Stops, prevents or reduces the activity of a cysteine-type endopeptidase, any enzyme that hydrolyzes peptide bonds in polypeptides by a mechanism in which the sulfhydryl group of a cysteine residue at the active center acts as a nucleophile.
Stops, prevents or reduces the activity of a kinase, an enzyme which catalyzes of the transfer of a phosphate group, usually from ATP, to a substrate molecule.
BACKGROUND: Diabetes leads to impaired glucose metabolism and insulin signaling in the heart, which may contribute to the development of diabetic cardiomyopathy. Insulin stimulates tyrosine phosphorylation of the insulin receptor and insulin receptor substrates. A two-fold increase in insulin-stimulated tyrosine phosphorylation has been reported in diabetic myocardium. The aim of the present study was to examine the effect of a putative inhibitor of tyrosine kinase phosphorylation, alpha(2)-Heremans Schmid glycoprotein (AHSG), on the mechanical dysfunction under a simulated diabetic environment. METHODS: Isolated ventricular myocytes from adult rats were maintained for 24 h in either normal glucose (NG, 5.5 mM) or high glucose (HG, 25.5 mM) medium with 10(-7) M insulin, and in the absence or presence of AHSG (50 micro g/ml). Contractile indices analyzed included: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and area underneath shortening and relengthening (Area/PS). RESULTS: Myocytes maintained in HG medium displayed reduced PS and prolonged TPS/TR(90), with enhanced area, compared to the NG myocytes. Interestingly, these HG-induced mechanical dysfunctions were abolished by AHSG. Removal of insulin from the culture medium did not affect the basal myocyte mechanics, but prevented AHSG from completely protecting against the HG-induced mechanical defects (i.e. HG-induced prolongation of TR(90) and area were only partially attenuated by AHSG in the absence of insulin). CONCLUSIONS: The present data support the notion of tyrosine phosphorylation in the pathogenesis of diabetic cardiomyopathy, and implicate the therapeutic value of tyrosine kinase phosphorylation inhibitors.
An acute inflammatory response that involves non-antibody proteins whose concentrations in the plasma increase in response to infection or injury of homeothermic animals.
Eur. J. Endocrinol. 147, 243-248 (2002)[PubMed:12153747]
OBJECTIVE: Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes. DESIGN: One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study. METHODS: Serum AHSG was determined by radial immunodiffusion. RESULTS: We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns. CONCLUSION: AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development.
Eur. J. Endocrinol. 147, 243-248 (2002)[PubMed:12153747]
OBJECTIVE: Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes. DESIGN: One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study. METHODS: Serum AHSG was determined by radial immunodiffusion. RESULTS: We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns. CONCLUSION: AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development.
BACKGROUND: Diabetes leads to impaired glucose metabolism and insulin signaling in the heart, which may contribute to the development of diabetic cardiomyopathy. Insulin stimulates tyrosine phosphorylation of the insulin receptor and insulin receptor substrates. A two-fold increase in insulin-stimulated tyrosine phosphorylation has been reported in diabetic myocardium. The aim of the present study was to examine the effect of a putative inhibitor of tyrosine kinase phosphorylation, alpha(2)-Heremans Schmid glycoprotein (AHSG), on the mechanical dysfunction under a simulated diabetic environment. METHODS: Isolated ventricular myocytes from adult rats were maintained for 24 h in either normal glucose (NG, 5.5 mM) or high glucose (HG, 25.5 mM) medium with 10(-7) M insulin, and in the absence or presence of AHSG (50 micro g/ml). Contractile indices analyzed included: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and area underneath shortening and relengthening (Area/PS). RESULTS: Myocytes maintained in HG medium displayed reduced PS and prolonged TPS/TR(90), with enhanced area, compared to the NG myocytes. Interestingly, these HG-induced mechanical dysfunctions were abolished by AHSG. Removal of insulin from the culture medium did not affect the basal myocyte mechanics, but prevented AHSG from completely protecting against the HG-induced mechanical defects (i.e. HG-induced prolongation of TR(90) and area were only partially attenuated by AHSG in the absence of insulin). CONCLUSIONS: The present data support the notion of tyrosine phosphorylation in the pathogenesis of diabetic cardiomyopathy, and implicate the therapeutic value of tyrosine kinase phosphorylation inhibitors.
An endocytosis process that results in the uptake of liquid material by cells from their external environment; literally 'cell drinking'. Liquid is enclosed in vesicles, called pinosomes, formed by invagination of the plasma membrane.
This comment describes the study by Jersmann and co-workers in this issue of Clinical Science reporting the results of a study of the role of the serum glycoprotein fetuin in the uptake of apoptotic cells by macrophages. They show that fetuin is able to stimulate the macropinocytosis of apoptotic cells in vivo, which would be therapeutically useful following chemotherapy when the increased numbers of apoptotic cells could exceed the capacity of the macrophage network.
Inflammatory diseases are associated with reduced serum concentrations of alpha(2)-HS glycoprotein (the human homologue of bovine fetuin), but the role of fetuin in inflammation is poorly understood. We hypothesized that fetuin may influence the resolution of inflammation by modulating the phagocytosis of apoptotic cells by macrophages. Using an in vitro flow cytometry-based phagocytosis assay, we investigated the role of fetuin in apoptotic cell clearance. Bovine fetuin and human alpha(2)-HS glycoprotein significantly augmented the phagocytosis of apoptotic cells by human peripheral blood monocyte-derived macrophages, whereas the control proteins BSA, sialylated BSA and asialofetuin were ineffective. The enhancement of phagocytosis was concentration-dependent, and required the presence of intact fetuin at the time of interaction between macrophages and apoptotic cells. Fetuin also substantially increased the uptake of labelled dextran 70000 by macrophages, which occurs by macropinocytosis, suggesting that this may be one of the mechanisms utilized for apoptotic cell uptake.
Proc. Natl. Acad. Sci. U.S.A. 84, 4403-4407 (1987)[PubMed:3474608]
The alpha 2-HS-glycoprotein (AHSG) is a plasma protein reported to play roles in bone mineralization and in the immune response. It is composed of two subunits, the A and B chains. Recombinant plasmids containing human cDNA AHSG have been isolated by screening an adult human liver library with a mixed oligonucleotide probe. The cDNA clones containing AHSG inserts span approximately 1.5 kilobase pairs and include the entire AHSG coding sequence, demonstrating that the A and B chains are encoded by a single mRNA transcript. The cDNA sequence predicts an 18-amino-acid signal peptide, followed by the A-chain sequence of AHSG. A heretofore unseen connecting sequence of 40 amino acids was deduced between the A- and B-chain sequences. The connecting sequence demonstrates the unique amino acid doublets and collagen triplets found in the A and B chains; it is not homologous with other reported amino acid sequences. The connecting sequence may be cleaved in a posttranslational step by limited proteolysis before mature AHSG is released into the circulation or may vary in its presence because of alternative processing. The AHSG cDNA was utilized for mapping the AHSG gene to the 3q21----qter region of human chromosome 3. The availability of the AHSG cDNA clone will facilitate the analysis of its genetic control and gene expression during development and bone formation.
Any process that modulates the frequency, rate or extent of the inflammatory response, the immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
BACKGROUND: Vascular calcification is the most prominent underlying pathological finding in patients with uraemia, and is a predictor of mortality in this population. Fetuin-A (alpha2-Heremans Schmid glycoprotein; AHSG) is an important circulating inhibitor of calcification in vivo, and is downregulated during the acute-phase response. We aimed to investigate the hypothesis that AHSG deficiency is directly related to uraemic vascular calcification. METHODS: We did a cross-sectional study in 312 stable patients on haemodialysis to analyse the inter-relation of AHSG and C-reactive protein (CRP) and their predictive effect on all-cause and cardiovascular mortality, over a period of 32 months. Subsequently, we tested the capacity of serum to inhibit CaxPO4 precipitation in patients on long-term dialysis (n=17) with apparent soft-tissue calcifications, and in those on short-term dialysis (n=8) without evidence of calcifications and cardiovascular disease. FINDINGS: AHSG concentrations in serum were significantly lower in patients on haemodialysis (mean 0.66 g/L [SD 0.28]) than in healthy controls (0.72 [0.19]). Low concentrations of the glycoprotein were associated with raised amounts of CRP and with enhanced cardiovascular (p=0.031) and all-cause mortality (p=0.0013). Sera from patients on long-term dialysis with low AHSG concentrations showed impaired ex-vivo capacity to inhibit CaxPO4 precipitation (mean IC50: 9.0 microL serum [SD 3.1] vs 7.5 [0.8] in short-term patients and 6.4 [2.6] in controls). Reconstitution of sera with purified AHSG returned this impairment to normal. Interpretation AHSG deficiency is associated with inflammation and links vascular calcification to mortality in patients on dialysis. Activated acute-phase response and AHSG deficiency might account for accelerated atherosclerosis in uraemia.
The process whose specific outcome is the progression of the skeleton over time, from its formation to the mature structure. The skeleton is the bony framework of the body in vertebrates (endoskeleton) or the hard outer envelope of insects (exoskeleton or dermoskeleton).
Eur. J. Endocrinol. 147, 243-248 (2002)[PubMed:12153747]
OBJECTIVE: Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes. DESIGN: One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study. METHODS: Serum AHSG was determined by radial immunodiffusion. RESULTS: We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns. CONCLUSION: AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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