Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human serum albumin modified with 1-2 methylglyoxal residues per molecule of protein (MGmin-HSA) stimulated the synthesis and secretion of interleukin 1 beta (IL-1 beta) from human monocytic THP-1 cells in vitro. It was a more potent inducer of IL-1 beta synthesis than human serum albumin highly-modified with glucose-derived advanced glycation endproducts (AGE-HSA). With 20 microM ligand. IL-1 beta synthesis was (pg/10(6) cells): MGmin-HSA 484.5 +/- 50.3; AGE-HSA 30.6 +/- 2.0 (n = 3). IL-1 beta synthesis increased markedly with MGmin-HSA concentrations > 5 microM. IL-1 beta synthesis and secretion from monocytes in response to methylglyoxal-modified proteins in vivo may contribute to the development of macro- and micro-angiopathy, particularly in diabetes mellitus.
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PMID:Induction of synthesis and secretion of interleukin 1 beta in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation endproducts. 879 54

Human serum albumin minimally-modified by methylglyoxal (MGmin-HSA) stimulated the synthesis and secretion of macrophage-colony stimulating factor (M-CSF) by mature human monocytes in vitro. Human serum albumin minimally-modified by glucose-derived advanced glycation endproducts (AGEmin-HSA) and human serum albumin highly-modified by glucose-derived advanced glycation endproducts (AGE-HSA) stimulated much lower secretion of M-CSF from human monocytes than did MGmin-HSA. MGmin-HSA and AGE-HSA but not AGEmin-HSA also stimulated the growth of human monocytic THP-1 cells in vitro which was inhibited by polyclonal antibodies to human M-CSF. For MGmin-HSA, the median growth stimulatory concentration EC50 value was 0.24 +/- 0.07 microM and the maximal increase in cell growth was 36% of control cell growth (n = 24). Similar induction of secretion of M-CSF from monocytes in vivo may contribute to atherosclerosis in macro- and micro-angiopathy, particularly in the development of diabetic complications.
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PMID:Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. 894 11

Human serum albumin minimally-modified by methylglyoxal (MGmin-HSA) stimulated the synthesis and secretion of tumour necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro. Human serum albumin minimally-modified by glucose-derived advanced glycation endproducts (AGEmin-HSA) and human serum albumin highly-modified by glucose-derived advanced glycation endproducts (AGE-HSA) stimulated markedly lower synthesis and secretion of TNF-alpha from THP-1 cells than did MGmin-HSA. The median effective concentration EC50 value of MGmin-HSA for the secretion of TNF-alpha was 5.8 +/- 0.3 microM and the maximal secretion was 0.28 +/- 0.01 ng TNF-alpha/ml (n = 12) for incubations containing 5 x 10(5) cells/ml. MGmin-HSA (0.2-2.0 microM) also stimulated chemotaxis of THP-1 cells in vitro but AGE-HSA did not in this concentration range. The EC50 value of MGmin-HSA for the chemotactic response was 0.44 +/- 0.07 microM (n = 15). Similar induction of the synthesis and secretion of TNF-alpha and chemotaxis by monocytes in response to MGmin-HSA in vivo may contribute to atherosclerosis in macro- and micro-angiopathy, particularly in the development of chronic clinical complications of diabetes mellitus.
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PMID:Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. 929 94

Diabetes mellitus is complicated with vascular disorders such as atherosclerosis (macroangiopathy) and retinopathy (microangiopathy). In macroangiopathy, AGE plays an important role in atherogesis through NF-kappa B activation, that induces VCAM-1 and MCP-1. Diabetic retinopathy is based on the microangiopathy characteristic of angiogenesis. VEGF is a key substance in the angiogenesis in the retina. VEGF is produced from retinal cells exposed to AGE, adenosine, bFGF. VEGF elictes angiogenesis and increased vascular permeability (retinal edema). I consider that AGE is the most important substance in diabetic vascular disorder. Therefore, I expect a new application for diabetic angiopathy to suppress the effect of AGE.
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PMID:[Vascular endothelial cell dysfunction in diabetes mellitus]. 1019 36

Hyperglycaemia has been shown to play a central part in diabetic vascular disease, which is also influenced by individual background. Hyperglycaemia initiates the pathogenetic sequence through a series of interrelated biochemical abnormalities, including increased flux through the polyol and hexosamine pathways, oxidative stress, AGE formation and protein kinase C activation. These abnormalities are capable of modifying the function of resident and non-resident vascular cells by changing their production pattern of several autocrine and paracrine factors, including growth, vasoactive and coagulation factors and adhesion molecules. These mediators profoundly impair the physiologic turnover of the vessel wall, thus leading to an abnormal process of vascular remodelling, with alterations in cell and matrix turnover and contacts, vascular tone and permeability and coagulation pattern. This process has distinct features depending on the target tissue. The hallmark of nephropathy is an abnormal accumulation of extracellular matrix within the mesangium, sustained by an upregulation of TGF-beta, possibly triggered by a local activation of the renin-angiotensin system. The central pathological lesion in retinopathy is retinal ischaemia due to the formation of acellular capillaries. The resulting vascular endothelial growth factor-dependent neovascularization is a detrimental phenomenon leading to the formation of noncompetent vessels. Conversely, in macrovascular disease, arterial occlusion resulting from plaque formation with superimposed thrombosis elicits an angiogenic response which is impaired, but generates competent vessels, potentially compensating for reduced flow. Thus, upstream interventions interrupting the pathogenetic sequence at the level of hyperglycaemia (and related biochemical events) are the most effective, whereas downstream interventions should be targeted to the tissue affected.
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PMID:15th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodelling in diabetes. 1144 Mar 60

The cardiovascular complications of diabetes represent the leading cause of morbidity and mortality in affected subjects. The impact of hyperglycemia may be both direct and indirect: indirect consequences of elevated blood glucose lead to generation of advanced glycation endproducts, the products of nonenzymatic glycation/oxidation of proteins/lipids that accumulate in the vessel wall, and are signal transduction ligands for Receptor for AGE (RAGE). Although enhanced in diabetes, AGE accumulation also occurs in euglycemia and aging, albeit to lower degrees, driven by oxidant stress and inflammation. In hyperglycemia, production of 3-deoxyglucosone, at least in part via the polyol pathway, provides an amplification loop to sustain AGE generation, oxidant stress, and vascular activation. Furthermore, recruitment of inflammatory cells bearing S100/calgranulins, also ligands for RAGE, augments vascular dysfunction. We hypothesize that activation of RAGE is a final common pathway that transduces signals from these diverse biochemical and molecular species, leading to cardiovascular perturbation. Ultimately, these pathways synergize to construct a scaffold on which the complications of diabetes in the vasculature and heart may be built. We propose that antagonism of RAGE will provide a unique means to dismantle this scaffold and, thereby, suppress initiation/progression of vascular disease and cardiac dysfunction that accompany diabetes and aging.
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PMID:Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. 1467 Aug 31

At high levels as seen in diabetes, glucose reacts with and forms adducts (advanced glycation end products; AGEs) on macromolecules including proteins and DNA, eliciting cellular dysfunction and leading to vascular disease. The major means is through cellular receptors; the best characterized is the receptor for advanced glycation end products (RAGE). Accumulation of both AGE/RAGE in addition to other identified ligands of RAGE, including S100/calgranulins, is the hallmark of this receptor in disease pathogenesis. Blockade of ligand-receptor interaction directly at the protein level, or transgenetically, prevents development of micro vascular (nephropathy) and macro vascular (atherosclerosis/restenosis) disease in small animal models. Furthermore, allelic variants of RAGE exist that alter the protein function and gene expression, which may further affect disease outcome. In conclusion, RAGE is a target for drug development to prevent vascular disease in diabetic and nondiabetic subjects.
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PMID:RAGE: a novel target for drug intervention in diabetic vascular disease. 1529 Aug 45

Methylglyoxal (MG), which forms MG-derived AGE, is elevated in diabetic subjects with vascular disease. Detoxification of MG occurs through the glyoxalase system incorporating glyoxalase-1 (GLO1) and glyoxalase-2. Perturbations of the glyoxalase-1 gene (GLO1) may result in vulnerability to vascular complications through alterations in AGE interactions. We used bioinformatics to predict the structure, function and genetic variation of GLO1. We identified a previously unreported exon. Seventy single nucleotide polymorphisms (SNPs) were identified bioinformatically. The amino acid substitution Ala 111 Glu was confirmed and predicted to be tolerant. Though no alternative splice variants were identified, novel multiple alternative transcription start sites and alternative 3' UTRs were demonstrated. Ubiquitous expression of GLO1 was confirmed. Conserved regulatory regions were predicted 5' to the transcription start site and in the distal promoter, and several predicted conserved transcription regulatory elements were suggested in the 5' UTR. This study of GLO1 demonstrates multiple sequence variants at DNA and mRNA levels, areas of sequence conservation and SNPs that are predicted to affect function. A differential ability of glyoxalase-1 to reduce the formation and subsequent interaction of AGEs may have a role in the structural and functional manifestations of diabetic vascular disease.
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PMID:The characterisation and functional analysis of the human glyoxalase-1 gene using methods of bioinformatics. 1547 66

Vascular diseases, especially atherosclerosis, are the main cause of morbidity and mortality in diabetics. Diabetes greatly increases the risk of developing coronary heart disease, cerebral vascular accident and lower limb arteritis. The physiopathology of vascular disease in the diabetic patient involves endothelial and smooth muscle cell abnormalities. Metabolic disturbances which are characteristic of diabetes, such as hyperglycaemia or AGE accumulation, contribute to endothelial dysfunction and augment the inflammatory response at the vascular level. Atherosclerotic plaques in diabetics are more inflammatory than in non-diabetics, with an accumulation of macrophages and T lymphocytes, a larger lipid core and the presence of a greater number of macrophages and smooth muscle cells in apoptosis, which makes them more vulnerable.
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PMID:[Physiopathology of atherosclerosis in diabetics]. 1566 76

Despite the common use of immunohistochemistry in autopsy tissues, the stability of most proteins over extended time periods is unknown. The robustness of signal for 16 proteins (MMP1, MMP2, MMP3, MMP9, TIMP1, TIMP2, TIMP3, AGER, MSR, SCARB1, OLR1, CD36, LTF, LGALS3, LYZ, and DDOST) and two measures of advanced glycation end products (AGE, CML) was evaluated. Two formalin-fixed, paraffin-embedded human tissue arrays containing 16 tissues each were created to evaluate 48 hr of autolysis in a warm or cold environment. For these classes of proteins, matrix metalloproteinases and their inhibitors, scavenger receptors, and advanced glycation end product receptors, we saw no systematic diminution of signal intensity during a period of 24 hr. Analysis was performed by two independent observers and confirmed for a subset of proteins by digital analysis and Western blotting. We conclude that these classes of proteins degrade slowly and faithfully maintain their immunohistochemistry characteristics over at least a 24-hr time interval in devitalized tissues. This study supports the use of autopsy tissues with short postmortem intervals for immunohistochemical studies for diseases such as diabetic vascular disease, cancer, Alzheimer's disease, atherosclerosis, and other pathological states. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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PMID:Robust immunohistochemical staining of several classes of proteins in tissues subjected to autolysis. 1731 10


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