Phyllis Dan

Hebrew University of Jerusalem, Jerusalem, Jerusalem District, Israel

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Publications (10)33.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Skin inflammatory diseases are most commonly treated with corticosteroids, especially topical preparations, benefitting from high potency and unparalleled formulation flexibility. However, these benefits are limited due to side effects, especially under long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) which block the COX pathways have been used as safer alternatives to corticosteroids, and much effort and resources have been invested in developing COX inhibitors. However, synthetic NSAIDs are less potent than steroids, have limited formulation flexibility and have their own safety issues, thereby yielding unsatisfactory results, with some high-profile drugs (e.g., the COX-2 inhibitors Vioxx, Celebrex) being withdrawn from the market due to safety concerns. The potency and safety challenges of NSAIDs are related to inter-eicosanoid dynamics, pertaining to their pro-versus anti-inflammatory action, homeostatic functions and tissue-specific activities. Instead, the upstream control of phospholipase A2 (PLA2) enzymatic activity, which hydrolyzes cell membrane phospholipids to initiate the eicosanoid production, has been considered for inhibiting eicosanoid activation while maintaining the intricate balance needed for their homeostatic functions. Yet, PLA(2) inhibitors have hardly been tested for treating skin inflammatory/allergic conditions. In this article we review the involvement of PLA(2)s in skin physiology and pathology, and discuss the prospect of PLA(2) inhibition for the treatment of dermatological diseases.
    European journal of pharmacology 07/2012; 691(1-3):1-8. · 2.59 Impact Factor
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    ABSTRACT: SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is a result of mutations in the β subunit of the ADP-dependent isoform of the Krebs cycle succinyl-CoA synthase (SCS). The mechanism of tissue specificity and mtDNA depletion is elusive but complementation by the GDP-dependent isoform encoded by SUCLG2, and the association with mitochondrial nucleoside diphosphate kinase (NDPK), is a plausible link. We have investigated this relationship by studying SUCLA2 deficient fibroblasts derived from patients and detected normal mtDNA content and normal NDPK activity. However, knockdown of SUCLG2 by shRNA in both patient and control fibroblasts resulted in a significant decrease in mtDNA amount, decreased NDPK and cytochrome c oxidase activities, and a marked growth impairment. This suggests that, SUCLG2, to a higher degree than SUCLA2, is crucial for mtDNA maintenance and that mitochondrial NDPK is involved. Although results pertain to a cell culture system, the findings might explain the pathomechanism and tissue specificity in mtDNA depletion caused by defective SUCLA2.
    Biochimica et Biophysica Acta 02/2011; 1812(5):625-9. · 4.66 Impact Factor
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    ABSTRACT: Fatty acid 2-hydroxylase (FA2H) is the enzyme responsible for the hydroxylation of free fatty acids prior to their incorporation into 2-hydroxylated sphingolipids, which are the major constituents of the myelin leaflet. Mutated FA2H has been associated with neurodegenerative diseases. Decreased FA2H activity was demonstrated only in vitro, but not in patient tissues. In this study we characterized the 2-hydroxylated sphingomyelin (SM) profiles in blood and fibroblasts from patients harboring a deleterious FA2H mutatation, and found that hydroxylated fatty acid sphingomyelin is present in normal amounts in patient lymphocytes, but decreased to a different extent in fibroblasts and erythrocytes.
    Lipids in Health and Disease 01/2011; 10:84. · 2.31 Impact Factor
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    ABSTRACT: Congenital deficiency of the mitochondrial respiratory chain complex I (CI) is a common defect of oxidative phosphorylation (OXPHOS). Despite major advances in the biochemical and molecular diagnostics and the deciphering of CI structure, function assembly and pathomechanism, there is currently no satisfactory cure for patients with mitochondrial complex I defects. Small molecules provide one feasible therapeutic option, however their use has not been systematically evaluated using a standardized experimental system. In order to evaluate potentially therapeutic compounds, we set up a relatively simple system measuring different parameters using only a small amount of patient's fibroblasts, in glucose free medium, where growth is highly OXPOS dependent. Ten different compounds were screened using fibroblasts derived from seven CI patients, harboring different mutations.5-Aminoimidazole-4-carboxamide ribotide (AICAR) was found to be the most beneficial compound improving growth and ATP content while decreasing ROS production. AICAR also increased mitochondrial biogenesis without altering mitochondrial membrane potential (Δψ). Fluorescence microscopy data supported increased mitochondrial biogenesis and activation of the AMP activated protein kinase (AMPK). Other compounds such as; bezafibrate and oltipraz were rated as favorable while polyphenolic phytochemicals (resverastrol, grape seed extract, genistein and epigallocatechin gallate) were found not significant or detrimental. Although the results have to be verified by more thorough investigation of additional OXPHOS parameters, preliminary rapid screening of potential therapeutic compounds in individual patient's fibroblasts could direct and advance personalized medical treatment.
    PLoS ONE 01/2011; 6(10):e26883. · 3.53 Impact Factor
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    ABSTRACT: Phospholipase A2 (PLA2) plays a key role in the production of proinflammatory mediators, namely the arachidonic acid-derived eicosanoids, lysophospholipids, and platelet-activating factor, and indirectly influences the generation of cytokines, nitric oxide (NO), and free radicals. Accordingly, regulation of its activity is important in the treatment of inflammation. Since the main site of PLA2 action in inflammatory processes is the cell membrane, we synthesized extracellular PLA2 inhibitors (ExPLIs) composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers. These membrane-anchored lipid conjugates do not penetrate the cell and interfere with vital phospholipid metabolism or cell viability. The ExPLIs markedly inhibited central nervous system inflammation. This was reflected by the suppressed production and secretion of lipopolysaccharide-induced sPLA2, prostaglandin E2, and NO by glial cells and by the amelioration of experimental autoimmune encephalomyelitis in rats and mice.
    Glia 01/2004; 44(3):275-82. · 5.07 Impact Factor
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    ABSTRACT: This in vitro study aimed to elucidate the extent and kind of involvement of hyaluronic acid (HA) in the currently accepted view of synovial joint lubrication, in which surface-active phospholipids (SAPL) constitute the main boundary lubricant. The integrity of SAPL is apparently threatened by the lysing activity of phospholipase A(2) (PLA(2)). The effects of increasing concentrations of HA degraded by free radicals and non-degraded HA on the lysing activity of PLA(2) were examined in vitro. Liposomes (lipid model membrane) containing phosphatidylcholine (PC) were used as the substrate, on the assumption that they are appropriate representatives of SAPL. HA adhered to the phospholipid membrane (liposomes), inhibiting their lysis by PLA(2). However, in its degraded form, HA not only failed to inhibit PLA(2)-lysing activity, but accelerated it. It is reasonable to assume that HA plays an important indirect role in the steady state of the boundary lubrication process of joints by protecting SAPL from being lysed by PLA(2). However, as excessive loading generates free radicals within the joint (among other effects), the HA that is degraded in this way is incapable of protecting SAPL from lysis by PLA(2). When the rate of degradation exceeds that of synthesis, there will be insufficient replacement of HA and/or SAPL, resulting in denudation of the articular surfaces. These are then exposed to increasing friction, and hence increased danger of degenerative joint changes.
    Rheumatology 04/2001; 40(3):336-40. · 4.21 Impact Factor
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    ABSTRACT: We have previously shown that cell surface proteoglycans protect the cell membrane from the action of extracellular phospholipase A2 (PLA2) enzymes [Dan, P., Nitzan, D. W., Dagan, A., Ginsburg, I., and Yedgar, S. (1996) FEBS Lett. 383, 75-78]. Cell-impermeable PLA2 inhibitors (ExPLIs) were prepared by linking phosphatidylethanolamine (PE) to polymeric carriers, specifically, carboxymethylcellulose, heparin, or hyaluronic acid. The structure of these inhibitors enables the incorporation of their PE moiety into the membrane while the polymer remains at the membrane surface. In the present study, we show that the ExPLIs are effective inhibitors of the hydrolysis of different phospholipids in biological (Escherichia coli) and model (phospholipid vesicle) membranes, by diverse types of PLA2 enzymes, specifically human recombinant synovial fluid and C. atrox (type II), as well as Naja mocambique and porcine pancreatic (type I) PLA2. It is proposed that the external polymers of the ExPLIs, which are anchored to the membrane by the PE, mimic the naturally occurring cell surface proteoglycans and similarly protect membranes from the action of exogenous PLA2.
    Biochemistry 05/1998; 37(17):6199-204. · 3.38 Impact Factor
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    ABSTRACT: Phospholipase A2 (PLA2) and H2O2, secreted from activated inflammatory cells, play a central role in the tissue damage occurring in inflammatory processes. However, while exogenous PLA2 alone does not cause cell lysis, it readily does so when acting with H2O2. We have found that H2O2 degrades cell surface proteoglycans, thus rendering the membrane PL accessible to hydrolysis by exogenous PLA2. This novel mechanism introduces a role for cell surface proteoglycans in protection of cells from damage by pro-inflammatory agents, and may assign a central role for the combined action of H2O2 and PLA2 in inflammatory and bacteriocidal processes.
    FEBS Letters 04/1996; 383(1-2):75-8. · 3.58 Impact Factor
  • Geochimica et Cosmochimica Acta 01/1996; 60(22). · 3.88 Impact Factor
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    ABSTRACT: Cell-impermeable inhibitors of phospholipase A2 were prepared by linking inhibiting molecules to macromolecular carriers which prevent the inhibitor's internalization. These preparations inhibit the release of oxygen reactive species from neutrophils and cell death induced by inflammatory agents, as well as bleomycin-induced lung injury.
    Agents and actions. Supplements 02/1995; 46:77-84.

Publication Stats

169 Citations
33.21 Total Impact Points

Institutions

  • 1996–2012
    • Hebrew University of Jerusalem
      • • Institute of Biochemistry, Food Science and Nutrition
      • • Department of Oral and Maxillofacial Surgery
      Jerusalem, Jerusalem District, Israel
  • 2011
    • Hadassah Medical Center
      • Department of Genetics and Metabolic Diseases
      Yerushalayim, Jerusalem District, Israel