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  • 1
    Language: English
    In: International Archives of Medicine, June 21, 2010, Vol.3, p.12
    Description: Background Midkine is a heparin-binding cytokine and is involved in etiology of various diseases. Thus, midkine inhibitors are expected to be helpful in treatment of many diseases. Methods We developed a simple assay for midkine activity based on midkine-dependent migration of osteblastic cells. Midkine inhibitors were searched as materials that inhibit this midkine activity. To develop peptides that inhibit midkine activity, we constructed models in which C-terminal half of midkine interacted with [alpha].sub.4 [beta].sub.1 -integrin. Low molecular weight compounds which are expected to bind to midkine with high affinity were searched by in silico screening with the aid of Presto-X2 program. Results Among peptides in putative binding sites of midkine and the integrin, a peptide derived from [beta].sub.1 -integrin and that derived from the first [beta] sheet of the C-terminal half of midkine significantly inhibited midkine activity. Two low molecular weight compounds found by in silico screening exhibited no toxicity to target cells, but inhibited midkine activity. They are trifluoro compounds: one (PubChem 4603792) is 2-(2,6-dimethylpiperidin-1-yl)-4-thiophen-2-yl-6-(trifluoromethy)pyrimidine, and the other has a related structure. Conclusions The assay procedure is helpful in screening midkine inhibitors. All reagents described here might become mother material to develop clinically effective midkine inhibitors.
    Keywords: Cytokines -- Properties ; Enzyme Inhibitors -- Properties ; Etiology (Medicine) -- Research ; Biochemical Assays -- Methods
    ISSN: 1755-7682
    Source: Cengage Learning, Inc.
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  • 2
    Language: English
    In: International Archives of Medicine, June 21, 2010, Vol.3, p.12
    Description: Background Midkine is a heparin-binding cytokine and is involved in etiology of various diseases. Thus, midkine inhibitors are expected to be helpful in treatment of many diseases. Methods We developed a simple assay for midkine activity based on midkine-dependent migration of osteblastic cells. Midkine inhibitors were searched as materials that inhibit this midkine activity. To develop peptides that inhibit midkine activity, we constructed models in which C-terminal half of midkine interacted with [alpha].sub.4 [beta].sub.1 -integrin. Low molecular weight compounds which are expected to bind to midkine with high affinity were searched by in silico screening with the aid of Presto-X2 program. Results Among peptides in putative binding sites of midkine and the integrin, a peptide derived from [beta].sub.1 -integrin and that derived from the first [beta] sheet of the C-terminal half of midkine significantly inhibited midkine activity. Two low molecular weight compounds found by in silico screening exhibited no toxicity to target cells, but inhibited midkine activity. They are trifluoro compounds: one (PubChem 4603792) is 2-(2,6-dimethylpiperidin-1-yl)-4-thiophen-2-yl-6-(trifluoromethy)pyrimidine, and the other has a related structure. Conclusions The assay procedure is helpful in screening midkine inhibitors. All reagents described here might become mother material to develop clinically effective midkine inhibitors.
    Keywords: Cytokines -- Properties ; Enzyme Inhibitors -- Properties ; Etiology (Medicine) -- Research ; Biochemical Assays -- Methods
    ISSN: 1755-7682
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: International Archives of Medicine, 01 June 2010, Vol.3(1), p.12
    Description: Abstract Background Midkine is a heparin-binding cytokine and is involved in etiology of various diseases. Thus, midkine inhibitors are expected to be helpful in treatment of many diseases. Methods We developed a simple assay for midkine activity based on midkine-dependent migration of osteblastic...
    Keywords: Medicine
    ISSN: 1755-7682
    E-ISSN: 1755-7682
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  • 4
    In: Pediatrics International, February 2010, Vol.52(1), pp.75-79
    Description: Midkine (MK), a heparin‐binding growth factor, is a secreted protein and can be detected in a patient's sera. MK was studied in the sera of 215 children and adolescents without malignant disease using an enzyme‐linked immunosorbent assay in order to determine the distribution of concentrations in a control population for pediatric oncology patients. Tested subjects either underwent surgical procedures or suffered from endocrinological diseases. Elevated MK levels were found in patients with short stature, diabetes mellitus, obesity, and cleft lip and palate. These patients were subsequently excluded from the “non‐cancer” group. MK serum levels did neither correlate with sex, age, weight or height nor showed a normal distribution (= 152, range: 0.0–5.58 ng/ml, median: 0.0 ng/ml, mean: 0.26 ng/ml, SD: ±0.61). MK serum values in children and adolescents are widely spread and not normally distributed. The present results indicate that the MK expression is influenced by many factors apart from cancer, which have not yet been identified.
    Keywords: Elisa ; Midkine ; Non‐Cancer Value ; Pediatric Population
    ISSN: 1328-8067
    E-ISSN: 1442-200X
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  • 5
    Language: English
    In: FEBS Letters, 2006, Vol.580(17), pp.4051-4056
    Description: Receptor-type protein tyrosine phosphatases (RPTPs) are considered to transduce extracellular signals across the membrane through changes in their PTP activity, however, our understanding of the regulatory mechanism is still limited. Here, we show that pleiotrophin (PTN), a natural ligand for protein tyrosine phosphatase receptor type Z (Ptprz) (also called PTPζ/RPTPβ), inactivates Ptprz through oligomerization and increases the tyrosine phosphorylation of substrates for Ptprz, G protein-coupled receptor kinase-interactor 1 (Git1) and membrane associated guanylate kinase, WW and PDZ domain containing 1 (Magi1). Oligomerization of Ptprz by an artificial dimerizer or polyclonal antibodies against its extracellular region also leads to inactivation, indicating that Ptprz is active in the monomeric form and inactivated by ligand-induced oligomerization.
    Keywords: Ptprz/Ptpζ/Rptpβ ; Tyrosine Phosphorylation ; Pleiotrophin ; Oligomerization ; Git1 ; Magi1 ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 6
    Language: English
    In: Journal of Biological Chemistry, 05/11/2001, Vol.276(19), pp.15868-15875
    Description: Midkine, a heparin-binding growth factor, plays a critical role in cell migration causing suppression of neointima formation in midkine-deficient mice. Here we have determined the molecules essential for midkine-induced migration. Midkine induced haptotaxis of osteoblast-like cells, which was abrogated by the soluble form of midkine or pleiotrophin, a midkine-homologous protein. Chondroitin sulfate B, E, chondroitinase ABC, B, and orthovanadate, an inhibitor of protein-tyrosine phosphatase, suppressed the migration. Supporting these data, the cells examined expressed PTPzeta, a receptor-type protein-tyrosine phosphatase that exhibits high affinity to both midkine and pleiotrophin and harbors chondroitin sulfate chains. Furthermore, strong synergism between midkine and platelet-derived growth factor in migration was detected. The use of specific inhibitors demonstrated that mitogen-activated protein (MAP) kinase and protein-tyrosine phosphatase were involved in midkine-induced haptotaxis but not PDGF-induced chemotaxis, whereas phosphatidylinositol 3 (PI3)-kinase and protein kinase C were involved in both functions. Midkine activated both PI3-kinase and MAP kinases, the latter activation was blocked by a PI3-kinase inhibitor. Midkine further recruited PTPzeta and PI3-kinase. These results indicate that PTPzeta and concerted signaling involving PI3-kinase and MAP kinase are required for midkine-induced migration and demonstrate for the first time the synergism between midkine and platelet-derived growth factor in cell migration.
    Keywords: Brain -- Metabolism ; Carrier Proteins -- Pharmacology ; Mitogen-Activated Protein Kinases -- Metabolism ; Platelet-Derived Growth Factor -- Pharmacology ; Protein Tyrosine Phosphatases -- Metabolism;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 7
    In: Human Reproduction, 2005, Vol.20(4), pp.1084-1089
    Description: BACKGROUND: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis. METHODS: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2-deoxyuridine (BrdU) incorporation. Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay. The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RTPCR. RESULTS: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells. The MK concentrations in the PF of the women with advanced endometriosis (stages II, III and IV) Median: 1.21ng/ml; interquartile range 0.802.27 were significantly higher than those of the women without endometriosis and with stage I endometriosis (0.06ng/ml, 0.671.26, P 0.05). As for the menstrual phase, the MK concentration in PF in the inteal phase (1.32ng/ml. 0.722.21) were significantly higher than those in the follicular phase (0.95ng/ml, 0.681.24, P 0.05). In addition, women with adnexal adhesions had higher concentrations of MK in PF than those without adhesions ( P 0.05). The MK concentrations of the women under GnRH agonist treatment were significantly lower than those of the other groups ( P 0.001). The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues. CONCLUSIONS: The present findings suggest that MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis.
    Keywords: Adhesions; Endometriosis; Midkine; Peritoneal Fluid; Cell Proliferation
    ISSN: 0268-1161
    E-ISSN: 1460-2350
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  • 8
    Language: English
    In: Nucleic Acids Research, 1992, Vol.20(7), pp.1617-1622
    Description: The region preceding the beta -lactamase promoter of Escherichia coli plasmid pUC19 has a curved DNA (bent DNA) structure. The center of the curvature was revealed to exist around nucleotide position 2580 of the plasmid, which is just beside RNA polymerase binding region. It was indicated that the identified region is curved even at 60 degree C. The gross geometry of the curvature was altered by inserting synthetic double-stranded oligonucleotides between positions 2585 and 2586. Effect of the alteration on strength of the promoter was not detected in vitro. However, in vivo analyses showed that the promoter strength is apparently dependent, in part, on the gross geometry of the curvature. Insertions of 4 and 16 bp, both of which altered the gross geometry of the curvature greatly, caused considerable reductions of in vivo level of beta -lactamase mRNA. In vivo, overall three-dimensional structure of the region covering the promoter and the curvature seems to play some significant role in transcription of the gene.
    Keywords: Plasmids ; Promoters ; Transcription ; Structure ; Curvature ; Plasmids ; Promoters ; Transcription ; Structure ; Curvature ; Miscellaneous ; Plasmids ; Plasmid Puc19 ; Beta -Lactamase ; Plasmid Puc19 ; Beta -Lactamase ; Beta -Lactamase ; Plasmid Puc19;
    ISSN: 0305-1048
    E-ISSN: 1362-4962
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  • 9
    In: Nature, 1976, Vol.262(5567), p.414
    Keywords: Cell Line–Metabolism ; Cytomegalovirus–Metabolism ; Cytomegalovirus Infections–Biosynthesis ; DNA, Mitochondrial–Biosynthesis ; DNA, Viral–Pharmacology ; Ethidium–Drug Effects ; Time Factors–Drug Effects ; Virus Replication–Drug Effects ; DNA, Mitochondrial ; DNA, Viral ; Ethidium;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 10
    Language: English
    In: Brain Research, 2001, Vol.894(1), pp.46-55
    Description: Midkine (MK) is a growth factor with neurotrophic activities, and is expressed during the early stages of experimental cerebral infarction in rats in the zone surrounding the infarct. To evaluate in vivo activity of MK in preventing neuronal death, MK produced in yeast (Pichia pastoris) was administered into the brain ventricle immediately before occlusion of the bilateral common carotid artery of Mongolian gerbils. MK administration at the dose of 0.5-2 microg immediately before occlusion was found to ameliorate delayed neuronal death in the hippocampal CA1 region caused by transient ischemia 7 days after the insult. The hippocampal neurons of the MK-administered gerbils tended to degenerate 14 and 21 days after the insult, but their numbers remained higher than those in saline-administered controls; however, the hippocampal neurons were degenerated 28 days after the insult. MK administration at 2 h after occlusion did not ameliorate the neuronal death. These findings suggested that the therapeutic time window was narrow. The two to four times repeated administration of 2 microg MK immediately before and at 1, 2, or 3 weeks after the occlusion were not significantly different for the hippocampal neuronal death at 28 days after the insult compared with a single injection, but were significantly effective compared with vehicle administration alone. These findings suggested that the therapeutic time window was relatively narrow. The potent neuroprotective activity of MK observed in vivo suggested that MK might be useful as a therapeutic reagent for prevention of neuronal death in neurodegenerative diseases.
    Keywords: Hippocampus ; Ischemia ; Midkine ; Mongolian Gerbil ; Delayed Neuronal Death ; Neurotrophic Factor ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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