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Summary Heavy meromyosin subfragment-1 (HMM S-1) was prepared by papain digestion of arterial myosin or actomyosin and was purified by agarose-ATP affinity chromatography. Proteolysis of crude arterial myosin suspensions was preceded by solubilization. HMM-S-1 thus obtained consisted mainly of a 90,000 dalton polypeptide and fully retained the K+- and Ca2+-ATPase of the parent myosin. Its affinity to agarose-ATP was comparable to that of skeletal muscle HMM S-1.The support of this work by an EMBO short time fellowship (to R. L.) and by the Deutsche Forschungsgemeinschaft (No. SFB 90, B 7) and the excellent technical assistance byM. Troschka andC. Köhler are gratefully acknowledged. 相似文献
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Knabl J Witschi R Hösl K Reinold H Zeilhofer UB Ahmadi S Brockhaus J Sergejeva M Hess A Brune K Fritschy JM Rudolph U Möhler H Zeilhofer HU 《Nature》2008,451(7176):330-334
Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics. 相似文献
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Svenja D. Steinbrink Carlo Pergola Ulrike Bühring Sven George Julia Metzner Astrid S. Fischer Ann-Kathrin Häfner Joanna M. Wisniewska Gerd Geisslinger Oliver Werz Dieter Steinhilber Thorsten J. Maier 《Cellular and molecular life sciences : CMLS》2010,67(5):797-806
Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug’s chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC50 ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC50 = 18.7 μM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC50 of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy. 相似文献
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The bacterial SoxAX cytochromes 总被引:1,自引:0,他引:1
SoxAX cytochromes are heme-thiolate proteins that play a key role in bacterial thiosulfate oxidation, where they initiate the reaction cycle of a multi-enzyme complex by catalyzing the attachment of sulfur substrates such as thiosulfate to a conserved cysteine present in a carrier protein. SoxAX proteins have a wide phylogenetic distribution and form a family with at least three distinct types of SoxAX protein. The types of SoxAX cytochromes differ in terms of the number of heme groups present in the proteins (there are diheme and triheme versions) as well as in their subunit structure. While two of the SoxAX protein types are heterodimers, the third group contains an additional subunit, SoxK, that stabilizes the complex of the SoxA and SoxX proteins. Crystal structures are available for representatives of the two heterodimeric SoxAX protein types and both of these have shown that the cysteine ligand to the SoxA active site heme carries a modification to a cysteine persulfide that implicates this ligand in catalysis. EPR studies of SoxAX proteins have also revealed a high complexity of heme dependent signals associated with this active site heme; however, the exact mechanism of catalysis is still unclear at present, as is the exact number and types of redox centres involved in the reaction. 相似文献
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Rosendahl J Witt H Szmola R Bhatia E Ozsvári B Landt O Schulz HU Gress TM Pfützer R Löhr M Kovacs P Blüher M Stumvoll M Choudhuri G Hegyi P te Morsche RH Drenth JP Truninger K Macek M Puhl G Witt U Schmidt H Büning C Ockenga J Kage A Groneberg DA Nickel R Berg T Wiedenmann B Bödeker H Keim V Mössner J Teich N Sahin-Tóth M 《Nature genetics》2008,40(1):78-82
Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. 相似文献
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Jung A Maier R Vartanian JP Bocharov G Jung V Fischer U Meese E Wain-Hobson S Meyerhans A 《Nature》2002,418(6894):144
The genome of the human immunodeficiency virus is highly prone to recombination, although it is not obvious whether recombinants arise infrequently or whether they are constantly being spawned but escape identification because of the massive and rapid turnover of virus particles. Here we use fluorescence in situ hybridization to estimate the number of proviruses harboured by individual splenocytes from two HIV patients, and determine the extent of recombination by sequencing amplified DNA from these cells. We find an average of three or four proviruses per cell and evidence for huge numbers of recombinants and extensive genetic variation. Although this creates problems for phylogenetic analyses, which ignore recombination effects, the intracellular variation may help to broaden immune recognition. 相似文献
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Timm Schubert Corinna Gleiser Peter Heiduschka Christoph Franz Kerstin Nagel-Wolfrum Ayse Sahaboglu Nicole Weisschuh Gordon Eske Karin Rohbock Norman Rieger François Paquet-Durand Bernd Wissinger Uwe Wolfrum Bernhard Hirt Wibke Singer Lukas Rüttiger Ulrike Zimmermann Marlies Knipper 《Cellular and molecular life sciences : CMLS》2015,72(20):3953-3969