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11.
Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland 总被引:3,自引:0,他引:3
Muccioli G Papotti M Locatelli V Ghigo E Deghenghi R 《Journal of endocrinological investigation》2001,24(3):RC7-RC9
Ghrelin has been proposed as a natural ligand of the GH secretagogue receptor(s) (GHS-R), which was an orphan receptor activated by synthetic peptidyl (hexarelin) and non-peptidyl (MK-0677) GHS to strongly release GH in animals and humans. Herein we studied: 1) the binding of 125I-labeled human ghrelin to membranes from human hypothalamus and pituitary gland; 2) the ability of human ghrelin (either octanoylated or desoctanoylated), as well as of some GHS and neuropeptides to compete with the radioligand. The saturation binding analysis showed, in both tissues, the existence of a single class of high-affinity binding sites with limited binding capacity. The Bmax (maximal number of binding sites) values of ghrelin receptors in the hypothalamus were significantly greater (p<0.001) than those detected in the pituitary, whereas the Kd (dissociation constant) values in the two tissues were similar. 125I-ghrelin bound to hypothalamic membranes was displaced by ghrelin, hexarelin, MK-0677, various GHS antagonists (EP-80317, [D-Arg1-D-Phe5-D-Trp7,9-Leu11]-substance P) and some natural (cortistatin-14) and synthetic (vapreotide) SRIH-14 agonists. In contrast, no competition was seen in the presence of GHRH-44, SRIH-14 or desoctanoylated ghrelin, a ghrelin precursor that is devoid of GH-releasing properties. In conclusion, this preliminary study firstly demonstrates that ghrelin needs octanoylation to bind its hypothalamo-pituitary receptors. These receptors are the specific binding sites for GHS and their antagonists, as well as for SRIH analogs (vapreotide and cortistatin- 14), but not for native SRIH. 相似文献
12.
Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer 总被引:3,自引:3,他引:3
Onishi M; Mui AL; Morikawa Y; Cho L; Kinoshita S; Nolan GP; Gorman DM; Miyajima A; Kitamura T 《Blood》1996,88(4):1399-1406
Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5. 相似文献
13.
Broglio F Boutignon F Benso A Gottero C Prodam F Arvat E Ghè C Catapano F Torsello A Locatelli V Muccioli G Boeglin D Guerlavais V Fehrentz JA Martinez J Ghigo E Deghenghi R 《Journal of endocrinological investigation》2002,25(8):RC26-RC28
EP1572 UMV1843 [Aib-DTrp-DgTrp-CHO]) is a new peptido-mimetic GH secretagogue (GHS) showing binding potency to the GHS-receptor in animal and human tissues similar to that of ghrelin and peptidyl GHS. EP1572 induces marked GH increase after s.c. administration in neonatal rats. Preliminary data in 2 normal young men show that: 1) acute i.v. EP1572 administration (1.0 microg/kg) induces strong and selective increase of GH levels; 2) single oral EP1572 administration strongly and reproducibly increases GH levels even after a dose as low as 0.06 mg/kg. Thus, EP1572 is a new peptido-mimetic GHS with potent and selective GH-releasing activity. 相似文献
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16.
Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non‐bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high‐dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate‐related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen. 相似文献
17.
Arvat E Di Vito L Lanfranco F Broglio F Giordano R Benso A Muccioli GP Deghenghi R Ghigo E 《Journal of endocrinological investigation》1999,22(2):91-97
Hexarelin (HEX) and GHRP-2 are two synthetic hexapeptides, superanalogs of GHRP-6, belonging to GH secretagogue (GHS) family. GHS act via specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. However, GHS also possess significant PRL- and ACTH/cortisol-releasing activity. Tyr-Ala-HEX as well as Tyr-Ala-GHRP-6 are, in turn, synthetic octapeptides generally used to perform binding studies because of their easy iodination. However, their endocrine activities have never been studied in humans. To clarify the endocrine activities of Tyr-Ala-HEX, in 7 young adult volunteers we compared the effects of the maximal effective dose of HEX (2.0 microg/kg i.v.) or GHRP-2 (2.0 microg/kg i.v.) with the same one of Tyr-Ala-HEX on GH, PRL, ACTH and cortisol levels. Basal GH, PRL, ACTH and cortisol levels in all testing sessions were similar. The administration of placebo did not modify hormonal levels. HEX and GHRP-2 administration induced the well known strong GH response (Cmax, mean+/-SE: 77.3+/-6.0 and 74.1+/-12.1 microg/l; AUC, mean+/-SE: 2596.7+/-251.1 and 2480.0+/-343.6 microg*min/l). These responses were similar to that induced by Tyr-Ala-HEX (63.7+/-18.5 microg/l; 1986.6+/-622.4 microg*min/l). Moreover, HEX, GHRP-2 and Tyr-Ala-HEX had the same significant stimulatory effect on PRL (14.9+/-2.5, 12.3+/-2.0 and 10.0+/-1.5 microg/l; 497.8+/-61.8, 480.4+/-66.9 and 415.8+/-58.5 microg*min/l), ACTH (48.0+/-10.1, 51.4+/-10.6 and 44.9+/-12.2 pg/ml; 1531.6+/-235.7, 1586.7+/-277.0 and 1338.1+/-164.5 pg*min/ml) and cortisol (179.9+/-10.0, 181.2+/-14.1 and 149.7+/-20.1 microg/l; 8465.0+/-406.6, 8689.2+/-788.1 and 6295.2+/-797.0 microg*min/l). Also the mean Tmax of the endocrine responses to HEX, GHRP-2 and Tyr-Ala-HEX were similar. In conclusion, the present results demonstrate that in humans Tyr-Ala-HEX is a GH secretagogue as potent as HEX and GHRP-2, two GHRP-6 superanalogs. Tyr-Ala-HEX also shares with HEX and GHRP-2 the same PRL- ACTH- and cortisol-releasing activity. 相似文献
18.
NCE Smith GP Findlay D Weyman H Freeth 《Annals of the Royal College of Surgeons of England》2013,95(2):101-106
Introduction
In 2006 the National Confidential Enquiry into Patient Outcome and Death undertook a large prospective study of trauma care, which revealed several findings pertaining to the management of head injuries in a sample of 493 patients.Methods
Case note data were collected for all trauma patients admitted to all hospitals accepting emergencies in England, Wales, Northern Ireland and the Channel Islands over a three-month period. Severely injured patients with an injury severity score (ISS) of ≥16 were included in the study. The case notes for these patients were peer reviewed by a multidisciplinary group of clinicians, who rated the overall level of care the patient received.Results
Of the 795 patients who met the inclusion criteria for the study, 493 were admitted with a head injury. Room for improvement in the level of care was found in a substantial number of patients (265/493). Good practice was found to be highest in high volume centres. The overall head injury management was found to be satisfactory in 84% of cases (319/381).Conclusions
This study has shown that care for trauma patients with head injury is frequently rated as less than good and suggests potential long-term remedies for the problem, including a reconfiguration of trauma services and better provision of neurocritical care facilities. 相似文献19.
Nicola Lopomo Cecilia Signorelli Tommaso Bonanzinga Giulio Maria Marcheggiani Muccioli Maria Pia Neri Andrea Visani Maurilio Marcacci Stefano Zaffagnini 《International orthopaedics》2014,38(6):1167-1172