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M Brownlee

Publications and source records attributed to M Brownlee.

At least 91 records · Page 5Linked to original sources
PubMed1991

Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy.

Retinal capillary closure induced by hyperglycemia is the principal pathophysiologic abnormality underlying diabetic retinopathy, but the mechanisms by which this induction occurs are not clear. Treatment of diabetic rats for 26 weeks with aminoguanidine, an inhibitor of advanced glycosylation product formation, prevented a 2.6-fold accumulation of these products at branching sites of precapillary arterioles where abnormal periodic acid/Schiff reagent-positive deposits also occurred. Aminoguanidine treatment completely prevented abnormal endothelial cell proliferation and significantly diminished pericyte dropout. After 75 weeks, untreated diabetic animals developed an 18.6-fold increase in the number of acellular capillaries and formed capillary microaneurysms, characteristic pathologic features of background diabetic retinopathy. In contrast, aminoguanidine-treated diabetic animals had only a 3.6-fold increase in acellular capillaries and no microaneurysms. These findings indicate that advanced glycosylation product accumulation contributes to the development of diabetic retinopathy and suggest that aminoguanidine may have future therapeutic use in this disorder.

Animals↗
PubMed1991

Alcohol abuse in chronic schizophrenics: implications for management in the community.

This study was designed to investigate the effects of regular alcohol consumption on chronic schizophrenic patients maintained on fluphenazine decanoate in the community. A group of patients who consumed more than 20 units of alcohol per week was compared with those who did not drink or did so only occasionally. It was found that patients in the alcohol group had a higher frequency of previous relapses, a greater severity of positive symptoms and a lower incidence of extrapyramidal side effects except tardive dyskinesia for which there was no difference. Serum fluphenazine levels were lower in this group (NS). It was concluded that patients who regularly consume alcohol tend to be clinically unstable, perhaps because of poor therapeutic control.

Adult↗
PubMed1991

Glycosylation products as toxic mediators of diabetic complications.

Hyperglycemia causes excessive amounts of irreversible advanced glycosylation end products (AGEPs) to accumulate on long-lived extracellular matrix proteins and probably also on DNA in tissues that develop diabetic complications. AGEPs induce permanent abnormalities in extracellular protein cross-linking, cell-matrix interactions, and DNA structure in vitro. Pharmacologically inhibiting AGEP formation in long-term diabetic animals prevents both retinal capillary pathology and thickening of the glomerular basement membrane.

Animals↗
PubMed1991

Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells.

Cross-linking of cell matrix components by nonenzymatic glycosylation may contribute to diabetic glomerulopathy. We examined the effects of modification of matrix by nonenzymatic glycosylation on mesangial cell function. Matrix was generated by growing mesangial cells in tissue culture for 2 wk and removing the cells with a detergent cell-lysis solution. By indirect immunofluorescence and Northern-blot analysis, the remaining matrix contained laminin, fibronectin, and collagens type I and IV. The matrix was modified by incubation for 24 h with 50 mM glycolaldehyde, a highly reactive cross-linking nonenzymatic glycosylation product, or for 2 wk with 200 mM glucose-6-phosphate (G6P). Modification was carried out with or without equimolar aminoguanidine, an inhibitor of cross-link formation. Nonenzymatic glycosylation of the matrix by glycolaldehyde or G6P was confirmed by fluorometry and [14C]G6P incorporation and was prevented by aminoguanidine. [3H]thymidine incorporation for 24 h by mesangial cells plated onto unmodified or modified matrix was then performed. Modification of matrix had no effect on attachment of mesangial cells, determined 4 h after plating. Nonenzymatic glycosylation of matrix by glycolaldehyde or G6P significantly inhibited thymidine incorporation by mesangial cells. This effect was partially reversible by aminoguanidine. Aminoguanidine-modified matrix had no effect on thymidine incorporation. Thymidine-incorporation results were confirmed by direct cell counting. We conclude that modification of matrix by nonenzymatic glycosylation influences growth of mesangial cells, which could contribute to the mesangial abnormalities of diabetic glomerulopathy.

Animals↗
PubMed1990

Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes.

Non-enzymatic glycation of reactive amino groups in model proteins increased the rate of free radical production at physiologic pH by nearly fifty-fold over non-glycated protein. Superoxide generation was confirmed by electron paramagnetic resonance measurements with the spin-trap phenyl-t-butyl-nitrone. Both Schiff base and Amadori glycation products were found to generate free radicals in a ratio of 1:1.5. Free radicals generated by glycated protein increased peroxidation of membranes of linoleic/arachidonic acid vesicles nearly 2-fold over control, suggesting that the increased glycation of proteins in diabetes may accelerate vascular wall lipid oxidative modification.

Arteriosclerosis↗
PubMed1989

Macrophage receptor-mediated processing and regulation of advanced glycosylation endproduct (AGE)-modified proteins: role in diabetes and aging.

Tissue and cell surface proteins modified nonenzymatically by glucose are shown to be removed by macrophages through a recently characterized high affinity receptor. Insulin appears to be a potent suppressor of this macrophage AGE removal activity, while TNF acts as a stimulant. Coupling of AGE-proteins to their AGE-receptor results in TNF and IL-1 synthesis and secretion. This suggests that AGE may act as a signal for growth-promoting factor secretion in a coordinated replacement process during tissue remodeling. A greater than 2-fold decrease in receptor number and binding capacity found in cells from aged mice as compared to young suggests that aging may adversely affect the AGE-receptor-efficiency and by impeding crosslinked AGE-protein removal add to ongoing aging tissue damage.

Aging↗
PubMed1988

Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling.

Proteins undergo a series of nonenzymatic reactions with glucose over time to form advanced glycosylation end products (AGEs). Macrophages have a receptor that recognizes the AGE moiety and mediates the uptake and degradation of AGE proteins. This removal process is associated with the production and secretion of cachectin (tumor necrosis factor) and interleukin-1, two cytokines with diverse and seemingly paradoxical biological activities. The localized release and action of these cytokines could account for the coordinated removal and replacement of senescent extracellular matrix components in normal tissue homeostasis.

Glycosylation↗
PubMed1988

Specific macrophage receptor activity for advanced glycosylation end products inversely correlates with insulin levels in vivo.

A high-affinity macrophage receptor has been shown to mediate the removal of proteins modified by advanced nonenzymatic glycosylation end products (AGEs) in both animals and humans. To characterize the effect of diabetes on this receptor system, resident peritoneal macrophages from experimentally induced and genetically diabetic mice were studied. Binding and degradation of radioiodinated AGE-bovine serum albumin (AGE-BSA) were determined from saturation kinetics and compared with glucose and insulin levels of each subgroup. Scatchard plot analysis of nondiabetic mouse macrophages has indicated 1.5 X 10(5) receptors/cell, with a binding affinity of 1.7 X 10(7) M-1. The in vitro exposure of macrophages to either elevated glucose or insulin concentrations failed to demonstrate a short-term regulatory effect on AGE-receptor function. However, macrophages from hypoinsulinemic alloxan-induced diabetic mice indicated a two- to threefold increase in AGE-receptor number per cell (2.98 +/- 0.25 X 10(5)/cell), and macrophages from C57BL/KsJ (db/db) mice showed an almost threefold greater receptor number (2.86 +/- 0.2 X 10(5)/cell), with binding affinity remaining essentially unchanged (1.24 +/- 0.05 X 10(7) and 1.21 +/- 0.07 X 10(7) M-1, respectively). In addition, a moderate increase (25-30%) of 125I-labeled AGE-BSA degradation was observed in these two insulin-deficient diabetic macrophage groups compared with the normal control group. In contrast, macrophages from hyperinsulinemic and hyperglycemic C57BL/6J (db/db) mice demonstrated a distinct reduction in both AGE-receptor number (0.67 +/- 0.03 X 10(5)/cell) and binding affinity (0.37 +/- 0.03 X 10(7) M-1), with a decrease of AGE-BSA degradation of approximately 50% compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Advanced glycosylation endproducts on erythrocyte cell surface induce receptor-mediated phagocytosis by macrophages. A model for turnover of aging cells.

Glucose can react nonenzymatically with amino groups of proteins to form covalent Amadori products. With time these adducts undergo further rearrangements to form irreversible advanced glycosylation endproducts (AGE), which accumulate with protein age. A specific AGE, 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole (FFI), has been identified on proteins in vivo. We have recently shown that a macrophage receptor specifically recognizes and internalizes proteins modified by AGE such as FFI, thus preferentially degrading senescent macromolecules. Reasoning that cellular turnover may be mediated by macrophage recognition of AGE-membrane proteins, we prepared human RBCs with FFI attached chemically. Human monocytes were incubated with either FFI-RBCs, IgG-opsonized RBCs, or PBS-treated RBCs. Erythrophagocytosis of FFI-RBCs was significantly higher than that of PBS-RBCs (55 vs. 4%; p less than 0.0025) and almost as high as that of IgG-RBCs (70%), and was competitively inhibited by AGE-BSA. AGE-RBCs were also prepared by incubating RBCs with various sugars. Human monocytes showed a 15% ingestion of glucose-RBCs, and a 26% ingestion of glucose-6-phosphate-RBCs, compared to 6% for PBS-RBCs. Similarly, diabetic mouse RBCs were phagocytosed by nearly three times more cells (21%) than normal mouse RBCs when exposed to syngeneic mouse macrophages. This phagocytosis was competitively inhibited (70%) by addition of excess AGE-BSA. The in vivo half-life of 51Cr-labeled mouse FFI-RBCs injected into syngeneic mice was reduced to 7 d, as compared to a half-life of 20 d for the controls. These data suggest that the macrophage receptor for the removal of glucose-modified proteins may also mediate the endocytosis of RBCs with AGE formed on their surface, and thus be responsible in part for the removal of some populations of aging cells.

Animals↗
PubMed1986

Novel macrophage receptor for glucose-modified proteins is distinct from previously described scavenger receptors.

A high-affinity macrophage receptor has been identified that recognizes proteins modified by a common in vivo process, long-term nonenzymatic reaction of glucose with proteins (AGE proteins). This receptor for glucose-modified proteins is now shown to be distinct from previously described scavenger receptors, using competition and crosscompetition experiments between AGE-modified protein and a variety of in vitro-modified scavenger receptor ligands, including unmodified BSA, unmodified low-density lipoproteins (LDL), acetyl-LDL, maleyl-BSA, and formaldehyde-treated BSA. Furthermore, the specific pattern of AGE-protein receptor inhibition by the polyanionic compounds polyinosinic acid, polyadenylic acid, polyglutamic acid, polycytidylic acid, fucoidin, and heparin was distinctly different from that of acetyl-LDL. By thus selectively recognizing a time-dependent in vivo protein modification, macrophages may preferentially degrade senescent macromolecules, thereby having an important role in the regulation of extracellular protein turnover.

Aging↗
PubMed1986

Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking.

Age-associated increases in collagen cross-linking and accumulation of advanced glycosylation products are both accelerated by diabetes, suggesting that glucose-derived cross-link formation may contribute to the development of chronic diabetic complications as well as certain physical changes of aging. Aminoguanidine, a nucleophilic hydrazine compound, prevented both the formation of fluorescent advanced nonenzymatic glycosylation products and the formation of glucose-derived collagen cross-links in vitro. Aminoguanidine administration to rats was equally effective in preventing diabetes-induced formation of fluorescent advanced nonenzymatic glycosylation products and cross-linking of arterial wall connective tissue protein in vivo. The identification of aminoguanidine as an inhibitor of advanced nonenzymatic glycosylation product formation now makes possible precise experimental definition of the pathogenetic significance of this process and suggests a potential clinical role for aminoguanidine in the future treatment of chronic diabetic complications.

Animals↗
PubMed1986

Role of nonenzymatic glycosylation in atherogenesis.

This review summarizes progress in nonenzymatic glycosylation research of potential relevance to atherosclerosis using a hypothetical model based on current concepts of atherogenesis. Recently, new information has been presented showing that the initial Amadori product undergoes a series of further reactions and rearrangements to form adducts, called advanced glycosylation end products (AGE). These products are irreversible and accumulate indefinitely on long-lived molecules. These AGE covalently trap soluble plasma proteins, act as signals for macrophage recognition and uptake, and induce mutations in double-stranded plasmid DNA. Covalent trapping of low-density lipoprotein (LDL) by AGE on collagen or elastin could promote lipid accumulation in the arterial wall, whereas AGE trapping of von Willebrand factor would increase platelet adhesion and aggregation leading to intimal smooth muscle cell proliferation. Recognition and uptake of AGE-proteins by scavenging macrophages could further contribute to the process of atherogenesis by stimulating release of macrophage secretory products such as macrophage-derived growth factor. Accumulation of AGE on smooth muscle cell DNA might also enhance arterial smooth muscle cell proliferation by increasing the rate of mutations affecting growth controls. This model should provide the basis for future experiments.

Arteriosclerosis↗
PubMed1986

Trapped immunoglobulins on peripheral nerve myelin from patients with diabetes mellitus.

Diabetic peripheral neuropathy is characterized by endoneurial capillary closure and by segmental demyelination and axonal degeneration in a spatial pattern consistent with ischemic damage. The increased permeability of human diabetic endoneurial capillaries to plasma proteins may contribute to the pathogenesis of these structural changes in peripheral nerve by further accelerating the rate at which plasma proteins are trapped by reactive nonenzymatic glycosylation products on long-lived proteins such as myelin. We have measured trapped immunoglobins (Ig) G and M on peripheral nerve myelin from diabetic and nondiabetic patients by an enzyme-linked immunosorbent assay to determine whether plasma proteins accumulate on nerves as they do in the glomerular matrix of diabetics. The amount of trapped IgG on brain myelin from these subjects was also determined. Peripheral nerve myelin from diabetics had on average greater than 14 times the amount of trapped IgM found in identically prepared samples from nondiabetics (0.90 +/- 0.2 vs. 0.06 +/- 0.004 OD/micrograms myelin protein) and greater than 4 times the amount of trapped IgG (6.40 +/- 1.92 vs. 1.5 +/- 0.25 OD/micrograms myelin protein). In contrast, no significant trapping of IgG was detected in any samples of brain myelin. This most likely reflects effective exclusion of IgG by the blood-brain barrier. These data suggest that excessive trapping of Igs and other plasma proteins by diabetic peripheral nerve myelin may contribute to the development of peripheral nerve damage, whereas the lack of such trapping by brain myelin may partly explain the rarity of diabetic central neuropathy.

Adult↗