15 research outputs found
Influence of gem-Dimethyl Substitution on the Stability, Kinetics and Relaxometric Properties of PDTA Complexes
Preliminary studies of the effects of vascular adhesion protein-1 inhibitors on experimental corneal neovascularization
Vascular adhesion protein-1 (VAP-1) controls
the adhesion of lymphocytes to endothelial cells and is
upregulated at sites of inflammation. Moreover, it expresses
amine oxidase activity, due to the sequence identity
with semicarbazide-sensitive amine oxidase. Recent
studies indicate a significant role for VAP-1 in neovascularization,
besides its contribution to inflammation. Pathological
blood vessel development in severe ocular diseases
(such as diabetes, age-related macula degeneration, trauma
and infections) might lead to decreased visual acuity and
finally to blindness, yet there is no clear consensus as to its
appropriate treatment. In the present case study, the effects
of two VAP-1 inhibitors on experimentally induced corneal
neovascularization in rabbits were compared with the
effects of a known inhibitor of angiogenesis, bevacizumab,
an anti-vascular endothelial growth factor antibody.
In accordance with recent literature data, the results of
the preliminary study reported here indicate that the
administration of VAP-1 inhibitors is a potentially valuable
therapeutic option in the treatment of corneal neovascularizatio
Identification of a blaVIM-4 gene in the internationally successful Klebsiella pneumoniae ST11 clone and in a Klebsiella oxytoca strain in Hungary
A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects
The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope that is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is disease-specific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits
Aryl-phosphonate lanthanide complexes and their fluorinated derivatives: investigation of their unusual relaxometric behaviour and potential application as dual frequency 1H/19F MRI probe
Calcium plays a vital role in
the human body and especially in the central nervous system. Precise maintenance of Ca2+ levels is very crucial for
normal cell physiology and health. The deregulation of calcium homeostasis can lead to neuronal cell death and
brain damage. To study this functional role played by Ca2+ in the brain noninvasively
by using magnetic resonance
imaging, we have synthesized a new set of Ca2+-sensitive smart contrast agents (CAs). The agents were found to be
highly selective to Ca2+ in the presence of other competitive anions and cations
in buffer and in physiological fluids. The structure of CAs comprises Gd3+-DO3A (DO3A=1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane)
coupled to a Ca2+ chelator
o-amino phenol-N,N,O-triacetate (APTRA). The agents are designed to sense Ca2+ present in extracellular
fluid of the brain where its concentration is relatively high, that is, 1.2\u20130.8 mm. The determined dissociation
constant of the CAs to Ca2+ falls in the range required to sense and report changes in extracellular Ca2+ levels followed by an increase in neural activity. In buffer, with the addition of Ca2+ the
increase in relaxivity ranged from 100\u2013157%, the highest ever known for any T1-based Ca2+-sensitive smart CA. The
CAs were analyzed extensively by the measurement of luminescence lifetime
measurement on Tb3+ analogues, nuclear magnetic relaxation dispersion (NMRD), and 17O NMR transverse relaxation and shift experiments. The results
obtained confirmed that the large relaxivity enhancement observed upon Ca2+ addition is due to the increase of the hydration state of the complexes together with the slowing down of the molecular rotation and the retention of
a significant contribution of the water molecules of the second sphere of hydration
Lanthanide complexes of Tris-3,4-HOPO as potential imaging probes: complex stability, magnetic and Vis/NIR luminescence properties"
There is a growing interest on the development of new medical diagnostic tools with higher sensibility and less damage for the patient body, namely on imaging reporters for the management of diseases and optimization of treatment strategies. This article examines the properties of a new class of lanthanide complexes with a tripodal tris-3-hydroxy-4-pyridinone (Tris-3,4-HOPO) ligand - NTP(PrHP)3. Among the studies herein performed, a major relevance is given to the thermodynamic stability of the complexes with a series of Ln3+ ions (Ln = La, Pr, Gd, Er, Lu) and to the magnetic relaxation properties of the Gd3+ complex. This hexadentate ligand enables the formation of 1:1 Ln3+ complexes with high thermodynamic stability following the usual trend, while the Gd-chelates show improved relaxivity (higher hydration number), as compared with commercially available Gd-based contrast agents (CAs); transmetallation of the Gd3+-L complex with Zn2+ proved to be thermodynamically and kinetically disfavored. Therefore, NTP(PrHP)3 emerges as part of a recently proposed new generation of CAs with prospective imaging sensitivity gains
A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects
The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope that is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is disease-specific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits
New tris-3,4-HOPO lanthanide complexes as potential imaging probes: complex stability and magnetic properties
There is a growing interest in the development of new medical diagnostic tools with higher sensibility
and less damage for the patient body, namely on imaging reporters for the management of diseases and
optimization of treatment strategies. This article examines the properties of a new class of lanthanide
complexes with a tripodal tris-3-hydroxy-4-pyridinone (tris-3,4-HOPO) ligand \u2013 NTP(PrHP)3. Among the
studies herein performed, major relevance is given to the thermodynamic stability of the complexes with
a series of Ln3+ ions (Ln = La, Pr, Gd, Er, Lu) and to the magnetic relaxation properties of the Gd3+ complex.
This hexadentate ligand enables the formation of (1 : 1) Ln3+ complexes with high thermodynamic stability
following the usual trend, while the Gd-chelates show improved relaxivity (higher hydration number), as
compared with the commercially available Gd-based contrast agents (CAs); transmetallation of the Gd3+\u2013L
complex with Zn2+ proved to be thermodynamically and kinetically disfavored. Therefore, NTP(PrHP)3
emerges as part of a recently proposed new generation of CAs with prospective imaging sensibility gains
Autoantibodies Against the Exocrine Pancreas in Autoimmune Pancreatitis: Gene and Protein Expression Profiling and Immunoassays Identify Pancreatic Enzymes as a Major Target of the Inflammatory Process
OBJECTIVES:Autoimmune pancreatitis (AIP) is thought to be an immune-mediated inflammatory process, directed against the epithelial components of the pancreas. The objective was to identify novel markers of disease and to unravel the pathogenesis of AIP.METHODS:To explore key targets of the inflammatory process, we analyzed the expression of proteins at the RNA and protein level using genomics and proteomics, immunohistochemistry, western blot, and immunoassay. An animal model of AIP with LP-BM5 murine leukemia virus-infected mice was studied in parallel. RNA microarrays of pancreatic tissue from 12 patients with AIP were compared with those of 8 patients with non-AIP chronic pancreatitis.RESULTS:Expression profiling showed 272 upregulated genes, including those encoding for immunoglobulins, chemokines and their receptors, and 86 downregulated genes, including those for pancreatic proteases such as three trypsinogen isoforms. Protein profiling showed that the expression of trypsinogens and other pancreatic enzymes was greatly reduced. Immunohistochemistry showed a near-loss of trypsin-positive acinar cells, which was also confirmed by western blotting. The serum of AIP patients contained high titers of autoantibodies against the trypsinogens PRSS1 and PRSS2 but not against PRSS3. In addition, there were autoantibodies against the trypsin inhibitor PSTI (the product of the SPINK1 gene). In the pancreas of AIP animals, we found similar protein patterns and a reduction in trypsinogen.CONCLUSIONS:These data indicate that the immune-mediated process characterizing AIP involves pancreatic acinar cells and their secretory enzymes such as trypsin isoforms. Demonstration of trypsinogen autoantibodies may be helpful for the diagnosis of AIP.Am J Gastroenterol advance online publication, 20 April 2010; doi:10.1038/ajg.2010.141