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 effect of the key iron homeostasis proteins transferrin and ferritin on the activity of partially purified brain calcium-calmodulin-dependent phosphodiesterase (CaM-PDE, EC 3.4.1.17) were studied. Transferrin and ferritin were found to be potent natural activators of CaM-PDE. The key factor determining the degree of activation by these proteins is their saturation with iron: apotransferrin activated CaM-PDE 6-7-fold; iron-poor brain ferritin and liver apoferritin (taken for comparison) activated the enzyme 4-5- and 2-fold, respectively. Diferric transferrin and iron-rich liver ferritin had no effects on the enzyme activity. Transferrin and ferritin (both in apo- and iron-saturated forms) did not change the activity of calmodulin-phosphodiesterase complex. The data suggest that apotransferrin and iron-poor transferrin are involved in the regulation of cyclic nucleotide content in nervous tissue.
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PMID:Transferrin and ferritin modulate the activity of brain calcium-calmodulin-dependent phosphodiesterase. 915 70

Because of the importance of oligodendrocytes (OL) in forming and maintaining myelin in the CNS and the fact that the remyelination in the CNS is very limited in contrast to the peripheral nervous system, we investigated the effect of a chemically defined medium OLDEM, previously characterized by the maintenance of mature myelinating OL, on oligodendroblasts (or OL progenitors) in culture. The effect of each component of this medium as well as different combinations of them were also examined. Cultures were examined at different developmental stages immunocytochemically for developmental markers, such as transferrin, sulfatides, myelin basic protein and proteolipid protein. OLDEM accelerated the appearance of developmental markers and concomitant morphological changes. Furthermore, myelin-specific enzymes such as glycerophosphorylcholine phosphodiesterase; p-nitro-phenolphosphocholine phosphodiesterase; 2'3'-cyclic nucleotide 3'-phosphodiesterase and UDP galactose: ceramide galactosyltransferase had enzymatic activities similar to values found in pure myelin, indicating that OLDEM allows the optimal expression of myelin-related genes. The effect of each OLDEM constituent was evaluated by immunocytochemistry and by measurement of enzymatic activities. With each single additive or multiple combinations, oligodendrocytes displayed different degrees of maturation. Deletion of selenium, glucose, and galactose severely affected cell survival as well as enzymes expression in young cultures. However, older cultures were more resistant to these deletions. Putrescine and insulin did not cause such effects on survival, but their absence affected cell maturation. None of the OLDEM additives individually supported survival and/or maturation. Enzyme assays performed on isolated myelin-like membranes or the cells soma revealed a redistribution of the activity between these fractions as the cell matured. The biological role of each of these constituents on the maturation of the oligodendroglial cells is discussed. These observations indicate that OLDEM constituents have a powerful effect on OL progenitor maturation, and membrane formation. This medium will be used for investigating the remyelination potential of adult OL progenitors.
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PMID:Acceleration of the maturation of oligodendroblasts into oligodendrocytes and enhancement of their myelinogenic properties by a chemically defined medium. 921 75

Neuroleptic-induced tardive dyskinesia has been linked to impaired iron homeostasis in the central nervous system attributed to increased iron levels. A chlorpromazine stimulatory effect upon iron uptake from 55Fe-citrate and 55Fe-transferrin by cortical synaptosome preparations of rats was recently demonstrated. The present work extends this study to other neuroleptic drugs such as thioridazine, haloperidol, clozapine and fluphenazine. Like chlorpromazine, thioridazine showed a stimulatory effect upon iron uptake from both iron donors whereas fluphenazine highly increased uptake from 55Fe-citrate but not from 55Fe-transferrin. Haloperidol and clozapine had no effect. Stimulation of iron uptake by neuroleptics is probably related to their property of calmodulin antagonism, since calmidazolium also stimulated synaptosomal iron uptake from both donors. Calmidazolium-stimulated uptake from 55Fe-citrate was approx. 5-fold when compared to control samples while uptake from 55Fe-transferrin was 250% higher. The results are in agreement with the iron uptake magnitude observed with the different drugs for the two iron donors used and the reported Ki values of neuroleptic drugs for calmodulin antagonism evaluated by the inhibition of 3',5'-monophosphate phosphodiesterase activity. Moreover, vanadate, an inhibitor of protein phosphorylation and KCl-promoted membrane depolarization, greatly inhibited iron uptake from 55Fe-citrate by both chlorpromazine-treated and untreated synaptosome preparations.
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PMID:Neuroleptic drug-stimulated iron uptake by synaptosome preparations of rat cerebral cortex. 963 75

The iron storage protein ferritin was purified to electrophoretic homogeneity from cow uterine myometrium. Its Mr did not exceed 440, 000 and H-chains predominated in the subunit composition; the iron saturation was 43 iron ions per protein molecule. The uterine myometrial ferritin was a potent natural modulator of Ca-calmodulin-independent phosphodiesterase (Ca-CM-independent PDE, EC 3.1.4.17) isolated from the same tissue. Addition of iron-poor ferritin from uterine myometrium and iron-reach liver ferritin caused three- and two-fold inhibition of the enzyme activity, respectively. The iron transport protein transferrin in iron-saturated and iron-depleted forms can also inhibit Ca-CM-independent PDE activity by two-fold. In both cases, the degree of saturation with iron was not crucial for the inhibitory effects of these proteins on the enzyme activity. These data suggest that iron homeostasis proteins can modulate the cyclic nucleotide level in non-nervous tissue via interaction with enzymes involved in cyclic nucleotide hydrolysis.
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PMID:Uterine myometrial ferritin and blood plasma transferrin as natural modulators of Ca-calmodulin-independent cyclic nucleotide phosphodiesterase from cow uterine myometrium. 1081 Jan 82

Aluminium (Al.) is an ubiquitous element found in every food product. The sources of Al. are especially corn, yellow cheese, salt, herbs, spices, tea and tap water. In household Al.-made ware is a major source of the element. Al. may cause diseases in humans, especially hampers many metabolic processes especially turnover of calcium, phosphorus and iron. Salts of Al. may bind to DNA, RNA, inhibit such enzymes as hexokinase, acid and alkaline phosphatases, phosphodiesterase and phosphooxydase. Al. salts are especially harmful to nervous, hematopoietic systems and to skeleton. Al. gets to organism with food, water, cosmetics, from aluminium ware and containers. Toxicity comes from substitution of Mg and Fe ions effecting in disturbances in intracellular signaling, excretory functions and cellular growth. Neurotoxic action of Al. probably comes from substitution of Mg ions in ATP, what finally influences function of every ATP using-enzymes. There are observations in experimental models proving Al. salts are responsible for Alzheimer disease development. Toxicity of Al. to skeletal system results in diminished resistance thus tendencies to breaking, and comes from lower collagen synthesis and slowing down of mineralisation. Low erythropoietin production, inhibition of hem-synthesing enzymes and binding of Al. to transferrin, effects in anaemia. Carcinogenic effects of Al. were nor proved nor denied, but high concentrations of Al. were found in many neoplastic cells. In conclusion, we should introduce prophylactic measures effecting in less Al. intake esp. avoiding use of Al.-made ware nad controlling food for Al. content.
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PMID:[Aluminum--occurrence and toxicity for organisms]. 1129 16

Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate delivery of the drugs/compounds to the tumor site. Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to administration of such complexes.
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PMID:Targetting cancer with Ru(III/II)-phosphodiesterase inhibitor adducts: a novel approach in the treatment of cancer. 2358 78

Much emphasis has been given to vanadium compounds as potential therapeutic reagents for the treatment of diabetes mellitus. Thus far, no vanadium compound has proven efficacious for long-term treatment of this disease in humans. Therefore, in review of the research literature, our goal has been to identify properties of vanadium compounds that are likely to favor physiological and biochemical compatibility for further development as therapeutic reagents. We have, therefore, limited our review to those vanadium compounds that have been used in both in vivo experiments with small, laboratory animals and in in vitro studies with primary or cultured cell systems and for which pharmacokinetic and pharmacodynamics results have been reported, including vanadium tissue content, vanadium and ligand lifetime in the bloodstream, structure in solution, and interaction with serum transport proteins. Only vanadyl (VO²⁺) chelates fulfill these requirements despite the large variety of vanadium compounds of different oxidation states, ligand structure, and coordination geometry synthesized as potential therapeutic agents. Extensive review of research results obtained with use of organic VO²⁺-chelates shows that the vanadyl chelate bis(acetylacetonato)oxidovanadium(IV) [hereafter abbreviated as VO(acac)₂], exhibits the greatest capacity to enhance insulin receptor kinase activity in cells compared to other organic VO²⁺-chelates, is associated with a dose-dependent capacity to lower plasma glucose in diabetic laboratory animals, and exhibits a sufficiently long lifetime in the blood stream to allow correlation of its dose-dependent action with blood vanadium content. The properties underlying this behavior appear to be its high stability and capacity to remain intact upon binding to serum albumin. We relate the capacity to remain intact upon binding to serum albumin to the requirement to undergo transcytosis through the vascular endothelium to gain access to target tissues in the extravascular space. Serum albumin, as the most abundant transport protein in the blood stream, serves commonly as the carrier protein for small molecules, and transcytosis of albumin through capillary endothelium is regulated by a Src protein tyrosine kinase system. In this respect it is of interest to note that inorganic VO²⁺ has the capacity to enhance insulin receptor kinase activity of intact 3T3-L1 adipocytes in the presence of albumin, albeit weak; however, in the presence of transferrin no activation is observed. In addition to facilitating glucose uptake, the capacity of VO²⁺- chelates for insulin-like, antilipolytic action in primary adipocytes has also been reviewed. We conclude that measurement of inhibition of release of only free fatty acids from adipocytes stimulated by epinephrine is not a sufficient basis to ascribe the observations to purely insulin-mimetic, antilipolytic action. Adipocytes are known to contain both phosphodiesterase-3 and phosphodiesterase-4 (PDE3 and PDE4) isozymes, of which insulin antagonizes lipolysis only through PDE3B. It is not known whether the other isozyme in adipocytes is influenced directly by VO²⁺- chelates. In efforts to promote improved development of VO²⁺- chelates for therapeutic purposes, we propose synergism of a reagent with insulin as a criterion for evaluating physiological and biochemical specificity of action. We highlight two organic compounds that exhibit synergism with insulin in cellular assays. Interestingly, the only VO²⁺- chelate for which this property has been demonstrated, thus far, is VO(acac)₂.
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PMID:The Structural Basis of Action of Vanadyl (VO²⁺) Chelates in Cells. 2523 7


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