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)

We reported previously that, in addition to direct effects, somatostatin (SST) affects tumor growth inhibiting the tumoral neoangiogenesis, via an interference with NO synthesis. Here, we analyzed the effects of SST on nitric oxide (NO) production induced by different agonists [basic fibroblast growth factor (bFGF), insulin, cholecystokinin (CCK)] and the intracellular signaling involved, using Chinese hamster ovary-k1 cells stably transfected with individual SSTR1-SSTR4. bFGF and insulin induced endothelial nitric oxide synthase activity via the generation of ceramide or the Akt-dependent phosphorylation of endothelial nitric oxide synthase, respectively. CCK regulates neuronal nitric oxide synthase activity in a Ca++-dependent manner. SST inhibited NO production stimulated by bFGF through SST receptor 1 (SSTR1), SSTR2, and SSTR3 and by CCK through SSTR2 and SSTR3. In all the cell lines, SST treatment did not modify NO synthesis induced by insulin. SSTR4 activation was not effective on any of the stimuli tested. The effects on bFGF-induced NO production were downstream from receptor phosphorylation and ceramide synthesis. SSTR2 and -3 on CCK activity were related to the inhibition of intracellular Ca++ mobilization, whereas the lack of effects on insulin was paralleled by the absence of SST activity on Akt phosphorylation. These data, identifying for the first time a selective receptor subtype-inhibitory role of SST on NO generation, may open new perspectives in the use of SST agonists to control tumoral angiogenesis.
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PMID:Somatostatin receptor subtype-dependent regulation of nitric oxide release: involvement of different intracellular pathways. 1538 96

Somatostatin, widely distributed in human cortical brain regions, acts through specific high affinity somatostatin receptors (SSTR1-5) to exert profound effects on motor, sensory, behavioral, cognitive and autonomic functions. Somatostatin levels are consistently decreased in the cortex of Alzheimer's disease (AD) brain and in cerebrospinal fluid, and have become reproducible markers of this disease. In the present study, the distributional pattern of SSTR1-5 antigens in the frontal cortex of AD and age-matched control brains was studied using antipeptide polyclonal rabbit antibodies directed against the five human somatostatin receptor subtypes. All five SSTRs were differentially expressed as membrane and cytoplasmic proteins in cortical neurons with significant variations in control vs. AD brain. In AD cortical brain region, somatostatin and neuropeptide-Y-positive neurons decreased (>70%), and glial fibrillary acidic protein-positive astrocytes significantly increased (>130%) in comparison to control brain. SSTR2 and 4 were the predominant subtypes followed by SSTR1, 3 and 5. AD cortex showed a marked reduction in neuronal expression of SSTR4 and 5 and a modest decrease in SSTR2-like immunoreactivity without any changes in SSTR1 immunoreactive neurons. In contrast, SSTR3 was the only receptor subtype that increased in AD cortex. In AD cortex, SSTR1-, 3- and 4-like immunoreactivities were strongly expressed in glial cells but not SSTR2 and 5. These findings suggest the differential loss of immunoreactivity of SSTR2, 4 and 5 but not SSTR1, and increased SSTR3 in frontal cortex of AD brain as well as subtype-selective glial expression in AD brain. In summary, subtype-selective changes in the expression of SSTRs at protein levels in AD cortical regions suggest that somatostatin and SSTR-containing neurons are pathologically involved in AD and could possibly be used as markers of this disease.
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PMID:Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer's disease brain: an immunohistochemical analysis. 1596 Dec 35

Somatostatin receptors (SSTRs) have been identified in most hormone-producing tumors as well as in breast cancer. In the present study, we determined SSTR1-5 expression in primary ductal NOS breast tumors through semi-quantitative RT-PCR and immunocytochemistry. The results from the analysis of 98 samples were correlated with several key histological markers and receptor expression. All five SSTR subtypes are variably expressed at the mRNA level in breast tumors with 91% of samples showing SSTR1, 98% SSTR2, 96% SSTR3, 76% SSTR4, and 54% SSTR5. SSTR1-5 are localized to both tumor cells and the surrounding peritumoral regions as detected by immunocytochemistry. Levels of SSTR mRNA, when corrected for beta-actin levels, were highest for SSTR3 followed by SSTR1, SSTR2, SSTR5, and SSTR4. Furthermore, there was good correlation between mRNA and protein expression with 84% for SSTR1, 79% for SSTR2, 89% for SSTR3, 68% for SSTR4, 68% for SSTR5, and 78% for all five receptors. SSTR1, 2 and 4 were correlated with ER levels whereas SSTR2 showed an additional correlation with PR levels. These correlations were independent of patient age and histological grade. Moreover, using immunocytochemistry, blood vessels exhibited receptor-specific localization for SSTR2 and SSTR5. Our results indicate significant correlations between mRNA and protein expression along with receptor-specific correlations with histological markers as well as ER and PR levels. Differential distribution of SSTR subtypes in tumors and receptor-specific expression in vascular structures may be considered as a novel diagnosis for breast tumors with receptor subtype agonists.
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PMID:Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1--5 and correlation with receptor protein expression and tumor pathology. 1598 28

The secretion of GH by somatotropes is inhibited by somatostatin (SRIF) through five specific membrane receptors (SSTRs). SRIF increases both transient outward (IA) and delayed rectifying (IK) K+ currents. We aim to clarify the subtype(s) of SSTRs involved in K+ current enhancement in GH3 somatotrope cells using specific SSTR subtype agonists. Expression of all five SSTRs was confirmed in GH3 cells by RT-PCR. Nystatin-perforated patch clamp was used to record voltage-gated K+ currents. We first established the presence of IA and IK type K+ currents in GH3 cells using different holding potentials (-40 or -70 mV) and specific blockers (4-aminopirimidine and tetraethylammonium chloride). SRIF (200 nM) increased the amplitude of both IA and IK in a fully reversible manner. Various concentrations of each specific SRTR agonist were tested on K+ currents to find the maximal effective concentration. Activation of SSTR2 and SSTR4 by their respective agonists, L-779,976 and L-803,087 (10 nM), increased K+ current amplitude without preference to IA or IK, and abolished any further increase by SRIF. Activation of SSTR1 and SSTR5 by their respective agonists, L-797,591 or L-817,818 (10 nM), increased K+ current amplitude, but SRIF evoked a further increase. The SSTR3 agonist L-797,778 (10 nM) did not affect the K+ currents or the response to SRIF. These results indicate that SSTR1, -2, -4, and -5 may all be involved in the enhancement of K+ currents by SRIF but that only the activation of SSTR2 or -4 results in the full activation of K+ current caused by SRIF.
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PMID:Somatostatin increases voltage-gated K+ currents in GH3 cells through activation of multiple somatostatin receptors. 1608 34

An attenuated neurogenic broncho-constriction underpinned by a decrease in sensory neuropeptide release has been shown to be characteristic of cisplatin-induced neuropathy. The present work was to explore if beyond neuropeptide release, cisplatin at a treatment schedule attaining sensory neuropathy, produced changes in the expression of the receptors of sensory neuropeptides such as somatostatin, calcitonin gene-related peptide (CGRP) and substance P (SP) in bronchial tissue of the rat. Twenty-four Wistar rats were divided into three groups. The animals in the "Treatment groups 1 and 2" were given cisplatin (1.5mgkg(-1)) and mannitol (75mgkg(-1)) over 5 days. The rats in the "Control" group were given mannitol+isotonic saline. Four animals from each group were used to study the expression pattern of the neuropeptide receptors in bronchial tissue. The levels of somatostatin receptor 4 (SSTR 4), neurokinin 1 (NK1), neurokinin 2 (NK2) and CGRP receptor expression were examined by quantitative real time polymerase chain reaction (RT-PCR) method, 11 and 22 days after the last cisplatin/vehicle dose. The cisplatin treatment significantly increased plasma somatostatin immunoreactivity and the expression of SSTR4 receptor detected both on the 11th and 22nd post-treatment days with no change in either CGRP, NK1, and NK2 receptor gene expression or plasma CGRP and substance P levels. We conclude that cisplatin neuropathy is accompanied by an increase in plasma somatostatin immunoreactivity with an increase in SSTR4 expression in rats.
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PMID:Changes in tracheo-bronchial sensory neuropeptide receptor gene expression pattern in rats with cisplatin-induced sensory neuropathy. 1634 17

The three-dimensional structure of a potent SSTR3-selective analogue of somatostatin, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-Agl(8)(N(beta) Me, 2-naphthoyl)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-Agl(8)(N(beta) Me, 2-naphthoyl)]-SRIF) (peptide 1) has been determined by (1)H NMR in water and molecular dynamics (MD) simulations. The peptide exists in two conformational isomers differing mainly by the cis/trans isomerization of the side chain in residue 8. The structure of 1 is compared with the consensus structural motifs of other somatostatin analogues that bind predominantly to SSTR1, SSTR2/SSTR5 and SSTR4 receptors, and to the 3D structure of a non-selective SRIF analogue, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-2Nal(8)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-2Nal(8)]-SRIF) (peptide 2). The structural determinant factors that could explain selectivity of peptide 1 for SSTR3 receptors are discussed.
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PMID:Conformational analysis of a potent SSTR3-selective somatostatin analogue by NMR in water solution. 1636 12

TT-232 is a structural analogue of somatostatin exhibiting strong and selective growth-inhibitory effects, inhibition of neurogenic inflammation, as well as general anti-inflammatory and analgesic potential without the wide-ranging endocrine side effects of the parent hormone and its "traditional" analogues. The anti-inflammatory action of TT-232 is mediated through the SSTR4 receptor, and its antitumor activity is mediated through the SSTR1 receptor and by the tumor-specific isoform of pyruvate kinase. Its mechanism of action is in line with a new era of molecular medicine called signal transduction therapy, where "false" intracellular or intercellular communication is inhibited or corrected without interfering with basic cell functions and machinery. TT232 has passed phase I clinical trials without toxicity and significant side effects, and phase II studies are running for oncological and anti-inflammatory indications, respectively. This compound has the perspective to become the first drug in molecularly targeted therapy of inflammation where a combined effect of anti-inflammatory, analgesic, and neurogenic inflammation-inhibiting activity can be achieved.
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PMID:TT232, a novel signal transduction inhibitory compound in the therapy of cancer and inflammatory diseases. 1639 13

Somatostatin (SST) is a regulatory peptide that activates G protein-coupled receptors comprised of five members (somatostatin receptors (SSTRs) 1-5). Despite the broad use of SST and its analogs in clinical practice, the spectrum of SST activities has been incompletely defined. Recently, it has been demonstrated that SST can be a chemoattractant for hematopoietic precursor cells. Since hepatic oval cells (HOCs) share common characteristics with hematopoietic stem cells, we hypothesized that SST could act as a chemoattractant for HOCs by stimulating SSTRs. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot assay revealed an increased expression of SST in the 2-acetyl-aminofluorene (2AAF)/partial hepatectomy (PHx) HOC induction model. Immunohistochemical staining showed the expression of SST in 2AAF/PHx-treated rat liver, as compared to normal liver. Proliferation and migration assays demonstrated that the increase of SST was related to migration of HOCs, but not their proliferation. RT-PCR and quantitative real-time PCR showed that SSTR4 was preferentially expressed by HOCs. Western blot assay and immunohistochemical staining confirmed the expression of SSTR4 by HOCs. In addition, pretreatment with anti-SSTR4 antibody cultures resulted in a dramatic reduction of cell migration as compared to that of control. Lastly, SST stimulated the rearrangement of actin filaments in HOCs, while HOCs treated with anti-SSTR4 antibody failed to do so. These results suggest a positive role for SST in the migration of HOCs, and that this effect is mediated through SSTR4.
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PMID:A potential role of somatostatin and its receptor SSTR4 in the migration of hepatic oval cells. 1653 98

Insulinomas are rare endocrine neoplasias that constitute the most frequent islet cell tumours. Somatostatin (SST) analogs are tentatively used to inhibit insulin secretion and control tumour growth in patients with local invasion or inoperative metastasis, but variable responses have been reported. Data regarding somatostatin receptor (SSTR) subtypes expression in insulinomas are conflicting. In this study, we evaluated 16 cases of primary insulinomas (including four primary plurihormonal tumours) and two hepatic metastases. Histopathological and immunohistochemical analysis for some features associated with tumour aggressiveness and semi-quantitative RT-PCR for SSTR1-5 and real-time qPCR for SSTR5 were performed. SSTR subtypes 1, 3, and 5 were expressed in 100%, SSTR2 in 89%, and SSTR4 only in 22% of the insulinomas. SSTR5 mRNA was positively correlated with histopathological features related to tumour aggressiveness (large tumour diameter, well-differentiated endocrine tumour with uncertain behaviour and higher number of cells with nuclear atypia). SSTR5 mRNA expression in primary insulinomas was lower than in primary plurihormonal tumours (P < 0.05). The observed positive correlation between SSTR5 expression and tumour size suggests that the use of SST analogues more specific to SSTR5 in the treatment of insulinomas deserves attention.
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PMID:Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas. 1660 Dec 80

SOM230 is a novel somatostatin analog which shows affinity to 4 of the 5 known somatostatin receptors (SSTR1-5). In binding experiments, SOM230 has a higher affinity to SSTR1, SSTR3 and SSTR5 and a slightly lower affinity to SSTR2 compared to octreotide. In addition, SOM230 has a >7-fold longer plasma half-life than octreotide (11 vs 1.5 h). It was suggested that SOM230 with its broader binding and activity profile compared to octreotide should have a stronger (usually inhibitory) effect on the secretion of hormones. In several animal species, SOM230 was a more potent inhibitor of GH and IGF-I than octreotide. This is in line with a strong expression of both SSTR2 and SSTR5. In the pituitary of patients with primary Cushing's disease, the SSTR5 is more frequently expressed than SSTR2. Accordingly, in rats SOM230 caused a stronger inhibition of ACTH and corticosterone secretion than octreotide. In contrast, most recent experiments showed that octreotide was more potent than SOM230 to inhibit ghrelin secretion in rats. This effect could be explained by the strong expression of SSTR2 in the rat stomach, whereas expression of SSTR3, SSTR4 and SSTR5 was poor or absent. Based on these data it can be concluded that in tissues (or tumors), where several SSTRs are expressed, SOM230 will generally have a stronger effect than octreotide. In cases where SSTR2 is the most important receptor mediating a response (e.g. ghrelin release in rats), the stronger inhibitory effect of octreotide can be explained by its higher affinity for SSTR2. In contrast to the long-lasting inhibitory effect of SOM230 on GH and IGF-I secretion, the inhibitory effects of both compounds on ghrelin show strong tachyphylaxis. These data are in line with the hypothesis that activation of the SSTR2 alone results in a rapid desensitization of the response. If, however, additional SSTR subtypes (especially SSTR5) are expressed and activated by multiligand analogs like SOM230, this might not only form the basis for a stronger response, but also the basis for a reduced tachyphylaxis.
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PMID:Short- and long-term effects of octreotide and SOM230 on GH, IGF-I, ACTH, corticosterone and ghrelin in rats. 1662 42


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