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1.
Calcif Tissue Int ; 78(5): 278-84, 2006 May.
Article in English | MEDLINE | ID: mdl-16691493

ABSTRACT

Ameloblastin (Ambn, also named "amelin" or "sheathlin") is a protein participating in enamel formation and mesenchymal-ectodermal interaction during early dentin formation in developing teeth. Experiments have demonstrated an association between Ambn expression and healing of acute pulp wounds. The purpose of this study was to investigate if local application of recombinant fusion Ambn (rAmbn) could influence reparative dentin formation in pulpotomized teeth. In this randomized, double-blinded study, pulpotomy was performed in 28 lower central incisors in 17 adult miniature pigs. Following the surgical procedure, the exposed pulp tissue was covered either with rAmbn or with calcium hydroxide. After 2, 4, or 8 weeks, the teeth were extracted and examined by histomorphometry and immunohistochemistry using antibodies against porcine ameloblastin, collagen type I, and dentin sialoprotein (DSP). In rAmbn-treated teeth, a substantial amount of newly formed reparative dentin was observed at the application site, completely bridging the pulpal wound. Dentin formation was also observed in calcium hydroxide-treated teeth; however, the amount of reparative dentin was significantly smaller (P < 0.001) than after rAmbn treatment. Immunohistochemistry confirmed that the new hard tissue formed was similar to dentin. This is the first time a direct link between ameloblastin and dentin formation has been made in vivo. The results suggest potential for rAmbn as a biologically active pulp-dressing agent for enhanced pulpal wound healing and reparative dentin formation after pulpotomy procedures.


Subject(s)
Dental Enamel Proteins/genetics , Dental Pulp/drug effects , Dentin/drug effects , Dentinogenesis/drug effects , Recombinant Fusion Proteins/therapeutic use , Regeneration/drug effects , Tooth Injuries/drug therapy , Animals , Dental Pulp/metabolism , Dental Pulp Diseases/drug therapy , Dental Pulp Diseases/metabolism , Dental Pulp Diseases/physiopathology , Dentin/cytology , Dentin/metabolism , Dentinogenesis/physiology , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/pharmacology , Regeneration/physiology , Sus scrofa , Tooth Injuries/metabolism , Tooth Injuries/physiopathology , Treatment Outcome , Wound Healing/drug effects , Wound Healing/physiology
2.
J Neurosci Res ; 66(3): 390-5, 2001 Nov 01.
Article in English | MEDLINE | ID: mdl-11746356

ABSTRACT

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two homologeous proteins that have been recognized as potent survival factors for distinct neuronal populations. GDNF and NTN act through a two-component receptor system consisting of the ligand-specific binding subunits GDNF family receptor (GFR)alpha-1 and GFRalpha-2 and the common transducing subunit c-Ret. In addition, it has been demonstrated that GDNF can signal through GFRalpha-1 in the absence of c-Ret. In the present study, we sought to determine whether a similar c-Ret-independent signaling applies for GFRalpha-2. In addition, we have characterized the ligand specificity of the c-Ret-independent action of GFRalphas. To establish an assay system for these studies, several neural cell lines were screened for the presence of GDNF and NTN receptor subunits by RT-PCR and immunoblot analysis. c-Ret expression was detectable only in Neuro2A cells, which did not express GFRalpha-1 or GFRalpha-2. The neuronal cell line LS expressed GFRalpha-2, and the glial cell line Mes42 expressed GFRalpha-1, whereas the neuronal cell line B104 expressed both GFRalpha-1 and GFRalpha-2. Stimulation of B104 and Mes42 cells with GDNF, but not with NTN, for 10 min resulted in CREB phosphorylation. In apparent contrast, neither NTN nor GDNF promoted CREB activation in LS and Neuro2A cells. Moreover, exposure of LS cells to NTN or GDNF also failed to activate AKT and ERK. Together these findings provide evidence that, in contrast to GFRalpha-1, GFRalpha-2 fails to signal in the absence of c-Ret. In addition, these observations reveal that c-Ret-independent signaling of GFRalpha-1 is ligand- specific and occurs only with GDNF.


Subject(s)
Central Nervous System/growth & development , Drosophila Proteins , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/deficiency , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction/physiology , Animals , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Central Nervous System/metabolism , Cyclic AMP Response Element-Binding Protein/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Fetus , Glial Cell Line-Derived Neurotrophic Factor , Glial Cell Line-Derived Neurotrophic Factor Receptors , Immunoblotting , Ligands , Mitogen-Activated Protein Kinases/drug effects , Mitogen-Activated Protein Kinases/metabolism , Nerve Growth Factors/pharmacology , Nerve Tissue Proteins/pharmacology , Neuroglia/drug effects , Neuroglia/metabolism , Neurons/drug effects , Neurturin , Phosphorylation/drug effects , Proto-Oncogene Proteins/drug effects , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-ret , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects
3.
Neuro Endocrinol Lett ; 22(6): 461-6, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11781545

ABSTRACT

OBJECTIVES: Neurotrophins and GDNF have been recently recognized as important local regulators of inflammatory processes of the gut. RESULTS: We now demonstrate that experimental TNBS-colitis is associated with the increased expression of neurotrophins and GDNF in the adrenal glands. In histological sections of the adrenals from untreated control animals, faint immunolabeling for BDNF, NT-3 and NGF was detectable in the adrenal cortex, with some additional labeling for NGF over the adrenal medulla, whereas GDNF immunolabeling was confined to the adrenal medulla. Induction of TNBS-colitis markedly increased NGF, BDNF, and NT-3 expression within the adrenal cortex after 8 h. NGF declined to basal levels after 7 days. In case of BDNF and NT-3 basal expression levels were reached after 14 days. GDNF expression was robustly upregulated in the adrenal medulla 8 h after induction of colitis and stayed elevated for up to 14 days. CONCLUSION: Together these observations suggest that neurotrophins and GDNF might act as local modulators of components of the HPA-axis during peripheral inflammation.


Subject(s)
Adrenal Glands/immunology , Colitis/immunology , Colitis/physiopathology , Nerve Growth Factors/genetics , Adrenal Glands/chemistry , Animals , Brain-Derived Neurotrophic Factor/analysis , Brain-Derived Neurotrophic Factor/genetics , Chromaffin Cells/physiology , Gene Expression/immunology , Glial Cell Line-Derived Neurotrophic Factor , Male , Nerve Growth Factor/analysis , Nerve Growth Factor/genetics , Nerve Growth Factors/analysis , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/genetics , Neuroimmunomodulation/physiology , Neurotrophin 3/analysis , Neurotrophin 3/genetics , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley
4.
Eur J Pharmacol ; 331(2-3): 97-107, 1997 Jul 23.
Article in English | MEDLINE | ID: mdl-9274967

ABSTRACT

We studied the effects of various intracerebroventricularly administered oligodeoxynucleotides on body temperature, locomotor activity, food intake and water consumption in rats during a 24 h period with a radio-telemetric system. Both complete phosphorothioate oligodeoxynucleotides and end-inverted oligodeoxynucleotides dose-dependently elevated body temperature, suppressed food and fluid intake and inhibited nighttime activity. Apparently these effects do not depend on the nucleotide sequence because antisense and sense arginine vasopressin and oxytocin oligodeoxynucleotides, as well as a missense oligodeoxynucleotide produced comparable changes in the autonomous and behavioral parameters. In control experiments neither contaminants from the chemical synthesis nor endotoxins produced such effects, whereas native DNA from salmon sperm did. Fever and sickness-like behavior in response to missense phosphorothioate oligodeoxynucleotides were accompanied by elevated concentrations of circulating corticosterone and by a marked increase in interleukin 6 mRNA in brain and spleen, indicating that centrally administered oligodeoxynucleotides stimulate the production of pyrogenic inflammatory mediators in both central nervous system and peripheral tissues. Our results indicate that centrally administered oligodeoxynucleotides produce beside their intended sequence-specific effects also transient and sequence-independent effects due to their nucleic acid structure.


Subject(s)
Oligonucleotides/pharmacology , Animals , Behavior, Animal/drug effects , Blotting, Northern , Body Temperature/drug effects , Corticosterone/metabolism , DNA/biosynthesis , Dose-Response Relationship, Drug , Drinking/drug effects , Eating/drug effects , Endotoxins/metabolism , Injections, Intraventricular , Interleukin-6/biosynthesis , Male , Motor Activity/drug effects , Oligonucleotides/administration & dosage , Rats , Rats, Wistar
5.
Neurosci Lett ; 217(2-3): 97-100, 1996 Oct 18.
Article in English | MEDLINE | ID: mdl-8916081

ABSTRACT

After intracerebroventricular (i.c.v.) injection of a missense oligodeoxynucleotide (MS-ODN) solution in rats, transcripts of the proinflammatory cytokine interleukin (IL)-6 were induced in hypothalamus, hippocampus, cortex and spleen and increased levels of circulating IL-6 and corticosterone were detected. Moreover, using a biotelemetric method body temperature of rats injected with ODN or Ringer solution was monitored over a period of 24 h after the injection. The i.c.v. injection of ODN induced a fever response which peaked at 6 h post-injection. These observations demonstrate that central administration of ODNs generates an inflammatory response in the central nervous system (CNS) and in the periphery as well.


Subject(s)
Brain Chemistry/drug effects , Interleukin-6/biosynthesis , Oligonucleotides, Antisense/pharmacology , RNA, Messenger/biosynthesis , Spleen/metabolism , Animals , Blotting, Northern , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Corticosterone/blood , Hippocampus/drug effects , Hippocampus/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Injections, Intraventricular , Male , Oligonucleotides, Antisense/administration & dosage , Rats , Rats, Wistar , Spleen/drug effects
6.
J Neuroendocrinol ; 8(2): 129-35, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8868260

ABSTRACT

We studied the effect of corticosterone on interleukin (IL)-1 beta synthesis, body temperature, general activity, food consumption and fluid intake in rats treated with bacterial lipopolysaccharide (LPS). Radiotelemetry was used to assess body temperature and locomotor activity in combination with continuous automated recordings of feeding and drinking. This technique was developed as a novel method to identify and measure sickness behavior in rodents. The animals were (a) sham-operated, (b) adrenalectomized or (c) sham-operated and treated with corticosterone (10 mg/kg, subcutaneously). They were then intraperitoneally injected with vehicle or LPS at a dose (100 micrograms/kg) that in sham-operated rats induced fever and anorexia, reduced spontaneous activity and increased IL1-beta mRNA in spleen and adrenals as determined by Northern blot analysis. Adrenalectomized rats produced larger amounts of splenic IL-1 beta mRNA, reduced their general activity much more and developed a mild adipsia as compared with adrenal-intact animals. Administration of corticosterone 1 h before LPS lowered the splenic IL-1 beta mRNA content compared to LPS-treated adrenal-intact rats that did not receive corticosterone and inhibited fever and anorexia, whereas the glucocorticoid did not attenuate the endotoxin-induced suppression of locomotor activity. Our data suggest that during inflammatory conditions body temperature, sickness behavior and the synthesis of IL-1 beta are controlled by corticosterone. Different components of sickness behavior seem to be independently regulated and are under differential control by glucocorticoids.


Subject(s)
Behavior, Animal/drug effects , Corticosterone/pharmacology , Interleukin-1/biosynthesis , Adrenal Glands/drug effects , Adrenal Glands/metabolism , Adrenalectomy , Animals , Blotting, Northern , Body Temperature/drug effects , Drinking/drug effects , Eating/drug effects , Lipopolysaccharides/pharmacology , Male , Motor Activity/drug effects , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Rats , Rats, Wistar , Spleen/drug effects , Spleen/metabolism
7.
FASEB J ; 9(8): 659-64, 1995 May.
Article in English | MEDLINE | ID: mdl-7768358

ABSTRACT

The pleiotropic cytokine interleukin-6 (IL-6) controls both the peripheral and central components of the acute-phase response. These activities are mediated via the IL-6 membrane receptor, but probably also via agonistic soluble IL-6 receptors (sIL-6Rs). In the present study we conducted dose-response experiments with rats that were intracerebroventricularly i.c.v.) injected with recombinant human IL-6 and sIL-6R and determined body temperature, locomotor activity, food intake, and water consumption using radiotelemetry and continuous recordings of feeding and drinking. IL-6 injected i.c.v. at 1, 10, and 100 ng increased body temperature and decreased locomotor activity and food intake, but it did not affect water consumption. When 10 ng sIL-6R, which lacked detectable biological activity, was injected i.c.v. 1 h before 1 ng IL-6, the central effects of IL-6 were enhanced and prolonged, and this was not due to endotoxin contamination of the recombinant proteins. Our data suggest that IL-6 plays an important role in the regulation of body temperature, general activity, and food intake in sick animals. Moreover, we have shown for the first time that it is possible to potentiate the effects of a mediator in vivo by administration of the corresponding receptor, which is a novel pharmacological tool for increasing receptor capacity.


Subject(s)
Interleukin-6/pharmacology , Receptors, Interleukin/metabolism , Animals , Body Temperature/drug effects , Drug Synergism , Eating/drug effects , Fever/chemically induced , Humans , Injections, Intraventricular , Interleukin-6/metabolism , Locomotion/drug effects , Male , Rats , Rats, Wistar , Receptors, Interleukin-6 , Recombinant Proteins/pharmacology , Solubility
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