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Osamu Hayaishi - One of the best experts on this subject based on the ideXlab platform.
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Cloning, Expression, Crystallization, anD Preliminary X-Ray Analysis of Recombinant Mouse Lipocalin-type ProstaglanDin D Synthase, a Somnogen-ProDucing Enzyme
Journal of biochemistry, 2003Co-Authors: Daisuke Irikura, Takashi Kumasaka, Masaki Yamamoto, Hideo Ago, Masashi Miyano, Kilunga Bruno Kubata, Hiroaki Sakai, Osamu HayaishiAbstract:Lipocalin-type ProstaglanDin D Synthase is the key enzyme for the proDuction of ProstaglanDin D 2 , a potent enDogenous somnogen, in the brain. We cloneD, proDuceD, anD crystallizeD the native enzyme anD selenomethionyl Cys 6 5 Ala mutants of the recombinant mouse protein by the hanging Drop vapor-Diffusion methoD with both malonate anD citrate as precipitants. The native crystals obtaineD with malonate belong to orthorhombic space group P2 1 2 1 2 1 with lattice constants a = 46.2, b = 66.8, anD c = 105.3 A. The selenomethionyl crystals obtaineD with citrate belong to orthorhombic space group C222 1 with lattice constants a = 45.5, b = 66.8, anD c = 104.5 A. The native crystals DiffracteD beyonD 2.1 A resolution.
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Cellular localization of lipocalin-type ProstaglanDin D Synthase (?-trace) in the central nervous system of the aDult rat
The Journal of comparative neurology, 2000Co-Authors: Carsten T. Beuckmann, Michael Lazarus, Dmitry Gerashchenko, Akira Mizoguchi, Sakashi Nomura, Ikuko Mohri, Akira Uesugi, Takeshi Kaneko, Noboru Mizuno, Osamu HayaishiAbstract:We applieD high-resolution laser-scanning microscopy, electron microscopy, anD non-raDioactive in situ hybriDization histochemistry to Determine the cellular anD intracellular localization of lipocalin-type ProstaglanDin D Synthase, the major brain-DeriveD protein component of cerebrospinal fluiD, anD its mRNA in leptomeninges, choroiD plexus, anD parenchyma of the aDult rat brain. Both immunoreactivity anD mRNA for ProstaglanDin D Synthase were locateD in arachnoiD barrier cells, arachnoiD trabecular cells, anD arachnoiD pia mater cells. Furthermore, meningeal macrophages anD perivascular microglial cells, iDentifieD by use of ED2 antiboDy, were immunopositive for ProstaglanDin D Synthase. In the arachnoiD trabecular cells, the immunoreactivity for ProstaglanDin D Synthase was locateD in the nuclear envelope, Golgi apparatus, anD secretory vesicles, inDicating the active proDuction anD secretion of ProstaglanDin D Synthase. In the meningeal macrophages, ProstaglanDin D Synthase was not founD arounD the nucleus but in lysosomes in the cytoplasm, pointing to an uptake of the protein from the cerebrospinal fluiD. Furthermore, the existence of meningeal cyclooxygenase (COX) -1 anD COX-2 was investigateD by Western blot, Northern blot, anD reverse transcriptase—polymerase chain reaction (RT-PCR), anD the colocalization of COX-2 anD ProstaglanDin D Synthase was DemonstrateD in virtually all cells of the leptomeninges, choroiD plexus epithelial cells, anD perivascular microglial cells, suggesting that these cells synthesize ProstaglanDin D2 actively. Alternatively, oligoDenDrocytes showeD ProstaglanDin D Synthase immunoreactivity without Detectable COX-2. The localization of lipocalin-type ProstaglanDin D Synthase in meningeal cells anD its colocalization with COX-2 proviDe eviDence for its function as a ProstaglanDin D2-proDucing enzyme. J. Comp. Neurol. 428:62–78, 2000. © 2000 Wiley-Liss, Inc.
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cellular localization of lipocalin type ProstaglanDin D Synthase trace in the central nervous system of the aDult rat
The Journal of Comparative Neurology, 2000Co-Authors: Carsten T. Beuckmann, Michael Lazarus, Dmitry Gerashchenko, Akira Mizoguchi, Sakashi Nomura, Ikuko Mohri, Akira Uesugi, Takeshi Kaneko, Noboru Mizuno, Osamu HayaishiAbstract:We applieD high-resolution laser-scanning microscopy, electron microscopy, anD non-raDioactive in situ hybriDization histochemistry to Determine the cellular anD intracellular localization of lipocalin-type ProstaglanDin D Synthase, the major brain-DeriveD protein component of cerebrospinal fluiD, anD its mRNA in leptomeninges, choroiD plexus, anD parenchyma of the aDult rat brain. Both immunoreactivity anD mRNA for ProstaglanDin D Synthase were locateD in arachnoiD barrier cells, arachnoiD trabecular cells, anD arachnoiD pia mater cells. Furthermore, meningeal macrophages anD perivascular microglial cells, iDentifieD by use of ED2 antiboDy, were immunopositive for ProstaglanDin D Synthase. In the arachnoiD trabecular cells, the immunoreactivity for ProstaglanDin D Synthase was locateD in the nuclear envelope, Golgi apparatus, anD secretory vesicles, inDicating the active proDuction anD secretion of ProstaglanDin D Synthase. In the meningeal macrophages, ProstaglanDin D Synthase was not founD arounD the nucleus but in lysosomes in the cytoplasm, pointing to an uptake of the protein from the cerebrospinal fluiD. Furthermore, the existence of meningeal cyclooxygenase (COX) -1 anD COX-2 was investigateD by Western blot, Northern blot, anD reverse transcriptase—polymerase chain reaction (RT-PCR), anD the colocalization of COX-2 anD ProstaglanDin D Synthase was DemonstrateD in virtually all cells of the leptomeninges, choroiD plexus epithelial cells, anD perivascular microglial cells, suggesting that these cells synthesize ProstaglanDin D2 actively. Alternatively, oligoDenDrocytes showeD ProstaglanDin D Synthase immunoreactivity without Detectable COX-2. The localization of lipocalin-type ProstaglanDin D Synthase in meningeal cells anD its colocalization with COX-2 proviDe eviDence for its function as a ProstaglanDin D2-proDucing enzyme. J. Comp. Neurol. 428:62–78, 2000. © 2000 Wiley-Liss, Inc.
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Enhancement of lipocalin-type ProstaglanDin D Synthase enzyme activity by guaniDine hyDrochloriDe.
Biochemical and biophysical research communications, 1999Co-Authors: Takashi Inui, Yoshihiro Urade, Tadayasu Ohkubo, Osamu HayaishiAbstract:Abstract The characterization of unfolDing of mouse recombinant lipocalin-type ProstaglanDin D Synthase (L-PGDS) by guaniDine hyDrochloriDe (GDnHCl) was carrieD out. In the presence of low concentrations of GDnHCl (up to 0.75 M), enhancement of the enzyme activity was observeD. However, above a 1 M concentration of GDnHCl, the enzyme activity was reDuceD in a concentration-DepenDent manner. The maximum enzyme activity inDuceD by GDnHCl was approximately 1.5-folD compareD with the activity unDer physiological conDitions without GDnHCl. The ellipticity in circular Dichroism (CD) spectrum of the L-PGDS at 218 nm, reflecting the β-sheet content, was DecreaseD by GDnHCl (up to 0.75 M), anD the minimum ellipticity was observeD at 0.5 M GDnHCl. The fluorescence quenching of the intrinsic tryptophan of L-PGDS Due to the binDing of bilirubin in the presence or absence of GDnHCl was measureD. The KD values obtaineD in the presence anD absence of 0.5 M GDnHCl were 447 anD 115 nM, respectively, inDicating lower affinity of the L-PGDS for bilirubin with GDnHCl than without it. Further, an NMR stuDy revealeD that the reorganization of hyDrogen-bonD network in the L-PGDS was observeD in the presence of 0.5 M GDnHCl. These results, taken together, inDicate that the enzyme activity of L-PGDS is enhanceD by the conformational change, especially by the change in the seconDary structure.
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BinDing of BiliverDin, Bilirubin, anD ThyroiD Hormones to Lipocalin-Type ProstaglanDin D Synthase†
Biochemistry, 1999Co-Authors: Carsten T. Beuckmann, Masaaki Aoyagi, Issay Okazaki, Takaaki Hiroike, Hiroyuki Toh, Osamu HayaishiAbstract:Lipocalin-type ProstaglanDin D Synthase is a major protein of the cerebrospinal fluiD anD was originally known as β-trace. We investigateD the binDing ability of ProstaglanDin D Synthase towarD bile pigments, thyroiD hormones, steroiD hormones, anD fatty aciDs in this present stuDy. We founD that the recombinant enzyme binDs bile pigments anD thyroiD hormones, resulting in quenching of the intrinsic tryptophan fluorescence, the appearance of inDuceD circular Dichroism of the lipophilic liganDs, anD a reD shift of the absorption spectra of bilirubin anD biliverDin. The binDing of ProstaglanDin D Synthase to lipophilic liganDs was also DemonstrateD by the resonant mirror technique anD surface plasmon resonance Detection. The Dissociation constants were calculateD to be 33 nM, 37 nM, 660 nM, 820 nM, anD 2.08 μM for biliverDin, bilirubin, l-thyroxine, 3,3‘,5‘-triioDo-l-thyronine, anD 3,3‘,5-triioDo-l-thyronine, respectively. BiliverDin anD bilirubin unDerwent a shift in their absorption peaks from 375 to 380 ...
Takashi Inui - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive Evaluation of the BinDing of Lipocalin-Type ProstaglanDin D Synthase to Poorly Water-Soluble Drugs.
Molecular pharmaceutics, 2017Co-Authors: Yoshiaki Teraoka, Satoshi Kume, Yuxi Lin, Shogo Atsuji, Takashi InuiAbstract:Low water solubility of canDiDate Drug compounDs is a major problem in pharmaceutical research anD Development. We DevelopeD a novel Drug Delivery system (DDS) for poorly water-soluble Drugs using lipocalin-type ProstaglanDin D Synthase (L-PGDS), which belongs to the lipocalin superfamily anD binDs a large variety of hyDrophobic molecules. In this stuDy, we comprehensively evaluateD the capability of L-PGDS to binD anD solubilize various poorly water-soluble Drugs using structure-baseD Docking. Docking simulations of 2892 commercially available approveD Drugs inDicateD that L-PGDS shows higher binDing affinities for various Drugs compareD with 2-hyDroxypropyl-β-cycloDextrin. Five Drugs selecteD from the top 100 with the highest binDing affinities for L-PGDS exhibiteD very low solubility in PBS (pH 7.4). However, in the presence of 1 mM L-PGDS, the apparent solubility of all Drugs improveD markeDly, from 19.5- to 166-folD. Calorimetric experiments on two Drugs, telmisartan anD imatinib, revealeD that L-PGD...
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Development of pH-InDepenDent Drug Release Formulation Using Lipocalin-Type ProstaglanDin D Synthase
Journal of pharmaceutical sciences, 2016Co-Authors: Masashi Mizoguchi, Masatoshi Nakatsuji, Junichi Takano, Osamu Ishibashi, Koichi Wada, Takashi InuiAbstract:The purpose of this stuDy was to Develop a pH-inDepenDent Drug release formulation using lipocalin-type ProstaglanDin D Synthase, a member of the lipocalin superfamily, with the function of forming complexes together with various small lipophilic molecules. DipyriDamole, a poorly water-soluble Drug, showing a pH-DepenDent solubility profile, was useD as the moDel Drug. The solubilization of DipyriDamole was achieveD by a simple complex formulation methoD with lipocalin-type ProstaglanDin D Synthase. The complex formulation was proDuceD successfully by spray Drying, anD the obtaineD powDer formulation showeD complete Dissolution in fasteD-state simulateD gastric fluiD (pH, 1.6) anD phosphate-buffereD solution (pH, 6.8). In aDDition, the potential stability of the complex formulation was assesseD, anD the Dissolution profile of the proDuceD powDer at pH 6.8 was maintaineD after 4-week storage unDer several storage conDitions. Furthermore, a pharmacokinetic stuDy using hypochlorhyDria moDel rats was performeD to verify the improvement of the intestinal absorption behavior, anD eventually the complex formulation overcame the problematic absorption profile of DipyriDamole in the elevateD gastric pH conDitions. These results, taken together, Demonstrate that the use of this well-DesigneD Drug-Delivery carrier is feasible for the Development of pH-inDepenDent Drug release formulations.
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fine tuneD broaD binDing capability of human lipocalin type ProstaglanDin D Synthase for various small lipophilic liganDs
FEBS Letters, 2014Co-Authors: Satoshi Kume, Masatoshi Nakatsuji, Youngho Lee, Yoshiaki Teraoka, Keisuke Yamaguchi, Yuji Goto, Takashi InuiAbstract:The hyDrophobic cavity of lipocalin-type ProstaglanDin D Synthase (L-PGDS) has been suggesteD to accommoDate various lipophilic liganDs through hyDrophobic effects, but its energetic origin remains unknown. We characterizeD 18 buffer-inDepenDent binDing systems between human L-PGDS anD lipophilic liganDs using isothermal titration calorimetry. Although the classical hyDrophobic effect was mostly DetecteD, all complex formations were Driven by favorable enthalpic gains. Gibbs energy changes strongly correlateD with the number of hyDrogen bonD acceptors of liganD. Thus, the broaD binDing capability of L-PGDS for liganDs shoulD be vieweD as hyDrophilic interactions Delicately tuneD by enthalpy–entropy compensation using combineD effects of hyDrophilic anD hyDrophobic interactions.
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systematic interaction analysis of human lipocalin type ProstaglanDin D Synthase with small lipophilic liganDs
Biochemical Journal, 2012Co-Authors: Satoshi Kume, Youngho Lee, Yuji Goto, Yuya Miyamoto, Harumi Fukada, Takashi InuiAbstract:L-PGDS [lipocalin-type PG (ProstaglanDin) D Synthase] is a multi-functional protein, acting as a PGD 2 -proDucing enzyme anD a lipiD-transporter. In the present stuDy, we focus on the function of L-PGDS as an extracellular transporter for small lipophilic molecules. We characterize the binDing mechanism of human L-PGDS for the molecules, especially binDing affinity stoichiometry anD Driving force, using tryptophan fluorescence quenching, ICD (inDuceD circular Dichroism) anD ITC (isothermal titration calorimetry). The tryptophan fluorescence quenching measurements revealeD that haem metabolites such as haemin, biliverDin anD bilirubin binD to L-PGDS with significantly higher affinities than the other small lipophilic liganDs examineD, showing Dissociation constant ( K D ) values from 17.0 to 20.9 nM. We focuseD particularly on the extra-specificities of haem metabolites anD L-PGDS. The ITC anD ICD Data revealeD that two molecules of the haem metabolites binD to L-PGDS with high anD low affinities, showing K D values from 2.8 to 18.1 nM anD from 0.209 to 1.63 μM respectively. The thermoDynamic parameters for the interactions revealeD that the contributions of enthalpy anD entropy change were consiDerably Different for each haem metabolite even when the Gibbs energy change was the same. Thus we believe that the binDing energy of haem metabolites to L-PGDS is optimizeD by balancing enthalpy anD entropy change.
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lipocalin type ProstaglanDin D Synthase protects against oxiDative stress inDuceD neuronal cell Death
Biochemical Journal, 2012Co-Authors: Ayano Fukuhara, Ko Fujimori, Mao Yamada, Yuya Miyamoto, Toshihide Kusumoto, Hidemitsu Nakajima, Takashi InuiAbstract:L-PGDS [lipocalin-type PGD (ProstaglanDin D) Synthase] is a Dual-functional protein, acting as a PGD2-proDucing enzyme anD a lipiD transporter. L-PGDS is a member of the lipocalin superfamily anD can binD a wiDe variety of lipophilic molecules. In the present stuDy we Demonstrate the protective effect of L-PGDS on H2O2-inDuceD apoptosis in neuroblastoma cell line SH-SY5Y. L-PGDS expression was increaseD in H2O2-treateD neuronal cells, anD the L-PGDS level was highly associateD with H2O2-inDuceD apoptosis, inDicating that L-PGDS protecteD the neuronal cells against H2O2-meDiateD cell Death. A cell viability assay revealeD that L-PGDS protecteD against H2O2-inDuceD cell Death in a concentration-DepenDent manner. Furthermore, the titration of free thiols in H2O2-treateD L-PGDS revealeD that H2O2 reacteD with the thiol of Cys65 of L-PGDS. The MALDI-TOF (matrix-assisteD laser-Desorption ionization-time-of-flight)-MS spectrum of H2O2-treateD L-PGDS showeD a 32 Da increase in the mass relative to that of the untreateD protein, showing that the thiol was oxiDizeD to sulfinic aciD. The binDing affinities of oxiDizeD L-PGDS for lipophilic molecules were comparable with those of untreateD L-PGDS. Taken together, these results Demonstrate that L-PGDS protecteD against neuronal cell Death by scavenging reactive oxygen species without losing its liganD-binDing function. The novel function of L-PGDS coulD be useful for the suppression of oxiDative stress-meDiateD neuroDegenerative Diseases.
Yoshihiro Urade - One of the best experts on this subject based on the ideXlab platform.
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lipocalin type ProstaglanDin D Synthase levels increase in patients with narcolepsy anD iDiopathic hypersomnia
Sleep, 2020Co-Authors: Peipei Wang, Yoshihiro Urade, Kosuke Aritake, Xiaosong Dong, Long Zhao, Han Yan, Zhili Huang, Kingman P Strohl, Jun Zhang, Fang HanAbstract:StuDy objectives Excessive Daytime sleepiness (EDS) is a frequent cause for consultation anD a Defining symptom of narcolepsy anD iDiopathic hypersomnia (IH). The associateD mechanisms remain unclear. Lipocalin-type ProstaglanDin D Synthase (LPGDS) is a plausible sleep-inDucing canDiDate. This stuDy is to compare cerebral spinal fluiD (CSF) anD serum LPGDS levels in patients group with hypersomnia of central origin, incluDing those with narcolepsy type 1 (NT1) anD type 2 (NT2) anD IH, to those in healthy controls (Con). MethoDs Serum LPGDS, CSF LPGDS anD CSF hypocretin-1(Hcrt-1) levels were measureD by ELISA in 122 narcolepsy patients (106 NT1, anD 16 NT2), 27 IH, anD 51Con. Results LPGDS levels in CSF (p=0.02) anD serum (p 0.05), except for slightly lower serum LPGDS in IH than in NT1(p=0.01). Serum L-PGDS correlateD moDestly anD negatively to sleep latency on MSLT(r=-0.227, p=0.007) in hypersomnia subjects. Conclusions As a somnogen-proDucing enzyme, CSF/serum LPGDS may serve as a new biomarker for EDS of central origin anD imply a common pathogenetic association, but woulD complement rather than replaces orexin markers.
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Role of Lipocalin‐type ProstaglanDin D Synthase in experimental osteoarthritis
Arthritis & rheumatology (Hoboken N.J.), 2020Co-Authors: Mehdi Najar, Yoshihiro Urade, Yassine Ouhaddi, Frederic Pare, Bertrand Lussier, Mohit Kapoor, Jeanpierre Pelletier, Mohamed Benderdour, Johanne Martel-pelletier, Hassan FahmiAbstract:OBJECTIVE Lipocalin-type ProstaglanDin D Synthase (L-PGDS) catalyzes the formation of ProstaglanDin D2 (PGD2 ), which has important roles in inflammation anD cartilage metabolism. We unDertook this stuDy to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse moDel. METHODS Experimental OA was inDuceD in wilD-type (WT) anD L-PGDS-Deficient (L-PGDS-/- ) mice (n = 10 per genotype) by Destabilization of the meDial meniscus (DMM). Cartilage DegraDation was evaluateD by histology. The expression of matrix metalloproteinase 13 (MMP-13) anD ADAMTS-5 was assesseD by immunohistochemistry. Bone changes were DetermineD by micro-computeD tomography. Cartilage explants from L-PGDS-/- anD WT mice (n = 6 per genotype) were treateD with interleukin-1α (IL-1α) ex vivo in orDer to evaluate proteoglycan DegraDation. Moreover, the effect of intraarticular injection of a recombinant aDeno-associateD virus type 2/5 (rAAV2/5) encoDing L-PGDS on OA progression was evaluateD in WT mice (n = 9 per group). RESULTS CompareD to WT mice, L-PGDS-/- mice haD exacerbateD cartilage DegraDation anD enhanceD expression of MMP-13 anD ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice DisplayeD increaseD synovitis anD subchonDral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showeD enhanceD proteoglycan DegraDation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoDing L-PGDS attenuateD the severity of DMM-inDuceD OA-like changes in WT mice (P < 0.05). The L-PGDS level was increaseD in OA tissues of WT mice (P < 0.05). CONCLUSION Collectively, these finDings suggest a protective role of L-PGDS in OA, anD therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.
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role of lipocalin type ProstaglanDin D Synthase in experimental osteoarthritis
Arthritis & Rheumatism, 2020Co-Authors: Mehdi Najar, Yoshihiro Urade, Yassine Ouhaddi, Frederic Pare, Bertrand Lussier, Mohit Kapoor, Jeanpierre Pelletier, Johanne Martelpelletier, Mohamed Benderdour, Hassan FahmiAbstract:OBJECTIVE Lipocalin-type ProstaglanDin D Synthase (L-PGDS) catalyzes the formation of ProstaglanDin D2 (PGD2 ), which has important roles in inflammation anD cartilage metabolism. We unDertook this stuDy to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse moDel. METHODS Experimental OA was inDuceD in wilD-type (WT) anD L-PGDS-Deficient (L-PGDS-/- ) mice (n = 10 per genotype) by Destabilization of the meDial meniscus (DMM). Cartilage DegraDation was evaluateD by histology. The expression of matrix metalloproteinase 13 (MMP-13) anD ADAMTS-5 was assesseD by immunohistochemistry. Bone changes were DetermineD by micro-computeD tomography. Cartilage explants from L-PGDS-/- anD WT mice (n = 6 per genotype) were treateD with interleukin-1α (IL-1α) ex vivo in orDer to evaluate proteoglycan DegraDation. Moreover, the effect of intraarticular injection of a recombinant aDeno-associateD virus type 2/5 (rAAV2/5) encoDing L-PGDS on OA progression was evaluateD in WT mice (n = 9 per group). RESULTS CompareD to WT mice, L-PGDS-/- mice haD exacerbateD cartilage DegraDation anD enhanceD expression of MMP-13 anD ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice DisplayeD increaseD synovitis anD subchonDral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showeD enhanceD proteoglycan DegraDation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoDing L-PGDS attenuateD the severity of DMM-inDuceD OA-like changes in WT mice (P < 0.05). The L-PGDS level was increaseD in OA tissues of WT mice (P < 0.05). CONCLUSION Collectively, these finDings suggest a protective role of L-PGDS in OA, anD therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.
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Molecular structure of a ProstaglanDin D Synthase requiring glutathione from the brown planthopper, Nilaparvata lugens
Biochemical and biophysical research communications, 2017Co-Authors: Kohji Yamamoto, Yoshihiro Urade, Kosuke Aritake, Akifumi Higashiura, Mamoru Suzuki, Atsushi NakagawaAbstract:Abstract ProstaglanDins are involveD in many physiological processes, anD ProstaglanDin Synthases facilitate the Detoxification of xenobiotics as well as enDogenous compounDs, such as through glutathione conjugation. Specifically, ProstaglanDin D Synthase (PGDS) catalyzes the isomerization of PGH2 to PGD2. Here we report the iDentification anD structural analysis of PGDS from the brown planthopper rice pest Nilaparvata lugens (nlPGDS), which belongs to the sigma-class glutathione transferases. The structure of nlPGDS in complex with glutathione was DetermineD at a resolution of 2.0 A by X-ray crystallography. BounD glutathione was localizeD to the glutathione-binDing site (G-site). Enzyme activity measurements following site-DirecteD mutagenesis of nlPGDS inDicateD that amino aciD resiDues Tyr8, Leu14, Trp39, Lys43, Gln50, Val51, Gln63, anD Ser64 in the G-site contribute to its catalytic activity. To our knowleDge, this represents the first report of a PGDS in insects. Our finDings proviDe insights into the mechanism of nlPGDS activity anD potentially that of other insects anD therefore may facilitate the Development of more effective anD safe insecticiDes.
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[149-POS]: Expression of lipocalin-type ProstaglanDin D Synthase in preeclampsia patients: A novel marker for preeclampsia
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2015Co-Authors: Jun Takeda, Naomi Eguchi, Yutaka Eguchi, Hiroshi Oda, Kazunori Kinoshita, Kikumi Matsuoka, Satoru Takeda, Yoshihiro UradeAbstract:Objectives To test the hypothesis that lipocalin-type ProstaglanDin D Synthase (L-PGDS), a marker of vascular epithelium DisorDers, may be a Diagnostic for preeclampsia. MethoDs Plasma anD urine were collecteD from 36 preeclamptic anD 94 non-symptomatic patients throughout their pregnancies. L-PGDS concentrations were DetermineD by sanDwich ELISA assay. Receiver operating characteristic (ROC) curve valiDateD the cut-off point of the assay. Results The plasma anD urinary L-PGDS concentrations were significantly higher in the preeclamptic than the non-symptomatic patients. L-PGDS concentrations in the urine of normal pregnant women were higher in the thirD trimester compareD to earlier pregnancy, while plasma concentrations remaineD unchangeD. Urinary L-PGDS levels were significantly higher in early onset of preeclampsia (onset Conclusions Our results inDicate the measurement of plasma anD urinary concentrations of L-PGDS may be a potential Diagnostic for preeclampsia. Disclosures J. TakeDa: None. K. Kinoshita: None. K. Matsuoka: None. S. TakeDa: None. Y. Eguchi: None. H. ODa: None. N. Eguchi: None. Y. UraDe: None.
Hiroshi Oda - One of the best experts on this subject based on the ideXlab platform.
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[149-POS]: Expression of lipocalin-type ProstaglanDin D Synthase in preeclampsia patients: A novel marker for preeclampsia
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2015Co-Authors: Jun Takeda, Naomi Eguchi, Yutaka Eguchi, Hiroshi Oda, Kazunori Kinoshita, Kikumi Matsuoka, Satoru Takeda, Yoshihiro UradeAbstract:Objectives To test the hypothesis that lipocalin-type ProstaglanDin D Synthase (L-PGDS), a marker of vascular epithelium DisorDers, may be a Diagnostic for preeclampsia. MethoDs Plasma anD urine were collecteD from 36 preeclamptic anD 94 non-symptomatic patients throughout their pregnancies. L-PGDS concentrations were DetermineD by sanDwich ELISA assay. Receiver operating characteristic (ROC) curve valiDateD the cut-off point of the assay. Results The plasma anD urinary L-PGDS concentrations were significantly higher in the preeclamptic than the non-symptomatic patients. L-PGDS concentrations in the urine of normal pregnant women were higher in the thirD trimester compareD to earlier pregnancy, while plasma concentrations remaineD unchangeD. Urinary L-PGDS levels were significantly higher in early onset of preeclampsia (onset Conclusions Our results inDicate the measurement of plasma anD urinary concentrations of L-PGDS may be a potential Diagnostic for preeclampsia. Disclosures J. TakeDa: None. K. Kinoshita: None. K. Matsuoka: None. S. TakeDa: None. Y. Eguchi: None. H. ODa: None. N. Eguchi: None. Y. UraDe: None.
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Association of Serum Lipocalin-Type ProstaglanDin D Synthase Levels with Subclinical Atherosclerosis in UntreateD Asymptomatic Subjects
Hypertension research : official journal of the Japanese Society of Hypertension, 2008Co-Authors: Yoshikazu Miwa, Hiroshi Oda, Yasuhiko Shiina, Kentaro Shikata, Motoo Tsushima, Satomi Nakano, Taro Maruyama, Shingo KyotaniAbstract:Association of Serum Lipocalin-Type ProstaglanDin D Synthase Levels with Subclinical Atherosclerosis in UntreateD Asymptomatic Subjects
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Lipocalin-type ProstaglanDin D Synthase in urine in aDriamycin-inDuceD nephropathy of mice.
Nephron. Physiology, 2004Co-Authors: Takamasa Tsuchida, Yutaka Eguchi, Hiroshi Oda, Kousuke Seiki, Atsushi Numabe, Hiroshi Nakajima, Rie Hakamada-taguchi, Yoshio UeharaAbstract:BackgrounD/Aims: Lipocalin-type ProstaglanDin D Synthase (L-PGDS), an enzyme converting ProstaglanDin H2 to ProstaglanDin D2, occurs particularly in the carDio
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Changes of lipocalin-type ProstaglanDin D Synthase level During pregnancy.
The journal of obstetrics and gynaecology research, 2004Co-Authors: Yasuhiko Shiki, Naomi Eguchi, Hiroshi Oda, Koichiro Shimoya, Yoshihiro Tokugawa, Tadashi Kimura, Masayasu Koyama, Chihiro Azuma, Yuji Murata, Yoshihiro UradeAbstract:AIM: ProstaglanDin D (PGD), synthesizeD by lipocalin-type ProstaglanDin D Synthase (L-PGDS), has markeD effects on a number of biological processes, incluDing the prevention of platelet aggregation anD the relaxation of vascular smooth muscle. The aim of the stuDy presenteD here was to examine the significance of L-PGDS in human pregnancy. METHODS: We measureD the concentration of plasma L-PGDS in pregnant anD non-pregnant women, anD the concentration of L-PGDS in the umbilical corD blooD, amniotic fluiD anD urine of newborns by enzyme-linkeD immunoabsorbent assay. To Determine the localization of L-PGDS, we performeD immunohistochemical analysis. To evaluate the usefulness of Diagnosis of rupture of membranes (ROM), we DetermineD the concentration of L-PGDS in cervicovaginal secretions. RESULTS: Pregnant women anD non-pregnant women haD similar L-PGDS concentrations (0.57 +/- 0.13 microg/mL vs 0.53 +/- 0.07 microg/mL). Umbilical corD blooD, amniotic fluiD anD newborn urine containeD higher L-PGDS concentrations (1.87 +/- 0.73 microg/mL, 2.62 +/- 0.86 microg/mL, 6.31 +/- 4.62 microg/mL, respectively) than maternal blooD. The concentration of L-PGDS in amniotic fluiD from 19 weeks onwarD was significantly greater than that at 15-18 weeks (3.201 +/- 0.384 microg/mL, n = 6 vs 1.735 +/- 0.477 microg/mL, n = 4; P < 0.05). Immunohistochemistry revealeD that the amniotic cells of the placenta expresseD L-PGDS. The sources of L-PGDS in amniotic fluiD are fetus urine anD amniotic cells. The concentration of L-PGDS in cervicovaginal secretions with rupture of membrane (ROM) were significantly higher than those without ROM. CONCLUSION: The measurement of L-PGDS in cervicovaginal fluiD was useful in the Detection of ROM During pregnancy.
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Lipocalin-type ProstaglanDin D Synthase (beta-trace) in cerebrospinal fluiD: a useful marker for the Diagnosis of normal pressure hyDrocephalus.
Neuroscience research, 2003Co-Authors: Mitsuhito Mase, Hiroshi Oda, Kazuo Yamada, Naoki Shimazu, Kosuke Seiki, Hiroya Nakau, Takashi InuiAbstract:Abstract Lipocalin-type ProstaglanDin D Synthase (PGDS) is consiDereD to be mainly proDuceD in the leptomeninges anD secreteD into cerebrospinal fluiD (CSF). We founD PGDS levels in CSF of patients with normal pressure hyDrocephalus (NPH) (8.99±2.59 μg/ml, mean±S.D., n=14) to be significantly lower than levels in a control (15.29±5.17, n=14, P
Satoshi Kume - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive Evaluation of the BinDing of Lipocalin-Type ProstaglanDin D Synthase to Poorly Water-Soluble Drugs.
Molecular pharmaceutics, 2017Co-Authors: Yoshiaki Teraoka, Satoshi Kume, Yuxi Lin, Shogo Atsuji, Takashi InuiAbstract:Low water solubility of canDiDate Drug compounDs is a major problem in pharmaceutical research anD Development. We DevelopeD a novel Drug Delivery system (DDS) for poorly water-soluble Drugs using lipocalin-type ProstaglanDin D Synthase (L-PGDS), which belongs to the lipocalin superfamily anD binDs a large variety of hyDrophobic molecules. In this stuDy, we comprehensively evaluateD the capability of L-PGDS to binD anD solubilize various poorly water-soluble Drugs using structure-baseD Docking. Docking simulations of 2892 commercially available approveD Drugs inDicateD that L-PGDS shows higher binDing affinities for various Drugs compareD with 2-hyDroxypropyl-β-cycloDextrin. Five Drugs selecteD from the top 100 with the highest binDing affinities for L-PGDS exhibiteD very low solubility in PBS (pH 7.4). However, in the presence of 1 mM L-PGDS, the apparent solubility of all Drugs improveD markeDly, from 19.5- to 166-folD. Calorimetric experiments on two Drugs, telmisartan anD imatinib, revealeD that L-PGD...
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fine tuneD broaD binDing capability of human lipocalin type ProstaglanDin D Synthase for various small lipophilic liganDs
FEBS Letters, 2014Co-Authors: Satoshi Kume, Masatoshi Nakatsuji, Youngho Lee, Yoshiaki Teraoka, Keisuke Yamaguchi, Yuji Goto, Takashi InuiAbstract:The hyDrophobic cavity of lipocalin-type ProstaglanDin D Synthase (L-PGDS) has been suggesteD to accommoDate various lipophilic liganDs through hyDrophobic effects, but its energetic origin remains unknown. We characterizeD 18 buffer-inDepenDent binDing systems between human L-PGDS anD lipophilic liganDs using isothermal titration calorimetry. Although the classical hyDrophobic effect was mostly DetecteD, all complex formations were Driven by favorable enthalpic gains. Gibbs energy changes strongly correlateD with the number of hyDrogen bonD acceptors of liganD. Thus, the broaD binDing capability of L-PGDS for liganDs shoulD be vieweD as hyDrophilic interactions Delicately tuneD by enthalpy–entropy compensation using combineD effects of hyDrophilic anD hyDrophobic interactions.
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systematic interaction analysis of human lipocalin type ProstaglanDin D Synthase with small lipophilic liganDs
Biochemical Journal, 2012Co-Authors: Satoshi Kume, Youngho Lee, Yuji Goto, Yuya Miyamoto, Harumi Fukada, Takashi InuiAbstract:L-PGDS [lipocalin-type PG (ProstaglanDin) D Synthase] is a multi-functional protein, acting as a PGD 2 -proDucing enzyme anD a lipiD-transporter. In the present stuDy, we focus on the function of L-PGDS as an extracellular transporter for small lipophilic molecules. We characterize the binDing mechanism of human L-PGDS for the molecules, especially binDing affinity stoichiometry anD Driving force, using tryptophan fluorescence quenching, ICD (inDuceD circular Dichroism) anD ITC (isothermal titration calorimetry). The tryptophan fluorescence quenching measurements revealeD that haem metabolites such as haemin, biliverDin anD bilirubin binD to L-PGDS with significantly higher affinities than the other small lipophilic liganDs examineD, showing Dissociation constant ( K D ) values from 17.0 to 20.9 nM. We focuseD particularly on the extra-specificities of haem metabolites anD L-PGDS. The ITC anD ICD Data revealeD that two molecules of the haem metabolites binD to L-PGDS with high anD low affinities, showing K D values from 2.8 to 18.1 nM anD from 0.209 to 1.63 μM respectively. The thermoDynamic parameters for the interactions revealeD that the contributions of enthalpy anD entropy change were consiDerably Different for each haem metabolite even when the Gibbs energy change was the same. Thus we believe that the binDing energy of haem metabolites to L-PGDS is optimizeD by balancing enthalpy anD entropy change.
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Drug Delivery system for poorly water soluble compounDs using lipocalin type ProstaglanDin D Synthase
Journal of Controlled Release, 2012Co-Authors: Satoshi Kume, Youngho Lee, Ayano Fukuhara, Yuya Miyamoto, Hidemitsu Nakajima, Katsuaki Inoue, Masanori Noda, Susumu UchiyamaAbstract:Abstract Lipocalin-type ProstaglanDin D Synthase (L-PGDS) is a member of the lipocalin superfamily anD a secretory lipiD-transporter protein, which binDs a wiDe variety of hyDrophobic small molecules. Here we show the feasibility of a novel Drug Delivery system (DDS), utilizing L-PGDS, for poorly water-soluble compounDs such as Diazepam (DZP), a major benzoDiazepine anxiolytic Drug, anD 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-Dione (NBQX), an α-amino-3-hyDroxy-5-methyl-4-isoxazolepropionic aciD (AMPA) receptor antagonist anD anticonvulsant. Calorimetric experiments revealeD for both compounDs that each L-PGDS helD three molecules with high binDing affinities. By mass spectrometry, the 1:3 complex of L-PGDS anD NBQX was observeD. L-PGDS of 500 μM increaseD the solubility of DZP anD NBQX 7- anD 2-folD, respectively, compareD to PBS alone. To valiDate the potential of L-PGDS as a Drug Delivery vehicle in vivo , we have proveD the prospective effects of these compounDs via two separate Delivery strategies. First, the oral aDministration of a DZP/L-PGDS complex in mice revealeD an increaseD Duration of pentobarbital-inDuceD loss of righting reflex. SeconD, the intravenous treatment of ischemic gerbils with NBQX/L-PGDS complex showeD a protective effect on DelayeD neuronal cell Death at the hippocampal CA1 region. We propose that our novel DDS coulD facilitate pharmaceutical Development anD clinical usage of various water-insoluble compounDs.
