| 1355925 |
Effects of acute and chronic desipramine treatment on somatostatin receptors in brain |
10.1007/BF02245124. |
Psychopharmacology (Berl) |
Effects of acute and chronic desipramine treatment on somatostatin receptors in brain
Abstract
- The effects of acute (5 mg/kg, IP twice daily for 2 days) and chronic (5 mg/kg IP twice daily for 21 days) administration of desipramine (DMI) on 125I-Tyr11-somatostatin binding sites in brain were examined. There was no change in 125ITyr11-somatostatin binding in membranes prepared from the frontal cortex, striatum, and hippocampus of rats acutely or chronically treated with DMI as compared to non treated animals. 125ITyr11-somatostatin binding was increased in membranes prepared from the rat nucleus accumbens only after chronic DMI administration. Scatchard analysis of the binding data from the nucleus accumbens showed that 125ITyr11-somatostatin labels a single population of somatostatin binding sites with an affinity constant, Kd, of 1.8 +/- 0.60 nM and a Bmax of 330 +/- 90 fmol/mg protein. Chronic treatment with DMI increased the Bmax (500 +/- 140 fmol/mg protein) but had no effect on the Kd. This finding shows a regional effect of DMI on 125ITyr11-somatostatin binding sites in rat brain and suggests that somatostatin may play a role in the pathophysiology of depression.
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| 1356016 |
Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications |
10.1016/0960-0760(92)90184-k. |
J Steroid Biochem Mol Biol |
Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications
Abstract
- Somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred tumors. SS-R were found in most neuroendocrine tumors, i.e. GH and TSH producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC) and small cell lung carcinomas. SS-R were also expressed in a majority of malignant lymphomas, in several brain tumors (all meningiomas, most astrocytomas) and in breast tumors. The majority of tumors expressing SS-R are rather differentiated (i.e. astrocytomas vs glioblastomas), but exceptions exist (high grade malignant lymphomas). An inverse relationship exists between SS-R and receptors for epidermal growth factor (EGF-R) incidence in lung tumors, glial tumors and most breast tumors, whereas meningiomas express simultaneously both receptors. A minority of tumors (ovarian tumors, MTC, insulinomas) express a subtype of SS-R, characterized by low affinity for the octapeptide SS analog octreotide. The function mediated by SS-R in human tumors may differ according to the tumor type. SS-R in pituitary and GEP tumor mediate hormone secretion inhibition with, in addition, possibly some antiproliferative effects. In meningiomas, however, activation of SS-R inhibits forskolin-stimulated adenylate cyclase activity, and weakly stimulates proliferation. Whereas SS-R seem to mediate antiproliferative effects in animal models and cell lines of lymphomas, breast and lung tumors, such an effect has not yet been convincingly documented in human primary tumors. The clinical implications of the presence of SS-R in tumors are manyfold: (1) as a predictive marker for efficient therapy with octreotide in pituitary and GEP tumors; (2) as a diagnostic marker: for pathobiochemical classification of tumors, using in vitro detection methods; for clinical evaluation using in vivo scanning techniques; (3) as a prognostic marker; and (4) as a potential radiotherapeutic target.
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| 1357093 |
Analogues of somatostatin bind selectively to brain somatostatin receptor subtypes |
10.1111/j.1471-4159.1992.tb08433.x. |
J Neurochem |
Analogues of somatostatin bind selectively to brain somatostatin receptor subtypes
Abstract
- Somatostatin (SRIF) is a neurotransmitter that produces its multiple effects in the CNS through interactions with membrane-bound receptors. Subtypes of SRIF receptors are found in the CNS that are distinguished by their sensitivities to the cyclic hexapeptide MK-678, such that SRIF1 receptors are sensitive to MK-678 and SRIF2 receptors are insensitive to MK-678. In the present study, we further examined the selectivities of a series of structurally diverse SRIF analogues for SRIF receptor subtypes. SRIF receptors were labeled by 125I-Tyr11-SRIF, which has indistinguishable affinities for SRIF receptor subtypes. The inhibition by MK-678 was incomplete, indicating this peptide is highly selective for a subtype of SRIF receptor that we have termed the SRIF1 receptor. The binding of 125I-MK-678 to SRIF1 receptors was monophasically inhibited by SRIF, the octapeptides (such as SMS-201-995), and the hexapeptides (such as MK-678), consistent with the highly selective labeling of a subtype of SRIF receptor. In contrast, the smaller CGP-23996-like analogues did not inhibit 125I-MK-678 binding to SRIF1 receptors. The binding of 125I-CGP-23996 to SRIF receptors was inhibited by SRIF and the octapeptides with Hill coefficients of less than 1, indicating that 125I-CGP-23996 labels multiple SRIF receptor subtypes. The hexapeptides and CGP-23996-like compounds produced only partial inhibitions of 125I-CGP-23996 binding, which were additive, indicating selective interactions of these compounds with the different receptor subpopulations labeled by 125I-CGP-23996. 125I-Tyr11-SRIF binding and 125I-CGP-23996 binding to SRIF receptors were likewise only partially affected by 100 microM guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a concentration that completely abolishes specific 125I-MK-678 binding to SRIF1 receptors. The component of 125I-CGP-23996 labeling that was sensitive to GTP gamma S was also MK-678 sensitive. Thus, two subpopulations of SRIF receptors exist in the CNS. The SRIF1 receptor is sensitive to cyclic hexapeptides such as MK-678 and to GTP gamma S but insensitive to smaller CGP-23996-like compounds. The SRIF2 receptor is sensitive to the CGP-23996-like compounds and can be selectively labeled by 125I-CGP-23996 in the presence of high concentrations of the hexapeptides or GTP gamma S because, unlike the SRIF1 receptor, the SRIF2 receptor is insensitive to these agents. The SRIF receptor subtype-selective peptide analogues will be useful in the future characterization of the functions mediated by SRIF receptor subtypes in the CNS."
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| 1357570 |
Estradiol regulation of somatostatin receptors in the arcuate nucleus of the female rat |
10.1159/000126234. |
Neuroendocrinology |
Estradiol regulation of somatostatin receptors in the arcuate nucleus of the female rat
Abstract
- Somatostatin receptors on lactotroph cells of the anterior pituitary are positively regulated by estradiol. In the present work, we investigated whether estradiol regulation of somatostatin receptors also occurred in the female rat brain. 125I-Tyr0-DTrp8-somatostatin (125I-SRIF: 780 Ci/mM) was used as a ligand. Female adult rats were ovariectomized and treated or not with estradiol benzoate (20 micrograms/day for 1 or 8 days). In female brains, 125I-SRIF binding, as assessed by film radioautography, was high in the basolateral amygdala, CA1 field and dentate gyrus of the hippocampus and locus coeruleus, moderate in the median habenula and deep layers all through the cortex. Castration or estradiol treatment did not modify 125I-SRIF binding in these regions. By light-microscopic radioautography, a subpopulation of 125I-SRIF-labeled cells was localized in the ventrolateral portion of the arcuate nucleus. Ovariectomy alone did not significantly affect the number and binding density of 125I-SRIF-labeled cells in the arcuate nucleus. However, estradiol treatment in ovariectomized animals significantly increased both parameters. Along the estrus cycle, the number of 125I-SRIF-labeled cells was not significantly modified but 125I-SRIF binding density was significantly higher in proestrus as compared to diestrus I, diestrus II and estrus. These results demonstrate that brain 125I-SRIF binding sites are positively regulated by estradiol only in the arcuate nucleus of the hypothalamus.
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| 1359642 |
Reductase activity encoded by the HM1 disease resistance gene in maize |
10.1126/science.1359642. |
Science |
Reductase activity encoded by the HM1 disease resistance gene in maize
Abstract
- The HM1 gene in maize controls both race-specific resistance to the fungus Cochliobolus carbonum race 1 and expression of the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)-dependent HC toxin reductase (HCTR), which inactivates HC toxin, a cyclic tetrapeptide produced by the fungus to permit infection. Several HM1 alleles were generated and cloned by transposon-induced mutagenesis. The sequence of wild-type HM1 shares homology with dihydroflavonol-4-reductase genes from maize, petunia, and snap-dragon. Sequence homology is greatest in the beta alpha beta-dinucleotide binding fold that is conserved among NADPH- and NADH (reduced form of nicotinamide adenine dinucleotide)-dependent reductases and dehydrogenases. This indicates that HM1 encodes HCTR.
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| 1359889 |
Molecular cloning of a truncated isoform of the human follicle stimulating hormone receptor. |
10.1016/0006-291x(92)91341-m |
Biochem. Biophys. Res. Commun. |
Molecular cloning of a truncated isoform of the human follicle stimulating hormone receptor.
Abstract
- Northern blot hybridization of human testicular poly (A)+ RNA to a human follicle stimulating hormone receptor probe revealed the existence of multiple mRNA transcripts. In order to investigate whether alternative splicing of the receptor occurs in the human testis we amplified the extracellular and the transmembrane domain of the human testicular follicle stimulating hormone receptor by reverse transcription polymerase chain reaction and subcloned the resulting DNA fragments. Sequence analysis of the recombinant clones revealed the existence of a truncated isoform of the human follicle stimulating hormone receptor which is spliced through a cassette exon mode without a change in the open reading frame, thereby deleting exon IX from the coding region of the receptor.
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| 1360156 |
Kinetics and mechanism of degradation of a cyclic hexapeptide (somatostatin analogue) in aqueous solution |
10.1023/a:1015813619192. |
Pharm Res |
Kinetics and mechanism of degradation of a cyclic hexapeptide (somatostatin analogue) in aqueous solution
Abstract
- A highly active cyclic hexapeptide analogue of somatostatin, Cyclo(N-Me-L-Ala-L-Tyr-D-Trp-L-Lys-L-Val-L-Phe), L-363,586, was found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The compound is reported to be relatively stable in blood, nasal cavity, and intestinal lumen but undergoes rapid degradation in aqueous solution. The objective of this study was to elucidate the degradation mechanisms based on the kinetic data and the structure of the degradation products. Both pH and temperature had a profound influence on the instability of the peptide in aqueous solution. The data indicated that the peptide was most stable at a pH of about 4.7. The pH-rate profile exhibited specific acid catalysis at a pH less than 3.0 and base catalysis above pH 10.5. The kinetic pKa was determined to be 9.7. This pKa could be attributed to the tyrosine residue. The mechanisms of degradation under acidic and alkaline conditions appear to be different. Identification of the fragments obtained using mass spectrometry and amino acid sequencing suggest that the cyclic compound was cleaved to yield a linear fragment, which underwent further cleavage at both peptide linkages alpha to the tryptophanyl residue. The indole group of that residue is probably the potential nucleophile attacking the adjacent carbonyls. A rate equation for the degradation of the hexapeptide has been proposed.
|
| 1360704 |
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. |
10.1126/science.1360704 |
Science |
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.
Abstract
- The doxorubicin-selected lung cancer cell line H69AR is resistant to many chemotherapeutic agents. However, like most tumor samples from individuals with this disease, it does not overexpress P-glycoprotein, a transmembrane transport protein that is dependent on adenosine triphosphate (ATP) and is associated with multidrug resistance. Complementary DNA (cDNA) clones corresponding to messenger RNAs (mRNAs) overexpressed in H69AR cells were isolated. One cDNA hybridized to an mRNA of 7.8 to 8.2 kilobases that was 100- to 200-fold more expressed in H69AR cells relative to drug-sensitive parental H69 cells. Overexpression was associated with amplification of the cognate gene located on chromosome 16 at band p13.1. Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression. The mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.
|
| 1361546 |
Brain as an eliminating organ? |
10.1111/j.2042-7158.1992.tb03245.x. |
J Pharm Pharmacol |
Brain as an eliminating organ?
Abstract
|
| 1362720 |
Pneumocandins from Zalerion arboricola. V. Glutamic acid- and leucine-derived amino acids in pneumocandin A0 (L-671,329) and distinct origins of the substituted proline residues in pneumocandins A0 and B0 |
10.7164/antibiotics.45.1953. |
J Antibiot (Tokyo) |
Pneumocandins from Zalerion arboricola. V. Glutamic acid- and leucine-derived amino acids in pneumocandin A0 (L-671,329) and distinct origins of the substituted proline residues in pneumocandins A0 and B0
Abstract
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| 1363723 |
Expression of P-glycoprotein on normal lymphocytes: enhancement of the doxorubicin-sensitivity of concanavalin A-responding mouse spleen cells by P-glycoprotein blockers |
None |
Oncol Res |
Expression of P-glycoprotein on normal lymphocytes: enhancement of the doxorubicin-sensitivity of concanavalin A-responding mouse spleen cells by P-glycoprotein blockers
Abstract
- The in vitro proliferative response of mouse spleen cells (SC) to the T-cell mitogen, concanavalin A (ConA), displays a doxorubicin (DOX)-resistant component. This T-cell proliferative response displays a much higher DOX sensitivity in the presence of novel potent inhibitors of P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), the cyclosporin (Cs) derivative, SDZ PSC 833, and the semi-synthetic cyclopeptolide, SDZ 280-446. Another resistance modulator, verapamil, might share this property, but its detection was impaired by the intrinsic toxicity of this calcium channel blocker for T-cell proliferation. A CD8+ cell-depleted SC suspension displayed a higher sensitivity to DOX alone, as well as a different sensitivity profile to SDZ 280-446. The CD8+ cells that are sensitized to DOX by the resistance modulating agents (RMA) might correspond to a formerly described T-cell subpopulation with the MDR phenotype, which seems to be essentially constituted of CD8+ (cytotoxic) T cells. Our results may open the way to a novel form of immunomodulation combining classical antineoplastic agents with Pgp-blocking Cs analogs (even non-immunosuppressive ones), which may be particularly useful when treating acute graft rejection.
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| 1364090 |
The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts responsiveness to octreotide |
None |
Yale J Biol Med |
The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts responsiveness to octreotide
Abstract
- In 77 percent of patients suffering from a malignant carcinoid syndrome, administration of the somatostatin analog, octreotide (SMS 201-995, Sandostatin) induced clinical improvement coupled with a decrease in 24-hour urinary 5-hydroxyindole acetic acid (5-HIAA). This finding prompted an evaluation to determine the correlation between the presence of somatostatin receptors in tumor tissue and the response to octreotide in patients with advanced, metastatic, neuroendocrine tumors. In tissues of 31 tumors (20 carcinoid, eight islet-cell carcinoma, three medullary thyroid carcinomas), the presence of somatostatin receptors was analyzed by binding of the somatostatin analog 125I-Tyr3-SMS 201-995 and autoradiography. Receptors were detected in 16 of 20 samples of carcinoid tissues; all but one patient with receptor-positive tumors improved clinically after treatment with octreotide, and the urine 5-HIAA level was reduced a median of 63 percent (range, 39-94 percent) compared to values before treatment. Of the receptor-negative carcinoid patients, only one showed clinical improvement, which was minimal, and there was a negligible reduction in 5-HIAA after octreotide therapy. All eight patients with metastatic islet-cell carcinomas were positive for somatostatin receptors. Symptomatic improvement and a > 50 percent decrease in the level of at least one of the pathologically elevated marker hormones was seen in all eight. of the three patients with medullary carcinoma of the thyroid had a decrease in calcitonin, and all three were initially somatostatin receptor-negative. We conclude that the presence of somatostatin receptors in malignant neuroendocrine tumor tissue appears to correlate with the response to octreotide therapy. Analysis of somatostatin receptors in malignant neuroendocrine carcinoma tissue should be included in future prospective clinical trials of this synthetic peptide.
|
| 1370395 |
Cytoskeletal changes in hepatocytes induced by Microcystis toxins and their relation to hyperphosphorylation of cell proteins |
10.1016/0009-2797(92)90033-h. |
Chem Biol Interact |
Cytoskeletal changes in hepatocytes induced by Microcystis toxins and their relation to hyperphosphorylation of cell proteins
Abstract
- The heptapeptide toxins produced by the blue-green alga (cyanobacterium) Microcystis aeruginosa are selectively hepatotoxic in mammals. The characteristic post-mortem pathology of the liver is extensive lobular disruption due to sinusoidal breakdown, leakage of blood into the tissue and hepatocyte disintegration. Isolated hepatocytes incubated with toxin show severe structural deformity and surface blebbing. This paper demonstrates the effects of Microcystis toxins on the contraction and aggregation of actin microfilaments, and on the relocation and breakdown of cytokeratin intermediate filaments, in cultured hepatocytes. Earlier work did not show changes in the assembly/disassembly of actin; however, this paper demonstrates the change in cytokeratin from intermediate filaments to distributed granules in the cytoplasm of toxin-affected cells. Acrylamide gel electrophoresis of cytoskeletal fractions from hepatocytes did not show changes in total cytokeratins; however, marked changes in the immunogenicity of cytokeratins at 52 and 58 kDa were seen on toxin exposure of cells. Measurement of 32P-phosphorylation of proteins in toxin-affected cells incubated with 32Porthophosphate showed a dramatic increase compared to control incubations. This is in agreement with research elsewhere describing phosphatase inhibition in vitro by Microcystis toxins. The data indicate that phosphorylated cytokeratin is a major component of cytoplasmic fraction phosphorylated protein after toxin exposure to hepatocytes. It is concluded that the mechanism of Microcystis toxicity to the hepatocyte is through cytoskeletal damage leading to loss of cell morphology, cell to cell adhesion and finally cellular necrosis. The underlying biochemical lesion is likely to be phosphatase inhibition causing hyperphosphorylation of a number of hepatocyte proteins, including those cytokeratins responsible for microfilament orientation and intermediate filament integrity.
|
| 1370760 |
Differential expression of translation-associated genes in benign and malignant human breast tumours |
10.1038/bjc.1992.12. |
Br J Cancer |
Differential expression of translation-associated genes in benign and malignant human breast tumours
Abstract
- The human gene sequences encoding the translation-associated functions of alpha-subunit of elongation factor 1 (EF-1 alpha) and the ubiquitin carboxyl extension protein (HUBCEP80) have been isolated by differential cDNA screening, and found to have significantly higher levels of expression in fibroadenomas (benign) compared with carcinomas (malignant) of the breast. These data parallel our previous findings that the acidic ribosomal phosphoprotein P2 also has higher expression levels in the benign breast tumours (Sharp et al., 1990). In situ hybridisation has shown these genes to be expressed predominantly in the epithelium of breast tumours.
|
| 1370808 |
Cloning of the human alpha 2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site. |
10.1007/bf00197266 |
Hum. Genet. |
Cloning of the human alpha 2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site.
Abstract
- Overlapping genomic clones of the human alpha 2-macroglobulin (alpha 2M) gene were isolated from a cosmid library and were used to map 80 kb of the chromosomal region of this gene. Fragments carrying the two exons encoding the bait region and the exon encoding the thiolester site were partially sequenced and PCR primers were designed for the amplification of both functional domains. By direct genomic sequencing of these domains in 30 healthy individuals and in 30 patients with chronic lung disease three mutations were detected. The first was a sequence polymorphism occurring near the thiolester site of the gene, changing Val1000 (GTC) to Ile1000 (ATC), with allele frequencies of 0.30 (GTC) and 0.70 (ATC), respectively. No difference of alpha 2M serum levels was observed for these two alleles. The second mutation occurred within the thiolester site of one patient, changing Cys972(TGT) to Tyr972(TAT). Since activation of the internal thiolester formed between Cys972 and Gln975 in each of the subunits of the tetrameric alpha 2M is involved in the covalent cross-linking of the activating proteinase, this mutation is predicted to interfere with alpha 2M function. The alpha 2M serum level was within the normal range in this patient. In one healthy individual we detected an alteration of the bait region sequence, which is usually encoded by two different exons separated by an intron of size 1.6 kb. In this individual, PCR amplification of genomic DNA using the bait region primers produced the common fragment of size 1.8 kb and an additional variant fragment of size 0.23 kb. This finding, and the genomic sequencing data of this individual, indicate that he carries two different alleles of the alpha 2M gene: one with the regular structure (bait exon I-intron-bait exon II), the other with the two bait exons fused into one. Direct genomic sequencing of the two alpha 2M functional domains is a useful tool for the detection of the genetic, and possibly the functional, heterogeneity of alpha 2M. This, in turn, may provide some insight into the hitherto unknown physiological role(s) of alpha 2M, by studying in vivo effects of naturally occurring mutations of the gene.
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