Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.2.1.7 (BAL)
 1,977 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of cyclic AMP (cAMP) to the cell surface receptor induces a transient activation of guanylate cyclase in Dictyostelium discoideum. A frigid mutant (HC85) which lacks G alpha 2, a guanine nucleotide binding protein, does not respond to cAMP. We found that 2,3-dimercapto-1-propanol (BAL) induced a continuous activation both in the frigid and in its parents. Therefore, the BAL-induced continuous activation of guanylate cyclase is independent of G alpha 2. We also found that cAMP enhanced the BAL-induced continuous activation in the frigid mutant. This result suggests that an unidentified signal transduction mechanism from the cAMP-receptor besides the one involving G alpha 2 plays a role in the enhancement of activation. Lastly, we found that the BAL-induced continuous activation was terminated by cAMP in the parental strain, but not in the frigid mutant. Therefore, the cAMP-induced suppression on the BAL-induced continuous activation is mediated through G alpha 2.
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PMID:Regulation of guanylate cyclase by a guanine nucleotide binding protein, G alpha 2, in Dictyostelium discoideum. 167 66

Binding of cyclic AMP (cAMP) to cell surface receptors induces activation and adaptation of adenylate cyclase while 2,3-dimercapto-1-propanol (BAL) acts only on the activation pathway. Here we show that an inhibitor of protein kinase (K252a) inhibits the cAMP-induced activation of the cyclase but not (rather enhances) the BAL-induced activation. These results suggest that protein kinase is involved in transduction of the activation signal and that phosphorylation might take place between the receptor and the action site of BAL. Since adaptation causes cessation of the activation, the enhancement of the BAL-induced cAMP accumulation by K252a might imply that K252a also blocks transduction of the adaptation signal.
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PMID:Involvement of protein kinase(s) in the intracellular signal transduction pathways for activation and adaptation of adenylate cyclase in Dictyostelium discoideum. 215 15

At present there is some indirect evidence for increased nocturnal inflammation in patients suffering from nocturnal asthma: 1. Circulating eosinophil numbers and activation, as reflected by increased levels of ECP and EDN and low-density eosinophils, are increased at night. 2. Circulating histamine levels are increased at night. 3. Hyperresponsiveness to AMP at night is increased compared with hyperresponsiveness to methacholine. However, most results of various studies point to nocturnal asthma's being an expression of more severe asthma: 1. Both AMP and propranolol responsiveness, indirect measures of airway hyperresponsiveness, are lower both at 4:00 A.M. and 4:00 P.M. in asthmatics with nocturnal asthma than those without nocturnal asthma. 2. Patients with nocturnal asthma have higher circulating numbers of eosinophils at both 4:00 A.M. and 4:00 P.M. than those without nocturnal asthma, and eosinophil survival is not different at these times. 3. Patients with nocturnal asthma have higher PGD2 levels in BAL both at 4:00 A.M. and 4:00 P.M. than those without nocturnal asthma, but show no significant difference between levels at these two times. 4. Two studies have shown no difference in BAL eosinophil numbers and activation parameters at night in nocturnal asthma. 5. Histamine levels in BAL fluid are comparable day and night in patients with and without nocturnal asthma. 6. Inflammatory mediators in BAL are higher in asthmatic patients than in normal subjects, but are not different between patients with and without nocturnal asthma. Thus, patients with nocturnal asthmatic symptoms show an overall increased burden of mediators released from mast cells and other inflammatory cells. In conclusion, we feel that the term "nocturnal asthma" is misleading, in that it does not describe a unique entity in certain patients with asthma. We prefer, in view of the previous arguments, to consider nocturnal asthma a mere expression of more severe asthma. Thus we suggest the term "nocturnal asthma" be changed to "asthma with nocturnal symptoms."
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PMID:Inflammation in nocturnal asthma? 795

Engagement of surface immunoglobulin on mature B cells leads to rescue from apoptosis and to proliferation. Levels of bcl-2 mRNA and protein increase with cross-linking of surface immunoglobulin. We have located the major positive regulatory region for control of bcl-2 expression in B cells in the 5'-flanking region. The positive region can be divided into an upstream and a downstream regulatory region. The downstream regulatory region contains a cyclic AMP-responsive element (CRE). We show by antibody supershift experiments and UV cross-linking followed by denaturing polyacrylamide gel electrophoresis that both CREB and ATF family members bind to this region in vitro. Mutations of the CRE site that result in loss of CREB binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays. The presence of an active CRE site in the bcl-2 promoter implies that the regulation of bcl-2 expression is linked to a signal transduction pathway in B cells. Treatment of the mature B-cell line BAL-17 with either anti-immunoglobulin M or phorbol 12-myristate 13-acetate leads to an increase in bcl-2 expression that is mediated by the CRE site. Treatment of the more immature B-cell line, Ramos, with phorbol esters rescues the cells from calcium-dependent apoptosis. bcl-2 expression is increased following phorbol ester treatment, and the increased expression is dependent on the CRE site. These stimuli result in phosphorylation of CREB at serine 133. The phosphorylation of CREB that results in activation is mediated by protein kinase C rather than by protein kinase A. Although the CRE site is necessary, optimal induction of bcl-2 expression requires participation of the upstream regulatory element, suggesting that phosphorylation of CREB alters its interaction with the upstream regulatory element. The CRE site in the bcl-2 promoter appears to play a major role in the induction of bcl-2 expression during the activation of mature B cells and during the rescue of immature B cells from apoptosis. It is possible that the CRE site is responsible for induction of bcl-2 expression in other cell types, particularly those in which protein kinase C is involved.
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PMID:Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. 881 67

Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smoke-induced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstructive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-beta1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.
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PMID:Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases. 1596 12

Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448) presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral), 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg) also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma.
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PMID:Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors. 2769 25