem cell therapy and anti-oxidant therapy are now being explored as potential treatments. The aim of this review is to study the various factors that are associated with neurodegeneration along with recent therapeutic strategies that are being employed in an attempt to treat neurodegenerative disorders.
Antioxidant potentials of tannic acid on lipid peroxidation induced by severa...Premier Publishers
Various prospective studies have indicated the antioxidant potency of tannic acid in several models. However, there is no clear-cut evidence revealing that the reported antioxidant properties of tannic acid remains potent regardless of the lipid sources and pro-oxidants employed for the oxidative assault. Hence, this study sought to investigate the antioxidant properties of tannic acid against cerebral and hepatic lipid peroxidation induced by several pro-oxidants (Iron (II) sulfate, Sodium nitroprusside, cyclophosphamide and acetaminophen) in vitro. Rats were decapitated under mild ether anesthesia and the tissues were rapidly dissected, placed on ice, weighed and immediately homogenized in cold 50 mM Tris-HCl, pH 7.4 (1/10, w/v). The homogenates were centrifuged for 10 min at 4000 g to yield a pellet that was discarded and a low-speed supernatant (S1). Our results indicated that Fe (II) showed the highest pro-oxidative effects in both tissues lipids. Furthermore, tannic acid demonstrated potent inhibitory effects against lipid peroxidation in both tissues lipids regardless of the pro-oxidant employed. To this end, there is a dire need to exploit the protective benefits of tannic acid as a potential exogenous antioxidant against lipid peroxidation with a view to providing solution to the global oxidative stress menace.
A physical process by which a polypeptide chain (sequence of amino acids) folds into its characteristic & functional native structure from a random coil or a linear sequence.
In medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the fuction of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a gain of toxic function) or they can lose their normal function. The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases), include such diseases as Alzheimer's disease, Parkinson's disease, prion disease, type 2 diabetes, amyloidosis, and a wide range of other disorders .
superoxide dismutase is a metal containing antioxidant enzyme that reduce harmful free radicals of oxygen formed during normal metabolic cell processes to oxygen and hydrogen peroxide.
Herbal origins provision for non-enzymatic Glycation, (NEGs) inhibitionPremier Publishers
The aldehyde or ketone groups of reducing sugars react non-enzymatically with the free amino groups of proteins, lipids and nucleic acids leading to the formation of advanced glycation end products (AGEs). These AGEs inhibitory API (active pharmaceutical ingredients carries a great deal of AGEs in reducing the risk to related diseases and puts the clinician in a predicament to find concise and reliable information for adequate class of drug and its anti-glycating activity.Thus far, some potentially is interesting inhibitors forms herbal origins with all possible mechanisms of inhibition of AGEs. The study have focused on herbal origins inhibitors API followwhich class ofinhibitor.A various in-vitro and in-vivomodel studythe evaluation AGEs inhibitory drugs.Present discussion concluded that the investigated Armed with herbal phytochemicals specific inhibitors, glycobiologists will be able to explore the biological function of the individual phytochemicals in NEGs and AGEs.
Neurodegeneration: Factors Involved and Therapeutic Strategiesinventionjournals
Neurodegenerative disorders are disorders of the nervous system which are characterized by a loss of neuronal structure and function. These changes lead to a loss of several abilities that include cognition and movement as observed in Alzheimer’s and Parkinson’s. Several factors like oxidative stress and protein misfolding have been found to play a vital role in the etiology of common neurological disorders. Whether these factors contribute to the progression of the disorders or are a consequence still remains elusive. Inspite of attempts to elucidate the molecular and pathological mechanisms of these pathways, many aspects still remain unclear. However, newer areas of therapeutic interventions like stem cell therapy and anti-oxidant therapy are now being explored as potential treatments. The aim of this review is to study the various factors that are associated with neurodegeneration along with recent therapeutic strategies that are being employed in an attempt to treat neurodegenerative disorders.
Antioxidant potentials of tannic acid on lipid peroxidation induced by severa...Premier Publishers
Various prospective studies have indicated the antioxidant potency of tannic acid in several models. However, there is no clear-cut evidence revealing that the reported antioxidant properties of tannic acid remains potent regardless of the lipid sources and pro-oxidants employed for the oxidative assault. Hence, this study sought to investigate the antioxidant properties of tannic acid against cerebral and hepatic lipid peroxidation induced by several pro-oxidants (Iron (II) sulfate, Sodium nitroprusside, cyclophosphamide and acetaminophen) in vitro. Rats were decapitated under mild ether anesthesia and the tissues were rapidly dissected, placed on ice, weighed and immediately homogenized in cold 50 mM Tris-HCl, pH 7.4 (1/10, w/v). The homogenates were centrifuged for 10 min at 4000 g to yield a pellet that was discarded and a low-speed supernatant (S1). Our results indicated that Fe (II) showed the highest pro-oxidative effects in both tissues lipids. Furthermore, tannic acid demonstrated potent inhibitory effects against lipid peroxidation in both tissues lipids regardless of the pro-oxidant employed. To this end, there is a dire need to exploit the protective benefits of tannic acid as a potential exogenous antioxidant against lipid peroxidation with a view to providing solution to the global oxidative stress menace.
A physical process by which a polypeptide chain (sequence of amino acids) folds into its characteristic & functional native structure from a random coil or a linear sequence.
In medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the fuction of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a gain of toxic function) or they can lose their normal function. The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases), include such diseases as Alzheimer's disease, Parkinson's disease, prion disease, type 2 diabetes, amyloidosis, and a wide range of other disorders .
superoxide dismutase is a metal containing antioxidant enzyme that reduce harmful free radicals of oxygen formed during normal metabolic cell processes to oxygen and hydrogen peroxide.
Herbal origins provision for non-enzymatic Glycation, (NEGs) inhibitionPremier Publishers
The aldehyde or ketone groups of reducing sugars react non-enzymatically with the free amino groups of proteins, lipids and nucleic acids leading to the formation of advanced glycation end products (AGEs). These AGEs inhibitory API (active pharmaceutical ingredients carries a great deal of AGEs in reducing the risk to related diseases and puts the clinician in a predicament to find concise and reliable information for adequate class of drug and its anti-glycating activity.Thus far, some potentially is interesting inhibitors forms herbal origins with all possible mechanisms of inhibition of AGEs. The study have focused on herbal origins inhibitors API followwhich class ofinhibitor.A various in-vitro and in-vivomodel studythe evaluation AGEs inhibitory drugs.Present discussion concluded that the investigated Armed with herbal phytochemicals specific inhibitors, glycobiologists will be able to explore the biological function of the individual phytochemicals in NEGs and AGEs.
Guest Lecture at University of Delhi - The Entangled Relationship between Dia...Vinod Nikhra
The talk at Ramjas College, University of Delhi on 18th Feb 2015. It highlights the latest issues in biological and molecular research which link overweight/obesity with diabetes, metabolic syndrome and aging.
Type 2 diabetes mellitus (T2DM) is a complex, heterogeneous group of metabolic disorders characterized by insulin resistance
and failure of pancreatic β-cell leading to chronic hyperglycemia. Hyperglycemia causes dysfunctions in multiple organs or tissues, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for healthcare systems. Therefore, the continually increasing of diabetes worldwide, understanding the pathophysiology, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence of formation of advanced glycation end products (AGEs), which are a complex and heterogeneous group of modified proteins and/or lipids with damaging potential, is one contributing factor. However, it has been reported that AGEs increase the level of reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications if they are causal or simply an effect is only partly understood. This review will highlight the mechanisms involvement of AGEs in the development and progression of T2DM and the role of AGEs in the development of diabetic complications.
Biomarker for the Association between Body Mass Index and Lipid Peroxidation ...ijtsrd
Obesity, diabetes, and the long term effects of these conditions are all associated with increases in biomarkers. The rising rates of diabetes and cardiovascular disease as a result of the obesity pandemic have made it all the more important to investigate the potential use of inflammatory biomarkers generated by adipose tissue in high risk individuals. Regrettably, no conclusive data supports the use of inflammatory indicators as a therapeutic intervention for people in transition at this time. In view of the therapeutic importance of temporary connections between biomarker elevations and various stages of type 2 diabetes, the current research seeks to address this question. Recent research has revealed that low grade inflammatory biomarkers like EN RAGE and IL 13 may be used to predict who will develop prediabetes and who will go on to develop diabetes. Biomarker tumour necrosis factor alpha TNF alpha has been proposed to track the development of albuminuria as a chronic complication of type 2 diabetes. Cardiac biomarkers may serve as predictors of cardiac events in people with diabetes. Nonetheless, several linkages between biomarkers have been proposed as prospective techniques for identifying T2DM. Dr. Dhruv Kundu "Biomarker for the Association between Body Mass Index and Lipid Peroxidation in T2DM with and without Microvascular Problems" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-7 | Issue-2 , April 2023, URL: https://www.ijtsrd.com.com/papers/ijtsrd53986.pdf Paper URL: https://www.ijtsrd.com.com/medicine/other/53986/biomarker-for-the-association-between-body-mass-index-and-lipid-peroxidation-in-t2dm-with-and-without-microvascular-problems/dr-dhruv-kundu
Brian Covello: Diabetes Research ProposalBrian Covello
Brian Covello's diabetes research proposal. Type 2 diabetes mellitus consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance to insulin action, inadequate insulin secretion, and excessive or inappropriate glucagon secretion.
Essential update: FDA approves subcutaneous albiglutide for management of DM2
The FDA has approved once-weekly injectable albiglutide (Tanzeum), a glucagonlike peptide 1 (GLP-1) receptor agonist, along with diet and exercise for the treatment of type 2 diabetes.[1, 2] This agent may be used either as monotherapy or in combination with metformin, glimepiride, pioglitazone, or insulin.
Albiglutide should not be used for the following[1, 2] :
Patients with type 1 diabetes
Patients with diabetic ketoacidosis
First-line therapy in patients who can’t be managed with diet and exercise
Patients who have a personal or family history of medullary thyroid carcinoma (MTC)
Patients who have multiple endocrine neoplasia syndrome type 2
The most common adverse reactions associated with albiglutide were nausea/diarrhea and injection-site reactions.
There will be a boxed warning on albiglutide’s labeling about thyroid C-cell tumors being observed in rodent studies with this class of drugs; it is currently unknown whether albiglutide causes these tumors in humans, including MTC.[1, 2] Moreover, the FDA is also requiring a number of postmarketing studies, including a pediatric trial; an MTC case registry (≥15 y); and a cardiovascular (CV)-outcomes trial in patients with a baseline high risk of CV disease.
Signs and symptoms
Many patients with type 2 diabetes are asymptomatic. Clinical manifestations include the following:
Classic symptoms: Polyuria, polydipsia, polyphagia, and weight loss
Blurred vision
Lower-extremity paresthesias
Yeast infections (eg, balanitis in men)
See Presentation for more detail.
Diagnosis
Diagnostic criteria by the American Diabetes Association (ADA) include the following[3] :
A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis
Whether a hemoglobin A1c (HbA1c) level of 6.5% or higher should be a primary diagnostic criterion or an optional criterion remains a point of controversy.
Indications for diabetes screening in asymptomatic adults includes the following[4, 5] :
Sustained blood pressure >135/80 mm Hg
Overweight and 1 or more other risk factors for diabetes (eg, first-degree relative with diabetes, BP >140/90 mm Hg, and HDL < 35 mg/dL and/or triglyceride level >250 mg/dL)
ADA recommends screening at age 45 years in the absence of the above criteria
See Workup for more detail.
Vitamin D : The missing link in osseointegrationDirk Neefs
The importance of Vitamin D in the activation of osteoblasts is a known fact. The general deficiency in Vitamin D often linked with high cholesterol could be a cause of initial dental implant loss.Since early implant failure can have several causes, elaboration of an extend questionnaire could be worthfull. Further multicenter study is recquired.
Microvascular complications of diabetes pathophysiologyMWIZERWA JEAN-LUC
it is presented by a MEDICAL STUDENT AT UNIVERSITY OF RWANDA
topic is about pathophysiology mechanisms of glypcerglycemia in causing microvascular complications. it will help medical student to know deep in cascade how high concentration ogf glucose is converted into other substances to affect blood vessels.
Microvascular complications of diabetes pathophysiology
bs2510essay
1. Protein glycation in the pathology of ageing: A review
Boris Shilov
-
1 Introduction
Biological ageing is a complex process and a long-standing enigma both in the history of
humanity and of biology. According to Jin (2010), the theories of ageing can generally be
split into two categories: programmed theories and damage theories.
Programmed theories postulate that ageing is an inherent, genetic process in the lifecy-
cle of an organism. The theories in this category include those that postulate that certain
genes switch on and off over time and result in various deficits, endocrine theories that
posit that there is a biological clock that regulates ageing hormonally and immune theo-
ries, which postulate that the gradual degradation of the immune system eventually leads
to the array of diseases whose risk increases drastically with old age. This also includes
the intriguing Hayflick limit theory, which posits that telomeres, the end regions of the
linear Eukariotic DNA, shorten with each successive division and, unless restored, a limit
is eventually reached and cellular division rendered impossible, or extremely damaging as
sections of coding DNA become lost.
Damage theories postulate that some form of damage to molecular structures of cells
results in ageing, with accumulation of damage over time leading to progressively worsened
outlook and eventually death. This includes wear and tear theory, where some vital com-
ponents of the cell, such organelles and long-term structural proteins accumulate damage
over time and eventually stop serving their function. Cross-linking theory which posits
that crosslink formation between proteins, DNA, lipids and other substances leads to a de-
crease in their function. Rate of living theory that posits that the lifespan of an organism
is inversely proportional to its basal metabolic rate. Free radical theory, one of the most
publicised, posits that free-radical species formed during normal metabolism may react
with various cellular components to cause damage. Further, DNA damage theory posits
that organisms continually incur damage to their DNA that, although mostly repaired,
accumulates over time, especially in mitochondria.
It is generally agreed that there is some substance to all of these theories, and that
they likely interact in complex ways to give the end result that organisms age (Jin 2010).
In this review, we will focus on how protein glycation affects the pathology of ageing. In
contrast to glycosylation, which is enzymatically mediated and serves a useful regulatory
1
2. Boris Shilov
function in the cell in most cases, glycation is a spontaneous, non-enzymatic reaction that
occurs at a slow but constant rate in physiological conditions. Glycation may result in the
formation of advanced glycation end (AGE) products, a very diverse class of molecules that
bind proteins, DNA and lipids and may result in denaturation, breaks, cross-linking and
participate in undesirable side reactions. AGEs are very difficult for the body to degrade,
and some persist for the entire lifespan on an organism. Thus the accumulation of AGE
products in the body has been of considerable interest to ageing researchers recently (Frye
et al. 1998). We will see how AGEs are involved in diseases that result from ageing, with
particular focus on Diabetes mellitus as one of the most studied diseases the incidence of
which correlates with ageing.
2 Chemical aspects
Glycation is the non-enzymatic attachment of sugars to proteins or lipid molecules, where
the carbonyl group of a reducing sugar spontaneously reacts with the amino group of an
amino acid or other molecule. Lysine residue glycation plays an especially important role
in the pathology of ageing due to the abundance of this residue in structural proteins with
slow turnover rates, such as collagen (Ansari et al. 2011).
2.1 The Maillard reaction
The Maillard reaction is the major AGE-producing reaction at physiological conditions.
It can be divided into an initiation, propagation and termination steps, which account for
the generation of a variety of intermediates. Fig. 1 shows the generalised initiation step
for the reaction, leading to the formation of Amadori product that can either be converted
to Nε-carboxymethyl-lysine through oxidative fragmentation or proceed to form a number
of reactive dicarbonyl compounds. Fig. 2 shows the propagation stage where the Amadori
product isomerises to form either 1,2-eneaminol or 2,3-eneaminol. 1,2-eneaminol proceeds
to form 3-deoxyosone, whilist 2,3-eneaminol may react to form either 1-deoxyosone or 4-
deoxyosone. The deoxyosones may then decompose to form a variety of secondary products
in what is referred to as the termination step. These are the advanced glycation end
products themselves, and include a large variety of possible structures such as pentosidine,
pyrroles, furans, pyrimidines, pyrazines, imidazoles and many others (Belitz et al. (2009),
Monnier (1990)).
2.2 Methylglyoxal and the glyoxalase system
According to Thornalley (1996), methylglyoxal is a product of the conversion of glyceraldehyde-
3-phosphate (G3P) to dihydroxyacetonephosphate in glycolysis, and since this reaction may
proceed nonenzymatically, the major source of methylglyoxal in cells is the spontaneous
breakdown of G3P. This generates very small amounts, but occurs in every cell in the
2
3. 2.3 The polyol pathway Boris Shilov
body, and over time would pose an unacceptable mutagenicity risk if methylglyoxal is not
properly deactivated. This is accomplished via the glyoxalase system.
The glyoxalase system converts methylglyoxal into D-lactate and S-D-lactoylglutathione.
It consist of the enzymes glyoxalase I and II. Glyoxalase I catalyzes the formation of S-
D-lactoylglutathione from hemithioacetal, which is nonenzymatically formed from methyl-
glyoxal and reduced glutathione. Glyoxalase II hydrolyses S-D-lactoylglutathione into D-
lactate and reforms reduced glutathione. Methyglyoxal may also be converted mostly to
hydroxyacetone by aldose dehydrogenase (Thornalley 1996).
Methyglyoxal’s mutagenic activity is complex. It can crosslink DNA strands in AT rich
regions, react with guanine and guanylate residues. It binds lysine and arginine residues in
proteins, preferring arginine. Methyglyoxal can create crosslinks between DNA and DNA
polymerase. This again occurs through reacting with a lysine residue (Murata-Kamiya &
Kamiya 2001).
2.3 The polyol pathway
Another way for AGE products to be generated in the cell is the polyol pathway. This is
activated when excess glucose enters the cell, beginning with the reduction of glucose to
sorbitol by aldose reductase, with the consumption of NADPH, and proceeding with sor-
bitol dehydrogenase, which converts sorbitol to fructose with the generation of NADH. The
fructose may then be converted to fructose-3-phosphate by 3-phosphokinase (Ramasamy
et al. 2005). 3-deoxyglucosone is generated in this reaction, a glucose-derived 3-deoxyosone,
which as previously mentioned may participate in a variety of reactions with proteins and
amino acids to generate pentosidine, pyralline and imidazolone. It is worth mentioning
that the rate of pentosidine generation is greatly accelerated by aerobic conditions, which
is the case in the cell (Niwa 1999).
The polyol pathway further complicates matters by the fact that fructose has been
shown to also generate AGEs and induce protein oxidation (Ramasamy et al. 2005).
3 Clinical aspects and implications
3.1 Diabetes mellitus
Although diabetes does not arise due to AGE products, the development of chronic hyper-
glycaemia leads to the occurrence of a multitude of diabetic complications, many caused by
increased AGE product generation. According to Thornalley (1996), intracellular hyper-
glycaemia is known to be the main mechanism of intra- and extracellular AGE generation.
Spontaneous oxidation of glucose to glyoxal and methylglyoxal formation are both more
pronounced as a result. The glyoxalase system that would usually detoxify these com-
pounds is overwhelmed in hyperglycaemia.
3
4. 3.1 Diabetes mellitus Boris Shilov
AGE products contribute to the observable clinical symptoms of diabetes via cellular
damage, including the abnormal function of glycated proteins, abnormal interactions of
glycated matrix proteins with integrins, and reactive oxygen species (ROS) production by
macrophages that have bound AGEs. Macrophage binding is of particular importance in
diabetes-induced vascular disease and it has been shown that blockade of the receptor for
AGE (RAGE) on macrophages suppresses macrovascular disease (Brownlee 2001). Bind-
ing of AGE receptors on macrophages eliminates glycated proteins via receptor-mediated
endocytosis and lysosomal degradation (Thornalley 1996).
The role of RAGE in the pathogenesis of diabetes and many other diseases is interesting.
Hudson et al. (2002) reports that RAGE is a signalling receptor family that is itself part
of the immunoglobulin receptor superfamily, some classifying it as a pattern recognition
receptor. It has three immunoglobulin domains, two V type and one C type, having one
transmembrane region as well as a cytosolic signalling tail. RAGE seems to be expressed
in very low amounts normally, but diabetes upregulates RAGE expression in vascular
endothelium and smooth muscle, at least in animal models, which may contribute to the
chronic inflammation sometimes observed in diabetes (Hudson et al. 2002).
Some major complications of diabetes mellitus include nephropathy, neuropathy and
retinopathy. It has been found that, both in insulin-dependent and insulin-independent
diabetes, the amount of glycated haemoglobin and glyoxylase I activity both strongly
correlated with the appearance of these complications. Furthermore, increased incidence
of glycated proteins leads to their recognition by macrophages and monocytes, which in
turns leads to increase secretion of proinflammatory cytokines IL-1β and CSF-1, both impli-
cated to contribute to atherosclerosis, glomerulosclerosis and proliferative vitreoretinopathy
(Thornalley 1996).
Glycated proteins are broken down in the cell as part of normal protein turnover.
According to Moheimani et al. (2010), it is known that the balance of protein synthesis
and degradation is disrupted in diabetes and other AGE-involving diseases, and although
it has also been found that pathways that detoxify and remove modified proteins are also
upregulated in response to this, they do not appear to be able to compete efficiently with
the increased rate of AGE formation in the cell. When molecular repair mechanisms
such as refolding by chaperones fail, the proteins are designated to either by degraded
by the proteasome or processed through the endolysosomal system, with the proteasome
degradation pathway being the major one for intracellular proteins. The proteasome is
a multienzyme complex resembling a barrel (X-ray crystallography structure shown in
Fig. 3) that consists of a family of proteases called N-terminal nucleophile hydrolases, and
includes six active sites: two trypsin-like sites, two caspase-like sites and two chymotrypsin-
like sites. It is known experimentally that glycated bovine serum albumin is able to inhibit
the proteasome, specifically the chymotrypsin-like and caspase-like sites. Several reasons
for this inhibition have been proposed, such as the possibility of intraprotein crosslinks
that stabilise the structure, formation of crosslinks with the proteasome subunits and
modulation of the α subunit that facilitates substrate entry into the proteasome. Another
4
5. 3.2 Alzheimer disease Boris Shilov
possible mechanism is the modulation of regulatory subunit conformation, which would
decrease proteasomal activity. It is interesting to note that only the long-term presence of
glycated protein seems to affect proteasome activity (Moheimani et al. 2010).
3.2 Alzheimer disease
Alzheimer disease is known to involve the deposition of insoluble β-amyloid protein ag-
gregates in neuronal cells. Studies suggest that AGE crosslinks may play a major role in
initiating the ”seed” required for these aggregates to form en masse (Vitek et al. 1994).
Damage results from several mechanisms, including ROS production from sugar autoxi-
dation, AGE-triggered interleukin-6 release and the subsequent immune reaction, leading
to lysis of nearby neurons through microglial overactivation. Microglia also posses RAGE
receptors, binding of which can lead to increase in oxidative stress. RAGE binding has also
been implicated in nonpathological neurite growth, and AGEs may interfere destructively
with this process. As mentioned previously, AGE-protein crosslinks lead to reduced pro-
teolytic susceptibility, which may contribute greatly to aggregate formation (M¨unch et al.
1997).
3.3 Rheumatoid arthritis
AGEs likely contribute to osteoporosis that is a major component of rheumatoid arthritis.
Hein (2006) asserts that AGEs are known to inhibit osteoblasts, cells that lay down the
extracellular matrix necessary to generate bone, and they are also known to increase bone
resorption by osteoclasts. Pentosidine is known to form collagen crosslinks, degrading the
mechanical properties necessary to maintain bone structure, and it has been found that
variation in pentosidine content partially accounts for differences in amount of strain bone
can sustain.
The modification of collagen in bone is hypothesised to be of major importance in
osteoporosis since collagen is a protein with an extremely low turnover. Accumulation of
AGE products in the bone matrix would presumably lead to hardening of the bone due to
denaturation of bone protein. However it is not currently clear if the increased incidence
of AGEs in bone is a cause of osteoporosis or an effect of it (Hein 2006).
4 Conclusion
AGEs remain poorly characterised as a group, despite intense research into their involve-
ment in disease. Further efforts are complicated by the heterogeneity of these compounds
and the difficulty in isolating them, and assays are available for few compounds, with pen-
tosidine and Nε-carboxymethyl-lysine being the best characterised AGE products. This
situation is similar for AGE receptors and their pathways, RAGE being the best charac-
terised receptor to date. Nonetheless, the field has seen steady progress and pharmaceu-
5
6. REFERENCES Boris Shilov
ticals that reverse or inhibit glycation could prove to be a powerful treatment or way to
postpone the onset of later stages of disease (Singh et al. 2001).
References
Ansari, N. A., Moinuddin & Ali, R. (2011), ‘Glycated lysine residues: a marker for non-
enzymatic protein glycation in age-related diseases.’, Dis Markers 30(6), 317–324.
Belitz, H., Grosch, W. & Schieberle, P. (2009), Food Chemistry, Springer Berlin Heidelberg.
Brownlee, M. (2001), ‘Biochemistry and molecular cell biology of diabetic complications’,
Nature 414(6865), 813–820.
Frye, E. B., Degenhardt, T. P., Thorpe, S. R. & Baynes, J. W. (1998), ‘Role of the mail-
lard reaction in aging of tissue proteins: Advanced glycation end product-dependent
increase in imidazolium cross-links in human lens proteins’, Journal of Biological Chem-
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Harshbarger, W., Miller, C., Diedrich, C. & Sacchettini, J. (2015), ‘Crystal structure of
the human 20s proteasome in complex with carfilzomib.’, Structure 23(2), 418–424.
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importance?’, Clinica Chimica Acta 371(1–2), 32–36.
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Niwa, T. (1999), ‘3-deoxyglucosone: metabolism, analysis, biological activity, and clini-
cal implication’, Journal of Chromatography B: Biomedical Sciences and Applications
731(1), 23–36.
Ramasamy, R., Vannucci, S. J., Yan, S. S. D., Herold, K., Yan, S. F. & Schmidt, A. M.
(2005), ‘Advanced glycation end products and rage: a common thread in aging, diabetes,
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8. REFERENCES Boris Shilov
R NH2
Amine group
+ H C
C
H O
OH
R
Reducing sugar
R NH CH C
OH
R
Schiff base
R NH CH2 C
O
R
Amadori product
Fe2+
O2
R NH CH2 COOH
Nε-Carboxymethyl-lysine
Figure 1: The generalised initiation step of the Maillard reaction. The Amadori product
may proceed to the propagation step. The oxidative fragmentation reaction that gives rise
to Nε-carboxymethyl-lysine is irreversible. Adapted from Monnier (1990).
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9. REFERENCES Boris Shilov
R NH CH2 C
O
R
Amadori product
R NH2
Regenerated amine
+ CH3 C
O
C
O
R
1-deoxyosone
R NH2 + H C
O
C
O
CH2 R
3-deoxyosone
R NH CH2 C
O
C
O
CH2 R
4-deoxyosone
Figure 2: The generalised propagation step of the Maillard reaction. The Amadori product
isomerises to form either 1,2-eneaminol or 2,3-eneaminol (not shown), which proceed to
form different deoxyosones. The deoxyosones themselves are then free to assume a variety
of cyclic hemiacetal forms (not shown), and participate in termination reactions with a
variety of compounds. Adapted from Monnier (1990).
9
10. REFERENCES Boris Shilov
Figure 3: The human 20S proteasome complexed with carfilzomib, a 28-meric protein
complex, viewed from the side. From Harshbarger et al. (2015)
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