Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe in this study a reliable method for the breeding of the Watanabe heritable hyperlipidemic (WHHL) rabbit. Placing a male and a female WHHL rabbit in the same cage for the purpose of mating resulted in only two pregnancies out of a total of 227 mating attempts (0.9%). After manually assisting the rabbits, 15% of the matings resulted in pregnancies. When the female rabbits were injected with 40 I.U. of human chorionic gonadotropin within 1 hr of this procedure, 56% of the matings resulting in pregnancies. We feel that the inherent difficulty in breeding the WHHL rabbit, a model for the disease familial hypercholesterolemia, can be significantly overcome by the methods discussed in this report.
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PMID:Notes on the breeding of the WHHL rabbit: an animal model of familial hypercholesterolemia. 403 57

The fifth ligand binding repeat (LR5) of the low density lipoprotein (LDL) receptor was assessed ex vivo as an 'analytical reagent' to distinguish LDL state, in atherosclerosis risk monitoring. LR5 was immobilized to mercaptoundecanoic acid modified gold surfaces via a glycine linker. Surface plasmon resonance (SPR) was used to monitor LDL binding. Unfolded LR5 was ineffectual as an affinity ligand for LDL but refolded LR5 showed a high affinity for native LDL but little affinity for oxidized LDL. LR5 refolded in the presence of calcium or EDTA gave the equivalent LDL binding capacity. However, EDTA-LR5 was less stable than Ca-LR5 at pH 5 and, from tryptophan fluorescence evidence, they appeared to involve different regions of LR5 and/or LDL in the binding. Involvement of amino acid residues of the calcium cage of LR5 was tested in LDL binding by monitoring calcium ion release with a calcium ionophore. The results were consistent with approximately 7-8 LR5 binding per LDL, of which only some induce calcium release (a maximum of approximately 25 mol% calcium, based on LR5, was released during LDL binding). For LDL binding to the LDL receptor in vivo more than one ligand-binding repeat is needed and this may be consistent with LR5 acting here also at binding sites which other LRs normally occupy in the LDL-LDL receptor complex. This initial study is encouraging for the use of a minimum peptide repeat array based on the conserved region of the LRs as an affinity surface for atherosclerosis risk monitoring.
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PMID:Assessment of the fifth ligand-binding repeat (LR5) of the LDL receptor as an analytical reagent for LDL binding. 1128 34

We report that a lipoprotein-based nanoplatform generated by conjugating tumor-homing molecules to the protein components of naturally occurring lipoproteins reroutes them from their normal lipoprotein receptors to other selected cancer-associated receptors. Multiple copies of these targeting moieties may be attached to the same nanoparticle, or a variety of different targeting moieties can be attached. Such a diverse set of tumor-homing molecules could be used to create a variety of conjugated lipoproteins as multifunctional, biocompatible nanoplatforms with a broad application to both cancer imaging and treatment. The same principle can be applied to imaging and treatment of other diseases and for monitoring specific tissues. To validate this concept, we prepared a low-density lipoprotein (LDL)-based folate receptor (FR)-targeted agent by conjugating folic acid to the Lys residues of the apolipoprotein B (apoB)-100 protein. To demonstrate the ability of the lipoprotein-based nanoplatform to deliver surface-loaded and core-loaded payloads, the particles were labeled either with the optical reporter 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine that was intercalated in the phospholipid monolayer or with the lipophilic photodynamic therapy agent, tetra-t-butyl-silicon phthalocyanine bisoleate, that was reconstituted into the lipid core. Cellular localization of the labeled LDL was monitored by confocal microscopy and flow cytometry in FR-overexpressing KB cells, in FR-nonexpressing CHO and HT-1080 cells, and in LDL receptor-overexpressing HepG2 cells. These studies demonstrate that the folic acid conjugation to the Lys side-chain amino groups blocks binding to the normal LDL receptor and reroutes the resulting conjugate to cancer cells through their FRs.
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PMID:Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. 1630 63

Ezetimibe blocks intestinal absorption of sterols via interaction with the Neimann-Pick C1-Like 1 (NPC1L1) transporter and is approved for use in the treatment of primary hyperlipidemia (heterozygous familial and non-familial), homozygous familial hypercholesterolemia, and homozygous sitosterolemia. A recently completed randomized clinical trial [simvastatin and ezetimibe in aortic stenosis (SEAS)] testing the effectiveness of Vytorin (a combination of simvastatin and ezetimibe) in patients with aortic stenosis reported an unexpected safety finding: an increase in overall cancer incidence and cancer-associated mortality (all types) in the treated groups relative to the placebo control. A subsequent meta-analysis utilizing a much larger database from two ongoing clinical trials indicated that the observed findings in the SEAS trial were likely due to chance and not a true drug-induced effect. Nonetheless, it has been suggested by various commentators on the SEAS trial that ezetimibe may be carcinogenic. The extensive nonclinical database for ezetimibe was used to test the hypothesis that ezetimibe may be a direct or indirect carcinogen. Using two different in silico approaches, ezetimibe showed no structural alerts for genetic toxicity or carcinogenicity. Ezetimibe was not genotoxic in two reverse mutation assays, one in vitro clastogenicity assay, and two mouse micronucleus assays. No evidence of proliferative lesions was observed in three species in studies of 1-12 months in duration. Ezetimibe was not carcinogenic in standard 2-year bioassays in mice and rats. Additionally, in these 2-year bioassays, no drug-related non-neoplastic lesions were noted. The absence of drug-induced non-neoplastic or proliferative lesions in these studies indicates that ezetimibe treatment was not associated with findings characteristic of carcinogens (i.e., DNA reactivity or cell proliferation) Administration of pharmacologic doses of ezetimibe to mice did not alter hepatic expression patterns of genes associated with apoptosis, cell proliferation, or epithelial-mesenchymal transition. No evidence of drug-induced tumors was observed in mice in which the molecular target of ezetimibe (NPC 1L1) was knocked out over the life span of the animal. In conclusion, the nonclinical data do not support the proposed hypothesis based on the single observation from the SEAS trial and, rather, support the conclusion that ezetimibe does not represent a carcinogenic hazard to humans using this drug in a therapeutic setting.
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PMID:An assessment of the carcinogenic potential of ezetimibe using nonclinical data in a weight-of-evidence approach. 1942 31

The ligand binding domain of the LDL receptor (LDLR) contains seven structurally homologous repeats. The fifth repeat (LR5) is considered to be the main module responsible for the binding of lipoproteins LDL and beta-VLDL. LR5, like the other homologous repeats, is around 40-residue long and contains three disulfide bonds and a conserved cluster of negatively charged residues surrounding a hexacoordinated calcium ion. The calcium coordinating cage is formed by the backbone oxygens of W193 and D198, and side-chain atoms of D196, D200, D206, and E207. The functionality of LDLR is closely associated with the presence of calcium. Magnesium ions are to some extent similar to calcium ions. However, they appear to be involved in different physiological events and their concentrations in extracellular and intracellular compartments are regulated by different mechanisms. Whether magnesium ions can play a role in the complex cycle of LDLR internalization and recycling is not known. We report here a detailed study of the interaction between LR5 and these two cations combining ITC, emission fluorescence, high resolution NMR, and MD simulations, at extracellular and endosomal pHs. Our results indicate that the conformational stability and internal dynamics of LR5 are strongly modulated by the specific bound cation. It appears that the difference in binding affinity for these cations is somewhat compensated by their different concentrations in late LDL-associated endosomes. While the mildly acidic and calcium-depleted environment in late endosomes has been proposed to contribute significantly to LDL release, the presence of magnesium might assist in efficient LDLR recycling. Proteins 2010. (c) 2009 Wiley-Liss, Inc.
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PMID:Thermodynamics of protein-cation interaction: Ca(+2) and Mg(+2) binding to the fifth binding module of the LDL receptor. 1989 71