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1.
Gut ; 67(6): 1135-1145, 2018 06.
Article in English | MEDLINE | ID: mdl-28428344

ABSTRACT

OBJECTIVE: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC. DESIGN: We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium. RESULTS: The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4ß7+lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine-which can be secreted by inflamed colonic epithelium and gut bacteria-was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. CONCLUSIONS: VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients.


Subject(s)
Amine Oxidase (Copper-Containing)/metabolism , Biomarkers/metabolism , Cell Adhesion Molecules/metabolism , Cholangitis, Sclerosing/metabolism , Liver/immunology , Cholangitis, Sclerosing/immunology , Cholangitis, Sclerosing/pathology , Enzyme-Linked Immunosorbent Assay , Humans , Immunity, Mucosal , Immunohistochemistry , Intestinal Mucosa/immunology , Liver/metabolism , Liver Transplantation , Lymphocytes , Real-Time Polymerase Chain Reaction
2.
J Nucl Med ; 54(8): 1315-9, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23847292

ABSTRACT

UNLABELLED: Vascular adhesion protein-1 (VAP-1) is an endothelial glycoprotein mediating leukocyte trafficking from blood to sites of inflammation. BTT-1023 is a fully human monoclonal anti-VAP-1 antibody developed to treat inflammatory diseases. In this study, we preclinically evaluated radioiodinated BTT-1023 for inflammation imaging. METHODS: Rabbits were intravenously injected with radioiodinated BTT-1023. Distribution and pharmacokinetics were assessed by PET/CT up to 72 h after injection. Human radiation dose estimates for (124)I-BTT-1023 were extrapolated. Additionally, rabbits with chemically induced synovitis were imaged with (123)I-BTT-1023 SPECT/CT. RESULTS: Radioiodinated BTT-1023 cleared rapidly from blood circulation and distributed to liver and thyroid. Inflamed joints were delineated by SPECT/CT. The estimated human effective dose due to (124)I-BTT-1023 was 0.55 mSv/MBq, if blockage of thyroid uptake is assumed. CONCLUSION: The radioiodinated BTT-1023 was able to detect mild inflammation in vivo. Clinical (124)I-BTT-1023 PET studies with injected radioactivity of 0.5-0.7 MBq/kg may be justified.


Subject(s)
Amine Oxidase (Copper-Containing)/metabolism , Antibodies, Monoclonal , Cell Adhesion Molecules/metabolism , Molecular Imaging/methods , Neovascularization, Pathologic/diagnostic imaging , Amine Oxidase (Copper-Containing)/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Cell Adhesion Molecules/immunology , Humans , Inflammation/diagnostic imaging , Inflammation/metabolism , Inflammation/physiopathology , Iodine Radioisotopes , Multimodal Imaging , Positron-Emission Tomography , Rabbits , Radiation Dosage , Tomography, X-Ray Computed
3.
Clin Chim Acta ; 404(2): 149-53, 2009 Jun 27.
Article in English | MEDLINE | ID: mdl-19336232

ABSTRACT

BACKGROUND: The relationship between serum vascular adhesion protein-1 (VAP-1) and plasma glucose in normal and drug-naïve type 2 diabetes subjects is unclear. We examined if serum VAP-1 changed acutely to oral glucose loading and analyzed the relationship between serum VAP-1, fasting plasma glucose (FPG), hemoglobin A1c, and type 2 diabetes. METHODS: Adults without history of diabetes were included. Subjects taking anti-diabetic drugs were excluded. Serum VAP-1 was analyzed by time-resolved immunofluorometric assay. RESULTS: We recruited 333 subjects (186 females and 147 males), aged 56.1 +/- 11.6 y. After glucose challenge, serum VAP-1 rose significantly at 30 min (p < 0.0001) and lasted until 2 h (p < 0.0001). The change of serum VAP-1 between fasting and 30-min postload correlated inversely to the change of plasma insulin (r = -0.21, p = 0.049). Fasting serum VAP-1 was associated with FPG in those with FPG > or = 5.55 mmol/l (p = 0.025) but not in those with FPG < 5.55 mmol/l (p = NS). Fasting serum VAP-1 were higher in diabetic subjects (p = 0.04) and correlated positively to hemoglobin A1c (r = 0.18, p = 0.002) after adjusting for age, gender, and waist circumference. CONCLUSIONS: Serum VAP-1 is increased in both acute and chronic hyperglycemia. Whether serum VAP-1 is a good biomarker for hyperglycemia-associated complications merits further investigation.


Subject(s)
Amine Oxidase (Copper-Containing)/blood , Cell Adhesion Molecules/blood , Diabetes Mellitus, Type 2/complications , Hyperglycemia/blood , Acute Disease , Aged , Biomarkers/blood , Blood Glucose/analysis , Chronic Disease , Fasting/blood , Female , Glucose/administration & dosage , Glycated Hemoglobin/analysis , Humans , Hyperglycemia/etiology , Male , Middle Aged
4.
Clin Chim Acta ; 403(1-2): 97-101, 2009 May.
Article in English | MEDLINE | ID: mdl-19361461

ABSTRACT

BACKGROUND: We investigated if serum vascular adhesion protein-1 (SSAO/VAP-1) changed acutely following oral glucose loading and whether such changes are correlated with surrogate markers of atherosclerosis. METHODS: A total of 115 non-diabetics subjects were enrolled for an oral glucose tolerance test (OGTT). Carotid intima-medial thickness (IMT) was measured by ultrasonography. Serum SSAO/VAP-1 was analyzed by time-resolved immunofluorometric assay. Serum thiobarbituric acid reactive substances (TBARS) and advanced glycated end products (AGEs) were measured by fluorometric assays. RESULTS: Serum SSAO/VAP-1 increased significantly at 30 min after oral glucose loading and lasted to 2 h (p=0.0005 and p<0.0001, for 30 min and 2 h respectively). The area under curve of serum SSAO/VAP-1 during OGTT (AUC-VAP-1) correlated significantly with carotid IMT, independent of age, gender, low-density lipoprotein cholesterol, systolic blood pressure, hemoglobin A1c, serum TBARS, AGEs, and high-sensitivity C-reactive protein. Subjects with a positive AUC-VAP-1 had significantly higher serum TBARS and AGEs than subjects with a negative AUC-VAP-1 adjusted for age and gender. CONCLUSIONS: Serum SSAO/VAP-1 changed acutely following oral glucose loading in non-diabetic subjects. Change of serum SSAO/VAP-1 correlated independently to serum TBARS, AGEs, and carotid IMT. Our findings suggest that acute change of serum SSAO/VAP-1 is a novel marker for hyperglycemia-induced atherosclerosis.


Subject(s)
Amine Oxidase (Copper-Containing)/blood , Carotid Arteries/pathology , Cell Adhesion Molecules/blood , Glucose/pharmacology , Tunica Intima/pathology , Amine Oxidase (Copper-Containing)/metabolism , Atherosclerosis/blood , Atherosclerosis/pathology , Cell Adhesion Molecules/metabolism , Diabetes Mellitus , Fasting , Female , Glycation End Products, Advanced , Humans , Male , Middle Aged
5.
Clin Biochem ; 41(16-17): 1362-7, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18644360

ABSTRACT

OBJECTIVES: An increased level of serum vascular adhesion protein-1 (VAP-1) has been found in patients with diabetes mellitus and vascular disorders. This study examined whether serum VAP-1 levels are associated with chronic kidney disease (CKD). DESIGN AND METHODS: We included 262 subjects aged 30 and above with fasting plasma glucose level <7 mmol/L checked within 1 year. First morning urine specimens were collected. Microalbuminuria was defined if urinary albumin-to-creatinine ratio > or =30 microg/mg creatinine. The glomerular filtration rate (GFR) was estimated. CKD stages were defined according to the suggestions of the National Kidney Foundation. Serum VAP-1 levels were analyzed by immunofluorometric assay. RESULTS: Serum VAP-1 levels were positively associated with the urinary albumin-to-creatinine ratio (r=0.29, p<0.0001) and negatively associated with estimated GFR (r=-0.24, p=0.0001). Subjects with CKD stage 2 (N=51) and stage 3 (N=91) had significantly higher levels of serum VAP-1 than those without CKD (p=0.0003 and p=0.035, adjusted for age and gender, respectively). A high serum VAP-1 level was associated with the presence of CKD (OR 1.63 for 1 SD increase of VAP-1, p=0.018), adjusting for age, sex, and smoking. Ordered logit models revealed that high serum VAP-1 levels correlated with advanced stages of CKD. CONCLUSIONS: Serum levels of VAP-1 are associated with the severity of kidney damage or stages of kidney disease. The true mechanism which links the serum VAP-1 and CKD remains to be elucidated in further studies.


Subject(s)
Amine Oxidase (Copper-Containing)/blood , Cell Adhesion Molecules/blood , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/pathology , Adult , Albuminuria/blood , Disease Progression , Female , Humans , Male , Middle Aged
6.
J Neuroimmunol ; 177(1-2): 132-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16806498

ABSTRACT

Vascular adhesion protein-1 (VAP-1) is an endothelial cell molecule which controls leukocyte infiltration into tissues. Elevated serum soluble VAP-1-levels have been described in certain diseases with an inflammatory component. VAP-1 expression or function has not previously been studied in multiple sclerosis (MS). We report here that the concentration of soluble VAP-1 in serum is significantly higher in multiple sclerosis patients with ongoing inflammatory activity, as demonstrated by gadolinium-enhancing MRI lesions, when compared to patients with no gadolinium-enhancing lesions (555+/-195 vs. 388+/-102 ng/ml, p=0.0068). We propose that VAP-1 might participate in controlling leukocyte entry into inflamed brain.


Subject(s)
Amine Oxidase (Copper-Containing)/blood , Amine Oxidase (Copper-Containing)/immunology , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/immunology , Chemotaxis, Leukocyte/immunology , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/immunology , Adult , Aged , Blood-Brain Barrier/physiopathology , Cell Adhesion/immunology , Central Nervous System/immunology , Central Nervous System/pathology , Central Nervous System/physiopathology , Endothelial Cells/immunology , Female , Gadolinium , Humans , Leukocytes/immunology , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Predictive Value of Tests , Up-Regulation/immunology
7.
J Agric Food Chem ; 50(23): 6659-62, 2002 Nov 06.
Article in English | MEDLINE | ID: mdl-12405757

ABSTRACT

A rapid and simple immunochemical method was developed for the assessment of the creatine kinase (MM) isoenzyme [CK(MM)], a protein marker linked with animal welfare and meat quality. The one-step time-resolved immunofluorometric assay produced quantitative results from serum or whole blood samples in 20 min. The analytical limit of detection (mean + 2s) for the immunoassay was 17 ng/mL (n = 6), and the functional limit of detection for the analysis of porcine whole blood samples was 426 ng/mL (n = 24). The working range of the method was linear up to 50 micro g/mL, and the within-assay precision varied between 2.1 and 10.9%. The analysis of porcine serum samples showed that the results from the immunoassay method and colorimetric CK enzyme activity determination were highly correlated (r(2) = 0.965, n = 17, p < 0.001). The practicability of the assay was demonstrated by the analysis of 300 porcine whole blood samples in a slaughterhouse environment.


Subject(s)
Creatine Kinase/blood , Fluoroimmunoassay , Isoenzymes/blood , Animals , Biotinylation , Colorimetry , Creatine Kinase, MM Form , Electrophoresis, Polyacrylamide Gel , Meat , Muscle, Skeletal/enzymology , Quality Control , Swine/blood
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