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Berlin Brandenburg

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  • Humans  (11)
  • Chemistry
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  • 1
    Language: English
    In: Environmental Toxicology and Chemistry, 2001, Vol.20(9), p.2088
    Description: We studied the chronic effects of 4-nonylphenol (4-NP) on reproductive status of medaka (Oryzias latipes) over two generations of continuous exposure. The exposure study of the parental (F0) medaka was begun on embryos within 24 h post-fertilization and continued with monitoring through embryological development, hatching, posthatch survival, growth, sexual differentiation, and reproduction under flow-through exposures to mean measured 4-NP concentrations of 4.2, 8.2, 17.7, 51.5, and 183 µg/litre for up to 104 d. Eggs spawned from the F0 fish at 102 and 103 d posthatch were also examined for hatchability, survival after hatching, growth, and sexual differentiation until 60 d posthatch. The 183-µg/litre treatment significantly reduced the embryo survival and swim-up success of the F0 fish. The cumulative mortality after swim-up of the F0 fish exposed to 17.7 and 51.5 µg/litre were significantly higher than the control mortality. No concentration-related effect of 4-NP was observed on the growth of surviving F0 fish at 60 d posthatch. However, the sex ratio estimated from the appearance of their secondary sex characteristics was skewed toward female in the 51.5-µg/litre treatment. Additionally, gonadal histology showed that 20% of the fish in the 17.7-µg/litre treatment and 40% in the 51.5-µg/litre treatment had testis-ova, indicating that 4-NP affects the gonadal development and survival of medaka at similar concentrations in juveniles. The sex ratio of the F0 fish in the 51.5-µg/litre treatment was completely skewed toward female; subsequently, the effects on fecundity and fertility in this generation were monitored at mean measured concentrations of 4.2, 8.2, and 17.7 µg/litre from 71 to 103 d posthatch. Fecundity was unaffected by any of the treatments examined. The mean fertility in the 17.7-µg/litre treatment was reduced to 76% of that in the controls, although no statistically significant differences were determined. Overall, these results indicate that the lowest-observed-effect concentration (LOEC) and no-observed-effect concentration (NOEC) of 4-NP through the life cycle of the F0 medaka were 17.7 and 8.2 µg/litre, respectively. In the F1 medaka, no significant effects were observed on hatching success, posthatch mortality, or growth, but sexual differentiation at 60 d posthatch was affected. Induction of testis-ova in the gonads of the F1 fish was observed in both the 8.2- and the 17.7-µg/litre concentrations. The results indicate that 4-NP can have significant effects on reproductive potential of medaka at concentrations as low as 17.7 µg/litre.
    Keywords: Aquatic Animals ; Aquatic Organisms ; Embryonic Development ; Embryos ; Growth ; Mortality ; Nontarget Effects ; Ovaries ; Reproduction ; Sex Differentiation ; Survival ; Testes ; Toxic Substances ; Toxicity ; Toxicology ; Aquatic Species ; Death Rate ; Embryo Development ; Embryo Growth ; Nonylphenols ; Poisons ; Testicles ; Oryzias Latipes ; Oryzias ; Adrianichthyidae ; Beloniformes ; Osteichthyes ; Fishes ; Vertebrates ; Chordata ; Animals ; Eukaryotes;
    ISSN: 0730-7268
    E-ISSN: 1552-8618
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  • 2
    Language: English
    In: FEBS Letters, 20 December 2014, Vol.588(24), pp.4769-4775
    Description: C-X-C motif chemokine 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) signaling is involved in ontogenesis, hematopoiesis, immune function and cancer. Recently, the orphan chemokine CXCL14 was reported to inhibit CXCL12-induced chemotaxis – probably by allosteric modulation of CXCR4. We thus examined the effects of CXCL14 on CXCR4 regulation and function using CXCR4-transfected human embryonic kidney (HEK293) cells and Jurkat T cells. CXCL14 did not affect dose–response profiles of CXCL12-induced CXCR4 phosphorylation, G protein-mediated calcium mobilization, dynamic mass redistribution, kinetics of extracellular signal-regulated kinase 1 (ERK1) and ERK2 phosphorylation or CXCR4 internalization. Hence, essential CXCL12-operated functions of CXCR4 are insensitive to CXCL14, suggesting that interactions of CXCL12 and CXCL14 pathways depend on a yet to be identified CXCL14 receptor.
    Keywords: Cxcl12 ; Cxcr4 ; Cxcl14 ; Amd3465 ; Amd3100 ; Dynamic Mass Redistribution ; Cxcr4 Antagonist ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
    Source: ScienceDirect Journals (Elsevier)
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  • 3
    Language: English
    In: The Journal of biological chemistry, 22 October 2010, Vol.285(43), pp.32878-87
    Description: The corticotropin-releasing factor receptor type 2a (CRF(2(a))R) belongs to the family of G protein-coupled receptors. The receptor possesses an N-terminal pseudo signal peptide that is unable to mediate targeting of the nascent chain to the endoplasmic reticulum membrane during early receptor biogenesis. The pseudo signal peptide remains uncleaved and consequently forms an additional hydrophobic receptor domain with unknown function that is unique within the large G protein-coupled receptor protein family. Here, we have analyzed the functional significance of this domain in comparison with the conventional signal peptide of the homologous corticotropin-releasing factor receptor type 1 (CRF(1)R). We show that the presence of the pseudo signal peptide leads to a very low cell surface receptor expression of the CRF(2(a))R in comparison with the CRF(1)R. Moreover, whereas the presence of the pseudo signal peptide did not affect coupling to the G(s) protein, G(i)-mediated inhibition of adenylyl cyclase activity was abolished. The properties mediated by the pseudo signal peptide were entirely transferable to the CRF(1)R in signal peptide exchange experiments. Taken together, our results show that signal peptides do not only influence early protein biogenesis. In the case of the corticotropin-releasing factor receptor subtypes, the use of conventional and pseudo signal peptides have an unexpected influence on signal transduction.
    Keywords: Protein Sorting Signals ; Adenylyl Cyclases -- Metabolism ; Gtp-Binding Protein Alpha Subunits, Gi-Go -- Metabolism ; Gene Expression Regulation -- Physiology ; Receptors, Corticotropin-Releasing Hormone -- Biosynthesis ; Signal Transduction -- Physiology
    E-ISSN: 1083-351X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 4
    Language: English
    In: Biochemical and Biophysical Research Communications, 10 August 2012, Vol.424(4), pp.758-764
    Description: ► We demonstrate substantial antiapoptotic effects of TβMCA on hepatocyte apoptosis. ► TβMCA prevents bile acid-induced breakdown of the mitochondrial membrane potential (MMP). ► TβMCA also restores the MMP when the free fatty acid palmitate is used as a hepatotoxin. β-Muricholic acid (βMCA) is a trihydroxylated bile acid that constitutes the major bile acid in rat and mouse. βMCA is more hydrophilic than ursodeoxycholic acid and has been evaluated for dissolution of cholesterol gallstones. Since it is unknown if βMCA has beneficial effects on hepatocyte cell death we determined the effect of tauro-βMCA (TβMCA) on apoptosis . Human Ntcp-transfected HepG2 cells and primary hepatocytes from rat and mouse were incubated with the proapoptotic glycochenodeoxycholic acid (GCDCA) as well as the free fatty acid palmitate in the absence and presence of TβMCA. Apoptosis was quantified using caspase 3/7-assays and after Hoechst 33342 staining. The mitochondrial membrane potential (MMP) was measured fluorometrically using JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-benzimidazol-carbocyaniniodide). Immunoblotting was performed against the proapoptotic Bcl-2-protein Bax. In Ntcp-HepG2 cells, GCDCA markedly increased apoptosis after 4 h. Co-incubation with TβMCA reduced apoptosis to 49% ( 〈 0.01 vs. GCDCA, each; = 6). While GCDCA (100 μmol/L) reduced the MMP to 34% after 6 h, combination treatment with TβMCA restored the MMP to control levels at all time points ( = 4). TβMCA also restored breakdown of the MMP induced by palmitate. GCDCA induced a translocation of Bax from the cytosol to mitochondria that was inhibited by simultaneous treatment with TβMCA in eqimolar concentrations. TβMCA restricts hepatocellular apoptosis induced by low micromolar concentrations of GCDCA or palmitate via inhibition of Bax translocation to mitochondria and preservation of the MMP. Thus, further studies are warranted to evaluate a potential use of TβMCA in ameliorating liver injury in cholestasis.
    Keywords: Cholestasis ; Bile Acid ; Apoptosis ; Mitochondrial Membrane Potential ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 5
    Language: English
    In: The Journal of biological chemistry, 17 August 2012, Vol.287(34), pp.28362-77
    Description: CXCL12 signaling through G protein-coupled CXCR4 regulates cell migration during ontogenesis and disease states including cancer and inflammation. The second CXCL12-receptor CXCR7 modulates the CXCL12/CXCR4 pathway by acting as a CXCL12 scavenger and exerts G protein-independent functions. Given the distinct properties of CXCR4 and CXCR7, we hypothesized that the distinct C-terminal domains differently regulate receptor trafficking and stability. Here, we examined epitope-tagged wild type and C-terminal mutant receptors in human embryonic kidney cells (HEK293) with respect to trafficking, stability, (125)I-CXCL12 degradation, and G protein-coupling. The 24 CXCR7 C-terminal residues were sufficient to promote rapid spontaneous internalization. Replacement of the CXCR7 C terminus with that of CXCR4 (CXCR7-4tail mutant) abolished spontaneous internalization but permitted ligand-induced internalization and phosphorylation at the heterologous domain. The reverse tail-swap caused ligand-independent internalization of the resulting CXCR4-7tail mutant. Receptor-mediated (125)I-CXCL12 uptake and release of (125)I-CXCL12 degradation products were accelerated with receptors bearing the CXCR7 C terminus and impaired after conversion of CXCR7 C-terminal serine/threonine residues into alanines. C-terminal lysine residues were dispensable for plasma membrane targeting and the CXCL12 scavenger function but involved in constitutive degradation of CXCR7. Although the CXCR7 C terminus abolished G protein coupling in the CXCR4-7tail mutant, replacement of the CXCR7 C terminus, CXCR7 second intracellular loop, or both domains with the corresponding CXCR4 domain did not result in a G protein-coupled CXCR7 chimera. Taken together, we provide evidence that the CXCR7 C terminus influences the ligand-uptake/degradation rate, G protein coupling, and receptor stability. Regulatory pathways targeting CXCR7 C-terminal serine/threonine sites may control the CXCL12 scavenger activity of CXCR7.
    Keywords: Proteolysis ; Chemokine Cxcl12 -- Metabolism ; Receptors, Cxcr -- Metabolism
    E-ISSN: 1083-351X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: The Journal of biological chemistry, 14 May 2004, Vol.279(20), pp.21374-82
    Description: The physiological responses of somatostatin are mediated by five different G protein-coupled receptors. Although agonist-induced endocytosis of the various somatostatin receptor subtypes (sst(1)-sst(5)) has been studied in detail, little is known about their postendocytic trafficking. Here we show that somatostatin receptors profoundly differ in patterns of beta-arrestin mobilization and endosomal sorting. The beta-arrestin-dependent trafficking of the sst(2A) somatostatin receptor resembled that of a class B receptor in that upon receptor activation, beta-arrestin and the receptor formed stable complexes and internalized together into the same endocytic vesicles. This pattern was dependent on GRK2 (G protein-coupled receptor kinase 2)-mediated phosphorylation of a cluster of phosphate acceptor sites within the cytoplasmic tail of the sst(2A) receptor. Unlike other class B receptors, however, the sst(2A) receptor was rapidly resensitized and recycled to the plasma membrane. The beta-arrestin mobilization of the sst(3) and the sst(5) somatostatin receptors resembled that of a class A receptor in that upon receptor activation, beta-arrestin and the receptor formed relatively unstable complexes that dissociated at or near the plasma membrane. Consequently, beta-arrestin was excluded from sst(3)-containing vesicles. Unlike other class A receptors, a large proportion of sst(3) receptors was subject to ubiquitin-dependent lysosomal degradation and did not rapidly recycle to the plasma membrane. The sst(4) somatostatin receptor is unique in that it did not exhibit agonist-dependent receptor phosphorylation and beta-arrestin recruitment. Together, these findings may provide important clues about the regulation of receptor responsiveness during long-term administration of somatostatin analogs.
    Keywords: Arrestins -- Physiology ; Cyclic Amp-Dependent Protein Kinases -- Metabolism ; Endosomes -- Physiology ; Receptors, Somatostatin -- Physiology
    ISSN: 0021-9258
    E-ISSN: 1083351X
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  • 7
    In: EMBO Journal, 18 August 2004, Vol.23(16), pp.3282-3289
    Description: Morphine is a poor inducer of μ‐opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [‐Ala‐MePhe‐Gly‐ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy‐terminal residue 375 (Ser). Ser phosphorylation was sufficient and required for morphine‐induced desensitization of MOR. In the presence of full agonists, morphine revealed partial agonistic properties and potently inhibited MOR phosphorylation and internalization. Upon removal of the drug, DAMGO‐desensitized receptors were rapidly dephosphorylated. In contrast, morphine‐desensitized receptors remained at the plasma membrane in a Ser‐phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser.
    Keywords: Desensitization ; Morphine ; Opioid Receptor ; Phosphorylation ; Tolerance
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 8
    Language: English
    In: The Journal of biological chemistry, 19 December 2003, Vol.278(51), pp.51630-7
    Description: The micro-opioid receptor (MOR1) and the substance P receptor (NK1) coexist and functionally interact in nociceptive brain regions; however, a molecular basis for this interaction has not been established. Using coimmunoprecipitation and bioluminescence resonance energy transfer (BRET), we show that MOR1 and NK1 can form heterodimers in HEK 293 cells coexpressing the two receptors. Although NK1-MOR1 heterodimerization did not substantially change the ligand binding and signaling properties of these receptors, it dramatically altered their internalization and resensitization profile. Exposure of the NK1-MOR1 heterodimer to the MOR1-selective ligand [D-Ala2,Me-Phe4,Gly5-ol]enkephalin (DAMGO) promoted cross-phosphorylation and cointernalization of the NK1 receptor. Conversely, exposure of the NK1-MOR1 heterodimer to the NK1-selective ligand substance P (SP) promoted cross-phosphorylation and cointernalization of the MOR1 receptor. In cells expressing MOR1 alone, beta-arrestin directs the receptors to clathrin-coated pits, but does not internalize with the receptor. In cells expressing NK1 alone, beta-arrestin internalizes with the receptor into endosomes. Interestingly, in cells coexpressing MOR1 and NK1 both DAMGO and SP induced the recruitment of beta-arrestin to the plasma membrane and cointernalization of NK1-MOR1 heterodimers with beta-arrestin into the same endosomal compartment. Consequently, resensitization of MOR1-dependent receptor functions was severely delayed in coexpressing cells as compared with cells expressing MOR1 alone. Together, our findings indicate that MOR1 by virtue of its physical interaction with NK1 is sequestered via an endocytotic pathway with delayed recycling and resensitization kinetics.
    Keywords: Receptors, Opioid, Mu -- Metabolism ; Substance P -- Metabolism
    ISSN: 0021-9258
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 9
    Language: English
    In: Cellular Physiology and Biochemistry, August 2011, Vol.28(2), pp.185-198
    Description: Extracellular matrix proteins, adhesion molecules, and cytoskeletal proteins form a dynamic network interacting with signalling molecules as an adaptive response to altered gravity. An important issue is the exact differentiation between real microgravity responses of the cells or cellular reactions to hypergravity and/or vibrations. To determine the effects of real microgravity on human cells, we used four DLR parabolic flight campaigns and focused on the effects of short-term microgravity (22 s), hypergravity (1.8 g), and vibrations on ML-1 thyroid cancer cells. No signs of apoptosis or necrosis were detectable. Gene array analysis revealed 2430 significantly changed transcripts. After 22 s microgravity, the F-actin and cytokeratin cytoskeleton was altered, and ACTB and KRT80 mRNAs were significantly upregulated after the first and thirty-first parabolas. The COL4A5 mRNA was downregulated under microgravity, whereas OPN and FN were significantly upregulated. Hypergravity and vibrations did not change ACTB, KRT-80 or COL4A5 mRNA. MTSS1 and LIMA1 mRNAs were downregulated/slightly upregulated under microgravity, upregulated in hypergravity and unchanged by vibrations. These data indicate that the graviresponse of ML-1 cells occurred very early, within the first few seconds. Downregulated MTSS1 and upregulated LIMA1 may be an adaptive mechanism of human cells for stabilizing the cytoskeleton under microgravity conditions.
    Keywords: Original Paper ; Thyroid Cancer ; Extracellular Matrix ; Apoptosis ; Cytoskeleton ; Weightlessness ; Microgravity ; Hypergravity ; Vibration ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
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  • 10
    In: Traffic, January 2009, Vol.10(1), pp.2-15
    Description: The heptahelical G protein‐coupled receptors (GPCRs) are internalized following agonist treatment and either recycle rapidly to the plasma membrane or enter the lysosomal degradation pathway. Many conventional GPCR recycling assays suffer from the fact that receptors arriving from the secretory pathway may interfere with recycling receptors. In this study, we introduce a new methodology to study post‐endocytotic GPCR trafficking using fusions with the recently cloned Kaede protein. In contrast to the widely used green fluorescent protein, the fluorescence of Kaede can be converted from green to red using ultraviolet irradiation. Our methodology allows to study recycling of GPCRs microscopically in real‐time bypassing problems with secretory pathway receptors. Initially, receptors are internalized using an agonist. Fluorescence signals in endosomes are switched, and trafficking of the receptors to the plasma membrane can be easily visualized by monitoring their new fluorescence. Using this methodology, we show that the corticotropin‐releasing factor receptor type 1 belongs to the family of recycling GPCRs. Moreover, we demonstrate by fluorescence correlation spectroscopy that Kaede does not oligomerize when fused to membrane proteins, representing an additional advantage of this technique. The Kaede technology may be a powerful tool to study membrane protein trafficking in general.
    Keywords: Confocal Laser Scanning Microscopy ; Corticotropin‐Releasing Factor Receptor Type 1 ; Endosomes ; G Protein‐Coupled Receptors ; Internalization ; Kaede ; Lysosomes ; Recycling
    ISSN: 1398-9219
    E-ISSN: 1600-0854
    Source: John Wiley & Sons, Inc.
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