Biomedical subjects

D R Sell

Publications and source records attributed to D R Sell.

31 records · Page 2Linked to original sources

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

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

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

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↗

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↗

PubMed1984

The effects of sorghum tannin and methionine level on the performance of laying hens maintained in two temperature environments.

At the conclusion of a 31-day recovery period following a previous sorghum feeding trial (Sell et al., 1983), 128 White Leghorn hens were used in a subsequent 44-day study to investigate the effects of methionine supplementation of sorghum-soybean meal diets on laying hen performance. The hens were arrayed into four nutritional treatments in each of two constant environments (22 and 28 C) based on their egg production during the last 10 days of the recovery period within a previous treatment and environment so that equal numbers of hens from the previous treatments were represented in the new treatments. Nutritional treatments consisted of either low (RS610) or high (savanna) tannin sorghum-soybean meal diets containing 13% protein and supplemented with either .2% DL-methionine (Met) or an isonitrogenous level of L-glutamic acid (Glu). With both high (HTS) and low tannin sorghum (LTS) diets, Met supplementation resulted in greater egg production, egg weight, feed intake, and less hen weight loss as compared with Glu addition, but with the exception of hen weight loss, the magnitude of the response was much greater with HTS. Hens fed the HTS diet supplemented with Glu showed greatly reduced egg production and feed efficiency as compared with those fed LTS similarly supplemented. In contrast, little difference in egg production and feed efficiency was observed between hens fed HTS and LTS diets supplemented with Met. All parameters studied except hen weight appeared to be reduced slightly by the higher temperature.

Animals↗

PubMed1983

Effects of sorghum grain tannins and dietary protein on the activity of liver UDP-glucuronyltransferase.

The activity of liver microsomal UDP-glucuronyltransferase (EC 2.4.1.17), an enzyme known to detoxify phenolic compounds, was measured in chicks and rats fed high- (HTS) and low-tannin sorghums (LTS). In an initial investigation, activity was significantly elevated in chicks fed HTS-soybean meal diets over those fed the LTS control diet. Other studies were designed to differentiate between the effects due to tannin and those resulting from a protein deficiency which had previously been reported to increase the activity of this enzyme. In general, only a relatively small part of the increased activity observed by feeding HTS to chicks could be attributed to a tannin-induced protein deficiency. The same phenomenon of elevated activity produced by feeding HTS to chicks was not observed in the rat. These results would suggest that sorghum tannins, or their breakdown products, are absorbed and activating UDP-glucuronyltransferase in the chick, but not the rat.

Animals↗

PubMed1983

The effects of sorghum tannin and protein level on the performance of laying hens maintained in two temperature environments.

A study was conducted to investigate the effect of sorghum grain tannins on the performance of laying hens. A total of 144 White Leghorn hens were arrayed according to egg production during a 10-day preexperimental period into eight groups consisting of four nutritional treatments in each of two constant temperature environments (22 and 28 C). The nutritional treatments consisted of low (RS610) and high (Savanna) tannin sorghum grains compared isonitrogenously within a protein level at two protein levels (11.5 and 14.5%) in sorghum-soybean meal diets. These diets were fed for an experimental period of 6 weeks. Egg production and feed efficiency were reduced and weight loss was increased by 11.5% protein as compared with 14.5% protein. Tannin significantly reduced egg production and feed efficiency at both protein levels while egg specific gravity and shell thickness were adversely affected only at the lower level of protein. Egg weight and weight loss of hens were not affected by tannin. Except for weight loss, all parameters were slightly reduced by the higher temperature. At the end of the experiment, all hens were placed on a commercial laying ration for a 31-day period. Recovery from the treatment effects was evidenced by the similar egg production, body weight, egg weight, and shell characteristics among the previous treatments at the end of this period.

Animals↗

PubMed1980

Methionine-cystine interrelationships in chicks and rats fed diets containing suboptimal levels of methionine.

Studies were continued with both chicks and rats on the previously reported (featherston and Rogler, 1978) growth depression observed when a crystalline amino acid diet adequate in all nonsulfur-containing amino acids and containing .2% DL-methionine and .2% L-cystine was supplemented with an additional .2% L-cystine. In the present investigation, an average growth depression of 37% was observed in chicks fed a diet containing .4% L-cystine and .2% DL-methionine as compared with chicks fed a diet containing .2% L-cystine and the same level of methionine. A comparable depression was noted when cystine was replaced by L-cysteine. In contrast, an additional .2% of another amino acid (L-tryptophan) did not depress growth. When the high and low cystine diets were meal-fed, results obtained were similar to those observed with ad libitum feeding, but the magnitude of the difference was reduced. Foot-pad lesions, similar to those described in turkey poults fed methionine-deficient diets, were observed in two experiments. Factorial analysis of plasma amino acids indicated that the total of all amino acids analyzed was significantly (P < .05) higher in chicks fed the lower cystine or cysteine diets. Plasma methionine was slightly lower (P < .10) but plasma cystine was significantly (P < .05) higher in chicks fed the cystine or cysteine supplemented diets. A study with .2 and .4% L-cystine and 200, 600, and 2000 mg/kg of choline (factorial design) demonstrated a significant (P < .05) depression in weight gain due to the added L-cystine, no significant (P < .05) differences due to choline, and the absence of a cystine-choline interaction. No detrimental effects were observed when weanling rats were fed a crystalline amino acid diet containing .1% DL-methionine and .2% L-cystine supplemented with additional L-cystine.

Animal Nutritional Physiological Phenomena↗

PubMed1980

Influence of dietary cystine on intestinal absorption and tissue distribution of methionine in the chick.

Studies were conducted on intestinal absorption and tissue distribution of methionine by chicks fed a crystalline amino acid diet containing .2% DL-methionine and .2 or .4% L-cystine or L-cysteine. Chicks fed the higher level of cystine or cysteine had previously been shown to exhibit depressed growth as opposed to chicks fed the lower level of these amino acids. In two experiments, 35S radioactivity of whole plasma and the protein and supernatant fractions were compared among chicks fed the different treatments at 30 or 60 min after oral intubation of L-[35S]-methionine into the crops. When the data were analyzed factorially, a significant level effect was noted for whole plasma and the protein and supernatant fractions, all of which were higher for chicks fed .2% L-cystine than those fed .4% L-cystine. Results with chicks fed the two levels of L-cysteine generally agreed with those of chicks fed L-cystine, although the differences were not as great. The labeled methionine was also added to diets containing .2 or .4% L-cystine of meal-fed chicks. Higher levels of radioactivity were observed in the liver but not in muscle or plasma of chicks fed the lower level of cystine at 7 hr after oral consumption of the isotope. No significant differences in liver, muscle, or plasma radioactivity were noted in a fourth experiment between chicks fed .2 or .4% L-cystine at 24 hr after intraperitoneal injection of L-[35S]-methionine. In vitro studies showed no differences in methionine accumulation by isolated intestinal segments incubated with three levels of cystine.

Animals↗