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)

It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.
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PMID:Generic low-molecular-weight heparins: some practical considerations. 1563 Jun 77

Many reports have described the bioavailability of anthocyanins; however, most of these reports investigated only the amount of anthocyanins excreted in urine. In the present study, we calculated the pharmacokinetic bioavailability of anthocyanins in rats by measuring the plasma concentration of delphinidin-3-rutinoside that had been administered orally or intravenously. Delphinidin-3-rutinoside was primarily absorbed in the blood and excreted into urine as unmetabolized forms with a T(max) of 26.3 min and a C(max) of 0.285 +/- 0.071 micromol/L. We detected small amounts of the metabolite 4'-O-methyl-delphinidin-3-rutinoside in the plasma, but we detected neither anthocyanidin (aglycone) nor glucuro- or sulfoconjugates. For the 8 h period after intake, delphinidin-3-rutinoside and 4'-O-methyl-delphinidin-3-rutinoside were excreted to urine at 795 +/- 375 and 12.3 +/- 2.91 nmol, respectively. Relative to intravenous injection, oral administration of delphinidin-3-rutinoside resulted in complete bioavailability (0.49 +/- 0.06%). Analysis of delphinidin-3-rutinoside plasma concentrations in bile cannulated rats revealed that, for the 8-h period after intake, the intact delphinidin-3-rutinoside excretion ratio in bile was 11% of the excretion ratio of 4'-O-methyl-delphinidin-3-rutinoside, 1.91 +/- 0.35 nmol versus 17.4 +/- 8.67 nmol, respectively. Setting the bile duct cannulation in a Bollman-type cage, however, significantly increased the bioavailability of orally administered delphinidin-3-rutinoside (18.14 +/- 6.24%). This effect appears to stem immobilization stress by reducing gastrointestinal motility. The cumulative excretion of delphinidin-3-rutinoside and 4'-O-methyl-delphinidin-3-rutinoside in urine and bile was 2.67 +/- 1.24% (w/w) of the dose ingested. Studies report that several metabolites are formed after oral ingestion of anthocyanins. Examples include glucuronyl from cyanidin-3-glucoside and both glucuronyl and sulfate conjugates from pelargonidin-3-glucoside. Our results indicate that delphinidin-3-rutinoside might be metabolized differently from cyanidin-3-glucoside and pelargonidin-3-glucoside.
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PMID:Ingested delphinidin-3-rutinoside is primarily excreted to urine as the intact form and to bile as the methylated form in rats. 1641 24

Attention to addiction of women alone for fetus and infant's health has caused the possible role of father's status was less considered, while some developmental impairments including decrease of liter size, weight loss, congenital deficiencies, behavioral disorders, and learning and memory impairments in offspring with addicted father have been reported. In this study the effects of addiction of one or both parents to morphine on male and female offspring hippocampal long-term potentiation (LTP), were assessed. One hundred twenty female and 48 male rats (4-5 months, 250-270 g) were used. Forty females and 16 males were addicted by oral administration of morphine (32 mg/kg twice daily) for 5 days before mating. Then each two males with five females were housed (coupled) per cage as five groups for coupling: (A) addicted females+5% dextrose males (add.F); (B) addicted males+5% dextrose females (add.M); (C) addicted females+addicted males (add.MF); (D) 5% dextrose females+intact males (dex.F); (E) 5% dextrose males+intact females (dex.M). In puberty offspring LTP was induced in hippocampal dentate gyrus by stimulation of perforant path (pp). Changes of population spikes (PS) amplitude and LTP slope at 0, 5, 30, 60 and 120 min were evaluated. Slope of LTP at 30, 60 and 120 min, and amplitude of PS at 60 and 120 min in add.F and add.M offspring were significantly lower than dextrose groups (P<0.01). LTP slope and PS amplitude of male and female offspring did not different between add.F and add.M groups. Our results suggest that both parental and paternal addiction to morphine may cause memory deficiency through reduction of LTP in hippocampus.
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PMID:Effect of parental morphine addiction on hippocampal long-term potentiation in rats offspring. 1786 30

A smart contrast agent for magnetic resonance imaging (MRI) can be used to exploit an enzymatic activity specific to the tissue or disease state signified by converting an MRI-inactivated agent to an activated MRI agent. In this study, a beta-galactopyranose-containing gadolinium(III) complex [Gd(DOTA-FPG)(H 2O)] was designed, synthesized, and characterized as being potentially suitable for a bioactivated MRI contrast agent. The (17)O NMR experiments were conducted to estimate the water exchange rate k e x 298 and rotational correlation time tau R 298 . The k ex 298 value of [Gd(DOTA-FPG)(H 2O)] is similar to that of [Gd(DO3A-bz-NO 2)(H 2O)]. The rotational correlation time value of [Gd(DOTA-FPG)(H 2O)] is dramatically longer than that of [Gd(DOTA)(H 2O)] (-) Relaxometric studies show that the percentage change in the T 1 value of [Gd(DOTA-FPG)(H 2O)] decreases dramatically in the presence of beta-galactosidase and human serum albumin. The T(1) change percentage of [Gd(DOTA-FPG)(H 2O)] (60%) is significantly higher than those of Egad and gadolinium(III)-1-(4-(2-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl)))-ethylcarbamoyloxymethyl)-2-nitrophenyl)-beta- d-glucopyronuronate. The signal intensity of the MR image for [Gd(DOTA-FPG)(H 2O)] in the presence of human serum albumin and beta-galactosidase (2670 +/- 210) is significantly higher than that of [Gd(DOTA-FPG)(H 2O)] in the sodium phosphate buffer solution (1490 +/- 160). In addition, the MR images show a higher-intensity enhancement in CT26/beta-gal tumor with beta-galactosidase gene expression but not for the CT26 tumor without beta-galactosidase gene expression. We conclude that [Gd(DOTA-FPG)(H 2O)] is a suitable candidate for a bioactivated MRI contrast agent in tracing gene expression.
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PMID:Synthesis and characterization of a new bioactivated paramagnetic gadolinium(III) complex [Gd(DOTA-FPG)(H2O)] for tracing gene expression. 1793 89

A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [18F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.
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PMID:The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. 1841 8

The influence of the form of phytic acid on the regulation of mucin and endogenous losses of amino acids, nitrogen and energy in chickens was investigated. Forty-eight 10-week-old male broilers were grouped by weight into eight blocks of six cages with one bird per cage. Birds received by intubation six dextrose-based combinations of phytic acid and phytase arranged in a 3 x 2 factorial consisting of phytic acid form (no phytic acid, 1.0 g free phytic acid or 1.3 g magnesium-potassium phytate) and phytase (0 or 1000 units). Each bird received the assigned combination added to 25 g dextrose at each of the two feedings on the first day of experimentation. All excreta were collected continuously for 54 h following feeding and frozen until analysed. Frozen excreta were thawed, pooled for each bird, lyophilised, ground, and analysed for DM, energy, nitrogen, amino acids, mucin, and sialic and uric acids. Chickens fed either magnesium-potassium phytate or free phytic acid showed increased (P < 0.05) loss of crude mucin and sialic acid. The amount of crude mucin lost was significantly greater (P < 0.05) with magnesium-potassium phytate than with free phytic acid treatment. Both phytic acid treatments also increased (P < 0.05) endogenous loss of threonine, proline and serine. In conclusion, the form of phytic acid fed to chickens affects the extent of mucin and endogenous amino acid losses from the gastrointestinal tract.
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PMID:Phytic acid increases mucin and endogenous amino acid losses from the gastrointestinal tract of chickens. 1876 81

[2-(14)C]quercetin-4'-glucoside (4 mg/kg body weight) was fed by gavage to rats housed in metabolic cages, and over an ensuing 72 h period, radiolabeled products in body tissues, plasma, feces, and urine were monitored by high-performance liquid chromatography with online radioactivity and MS2 detection. One and 6 h after ingestion, while in the small intestine, the flavonol glucoside was converted to glucuronide and methylated and sulfated derivatives of quercetin, but only trace amounts of these metabolites were excreted in urine. On entering the cecum and the colon, the flavonol metabolites declined as they were converted to phenolic acids, principally 3-hydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid, by the colonic microflora. Feces contained mainly 3-hydroxyphenylacetic acid. Urine collected 0-12 and 0-24 h after ingestion contained radiolabeled hippuric acid and 3-hydroxyphenylacetic acid. 14C-Hippuric acid declined markedly in the 24-48 and 48-72 h urine samples, and there was a concomitant increase in labeled benzoic acid. There was minimal accumulation of radioactivity in plasma, despite a 69% recovery of label in urine over the 72 h period, and likewise, very little radioactivity was detected in body tissues out with the gastrointestinal tract. This is reflected in the fact that 72 h after ingestion 96% of the ingested radioactivity was recovered in feces, urine, and the cage washes, which comprise a mixture of urine and feces. The study reveals that as it passes through the gastrointestinal tract, almost all of the of [2-(14)C]quercetin-4'-glucoside is converted to phenolic acids, compounds not monitored in previous flavonol bioavailability studies with model animal systems, some of which have used exceedingly high doses of the aglycone quercetin (500 mg/kg body weight), which is not a normal dietary component.
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PMID:Bioavailability of [2-(14)C]quercetin-4'-glucoside in rats. 1905 21

The presence of distant metastases from differentiated thyroid carcinoma decreases the 10-year survival rates of patients by 50%. This is a report of a 61-year-old female with follicular thyroid carcinoma who presented initially with low back pain. 2-deoxy-2-[18F] fluoro-D-glucose whole-body positron emission tomography/computed tomography (PET/CT) demonstrated a hypointensity lesion in the left thyroid gland with malignant uptake in L1 vertebra and magnetic resonance images revealed paravertebral and epidural extension of mass in L1 vertebra. After thyroidectomy, histopathological study showed a follicular carcinoma. We performed L1 total en bloc spondylectomy with expandable cage for long-term local control. The technical details of total en bloc spondylectomy in follicular carcinoma are described herein.
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PMID:Total en bloc lumbar spondylectomy of follicular thyroid carcinoma. 1935 84

Changes in the expression of cell surface glycan are often associated with malignant metastasis. The expression level may be dramatically enhanced during tumor progression. A highly sensitive assay that is capable of detecting low levels of cancer-associated carbohydrate antigens can be a powerful tool for early diagnosis. In this work, an ultrasensitive glycans array using iron oxide/gold core/shell nanoparticles conjugated with antibodies or proteins is developed. A magnetic field is applied to quickly bring nanoparticle labeled proteins or antibodies from a solution to an array of carbohydrates immobilized on glass slides and to help them to encounter the carbohydrates at very low concentration. The gold shell provides a well established platform for conjugation of biomolecules. Well-defined recognition systems, namely, mannose derivatives (Man1, Man4, and Man9) with a mannose binding lectin (Concanavalin A) and a stage-specific embryonic antigens-3 (SSEA-3) with a monoclonal antibody (anti-SSEA-3) were chosen to establish this detection tool. Array systems were conducted to determine their surface dissociation constant (K(D,surface)) and their binding specificity for qualitative and quantitative analysis of carbohydrate-protein and carbohydrate-antibody interactions. When coupled with a signal amplification method based on nanoparticle-promoted reduction of silver, the sensitivity of an iron oxide/gold core/shell nanoparticle-based assay reached to subattomole level in carbohydrate detection.
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PMID:Iron oxide/gold core/shell nanoparticles for ultrasensitive detection of carbohydrate-protein interactions. 1968 35

Altered glycosylation on the surfaces or secreted proteins of tumor cells is common in pancreatic cancer and is thought to promote cancer progression, but the factors leading to the changes in carbohydrate structures are incompletely understood. We hypothesized that pro-inflammatory conditions can lead to alterations in cancer-associated glycans on mucins produced by pancreatic-cancer cells. With the use of a novel antibody-glycan microarray method, we measured the effects of pro-inflammatory stimuli (oxidative stress and treatment with the cytokines IFNgamma, IL-1alpha, and TNFalpha) on the expression and glycosylation of the mucins MUC1, MUC5AC, and MUC16 in multiple pancreatic cancer cell lines. Mucin glycosylation was significantly affected in specific cell lines, particularly in structures involving terminal galactose or N-acetylgalactosamine. In addition, the responses of the cell lines grouped according to the expression of cell-surface markers that are associated with tumorigenicity, as cell lines bearing minimal surface markers, showed evidence of increased O-glycan extension and decreased presentation of terminal beta1,4-linked galactose, opposite to cell lines bearing multiple markers. These results suggest mechanisms whereby inflammation might influence tumor behavior in a cell-type specific manner through modulating the presentation of cancer-associated glycans.
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PMID:Mucin glycosylation is altered by pro-inflammatory signaling in pancreatic-cancer cells. 1971 13


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