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1.
Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition 总被引:2,自引:0,他引:2
K. Brune W. S. Beck G. Geisslinger S. Menzel-Soglowek B. M. Peskar B. A. Peskar 《Cellular and molecular life sciences : CMLS》1991,47(3):257-261
Summary Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics. 相似文献
2.
Functional diversification of closely related ARF-GEFs in protein secretion and recycling 总被引:1,自引:0,他引:1
Richter S Geldner N Schrader J Wolters H Stierhof YD Rios G Koncz C Robinson DG Jürgens G 《Nature》2007,448(7152):488-492
Guanine-nucleotide exchange factors on ADP-ribosylation factor GTPases (ARF-GEFs) regulate vesicle formation in time and space by activating ARF substrates on distinct donor membranes. Mammalian GBF1 (ref. 2) and yeast Gea1/2 (ref. 3) ARF-GEFs act at Golgi membranes, regulating COPI-coated vesicle formation. In contrast, their Arabidopsis thaliana homologue GNOM (GN) is required for endosomal recycling, playing an important part in development. This difference indicates an evolutionary divergence of trafficking pathways between animals and plants, and raised the question of how endoplasmic reticulum-Golgi transport is regulated in plants. Here we demonstrate that the closest homologue of GNOM in Arabidopsis, GNOM-LIKE1 (GNL1; NM_123312; At5g39500), performs this ancestral function. GNL1 localizes to and acts primarily at Golgi stacks, regulating COPI-coated vesicle formation. Surprisingly, GNOM can functionally substitute for GNL1, but not vice versa. Our results suggest that large ARF-GEFs of the GBF1 class perform a conserved role in endoplasmic reticulum-Golgi trafficking and secretion, which is done by GNL1 and GNOM in Arabidopsis, whereas GNOM has evolved to perform an additional plant-specific function of recycling from endosomes to the plasma membrane. Duplication and diversification of ARF-GEFs in plants contrasts with the evolution of entirely new classes of ARF-GEFs for endosomal trafficking in animals, which illustrates the independent evolution of complex endosomal pathways in the two kingdoms. 相似文献
3.
Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome 总被引:6,自引:0,他引:6
Windpassinger C Auer-Grumbach M Irobi J Patel H Petek E Hörl G Malli R Reed JA Dierick I Verpoorten N Warner TT Proukakis C Van den Bergh P Verellen C Van Maldergem L Merlini L De Jonghe P Timmerman V Crosby AH Wagner K 《Nature genetics》2004,36(3):271-276
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration. 相似文献
4.
5.
Terhi Vihervaara Riikka-Liisa Uronen Gerd Wohlfahrt Ingemar Björkhem Elina Ikonen Vesa M. Olkkonen 《Cellular and molecular life sciences : CMLS》2011,68(3):537-551
ORP1L is an oxysterol binding homologue that regulates late endosome (LE) positioning. We show that ORP1L binds several oxysterols
and cholesterol, and characterize a mutant, ORP1L Δ560–563, defective in oxysterol binding. While wild-type ORP1L clusters
LE, ORP1L Δ560–563 induces LE scattering, which is reversed by disruption of the endoplasmic reticulum (ER) targeting FFAT
motif, suggesting that it is due to enhanced LE–ER interactions. Endosome motility is reduced upon overexpression of ORP1L.
Both wild-type ORP1L and the Δ560–563 mutant induce the recruitment of both dynactin and kinesin-2 on LE. Most of the LE decorated
by overexpressed ORP1L fail to accept endocytosed dextran or EGF, and the transfected cells display defective degradation
of internalized EGF. ORP1L silencing in macrophage foam cells enhances endosome motility and results in inhibition of [3H]cholesterol efflux to apolipoprotein A-I. These data demonstrate that LE motility and functions in both protein and lipid
transport are regulated by ORP1L. 相似文献
6.
Ann-Karin Haas Gunnar Kleinau Inna Hoyer Susanne Neumann Jens Furkert Claudia Rutz Ralf Schülein Marvin C. Gershengorn Gerd Krause 《Cellular and molecular life sciences : CMLS》2011,68(1):159-167
The thyrotropin receptor (TSHR) exhibits elevated cAMP signaling in the basal state and becomes fully activated by thyrotropin.
Previously we presented evidence that small-molecule ligands act allosterically within the transmembrane region in contrast
to the orthosteric extracellular hormone-binding sites. Our goal in this study was to identify positions that surround the
allosteric pocket and that are sensitive for inactivation of TSHR. Homology modeling combined with site-directed mutagenesis
and functional characterization revealed seven mutants located in the allosteric binding site that led to a decrease of basal
cAMP signaling activity. The majority of these silencing mutations, which constrain the TSHR in an inactive conformation,
are found in two clusters when mapped onto the 3D structural model. We suggest that the amino acid positions identified herein
are indicating locations where small-molecule antagonists, both neutral antagonists and inverse agonists, might interfere
with active TSHR conformations. 相似文献
7.
Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction
Tegenge MA Rockel TD Fritsche E Bicker G 《Cellular and molecular life sciences : CMLS》2011,68(12):2089-2099
Neuronal migration is one of the most critical processes during early brain development. The gaseous messenger nitric oxide
(NO) has been shown to modulate neuronal and glial migration in various experimental models. Here, we analyze a potential
role for NO signaling in the migration of fetal human neural progenitor cells. Cells migrate out of cultured neurospheres
and differentiate into both neuronal and glial cells. The neurosphere cultures express neuronal nitric oxide synthase and
soluble guanylyl cyclase that produces cGMP upon activation with NO. By employing small bioactive enzyme activators and inhibitors
in both gain and loss of function experiments, we show NO/cGMP signaling as a positive regulator of migration in neurosphere
cultures of early developing human brain cells. Since NO signaling regulates cell movements from developing insects to mammalian
nervous systems, this transduction pathway may have evolutionary conserved functions. 相似文献
8.
Sayer JA Otto EA O'Toole JF Nurnberg G Kennedy MA Becker C Hennies HC Helou J Attanasio M Fausett BV Utsch B Khanna H Liu Y Drummond I Kawakami I Kusakabe T Tsuda M Ma L Lee H Larson RG Allen SJ Wilkinson CJ Nigg EA Shou C Lillo C Williams DS Hoppe B Kemper MJ Neuhaus T Parisi MA Glass IA Petry M Kispert A Gloy J Ganner A Walz G Zhu X Goldman D Nurnberg P Swaroop A Leroux MR Hildebrandt F 《Nature genetics》2006,38(6):674-681
9.
Marthe-Susanna Wegner Nina Schömel Lisa Gruber Stephanie Beatrice Örtel Matti Aleksi Kjellberg Peter Mattjus Jennifer Kurz Sandra Trautmann Bing Peng Martin Wegner Manuel Kaulich Robert Ahrends Gerd Geisslinger Sabine Grösch 《Cellular and molecular life sciences : CMLS》2018,75(18):3393-3410
The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance. 相似文献
10.
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