Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At present, infrasound (0-20 Hz) and low-frequency noise (20-500 Hz) (ILFN, 0-500 Hz) are agents of disease that go unchecked. Vibroacoustic disease (VAD) is a whole-body pathology that develops in individuals excessively exposed to ILFN. VAD has been diagnosed within several professional groups employed within the aeronautical industry, and in other heavy industries. However, given the ubiquitous nature of ILFN and the absence of legislation concerning ILFN, VAD is increasingly being diagnosed among members of the general population, including children. VAD is associated with the abnormal growth of extra-cellular matrices (collagen and elastin), in the absence of an inflammatory process. In VAD, the end-product of collagen and elastin growth is reinforcement of structural integrity. This is seen in blood vessels, cardiac structures, trachea, lung, and kidney of both VAD patients and ILFN-exposed animals. VAD is, essentially, a mechanotransduction disease. Inter- and intra-cellular communication is achieved through both biochemical and mechanotranduction signalling. When the structural components of tissue are altered, as is seen in ILFN-exposed specimens, the mechanically mediated signalling is, at best, impaired. Common medical diagnostic tests, such as EKG, EEG, as well as many blood chemistry analyses, are based on the mal-function of biochemical signalling processes. VAD patients typically present normal values for these tests. However, when echocardiography, brain MRI or histological studies are performed, where structural changes can be identified, all consistently show significant changes in VAD patients and ILFN-exposed animals. Frequency-specific effects are not yet known, valid dose-responses have been difficult to identify, and large-scale epidemiological studies are still lacking.
Prog Biophys Mol Biol
PMID:Vibroacoustic disease: biological effects of infrasound and low-frequency noise explained by mechanotransduction cellular signalling. 1693 59

The ferroportin-related disorder is an increasingly recognized cause of hereditary iron overload. Based on the in vitro behavior of different ferroportin mutant subsets, it was suggested that different forms of the disorder might exist in humans. We used MRI to address this question in vivo in 22 patients from four different pedigrees carrying different ferroportin mutations: A77D, N144H, G80S and Val 162del. We found that, based on the iron status of spleen and bone macrophages, two different forms of the disease can be identified: a classic, common form, characterized by hepatocyte, splenic macrophage and bone marrow macrophage iron retention in patients carrying the A77D, G80S and Val 162del ferroportin variants; a rarer non-classic form, associated with liver iron overload but normal spleen and bone marrow iron content in patients with the N144H mutation. The two forms are likely caused by lack- or gain-of-protein function, respectively. Interestingly, in treated patients with the classic form, the spleen and the spine show appreciable iron accumulation even when serum ferritin is normal and liver iron content low. In conclusion, MRI is a useful non-invasive diagnostic tool to categorize and diagnose the disorder, monitor the status of iron depletion and gain insights on its natural history and management.
Blood Cells Mol Dis
PMID:Magnetic resonance imaging to identify classic and nonclassic forms of ferroportin disease. 1705 26

A high-molecular weight tetrametallic supramolecular complex [(Ln-DTPA-phen)3Fe]- (Ln = Gd, Eu, La) has been obtained upon self-assembly around one iron(II) ion of three 1,10-phenantroline-based molecules substituted in 5'-position with the polyaminocarboxylate diethylenetriamine-N,N,N',N',N'-pentaacetate, DTPA-phen(4-). The ICP-MS measurements indicated that the lanthanide:iron ratio is 3:1. Photoluminescence spectra of [Eu-DTPA-phen](-) and of [(Eu-DTPA-phen)3Fe]- are nearly identical, implying that the first coordination sphere of the lanthanide(III) ion has not been changed upon coordination of phenantroline unit to iron(II) ion. NMRD measurements revealed that at 20 MHz and 310 K the relaxivity of the [(Gd-DTPA-phen)3Fe]- is equal to 9.5 +/- 0.3 s(-1) mM(-1) of Gd (28.5 s(-1) per millimole per liter of complex) which is significantly higher than that for Gd-DTPA (3.9 s(-1) mM(-1)). The pharmacokinetic parameters of [(Gd-DTPA-phen)3Fe]- in rats indicate that the elimination of [(Gd-DTPA-phen)3Fe]- is significantly slower than that of Gd-DTPA and is correlated with a reduced volume of distribution. The low volume of distribution and the longer elimination time (T(e1/2)) suggest that the agent is confined to the blood compartment, so it could have an important potential as a blood pool contrast agent. The biodistribution profile of [(Gd-DTPA-phen)3Fe]- 2 h after injection indicates significantly higher concentrations of [(Gd-DTPA-phen)3Fe]- as compared with Gd-DTPA in kidney, liver, lungs, heart and spleen. The images obtained on rats by MR angiography show the enhancement of the abdominal blood vessels. The signal intensity reaches a maximum of 55% at 7 min post-contrast and remains around 25% after 90 min. MRI-histomorphological correlation studies of [Gd-DTPA-phen]- and [(Gd-DTPA-phen)3Fe]- showed that both agents displayed potent contrast enhancement in organs including the liver. The necrosis avidity tests indicated that, in contrast to the [Gd-DTPA-phen](-) precursor complex, the supramolecular complex [(Gd-DTPA-phen)3Fe]- exhibits necrosis avidity.
Contrast Media Mol Imaging
PMID:Pharmacokinetic and in vivo evaluation of a self-assembled gadolinium(III)-iron(II) contrast agent with high relaxivity. 1719 67

The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [(153)Sm](3+) or Gd(3+) complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled [(153)Sm]-DOTAGal(2) by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50% by the presence of its high-affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmacokinetic studies on Wistar rats using the [(153)Sm](3+)-labeled glycoconjugates show a high uptake in the receptor-rich organ liver of the radiolabeled compounds containing terminal galactosyl groups, but very little uptake for those compounds with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd(3+) chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. This probably results from the quick wash-out from the liver of these highly hydrophilic complexes, before they can be sufficiently concentrated within the hepatocytes via receptor-mediated endocytosis.
Contrast Media Mol Imaging
PMID:Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies. 1719 65

{Fe[Gd(2)bpy(DTTA)(2)(H(2)O)(4)](3)}(4-) is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd(3+) centres confined into a small molecular space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r(1) = 15.8 mM(-1) s(-1) at 200 MHz, 37 degrees C, in H(2)O). Here we report the first in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched compound. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small molecular weight contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H(2)O)](-) = GdDOTA). The metallostar was well tolerated by the animals at the concentrations of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg(-1) body weight; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg(-1) BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T(1)), as calculated from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate molecular weight, the metallostar does not function as a blood pool agent. The dynamic gamma scintigraphic studies performed in Wistar rats with the metallostar compound having (153)Sm enrichment also proved the renal elimination pathway. The biodistribution experiments are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.
Contrast Media Mol Imaging
PMID:First in vivo MRI assessment of a self-assembled metallostar compound endowed with a remarkable high field relaxivity. 1719 98

One of the attractions of molecular imaging using 'smart' bioactive contrast agents is the ability to provide non-invasive data on the spatial and temporal changes in the distribution and expression patterns of specific enzymes. The tools developed for that aim could potentially also be developed for functional imaging of enzyme activity itself, through quantitative analysis of the rapid dynamics of enzymatic conversion of these contrast agents. High molecular weight hyaluronan, the natural substrate of hyaluronidase, is a major antiangiogenic constituent of the extracellular matrix. Degradation by hyaluronidase yields low molecular weight fragments, which are proangiogenic. A novel contrast material, HA-GdDTPA-beads, was designed to provide a substrate analog of hyaluronidase in which relaxivity changes are induced by enzymatic degradation. We show here a first-order kinetic analysis of the time-dependent increase in R(2) as a result of hyaluronidase activity. The changes in R(2) and the measured relaxivity of intact HA-GdDTPA-beads (r(2B)) and HA-GdDTPA fragments (r(2D)) were utilized for derivation of the temporal drop in concentration of GdDTPA in HA-GdDTPA-beads as the consequence of the release of HA-GdDTPA fragments. The rate of dissociation of HA-GdDTPA from the beads showed typical bell-shaped temperature dependence between 7 and 36 degrees C with peak activity at 25 degrees C. The tools developed here for quantitative dynamic analysis of hyaluronidase activity by MRI would allow the use of activation of HA-GdDTPA-beads for the determination of the role of hyaluronidase in altering the angiogenic microenvironment of tumor micro metastases.
Contrast Media Mol Imaging
PMID:Kinetic analysis of hyaluronidase activity using a bioactive MRI contrast agent. 1719 86

A constrained derivative of Gd-PCTA12, Gd-cyclo-PCTA12, in which one ethylene bridge connecting two nitrogen atoms of the triamine block is replaced by a cyclohexylene bridge, was synthesized and the impact of rigidification was studied by comparing the physicochemical and relaxometric properties of both gadolinium MRI contrast agents, Gd-PCTA12 and Gd-cyclo-PCTA12. The new complex has higher proton relaxivity than the parent compound (r(1) = 6.1 s(-1) mM(-1) at 20 MHz and 310 K). The rigidification of the PCTA12 scaffold proved to have no impact on the inertness towards transmetallation by endogenous ions such as Zn(2+). Moreover, for both contrast agents, the relaxivity was not quenched by endogenous anions. The oxygen-17 NMR study and the NMRD profile demonstrated that the rigidification of the PCTA scaffold had no impact on the electronic relaxation of Gd-cyclo-PCTA12. However, the rigidity of this complex induced an acceleration of the exchange rate of the inner-sphere water molecules as a result of steric crowding around the gadolinium ion. The value of tau(M) (310) thus approached the optimal value required to attain high relaxivity once the chelate is immobilized by covalent or non-covalent binding to macromolecules.
Contrast Media Mol Imaging
PMID:Impact of rigidification on relaxometric properties of a tricyclic tetraazatriacetic gadolinium chelate. 1719 88

The rationale and objectives were to define the MRI tumor-characterizing potential of a new protein-avid contrast agent, Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg(-1), was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), 45-250 mg kg(-1). These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two-compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K(PS)) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff-Bloom-Richardson score) and location of necrosis. Eighteen tumor-bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K(PS) and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K(PS) and fEV* but not fPV were significantly lower in a group consisting of benign and low-grade malignant tumors compared with the group of less-differentiated high-grade tumors (1.61 +/- 0.64 vs 3.37 +/- 1.49, p < 0.01; 0.45 +/- 0.17 vs 0.78 +/- 0.24, p < 0.01; and 0.076 +/- 0.048 vs 0.121 +/- 0.088, p = 0.24, respectively). It is concluded that the protein-avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low-grade malignant lesions from high-grade cancers.
Contrast Media Mol Imaging
PMID:MRI tumor characterization using Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M), a protein-avid contrast agent. 1719 87

Recent studies have shown that cell migration can be monitored in vivo by magnetic resonance imaging after intracellular contrast agent incorporation. This is due to the dephasing effect on proton magnetization of the local magnetic field created by a labelled cell. Anionic iron oxide nanoparticles (AMNP) are among the most efficient and non-toxic contrast agents to be spontaneously taken up by a wide variety of cells. Here we measured the iron load and magnetization of HeLa tumour cells labelled with AMNP, as a function of the external magnetic field. High-resolution gradient echo 9.4 T MRI detected individual labelled cells, whereas spin echo sequences were poorly sensitive. We then conducted a systematic study in order to determine the gradient echo sequence parameters (echo time, cell magnetization and resolution) most suitable for in vivo identification of single cells.
Contrast Media Mol Imaging
PMID:Single-cell detection by gradient echo 9.4 T MRI: a parametric study. 1719 93

The production of disease-targeted agents requires the covalent conjugation of a targeting molecule with a contrast agent or therapeutic, followed by purification of the product to homogeneity. Typical targeting molecules, such as small molecules and peptides, often have high charge-to-mass ratios and/or hydrophobicity. Contrast agents and therapeutics themselves are also diverse, and include lanthanide chelates for MRI, (99m)Tc chelates for SPECT, (90)Y chelates for radiotherapy, (18)F derivatives for PET, and heptamethine indocyanines for near-infrared fluorescent optical imaging. We have constructed a general-purpose HPLC/mass spectrometry platform capable of purifying virtually any targeted agent for any modality. The analytical sub-system is composed of a single dual-head pump that directs mobile phase to either a hot cell for the purification of radioactive agents or to an ES-TOF MS for the purification of nonradioactive agents. Nonradioactive agents are also monitored during purification by ELSD, absorbance and fluorescence. The preparative sub-system is composed of columns and procedures that permit rapid scaling from the analytical system. To demonstrate the platform's utility, we describe the preparation of five small molecule derivatives specific for prostate-specific membrane antigen (PSMA): a gadolinium derivative for MRI, indium, rhenium and technetium derivatives for SPECT, and an yttrium derivative for radiotherapy. All five compounds are derived from a highly anionic targeting ligand engineered to have a single nucleophile for N-hydroxysuccinimide-based conjugation. We also describe optimized column/mobile phase combinations and mass spectrometry settings for each class of agent, and discuss strategies for purifying molecules with extreme charge and/or hydrophobicity. Taken together, our study should expedite the development of disease-targeted, multimodality diagnostic and therapeutic agents.
Contrast Media Mol Imaging
PMID:An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate-specific membrane antigen small molecule derivatives. 1719 97


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