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Biomedical subjects

V M Monnier

Publications and source records attributed to V M Monnier.

At least 73 records · Page 4Linked to original sources
PubMed1992

Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM.

Pentosidine is an advanced glycosylation end product and protein cross-link that results from the reaction of pentoses with proteins. Recent data indicate that long-term glycation of proteins with glucose also leads to pentosidine formation through sugar fragmentation. In this study, the relationship between the severity of diabetic complications and pentosidine formation was investigated in collagen from skin-punch biopsies from 25 nondiabetic control subjects and 41 IDDM patients with diabetes duration greater than 17 yr. Pentosidine was significantly elevated in all IDDM patients versus control subjects (P less than 0.0001). It correlated strongly with age (P less than 0.0001) and weakly with duration (P less than 0.082). Age-adjusted pentosidine levels were highest in grade 2 (severe) versus grade 1 and 0 complication in all four parameters tested (retinopathy, proteinuria, arterial stiffness, and joint stiffness). Significant differences were found for retinopathy (P less than 0.014) and joint stiffness (P less than 0.041). The highest degree of association was with the cumulative grade of individual complication (P less than 0.005), determined by summing indexes of all four parameters. Pentosidine also was significantly elevated in the serum of IDDM patients compared with control subjects (P less than 0.0001), but levels were not significantly correlated with age, diabetes duration, complication, or skin collagen pentosidine (P greater than 0.05). A high correlation between pentosidine levels and long-wave collagen-linked fluorescence also was observed, suggesting that pentosidine is a generalized marker of accelerated tissue modification by the advanced glycosylation/Maillard reaction, which is enhanced in IDDM patients with severe complications.

Adult↗
PubMed1992

Chromatographic quantitation of plasma and erythrocyte pentosidine in diabetic and uremic subjects.

Pentosidine is a fluorescent advanced Maillard/glycosylation product and protein cross-link present in elevated amounts in skin from diabetic and uremic subjects. A high-performance liquid chromatographic (HPLC) assay was developed to quantitate pentosidine in plasma and erythrocytes and other tissue proteins with low levels of pentosidine. High protein content and presence of basic amino acids and O2 during acid hydrolysis led to the formation of fluorescent artifacts that could be separated from true pentosidine through combined reverse-phase ion-exchange HPLC. No true pentosidine was formed during acid hydrolysis of ribated protein, suggesting that Amadori products do not generate artifactual pentosidine during hydrolysis. With the combined reverse-phase ion-exchange chromatographic assay, we found a 2.5-fold (P less than 0.001) and a 23-fold (P less than 0.001) elevation of mean +/- SD plasma protein pentosidine in diabetic (2.4 +/- 1.2 pmol/mg) and uremic (21.5 +/- 10.8 pmol/mg) subjects compared with healthy (0.95 +/- 0.33 pmol/mg) subjects. Pentosidine in hemolysate was normal in diabetes but dramatically elevated in uremia (0.6 +/- 0.4 pmol/mg hemoglobin, P less than 0.001). Although the precise nature of the pentosidine precursor sugar is unknown, plasma pentosidine may be a useful marker for monitoring the biochemical efficacy of trials with aminoguanidine or other treatment modalities. Furthermore, pentosidine in plasma proteins may act as a signal for advanced glycosylation end product-mediated receptor uptake by macrophages and other cells and contribute to accelerated atherosclerosis in diabetes and uremia.

Analysis of Variance↗
PubMed1992

Maillard reaction-mediated molecular damage to extracellular matrix and other tissue proteins in diabetes, aging, and uremia.

Recent progress in structure elucidation of products of the advanced Maillard reaction now allows probing specifically for the role of this reaction in the pathogenesis of age- and diabetes-related complications. Pyrraline is a glucose-derived advanced glycation end product against which polyclonal and monoclonal antibodies have been raised. Immunohistochemical localization studies revealed that pyrraline is found predominantly in the sclerosed extracellular matrix of glomerular and arteriolar renal tissues from both diabetic and aged nondiabetic individuals. Pentosidine and carboxymethyllysine are Maillard end products derived from both glucose and ascorbate. In addition, pentosidine can be formed from several other sugars under oxidative conditions, and in vitro studies suggest that a common intermediate involving a pentose is a necessary precursor molecule. The highest levels of these advanced Maillard products are generally found in the extracellular matrix, but these products are also present in lens proteins and in proteins with a fast turnover such as plasma proteins. Diabetes, and especially uremia, greatly catalyzes pentosidine formation. Both conditions are characterized by accelerated cataractogenesis, atherosclerosis, and neuropathy, suggesting that molecular damage by advanced Maillard reaction products may be a common mechanism in their development.

Aging↗
PubMed1991

High correlation between pentosidine protein crosslinks and pigmentation implicates ascorbate oxidation in human lens senescence and cataractogenesis.

Pentosidine is a recently discovered protein crosslink, involving lysine and arginine residues linked together in an imidazo [4,5,6] pyridinium ring formed by a 5-carbon sugar during nonenzymatic browning (Maillard reaction). The presence of high ascorbate levels in the human lens and its ability to undergo nonenzymatic browning led us to investigate pentosidine formation in the aging human lens. Incubation of lens crystallins with ascorbate and its oxidation products dehydroascorbate and 2,3-diketogulonate leads progressively to the formation of pentosidine crosslinks in the presence of oxygen. Under nitrogen, however, pentosidine forms only from 2,3-diketogulonate or xylosone, a degradation product of 2,3-diketogulonate. A high correlation between pentosidine crosslinks and the degree of lens pigmentation is noted in cataractous lenses. Pentosidine is found to be primarily associated with alpha-crystallin fractions of 300-5000 kDa. These results suggest that redox imbalance in cellular senescent systems such as the ocular lens may lead to irreversible ascorbate oxidation and protein crosslinking by xylosone. This mechanism may play an important role in the pathogenesis of "brunescent" cataracts.

Adult↗
PubMed1991

Mechanism of formation of the Maillard protein cross-link pentosidine. Glucose, fructose, and ascorbate as pentosidine precursors.

Pentosidine is a recently discovered fluorescent protein cross-link from human extracellular matrix that involves lysyl and arginyl residues in an imidazo (4, 5b) pyridinium ring. Pentosidine could be synthesized in vitro by the reaction of ribose, lysine, and arginine. The potential biological significance of the molecule prompted us to investigate its mechanism of formation from D-ribose and key Maillard intermediates, as well as from other potential precursor sugars. The yield of pentosidine from N alpha-t-Boc-lysine, N alpha-t-Boc-arginine, and D-ribose was highest at pH 9.0 and 65 degrees C, but was unaffected by reactant ratios at alkaline pH suggesting an important role for base catalysis. Ribated Boc-lysine on incubation with N alpha-t-Boc-arginine afforded a fluorescent compound with UV, fluorescence, 1H NMR, and MS properties identical with those from native or synthetic pentosidine. 3-Deoxypentosone, however, was not a major pentosidine precursor. Pentosidine became slowly detectable in bovine serum albumin incubated with 0.25 M and 1.0 M glucose and reached, at 30 days, 13.2 and 17 pmol/mg bovine serum albumin, respectively. Spectroscopical properties of glucose-derived pentosidine were identical with those from ribose-derived pentosidine. Pentosidine formed from glucated Boc-lysine with N alpha-t-Boc-arginine in higher yields than from glucose under standard conditions. Fructose, and unexpectedly ascorbate, also formed pentosidine in similar yields as glucose. The discovery that pentosidine can form not only from pentoses but also from hexoses and ascorbate raises major new questions concerning biochemical pathways of the Maillard reaction in vivo.

Arginine↗
PubMed1991

Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia.

Collagen undergoes progressive browning with age and diabetes characterized by yellowing, fluorescence, and cross-linking. The present research was undertaken in order to investigate the nature of the collagen-linked fluorescence. Human collagen was exhaustively cleaved into peptides by enzymatic digestion. Upon purification, a highly fluorescent chromophore was identified and purified from old human collagen. Structure elucidation revealed the presence of an imidazo [4,5-b] pyridinium-type structure acting as a cross-link between arginine, lysine, and a pentose. This advanced glycosylation end-product and protein cross-link results from the reaction of pentoses with proteins and was named pentosidine. Further work indicated that long-term glycosylation of proteins with hexoses also leads to pentosidine formation through sugar fragmentation. The proposed mechanism of pentosidine formation involves the dehydration of the pentose-derived Amadori compound to form an intermediate which is attacked under base catalysis by the guanido group of arginine. The strict requirement for the Amadori rearrangement is uncertain. However, oxidation is definitely involved since pentosidine is not formed in the absence of oxygen. Five-carbon sugars contributing to pentosidine formation could be formed from larger sugars by oxidative fragmentation or from trioses, tetroses, and ketoses by condensation and/or reverse aldol reactions. Pentosidine increases exponentially in human skin at autopsy. Mean age-adjusted skin levels were significantly increased in subjects with uremia and especially in type 1 diabetics with uremia vs. controls. In skin biopsy, levels were significantly elevated in all diabetic (type 1) vs. control subjects. The highest degree of association was with the cumulative grade of diabetic complication (retinopathy, nephropathy, arterial stiffness, and joint stiffness). Pentosidine also forms in various proteins other than collagen, although to a much lesser extent. In blood, pentosidine is mainly associated with plasma proteins and is highly elevated during uremia. In the lens, it is associated with both water-soluble and -insoluble protein fractions and is especially elevated during brunescent cataract formation. The origin of pentosidine in vivo is uncertain. Evidence suggests that the pentoses are the most reactive sugars in pentosidine formation in vitro; however, the origin and importance of free pentoses in vivo, especially during the diabetic state, are not certain. Possible origins include hemolysis and/or a defect in the primary pentose metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1991

Mechanisms of protection against damage mediated by the Maillard reaction in aging.

In order to prevent or escape the ongoing damage to proteins and DNA resulting from amino-carbonyl reactions, the organism has to have powerful defense mechanisms. If the Maillard reaction played a role in determining longevity among mammalian species, one would expect protective mechanisms to be more developed in long- versus short-lived species. This article summarizes current knowledge in this field, and discusses the concept of anti-Maillard mechanisms as a basis for the genetic regulation of molecular damage by reducing sugars in aging and diabetes.

Aging↗
PubMed1991

Tissue-specific effects of aldose reductase inhibition on fluorescence and cross-linking of extracellular matrix in chronic galactosemia. Relationship to pentosidine cross-links.

Chronic experimental hyperglycemia mediated by galactose has been shown to induce browning and cross-linking of rat tail tendon collagen that could be duplicated in vitro by nonenzymatic galactosylation. To investigate the nature of these changes, Sprague-Dawley rats were placed on a 33% galactose diet without and with sorbinil for 6 and 12 mo. Collagen-linked fluorescence and pentosidine cross-links increased with age and galactosemia in tail tendons (P less than 0.001) and skin but were essentially unresponsive to aldose reductase inhibition (ARI). In contrast, tendon breaking time in urea, a likely parameter of cross-linking, was markedly improved (P less than 0.001) by ARI. Fluorescence that was inhibited by sorbinil treatment was increased in pepsin and proteinase K digest of aortic tissue from galactosemic rats (P less than 0.001), but impaired enzymatic digestibility was not observed. Systolic blood pressure as potential consequence of aortic stiffening was not increased in galactosemia. These data suggest that fluorescence in skin and tendon might be in part due to advanced glycosylation and pentosidine formation because these were not decreased by ARI. However, they also suggest that nonfluorescent cross-links may also be forming because, in contrast to fluorescence, tail tendon breaking time was partly corrected by ARI. Thus, it appears that extracellular matrix changes in chronic galactosemia are complex, being partly attributable to advanced glycosylation and partly to polyol-pathway activation.

Aldehyde Reductase↗
PubMed1990

Non-tryptophan fluorescence and high molecular weight protein formation in lens crystallins of rats with chronic galactosemia: prevention by the aldose reductase inhibitor sorbinil.

Crystallin-bound non-tryptophan fluorescence and protein cross-linking were studied in chronic galactosemia. Fluorescence (excitation/emission--370/440 nm) was significantly higher in galactosemic rats compared to controls (P less than 0.001). Accumulation of fluorescence was significantly reduced both in water soluble (P less than 0.001) and insoluble (P less than 0.005) lens fractions in galactosemic rats receiving the aldose reductase inhibitor sorbinil. High performance liquid chromatography of water soluble lens crystallins showed an increase in the content of high molecular weight proteins and the fluorescence associated with it. Sorbinil partly prevented the formation of such fluorescent high molecular weight proteins. Under reducing conditions, sodium dodecyl sulfate polyacrylamide gel electrophoresis of water soluble proteins revealed a distinct high molecular weight protein of 60 kDa in galactosemia. Sorbinil treatment completely abolished the formation of this protein. Western blotting using rabbit antiserum to bovine alpha-, beta- and gamma-crystallins revealed the presence of gamma, but not alpha- and beta-crystallins in the 60-kDa protein. Formation of this protein may result from trimerization of gamma-crystallins or from an association of gamma-crystallin with a non-crystallin cytosolic protein or mixed protein cross-linking of gamma-crystallins with membrane protein(s). The present study shows that polyol pathway in cataractogenesis also extends to protein cross-linking and formation of fluorescent compounds, the nature of which remains to be elucidated.

Aldehyde Reductase↗
PubMed1990

End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen.

Structure elucidation of a specific fluorophore from the aging extracellular matrix revealed the presence of a protein crosslink formed through nonenzymatic glycosylation of lysine and arginine residues. The unexpected finding that a pentose instead of a hexose is involved in the crosslinking process suggested that the crosslink, named pentosidine, might provide insight into abnormalities of pentose metabolism in aging and disease. This hypothesis was investigated by quantitating pentosidine in hydrolysates of 103 human skin specimens obtained randomly at autopsy. Pentosidine level was found to increase exponentially from 5 to 75 pmol/mg collagen over lifespan (r = 0.86, P less than 0.001). A three- to tenfold increase was noted in insulin-dependent diabetic and nondiabetic subjects with severe end-stage renal disease requiring hemodialysis (P less than 0.001). Moderately elevated levels were also noted in some very old subjects, some subjects with non-insulin dependent diabetes, and two subjects with cystic fibrosis and diabetes. The cause of the abnormal pentose metabolism in these conditions is unknown but may relate to hemolysis, impaired pentose excretion, cellular stress, and accelerated breakdown of ribonucleotides. Thus, pentosidine emerges as a useful tool for assessment of previously unrecognized disorders of pentose metabolism in aging and disease. Its presence in red blood cells and plasma proteins suggests that it might be used as a measure of integrated pentosemia in analogy to glycohemoglobin for the assessment of cumulative glycemia.

Adult↗
PubMed1989

Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process.

Isolation and structure elucidation of an acid-resistant fluorescent molecule from human extracellular matrix revealed the presence of an imidazo[4,5-b]pyridinium molecule comprising a lysine and an arginine residue cross-linked by a pentose. Structure confirmation was achieved in vitro by the nonenzymatic reaction of ribose with lysine and arginine residues. The cross-link, named pentosidine, could also be synthesized with isomers of ribose, arabinose, xylose, and lyxose as well as by incubating young human collagen with these sugars at 37 degrees C. Pentosidine was found in a variety of human tissues including plasma proteins and red blood cells. Its presence in cells grown in culture strongly suggests ribose or ribonucleotide metabolites as precursors. The unexpected discovery of pentose-mediated protein cross-linking raises new questions concerning the aging process.

Aging↗
PubMed1989

Aging of proteins: immunological detection of a glucose-derived pyrrole formed during maillard reaction in vivo.

Recent work from this laboratory revealed that glucose-derived pyrroles can form with model amines under physiological conditions (Niroge, F. G., Sayre, L. M., and Monnier, V. M. (1987) Carbohydr. Res. 167, 211-220). The major extractable product, 5-hydroxymethyl-1-alkylpyrrole-2-carbaldehyde (named by us pyrraline) was labile to acid hydrolysis. To allow its detection in proteins undergoing advanced glycosylation, an enzyme-linked immunosorbent assay was developed. An immunogen consisting of epsilon-caproyl pyrraline (hapten) was linked onto poly-L-lysine (114:1) and used to raise polyclonal antibodies in the rabbit. High antibody titers were obtained 16 weeks after immunization. The antibody cross-reacted with butyl pyrraline (88%), propyl pyrraline (8%), lysyl pyrraline (2%), and neopentyl pyrraline (1.3%). A time-related increase in pyrraline immunoreactivity was observed in bovine serum albumin incubated with glucose (1000 mM), glycated lysine (50 mM), and 3-deoxyglucosone (50 mM) which reached 25, 300, and 350 pmol/mg, respectively, after 30 days. Mean level of protein pyrraline immunoreactivity were 27.0 +/- 7.2 and 43.3 +/- 11.7 pmol/mg in serum albumin from control and diabetic subjects, respectively (p less than 0.001). The pathobiological relevance of pyrraline may relate to its reported antiproteolytic and mutagenic properties. In addition, glucose-derived pyrroles may play a role in diabetic neuropathy in analogy to pyrroles formed during hexane-induced neuropathy.

Aging↗
PubMed1989

Isolation, purification and partial characterization of novel fluorophores from aging human insoluble collagen-rich tissue.

Collagen undergoes progressive browning with aging and diabetes characterized by yellowing, fluorescence and crosslinking, the cause of which remains unelucidated. As an initial step towards understanding the mechanism(s) of insolubilization of collagen in aging, the major fluorophores/chromophores from the insoluble fraction of human dura mater were isolated and their spectroscopic properties were characterized. High molecular weight tryptic peptides of insoluble collagen were cleaved by sequential enzymatic digestion followed by separation into high (HMW) and low molecular weight (LMW) fractions by gel filtration chromatography. LMW was further separated by paper and reverse phase chromatography (HPLC). Two fluorescent peaks, nicknamed P and M, were obtained from LMW which had UV maxima at 325 and 350 nm and excitation/fluorescence maxima at 335/385 and 360/460 nm, respectively. Fluorophore M was borohydride reducible and unstable to acid-hydrolysis, while P remained unaffected. Large quantities of fluorophore M and pyridinoline were found in the highly crosslinked HMW fraction remaining following exhaustive proteolytic digestion. Fluorophore P and M were the major fluorophores recovered from the tryptic digest of insoluble dura mater. Fluorescence spectra of M suggest an iminopropene type of configuration which could result from nonenzymatic browning of collagen with, e.g., glucose or malonyldialdehyde, as a result of lipid peroxidation. Spectroscopic and chemical properties of fluorophore P were reminiscent but not identical with those of pyridinium crosslinks. Structure elucidation of these fluorophores is expected to provide important insight into the aging processes of the extracellular matrix.

Aging↗
PubMed1989

Toward a Maillard reaction theory of aging.

The inescapable chronic exposure of cellular and extracellular matrix molecules to reducing sugars which can initiate the Maillard reaction in vivo suggests that the fundamental aging process might be mediated by the Maillard reaction. An attempt to explain aging on the basis of the Maillard reaction, however, raises a number of conceptual questions. These questions are formulated below as a basis for a theory of aging based on the Maillard reaction.

Aging↗
PubMed1989

The chemistry of the Maillard reaction under physiological conditions: a review.

The chemistry of the Maillard reaction is one of the most challenging to study due to its extreme complexity. When it come to elucidating the structure of Maillard products bound to macromolecules, whether in foodstuffs or biological proteins, the difficulty becomes enormous. Although the structure of a variety of Maillard compounds has been elucidated in model systems at higher temperature, it is presently unknown to what extent they occur in vivo. Past and current approaches to obtain clues on the chemical nature of Maillard products formed under physiological conditions are reviewed.

Amines↗
PubMed1988

Mechanism of formation of the putative advanced glycosylation end product and protein cross-link 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole.

2-(2-Furoyl)-4(5)-(2-furanyl)-1H-imidazole (FFI) is a fluorescent molecule which was originally discovered in chloroform extract of ammoniacal solution of acid-hydrolyzed glycated proteins and proposed to represent a protein cross-link. The absence of a lysyl residue side chain and other observations promoted a detailed study of its mechanism of formation. Glycated alpha-t-Butoxycarbonyllysine was incubated for 29 days and periodically assayed for FFI and FFI-like fluorescence. Whereas fluorescence increased over time, FFI recovery was unexpectedly highest on day 0 and lowest on day 29, suggesting that FFI was directly derived from Amadori products. FFI was also recovered from hydrolysates of glycated neopentylamine, furosine, and browned poly-L-lysine but was virtually undetectable in similar solutions basified with NaOH, triethylamine, or pyridine instead of ammonia. Gas chromatography-mass spectrometry analysis of FFI from similar hydrolysates basified in the presence of 15N-enriched NH4Cl revealed for all precursors a parent ion peak at 230 instead of 228 m/e units, suggesting that the two imidazole nitrogen atoms had been incorporated from free ammonia into FFI. Spontaneous FFI synthesis occurred when furosine was reacted with aqueous ammonia at room temperature. These results do not support the proposition that FFI is an advanced glycosylation end product or a protein cross-link. They suggest that FFI is formed from ammonia and furosine which are by-products of acid-hydrolyzed glycated proteins.

Chromatography, High Pressure Liquid↗
PubMed1988

Collagen browning and cross-linking are increased in chronic experimental hyperglycemia. Relevance to diabetes and aging.

Diabetes and aging are associated with an increase in collagen-linked fluorescence and cross-linking that can be duplicated by incubating collagen with glucose. We have tested the hypothesis that browning and cross-linking can occur in vivo in rats by feeding them a diet containing 33% galactose. No significant increase in tail tendon browning or cross-linking, measured by tail tendon breaking time in urea, was observed after 3 mo of galactosemia. After 12 mo, however, twofold increases in tendon breaking time and collagen-linked chromophores absorbing greater than 300 nm and fluorophores at 430 nm (excitation 355 nm, P less than .001) analogous to those of diabetic and aging individuals were observed. The observed changes in collagen are attributed to the advanced Maillard (nonenzymatic glycosylation) reaction based on circumstantial evidence. With this premise, our data suggest that chronic galactosemia should be a powerful tool for investigating the role of the advanced Maillard reaction in complications of diabetes and aging.

Aging↗