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)

The development of theories of water structure has been hindered in the past by the difficulty of experimental measurement. Both measurement and computer modelling studies have now reached the stage where theoretical treatments of water structure are converging to a broadly acceptable model. In current understanding, water is a mixture of randomly hydrogen-bonded molecules and larger structures comprised of tetrahedral oxygen centres which, when hydrogen-bonded to each other, lead to five-membered and other rings which can aggregate to form three-dimensional structures. Evidence is taken from studies of the ices, from clathrates and other solid solutions, as well as from liquid solutions, that certain motifs occur very frequently and have relatively high stability, such as the (H2O)20 cavity-forming structure known from studies on clathrates. The implications of recent models of water structure for an understanding of biological events, including the interactions of drugs with receptors, are profound. It is becoming clear that modelling of aqueous solutions of any molecule must consider the explicit interactions with water molecules, which should not be regarded as a continuum: water itself is not a continuum. Solute molecules which possess hydrogen-bonding groups will provoke the formation of further hydrogen-bonding chains of water molecules: if these can form rings, such ringswilltend to persist longerthan chains, givingthesolute a secondary identity of associated water which may play a role in molecular recognition. Solutes that do not have hydrogen-bonding capability, or regions of solutes which are non-polar, may also produce partial cage-like water structures that are characteristic of the solute. The classification of many solutes as structure makers or structure breakers has relevance to the interactions between ligands and large biomolecules such as proteins. While it is generally accepted that sulfate and urea, respectively structure maker and breaker, may alter protein conformation through effects on water, it has not been recognised that bioactive ligands, which also change the conformation of proteins, may do so by a related, but more selective, mechanism. Very early studies of cell contents suggested that the associated water might be different from bulk water, a concept that lost support in the mid-20th century. Current theories of water structure may invite a reappraisal of this position, given the observation that structuring may extend for many molecular diameters from an ordered surface.
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PMID:Water structure theory and some implications for drug design. 1235 70

Forty-eight Wistar rats were treated for 3 weeks with water containing 0.7% ethylene-glycol and divided into four groups. The first group, used as control, has received sodium chloride at 1 ml/100 g BW daily. The second group was intraperitoneally injected with selenium at 10 micrograms/d per 100 g BW as NaSeO3 for 3 weeks. The third group was intraperitoneally administered with 15 mg Vit E/d per 100 g BW as alpha-tocopherol acetate for 3 weeks. The last group was simultaneously administered vitamin E and Se at the same doses and periods as the precedent groups. One day before the end of the treatment, each animal was placed in a metabolic cage for collection of 24 h urine samples and determination of urinary creatinin, urea, calcium, magnesium, phosphate and oxalate levels. Immediately thereafter, all the rats were anesthetized and aortic blood was collected to determine the same parameters as in urine. The kidneys were also removed to determine calcium oxalate deposits, dry weight and to conduct a histological examination. Our results showed decreased ionic product and increased magnesium fractional reabsorption in the group receiving only selenium and in the group receiving selenium in combination with vitamin E, in comparison with the control animals. In view of the knowledge concerning the same protective action of Vit E and selenium, regardless of tubular membrane alteration, the absence of any inhibitory effect of Vit E on calcium oxalate formation suggests that selenium, like other minerals, could be stuck onto the crystal surface and would inhibit induction of new crystals, growth and aggregation.
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PMID:Effects of intraperitoneally administered vitamin E and selenium on calcium oxalate renal stone formation: experimental study in rat. 1274 Nov 89

Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.
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PMID:Acute nephrotoxicity of aristolochic acids in mice. 1500 81

In conclusion, we have discussed a reverse genetics approach to studying seizure disorders in mice (Fig. 1), employing a targeted mutagenesis method to exploit the genetic defects identified in human epilepsy families. After detailed characterization of the nature of the human mutation and the mouse counterpart gene, a targeting vector containing the human disease allele is created. The endogenous mouse gene is replaced by the human disease allele through homologous recombination in ES cells, leading to the generation of chimeric animals. Mice carrying one copy or both copies of the human mutation can be bred to study the phenotypic effect of heterozygous and homozygous mutations. At this stage, one may want to split the newly created mice into two groups. One group will go through seizure phenotyping tests, while the other group will be used to generate disease allele-carrying mice on a different genetic background. Phenotypic characterization of mice on different inbred strains includes behavioral monitoring and EEG analysis looking for the occurrence of spontaneous seizures, as well as routine cage examination looking for handling-provoked seizure and ECT- and PTZ- induced seizure paradigms looking for sensitivity to these stimuli. A complete evaluation of the seizure phenotype at the whole-animal level establishes the relevance of the mouse model to the human condition. Further investigation including imaging, electrophysiology and AED response in these mouse models will shed light on the mechanistic basis of the convulsive disorder. Current epilepsy research in mouse genetics offers promise for understanding the molecular mechanisms that underlie epileptogenesis in humans. A large-scale forward genetic effort to create novel mouse mutants with seizure phenotypes by in vivo chemical mutagenesis with ethyl-nitroso urea (ENU) is underway at the Jackson Laboratory (http://www.jax.org/nmf/). Genetic mapping and isolation of the affected genes in these seizure-prone models will provide additional molecular pathways involved in seizures. The mutant mice generated through both forward and reverse genetic approaches will be a valuable resource for the biomedical community to study epilepsy at the molecular level and to characterize the pathological consequences of seizures in the whole organism.
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PMID:Genetic approaches to studying mouse models of human seizure disorders. 1525 May 82

The fruit of Indian Eugenia jambolana have been shown to have therapeutic properties, but because the therapeutic potential of a plant is related to the geographic region in which the plant was grown and to the part of the plant used, we investigated Brazilian Eugenia jambolana fruit using the same preparation and experimental methods as have been used in India. The well-established metabolic cage model was used to evaluate the physiological and metabolic parameters associated with streptozotocin-induced diabetes in rats (n=10) which had been administered, by gavage, 50 mg per day of lyophilised Eugenia jambolana fruit-pulp extract for 41 days. We found that, compared to untreated controls, rats treated with the lyophilised fruit-pulp showed no observable difference in body weight, food or water intake, urine volume, glycaemia, urinary urea and glucose, hepatic glycogen, or on serum levels of total cholesterol, HDL cholesterol or triglycerides. No change was observed in the masses of epididymal or retroperitoneal adipose tissue or of soleus or extensor digitorum longus muscles. This lack of any apparent effect on the diabetes may be attributable to the regional ecosystem where the fruit was collected and/or to the severity of the induced diabetes.
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PMID:Fruit of the jambolan tree (Eugenia jambolana Lam.) and experimental diabetes. 1558 49

The aim of this study was to determine whether protein, administered alone or simultaneously with a hypercalcic diet, was able to aggravate calcium oxalate stone formation in rats. Thirty-two male Wistar rats were randomly divided into four groups of 8 rats each and assigned a calcium oxalate lithogenic diet added to their drinking water for 3 weeks. One group, used as reference, received a standard diet prepared in our laboratory. The second was assigned the same diet but supplemented with 7.5 g animal proteins/100 g diet. The third received a diet containing 500 mg calcium more than the standard group. The diet given to the last group was supplemented with calcium and protein at the same doses indicated previously. One day before the end of treatment, each animal was placed in a metabolic cage to collect 24-hour urine samples and determine urinary creatinine, urea, calcium, magnesium, phosphate, uric acid, citric acid and oxalate levels. Immediately thereafter, aortic blood was collected to determine the same parameters as in urine. The kidneys were also removed to determine calcium oxalate deposits. Our results showed an increased 24-hour urinary excretion of calcium, oxalate and uric acid and decreased urinary citric acid excretion only in groups that received protein supplementation. At the same time, calcium oxalate deposits were found significantly higher in hyperprotidic diets than reference or calcium-supplemented groups. According to these findings, glomerular filtration, fractional excretion of urea and reabsorption of water, calcium and magnesium were found significantly lower in hyperprotidic diets compared to other groups. These results demonstrate that proteins could seriously aggravate calcium oxalate stones and cause renal disturbances.
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PMID:Effect of hyperprotidic diet associated or not with hypercalcic diet on calcium oxalate stone formation in rat. 1586 Sep 12

A 4.5-year-old female degu (Octodon degus) was minimally responsive with a poor body condition, a rough haircoat, and moderate dehydration. Blood was present around its urethral orifice and on the cage bedding. Laboratory analyses revealed leukocytosis with neutrophilia and anemia; hypoproteinemia and hypoalbuminemia; hyperglycemia, hyperphosphatemia, and elevated alanine aminotransferase, blood urea nitrogen, and creatinine; and hematuria and pyuria with occasional squamous and transitional epithelial cells. A urine culture was positive for coagulase-negative Staphylococcus sp. On gross necropsy, the right kidney was enlarged, cystic, and greenish-brown, with a 10-mm, hemorrhagic, granular mass extending from the renal pelvis into the cranial cortex. Only a small amount of renal cortex appeared normal. The urinary bladder had focal areas of hemorrhage and contained frank blood. Histologically, the papillary mass in the right renal pelvis comprised basophilic, moderately anaplastic, clustered epithelial transition cells consistent with a transitional cell carcinoma. Internally, the tumor showed squamous metaplasia and moderate multifocal interstitial fibrosis. The right kidney cortex contained a choristoma comprising trabecular bone, mature adipocytes, and cellular infiltrates suggestive of osteocytes, lymphocytes, and plasma cells. The urinary bladder had mild to moderate, focal, hemorrhage with neutrophilic inflammation and contained focal areas of mild transitional cell epithelial hyperplasia; these changes may have been secondary to irritation by hemorrhage in the renal pelvis. There was no evidence of metastasis. Renal transitional cell tumors are rare in rodents. This is the first report of both a renal transitional cell carcinoma and a renal choristoma in a degu.
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PMID:Renal transitional cell carcinoma and choristoma in a degu (Octodon degus). 1593 23

The coat protein (CP) of certain plant viruses may reassemble into empty virus-like particles (VLPs) and these protein cages may serve as potential drug delivery platforms. In this paper, the production of novel VLPs from the Hibiscus chlorotic ringspot virus (HCRSV) is reported and the capacity to load foreign materials was characterized. VLPs were readily produced by destabilizing the HCRSV in 8 M urea or Tris buffer pH 8, in the absence of calcium ions, followed by removal of viral RNA by ultrahigh-speed centrifugation and the reassembly of the CP in sodium acetate buffer pH 5. The loading of foreign materials into the VLPs was dependent on electrostatic interactions. Anionic polyacids, such as polystyrenesulfonic acid and polyacrylic acid, were successfully loaded but neutrally charged dextran molecules were not. The molecular-mass threshold for the polyacid cargo was about 13 kDa, due to the poor retention of smaller molecules, which readily diffused through the holes between the S domains present on the surface of the VLPs. These holes precluded the entry of large molecules, but allowed smaller molecules to enter or exit. The polyacid-loaded VLPs had comparable size, morphology and surface-charge density to the native HCRSV, and the amount of polyacids loaded was comparable to the weight of the native genomic materials. The conditions applied to disassembly-reassembly of the virions did not change the structural conformation of the CP. HCRSV-derived VLPs may provide a promising nano-sized protein cage for delivery of anionic drug molecules.
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PMID:In vitro-reassembled plant virus-like particles for loading of polyacids. 1689 16

Streptococcus agalactiae is an etiological agent of several infective diseases in humans. We previously demonstrated that FbsA, a fibrinogen-binding protein expressed by this bacterium, elicits a fibrinogen-dependent aggregation of platelets. In the present communication, we show that the binding of FbsA to fibrinogen is specific and saturable, and that the FbsA-binding site resides in the D region of fibrinogen. In accordance with the repetitive nature of the protein, we found that FbsA contains multiple binding sites for fibrinogen. By using several biophysical methods, we provide evidence that the addition of FbsA induces extensive fibrinogen aggregation and has noticeable effects on thrombin-catalyzed fibrin clot formation. Fibrinogen aggregation was also found to depend on FbsA concentration and on the number of FbsA repeat units. Scanning electron microscopy evidentiated that, while fibrin clot is made of a fine fibrillar network, FbsA-induced Fbg aggregates consist of thicker fibers organized in a cage-like structure. The structural difference of the two structures was further indicated by the diverse immunological reactivity and capability to bind tissue-type plasminogen activator or plasminogen. The mechanisms of FbsA-induced fibrinogen aggregation and fibrin polymerization followed distinct pathways since Fbg assembly was not inhibited by GPRP, a specific inhibitor of fibrin polymerization. This finding was supported by the different sensitivity of the aggregates to the disruptive effects of urea and guanidine hydrochloride. We suggest that FbsA and fibrinogen play complementary roles in contributing to thrombogenesis associated with S. agalactiae infection.
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PMID:Multiple interactions of FbsA, a surface protein from Streptococcus agalactiae, with fibrinogen: affinity, stoichiometry, and structural characterization. 1704 2

The p53-inhibitory function of the oncoprotein MDM2 is regulated by a number of MDM2-binding proteins, including ARF and ribosomal proteins L5, L11, and L23, which bind the central acidic domain of MDM2 and inhibit its E3 ubiquitin ligase activity. Various human cancer-associated MDM2 alterations targeting the central acidic domain have been reported, yet the functional significance of these mutations in tumor development has remained unclear. Here, we show that cancer-associated missense mutations targeting MDM2's central zinc finger disrupt the interaction of MDM2 with L5 and L11. We found that the zinc finger mutant MDM2 is impaired in undergoing nuclear export and proteasomal degradation as well as in promoting p53 degradation, yet retains the function of suppressing p53 transcriptional activity. Unlike the wild-type MDM2, whose p53-suppressive activity can be inhibited by L11, the MDM2 zinc finger mutant escapes L11 inhibition. Hence, the MDM2 central zinc finger plays a critical role in mediating MDM2's interaction with ribosomal proteins and its ability to degrade p53, and these roles are disrupted by human cancer-associated MDM2 mutations.
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PMID:Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation. 1711 89


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