Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Growth hormone (GH) secretion from the anterior pituitary gland is mainly regulated by hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIF). Somatostatin reduces both spontaneous and GHRH-stimulated GH secretion. 2. Exocytosis of GH is mainly determined by the intracellular free Ca2+ concentration ([Ca2+]i), which is regulated by the influx of Ca2+ via membrane Ca2+ channels. Somatostatin reduces the influx of Ca2+ through two separate mechanisms, namely a direct action on Ca2+ channels and an indirect action on membrane potentials through the activation of K+ channels. 3. In the present experiments, somatotroph-enriched cells were obtained from the ovine pituitary gland by means of collagenase dissociation and Percoll-gradient centrifugation. Further identification was based on the effect of SRIF (10 nmol/L) on Ca2+ or K+ currents. 4. A significant reduction in Ca2+ currents and an increase in K+ currents was obtained in response to local application of SRIF (10 nmol/L), but vehicle application had no effect. The responses of Ca2+ and K+ currents to SRIF were reversible after removal of SRIF. 5. Dialysis of GTP-gamma-s (200 mumol/L) abolished the recovery phase of K+ current response to SRIF after its removal, whereas GDP-beta-s (200 mumol/L) totally blocked the response. Pretreatment of the cells with pertussis toxin (100 nmol/L) overnight abolished the Ca2+ current response to SRIF. 6. Intracellular dialysis of antibodies to alpha o, alpha i1-3, alpha i1-2 and alpha i3 subunits of the G-proteins into cells via whole-cell patch-clamp pipettes was confirmed by immunofluorescent staining of the antibodies. 7. Dialysis of anti-alpha i1-3 or anti-alpha i3 antibodies significantly attenuated the increase in the K+ current in response to 10 nmol/L SRIF, whereas neither anti-alpha o nor anti-alpha i1-2 antibodies diminished the effect of SRIF on the K+ current. 8. Dialysis of anti-alpha o antibodies significantly attenuated the reduction in the Ca2+ current that was obtained upon application of 10 nmol/L SRIF. Neither anti-alpha i1-2 nor anti-alpha i3 antibody dialysis diminished the effect of SRIF on the Ca2+ current. 9. Dialysis of the alpha o common antisense oligonucleotides (ASm) but not the alpha i3 AS significantly diminished the inhibitory effect of SRIF on the Ca2+ current. This effect of alpha o ASm dialysis occurred at 12 h incubation after dialysis, reaching a maximal level at 48 h and partially recovering at 72 h incubation. Antisense oligonucleotides specific for alpha o1 (alpha o1 AS) or alpha o2 (alpha o2 AS) were dialysed into somatotrophs and only alpha o2 AS significantly attenuated the inhibition of SRIF on the Ca2+ current. 10. It is concluded that the Gi3 protein mediates the effect of SRIF on the K+ current and that the G(o)2 protein mediates the effect of SRIF on the Ca2+ current in primary cultured ovine somatotrophs.
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PMID:G(o)2 and Gi3 proteins mediate the action of somatostatin on membrane Ca2+ and K+ currents in ovine pituitary somatotrophs. 926 41

Glucagon-like peptide-1(7-36)amide (GLP-1) is a potent insulinotropic peptide released from the small intestine. To investigate the regulation of GLP-1 secretion, we established a GLP-1 release assay based on primary canine intestinal L-cells. The ileal mucosa was digested with collagenase/EDTA to a single cell suspension and enriched for L-cells by counterstream centrifugal elutriation. We performed release assays on the cultured cells after 36 h, and GLP-1 in the supernatant was determined by enzyme-linked immunoabsorbent assay (ELISA). Glucose-dependent insulinotropic peptide (GIP) dose dependently stimulated the release of GLP-1 and resulted in a 2-fold increase at 100 nM GIP. This effect was fully inhibited by 10 nM somatostatin. However, neither basal or GIP stimulated GLP-1 secretion were affected by ambient glucose concentrations from 5-25 mM. The receptor-independent secretagogues beta phorbol myristate acetate and forskolin dose dependently increased the secretion of GLP-1; effects inhibited by staurosporine and H8 respectively. Costimulation with GIP and phorbol ester, but not forskolin, resulted in an additive response. Furthermore, the effect of GIP could be inhibited by H8 but not by staurosporine. These results indicate that glucose does not directly stimulate canine L-cells. It is more probable that glucose releases GIP from the upper intestine that in turn stimulates GLP-1 secretion. The ability of GIP to stimulate GLP-1 secretion is probably mediated through activation of protein kinase A.
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PMID:Glucagon-like-peptide-1 secretion from canine L-cells is increased by glucose-dependent-insulinotropic peptide but unaffected by glucose. 952 97

The transcription factor CHOP (C/EBP homologous protein 10) is a bZIP protein induced by a variety of stimuli that evoke cellular stress responses and has been shown to arrest cell growth and to promote programmed cell death. CHOP cannot form homodimers but forms stable heterodimers with the C/EBP family of activating transcription factors. Although initially characterized as a dominant negative inhibitor of C/EBPs in the activation of gene transcription, CHOP-C/EBP can activate certain target genes. Here we show that CHOP interacts with members of the immediate-early response, growth-promoting AP-1 transcription factor family, JunD, c-Jun, and c-Fos, to activate promoter elements in the somatostatin, JunD, and collagenase genes. The leucine zipper dimerization domain is required for interactions with AP-1 proteins and transactivation of transcription. Analyses by electrophoretic mobility shift assays and by an in vivo mammalian two-hybrid system for protein-protein interactions indicate that CHOP interacts with AP-1 proteins inside cells and suggest that it is recruited to the AP-1 complex by a tethering mechanism rather than by direct binding of DNA. Thus, CHOP not only is a negative or a positive regulator of C/EBP target genes but also, when tethered to AP-1 factors, can activate AP-1 target genes. These findings establish the existence of a new mechanism by which CHOP regulates gene expression when cells are exposed to cellular stress.
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PMID:CHOP enhancement of gene transcription by interactions with Jun/Fos AP-1 complex proteins. 1052 47

Neonatal porcine pancreas has considerable capacity for growth and differentiation, making it an attractive potential source of islet tissue for xenotransplantation. Pancreases from 1-3-day-old newborn pigs were digested with collagenase and cultured for 8 days. The resulting cellular aggregates are called porcine neonatal pancreatic cell clusters (NPCCs). The mean yield of NPCCs from a newborn pig was 28,200 +/- 1700 islet equivalents. Cytokeratin 7 (CK7) was used as a marker for the immunostaining of pancreatic duct cells. In neonatal pancreas, 18% of the insulin-positive cells co-stained for CK7, thus being protodifferentiated. NPCCs also contained protodifferentiated cells; insulin/PP and insulin/somatostatin co-stained cells were more common than insulin/glucagon cells. Between 1 and 8 days of culture, the DNA content of the NPCCs fell to 16% and the insulin content to 33% of the starting value, mainly due to the preferential loss of exocrine cells. Transplantation of 2000 or 4000 NPCCs into diabetic nude mice typically normalized glucose values in 10-20 weeks. Mice with successful grafts had lower fasting blood glucose levels than normal mice and accelerated glucose clearance after an i.p. glucose load. The starting NPCCs consisted of 17% insulin-staining cells, but the grafts of mice with reversed diabetes consisted of 94% beta cells, with some co-stained for CK7, indicating that the grafts still contained immature cells. The mass of insulin-producing cells rose from 0.22 +/- 0.08 mg 1 week after transplantation to 4.34 +/- 0.27 mg in mice sacrificed at 27-35 weeks. In summary, NPCCs contain mostly islet precursor cells, which when transplanted into nude mice undergo striking differentiation and beta cell expansion.
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PMID:Differentiation and expansion of beta cell mass in porcine neonatal pancreatic cell clusters transplanted into nude mice. 1070 96

Whereas several reports describing the ultrastructure of the intact pancreatic islets have been recorded, published experience with the ultrastructural integrity of the cultured pancreatic islets is limited. The present study was, therefore, undertaken to provide an ultrastructure identification of the different cells in the cultured islets of the adult rat pancreas, after marking their secretory granules with gold particles. Pancreatic islets were isolated from adult male Wistar rats by the intraductal perfusion of collagenase technique. The islets were cultured in RPMI-1640 medium for 3 days and processed for preparation of ultrathin sections. The sections were stained with the indirect immunogold technique for insulin, glucagon, somatostatin, and pancreatic polypeptide. Ultrastructural examination of the cultured islets clearly identified the presence of B, A, D and PP-cells, as indicated by the numerous gold particles concentrated predominantly over the secretory granules. The secretory granules of the various cell types of the cultured islets demonstrated several similarities as well as differences from the recorded results of the corresponding secretory granules of the intact islets. The differences probably reflect a deviation in the underlying mechanisms of synthesis, maturation and secretion of the different secretory products of the cells in the cultured islets as they adapt to the in vitro environment.
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PMID:Ultrastructural immunogold study on the various cell types of cultured pancreatic islets of adult rats. 1110 96

We previously demonstrated the presence of an enhancer that is located between nucleotides - 2264 and - 2495 in the 5' flanking region of the rat sodium/iodide symporter (NIS) gene (Ohno et al., 1999). When attached to NIS or heterologous promoters, this 232 bp fragment, which we call NUE, is able to stimulate transcription in a thyroid-specific and cAMP-dependent manner. A paired-domain transcription factor Pax8 binds to this enhancer and can stimulate the transcription in non-thyroid cells that do not normally support the NUE activities. Cotransfection of PKA, a downstream effector of cAMP, further potentiates the Pax8-mediated transactivation. However, this transcriptional machinery containing pax8 seems to require contributions from the neighboring cis-acting element that is similar to CRE/AP-1 consensus sequences. Modification of this putative CRE/AP-1 site not only represses the NUE transcriptional activities by 90% in FRTL-5 cells, but also nullifies the synergistic effect of PKA on pax8-mediated transactivation in HeLa cells. In this report, we have further characterized the putative CRE/AP-1 site within the NIS upstream enhancer using gel mobility shift assay. An oligonucleotide probe with NIS CRE/AP-1 sequence produced complex binding patterns in both FRTL-5 and HeLa cell, reflecting the presence of diverse classes of binding factors. When compared with CRE or AP-1 elements in other genes, the mobility shift pattern of NIS CRE/AP-1 was similar to those of collagenase TRE, c-Jun TRE, and somatostatin CRE, but the relative intensities of the binding complexes were quite different. This observation raises a possibility that the NIS CRE/AP-site is regulated by a novel mechanism.
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PMID:Characterization of the upstream enhancer of the rat sodium/iodide symporter gene. 1157 34

Though sex steroids are found to influence thyroid pathogenesis in human and in animals, their role in normal thyroid growth and thyrocyte proliferation is not yet understood fully. The present study is addressed to know the effect of testosterone and estradiol on the basal and TSH-induced thyrocyte proliferation in immature and adult rats in vitro. The male and female Wistar rats were gonadectomized (GDX) and one group of GDX rats were supplemented with either testosterone or estradiol. After the experimental period, the rats were sacrificed by decapitation and thyroid glands were removed, washed in Hank's Balanced Salt Solution (HBSS), pH 7.4 and digested with the enzyme mixture containing 0.08% collagenase and 0.12% dispase in HBSS. The isolated follicles were washed thrice with Dulbecco's modified Eagle's medium (DMEM) containing 0.5% fetal bovine serum (FBS), and were cultured in Falcon's tissue culture flasks containing 5 ml DMEM with FBS (5%) transferrin (5 microg/ml), hydrocortisone (10(-8) M), somatostatin (10 microg/ml), insulin (10 microg/ml) and glycyl-L-histidyl-L-lysine acetate (10 microg/ml). The cells (2.5 x 10(4)) were exposed to various exponential doses of TSH or testosterone (6.25-800 ng/ml) or estradiol (6.25-800 pg/ml). It is suggested from the present study that both TSH and sex steroids enhance thyrocyte proliferation. The mitogenic effect of TSH is greater than that of sex steroids. Sex steroids modulate TSH-induced cell proliferation in a gender-specific manner.
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PMID:Testosterone and estradiol differentially regulate TSH-induced thyrocyte proliferation in immature and adult rats. 1199 29

The purpose of this study was to investigate the effect of culture microenvironment on the cell death of isolated rat pancreatic islets. After isolation by the conventional collagenase digestion technique, the islets were cultured in a hydrogel of collagen type I mixed with collagen type III, type IV, and laminin. Irrespective of the type of mixture, islet cell death was significantly suppressed by their co-culture with the collagen hydrogel mixtures, although no change in islet morphology was observed. Co-culture with the collagen mixtures had no influence on the expressed mRNA level of insulin, glucagon, and somatostatin of the islets, or the islet secretion of hepatocyte growth factor (HGF), interleukin (IL)-1alpha, and IL-1beta. These findings suggest that three-dimensional culture in the collagen hydrogel and the mixture of laminin is able to maintain the cell viability of islets.
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PMID:Co-culture of extracellular matrix suppresses the cell death of rat pancreatic islets. 1218 60

Kupffer cells may be involved in liver fibrogenesis through production of TGF-beta1. Their role in fibrinolysis is less clear. Octreotide, a synthetic analogue of somatostatin, is often used in cirrhotic patients. Its effect on Kupffer cells was studied. Isolated rat Kupffer cells were cultured in the presence of lipopolysaccharide and/or octreotide. TGF-beta1, leptin, collagenase (MMP-1), and urokinase-type plasminogen activator (uPA) were assessed in supernatants by ELISA, and MMP-2 and MMP-9 by zymography. Kupffer cells produced large amounts of MMP-1 and lipopolysaccharide induced a significant (P < 0.02) early increase. Octreotide and lipopolysaccharide caused a synergistic effect on MMP-1 secretion. By contrast, MMP-9 production stimulated by lipopolysaccharide was suppressed by octreotide. Kupffer cells produced a basal amount of uPA, significantly increased after lipopolysaccharide or octreotide incubation (P < 0.001). Large amounts of TGF-beta1 were produced in a time-dependent manner by unstimulated Kupffer cells. Lipopolysaccharide and octreotide, alone or in combination, induced a significant inhibition of this production (P < 0.01). Kupffer cells did not produce leptin, a recently identified mediator of liver fibrosis, or MMP-2. Kupffer cells may play a significant role in liver fibrinolysis. Octreotide, acting on TGF-beta1, uPA, and MMP-1 production, may be a useful agent for fibrosis resolution.
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PMID:Production of pro- and anti-fibrotic agents by rat Kupffer cells; the effect of octreotide. 1590 72

The aim of the work was to investigate the effects of somatostatin analogs acting selectively on sst1 (BIM-23926), sst2 (BIM-23120) and sst5 (BIM-23206) receptor subtypes on the viability of "clinically non-functioning" pituitary adenomas in vitro. The effects of native SST (SST-14), a SST/DA chimera (BIM-23A387) and a D(2)-dopamine receptor agonist bromocriptine (BC) were also examined. The study was performed on 10 surgically removed pituitary macroadenomas, diagnosed before surgery as "non-functioning". A part of each tumor was mechanically dispersed and digested with collagenase to isolate the tumoral cells. Another part of each tumor was fixed, embedded in paraffin and immunostained to reveal the pituitary hormones and SST receptor subtypes (sst1, sst2A, sst2B, sst3, sst4, sst5). The tumoral cell suspensions were incubated for 24 h with the substances mentioned above. The quantity of viable cells was estimated using the EZ4U system. The results were compared with the immunohistochemical evaluation of the hormonal profile of adenoma and the sst receptor subtype immunoreactivities present. The findings indicate that selective sst1, sst2 and sst5 receptors agonists, SST/DA chimera and D(2)-dopamine receptor agonist bromocriptine affect the viability of some, but not all, "clinically non-functioning" pituitary adenomas in vitro. The most effective was bromocriptine. The investigated somatostatin analogs including SST/DA chimera exerted roughly similar inhibitory effects. Further studies are needed to fully evaluate the potential usefulness of these compounds in the pharmacological treatment of "non-functioning" pituitary tumors.
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PMID:The effect of selective sst1, sst2, sst5 somatostatin receptors agonists, a somatostatin/dopamine (SST/DA) chimera and bromocriptine on the "clinically non-functioning" pituitary adenomas in vitro. 1611 52


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