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  • 1
    Online Resource
    Online Resource
    A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 6 ( 2009-02-10), p. 1737-1742
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 6 ( 2009-02-10), p. 1737-1742
    Abstract: As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae . Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0811275106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
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  • 2
    Online Resource
    Online Resource
    Dopamine Quinones Activate Microglia and Induce a Neurotoxic Gene Expression Profile : Relationship to Methamphetamine‐Induced Nerve Ending Damage
    Wiley ; 2006
    In:  Annals of the New York Academy of Sciences Vol. 1074, No. 1 ( 2006-08), p. 31-41
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1074, No. 1 ( 2006-08), p. 31-41
    Abstract: Abstract:  Methamphetamine (METH) intoxication leads to persistent damage of dopamine (DA) nerve endings of the striatum. Recently, we and others have suggested that the neurotoxicity associated with METH is mediated by extensive microglial activation. DA itself has been shown to play an obligatory role in METH neurotoxicity, possibly through the formation of quinone species. We show presently that DA‐quinones (DAQ) cause a time‐dependent activation of cultured microglial cells. Microarray analysis of the effects of DAQ on microglial gene expression revealed that 101 genes were significantly changed in expression, with 73 genes increasing and 28 genes decreasing in expression. Among those genes differentially regulated by DAQ were those often associated with neurotoxic conditions including inflammation, cytokines, chemokines, and prostaglandins. In addition, microglial genes associated with a neuronally protective phenotype were among those that were downregulated by DAQ. These results implicate DAQ as one species that could cause early activation of microglial cells in METH intoxication, manifested as an alteration in the expression of a broad biomarker panel of genes. These results also link oxidative stress, chemical alterations in DA to its quinone, and microglial activation as part of a cascade of glial–neuronal crosstalk that can amplify METH‐induced neurotoxicity.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Article
    DOI: 10.1196/annals.1369.003
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2006
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  • 3
    Online Resource
    Online Resource
    Dopamine Disposition in the Presynaptic Process Regulates the Severity of Methamphetamine‐Induced Neurotoxicity
    Wiley ; 2008
    In:  Annals of the New York Academy of Sciences Vol. 1139, No. 1 ( 2008-10), p. 118-126
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1139, No. 1 ( 2008-10), p. 118-126
    Abstract: Methamphetamine (METH) is well known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood, but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade, and it appears that extensive cross‐talk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L‐DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L‐DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly synthesized pool of DA can cause substantial changes in the severity of METH‐induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1196/nyas.2008.1139.issue-1
    DOI: 10.1196/annals.1432.026
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2008
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    SSG: 11
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 38 ( 2008-09-23), p. 14632-14637
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 38 ( 2008-09-23), p. 14632-14637
    Abstract: Cranial radiation therapy is commonly used in the treatment of childhood cancers. It is associated with cognitive impairments tentatively linked to the hippocampus, a neurogenic region of the brain important in memory function and learning. Hippocampal neurogenesis is positively regulated by voluntary exercise, which is also known to improve hippocampal-dependent cognitive functions. In this work, we irradiated the brains of C57/BL6 mice on postnatal day 9 and evaluated both the acute effects of irradiation and the effects of voluntary running on hippocampal neurogenesis and behavior 3 months after irradiation. Voluntary running significantly restored precursor cell and neurogenesis levels after a clinically relevant, moderate dose of irradiation. We also found that irradiation perturbed the structural integration of immature neurons in the hippocampus and that this was reversed by voluntary exercise. Furthermore, irradiation-induced behavior alterations observed in the open-field test were ameliorated. Together, these results clearly demonstrate the usefulness of physical exercise for functional and structural recovery from radiation-induced injury to the juvenile brain, and they suggest that exercise should be evaluated in rehabilitation therapy of childhood cancer survivors.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0711128105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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