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)

Corticotropin-releasing factor (CRF) acts centrally to suppress gastric emptying and increase plasma levels of somatostatin in rats. The experiments were conducted to examine whether cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), which acts as a somatostatin antagonist in vivo, blocks the effect of CRF on gastric emptying of glucose. Sprague-Dawley rats were implanted with chronic intragastric fistulas and guide cannulas for fourth intracerebroventricular (4th i.c.v.) delivery. The stomach was evacuated after the offset of a 12-min intragastric glucose infusion (12.5%, 1.0 ml/min). CRF, (1000 pmol) injected 4th i.c.v. suppressed solute emptying by 44% as compared to vehicle (P < 0.001). Pretreatment with cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), 40 microg/kg, s.c., having no effect when delivered alone, blocked the effect of CRF on emptying. The results suggest that endogenously released somatostatin participates in CRF-induced suppression of gastric emptying during gastric fill.
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PMID:Corticotropin-releasing factor-induced suppression of gastric emptying in the rat is blocked by cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL], an in vivo somatostatin antagonist. 1002 95

The human T cell leukemia virus type I (HTLV-I) Tax protein activates transcription from the viral long terminal repeat and select cellular promoters by interacting with cellular DNA-binding proteins. The HTLV-I promoter contains three copies of a Tax-responsive element (TRE-1), each of which possesses a core cAMP response element (CRE). The cAMP response element-binding protein, CREB, binds TRE-1 and mediates Tax association with, and transactivation of, the viral promoter. These activities depend on DNA sequences that flank the core CRE. Although CREs are found in a variety of cellular promoters, cellular CREs vary in sequence from TRE-1, especially in the flanking regions, and are generally not Tax responsive. The molecular basis for differential Tax responsiveness of viral and cellular CREs has not been determined. Here we demonstrate that the conformation of CREB is influenced by the nucleotide sequence of its DNA-binding element. CREB showed altered sensitivity to V8, chymotrypsin, and trypsin proteases when bound to the HTLV-I TRE-1 element as compared to the rat somatostatin CRE element. The phosphorylation state of CREB did not influence its protease sensitivity on either element. Sequences flanking the core CRE-binding site in each element were found to specify protease sensitivity. Since the TRE-1-flanking sequences also modulate Tax association with CREB, and Tax transactivation of CREB-dependent LTR transcription, these results suggest that CREB conformation may determine the ability of Tax to bind CREB.
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PMID:Sequences flanking the cAMP responsive core of the HTLV-I tax response elements influence CREB protease sensitivity. 1079 92

The symptomatology of the fibromyalgia syndrome (FMS) often resembles an alteration in central nervous set points at least in three systems. The patients suffer under chronic pain in the region of the locomotor system, presumably reflecting a disturbed central processing of pain. Anxiety and depression often characterizes the clinical picture. Almost all of the hormonal feedback mechanisms controlled by the hypothalamus are altered. Characteristic for FMS patients are the elevated basal values of ACTH, follicle-stimulating hormone (FSH), and cortisol as well as lowered basal values of insulin-like growth factor 1 (IGF-1, somatomedin C), free triiodothyronine (FT3), and oestrogen. In FMS patients, the systemic administration of the relevant releasing hormones of corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), thyreotropin-releasing hormone (TRH), and luteinizing hormone-releasing hormone (LHRH) leads to increased secretion of ACTH and prolactin, whereas the degree to which TSH can be stimulated is reduced. The stimulation of the hypophysis with LHRH in female FMS patients during their follicular phase results in a significantly reduced LH response. All in all, the typical alterations in set points of hormonal regulation that are typical for FMS patients can be explained as a primary stress activation of hypothalamic CRH neurons caused by the chronic pain. In addition to the stimulation of pituitary ACTH secretion, CRH activates somatostatin on the hypothalamic level, which in turn inhibits the release of GH and TSH on the hypophyseal level. The lowered oestrogen levels could be accounted for both via an inhibitory effect of the CRH on the hypothalamic release of LHRH or via a direct CRH-mediated inhibition of the FSH-stimulated oestrogen production in the ovary. Serotonin (5HT), precursors like tryptophan (5HTP), drugs which release 5HT or act directly on 5HT receptors stimulate HPA axis, indicating a stimulatory serotonergic influence on HPA axis function. Therefore activation of the HPA axis may reflect an elevated serotonergic tonus in the central nervous system of FMS patients.
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PMID:Neuroendocrine and hormonal perturbations and relations to the serotonergic system in fibromyalgia patients. 1102 24

A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.
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PMID:Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. 1108 55

Insulin, glucagon, somatostatin-14, and three structurally related molecular forms of peptide tyrosine-tyrosine (PYY) were isolated from an extract of the combined pancreas and gastrointestinal tract of the pallid sturgeon, Scaphirhynchus albus. Pallid sturgeon insulin was identical to insulin from the Russian sturgeon, Acipenser guldenstaedti, and to insulin-2 from the paddlefish, Polyodon spathula, and was approximately twofold less potent than human insulin in inhibiting the binding of [3-[(125)I] iodotyrosine-A14] human insulin to the soluble human insulin receptor. The sturgeon glucagon (HSQGMFTNDY(10)-SKYLEEKLAQ(20) EFVEWLKNGK(30)S), like the two paddlefish glucagons, contains 31 rather than 29 amino acid residues, indicative of an anomalous pathway of posttranslational processing of proglucagon. Pallid sturgeon somatostatin, identical to human somatostatin-14, was also isolated in a second molecular form containing an oxidized tryptophan residue, but [Pro(2)]somatostatin-14, previously isolated from the pituitary of A. guldenstaedti, was not identified. Sturgeon PYY (FPPKPEHPGD(10)DAPAEDVAKY(20)YTALRHYINL(30) ITRQRY.HN(2)) was also isolated in variant forms containing the substitutions (Phe(1) --> Ala) and (Ala(18) --> Val), indicative of at least two gene duplications occurring within the Acipenseriformes lineage. The amino acid sequences of the pallidsturgeon PYY peptides are appreciably different from the proposed "ancestral" PYY sequence that has otherwise been very strongly conserved among the actinopterygian and elasmobranch fish.
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PMID:Gastroenteropancreatic hormones (insulin, glucagon, somatostatin, and multiple forms of PYY) from the pallid sturgeon, Scaphirhynchus albus (Acipenseriformes). 1112

[reaction: see text] The synthesis of four bioactive analogues of the somatostatin (SRIF-14) mimetic, beta-d-glucoside (+)-2, in which the C1 indole side chain is replaced with indole surrogates, has been achieved. These congeners, possessing the naphthyl, benzothiophene, benzyl, and benzofuran substituents, were predicted to satisfy the electrostatic requirements of the tryptophan binding pocket of SRIF. Unlike the previously described C4 picolyl and pyrazinyl congeners, these ligands bind the hSST4 receptor.
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PMID:Synthesis and binding affinities of novel SRIF-mimicking beta-D-glucosides satisfying the requirement for a pi-cloud at C1. 1576 Jan 54

The application of second derivative tryptophan (Trp) fluorescence spectroscopy to characterize partially unfolded intermediates of proteins relevant to protein formulation was investigated. The second derivatives of the normalized emission scans of N-acetyl tryptophanamide (NATA), single-Trp containing proteins, somatostatin and human serum albumin (HSA), and two-Trp containing proteins previously shown to form partially unfolded intermediates, beta-lactoglobulin (beta Lg) and interferon alpha-2a (IFN alpha 2a), were studied in solution. The second derivative of NATA in water showed three bands at 340, 348 and 367 nm. The 340 nm band showed a blue shift, whereas the intensity of all three bands was affected by a decrease in solution polarity. Second derivative of single-Trp containing proteins, somatostatin and HSA, showed three negative bands, whereas, the second derivative of the two-Trp containing proteins, beta Lg and IFN alpha 2a, showed four bands, two of which lie in the 320-340 nm range. These two bands were attributed to the presence of the Trps in different microenvironments. The characteristic changes in the intensities of these two bands on addition of guanidine hydrochloride (beta Lg) and with a decrease in solution pH (IFN alpha 2a) were related to the presence of partially unfolded intermediates of these proteins. Thus, second derivative Trp fluorescence spectroscopy can be used as an important tool to identify partially unfolded states of proteins during formulation utilizing order of magnitude lower concentrations compared to such other technique as near UV CD.
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PMID:Second derivative tryptophan fluorescence spectroscopy as a tool to characterize partially unfolded intermediates of proteins. 1581 44

A novel synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin (DMJ) scaffold has been developed. This involved development of a route suitable for the strategic grafting of pharmacophoric tryptophan and lysine side chains to the nitrogen atom of the piperidine ring and to the primary hydroxyl group of DMJ, respectively. The novel peptidomimetics were found to bind with higher affinity to sst4 receptors than to sst5 receptors.
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PMID:Synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin scaffold. 1620 3

The synthesis of novel somatostatin mimetics from 1-deoxynojirimycin (DNJ) is described. The dipeptide mimetic, which respectively displayed the side chains of tryptophan and lysine at the nitrogen and O6 atoms of the iminosugar scaffold is a ligand (K(i)=3.2 microM) for the human somatostatin receptor subtype 4 (hSSTR4) but has lower affinity (K(i)>100 microM) for hSSTR5. A benzylated analogue of the Trp-Lys mimetic displays higher affinity for hSSTR5 (K(i)=5 microM).
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PMID:Synthesis of somatostatin mimetics based on 1-deoxynojirimycin. 1841 32

Neuroendocrine tumors can originate almost everywhere in the body and consist of a great variety of subtypes. This paper focuses on molecular imaging methods using nuclear medicine techniques in neuroendocrine tumors, coupling molecular uptake mechanisms of radiotracers with clinical results. A non-systematic review is presented on receptor based and metabolic imaging methods. Receptor-based imaging covers the molecular backgrounds of somatostatin, vaso-intestinal peptide (VIP), bombesin and cholecystokinin (CCK) receptors and their link with nuclear imaging. Imaging methods based on specific metabolic properties include meta-iodo-benzylguanide (MIBG) and dimercapto-sulphuric acid (DMSA-V) scintigraphy as well as more modern positron emission tomography (PET)-based methods using radio-labeled analogues of amino acids, glucose, dihydroxyphenylalanine (DOPA), dopamine and tryptophan. Diagnostic sensitivities are presented for each imaging method and for each neuroendocrine tumor subtype. Finally, a Forest plot analysis of diagnostic performance is presented for each tumor type in order to provide a comprehensive overview for clinical use.
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PMID:Molecular imaging in neuroendocrine tumors: molecular uptake mechanisms and clinical results. 1936 10


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