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)

Our studies of mononuclear leukocyte peripheral blood homogenates demonstrate significantly increased cyclic adenosine monophosphate-specific phosphodiesterase activity in patients with atopic dermatitis who were untreated for 1 week, compared with normal adult nonatopic control subjects. Phosphodiesterase activity is not related to the extent or activity of the patient's disease or the presence or absence of allergic respiratory disease. Enzyme kinetic studies showed a triphasic plot in normal mononuclear leukocytes but a biphasic plot in atopic dermatitis. This may be interpreted as an absence of an enzyme with a low (0.080) Michaelis Menton constant (Km) in atopic dermatitis samples. One week of therapy with a topical fluorinated steroid ointment caused a significant reduction in disease activity. Although a slight reduction in mean total phosphodiesterase activity occurred, it did not reach statistical significance. One week's treatment, however, caused the abnormal biphasic kinetic plot to revert to a triphasic plot with return of the low Km enzyme form in those patients who showed a fall in phosphodiesterase activity. This finding suggests that the elevated phosphodiesterase activity in atopic dermatitis may be responsive in a limited degree to topical steroid therapy.
J Am Acad Dermatol 1989 Jul
PMID:Response of mononuclear leukocyte cyclic adenosine monophosphate-phosphodiesterase activity to treatment with topical fluorinated steroid ointment in atopic dermatitis. 254 50

Significantly elevated activity of peripheral blood mononuclear cell cAMP specific phosphodiesterase (PDE) activity has been previously reported in adults with atopic dermatitis and in the cord blood of children born to atopic parents. We have been unable to confirm such a significant elevation in children with atopic dermatitis, and we have not found any correlation with dermatitis severity, age or total serum IgE.
Br J Dermatol 1989 May
PMID:Peripheral blood mononuclear leukocyte cyclic adenosine monophosphate specific phosphodiesterase activity in childhood atopic dermatitis. 254 17

Increased cyclic AMP (cAMP) phosphodiesterase activity (PDE) is present in the peripheral blood mononuclear leucocytes (MNL) of patients suffering from atopic dermatitis. It is unknown whether this is a primary abnormality or whether it is a consequence of MNL exposure to inflammatory mediators. In this study we have compared the responses of MNL PDE from untreated atopic dermatitis patients, patients on prolonged therapy with topical fluorinated steroids, and normal controls following exposure in vitro to low concentrations of histamine. We have confirmed that PDE activity is elevated in the MNL of patients suffering from atopic dermatitis who have used emollients only for 1 week. However, patients on therapy with topical fluorinated steroids have MNL PDE activity similar to normal controls in spite of the persistence of some active eczema. Exposure to histamine in vitro results in a similar increase of MNL PDE in untreated patients and normal controls. However, treated patients show no elevation of MNL PDE activity following in vitro histamine exposure. The results suggest that the normal MNL PDE values seen in patients treated with topical fluorinated steroids may not be the consequence of reduced cutaneous inflammation, but the result of a direct action of topical steroids on MNL. This action abrogates any in vitro response to histamine and presumably acts in a similar fashion in vivo.
Clin Exp Dermatol 1989 May
PMID:The effect of in vitro exposure to histamine on mononuclear leucocyte phosphodiesterase activity in atopic dermatitis. 255 25

Compounds related to the flavonoid group of natural products may have potential as antipsoriatic drugs. The dihydrochalcone phloretin, its glycoside derivative phloridzin, and the structurally related compound nordihydroguaiaretic acid (NDGA) were selected for study. Phloretin and NDGA strongly inhibited keratinocyte growth but had no effect on isoproterenol-stimulated adenylate cyclase; phloridzin had no effect on growth but potentiated the response of the enzyme. None had any effect on phosphodiesterase. Neither phloretin or phoridzin inhibited lipoxygenase or, surprisingly, decreased deoxyglucose transport. Phloretin and NDGA should be considered antipsoriatic agents.
Int J Dermatol 1987 Dec
PMID:Effects of nordihydroguaiaretic acid, phloretin, and phloridzin on the activity of adenylate cyclase, lipoxygenase and hexose transport, and growth of cultured keratinocytes. 282 56

8-Methoxypsoralen (8-MOP) and 4,5',8-trimethylpsoralen (TMP) were assessed for their effects on cyclic AMP (cAMP) accumulation in normal human fibroblasts, epithelial cells, and mononuclear leukocytes in vitro. In the absence of ultraviolet A radiation, 8-MOP and TMP caused an increase in the concentration of cAMP, but not cyclic GMP, in all of these cells. The effect was seen within 1 min and was sustained over control levels for at least 6 h. At 15 min, the highest dose of 8-MOP or TMP increased the cAMP concentration of fibroblasts by 52% and 69%, respectively. In mononuclear leukocytes, 8-MOP led to a 142% increase in cAMP after 20 min. Several analogs of 8-MOP and TMP had no effect on the cyclic nucleotide system of the cells. The pattern of the time-dependent increase in cAMP indicated that the effect was probably due to an inhibition of phosphodiesterase, rather than an activation of adenylyl cyclase. These results demonstrate that clinically effective psoralens, in the absence of UV radiation, can alter the cAMP concentration of human fibroblasts, epithelial cells, and mononuclear leukocytes in vitro.
J Invest Dermatol 1985 Sep
PMID:Psoralens increase the concentration of cyclic AMP in human cells in vitro. 299 27

Although retinoids reveal various biologic and biochemical activities on epidermal keratinocytes, their effects on the epidermal cyclic AMP (cAMP) system has been less well characterized. In order to elucidate the relation between them, an in vitro pig skin-slice incubation system was employed. After a long-term (up to 24 h) incubation in vitro, control skin responded to epinephrine only slightly. The addition of Ro 10-1670, an active derivative of Ro 10-9359 (etretinate) in the incubation medium, resulted in an increase of the beta-adrenergic adenylate cyclase response of epidermis. On the other hand, histamine-induced cAMP accumulation was decreased by the retinoid treatment after long-term incubation. The augmentation of the beta-adrenergic response was observed at 1 microM concentration and the maximal effect was observed at 10 microM. There was no significant difference in cAMP phosphodiesterase activities between the control and retinoid-treated skin. The effect was also observed by the addition of all-trans-retinoic acid, retinol, and Ro 10-9359; the latter two compounds revealed much lesser effects. The addition of combinations of various drugs (Ro 10-1670 and hydrocortisone; Ro 10-1670 and colchicine) resulted in more marked (additive or synergistic) effects than the single addition of each chemical. On the other hand, the addition of Ro 10-1670 and all-trans-retinoic acid resulted in neither additive nor synergistic effect, suggesting that they probably work on the same site. Our data indicate that the epidermal beta-adrenergic adenylate cyclase response is modulated by retinoids probably as an independent mechanism stimulated by glucocorticoids or colchicine.
J Invest Dermatol 1985 Oct
PMID:Effects of retinoids on the cyclic AMP system of pig skin epidermis. 299 98

In order to elucidate a part of calmodulin actions in the hyperproliferative state in human epidermis, calmodulin activities in the psoriatic and in the normal human epidermis were determined using calmodulin-deficient phosphodiesterase from bovine heart and purified pig skin epidermal calmodulin as a standard. Skin samples were obtained from 11 normal healthy controls and from both the uninvolved and involved regions of 8 nonconsanguineous psoriatic patients. Pure epidermal samples, prepared by the microdissection method, were used for calmodulin assays. Normal human epidermis contained 270 +/- 13 ng/mg dry weight, whereas calmodulin activities were significantly increased in psoriatic epidermis, 412 +/- 29 ng/mg dry weight for the uninvolved epidermis and 747 +/- 46 ng/mg dry weight for the involved epidermis, respectively. These results suggest that calmodulin may play an important role in cell proliferation in human epidermis.
J Invest Dermatol 1985 Nov
PMID:Calmodulin activities are significantly increased in both uninvolved and involved epidermis in psoriasis. 299 34

Epidermal calmodulin (CaM) has been reported to be elevated in psoriasis and to decrease following clearance of psoriasis with treatment. We set out to investigate whether any of the principle drugs used in the treatment of psoriasis had inherent CaM antagonist activity. Utilizing a CaM-activated phosphodiesterase we have demonstrated that even at very high concentrations, the systemic drugs etretinate, methotrexate, and 8-methoxypsoralen, and the topical agents hydrocortisone and crude coal tar showed minimal CaM inhibitory activity. Dithranol (anthralin), however, whether freshly prepared or oxidized, produced substantial inhibition of CaM activity and was demonstrated to be a potent competitive antagonist of CaM, suggesting another possible therapeutic mode of action of dithranol in psoriasis.
J Invest Dermatol 1986 Aug
PMID:An investigation of the ability of antipsoriatic drugs to inhibit calmodulin activity: a possible mode of action of dithranol (anthralin). 301 2

Patients with atopic dermatitis (AD) manifest a number of immune abnormalities which correlate with in vitro defects including lymphocyte transformation, chemotaxis, and cytotoxicity. Past studies have shown reduced leukocyte cyclic 3',5'-adenosine monophosphate (cAMP) levels after exposure to adenylate cyclase-active agonists, and we have demonstrated that this results from increased catabolism due to elevated cAMP-phosphodiesterase activity. These results were obtained in preparations containing mixtures of lymphocytes and monocytes. In order to determine more precisely the cellular site of the defect we have separated the leukocytes into lymphocyte- and monocyte-enriched preparations using either Percoll-gradient centrifugation or adherence isolation. Both techniques yielded over 93% pure lymphocytes, whereas the former yielded 64% monocytes compared with the latter method which generated 94% pure monocytes. Atopic monocytes, obtained by either technique, consistently showed elevated phosphodiesterase activity compared with those of the nonatopic monocytes. Such differences were not evident in lymphocyte preparations from normal and atopic subjects. In spite of the increased rate of cAMP degradation in atopic leukocytes, the resting cAMP levels do not differ from those of normal subjects. We questioned whether this is caused by increased cAMP synthesis and evaluated cellular adenylate cyclase activity. We found no evidence in AD cells for an increased rate of adenylate cyclase catalysis, either basal activity or after stimulation by forskolin. Therefore, the resting cAMP levels must have been compensated by other mechanisms. Impaired cyclic nucleotide metabolism in atopic monocytes may affect a number of immunologic and inflammatory reactions and could account for many of the clinical abnormalities in atopic diseases.
J Invest Dermatol 1986 Sep
PMID:Monocyte localization of elevated cAMP phosphodiesterase activity in atopic dermatitis. 301 7

Previous studies have demonstrated elevated cyclic-AMP-specific phosphodiesterase (PDE) activity in mononuclear leukocytes (MNL) from patients with atopic dermatitis (AD). We questioned whether increased kinase activation could account for this observation. In these studies, we measured abnormally lower basal calcium/phospholipid-dependent protein kinase (PK-C) phosphorylation in MNL from patients with AD. Basal cAMP-dependent protein kinase (PK-A) phosphorylation was concomitantly higher in MNL from patients with AD. These results are in agreement with earlier reports that PK-A activity may have a negative influence on PK-C activity in certain cell systems. Stimulation with the H1-histamine agonist, thiazolylethylamine (TEA), of MNL from normal donors but not patients with AD, resulted in statistically significant increases in PK-C phosphorylation. This implies receptor down regulation or functional desensitization in AD cells. Altered basal protein kinase phosphorylation and abnormal response to selective histamine agonists seen in MNL from patients with AD could explain elevated PDE activity.
J Invest Dermatol 1988 Apr
PMID:Altered leukocyte protein kinase activity in atopic dermatitis. 335 35


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