Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that Trypanosoma cruzi infection of endothelial cells results in alterations in the metabolism of Ca2+, inositol triphosphate (IP3), and prostacycline (PGI2). In this report, we demonstrate that infection also alters the metabolism of cAMP. Infection of endothelial cells does not significantly alter beta-adrenergic receptor density or affinity, adenylate cyclase activity, and whole-cell cAMP levels. However, incubation of infected endothelial cells with the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) resulted in less than a 60% increase in cell cAMP in contrast to the greater than a 100% increase observed in uninfected endothelial cells under otherwise identical reaction conditions. Infected endothelial cells demonstrated a twofold increase in phosphodiesterase activity when measured directly. Moreover, homogenates prepared from infected endothelial cells previously incubated with isoproterenol for 20 min showed little or no change in PDE activity. In contrast, homogenates prepared from uninfected endothelial cells treated under otherwise identical reaction conditions showed a 5.7-fold increase in PDE activity. In the presence of IBMX, isoproterenol-dependent stimulation of cAMP levels in infected endothelial cells reached a maximum level at 5 min of incubation, and thereafter rapidly declined. In contrast, cAMP levels in uninfected endothelial cells reached a maximum at 2 min of incubation, and thereafter remained elevated throughout the duration of the incubation. Infection-associated changes in isoproterenol dependent stimulation of cAMP accumulation appear to relate, in part, to changes in PDE activity.
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PMID:Trypanosoma cruzi: alteration of cAMP metabolism following infection of human endothelial cells. 130 2

Infection of Escherichia coli with phage T4 gene 2am was used to transport 3H-labeled linear duplex DNA into cells to follow its degradation in relation to the cellular genotype. In wild-type cells, 49% of the DNA was made acid soluble within 60 min; in recB or recC cells, only about 5% of the DNA was made acid soluble. Remarkably, in recD cells about 25% of the DNA was rendered acid soluble. The DNA degradation in recD cells depended on intact recB and recC genes. The degradation in recD cells was largely decreased by mutations in recJ (which eliminates the 5' single-strand-specific exonuclease coded by this gene) or xonA (which abolishes the 3' single-strand-specific exonuclease I). In a recD recJ xonA triple mutant, the degradation of linear duplex DNA was roughly at the level of a recB mutant. Results similar to those with the set of recD strains were also obtained with a recC++ mutant (in which the RecD protein is intact but does not function) and its recJ, xonA, and recJ xonA derivatives. The observations provide evidence for a recBC-dependent DNA-unwinding activity that renders unwound DNA susceptible to exonucleolytic degradation. It is proposed that the DNA-unwinding activity causes the efficient recombination, DNA repair, and SOS induction (after application of nalidixic acid) in recD mutants. The RecBC helicase indirectly detected here may have a central function in Chi-dependent recombination and in the recombinational repair of double-strand breaks by the RecBCD pathway.
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PMID:Evidence that recBC-dependent degradation of duplex DNA in Escherichia coli recD mutants involves DNA unwinding. 132 85

Border disease (BD) was induced in lambs by inoculation of their dams at 50 days gestation with Border disease virus (BDV) isolate #31. At birth, the clinically affected lambs had diffuse spinal cord hypomyelination, confirmed by immunocytochemical staining for myelin-associated glycoprotein and myelin basic protein. In the BD lambs, large numbers of thyroid follicular epithelial cells and scattered pituitary cells contained BDV antigen by immunofluorescence staining. Double labeling techniques demonstrated the BDV-infected pituitary cells to contain growth hormone, adrenocorticotrophic hormone, prolactin, or luteinizing hormone. Cells containing thyroid stimulating hormone were rare and were not positive for BDV antigen. Infection of the pituitaries and thyroid glands caused no detectable morphologic changes as compared to controls. The BD lambs had statistically significantly (p less than 0.05) lower mean serum concentrations of thyroxine and L-3,3',5-triiodothyronine as compared to age-matched uninfected controls. Similar significant differences in the mean plasma levels of growth hormone and thyroid stimulating hormone were not found. In addition, the BD lambs had a statistically significant (p less than 0.05) lower mean activity of the myelin-associated, thyroid hormone dependent enzyme, 2',3'-cyclic nucleotide-3'-phosphodiesterase in spinal cord tissue. Although not conclusive, these results indicate that the hypomyelination in BD may be due to depressed levels of circulating thyroid gland hormones secondary to a noninflammatory and noncytolytic infection of the thyroid gland by BDV. This is one of the first reports indicating that a virus-induced hormonal alteration may cause a congenital lesion in animals.
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PMID:Border disease. Virus-induced decrease in thyroid hormone levels with associated hypomyelination. 244 Nov 39

We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cAMP levels in lipopolysaccharide (LPS)-stimulated PBMC. Cicaprost (a stable analogue of prostacyclin) and pentoxifylline added simultaneously to LPS-stimulated PBMC (2.0 x 10(6)/ml) induced a rapid increase of cAMP to a level of 100 nM that peaked within 10 min and remained at a plateau for up to 4 h. Thus combined prostanoids and PDE inhibitors enhanced cAMP accumulation. TNF-alpha suppression in the presence of pentoxifylline and prostanoids exceeded that of either drug alone. The potency of different PDE inhibitors (theophylline, pentoxifylline, penthydroxifylline, albifylline, torbafylline, A 80 2715, amrinone and rolipram) to increase cAMP levels in combination with cicaprost was evaluated after 1 h of incubation. The dose-dependent increase of cAMP for all PDE inhibitors tested in this combined stimulation provided a useful tool for evaluating the potency of PDE inhibitors on cAMP accumulation. The effective concentration of PDE inhibitors, which raised cAMP levels to 300% of control, (EC300), correlated with the IC50 for TNF-alpha suppression (r = 0.930, p = 0.007, with theophylline excluded from the analysis). Interestingly, by contrast, the specific type IV PDE inhibitor rolipram caused only a moderate rise of accumulated cAMP in the same cells. Our data support cAMP as an essential mediator for TNF-alpha suppression by PDE inhibitors. Furthermore, an enhanced inhibiting effect on TNF-alpha production may prove therapeutically advantageous. It may occur in inflammatory and infectious diseases in vivo, since high levels of endogenous prostaglandins are liberated in these conditions.
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PMID:Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids. 784 25

Injury of peripheral nerves induces expression of several pro-protein convertases (PCs) involved in processing of precursor proteins into their diverse active end-products. In this study, the focus was on convertase PC1 which, although undetectable in control nerves, is strongly induced in injured nerves. High concentrations of PC1 mRNA of 9.0, 5.5, 3.0, 2.5 and 1.6 kb were observed on day 4 post-lesion in proximal and distal segments. By in situ hybridization PC1 mRNA was detected in most of endoneurial cells, which were further identified by immunocytochemistry as myelin 2', 3'-cyclic nucleotide 3'-phosphodiesterase containing Schwann cells. PC1 mRNA and protein were also present in cultured Schwann cells also containing convertases PC5, furin and PC7 as well as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Mostly unprocessed pro-NGF of 35 kDa and pro-BDNF of 35 kDa were found on Western blotting of Schwann cells. Expression of exogenous neurotrophins by infection with vaccinia virus vector showed that mouse pro-NGF and rat pro-BDNF are cleaved intracellularly on smaller forms of 13.5 kDa NGF and 14 kDa BDNF. Infection experiments demonstrated that Schwann cells contain active processing enzymes. In conclusion, this work provides in vivo evidence of the presence of several PCs in the injured rat sciatic nerve and ex vivo in cultured Schwann cells.
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PMID:The pro-protein convertase PC1 is induced in the transected sciatic nerve and is present in cultured Schwann cells: comparison with PC5, furin and PC7, implication in pro-BDNF processing. 972 4

Magnaporthe grisea, the causal agent of rice blast, is one of the most destructive fungal pathogens of rice throughout the world. Infection of rice by M. grisea requires the formation of an appressorium, a darkly pigmented, dome-shaped structure. The germ tube tip differentiates into an appressorium following germination of conidia on a leaf surface. When conidia germinate on growth medium or other noninductive surfaces, the emerging germ tube does not differentiate and continues to grow vegetatively. Little is known about the endogenous or exogenous signals controlling the developmental process of infection structure formation. We show here that a hydrophobic surface was sufficient for the induction of the appressorium. Furthermore, we demonstrate that the addition of cAMP, its analogs (8-bromo cAMP and N6-monobutyryl cAMP), or 3-isobutyl-1-methylxanthine (an inhibitor of phosphodiesterase) to germinating conidia or to vegetative hyphae induced appressorium formation on noninductive surfaces. The identification of cAMP as a mediator of infection structure formation provides a clue to the regulation of this developmental process. Elucidation of the mechanism involved is not only of biological interest but may also provide the basis for new disease control strategies.
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PMID:cAMP Regulates Infection Structure Formation in the Plant Pathogenic Fungus Magnaporthe grisea. 1227 Oct 80

The five-part "Pointers in Practical Pharmacology" immunomodulation series has presented some of the agents researchers are investigating in hopes of finding the means to effectively prevent and treat infectious processes in neonates. The phosphodiesterase inhibitor pentoxifylline appears promising, but large, randomized, clinical trials are still lacking. So far, there is no clear evidence to support the use of G-CSF for either the prevention or the treatment of sepsis. The results of a large, randomized, clinical trial of G-CSF in the United Kingdom are pending. Although intravenous immunoglobulin (IVIG) therapy does not appear to be useful in the prevention of sepsis, its effectiveness in the treatment of sepsis is uncertain. It is hoped that the results of the International Neonatal Immunotherapy Study will provide definitive answers regarding treatment of sepsis with IVIG. The "conditionally essential" amino acid glutamine administered either enterally or parenterally does not make a difference in the rate of systemic infection or NEC in very low birth weight infants. Finally, probiotics appear promising as documented by at least two of the three randomized, clinical trials described here. As the search continues for agents to enhance the neonate's immune system and prevent and treat infectious diseases, remember that our best prevention tool is excellent and consistent hand hygiene.
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PMID:Immunomodulation, Part V: probiotics. 1728 88

Cultures of endogenous GnRH neurons and the GT1 GnRH neuronal cell line release GnRH in pulses (intrinsic pulsatile release) with an interpulse frequency similar to that seen in castrated animals. In both GT1 cells and transgenic rats, lowering cAMP levels by expression of a phosphodiesterase decreased the frequency of intrinsic GnRH pulsatility. We asked whether the cyclic nucleotide-gated cation (CNG) channels expressed in GT1 cells participated in cAMP modulation of intrinsic GnRH pulsatility. Because expression of the CNGA2 subunit is essential for formation of functional CNG channels, we developed an adenovirus (Ad) vector expressing a short interference RNA (siRNA) to the CNGA2 subunit (Ad-CNG-siRNA) or as an infection control, to the coding region of luciferase (Ad-Luc-siRNA). Infection with the Ad-CNG-siRNA of COS cells transfected with a CNGA2 expression vector significantly inhibited CNGA2 protein levels by 74% by Western blot. Infection of GT1-1 cells with Ad-CNG-siRNA resulted in a 68% decrease in the levels of CNGA2 mRNA, a 44% decrease in protein levels, and a clear decrease in immunostaining with an antibody to CNGA2. Infection of GT1-1 cells with Ad-CNG-siRNA decreased spontaneous Ca2+ oscillations compared with Ad-Luc-siRNA-infected or uninfected cells by 71%. Furthermore infection with Ad-CNG-siRNA resulted in a 2-fold increase in the interpulse interval in GnRH secretion (49.4+/-9.1 min) compared with uninfected cells (25.9+/-2.5 min) or Ad-Luc-siRNA (29.3+/-2.8 min)-infected cells. These data provide the first direct evidence that the CNG channel is a downstream signaling molecule in the regulation of the frequency of intrinsic GnRH pulsatility by cAMP.
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PMID:Frequency of intrinsic pulsatile gonadotropin-releasing hormone secretion is regulated by the expression of cyclic nucleotide-gated channels in GT1 cells. 1739 96

Tumor necrosis factor-alpha (TNF-alpha) is known to have numerous biological properties relating to inflammation. This cytokine participates in the tissue damage of chronic inflammatory, autoimmune and infectious diseases. Pentoxifylline is a methylxanthine that inhibits phosphodiesterase IV, which inhibits the degradation of the cAMP and prostanoids. The increased intracellular concentration of the cAMP leads to a negative regulation of NF-kappaB and NF-AT transcription factors and suppresses TNF-alpha production. This review describes studies that support evidences that TNF-alpha is involved in the pathogenesis of HTLV-1 associated myelopathy and of cutaneous and mucosal leishmaniasis. Additionally, it demonstrates the effect of pentoxifylline in vitro in inhibiting TNF-alpha and IFN-gamma spontaneous production in PBMC from HTLV-1-infected patients, as well as its in vivo effect in inhibiting TNF-alpha in sera from mucosal leishmaniasis patients. Moreover, we review the results of clinical studies from the last 10 years using pentoxifylline to treat HTLV-1 associated myelopathy and cutaneous and mucosal leishmaniasis.
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PMID:Pentoxifylline down modulate in vitro T cell responses and attenuate pathology in Leishmania and HTLV-I infections. 1868 97

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-alpha-induced NF-kappaB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-alpha- or LPS-induced up-regulation of proinflammatory mediators, including TNF-alpha, IL-1beta, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-alpha- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-kappaB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca(2+) regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.
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PMID:Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism. 2049 91


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