bluuebunny/crossref_metadata_2025_split huggingface dataset:
Purinergic P2X7 receptor function in lung alveolar macrophages: Pharmacologic characterization and bidirectional regulation by Th1 and Th2 cytokines
Authors: Lemaire Irma , Leduc Natacha 
Published: May 2003

AbstractPurinergic P2X7 receptors have been shown in the lung, but little is known concerning P2X7 function in pulmonary macrophages. In this study we characterized P2X7‐dependent responses to extracellular ATP in resident and activated alveolar macrophages (AM) obtained by bronchoalveolar lavage of rats. Incubation of AM with high concentrations of ATP (5mM) or 3′‐O‐(4‐benzoyl)benzoyl‐ATP (BzATP) (0.5mM), a P2X7 agonist, induced: 1) rapid pore formation, 2) apoptosis, and 3) enhanced release of IL‐1α, IL‐1β, and IL‐6, but not TNF‐α following priming with lipopolysaccharide (LPS). Furthermore, higher expression of P2X7 receptor in AM was associated with increased formation of Type 2 multinucleated giant cells (Type 2 MGC) in response to GMCSF. Immunopharmacological analysis also showed that P2X7‐dependent pore formation in AM was significantly increased by LPS (1 µg/ml) and the T helper 1 (Th1) cytokines, interferon‐γ (100U/ml), and, to a lesser extent, TNF‐α (>20 ng/ml). In contrast, the T helper 2 (Th2) cytokines IL‐4 (1pg/ml) as well as IL‐10 (1ng/ml) significantly inhibited these P2X7 receptor functions. Transforming growth factor‐β (TGF‐β), a known deactivator of macrophages, had no significant effect. Our results demonstrate that AM exhibit all the characteristics of a functional P2X7 receptor which upon appropriate stimulation activates the proinflammatory IL‐1→IL‐6 cytokine cascade and the formation of MGC, a hallmark of granulomatous reactions. Moreover, Th1 and Th2 cytokines reciprocally regulate P2X7 function, suggesting a role for P2X7 in pulmonary diseases associated with chronic inflammatory responses. Drug Dev. Res. 59:118–127, 2003. © 2003 Wiley‐Liss, Inc.
Gene knockout approach to adenosine A2A receptors in Parkinson's disease
Authors: Chen Jiang‐Fan , Schwarzschild Michael A. 
Published: May 2003

AbstractRecently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.
Immunoreactivity for glial fibrillary acidic protein and P2 receptor expression on astrocytes in vivo
Authors: Franke Heike , Krügel Ute , Grosche Jens , Illes Peter 
Published: May 2003

AbstractChanges in glial fibrillary acidic protein (GFAP) are believed to be a sensitive and specific marker for astroglial responses to various kinds of injury. Neurotrophic factors and their receptors involved in the physiological and pathological responses of astrocytes are of special interest. For example, ATP, released from damaged or dying cells, may represent one of the endogenous factors mediating the activation of astrocytes. In the present study, the influence of different ATP analogs on the GFAP‐immunoreactivity (IR) and on the expression of P2 receptors on GFAP‐labeled cells were studied. Microinjection of the selective P2 receptor agonists α,β‐methylene ATP (α,β‐meATP; P2X1,3), adenosine 5′‐O‐(2‐thiodiphosphate) (ADP‐β‐S; P2Y1,12), and uridine 5′‐O‐(3‐thiotriphosphate) (UTP‐γ‐S; P2Y2,4,6) in the nucleus accumbens (NAc) of rats resulted in an increase of GFAP‐IR in comparison to the treatment with artificial cerebrospinal fluid. The agonist‐induced morphogenic changes documented a strong potency of α,β‐meATP and ADP‐β‐S. The effect of UTP‐γ‐S was small. Blockade of P2 receptors with the nonselective antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) decreased the injury‐induced elevation of GFAP‐IR when given alone and in addition inhibited the agonist effects. Double immunofluorescence measurements confined the localization of P2X2–4 and P2Y1 receptor subtypes to GFAP‐labeled astrocytes of untreated rats. The receptor subtypes P2X1,5,7 were not present in the NAc of native rats, but became expressed after mechanical damage. P2X6 receptor‐labeling was absent both with and without mechanical damage. After microinjection of α,β‐meATP and ADP‐β‐S into the NAc, the P2X1,3‐ and P2Y1‐IR, respectively, appeared to increase. These results show that the stimulation of P2 receptors influences the expression of GFAP‐IR in vivo. GFAP‐positive astrocytes possess P2X as well as P2Y receptor subtypes and change the expression of these receptors after injury and subsequent long‐term activation by ATP. Drug Dev. Res. 59:175–189, 2003. © 2003 Wiley‐Liss, Inc.
Proliferating intestinal γ/δ T cells recirculate rapidly and are a major source of the γ/δ T cell pool in the peripheral blood
Authors: Thielke Karl‐Heinz , Hoffmann‐Moujahid Astrid , Weisser Clemens , Waldkirch Eginhard , Pabst Reinhard , Holtmeier Wolfgang , Rothkötter Hermann J. 
Published: May 2003

AbstractThe proliferation, recirculation and repertoire of gut‐derived γ/δ T cells were studied in pigs in vivo. Proliferating γ/δ T cells (detected by BrdU labeling) are present in all intestinal compartments. In the gut lymph ∼0.5% of all γ/δ T cells were proliferating. These gut‐derived BrdU+ γ/δ T cells re‐enter the intestinal tissues, and re‐appear in the intestinal lymph far more often than other cells: about 22% of i.v.‐injected BrdU+ γ/δ T cells were recovered again from the intestinal lymph within 72 h (compare with BrdU+ B cells 2%, and other BrdU+ T cells 10%). The contribution of the gut to the migrating γ/δ T cell pool in the blood became obvious: the proportion of BrdU+ γ/δ T cells was three‐times larger in control versus cannulated pigs. In 9‐month‐old pigs, clonally expanded T cells were identified in the intestine by complementarity‐determining region 3 spectratyping of TCR‐δ transcripts. Such expansions were not visible in the blood or intestinal lymph. The distribution of γ/δ T cells within the intestinal tract is likely to depend to a large degree on the proliferation and the migratory properties of these cells which are different to those of α/β T cells and B lymphocytes.
Longitudinal analysis of Mycobacterium tuberculosis 19‐kDa antigen‐specific T cells in patients with pulmonary tuberculosis: association with disease activity and cross‐reactivity to a peptide from HIVenv gp120
Authors: Höhn Hanni , Kortsik Cornelius , Tully Glenn , Nilges Katja , Necker Antje , Freitag Kirsten , Neukirch Claudia , Galle Peter , Löhr Hans , Maeurer Markus J. 
Published: May 2003

AbstractCD8+ T cells play a central role in immune protection against infection with Mycobacterium tuberculosis. One of the target epitopes for anti‐M. tuberculosis directedCD8+ T cells is the HLA‐A2‐restricted 19‐kDa lipoprotein peptide VLTDGNPPEV. T cell clones directed against this epitope recognized not only the nominal peptide ligand, but also a closely related peptide (VPTDPNPPEV) from the HIV envelope gp120 (HIVenv gp120) protein characterized by IFN‐γ release. This cross‐reactivity was confirmed in ex vivo in M. tuberculosis 19‐kDa tetramer‐sorted T cells from patients with tuberculosis and in HIVgp120 tetramer‐reactive T cells sorted from HIV+ patients. M. tuberculosis 19‐kDa antigen‐reactive T cells were present in HLA‐A2+ patients (10/10) with HIV infection with no evidence of M. tuberculosis infection, but they are absent in peripheral blood lymphocytes from healthy HLA‐A2+ individuals (10/10). M. tuberculosis 19‐kDa antigen‐reactive T cells were elevated in acute pulmonary tuberculosis, declined with response to therapy (7/10 patients) and resided in the terminally differentiated CD8+ T cell subset. CD8+ cross‐reactive T cells recognizing HIVenv or M. tuberculosis 19‐kDa antigens may contribute to pathogenesis in individuals co‐infected with both pathogens and may also present a marker for active tuberculosis.
PU.1 is required for transcriptional activation of the Stat6 response element in the Igϵ promoter
Authors: Pesu Marko , Aittomäki Saara , Välineva Tuuli , Silvennoinen Olli 
Published: May 2003

AbstractSignal transducer and activator of transcription 6 (Stat6) has a crucial role in regulation of IL‐4‐induced gene responses. Stat6‐binding sites are present in the promoters of both ubiquitously and cell‐type‐specifically expressed genes. The promoter regions of IL‐4‐inducible genes contain cis‐acting elements for several transcription factors that act in concert with Stat6 and are also likely to modulate lineage‐specific gene expression. We have observed that the Stat6 response element from the B‐cell‐specific Igϵ promoter is readily activated upon IL‐4 stimulation in B cells but not in non‐hematopoietic cells. A minimal low‐affinity PU.1‐core‐binding sequence (5′‐AGAA‐3′) was identified within the Stat6 DNA‐binding site in the Igϵ promoter. Ectopic expression of the myeloid‐ and B‐cell‐specific transcription factor PU.1 restored the IL‐4‐inducibility of the Igϵ‐Stat6 response element in HepG2 cells, and the induction required an intact PU.1‐binding sequence. Both the transactivation and the DNA‐binding domains of PU.1 were required for induction of Stat6‐mediated transcription. The co‐operation between PU.1 and Stat6 in transactivation of the Igϵ gene represents a molecular mechanism for the fine‐tuning of cell‐type‐restricted expression of IL‐4‐induced gene responses.
MUC1‐derived glycopeptide libraries with improved MHC anchors are strong antigens and prime mouse T cells for proliferative responses to lysates of human breast cancer tissue
Authors: Gad Monika , Jensen Teis , Gagne Rod , Komba Shiro , Daugaard Søren , Kroman Niels , Meldal Morten , Werdelin Ole 
Published: May 2003

AbstractMulti‐component glycopeptide libraries and single glycopeptides were used for immunization of mice with the aim of inducing strong T helper cell responses to the repetitive sequence of MUC1 expressed by human tumor cells. The glycopeptides and glycopeptide libraries were modeled upon the native human MUC1 amino acid variable number of tandem repeats sequence by introduction of modifications in the MHC anchor positions to optimally fulfil the binding requirements of the Ad MHC class II molecule in the BALB/c mouse. The immunogenicity of the MUC1 glycopeptides in BALB/c micewas determined by immunization in complete Freund's adjuvant and assaying lymph node T cells for a proliferative response to the glycopeptide used. Strong proliferative responses with stimulation indices over 50 were obtained with anchor‐improved glycopeptide libraries as well as with single glycopeptides. Immunization with one of the glycopeptide libraries primed T cells for a proliferative cross‐response to the native MUC1 glycopeptide, which by itself was nonimmunogenic. In addition, immunization with the same glycopeptide library primed T cells for a strong response to lysate of a MUC1‐expressing human breast cancer, and immunization with the tumor lysate primed T cells for a response to the glycopeptide library. The T cells responding in the assay for proliferation were restricted to the Ad MHC class II molecule. The results indicate that immunization with MHC anchor‐improved MUC1 glycopeptide libraries can effectively prime T helper cells and may induce long‐term memory. The approach may be useful in the design of preventive cancer vaccines for use in humans.
Impaired contact hypersensitivity in macrophage migration inhibitory factor‐deficient mice
Authors: Shimizu Tadamichi , Abe Riichiro , Nishihira Jun , Shibaki Akihiko , Watanabe Hirokazu , Nakayama Toshinori , Taniguchi Masaru , Ishibashi Teruo , Shimizu Hiroshi 
Published: May 2003

AbstractTo determine whether macrophage migration inhibitory factor (MIF) is required for contact hypersensitivity (CHS) response, MIF‐deficient (MIF KO) and wild‐type (WT) mice were sensitized with trinitrochlorobenzene (TNCB) or oxazolone on their abdominal skin and challenged on the dorsum skin of one ear 5 days later. Significant ear swelling was observed in the WT mice, but this response was inhibited in the MIF KO mice (p<0.01 for MIF KO vs. WT mice in 24 h). In addition, lymph node cells from hapten‐sensitized MIF KO mice showed a decreased capacity for transferring the CHS response. A topical application of TNCB (200 μg) caused a significant decline in epidermal Langerhans cell (LC) density (20.3%; p<0.01 compared with vehicle) 4 h after application in WT mice, but it failed to provoke a significant epidermal LC migration in MIF KO mice (7.4%). By mixed lymphocyte reaction, the T cell proliferative response to alloantigen was significantly decreased in the MIF KO mice compared with WT mice (p<0.005). Taken together, these results indicate that MIF is pivotal in the regulation of cutaneous immune responses and plays a central role in LC migration and T cell proliferation for the CHS response.
Epstein‐Barr virus (EBV)‐positive lymphoproliferations in post‐transplant patients show immunoglobulin V gene mutation patterns suggesting interference of EBV with normal B cell differentiation processes
Authors: Bräuninger Andreas , Spieker Tilmann , Mottok Anja , Baur Audrey Sylvia , Küppers Ralf , Hansmann Martin‐Leo 
Published: May 2003

AbstractIn a model for persistent infection, Epstein‐Barr virus (EBV) uses the germinal center (GC) reaction to establish persistence in memory B cells. To study whether EBV adopts to normal B cell differentiation processes also in EBV‐associated lymphoproliferative diseases, we micromanipulated EBV+ cells from biopsies of five patients with post‐transplantation lymphoproliferative disease (PTLD) and one unusual Hodgkin lymphoma with many small EBV+ cells, and analyzed rearranged V genes of single cells. In all cases clonal expansions of EBV+ B cells were identified. The vast majority of these clones carried mutated V gene rearrangements and a fraction of clones showed ongoing hypermutation. Hence, PTLD likely derive from GC and/or post‐GC B cells. In two clones hypermutation occurred in the absence of follicular dendritic and CD4+ T cells, important interaction partners of normal GC B cells. Furthermore, in one case sustained somatic hypermutation occurred without expression of a functional antigen receptor. Hence, EBV+ B cells in PTLD can retain or acquire features of GC B cells in an unphysiological setting and may continue to undergo somatic hypermutation uncoupled from normal selection processes, suggesting that EBV interferes with normal B cell differentiation and selection processes in PTLD.
Interaction of VIVO, VVO2 and CuII with a Peptide Analogue SalGly‐L‐Ala
Authors: Jakusch Tamás , Dörnyei Ágnes , Correia Isabel , Rodrigues Lígia M. , Tóth Gábor K. , Kiss Tamás , Pessoa João Costa , Marcão Susana 
Published: May 2003

AbstractThe formation of complexes of a tripeptide analogue, salicylglycyl‐L‐alanine [HOC6H4C(O)NHCH2C(O)NHCH(CH3)COOH, H2SalGly‐L‐Ala], was studied with CuII, VIVO and VVO2 in aqueous solution using pH‐potentiometric and spectroscopic (UV/Vis, CD, EPR and 51V NMR) techniques. The results demonstrated the ambidentate character of the ligand. The metal ion‐induced deprotonation and subsequent coordination of the two neighbouring amide groups was shown to occur in a cooperative way in the pH range 5−6. At pH ≈︁ 6.5 a complex with an (O−, 2 × CON−, COO−) binding set becomes predominant for both CuII and VIVO. The affinity of the phenolate‐O− for VIVO is high and the ligand is bound to this metal ion even at pH values greater than 10. Conversely, the affinity for VVO2 is significantly lower and no interaction between this metal oxo‐ion and the ligand could be detected in the pH range 2−12. In contrast, with the dipeptide analogue H2SalGly, chelation involving the deprotonated amide‐N− could be unambiguously detected. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Iron‐Fragment‐Substituted Heterosiloxanes of Gallium [Cp(OC)2Fe−SiR2OGaR′2]2(R, R′ = Alkyl, Aryl) − Structures of [Cp(OC)2Fe−SiR2OGaMe2]2(R = Me, Ph)
Authors: Malisch Wolfgang , Schumacher Dirk , Schmiedeskamp Bernd , Jehle Heinrich , Eisner Dirk , Schoeller Wolfgang W. , Nieger Martin 
Published: May 2003

AbstractThe trialkylgallanes GaR′′3[R′ = Me,iPr (2aand2b)] react with the ferrio‐silanols Cp(OC)2Fe−Si(R)(R′)OH [R = R′ = Me,iPr, Ph (1a−c), R = Me, R′ = Ph (1d)] by alkane elimination to yield the iron‐substituted siloxy‐gallanes [Cp(OC)2Fe−Si(R)(R′)OGaR′′2]2(3a−e). According to molecular mass determination in benzene (3a,3b,3d), X‐ray analyses (3a,3d) and NMR spectroscopy (3e), the novel hetero‐siloxanes exist as dimers both in solution and in the solid state. The bonding situation and geometry of the ferrio‐heterosiloxane [Cp(OC)2Fe−SiH2OGaH2]2has been analyzed by density functional calculation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Tris(pyrazolyl)methanesulfonates: More Than Just Analogues of Tris(pyrazolyl)borate Ligands; N,N,N‐, N,N,O‐, and Other Coordination Modes
Authors: Kläui Wolfgang , Berghahn Michael , Frank Walter , Reiß Guido J. , Schönherr Thomas , Rheinwald Gerd , Lang Heinrich 
Published: May 2003

AbstractThe thallium(I) salts of tris(pyrazolyl)methanesulfonate (Tpms) and tris(3‐tert‐butylpyrazolyl)methanesulfonate (TpmstBu) have been used to prepare the following complexes: [(TpmstBu)ZnX] [X = Cl (1a), Br (1b), I (1c), Et (3), OAc (5a)], [(TpmstBu)NiX] [X = Cl (2a), Br (2b)], [(TpmstBu)CoCl(HpztBu)] (3), [(TpmstBu)Zn(μ‐OAc)(μ‐OH)Zn(TpmstBu)] (5b), [(TpmstBu)Cu(CO)] (6a), and [(Tpms)Cu(CO)] (6b). The solid‐state structures of 1b, 2a, 3, and 5b have been determined by X‐ray analysis. The optical spectra of 2a and 3 were investigated by means of the angular overlap model to elucidate their electronic structures in view of the underlying molecular geometries. Variable‐temperature NMR and IR spectroscopic studies show that Tpms and TpmstBu can act as N,N,N and N,N,O ligands. Both coordination modes are present in solution for the zinc complexes 1a,b and the copper carbonyl complexes 6a,b. The N,N,O bonding mode is entropically favoured in solution. For the nickel complexes 2a,b, the TpmstBu ligand acts as a tripodal nitrogen ligand in the solid state and in solution. For the dinuclear zinc complex 5b, one of the TpmstBu ligands acts as an N,N,O ligand and one as an N,O ligand. Complex 5b is one of the very few structural models of the dinuclear zinc enzymes phospholipase C and phosphotriesterase. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Synthesis and Characterization of Pentaarylated [60]Fullerene Coordinated Complexes [(η2‐Ar5C60H)M(PPh3)2] (M = Pt, Pd) and an ab initio Study on Their Isomerism
Authors: Song Li‐Cheng , Liu Peng‐Chong , Hu Qing‐Mei , Lin Zhenyang , Wang Yi‐Bo 
Published: May 2003

AbstractThis paper reports on the first examples of η2‐pentaarylated [60]fullerene organometallic complexes [(η2‐Ar5C60H)M(PPh3)2] (1: Ar = Ph, M = Pt;2: Ar =m‐MeC6H4, M = Pt;3: Ar =p‐MeC6H4, M = Pt;4: Ar = Ph, M = Pd;5: Ar =m‐MeC6H4, M = Pd;6: Ar =p‐MeC6H4, M = Pd), which were synthesized by treatment of [M(PPh3)4] with Ar5C60H and fully characterized by elemental analyses and their1H NMR,31P NMR, IR, UV/Vis, and FAB‐MS data. The1H NMR spectra displayed by the protons directly bonded to the C60core and the31P NMR spectra caused by the PPh3ligands indicated that complexes1−6exist as mixtures of isomers. To gain insights into the isomerism of1−6, the regioselectivity of the pentaarylated derivatives Ar5C60H as ligands coordinated to Pt0or Pd0has been studied by means of ab initio calculations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Calculated Enthalpies for Dimerisation of Binary, Unsaturated, Main‐Group Element Hydrides as a Means to Analyse Their Potential for Multiple Bonding
Authors: Himmel Hans‐Jörg 
Published: May 2003

AbstractHerein, the dimerisation of subvalent, binary, main‐group element hydrides with the potential for multiple bonding is studied using both hybrid DFT (B3LYP) and ab initio [MP2 and CCSD(T)] methods. The [2+2] cycloaddition is an important and characteristic reaction of derivatives of ethylene. A comparison of dimerisation reactions for several compounds with the potential for multiple bonding should, therefore, shed light on the properties of these species. Our study includes the hydrides E2H2 (E = B, Al, Ga, N P or As), E2H4 (E = C, Si or Ge) and ENH4 (E = B, Al or Ga) and their dimers. Several isomeric forms of the monomers and dimers have to be considered. The trends within a group and a period are established and the factors responsible for them are discussed. It turns out that, generally, the enthalpies for dimerisation increase for heavier homologues, reflecting that the most important factor is the reduced strength of the E−E bonds in the monomers prior to dimerisation and, to some degree, also the reduced ring strain in the cyclic dimers. The exceptions are the dimerisations of B2H2 and Al2H2, both of which lead to the tetrahedral E4H4 species (E = B or Al). Dimerisation of Al2H2 is associated with a smaller enthalpy than that for the dimerisation of B2H2. Comparisons and analyses are made complicated because of the changes in the structures of the isomeric global minima between homologues. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)