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S D Yan

Publications and source records attributed to S D Yan.

At least 55 records · Page 3Linked to original sources
PubMed1994

Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications.

Vascular complications are an important cause of morbidity and mortality in patients with diabetes. The extent of vascular complications has been linked statistically to enhanced adherence of diabetic erythrocytes to endothelial cells (ECs) and to the accumulation of a class of glycated proteins termed advanced glycation end products (AGEs). We hypothesized that formation of AGEs on the surface of diabetic erythrocytes could mediate their interaction with ECs leading to binding and induction of vascular dysfunction. Enhanced binding of diabetic erythrocytes to ECs was blocked by preincubation of erythrocytes with anti-AGE IgG or preincubation of ECs with antibodies to the receptor for AGE (RAGE). Immunoblotting of cultured human ECs and immunostaining of normal/diabetic human tissue confirmed the presence of RAGE in the vessel wall. Binding of diabetic erythrocytes to endothelium generated an oxidant stress, as measured by production of thiobarbituric acid-reactive substances (TBARS) and activation of the transcription factor NF-kappa B, both of which were blocked by probucol or anti-RAGE IgG. Erythrocytes from diabetic rats infused into normal rats had an accelerated, early phase of clearance that was prevented, in part, by antibody to RAGE. Liver tissue from rats infused with diabetic erythrocytes showed elevated levels of TBARS, which was prevented by pretreatment with anti-RAGE IgG or probucol. Thus, erythrocyte surface AGEs can function as ligands that interact with RAGE on endothelium. The extensive contact of diabetic erythrocytes bearing surface-associated AGEs with vessel wall RAGE could be important in the development of vascular complications.

Animals↗
PubMed1994

Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress.

The stability of proteins that constitute the neurofibrillary tangles and senile plaques of Alzheimer disease suggests that they would be ideal substrates for nonenzymatic glycation, a process that occurs over long times, even at normal levels of glucose, ultimately resulting in the formation of advanced glycation end products (AGEs). AGE-modified proteins aggregate, and they generate reactive oxygen intermediates. Using monospecific antibody to AGEs, we have colocalized these AGEs with paired helical filament tau in neurofibrillary tangles in sporadic Alzheimer disease. Such neurons also exhibited evidence of oxidant stress: induction of malondialdehyde epitopes and heme oxygenase 1 antigen. AGE-recombinant tau generated reactive oxygen intermediates and, when introduced into the cytoplasm of SH-SY5Y neuroblastoma cells, induced oxidant stress. We propose that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction.

Alzheimer Disease↗
PubMed1994

Advanced Maillard reaction end products are associated with Alzheimer disease pathology.

During aging long-lived proteins accumulate specific post-translational modifications. One family of modifications, termed Maillard reaction products, are initiated by the condensation between amino groups of proteins and reducing sugars. Protein modification by the Maillard reaction is associated with crosslink formation, decreased protein solubility, and increased protease resistance. Here, we present evidence that the characteristic pathological structures associated with Alzheimer disease contain modifications typical of advanced Maillard reaction end products. Specifically, antibodies against two Maillard end products, pyrraline and pentosidine, immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease. In contrast, little or no staining is observed in apparently healthy neurons of the same brain. The Maillard-reaction-related modifications described herein could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.

Alzheimer Disease↗
PubMed1994

The endothelial cell binding site for advanced glycation end products consists of a complex: an integral membrane protein and a lactoferrin-like polypeptide.

Advanced glycation end products (AGEs), formed as the result of the extended interaction of proteins with ketoses, modulate central properties of endothelial cells and mononuclear phagocytes by interacting with a cell surface binding site comprised of a novel integral membrane protein (receptor for AGE = RAGE) and a lactoferrin-like polypeptide (LF-L), the latter having sequence identity to lactoferrin (LF). To further understand this cellular binding site, the interaction of RAGE with LF-L and LF was characterized. By ligand blotting and a solid state competitive binding assay, 125I-LF-L and 125I-LF bound to RAGE immobilized on nitrocellulose membranes or polypropylene tubes in a time-dependent and reversible manner, demonstrating a high affinity component with Kd approximately 100 pM. The interaction of 125I-LF-L and 125I-LF with RAGE was independent of iron in LF and was competed by addition of an excess of unlabeled carboxyl-terminal portion of LF. Cross-linking studies with purified 125I-LF-L and RAGE, in the presence of disuccinimidyl suberate, showed a new, slowly migrating band, corresponding to a complex of RAGE and LF-L, and cross-linking on mouse aortic endothelial cells showed two new slowly migrating bands on immunoblotting visualized with both anti-RAGE IgG and anti-LF-L IgG. These data lead us to propose that the endothelial cell surface binding site for AGEs consists of LF-L bound noncovalently to RAGE anchored in the cell membrane.

Amino Acid Sequence↗
PubMed1994

Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins.

Attack by reactive oxygen intermediates, common to many kinds of cell/tissue injury, has been implicated in the development of diabetic and other vascular diseases. Such oxygen-free radicals can be generated by advanced glycation end products (AGEs), which are nonenzymatically glycated and oxidized proteins. Since cellular interactions of AGEs are mediated by specific cellular binding proteins, receptor for AGE (RAGE) and the lactoferrin-like polypeptide (LF-L), we tested the hypothesis that AGE ligands tethered to the complex of RAGE and LF-L could induce oxidant stress. AGE albumin or AGEs immunoisolated from diabetic plasma resulted in induction of endothelial cell (EC) oxidant stress, including the generation of thiobarbituric acid reactive substances (TBARS) and resulted in the activation of NF-kappa B, each of which was blocked by antibodies to AGE receptor polypeptides and by antioxidants. Infusion of AGE albumin into normal animals led to the appearance of malondialdehyde determinants in the vessel wall and increased TBARS in the tissues, activation of NF-kappa B, and induction of heme oxygenase mRNA. AGE-induced oxidant stress was inhibited by pretreatment of animals with either antibodies to the AGE receptor/binding proteins or antioxidants. These data indicate that interaction of AGEs with cellular targets, such as ECs, leads to oxidant stress resulting in changes in gene expression and other cellular properties, potentially contributing to the development of vascular lesions. Further studies will be required to dissect whether oxidant stress occurs on the cell surface or at an intracellular locus.

Adrenal Glands↗
PubMed1994

Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions.

Advanced glycation end products (AGEs) form by the interaction of aldoses with proteins and the subsequent molecular rearrangements of the covalently linked sugars, eventuating in a diverse group of fluorescent compounds of yellow-brown color. This heterogeneous class of nonenzymatically glycated proteins or lipids is found in the plasma and accumulates in the vessel wall and tissues even in normal aging. As a consequence of hyperglycemia, AGE formation and deposition are much enhanced in diabetes, in which their presence has been linked to secondary complications, especially microvascular disease. This review summarizes the cellular interactions of AGEs and describes the central role of a novel receptor for AGE (RAGE). RAGE, an immunoglobulin superfamily member, mediates the binding of AGEs to endothelial cells and mononuclear phagocytes, interacts with a lactoferrin-like polypeptide that also binds AGEs, and appears to activate intracellular signal transduction mechanisms consequent to its interaction with the glycated ligand. RAGE is expressed by ECs, mononuclear phagocytes, smooth muscle cells, mesangial cells, and neurons, indicating a potential role in the regulation of their properties in homeostasis and/or their dysfunction in the development of diabetic complications. Since AGEs have been shown to generate reactive oxygen intermediates, tethering of AGEs to the cell surface by their receptors focuses oxidant stress on cellular targets, resulting in changes in gene expression and the cellular phenotype. The discovery of RAGE and development of reagents to block its interaction with AGEs should provide insights into the role of this ligand-receptor interaction in the pathogenesis of diabetic complications and, potentially, atherosclerosis.

Animals↗
PubMed1994

Hypoxic induction of interleukin-8 gene expression in human endothelial cells.

Because leukocyte-mediated tissue damage is an important component of the pathologic picture in ischemia/reperfusion, we have sought mechanisms by which PMNs are directed into hypoxic tissue. Incubation of human endothelial cells (ECs) in hypoxia, PO2 approximately 14-18 Torr, led to time-dependent release of IL-8 antigen into the conditioned medium; this was accompanied by increased chemotactic activity for PMNs, blocked by antibody to IL-8. Production of IL-8 by hypoxic ECs occurred concomitantly with both increased levels of IL-8 mRNA, based on polymerase chain reaction analysis, and increased IL-8 transcription, based on nuclear run-on assays. Northern analysis of mRNA from hypoxic ECs also demonstrated increased levels of mRNA for macrophage chemotactic protein-1, another member of the chemokine superfamily of proinflammatory cytokines. IL-8 gene induction was associated with the presence of increased binding activity in nuclear extracts from hypoxic ECs for the NF-kB site. Studies with human umbilical vein segments exposed to hypoxia also demonstrated increased elaboration of IL-8 antigen compared with normoxic controls. In mice exposed to hypoxia (PO2 approximately 30-40 Torr), there was increased pulmonary leukostasis, as evidenced by increased myeloperoxidase activity in tissue homogenates. In parallel, increased levels of transcripts for IP-10, a murine homologue in the chemokine family related to IL-8, were observed in hypoxic lung tissue. Taken together, these data suggest that hypoxia constitutes a stimulus for leukocyte chemotaxis and tissue leukostasis.

Animals↗
PubMed1994

Tumor necrosis factor-alpha production in human head and neck squamous cell carcinoma.

Recent studies suggest that tumor necrosis factor-alpha (TNF-alpha), a pleiotropic cytokine, is responsible for some of the systemic and local effects, including tumor-associated cachexia and neoplastic bone destruction, seen in patients with cancer. This study was undertaken to determine if TNF-alpha is produced by human squamous cell carcinoma of the head and neck, and, if so, to determine its source and cellular distribution. Tumor specimens from nine patients with squamous cell carcinoma of the head and neck region were immunohistochemically examined for the presence of TNF-alpha. TNF-alpha was localized with antibody to human TNF-alpha by the immunoperoxidase method to the tumor and vessel endothelial cells in all nine specimens. By Western blot analysis, two protein bands recognized by anti-human TNF-alpha antibody in the soluble proteins of the tumor specimens were identified. These proteins--25 KD and 17 KD--represent the precursor and mature forms of TNF-alpha. To verify squamous cell carcinoma production of TNF-alpha, a cell culture of human head and neck squamous carcinoma was examined. The 25 KD immunoreactive protein, the TNF-alpha precursor, was found in extracts from this culture by Western blot analysis. These findings suggest that tumor cells are able to produce TNF-alpha; this production may explain some of the systemic and local effects seen in patients with squamous cell carcinoma of the head and neck.

Biomarkers, Tumor↗
PubMed1994

Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease.

Heme oxygenase-1 is an important enzyme that degrades heme, a pro-oxidant, leading to the formation of antioxidant molecules. In this study we demonstrate by immunocytochemistry close association of heme oxygenase-1 with Alzheimer neurofibrillary pathology and with the neurofibrillary tangles found in progressive supranuclear palsy and subacute sclerosing panencephalitis. In Alzheimer's disease, using two different rabbit antisera against heme oxygenase-1 protein, we localized, using immunocytochemical methods, heme oxygenase-1 to neurofibrillary tangles, senile plaque neurites, granulovacuolar degeneration, and neuropil threads. Only light background staining was seen in young controls and sporadic lesion-related immunoreactivity in age-matched controls. The increase in heme oxygenase-1 protein in association with the neurofibrillary pathology of Alzheimer's disease and other diseases characterized by neurofibrillary tangles supports the notion that the generation of free radicals and oxidative stress plays a role in the pathogenesis of neurofibrillary pathology.

Aged↗
PubMed1993

Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products.

Nonenzymatic glycation of proteins occurs at an accelerated rate in diabetes and can lead to the formation of advanced glycation end products of proteins (AGEs), which bind to mononuclear phagocytes (MPs) and induce chemotaxis. We have isolated two cell surface-associated binding proteins that mediate the interaction of AGEs with bovine endothelial cells. One of these proteins is a new member of the immunoglobulin superfamily of receptors (termed receptor for AGEs or RAGE); and the second is a lactoferrin-like polypeptide (LF-L). Using monospecific antibodies to these two AGE-binding proteins, we detected immunoreactive material on Western blots of detergent extracts from human MPs. Radioligand-binding studies demonstrated that antibody to the binding proteins blocked 125I-AGE-albumin binding and endocytosis by MPs. Chemotaxis of human MPs induced by soluble AGE-albumin was prevented in a dose-dependent manner by intact antibodies raised to the AGE-binding proteins, F(ab')2 fragments of these antibodies and by soluble RAGE. When MP migration in response to N-formyl-Met-Leu-Phe was studied in a chemotaxis chamber with AGE-albumin adsorbed to the upper surface of the chamber membrane, movement of MPs to the lower compartment was decreased because of interaction of the glycated proteins with RAGE and LF-L on the cell surface. The capacity of AGEs to attract and retain MPs was shown by implanting polytetrafluoroethylene (PTFE) mesh impregnated with AGE-albumin into rats: within 4 d a florid mononuclear cell infiltrate was evident in contrast to the lack of a significant cellular response to PTFE with adsorbed native albumin. These data indicate that RAGE and LF-L have a central role in the interaction of AGEs with human mononuclear cells and that AGEs can serve as a nidus to attract MPs in vivo.

Animals↗
PubMed1993

Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues.

Advanced glycation end products (AGEs), the final products of nonenzymatic glycation and oxidation of proteins, are found in the plasma and accumulate in the tissues during aging and at an accelerated rate in diabetes. A novel integral membrane protein, termed receptor for AGE (RAGE), forms a central part of the cell surface binding site for AGEs. Using monospecific, polyclonal antibody raised to human recombinant and bovine RAGE, immunostaining of bovine tissues showed RAGE in the vasculature, endothelium, and smooth muscle cells and in mononuclear cells in the tissues. Consistent with these data, RAGE antigen and mRNA were identified in cultured bovine endothelium, vascular smooth muscle, and monocyte-derived macrophages. RAGE antigen was also visualized in bovine cardiac myocytes as well as in cultures of neonatal rat cardiac myocytes and in neural tissue where motor neurons, peripheral nerves, and a population of cortical neurons were positive. In situ hybridization confirmed the presence of RAGE mRNA in the tissues, and studies with rat PC12 pheochromocytes indicated that they provide a neuronal-related cell culture model for examining RAGE expression. Pathological studies of human atherosclerotic plaques showed infiltration of RAGE-expressing cells in the expanded intima. These results indicate that RAGE is present in multiple tissues and suggest the potential relevance of AGE-RAGE interactions for modulating properties of the vasculature as well as neural and cardiac function, prominent areas of involvement in diabetes and in the normal aging process.

Animals↗
PubMed1992

Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins.

Advanced glycosylation end products of proteins (AGEs) are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. A approximately 35-kDa polypeptide with a unique NH2-terminal sequence has been isolated from bovine lung and found to be present on the surface of endothelial cells where it mediates the binding of AGEs (receptor for advanced glycosylation end product or RAGE). Using an oligonucleotide probe based on the amino-terminal sequence of RAGE, an apparently full-length cDNA of 1.5 kilobases was isolated from a bovine lung cDNA library. This cDNA encoded a 394 amino acid mature protein comprised of the following putative domains: an extracellular domain of 332 amino acids, a single hydrophobic membrane spanning domain of 19 amino acids, and a carboxyl-terminal domain of 43 amino acids. A partial clone encoding the human counterpart of RAGE, isolated from a human lung library, was found to be approximately 90% homologous to the bovine molecule. Based on computer analysis of the amino acid sequence of RAGE and comparison with databases, RAGE is a new member of the immunoglobulin superfamily of cell surface molecules and shares significant homology with MUC 18, NCAM, and the cytoplasmic domain of CD20. Expression of the RAGE cDNA in 293 cells allowed them to bind 125I-AGE-albumin in a saturable and dose-dependent manner (Kd approximately 100 nM), blocked by antibody to RAGE. Western blots of 293 cells transfected with RAGE cDNA probed with anti-RAGE IgG demonstrated expression of immunoreactive protein compared to its absence in mock-transfected cells. These results suggest that RAGE functions as a cell surface receptor for AGEs, which could potentially mediate cellular effects of this class of glycosylated proteins.

Albumins↗
PubMed1991

Lymphotoxin in human middle ear cholesteatoma.

The progressive growth of epidermis appears to be a crucial factor in the pathogenesis of cholesteatoma. How this growth is encouraged is still not well understood. In the present study, lymphotoxin was found in human middle ear cholesteatoma tissues by the immunoperoxidase method using rabbit anti-human lymphotoxin immunoglobulin G (IgG). Lymphotoxin was localized in the epithelium and connective tissues of the cholesteatomas studied. The epithelium of normal external ear canal skin was lightly stained, but the stain was much weaker than that of the cholesteatomas. In vitro, recombinant human lymphotoxin stimulated proliferation, protein synthesis, and terminal differentiation of basal keratinocytes. These findings suggest that lymphotoxin may be one of the mediators involved in the development of cholesteatoma.

Animals↗
PubMed1991

Tumor necrosis factor alpha in middle ear cholesteatoma and its effect on keratinocytes in vitro.

Tumor necrosis factor alpha (TNF-alpha) was found in human middle ear cholesteatoma tissues by the immunoperoxidase method using rabbit anti human TNF-alpha immunoglobulin G. It appeared to be localized in the epithelium and connective tissue of cholesteatomas studied, particularly on basal and spinous cells, and macrophages. The epithelium of normal external ear canal skin was lightly stained, but the staining was much weaker than that of the cholesteatomas observed. In vitro, recombinant mouse TNF-alpha stimulated proliferation, protein synthesis, and terminal differentiation of basal keratinocytes. These stimulatory effects were blocked by the anti-TNF-alpha immunoglobulin G, which by itself had no effect on basal keratinocytes. These findings suggest that TNF-alpha plays an important role in the development of cholesteatomas seen clinically.

Cells, Cultured↗
PubMed1990

Effects of indomethacin and calcitonin on bone absorption in type II collagen-induced otosclerosis-like lesions in rats.

In this study, we determined the effects of indomethacin and calcitonin on bone resorption in otosclerosis-like lesions in rats. Morphometric analysis showed that both indomethacin and calcitonin inhibited active otosclerosis-like lesions (bone resorption) and rats immunologically induced with type II collagen, and indomethacin had a much higher inhibitory effect than calcitonin. In in vitro studies we found that conditioned medium from splenic lymphocytes of rats immunized with type II collagen stimulated collagenase production by macrophages and fibroblasts. Collagenase is the major enzyme for degradation of the organic components of bone. Treatment of the immunized rats with indomethacin and calcitonin significantly reduced the stimulatory effect of the lymphocyte-conditioned medium on collagenase production. Indomethacin caused a greater reduction of the stimulatory effect of the lymphocytes on collagenase production than calcitonin. These findings are in agreement with results of the morphometric study. Results of the present study also suggest that cell-to-cell interaction plays an important role in collagenase production for degradation of organic components of bone resorption in otosclerotic lesions.

Animals↗
PubMed1988

Ultrastructure of the secondary tympanic membrane in the human fetus.

The normal secondary tympanic membrane in human fetuses was examined by transmission electron microscopy. The membranes in 5- to 9-month-old fetuses consist of the following three layers: (1) an outer squamous epithelial layer facing the middle ear, which is not formed until 4 months old; (2) a middle fibrous layer containing collagen, elastin, fibroblasts and fibrocytes, and (3) an inner layer of flat cells facing the scala tympani. Following the maturation of the fetus the epithelium is getting thinner and fibroblasts are reduced in number, but fibrocytes are increased and collagen and elastin grow gradually in density. The ultrastructure of the secondary tympanic membrane at 8 month is mature in type and shows the same characteristics as in the adult. This membrane has an important and complicated physiological function. The epithelium of the outer layer, with tight junctions and multiple desmosomes, provides a barrier to keep harmful substances out. The stability of the membrane provides protection against rupture, while the elasticity plays a role in the physiology of hearing as well.

Fetus↗