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

---

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

The marine natural products manoalide and scalaradial are potent anti-inflammatory agents that inactivate the enzyme phospholipase A2 (PLA2) in vitro. To study the mechanism of inhibition of prostaglandin E2 (PGE2) production in human monocytes by manoalide and scalaradial, lipopolysaccharide (LPS)-induced prostaglandin biosynthesis and induction of prostaglandin H synthase (PGHS) were evaluated. LPS (10 ng/mL) and interleukin-1 beta (IL-1 beta, 50-1000 ng/mL) but not tumor necrosis factor alpha (TNF alpha, 300 ng/mL) induced the expression of the PGHS-2 isoform as determined by immunoblot analysis with a specific polyclonal antibody for PGHS-2. Manoalide and scalaradial (1-10 microM) inhibited LPS-induced endogeneous PGE2 production, reduced the LPS-induced PGHS activity, and reduced the expression of PGHS-2. Indomethacin [a PGHS inhibitor (0.01 to 0.1 microM)], zileuton [a 5-lipoxygenase inhibitor (3-10 microM)], and WEB-2806 [a platelet-activating factor (PAF) antagonist (30 microM)] did not affect the LPS-induced expression of PGHS-2 in human monocytes. These results suggest that modulation of lipid mediator production by manoalide or scalaradial may not be involved in the observed effects on the expression of PGHS-2. Manoalide and scalaradial also inhibited the release of IL-1 beta and TNF alpha from LPS-stimulated monocytes. Expression of PGHS-2 induced by either LPS or IL-1 beta was blocked by the IL-1 receptor antagonist (IL-1ra, 2 micrograms/mL) but not by rolipram, a phosphodiesterase IV inhibitor that inhibits TNF alpha but not IL-1 beta release. Similar to LPS, IL-1 beta-induced PGHS-2 expression was apparently not regulated by lipid mediators such as prostaglandins, leukotrienes or PAF as determined with specific inhibitors and antagonists. Scalaradial and to some extent manoalide were capable of blocking the IL-1 beta-induced expression of PHGS-2. These results indicate that IL-1 beta is the predominant cytokine responsible for the induction of PGHS-2 in the human monocyte. Furthermore, marine natural products such as scalaradial have novel effects on the IL-1 beta-mediated induction of PGHS-2 in human monocytes, which appears to be independent of effects on lipid mediator production.
...
PMID:Regulation of prostaglandin H synthase 2 expression in human monocytes by the marine natural products manoalide and scalaradial. Novel effects independent of inhibition of lipid mediator production. 757 73

One of the challenges in the therapy with anti-inflammatory drugs is the avoidance of gastrointestinal side effects, which may be achieved by selective inhibition of cyclooxygenase (COX) -2. CGP 28238 is reported with these characteristics inhibiting selectively the COX-2 activity at nanomolar concentrations. However, we report here on a novel action of this compound uncovered during the application of higher concentrations. In rat mesangial cells, CGP 28238 induced the mRNA and the protein of COX-2 as well as those of inducible nitric oxide synthase and soluble phospholipase A2. In the case of COX-2, this stimulation had no effect on the production of COX-2 metabolites because of the effective blockade of the enzyme. In contrast, the level of NO produced by the cells increased in a concentration-dependent manner from 1.2 to 12.5 nmol of nitrite/3 x 10(5) cells. Furthermore, in combination with low doses of IL-1 CGP 28238 superinduced the formation of nitrite. The observed effects were independent of the inhibition of prostaglandin formation, as suggested by the failure of the potent COX inhibitor diclofenac to cause similar effects. Furthermore, the activity and expression of enzymes downstream of the COX step, such as prostacyclin synthase, were unaffected by CGP 28238. The inductive action of CGP 28238 could be blocked by inhibitors for tyrosine kinases and protein kinase A, such as genistein and KT5720, respectively. The increase in intracellular cAMP concentration in rat mesangial cells and the inhibition by CGP 28238 of phosphodiesterase 4 activity with an IC50 value of 23 muM gave a rationale to explain the underlying mechanisms for the induction of the inflammatory response genes COX-2, soluble phospholipase A2 and inducible NO synthase in rat mesangial cells.
...
PMID:On the induction of cyclooxygenase-2, inducible nitric oxide synthase and soluble phospholipase A2 in rat mesangial cells by a nonsteroidal anti-inflammatory drug: the role of cyclic AMP. 949 2

Human airway smooth muscle (HASM) cells release granulocyte macrophage-colony stimulating factor (GM-CSF) and express cyclooxygenase (COX)-2 (resulting in the release of prostaglandin [PG] E2) after stimulation with cytokines. Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cyclic adenosine monophosphate (cAMP), on GM-CSF release by HASM cells. Cells stimulated with a combination of proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released significant amounts of PGE2 (measured by radioimmunoassay) and GM-CSF (measured by enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 inhibitors caused concentration-dependent inhibitions of PGE2 concomitantly with increases in GM-CSF formation. Addition of exogenous PGE2 or the beta2-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cells had no effect on GM-CSF release unless COX activity was first blocked with indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SB 207499 both caused concentration-dependent reductions in GM-CSF production. Thus, when HASM cells are activated with cytokines they release PGE2, which acts as a "braking mechanism" to limit the coproduction of GM-CSF. Moreover, agents that elevate cAMP also reduce GM-CSF formation by these cells.
...
PMID:Effects of prostaglandin E2 and cAMP elevating drugs on GM-CSF release by cultured human airway smooth muscle cells. Relevance to asthma therapy. 1115 49

1. Since the cyclo-oxygenase (COX) isoform-nonselective inhibitor indomethacin is known to modify intestinal motility, we analysed the effects of COX-1 and COX-2 inhibition on intestinal peristalsis. 2. Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the pressure changes associated with peristalsis. 3. The COX-1 inhibitor SC-560, the COX-2 inhibitor NS-398 (both at 0.1 -- 1 microM) and the isoform-nonselective inhibitors flurbiprofen (0.01 - 10 microM) and piroxicam (0.1 - 50 microM) were without major influence on peristalsis, whereas indomethacin and etodolac (0.1 -- 10 microM) disturbed the regularity of peristalsis by causing nonpropulsive circular muscle contractions. 4. Radioimmunoassay measurements showed that SC-560, NS-398, indomethacin and etodolac (each at 1 microM) suppressed the release of 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)) from the intestinal segments. 5. Reverse transcription - polymerase chain reaction tests revealed that, relative to glyceraldehyde-3 phosphate dehydrogenase ribonucleic acid, the expression of COX-1 mRNA increased by a factor of 2.0 whereas that of COX-2 mRNA rose by a factor of 7.9 during the 2 h experimental period. 6. Pharmacological experiments indicated that the action of indomethacin to disturb intestinal peristalsis was unrelated to inhibition of L-type calcium channels, adenosine triphosphate-sensitive potassium channels or phosphodiesterase type IV. 7. These results show that selective inhibition of COX-1 and COX-2 does not grossly alter peristaltic motor activity in the guinea-pig isolated small intestine and that the effect of indomethacin to disturb the regular pattern of propulsive motility in this species is unrelated to COX inhibition.
...
PMID:Disturbance of peristalsis in the guinea-pig isolated small intestine by indomethacin, but not cyclo-oxygenase isoform-selective inhibitors. 1125 Aug 81

NSAIDs represent one of the most commonly used therapeutic drug groups world wide. 1.5% of the world's population is estimated as taking NSAIDs. However, their use is not risk free and gastrointestinal (GI) lesions do appear, which is indeed the main reason for their toxicity. Frequently (50%) NSAID-induced GI lesions are asymptomatic, and perforations or hemorrhages could occur without any previous symptoms. 71% of GI perforations and 50% of upper gastric hemorrhages (UGH) are associated with taking NSAIDs. How frequent GI lesions appear is directly related to whether the patient is in a risk group or not. Factors increasing the risk of GI lesions occurring are the following: being older than 60, using corticoids or other NSAIDs concomitantly, having a history of duodenal ulcer, alcohol consumption, smoking or taking oral anticoagulants. As the toxicity and how frequent the lesions appear depend on which drug is used, there is a need for research into new drugs which are both clinically effective and safer to use. GI toxicity of NSAIDs is mediated by two mechanisms, direct toxicity and prostaglandin synthesis inhibition or sistemic mechanism. Due to the relatively recent discoveries concerning the physiopathology of inflammation and gastric physiology, research into new NSAID derivatives is taking place. Such derivatives are prodrugs, galenic buffer forms, selective COX-2 inhibitors, isomeric compounds, NO-donors, and as a future possibility, phosphodiesterase inhibitors.
...
PMID:Antiinflamatory agents less dangerous for gastrointestinal tract. 1147 49

Phosphodiesterase 4D5 is the sole PDE4D cAMP phosphodiesterase isoform expressed in human aortic smooth muscle cells (HASMC). Phorbol 12-myristate 13-acetate (PMA) challenge of HASMC rapidly activated PDE4D5 through a process ablated by the mitogen-activated protein kinase kinase inhibitor PD98059. PMA elicited an inhibitory effect on PDE4D5 activity in HASMC treated with the cyclooxygenase (COX) inhibitor indomethacin, the COX-2 selective inhibitor NS-398, the phospholipase A(2) inhibitor quinacrine, and the cAMP-dependent protein kinase A (PKA) inhibitor H89. PMA challenge of COS-1 cells elicited the rapid inhibition and phosphorylation of both recombinant and endogenous PDE4D5 in a manner ablated by PD98059 and not seen in S651A mutant PDE4D5. PMA promoted the generation of PGE(2) in the medium of HASMC and caused activation of both extracellular signal-regulated kinase (ERK) and PKA through a process ablated by indomethacin, NS-398, quinacrine, and PD98059. Exogenous prostaglandin (PG) E(2) increased cAMP levels and activated PKA in HASMC. COX-2 was expressed in HASMC but not in COS-1 cells. Forskolin challenge of COS-1 cells activated PDE4D5 by causing the PKA-mediated phosphorylation of Ser126 as detected using a novel phosphospecific antiserum. PMA challenge of HASMC elicited phosphorylation of the stimulatory PKA-specific phosphorylation site, Ser126 in PDE4D5 in a manner ablated by PD98059, indomethacin, and H89. We propose that, in HASMC, PMA activates PDE4D5 through an ERK-controlled autocrine mechanism. This involves PGE(2) generation, which causes activation of adenylyl cyclase, allowing PKA to elicit net activation of PDE4D5 by phosphorylation at Ser126.
...
PMID:Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal regulated kinase (ERK). 1164 39

Angiogenesis is reportedly enhanced by prostaglandins (PGs). In the present experiment, we tested whether or not COX-2 and adenylate cyclase/protein kinase A (AC/PKA)-dependent VEGF induction enhanced angiogenesis in this model. Angiogenesis was enhanced by topical injection of human recombinant basic fibroblast growth factor (bFGF). The enhanced angiogenesis by bFGF was inhibited by indomethacin or selective COX-2 inhibitors, NS398, nimesulide, and JTE-522. Topical daily injections of 8-bromo-cAMP enhanced angiogenesis in a dose-dependent manner. Forskolin, an activator of AC, also facilitated angiogenesis in a dose-dependent manner, as did amrinone, an inhibitor of phosphodiesterase. VEGF induction was confirmed by the increased levels in the fluids in the sponge matrix after topical injection of 8-bromo-cAMP. Immunohistochemical investigation further revealed the VEGF-expressed cells in the sponge granulation tissues to be fibroblasts, and the intensity of positive reactions was enhanced by bFGF, 8-bromo-cAMP, forskolin, and amrinone. Angiogenesis was inhibited by indometacin or selective COX-2 inhibitors, NS-398, nimesulide, and JTE-522. In addition, angiogenesis without topical injections of the above compounds was also suppressed by SQ22,536, an inhibitor for AC. or H-89, an inhibitor for PKA, with concomitant reductions in VEGF levels. Daily topical injections of neutralizing antibody or anti-sense oligonucleotide against VEGF significantly suppressed angiogenesis. These results suggested that COX-2 and AC/PKA-dependent induction of VEGF certainly enhanced angiogenesis, and that pharmacological tools for controlling this signaling pathway may be able to facilitate the management of conditions involving angiogenesis.
...
PMID:Cyclooxygenase-2 and adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in rat sponge implants. 1212 60

The present study aimed to evaluate the anti-inflammatory effects of pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor in the rat. Acute inflammation was induced by subplantar injection of carrageenan (1%) in the rat hind paw. Results showed that intraperitoneal (i.p.) administration of PTX (36 or 72 mg kg(-1)) 30 min prior to carrageenan reduced the paw oedema response in dose-dependent manner with a maximal effect of 18.9 and 40.1%, respectively, at 2h post-carrageenan (P<0.001 and <0.001 at respective doses). Theophylline given at equimolar doses (29.9 or 45.8 mg kg(-1), i.p.) did not reduce the oedema response. With higher doses of PTX (144-300 mg kg(-1), i.p.) the anti-oedema effect of the drug was more pronounced, but mainly confined to the first 2h following carrageenan injection and decreasing rapidly thereafter. PTX (72 mg kg(-1), i.p.) given 30 min after carrageenan challenge reduced the oedema response by 24.7 and 26.2% at 1 and 2h after dosing (P<0.05 and <0.05, respectively). PTX (36 or 72 mg kg(-1), i.p.) co-administered with indomethacin (5 mg kg(-1), i.p.) 30 min before carrageenan had little modulatory effect on the anti-oedema effect of indomethacin, but the higher dose of PTX (144 mg kg(-1), i.p.) reduced the anti-inflammatory effect of indomethacin by 24% at 4h post-carrageenan. PTX (72 mg kg(-1), i.p.) enhanced the anti-oedema effect of the selective COX-2 inhibitor celecoxib (33 mg kg(-1), i.p.) by 55.1% at 4h post-carrageenan. In contrast, the higher dose of PTX (144 mg kg(-1), i.p.) reduced the anti-oedema effect of celecoxib by 46.8% at 4h post-carrageenan. PTX (36 or 72 mg kg(-1)) enhanced the anti-oedema effect of dexamethasone (0.1 mg kg(-1)) with maximal effect of 76 and 104.8% at 2h post-carrageenan (P<0.01 and <0.01 for respective doses). PTX (0.6 mg per paw) given with carrageenan into the rat hind paw reduced the oedema response with a maximal effect of 33.4% at 1h following carrageenan. PTX (0.6 mg per paw) given in the contralateral hind paw reduced the carrageenan-induced paw oedema for 1h by 32.2%. Thus, PTX, when given at doses comparable to those used in man for treatment of circulatory disorders displayed anti-inflammatory in vivo and enhanced the anti-inflammatory effect of a selective COX-2 inhibitor or dexamethasone. PTX may have therapeutic potential as anti-inflammatory agent either alone or in combination with non-steroidal anti-inflammatory drugs or with steroids. There is also an intriguing possibility for the use of topical preparations for the management of local inflammatory conditions.
...
PMID:The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat. 1264 91

Thalidomide the first commercially available immune modulatory drug (IMiD), has activity in the treatment of Waldenstrom's macroglobulinemia (WM), as well as multiple myeloma, myelodysplastic syndrome, myelofibrosis with myeloid metaplasia, chronic lymphocytic leukemia (CLL), and B-cell lymphomas. Although its molecular mechanisms of action have not yet been elucidated, thalidomide and the IMiDs affect a variety of cytokines and inflammatory mediators including tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, interferon gamma (IFNgamma), IL-6, IL-10, IL-12, and COX-2 and angiogenesis factors such as vascular endothelial growth factor (VEGF) and its receptor. The IMiDs also affect adhesion molecules such as ICAM-1, ICAM-2, and L-CAM, in addition to preferentially stimulating CD8 cells and expanding natural killer (NK) cell populations. Since most IMiDs share these properties, it would be expected that the second-generation IMiDs (REVIMID, ACTIMID) would have activity similar to thalidomide in WM with an improved safety profile. TNFalpha and angiogenesis most likely play a role in promoting the growth and development of WM. The selective cytokine inhibitory drugs (SelCIDs) are potent phosphodiesterase 4 (PDE-4) inhibitors that inhibit TNFalpha production and are highly antiangiogenic. In addition, inhibition of PDE-4 induces apoptosis in human CLL lymphocytes. It is therefore expected that the SelCIDs might have activity in Waldenstrom's tumors. Jun N-terminal kinase (JNK) is a component of signaling cascades that modulate apoptosis, the induction of an inflammatory response via the AP-1 pathway, and modulation of cellular proliferation. In a variety of tumors, including multiple myeloma, JNK is induced as part of a protective mechanism. It is hypothesized that inhibition of JNK activity might allow other chemotherapeutic agents to be more effective in a similar manner to corticosteroids. Work is in progress to evaluate this. Inhibitors of the E3 subunit of ubiquitin ligase may also selectively modulate the expression of receptors, growth factors, and transcription factors essential to the growth, survival, and spread of tumors. We hypothesize that the IMiDs, SelCIDs, JNK inhibitors, and ligase inhibitors will be the basis for a new nonchemotherapeutic approach to the treatment of WM and other related diseases.
...
PMID:Potential new therapeutics for Waldenstrom's macroglobulinemia. 1272 Jan 52

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E2 (PGE2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE2 mediated cyclic (c) AMP pathway because PGE2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate cAMP levels) decreased GM-CSF release, in the presence of PGE2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.
...
PMID:NSAIDs increase GM-CSF release by human synoviocytes: comparison with nitric oxide-donating derivatives. 1568 Feb 49


1 2 3 Next >>

---