Showing papers by "Novum published in 1995"
TL;DR: The elucidation of the structures of the two high affinity Ah receptor ligands 6,12-diformylindolo[3,2-b]carbazole and 6-formylindol[3-2- b]carbzole provides the necessary basis for further mechanistic studies of this important group of compounds, and will help in determining the natural role of the Ah receptor.
202 citations
TL;DR: A minimal ligand binding domain is defined and isolated from the central PAS region of the dioxin receptor, comprising of amino acids 230 to 421, and this domain is found to interact with hsp90 in vitro, implying that the central ligandbinding pocket may exist to accommodate all classes of specific dioxIn receptor ligands, and that this pocket is critically dependent upon hSp90 for its ligand bound conformation.
167 citations
TL;DR: It is suggested that GH stimulates the association of SHC proteins with JAK2•GHR complexes via the SHC-SH2 domain, tyrosyl phosphorylation ofSHC proteins, and subsequent Grb2 association with SHC protein.
164 citations
TL;DR: The 32P-postlabelling method was further validated by the detection of acetaldehyde adducts in liver DNA from mice treated with ethanol, as analyzed by reversed-phase HPLC with online detection of radioactivity.
Abstract: A 32P-postlabelling assay was developed for the analysis of adducts arising from the reaction of 2'-deoxyguanosine-3'-monophosphate with acetaldehyde, the primary oxidative metabolite of ethanol. The 32P-postlabelling reaction was optimized by testing various parameters such as the kinetics of phosphorylation by T4 polynucleotide kinase, substrate-concentration-dependent labelling efficiency and the concentration of the various ingredients of the phosphorylation reaction. The sensitivity to 3'-monophosphate dephosphorylation activity of nuclease P1 was also studied. Three stable adducts were separated by reversed-phase HPLC. The major stable adduct was structurally characterized and identified as N2-ethyl-2'-deoxyguanosine and could be detected, after reduction with NaBH4 or a mixture of ascorbic acid and GSH, in calf thymus DNA samples that had been reacted in vitro with acetaldehyde. DNA adducts were isolated after enzymatic digestion to mononucleotides followed by nuclease P1 digestion of normal nucleotides. The average levels of acetaldehyde-DNA adducts detected in these samples were 12.1 +/- 2.3 (n = 17) and 4.9 +/- 0.9 (n = 9) adducts/10(7) nucleotides after reduction with NaBH4, or ascorbic acid and GSH respectively. The 32P-postlabelling method was further validated by the detection of acetaldehyde adducts in liver DNA from mice treated with ethanol. The average concentration of the adducts detected in these animals was 1.5 +/- 0.8 (n = 7) adducts/10(8) nucleotides, as analyzed by reversed-phase HPLC with online detection of radioactivity.
121 citations
TL;DR: Levels of sensory neuropeptides are increased under conditions of joint inflammation, especially in ankle joints and in dorsal root ganglia.
Abstract: Objective. To analyze the occurrence of substance P (SP) and calcitonin gene–related peptide (CGRP) in ankle joints and corresponding dorsal root ganglia (L2–L6) of rats with adjuvant arthritis.
Methods. Arthritis was induced by inoculation with heat-killed mycobacteria. The morphologic distribution of SP and CGRP was assessed by immunohistochemical analysis. Tissue concentrations of the neuropeptides were determined by radioimmunoassay.
Results. Neuronal CGRP-like immunoreactivity was clearly increased in the synovium and the dorsal root ganglia, whereas the increase in SP-positive structures was less pronounced. The tissue concentrations of SP and CGRP were significantly increased both in ankle joints and in dorsal root ganglia.
Conclusion. Levels of sensory neuropeptides are increased under conditions of joint inflammation.
93 citations
TL;DR: Data is reported on the kinetics of the reactions, the stability of the adducts at physiological pH, product yields, UV-spectroscopic data at different pH values, and the synthesis, isolation and structural characterization by FAB/MS and NMR of the stableadducts of acetaldehyde with dGuo.
80 citations
TL;DR: Because both oral regimens provide equivalent absorption, the 1,000-mg TID regimen may be preferred for the convenience and potentially greater compliance associated with fewer daily doses, and because the extent of ganciclovir absorption, peak concentrations, and average concentration at steady state were not statistically different between the two oral regimen.
75 citations
TL;DR: The present study of adjuvant induced arthritis shows that Capsaicin administration reduces the otherwise up-regulated levels of sensory neuropeptides in dorsal root ganglia and ankle joints, however, capsaicin at the dose given can only mitigate, not completely prevent the development of joint inflammation.
63 citations
TL;DR: In this article, an improved 2,2′-biindolyl (1) is described and potential syntheses of indolocarbazole alkaloids from such derivatives are outlined.
54 citations
TL;DR: The study indicates that the IL-1β induced PGE2 formation is mediated by an enhanced gene expression of COX-2 in gingival fibroblasts suggesting that the enzyme COX -2 may play an important role in the regulation of prostanoid formation at inflammatory lesions inGingival tissue.
Abstract: The effect of interleukin-1β (IL-1β) on the expression of cyclooxygenase-1 and −2 (COX-1 and COX-2) mRNA and its relation to prostaglandin E2 (PGE2) biosynthesis in human gingival fibroblasts was studied. IL-1β increased levels of mRNA for COX-2 whereas the COX-1 mRNA level was unaffected. The increased COX-2 mRNA levels were accompanied by enhanced PGE2 formation. The phorbol, 12-myristate 13-acetate (PMA), known to stimulate protein kinase C (PKC), also induced expression of COX-2 mRNA. When gingival fibroblasts were treated simultaneously with IL-1β and PMA, the cytokine IL-1β synergistically increased levels of COX-2 mRNA, accompanied by a corresponding increase in PGE2 biosynthesis. The anti-inflammatory steroid, dexamethasone (DEX) abolished the enhanced expression of COX-2 mRNA as well as PGE2 formation induced by IL-1β, PMA or the combination of IL-1β and PMA. The study indicates that the IL-1β induced PGE2 formation is mediated by an enhanced gene expression of COX-2 in gingival fibroblasts suggesting that the enzyme COX-2 may play an important role in the regulation of prostanoid formation at inflammatory lesions in gingival tissue.
52 citations
TL;DR: TFA-induced dimerization of indole-3-acetic acid (IAA) gave 5a. The corresponding methyl ester gave the diester 5b or the lactam 6.
TL;DR: The Pax-1 gene has been found to play an important role in the development of the vertebral column and is continuously expressed in the intervertebral discs of murine embryos and therefore seems to be important for the process of resegments.
Abstract: The Pax-1 gene has been found to play an important role in the development of the vertebral column. The cervico-occipital transitional zone is a specialized region of the vertebral column, and malformations of this region have frequently been described in humans. The exact embryonic border between head and trunk is a matter of controversy. In order to determine a possible role of Pax-1 in the development of the cervico-occipital transitional zone we studied the expression of this gene in a series of quail embryos and murine fetuses with in situ hybridization and immunohistochemistry. Pax-1 is expressed in all somites of the embryo, including the first five occipital ones. During embryonic days 3–5 the gene is down-regulated in the caudal direction within the first five somites, whereas more caudally Pax-1 is strongly expressed in the cells of the perinotochordal tube. In 5-day-old quail embryos, the cartilaginous anlage of the basioccipital bone has developed and there is no more expression of Pax-1 in this region. The fusion of the dens axis with the body of the axis also coincides with switching off of the Pax-1 gene. More caudally, the gene is continuously expressed in the intervertebral discs of murine embryos and therefore seems to be important for the process of resegmentation. Quail embryos do not possess permanent intervertebral discs. “Hyper-” or “hyposegmentation” defects may be explained by an over- or under-expression of Pax-1 during development. We also reinvestigated the border between the head and trunk in chick embryos by performing homotopical grafting experiments of the 5th somite between chick and quail embryos. Grafted quail cells formed mainly the caudal end of the basioccipital bone. They were also located in the cranial half of the ventral atlantic arch, and only a few cells were found in the tip of the dens axis.
TL;DR: It is concluded that disruptions of the phosphoinositide hydrolysis pathway in Alzheimer's disease brain are associated with a selective loss of calcium mobilising Ins(1,4,5)P3, but not Ins( 1,3, 4, 5)P4 receptor sites, providing one reason for the lack of success of cholinergic replacement therapies aimed at enhancing muscarinic receptor-mediated phosphatidylinositol Hydrolysis.
TL;DR: Signal transduction processes are severely compromised in Alzheimer’s disease, and disturbances are also seen in cultured fibroblasts from Alzheimer's disease patients, indicating that they are neither restricted to areas of histopathological change, nor non-specific changes found late in the course of the disease.
Abstract: Many of the treatments directed towards alleviation of symptoms in Alzheimer’s disease assume that target receptor systems are functionally intact. However, there is now considerable evidence that this is not the case. In human post-mortem brain tissue samples, the function of the GTP-binding protein Gs in regulating adenylyl cyclase is severely disabled, whereas that of G. is intact. This difference in the function of the two G-protein types is also found in G-protein regulation of high- and low-affinity receptor recognition site populations. Measurement of G-protein densities using selective antibodies has indicated that the dysfunction in Gs-stimulation of cAMP production correlates with the ratio of the large to small molecular weight isoforms of the Gsa subunit. With respect to intracellular second messenger effects, there is a dramatic decrease in the density of brain receptor recognition sites for Ins(l,4,5)P3 that is not accompanied by a corresponding change in the Ins(l,3,4,5)P4 recognition site density. Protein kinase C function is also altered in Alzheimer’s disease, a finding that may be of importance for the control of β-amyloid production. These studies indicate that signal transduction processes are severely compromised in Alzheimer’s disease. Some of these disturbances are also seen in cultured fibroblasts from Alzheimer’s disease patients, indicating that they are neither restricted to areas of histopathological change, nor non-specific changes found late in the course of the disease. Cellular models to investigate the relation between amyloid production and deficits in signal transduction are also discussed.
TL;DR: The application of the recently developed technique of scintillating microtitration plates in the study of protein-DNA interactions has a potential in basic research concerning characterization of DNA binding and is well suited to applied research as a tool in high-throughput screening of compound libraries in the search of agents inhibiting transcription factor binding to DNA.
TL;DR: The reduction of plasma LDL cholesterol in response to GH treatment in healthy adult men is not associated with detectable changes in biliary lipid metabolism, suggesting that GH therapy of adults probably does not result in an increased risk of cholesterol gallstone development.
Abstract: GH is important for the hepatic low density lipoprotein (LDL) receptor induction that occurs after estrogen treatment. GH treatment increases liver LDL receptors and lowers plasma LDL cholesterol in man. Estrogen treatment enhances biliary secretion of cholesterol, resulting in supersaturation of bile and an increased risk of gallstone formation. The present study was undertaken to investigate whether GH treatment also influences biliary lipid metabolism in humans. Twelve healthy male volunteers (mean age, 31 +/- 1 yr) were studied before and during the third week of treatment with recombinant human GH (0.1 IU/kg.day). Plasma lipids, bile acid kinetics, and biliary lipid composition were monitored. Plasma total and LDL cholesterol levels were reduced by 10% in response to therapy. However, no significant changes were observed in the biliary lipid composition or cholesterol saturation of gallbladder bile. Furthermore, there were no changes in chenodeoxycholic acid or cholic acid kinetics. The reduction of ...
TL;DR: The present study shows that an interruption of the nerve supply to joints cannot fully prevent the development of arthritis, although it significantly reduces the occurrence of sensory neuropeptides.
TL;DR: There was an intense fluorescence and significant increase (p < 0.01, 41%) in the number of NPY-positive megakaryocytes in the tibial bone marrow of arthritic rats and Capsaicin treatment did not affect the increased concentration of VIP-LI in the dorsal root ganglia.
TL;DR: The results indicate that the pharmacological properties and the functional integrity of G-protein coupling of the κ1 receptor recognition site are preserved in Alzheimer's disease temporal cortex.
TL;DR: The late occurrence and predominant distribution in marrow tissue would seem to imply that neuronal interleukin-1 does not participate in the early differentiation of bone cells, and the most important finding seems to be the presence of interleuko-1-positive nerve terminals in blood vessel walls and amidst marrow cells.
TL;DR: It is concluded that the pharmacological properties of the NMDA receptor recognition site labelled by [3H]-CGP 39653 are similar in the pig and rat cerebral cortices.
TL;DR: In this article, an improved 2,2′-biindolyl (1) is described and potential syntheses of indolocarbazole alkaloids from such derivatives are outlined.
Abstract: An improved synthesis of 2,2′-biindolyl (1) is described. Derivatives of 1 with a variety of substituents in the 3,3′-positions, such as the 3,3′-diformyl derivative 19 have been synthesized. Potential syntheses of indolocarbazole alkaloids from such derivatives are outlined.
TL;DR: It is demonstrated that effects of kappa-opioid receptor recognition site conformation are unlikely to explain the clinically observed synergy between local anaesthetics and opioids.
TL;DR: Investigation of whether nodules from male rats are to some extent withdrawn from the normal growth hormone (GH) regulation of these functions found that continuous infusion of both hGH and bGH feminized the expression of all the sex differentiated genes in male tissues and eliminated the previously detected differences between nodules and surrounding tissue.
Abstract: Sex differentiation of liver functions has been shown to be attenuated in preneoplastic rat liver nodules. The present study was performed to investigate whether nodules from male rats are to some extent withdrawn from the normal growth hormone (GH) regulation of these functions. Male and female Wistar rats were treated according to a modified resistant hepatocyte model (RH-model), with diethylnitrosamine initiation and promotion with intragastric administration of 2-acetylaminofluorene (2-AAF) combined with partial hepatectomy (PH). Eleven months post-initiation male rats were treated with either human (hGH) or bovine growth hormone (bGH) or ovine prolactin (oPRL) by continuous infusion for 1 week. The mRNA expression of a number of genes known to be sex differentiated in liver from adult control rats was compared in nodular and surrounding tissue from nodule-bearing male, female and hormone-treated male rats. The basal mRNA expression of the female-predominant cytochrome P4502C12 (CYP2C12) was increased and the male-predominant CYP2C11 was decreased in liver nodules from male rats compared with the surrounding liver. Expression of the prolactin receptor (PRL-r; female > male) and the steroid 5 alpha-reductase (female > male) genes was decreased in male nodules, whereas no difference was observed with respect to GH-receptor (GH-r; female > male) expression in nodules versus surrounding tissue. Early nodules obtained from males treated according to the original RH-model (dietary 2-AAF, 0.02%) and isolated 2 weeks after completion of the 2-AAF/PH treatment showed significantly lower GH-r mRNA levels than the total liver tissue. In hepatocellular carcinomas from hormonally unmanipulated males 11 months post-initiation the decrease in PRL-r expression was even more pronounced than in the nodules and a significant decrease in GH-r expression was seen. In female nodules the only significant difference with respect to the sex differentiated parameters was a lower 5 alpha-reductase expression than in the surrounding tissue. Continuous infusion of both hGH and bGH feminized the expression of all the sex differentiated genes in male tissues and eliminated the previously detected differences between nodules and surrounding tissue. oPRL also eliminated the differences between nodules and surrounding tissue in males and partly feminized the expression of both the 5 alpha-reductase and the PRL-r genes.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: Data indicate that the NMDA recognition site can be visualized in rat and mouse spinal cord byin vitro [3H]CGS 19755 autoradiography.
Abstract: The possibility to visualize the NMDA recognition site with [3H]CGS 19755in vitro autoradiography was evaluated in rat brain and spinal cord sections and thereafter used to study the distribution of the NMDA recognition site in rat and mouse spinal cord. The [3H]CGS 19755 binding was concentrated to the dorsal horn, in particular to the substantia gelatinosa. Notable binding was also seen in the intermediate area and ventral horn, while some binding was observed in the funiculi. No major differences were seen in [3H]CGS 19755 binding at various levels of the rat or mouse spinal cord, although a more dense binding was seen in the mouse. A similar distribution of the [3H]CGS 19755 specific binding and the NMDA receptor associated ion-channel site, labeled with [3H]TCP, was found in the mouse spinal cord. Taken together, our data indicate that the NMDA recognition site can be visualized in rat and mouse spinal cord byin vitro [3H]CGS 19755 autoradiography.
TL;DR: TFA-induced dimerization of indole-3-acetic acid (IAA) gave 5a. The corresponding methyl ester gave the diester 5b or the lactam 6.
Abstract: TFA-induced dimerization of indole-3-acetic acid (IAA) gave 5a . The corresponding methyl ester gave the diester 5b or the lactam 6 . Similar treatment of the 2,3-bis-(3-indolyl)-succinic ester 4b gave the tetrahydroindolo[2,3- a ]carbazole derivative 10 . The relation of these compounds to indolocarbazole alkaloids is discussed.