Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viral entry through the blood-brain barrier (BBB) has not been fully defined and identification of coreceptors that can facilitate this phenomenon is crucial in understanding disease progression. Using a RNAse protection assay to examine chemokine receptor families simultaneously, we analyzed the total RNA of in vitro BBB cultures treated with purified preparations of HIV gp120, gp41, TAT proteins and TNF-alpha. HIV tat protein affected CCRI and CCR3 mRNA expression whereas the other viral by-products had no effect. Interestingly, TNF-alpha was able to induce CCR1, CCR3 as well as CXCR1, CXCR2, CXCR4 receptors and Burkitt's lymphoma receptor BLR2. These results suggest that HIV-induced molecules can manipulate the surface receptor expression of the BBB to allow for their preferential entry into brain.
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PMID:Chemokine receptor mRNA expression at the in vitro blood-brain barrier during HIV infection. 1009 32

The effects of Duraflo II heparin coated cardiopulmonary bypass circuits, low-dose aprotinin, and steroids on the coagulation system, endothelial damage, and cytokine release were evaluated by comparing those treated with low-dose aprotinin and steroids. Twenty-four adult patients undergoing coronary artery bypass grafting, aortic valve replacement, or valve repair surgery were randomly assigned to 2 groups: either heparin-coated (Duraflo group, n = 12) or noncoated equipment (noncoated group, n = 12) groups. In the Duraflo group, the cardiopulmonary reservoir was also coated with heparin. There were no significant differences in age at the time of operation, aortic cross-clamp time, cardiopulmonary bypass time, and rectal temperature during cardiopulmonary bypass. Standard systemic heparinization was performed. Methylpredonisolone and low-dose aprotinin were given in both groups of patients. Serum XIIa factor, TAT, and IL-6 were significantly higher in the control group than in the Duraflo group during cardiopulmonary bypass (p < 0.01). Serum IL-8 was significantly higher in the control group than in the Duraflo group at 24 h after cardiopulmonary bypass (p < 0.05). No significant difference was found in serum thrombomodulin and TNF-alpha; both were within normal during the study period. These results indicate that the use of Duraflo II heparin coated equipment and a heparin-coated cardiopulmonary reservoir suppressed excess coagulation and inflammatory reaction induced by cardiopulmonary bypass.
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PMID:Effects of Duraflo II heparin-coated cardiopulmonary bypass circuits on the coagulation system, endothelial damage, and cytokine release in patients with cardiac operation employing aprotinin and steroids. 1061 29

Thrombomodulin (TM), a membrane-bound receptor for thrombin on the endothelial cell surface, contributes to the regulation of the coagulation system. TM is known to exist in human plasma and urine as soluble forms. We purified soluble TM from human urine (MR-33) and investigated the anticoagulant effects of MR-33 in vitro and in vivo. In human plasma, MR-33 inhibited not only the procoagulant activity of thrombin, but also the thrombin generation via accelerating the thrombin-catalyzed protein C activation. In rat disseminated intravascular coagulation (DIC) models, intravenous infusion of MR-33 improved the hematological abnormalities without excessive prolongation of APTT and bleeding time. Benefit (dose required for 50% inhibition of fibrinogen decrease: ED50) to risk (minimum dose required for significant prolongation of bleeding time) ratio was 1:27 for MR-33. Furthermore, the anticoagulant activities of MR-33 was independent of AT III activity, and MR-33 was effective on heparin-resistant DIC models with low AT III level in rats. Intravenous injection of MR-33 prevented the endotoxin-induced increases in TAT, TNF-alpha and IL-6 level and pulmonary vascular permeability in mice. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage, and this drug also has anti-inflammatory effects. Clinical trials of MR-33 for the treatment of DIC are now in progress in Japan.
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PMID:[Thrombomodulin]. 1121 78

The transcription factor NF-kappaB is regulated by the IkappaB family of proteins. The nonphosphorylatable, nondegradable superrepressor IkappaBalpha (srIkappaBalpha) mutant is a potent inhibitor of NF-kappaB activity when expressed in cells. We generated a form of srIkappaBalpha in which its N terminus is fused to the protein transduction domain of HIV TAT (TAT-srIkappaBalpha). Purified TAT-srIkappaBalpha protein rapidly and efficiently entered HeLa or Jurkat T cells. TAT-srIkappaBalpha, when exogenously added to HeLa cells, inhibited in a dose-dependent manner TNF-alpha- or IL-1beta-induced NF-kappaB activation and binding of NF-kappaB to its consensus DNA sequence. TAT-srIkappaBalpha was coimmunoprecipitated with the p65 subunit of NF-kappaB, and this interaction was resistant to stimulation with IL-1beta. Therefore, TAT-srIkappaBalpha-mediated inhibition could result from its nonreversible binding and sequestration of endogenous NF-kappaB. In contrast, exogenously added TAT-srIkappaBalpha did not inhibit IL-1beta-induced activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinases or the phosphorylation and degradation of endogenous IkappaBalpha. These results identify a novel way for direct regulation of NF-kappaB activity in diverse cell types that may be useful for therapeutic purposes.
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PMID:Inhibition of NF-kappa B activity by a membrane-transducing mutant of I kappa B alpha. 1219 29

Transplantation of islets is becoming an established method for treating type 1 diabetes. However, viability of islets is greatly affected by necrosis/apoptosis induced by oxidative stress and other insults during isolation and subsequent in vitro culture. Expression of cytoprotective proteins, such as heme oxygenase-1 (HO-1), reduces the deleterious effects of oxidative stress in transplantable islets. We have generated a fusion protein composed of HO-1 and TAT protein transduction domain (TAT/PTD), an 11-aa cell penetrating peptide from the human immunodeficiency virus TAT protein. Transduction of TAT/PTD-HO-1 to insulin-producing cells protects against TNF-alpha-mediated cytotoxicity. TAT/PTD-HO-1 transduction to islets does not impair islet physiology, as assessed by reversion of chemically induced diabetes in immunodeficient mice. Finally, we report that transduction of HO-1 fusion protein into islets improves islet viability in culture. This approach might have a positive impact on the availability of islets for transplantation.
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PMID:Heme oxygenase-1 fused to a TAT peptide transduces and protects pancreatic beta-cells. 1276 12

During chemotherapy with anthracyclines, attenuated neuregulin signaling by the erbB2 receptor inactivating antibody Trastuzumab enhances the heart failure risk. We compared the effects of attenuated neuregulin/erbB signaling and of daunorubicin on splicing of the Bcl-x gene and on mitochondrial activation of apoptosis in cardiomyocytes. Attenuating erbB signals in cultured neonatal rat cardiomyocytes by the erbB2 antagonist tyrphostin AG825, by the erbB1/4 antagonist AG1478 or by antisense-induced lowering of erbB2 receptors resulted in an augmented Bcl-xS/Bcl-xL ratio, mitochondrial release of cytochrome c, activation of caspase 9 and caspase 3, and nucleosome-sized DNA fragmentation. A similar DNA fragmentation and caspase 3 activation was induced by TNF-alpha, but without Bcl-xS/Bcl-xL increase, cytochrome c release or caspase 9 activation. A BH4-domain containing HIV TAT fusion protein added to cardiomyocytes under attenuated erbB signaling lowered the enhanced Bcl-xS/Bcl-xL ratio, the cytochrome c release, the caspase 3 activation and the DNA fragmentation, while apoptosis was not modified by the fusion protein in TNF-alpha treated cardiomyocytes. Enhancement of Bcl-xS/Bcl-xL by reducing Bcl-xL via siRNA transfection mimicked the mitochondrial apoptotic activation due to erbB signal attenuation. Daunorubicin also caused Bcl-xS/Bcl-xL enhancement and mitochondrial apoptotic activation in cultured cardiomyocytes; this was attenuated by BH4-fusion protein or by neuregulin-1 and augmented by siRNA-mediated Bcl-xL lowering. We conclude that activation of mitochondrial apoptosis due to altered Bcl-x splicing contributes as a common mechanism of anthracyclines and erbB signal attenuation to the enhanced heart failure risk under this combination.
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PMID:Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. 1573 8

The effect of fever on neutrophils has not been explored. We tested the hypothesis that fever-like temperature spikes affect neutrophil signaling and function. Prior 60 min, 42 degrees C heat exposure inhibited p38 MAPK, ERK, PI3-Kinase/Akt, and NF-kappaB activation in TNF-alpha-challenged suspended neutrophils. Using pharmacological inhibitors and an inhibitory peptide transduced into neutrophils by a HIV-TAT sequence, we found that p38 MAPK and NF-kappaB mediate TNF-alpha-mediated delayed apoptosis in suspended neutrophils. Heat exposure (39-42 degrees C) did not affect constitutive apoptosis but abrogated TNF-alpha-delayed apoptosis in these suspended cells. In contrast, adhesion-dependent functions were not inhibited. Furthermore, we found that heat exposure neither blocked p38 MAPK, ERK, and NF-kappaB activation in neutrophils on fibronectin nor prevented delayed apoptosis by TNF-alpha when cells interacted with fibronectin. Above and beyond apoptosis, TNF-alpha initiated NF-kappaB-dependent gene transcription. Heat exposure blocked this effect in suspended neutrophils but not in neutrophils on fibronectin. Finally, we show that beta2-integrins, which are not necessary for TNF-alpha-induced NF-kappaB activation at 37 degrees C, transduce costimulatory signals allowing NF-kappaB activation after heat exposure. The effect could protect circulating neutrophils from TNF-alpha activation, while not interfering with activation of adherent neutrophils. Fever could make neutrophils more parsimonious.
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PMID:The effect of fever-like temperatures on neutrophil signaling. 1575 71

A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.
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PMID:Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity. 1591 Dec 83

Gene therapy aimed at the respiratory epithelium holds therapeutic potential for diseases such as cystic fibrosis and lung cancer. Polyethylenimine (PEI) has been utilized for gene delivery to the airways. In this study, we describe a new modification of PEI, in which an oligopeptide related to the protein transduction domain of HIV-1 TAT was covalently coupled to 25 kDa PEI (PEI) through a heterobifunctional polyethylenglycol (PEG) spacer resulting in a TAT-PEG-PEI conjugate. Improved DNA reporter gene complexation and protection was observed for small (approximately 90 nm) polyplexes as well as significantly improved stability against polyanions, Alveofact, bronchial alveolar lining fluid and DNase. To determine polyplex toxicity in vitro, MTT assays were performed and, for in vivo testing, the mice bronchial alveolar lavage was investigated for total cell counts, quantity of neutrophils, total protein and TNF-alpha concentration. All parameters suggest significantly lower toxicity for TAT-PEG-PEI. Transfection efficiencies of both PEI and TAT-PEG-PEI polyplexes with DNA were studied under in vitro conditions (A549) and in mice after intratracheal instillation. While luciferase expression in A549 cells was much lower for TAT-PEG-PEI (0.2 ng/mg protein) than for PEI (2 ng/mg), significantly higher transfection efficiencies for TAT-PEG-PEI were detected in mice. Reporter gene expression was distributed through bronchial and alveolar tissue. Thus, TAT-PEG-PEI represents a new approach to non-viral gene carriers for lung therapy, comprising protection for plasmid DNA, low toxicity and significantly enhanced transfection efficiency under in vivo conditions.
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PMID:Nano-carriers for DNA delivery to the lung based upon a TAT-derived peptide covalently coupled to PEG-PEI. 1629 9

The protein C pathway serves as a modulating system with both anti-inflammatory and anticoagulant properties and is intimately involved in the pathophysiology of inflammation and sepsis. Treatment with recombinant human activated protein C (rhAPC) can reduce the mortality of severe sepsis. We investigated whether an elevation of plasma protein C levels to supra-normal levels by infusion of a protein C zymogen concentrate has an effect on coagulation, protein C activation or inflammation in a human endotoxemia model. Eleven healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Ten minutes after infusion of 2ng/kg endotoxin each volunteer received either placebo or a plasma-derived protein C zymogen concentrate (Ceprotin, Baxter) (150 U/kg as a slow bolus infusion followed by 30 U/kg/h continuous infusion until 4 hours after LPS-infusion). Protein C antigen and activity increased 4- to 5-fold after infusion of the concentrate. APC was generated during endotoxin-induced inflammation in the placebo (1.6 fold increase) and the protein C period (4.0-fold increase). The increase of APC levels correlated with the TNF-alpha and IL-6 release in both periods (r = 0.65-0.68; p < 0.05) and paralleled the protein C antigen and activity levels in the period with supranormal protein C levels. Supra normal protein C levels resulted in slightly, although non-significant, lower tissue factor mRNA expression and thrombin generation (TAT, F1+2). Systemic inflammation (TNF-alpha, IL-6) was not influenced by protein C zymogen concentrate administration. Infusion of protein C zymogen was safe and no adverse effects occurred. The increase of protein C levels several fold above the normal range resulted in a proportional increase of the APC levels, but had no major anticoagulant, anti-inflammatory or profibrinolytic effects. Low grade endotoxemia itself induces significant protein C activation, which correlates with the TNF release.
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PMID:The effects of supra-normal protein C levels on markers of coagulation, fibrinolysis and inflammation in a human model of endotoxemia. 1673 92


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