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)

The balance between different immunological stimuli is essential in the progression and stabilization of atherosclerotic plaques. Immune regulation has been suggested as potential target for the treatment of atherosclerotic disease. We sought to determine whether treatment with pentoxifylline, a phosphodiesterase inhibitor with immunomodulating properties, could reduce the pro-inflammatory response observed in patients with acute coronary syndromes (ACS) and increase anti-inflammatory activity. In a double-blind, prospective, placebo-controlled study, 64 patients with ACS were randomized to receive pentoxifylline 400mg TID or placebo for 6 months. Analysis of the pro-inflammatory markers, C-reactive protein (CRP), interleukin (IL)-6, IL-12, interferon-gamma and tumor necrosis factor (TNF)-alpha and the anti-inflammatory cytokines, transforming growth factor (TGF)-beta1 and IL-10 were done at baseline, 1 and 6 months. Pentoxifylline treatment significantly reduced the adjusted levels of CRP and TNF-alpha compared to placebo after 6 months (P=0.04 and P<0.01, respectively). IL-12 increase was significantly less pronounced with pentoxifylline (P=0.04). The levels of the anti-inflammatory cytokine, IL-10, also declined significantly less in the pentoxifylline group compared to placebo (P<0.01) with a trend towards a higher increase of TGF-beta1 in the former group (P=0.16). Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory response in patients with ACS and may have beneficial clinical effects on cardiovascular events.
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PMID:Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease--a randomized placebo-controlled study. 1719 8

Pentoxifylline (PTX) is a nonspecific phosphodiesterase inhibitor which has potent immunoregulatory and antiinflammatory effects. Although its immunomodulation property has been recognized, it is not clear whether PTX could affect dendritic cells (DCs), the most efficient antigen-presenting cells. The purpose of this study was to determine whether PTX could suppress DC differentiation, maturation, and its associated functions. Immature DCs (iDCs) were generated from human peripheral blood mononuclear cell CD14+ monocytes cultured with granulocyte macrophage colony stimulating factor and interleukin-4 for 5 days. PTX concentration-dependently suppressed the expression of iDC differentiation markers including CD54, CD80, CD86, and human leukocyte antigen-DR. In addition, PTX also inhibited DC maturation marker CD83 expression after stimulating DCs with lipopolysaccharide. Furthermore, PTX inhibited the antigen-uptake ability of DCs when tested by fluorescein isothiocyanate-dextran endocytosis assay. PTX significantly reduced the production of TNF-alpha and IFN-gamma in mature DCs (mDCs). Consequently, PTX-treated mDCs showed a reduced activity of mDC-induced T-cell allostimulation and proliferation by mixed-lymphocyte reaction (MLR) assay. Therefore, PTX significantly inhibits CD14+ monocyte-derived DC differentiation, maturation, antigen-uptake ability of iDCs, and antigen-presentation ability of mDCs possibly due to the suppression of TNF-alpha and IFN-gamma production. These results suggested that inhibitory effects of PTX on DCs may contribute its antiinflammatory and immunoregulatory functions.
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PMID:Effects of pentoxifylline on differentiation, maturation, and function of human CD14+ monocyte-derived dendritic cells. 1719 87

The H(+)-coupled transporter hPepT1 (SLC15A1) mediates the transport of di/tripeptides and many orally-active drugs across the brush-border membrane of the small intestinal epithelium. Incubation of Caco-2 cell monolayers (15 min) with the dietary phosphodiesterase inhibitors caffeine and theophylline inhibited Gly-Sar uptake across the apical membrane. Pentoxifylline, a phosphodiesterase inhibitor given orally to treat intermittent claudication, also decreased Gly-Sar uptake through a reduction in capacity (V(max)) without any effect on affinity (K(m)). The reduction in dipeptide transport was dependent upon both extracellular Na(+) and apical pH but was not observed in the presence of the selective Na(+)/H(+) exchanger NHE3 (SLC9A3) inhibitor S1611. Measurement of intracellular pH confirmed that caffeine was not directly inhibiting hPepT1 but rather having an indirect effect through inhibition of NHE3 activity. NHE3 maintains the H(+)-electrochemical gradient which, in turn, acts as the driving force for H(+)-coupled solute transport. Uptake of beta-alanine, a substrate for the H(+)-coupled amino acid transporter hPAT1 (SLC36A1), was also inhibited by caffeine. The regulation of NHE3 by non-nutrient components of diet or orally-delivered drugs may alter the function of any solute carrier dependent upon the H(+)-electrochemical gradient and may, therefore, be a site for both nutrient-drug and drug-drug interactions in the small intestine.
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PMID:Regulation of intestinal hPepT1 (SLC15A1) activity by phosphodiesterase inhibitors is via inhibition of NHE3 (SLC9A3). 1749 47

We have previously shown that catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cyclic adenosine monophosphate (cAMP) cascade in normal rats. In the present work, we investigated in vivo and in vitro effects of cAMP-phosphodiesterase inhibitors on protein metabolism in skeletal muscle from rats submitted to a model of acute sepsis. The in vivo muscle protein metabolism was evaluated indirectly by measurements of the tyrosine interstitial concentration using microdialysis. Muscle blood flow (MBF) was monitored by ethanol perfusion technique. Sepsis was induced by cecal ligation and puncture and resulted in lactate acidosis, hypotension, and reduction in MBF (-30%; P < 0.05). Three-hour septic rats showed an increase in muscle interstitial tyrosine concentration (approximately 150%), in arterial plasma tyrosine levels (approximately 50%), and in interstitial-arterial tyrosine concentration difference (approximately 200%; P < 0.05). Pentoxifylline (50 mg/kg of body weight, i.v.) infusion during 1 h after cecal ligation and puncture prevented the tumor necrosis factor alpha increase and significantly reduced by 50% (P < 0.05) the interstitial-arterial tyrosine difference concentration. In situ perfusion with isobutylmethylxanthine (IBMX; 10(-3) M) reduced by 40% (P < 0.05) the muscle interstitial tyrosine in both sham-operated and septic rats. Neither pentoxifylline nor IBMX altered MBF. The addition of IBMX (10(-3) M) to the incubation medium increased (P < 0.05) muscle cAMP levels and reduced proteolysis in both groups. The in vitro addition of H89, a protein kinase A inhibitor, completely blocked the antiproteolytic effect of IBMX. The data show that activation of cAMP-dependent pathways and protein kinase A reduces muscle protein catabolism during basal and septic state.
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PMID:Cyclic adenosine monophosphate-phosphodiesterase inhibitors reduce skeletal muscle protein catabolism in septic rats. 1750 10

Our previous studies demonstrated that Pentoxifylline (PTX), a phosphodiesterase inhibitor, could inhibit the lung homing of B16-F10 melanoma cells in C57BL/6 mice. In this study we have looked at the effect of PTX on cell surface integrin expression and integrin mediated adhesion of B16-F10 melanoma cells. B16-F10 cells treated with PTX when injected through the tail vein of mice showed a 75% reduction in pulmonary nodules as compared to control untreated cells. PTX brought about a significant reduction in the integrin mediated adhesion of F10 cells to Fibronectin and Vitronectin (58.75% +/- 3.4 S.E and 60% +/- 1.7 S.E respectively if control was considered as 100%). This inhibition in adhesion was evident up to four hours only and treatment for 24 hours brought about an increase in adhesion (135.5% +/- 0.5 S.E). Flow cytometric analysis showed higher surface expressions of alphav, alpha5 and alphaIIb integrin subunits in B16-F10 as compared to the low metastatic cell line B16-F1 suggesting a role for these integrins in determining the metastatic potential. PTX brought about a significant decrease in the cell surface expression of alpha5, alphaIIb and beta1 integrin subunits but not that of the alphav subunit on B16-F10 cells. PTX also brought about a reduction in the total cellular protein levels of beta1 and alphav integrin subunits. Various isoforms of Protein Kinase C (PKC) has been shown to regulate integrin expression, localization and activity. Hence we looked at the effect of PTX on total cellular PKC activity. PTX brought about a significant reduction in total cellular PKC activity (82.66 +/- 0.593). Collectively our results indicate that the antimetastatic action of PTX is mediated, at least in part through its effects on adhesion and the surface expression of specific integrin receptors.
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PMID:Pentoxifylline modulates cell surface integrin expression and integrin mediated adhesion of B16F10 cells to extracellular matrix components. 1798 56

High cervical spinal cord hemisection interrupts the descending respiratory drive from the medulla to the ipsilateral phrenic motoneurons, consequently leading to the paralysis of the ipsilateral hemidiaphragm. Previous studies have shown that chronic oral administration of theophylline, a phosphodiesterase inhibitor and an adenosine receptor antagonist, can restore function to the quiescent phrenic nerve and hemidiaphragm ipsilateral to hemisection. Both of these actions of theophylline result in an increase in 3'-5'-cyclic adenosine monophosphate (cAMP). Furthermore, the chronic theophylline-mediated respiratory recovery persists long after the animals have been weaned from the drug. To date, the precise cellular mechanisms underlying the recovery induced by theophylline are still not known. Since theophylline has two modes of action, in the present study we tested whether chronic administration of pentoxifylline, a non-selective phosphodiesterase inhibitor, rolipram, a phosphodiesterase-4 specific inhibitor, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, would induce recovery similar to that induced by theophylline in male Sprague-Dawley rats following a left C2 spinal cord lesion. Recovery of left phrenic nerve activity was assessed at 5 or 10 days after the last drug administrations to assess the persistent nature of the recovery. Pentoxifylline, rolipram and DPCPX, all capable of modulating 3',5'-cyclic monophosphate (cAMP) levels, brought about long-term respiratory recovery in the phrenic nerve ipsilateral to the left C2 lesion at 5 and 10 days after the last drug administration. Therefore, these results suggest that compounds capable of regulating cAMP levels may be therapeutically useful in promoting functional recovery following spinal cord injury.
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PMID:Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats. 1828 33

Cancer cell migration is a hallmark of metastatic cascade and compounds that can intervene in this process are clinically important. Pentoxifylline (PTX), a methyl xanthine derivative, inhibits B16F10 melanoma lung homing by inhibiting F10 invasion, MMP secretion and adhesion to matrix components. However, its effect on B16F10 migration remained unexamined, which we investigated in the present study. PTX significantly inhibits F10 migration in scratch wound assay. Elevation in cAMP levels inhibits F10 migration and PTX mediated inhibition of the process was found to be, in part, due to an increase in cellular cAMP levels. PTX induces Protein Kinase A (PKA) activity and PKA inhibitor partly reversed its effects on F10 motility. RhoA and Rac1 GTPases induce B16F10 motility and PTX was found to inhibit migration by affecting these molecules. Stress fibres and lamellipodial protrusions reduced significantly. This was accompanied with inhibition in RhoA and Rac1 membrane localisation. A stark inhibition in RhoA-GTP bound form was also observed. Taken together, the results indicate that PTX, through its phosphodiesterase action, inhibits RhoGTPases and associated actin organisation in B16F10 melanoma, thereby inhibiting cell motility.
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PMID:Pentoxifylline impedes migration in B16F10 melanoma by modulating Rho GTPase activity and actin organisation. 1849 74

Myasthenia gravis (MG) is frequently treated by corticosteroids such as methylprednisolone. However, continuous treatment with steroids often results in adverse effects. In the present study we evaluated the therapeutic potential of a combination of suboptimal doses of methylprednisolone (Solumedrol) and Pentoxifylline (PTX), a general phosphodiesterase (PDE) inhibitor, in rat experimental autoimmune MG (EAMG). This combined treatment resulted in a pronounced suppressive effect on EAMG and was by far more effective than each of the drugs administered separately at these low doses. The suppressive effect on EAMG was accompanied by decreased humoral and cellular responses to AChR as well as down-regulated mRNA expression levels of Th1 cytokines and IL-10 in lymph node cells and of PDE-4 and cathepsin-l in the muscle. This study demonstrates the potential of PTX as a steroid-sparing agent in the management of myasthenia gravis.
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PMID:Suppression of experimental autoimmune myasthenia gravis by combination therapy: pentoxifylline as a steroid-sparing agent. 1863 63

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

Loss of intestinal barrier function after burn injury allows movement of intraluminal contents across the mucosa, which can lead to the development of distant organ injury and multiple organ failure. Tight junction function is highly regulated by membrane-associated proteins including occludin and zonula occludens protein 1 (ZO-1), which can be modulated by systemic inflammation. We hypothesized that (1) burn injury leads to gut barrier injury, and (2) phosphodiesterase inhibition will attenuate these burn-induced changes. Male balb/c mice undergoing a 30% steam burn were randomized to resuscitation with normal saline or normal saline + pentoxifylline (PTX; 12.5 mg/kg). Intestinal injury was assessed by histological diagnosis and TNF-alpha levels using enzyme-linked immunosorbent assay. Intestinal permeability was assessed by measuring the plasma concentration of fluorescein isothiocyanate-dextran after intraluminal injection in the distal ileum. Occludin and ZO-1 levels were analyzed by immunoblotting and immunohistochemistry. Thirty percent total body surface area (TBSA) burn results in a significant increase in intestinal permeability. Treatment with PTX after burn attenuates intestinal permeability to sham levels. Burn injury resulted in a marked decrease in the levels of tight junction proteins occludin and ZO-1 at 6 and 24 h. The use of PTX after burn significantly decreases the breakdown of occludin and ZO-1. Pentoxifylline also attenuates the burn-induced increase in plasma and intestinal TNF-alpha. Confocal microscopy demonstrates that PTX attenuates the burn-induced reorganization of occludin and ZO-1 away from the tight junction. Pentoxifylline attenuates burn-induced intestinal permeability and decreases the breakdown and reorganization of intestinal occludin and ZO-1. Therefore, phosphodiesterase inhibition may be a useful adjunct strategy in the attenuation of burn-induced gut barrier injury.
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PMID:Burn-induced gut barrier injury is attenuated by phosphodiesterase inhibition: effects on tight junction structural proteins. 1879 95


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