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)

Chronic aethylism has always been a major social as well as health problem. It may lead, at least in some patients, to steatohepatitis (ASH) which is known to progress to cirrhosis more rapidly. Because of the fact that the prevalence of obesity in association with the metabolic syndrome (insulin resistance) is strikingly increasing in the Western world, we will more and more often be faced with a second form of steatohepatitis, the so called non-alcoholic steatohepatitis (NASH). Clinical differentiation between these two entities may often be difficult. The use of the CAGE-questions as well as interviewing family members can help to indentify hidden alcohol abuse. Clinically, the presence of both diseases can only be speculated. To get the diagnosis, liver biopsy must be performed to show the typical histologic feature of fatty liver with hepatocyte necrosis as well as infiltration of polymorphcellular leukocytes. Histology cannot differentiate between ASH and NASH. Therefore, similar pathogenetic mechanisms are supposed. However, therapeutic approaches are different. Treatment of choice in ASH is alcohol abstinence, that of NASH the reduction of insulin resistance, primarily by weight loss.
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PMID:[Alcoholic and non-alcoholic steatohepatitis]. 1545 67

The aim of our study was to investigate the importance of pulmonary distension and fetal breathing-like movements executed by the contractile activity of the intercostal respiratory muscles for proper lung growth and maturation. Lung development in Myf5-/- embryos, lacking the rib cage and functional intercostal musculature, was compared with wild-type controls at embryonic days 14.5, 16.5, and 18.5. Our data revealed that Myf5-/- embryos suffered from pulmonary hypoplasia in part due to the decreased number of proliferating lung cells and in part due to the increased number of terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) -positive cells. In addition, the proximal-to-distal expression gradient of thyroid transcription factor-1 observed in wild-type embryos was not maintained in Myf5-/- embryos. The number of lung cells expressing platelet-derived growth factor-BB, its receptor and insulin growth factor-I was significantly decreased in the hypoplastic lung. By contrast, no difference in the expression pattern of surfactant associated proteins or Clara cells marker was detected between wild-type and Myf5-/- embryos. Collectively, our data suggest that the mechanochemical signal transduction pathway used in vitro is also effective in vivo influencing lung growth but not lung cell maturation and resulting in lung hypoplasia. These data affirm the role of fetal breathing-like movements in lung organogenesis.
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PMID:Abnormal development of the intercostal muscles and the rib cage in Myf5-/- embryos leads to pulmonary hypoplasia. 1558 May 68

The hyperactivation of fatty acid synthase (FAS)-catalyzed de novo biosynthesis of fatty acids is a molecular marker linked to tumor virulence in population studies of human malignancies. This activation appears to be linked to neoplastic transformation, since high levels of FAS have also been identified in pre-malignant lesions. This dependence of cancer upon accelerated lipogenesis differs from normal human tissues, in which FAS is suppressed by the presence of small amounts of fatty acids in the diet. The molecular mechanisms by which cancer cells constitutively exhibit FAS overexpression and hyperactivity have begun to emerge. The active involvement of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) and phosphatidylinositol-3'-kinase (PI-3'K)/protein kinase B (AKT) transduction cascades in the overexpression of FAS has been recently demonstrated in several cancer cell models. Strikingly, insulin-regulated stimulation of FAS expression in adipose cells is also mediated by the PI-3'K pathway with AKT being involved as a downstream effector. Moreover, FAS overexpression in tumor cells has been demonstrated to occur through a modification of the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), the major regulatory factor of FAS in liver and adipose tissues, which, in turn, is known to be regulated by MAPK ERK1/2 and PI-3'K/AKT pathways. Therefore, the signal transduction pathways regulating FAS expression in normal and cancer cells seem to share several downstream elements. However, the upstream mechanisms controlling FAS expression in cancer cells must be different from those in normal tissues, since tumor-associated FAS expression seems to be insensitive to nutritional signals. In pre-neoplastic lesions, we hypothesize that the early activation of FAS in pre-malignant cells represents a survival strategy which occurs to compensate for an insufficiency of both oxygen and dietary fatty acids due to, e.g., lack of angiogenesis. Thus, FAS activation reflects an epigenetic dysregulation of the lipogenic pathway in response to the microenvironment of tumors containing regions of poor oxygenation. Upon this unusual metabolic situation, FAS up-regulation also represent a metabolic strategy to maintain high proliferation rates of surviving cells in the absence of exogenous dietary fatty acids. Concomitantly, a variety of oncogenic changes (H-ras, erb B-2, etc.) may result in the constitutive activation of MAPK and PI-3'K/AKT signaling cascades, which, in turn, can activate SREBP-1c and, subsequently, tumor-associated FAS-catalyzed endogenous lipogenesis. Thereafter, high levels of FAS are maintained in coordination with increased demand for fatty acid metabolism and/or membrane synthesis in response to cancer-related overexpression of growth factors (e.g., EGF, heregulin) and/or growth factor receptors (e.g., EGFR, Her-2/neu). The aberrant MAPK and PI-3'K/AKT cascades driven by these oncogenic changes subvert the downregulatory effects of physiological concentrations of dietary fatty acids, resulting in a cancer-associated FAS insensitivity to nutritional signals. This model does not exclude that fundamental differences in the ability of FAS gene to respond to normal fatty acid's downregulatory actions may also synergistically interact with oncogenic signals to constitutively maintain an elevated FAS-dependent de novo endogenous fatty acid biogenesis in cancer cells in spite of high levels of circulating dietary fatty acids.
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PMID:Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids? 1560 69

Glucose transporter 4 (GLUT4) is responsible for insulin-stimulated glucose transporting into the insulin-sensitive fat and muscle cells. The dynamics of GLUT4 storage vesicles (GSVs) remains to be explored and it is unclear how GSVs are arranged based on their mobility. We examined this issue in 3T3-L1 cells via investigating the three-dimensional mobility of single GSV labeled with EGFP-fused GLUT4. A thin layer of cytosol right adjacent to the plasma membrane was illuminated and successively imaged at 5 Hz under a total internal reflection fluorescence microscope with a penetration depth of 136 nm. Employing single particle tracking, the three-dimensional subpixel displacement of single GSV was tracked at a spatial precision of 22 nm. Both the mean square displacement and the diffusion coefficient were calculated for each vesicle. Tracking results revealed that vesicles moved as if restricted within a cage that has a mean radius of 160 nm, suggesting the presence of some intracellular tethering matrix. By constructing the histogram of the diffusion coefficients of GSVs, we observed a smooth distribution instead of the existence of distinct groups. The result indicates that GSVs are dynamically retained in a continuous and wide range of mobility rather than into separate classes.
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PMID:Dynamic tracking and mobility analysis of single GLUT4 storage vesicle in live 3T3-L1 cells. 1562 15

CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin (ET) converting enzyme-1 (ECE-1), with respective IC(50) values of 22, 2, and 55 nM. The aim of the present study was to establish the hemodynamic profile of Zucker diabetic fatty (Zdf)-Fatty rats, a high-fat diet gene-prone model developing spontaneous Type 2 diabetes (T2D) and the effects of CGS 35601. Male Zdf-Fatty (14 weeks, n = 17-23), Zdf-Lean (14 weeks, n = 8-10), and Wistar (14 weeks, n = 9-10) rats on distinct diets were implanted with a catheter in the left carotid and placed individually in a metabolic cage for 30 days. The hemodynamic profile and some metabolic biomarkers were assessed daily. After a 7-day stabilization period, the Zdf-Fatty rats were divided into two groups: Group 1, controls (n = 7-10) receiving vehicle-saline (250 microl/hr) and Group 2, (n = 10-13) receiving increasing doses of CGS 35601 (0.1, 1, and 5 mg/kg/day x 6 days each, intra-arterially) followed by a 5-day washout period. Mean arterial blood pressure (MABP) of young Zdf-Fatty rats was compared with age-matched Zdf-Lean and Wistar rats, which were found similar. MABP decreased by 5.9% (from baseline at 102 +/- 5 to 96 +/- 4 mmHg), 12.7% (to 89 +/- 6 mmHg) and 21.6% (to 80 +/- 4 mmHg), at 0.1, 1, and 5 mg/kg/day, respectively, in CGS 35601-treated Zdf-Fatty rats. Systolic and diastolic blood pressures were similarly reduced. The heart rate was not affected. Hyperglycemic status and insulin-resistance were not modulated by short-term treatment. CGS 35601 presented an excellent short-term safety profile. This novel molecule and class of VPI may be of interest for lowering vascular tone. Further long-term studies, once cardiovascular and renal complications have developed in this T2D rat model are warranted to define the efficacy of this class of VPI.
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PMID:The hemodynamic and metabolic profiles of Zucker diabetic fatty rats treated with a single molecule triple vasopeptidase inhibitor, CGS 35601. 1674 Oct 6

PYY(3-36) is a gut-derived hormone acting on hypothalamic nuclei to inhibit food intake. We recently showed that PYY(3-36) acutely reinforces insulin action on glucose disposal in mice. We aimed to evaluate effects of PYY(3-36) on energy metabolism and the impact of chronic PYY(3-36) treatment on insulin sensitivity. Mice received a single injection of PYY(3-36) or were injected once daily for 7 days, and energy metabolism was subsequently measured in a metabolic cage. Furthermore, the effects of chronic PYY(3-36) administration (continuous and intermittent) on glucose turnover were determined during a hyperinsulinemic-euglycemic clamp. PYY(3-36) inhibited cumulative food intake for 30 min of refeeding after an overnight fast (0.29 +/- 0.04 vs. 0.56 +/- 0.12 g, P = 0.036) in an acute setting, but not after 7 days of daily dosing. Body weight, total energy expenditure, and physical activity were not affected by PYY(3-36). However, it significantly decreased the respiratory quotient. Both continuous and intermittent PYY(3-36) treatment significantly enhanced insulin-mediated whole body glucose disposal compared with vehicle treatment (81.2 +/- 6.2 vs. 77.1 +/- 5.2 vs. 63.4 +/- 5.5 micromol.min(-1).kg(-1), respectively). In particular, PYY(3-36) treatment increased glucose uptake in adipose tissue, whereas its impact on glucose disposal in muscle did not attain statistical significance. PYY(3-36) treatment shifts the balance of fuel use in favor of fatty acids and enhances insulin sensitivity in mice, where it particularly promotes insulin-mediated glucose disposal. Notably, these metabolic effects of PYY(3-36) remain unabated after chronic administration, in contrast to its anorexic effects.
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PMID:Chronic PYY3-36 treatment promotes fat oxidation and ameliorates insulin resistance in C57BL6 mice. 1694 Apr 71

Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations.
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PMID:Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. 1705 Nov 98

Glucagon-like peptide-1 (GLP-1) and exendin-4 (Ex4) are homologous peptides with established potential for treatment of type 2 diabetes. They bind and activate the pancreatic GLP-1 receptor (GLP-1R) with similar affinity and potency and thereby promote insulin secretion in a glucose-dependent manner. GLP-1R belongs to family B of the seven transmembrane G-protein coupled receptors. The N-terminal extracellular domain (nGLP-1R) is a ligand binding domain with differential affinity for Ex4 and GLP-1: low affinity for GLP-1 and high affinity for exendin-4. The superior affinity of nGLP-1R for Ex4 was previously explained by an additional interaction between nGLP-1R and the C-terminal Trp-cage of Ex4. In this study we have combined biophysical and pharmacological approaches thus relating structural properties of the ligands in solution to their relative binding affinity for nGLP-1R. We used both a tracer competition assay and ligand-induced thermal stabilization of nGLP-1R to measure the relative affinity of full length, truncated, and chimeric ligands for soluble refolded nGLP-1R. The ligands in solution and the conformational consequences of ligand binding to nGLP-1R were characterized by circular dichroism and fluorescence spectroscopy. We found a correlation between the helical content of the free ligands and their relative binding affinity for nGLP-1R, supporting the hypothesis that the ligands are helical at least in the segment that binds to nGLP-1R. The Trp-cage of Ex4 was not necessary to maintain a superior helicity of Ex4 compared to GLP-1. The results suggest that the differential affinity of nGLP-1R is explained almost entirely by divergent residues in the central part of the ligands: Leu10-Gly30 of Ex4 and Val16-Arg36 of GLP-1. In view of our results it appears that the Trp-cage plays only a minor role for the interaction between Ex4 and nGLP-1R and for the differential affinity of nGLP-1R for GLP-1 and Ex4.
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PMID:Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain. 1744 18

We report on a 3-year-old male, born at 34 weeks of gestation, with marked pre- and postnatal overgrowth, birth weight of 6,600 g, length of 61 cm, and head circumference of 38.5 cm. A striking phenotype was recorded at birth, which became more evident during the follow-up period. He had macrobrachycephaly, facial abnormalities, small thoracic cage, long trunk, deformed spine, rhizomelia, large hands and feets, absent subcutaneous fat, small umbilical hernia, inguinal hernias, and large joints with mild contractures. Hypoglycemic episodes and obstructive apnea complicated the neonatal period. During follow-up, overgrowth continued with a height of 146 cm (+11.65 SDS) and a weight of 39 kg (BMI 18.3 kg/m(2)) at 3.5 years. Endocrinological work-up disclosed extremely low levels of growth hormone, insulin-like growth factors, and insulin. What makes our patient unique is the association of marked prenatal overgrowth; unusual phenotype; skeletal dysplasia caused by accelerated endochondral ossification resulting in cartilage hyperplasia of the skull base and spine, and postnatal gigantism; and complete absence of subcutaneous fat. Other well-known overgrowth syndromes were excluded. We hypothesize that autocrine/paracrine growth factors could be the cause of excessive endochondral ossification. Alternately, activating mutations in transcription factors involved in both growth and endocrine/metabolic homeostasis could be responsible for this unusual phenotype.
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PMID:Endochondral gigantism: a newly recognized skeletal dysplasia with pre- and postnatal overgrowth and endocrine abnormalities. 1761 4

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is involved in glucose homeostasis, and activation of GLP-1R in the plasma membrane of pancreatic beta-cells potentiates glucose-dependent insulin secretion. The N-terminal extracellular domain (nGLP-1R) is an important ligand binding domain that binds GLP-1 and the homologous peptide Exendin-4 with differential affinity. Exendin-4 has a C-terminal extension of nine amino acid residues known as the "Trp cage", which is absent in GLP-1. The Trp cage was believed to interact with nGLP-1R and thereby explain the superior affinity of Exendin-4. However, the molecular details that govern ligand binding and specificity of nGLP-1R remain undefined. Here we report the crystal structure of human nGLP-1R in complex with the antagonist Exendin-4(9-39) solved by the multiwavelength anomalous dispersion method to 2.2A resolution. The structure reveals that Exendin-4(9-39) is an amphipathic alpha-helix forming both hydrophobic and hydrophilic interactions with nGLP-1R. The Trp cage of Exendin-4 is not involved in binding to nGLP-1R. The hydrophobic binding site of nGLP-1R is defined by discontinuous segments including primarily a well defined alpha-helix in the N terminus of nGLP-1R and a loop between two antiparallel beta-strands. The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes.
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PMID:Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. 1828 2


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