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

Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.
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PMID:Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. 1831 Feb 90

Neuroendocrine tumors (NETs) are relatively rare and comprise carcinoids, gastrinomas, and poorly differentiated endocrine carcinomas (PDECs). Diagnostic procedures should include endoscopy with biopsy, computed tomography, or magnetic resonance imaging. Fluorodeoxyglucose positron-emission tomography is also useful for the detection of extraabdominal metastases. Complete resection with lymph node dissection, as recommended for other cancers, such as distal gastrectomy, total gastrectomy, and pancreaticoduodenectomy, should be attempted in localized NETs. Endoscopic submucosal dissection should also be attempted in early-stage disease. Both curative and palliative surgery is indicated for patients with liver metastases of foregut-origin NETs. Combination chemotherapy (cisplatin/carboplatin + etoposide) may be useful in treating PDECs with metastases. Combination therapies with streptozotocin, doxorubicin, and 5-fluorouracil are also useful for the treatment of carcinoid tumors. Somatostatin analogues, such as octreotide and SOM 230, have been registered for the control of hormonal symptoms in patients with gastrointestinal NETs.
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PMID:[Management of patients with neuroendocrine tumors of the esophagus, stomach, and duodenum]. 1853 18

To investigate the effect of somatostatin on the cross-excitation between adjacent primary afferent terminals in the rats, we recorded single unit activity from distal cut ends of dorsal cutaneous branches of the T10 and T12 spinal nerves in response to antidromic stimulation of the distal cut end of the T11 dorsal root in the presence and absence of somatostatin and its receptor antagonist applied to the receptive field of the recorded nerve. Afferent fibers were classified based upon their conduction velocity. Mean mechanical thresholds decreased and spontaneous discharge rates increased significantly in C and Adelta but not Abeta fibers of the T10 and T12 spinal nerves in both male and female rats following antidromic electrical stimulation (ADES) of the dorsal root from adjacent spinal segment (DRASS) indicating cross-excitation of thin fiber afferents. The cross-excitation was not significantly different between male and female rats. Microinjection of somatostatin into the receptive field of recorded units inhibited the cross-excitation. This inhibitory effect, in turn, was reversed by the somatostation receptor antagonist cyclo-somatostatin (c-SOM). Application of c-SOM alone followed by ADES of DRASS significantly decreased the mechanical thresholds and increased the discharge rates of C and Adelta fibers, indicating that endogenous release of somatostatin plays a tonic inhibitory role on the cross-excitation between peripheral nerves. These results suggest that somatostatin could inhibit the cross-excitation involved in peripheral hyperalgesia and have a peripheral analgesic effect.
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PMID:Somatostatin inhibits activation of dorsal cutaneous primary afferents induced by antidromic stimulation of primary afferents from an adjacent thoracic segment in the rat. 1864 Jan 4

Currently, the role of dopaminergic and somatostatinergic agonists in the treatment of pituitary adenomas is quite well established. Nevertheless, a clearer understanding of the expression of dopaminergic and somatostatinergic receptors at the cellular level of pituitary adenomas as well as the development of newer analogues compounds may drastically change current therapeutic modalities. In particular, the emphasis on the co-expression of different receptors types or subtypes in adenomatous cells highlights functional interactions between receptors leading to an increase in their activity. Newer molecules are also in the process of development : new somatostatin analogues with more universal binding properties to different receptors subtypes, as well as chimeric molecules capable of binding to somatostatinergic and dopaminergic receptors. In the midst of GH-secreting pituitary adenomas, a positive correlation exists between the expression of Sst2 mRNA and the inhibition of GH release by somatostatin analogues. The involvement of Sst5 subtype in adenomas resistant to preferential Sst2 agonists has recently been proved. Another recently developed compound has a more universal Sst binding profile. This compound, named SOM-230, has a 25, 5 and 40 times higher binding affinity to Sst1, Sst3 and Sst5 receptors respectively, and 2,5 times lower affinity to Sst2, when compared to octreotide. SOM-230 could therefore allow for much more effective methods in treating patients suffering from acromegaly. Besides, the use of a chimeric molecule presenting a binding affinity to both Sst2 and D2 subtypes (BIM-23A287) inhibits the secretion of GH in ways similar to the Sst2 or D2 agonists used alone or concurrently but however in a concentration 50 times lower than that of the latter. The discovery of Sst5 and D2 subtypes at the level of corticotropic adenomas reveals newer therapeutic perspectives with promising preliminary results with the use of SOM-230 ; these finding lead to a rise in interest in cabergoline. In the midst of non-functioning pituitary adenomas, the expression of Sst2, Sst3 and D2 receptors will perhaps allow the use of combined therapies associating the new somatostatin analogues to the dopaminergic agonists or even use dopastatin (BIM-23A760, chimeric molecule Sst2-Sst5-D2). The preliminary results obtained in vitro with this molecule are actually encouraging since they show a dose dependent inhibition of the cellular replication mechanisms in 60 % of the cases. Finally, concerning prolactinomas the discovery of Sst5 receptors lead to consider the use of somatostatinergic agonists specific to the Sst5 receptor, SOM-230 in particular. Nevertheless, it seems that adenomas resistant to dopaminergic agonist due to a lack of expression of D2 receptor fail to express Sst5 receptors as well. On the other hand, dopastatin appears to be more efficient than cabergoline in the management of this type of adenomas. Therefore, the growing awareness concerning the mechanisms involved in the control of pituitary secretions as well as cellular proliferation will perhaps allow physicians to treat the pathology of pituitary adenomas, macroadenomas in particular, using solely pharmacological means instead of invasive surgical procedures and/or radiotherapy.
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PMID:[New medical treatments in pituitary adenomas]. 1895 54

Schaffer collateral synapses in hippocampus show target-cell specific short-term plasticity. Using GFP-expressing Inhibitory Neuron (GIN) transgenic mice that express enhanced green fluorescent protein (EGFP) in a subset of somatostatin-containing interneurons (SOM interneurons), we previously showed that Schaffer collateral synapses onto SOM interneurons in stratum (S.) radiatum have unusually large (up to 6-fold) paired-pulse facilitation. This results from a low initial release probability and the enhancement of facilitation by synaptic activation of presynaptic kainate receptors. Here we further investigate the properties of these kainate receptors and examine their effects on short-term facilitation during physiologically derived stimulation patterns, using excitatory postsynaptic currents recorded in S. radiatum interneurons during Schaffer collateral stimulation in acute slices from juvenile GIN mice. We find that GluR5 and GluR6 antagonists decrease short-term facilitation at Schaffer collateral synapses onto SOM interneurons with no additive effects, suggesting that the presynaptic kainate receptors are heteromers containing both GluR5 and GluR6 subunits. The calcium-permeable receptor antagonist 1-napthyl acetyl spermine (NASPM) both mimics and occludes the effect of the kainate receptor antagonists, indicating that the presynaptic kainate receptors are calcium permeable. Furthermore, Schaffer collateral synapses onto SOM interneurons show up to 11-fold short-term facilitation during physiologically derived stimulus patterns, in contrast to other interneurons that have less than 1.5-fold facilitation. Blocking the kainate receptors reduces facilitation in SOM interneurons by approximately 50% during the physiologically derived patterns and reduces the dynamic range. Activation of calcium-permeable kainate receptors containing GluR5/GluR6 causes a dramatic increase in short-term facilitation during physiologically derived stimulus patterns, a mechanism likely to be important in regulating the strength of Schaffer collateral synapses onto SOM interneurons in vivo.
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PMID:Calcium-permeable presynaptic kainate receptors involved in excitatory short-term facilitation onto somatostatin interneurons during natural stimulus patterns. 1907 17

High-conductance apical K+ (BK) channels are present in surface colonocytes of mammalian (including human) colon. Their location makes them well fitted to contribute to the excessive intestinal K(+) losses often associated with infective diarrhea. Since many channel proteins are regulated by phosphorylation, we evaluated the roles of protein kinase A (PKA) and phosphatases in the modulation of apical BK channel activity in surface colonocytes from rat distal colon using patch-clamp techniques, having first increased channel abundance by chronic dietary K+ enrichment. We found that PKA activation using 50 micromol/l forskolin and 5 mmol/l 3-isobutyl-1-methylxanthine stimulated BK channels in cell-attached patches and the catalytic subunit of PKA (200 U/ml) had a similar effect in excised inside-out patches. The antidiarrheal peptide somatostatin (SOM; 2 micromol/l) had a G protein-dependent inhibitory effect on BK channels in cell-attached patches, which was unaffected by pretreatment with 10 micromol/l okadaic acid (an inhibitor of protein phosphatase type 1 and type 2A) but completely prevented by pretreatment with 100 micromol/l Na+ orthovanadate and 10 micromol/l BpV (inhibitors of phosphoprotein tyrosine phosphatase). SOM also inhibited apical BK channels in surface colonocytes in human distal colon. We conclude that cAMP-dependent PKA activates apical BK channels and may enhance colonic K+ losses in some cases of secretory diarrhea. SOM inhibits apical BK channels through a phosphoprotein tyrosine phosphatase-dependent mechanism, which could form the basis of new antidiarrheal strategies.
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PMID:Regulation of colonic apical potassium (BK) channels by cAMP and somatostatin. 1940 17

Octreotide is a somatostatin analogue binding on two receptor subtypes. In previous trials Octreotide showed inhibitory effects on tumour growth and liver metastasis in experimental pancreatic cancer. Thus we evaluated whether the new somatostatin analogue SOM-230 binding on 4 receptor subtypes has superior effects on carcinogenesis in pancreatic carcinoma. About 120 Syrian hamsters were randomised into six groups (n = 20): Gr.1: Aqua/Aqua, Gr.2: BOP/Aqua, Gr.3: Aqua/Octreotide, Gr.4: BOP/Octreotide, Gr.5: Aqua/SOM-230, Gr.6: BOP/SOM-230. Tumour groups 2,4,6 subcutaneously received 10 mg/kg body weight N-nitrosobis-2-oxopropylamin (BOP) weekly for 10 weeks, healthy control Gr.1,3,5 were given aqua. In the 17th week therapy started with Octreotide and SOM-230 for 16 weeks, after 32 weeks animals were sacrificed. Pancreas and liver were histopathologically analysed. Hepatic lipidperoxidation was determined by activities of antioxidative enzymes gluthation-peroxidase (GSH-Px) and superoxiddismutase (SOD) as well as concentration of thiobarbituric-acid reactive substances (TBARS). Incidence of liver metastases was 88.2% in Gr.2 (BOP/Aqua), it was decreased in Gr.4 (BOP/Octreo: 40%) and Gr.6 (BOP/SOM-230: 50%) (P < 0.05). Mean number/animal and mean-2-dimensional size of liver metastases did not differ between tumour groups. Comparing GSH-Px-activity in intrametastatic and extrametastatic hepatic tissue revealed a significant increase extrametastatically in Gr.2 (BOP/Aqua) and Gr.6 (BOP/SOM-230). SOD-activity in liver metastases was decreased in Gr.2 (1,801) (P < 0.05) versus Gr.4 (8,304) and Gr.6 (7,038). Intrametastatic TBARS concentration was increased in Gr.2 compared to Gr.4 (BOP/Octreotid) and Gr.6 (BOP/SOM-230) (P < 0.05). Octreotide and SOM-230 equally reduced liver metastasis in ductal pancreatic adenocarcinoma probably by a reduction of lipidperoxidation.
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PMID:Impact of Octreotide and SOM-230 on liver metastasis and hepatic lipidperoxidation in ductal pancreatic adenocarcinoma in Syrian Hamster. 1952 86

The purpose of this study was to investigate the effect of somatostatin (SST) in peripheral nerve terminals using local application of the SST receptor (SSTR) antagonist cyclo-somatostatin (c-SOM) injected into the receptive fields of cutaneous afferent fibers innervating the dorsal hairy skin in anesthetized rats. Single unit activity was recorded in teased filaments from the dorsal cutaneous nerve branch. Recordings were obtained from 206 primary afferent fibers. They were classified as C (n=70), Adelta (n=84) or Abeta (n=52) fibers based upon their conduction velocity. For C and Adelta fibers, mean discharge rate increased and mechanical threshold decreased significantly to 10 microL of 12.8 and 128 microM injected subcutaneously, but not to 0.128 and 1.28 microM c-SOM injection. For Abeta fibers, no dose of c-SOM changed their discharge rate or their mechanical sensitivity. In control experiments, injection of normal saline (NS) had no effect on any of the units tested. Octreotide (20 microM, 10 microL), an SSTR agonist, successfully reversed the increase in discharge rates and the decrease in mechanical thresholds in C and Adelta fibers when it was pre-administrated into the receptive field before c-SOM injection. These results provide evidence that somatostatin tonically inhibits the peripheral nerve terminals of small-diameter cutaneous afferent fibers.
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PMID:Tonic inhibition of somatostatin on C and Adelta afferent fibers in rat dorsal skin in vivo. 1959 79

This study reports on changes in the somatostatin-like immunoreactive (SOM-LI) nerve structures of the enteric nervous system (ENS) in the porcine descending colon, caused by chemically driven inflammation, proliferative enteropathy (PE), which is a "natural" inflammation with proliferative changes and nerve injury (axotomy). The distribution pattern of SOM-LI structures was studied using the immunofluorescence technique in the circular muscle layer, the myenteric (MP), outer submucous (OSP) and inner submucous plexuses (ISP) and also in the mucosal layer. Under physiological conditions SOM-LI perikarya have been shown to constitute 1.97+/-0.36%, 2.06+/-0.33% and 4.23+/-0.40% in the MP, OSP and ISP, respectively. Changes in SOM-immunoreactivity depended on the pathological factor and the part of the ENS studied. Numbers of the SOM-LI perikarya amounted 1.81+/-0.30, 1.97+/-0.24 and 11.15+/-0.95 during chemically induced colitis and 3.21+/-0.37%, 4.33+/-0.33% and 4.42+/-0.32% after axotomy in MP, OSP and ISP, respectively. Moreover during PE SOM-positive cell bodies were not observed at all in MP, whereas within OSP and ISP the number of SOM-LI perikarya amounted to 3.34+/-0.36 and 10.92+/-059, respectively. All processes studied resulted in a decrease in the number of SOM-LI nerve fibers in the mucosal layer, whereas within the circular muscle layer chemically induced inflammation and axotomy caused an increase in the number of the SOM-LI nerve fibers contrary to PE, which reduced the number of such fibers. The obtained results suggest that SOM-LI nerve structures of the ENS may participate in various pathological states within the porcine descending colon and their functions probably depend on the type of pathological factor.
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PMID:Changes in the somatostatin (SOM)-like immunoreactivity within nervous structures of the porcine descending colon under various pathological factors. 2013 63

The effectiveness of the long acting somatostatin analogues like octreotide and lanreotide depends on the expression of specific somatostatin receptors on the target cells. The immunohistochemical method performed on surgically removed tumors searches the expression of receptors at the level of receptor protein and gives us insight into receptor's cellular localization. The aim of study was to assess the presence of all the 5 subtypes of SSTR 1-5 (including 2A and 2B SSTR isoforms) in surgically treated human neuroendocrine tumors (NETs) to establish which receptor subtype is the dominant form of somatostatin receptor in particular tumor and thus to be able to predict which somatostatin analog will be effective in NETs treatment. 18 samples of neuroendocrine tumors (surgically excised tumors or biopsies) were immunostained with specific antibodies. Expression of SSTR was scored semiquantitatively. Only strong or moderate immunostaining was considered as positive reaction. The summarized expression pattern of SSTR in the investigated neuroendocrine tumors in our material was: SSTR 1> SSTR 5> SSTR 3> SSTR 2A> SSTR 2B. The receptors were distributed mainly in the area of cells cytoplasm with a few specimens showing only membranous or mixed: membranous--cytoplasmic localization. The observed pattern suggests that apart from octreotide and lanreotide, newly synthesized multiligand analogs such as SOM 230, KE 108 or SSTR 1 and SSTR 5 selective analogs could be effective in NETs treatment.
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PMID:SSTR1 and SSTR5 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors. 2052 30


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