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  • 1
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    Wylie Vale [Retrospectives] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-03-07
    Description: To die at the height of a man's career, the highest moment of his effort here in this world, universally honored and admired, to die while great issues are still commanding the whole of his interest, to be taken from us at a moment when he could already see ultimate success in view is not the most unenviable of fates.Winston Churchill (1940)Wylie Vale, professor and head of the Clayton Foundation Laboratories for Peptide Biology at The Salk Institute, member of the National Academy of Sciences, and leader in the field of neuroendocrinology, passed away in his sleep on January 3,...
    Keywords: PNAS Profiles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Characterization of a Pachymedusa dacnicolor-Sauvagine Analog as a New High-Affinity Radioligand for Corticotropin-Releasing Factor Receptor Studies [Neuropharmacology] (2015)
    The American Society for Pharmacology and Experimental Therapeutics
    Details
    Publication Date: 2015-03-25
    Description: The corticotropin-releasing factor (CRF) peptide family comprises the mammalian peptides CRF and the urocortins as well as frog skin sauvagine and fish urophyseal urotensin. Advances in understanding the roles of the CRF ligand family and associated receptors have often relied on radioreceptor assays using labeled CRF ligands. These assays depend on stable, high-affinity CRF analogs that can be labeled, purified, and chemically characterized. Analogs of several of the native peptides have been used in this context, most prominently including sauvagine from the frog Phyllomedusa sauvageii (PS-Svg). Because each of these affords both advantages and disadvantages, new analogs with superior properties would be welcome. We find that a sauvagine-like peptide recently isolated from a different frog species, Pachymedusa dacnicolor (PD-Svg), is a high-affinity agonist whose radioiodinated analog, [ 125 ITyr 0 -Glu 1 , Nle 17 ]-PD-Svg, exhibits improved biochemical properties over those of earlier iodinated agonists. Specifically, the PD-Svg radioligand binds both CRF receptors with comparably high affinity as its PS-Svg counterpart, but detects a greater number of sites on both type 1 and type 2 receptors. PD-Svg is also ~10 times more potent at stimulating cAMP accumulation in cells expressing the native receptors. Autoradiographic localization using the PD-Svg radioligand shows robust specific binding to rodent brain and peripheral tissues that identifies consensus CRF receptor–expressing sites in a greater number and/or with greater sensitivity than its PS-Svg counterpart. We suggest that labeled analogs of PD-Svg may be useful tools for biochemical, structural, pharmacological, and anatomic studies of CRF receptors.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics
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  • 3
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    Brain somatostatin receptor 2 mediates the dipsogenic effect of central somatostatin and cortistatin in rats: role in drinking behavior (2014)
    The American Physiological Society (APS)
    Details
    Publication Date: 2014-10-02
    Description: Intracerebroventricular injection of stable somatostatin (SST) agonists stimulates food and water intake in rats. We investigated the receptor subtype(s) involved in the dipsogenic effect of intracerebroventricular injection of SST agonists, mechanisms of action, and role. In nonfasted and non-water-deprived male rats with chronic intracerebroventricular cannula, intake of water without food or food without water was monitored separately to avoid any interactions compared with intracerebroventricular vehicle. SST-14 and cortistatin (CST-14) (1 μg/rat icv) increased water intake by 3.1- and 2.7-fold, respectively, while both peptides did not alter food intake at 1 h postinjection in the light phase. By contrast, the stable pan-somatostatin agonist ODT8-SST (1 μg/rat icv) increased both water and food intake by 4.9- and 3.7-fold, respectively. S-346-011, a selective receptor 2 (sst 2 ) agonist (1 μg/rat icv) induced water ingestion, while sst 1 or sst 4 agonist, injected under the same conditions, did not. The sst 2 antagonist S-406-028 (1 μg/rat icv) prevented the 1-h water intake induced by intracerebroventricular ODT8-SST and CST-14. Losartan (100 μg/rat icv), an angiotensin receptor 1 (AT 1 ) antagonist, completely blocked the water consumption induced by intracerebroventricular ODT8-SST, whereas intracerebroventricular injection of S-406-028 did not modify the intracerebroventricular ANG II-induced dipsogenic response. The sst 2 antagonist reduced by 40% the increase of the 3-h water intake in the early dark phase. These data indicate that SST-14 and CST-14 interact with sst 2 to exert a potent dipsogenic effect, which is mediated downstream by angiotensin-AT 1 signaling. These data also indicate that sst 2 activation by brain SST-14 and/or CST-14 may play an important role in the regulation of drinking behavior.
    Print ISSN: 0363-6119
    Electronic ISSN: 1522-1490
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 4
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    Inhibition of Voltage-gated Sodium Channels by {mu}O{section}-GVIIJ [Neurobiology] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-03-26
    Description: Cone snail toxins are well known blockers of voltage-gated sodium channels, a property that is of broad interest in biology and therapeutically in treating neuropathic pain and neurological disorders. Although most conotoxin channel blockers function by direct binding to a channel and disrupting its normal ion movement, conotoxin μO§-GVIIJ channel blocking is unique, using both favorable binding interactions with the channel and a direct tether via an intermolecular disulfide bond. Disulfide exchange is possible because conotoxin μO§-GVIIJ contains an S-cysteinylated Cys-24 residue that is capable of exchanging with a free cysteine thiol on the channel surface. Here, we present the solution structure of an analog of μO§-GVIIJ (GVIIJ[C24S]) and the results of structure-activity studies with synthetic μO§-GVIIJ variants. GVIIJ[C24S] adopts an inhibitor cystine knot structure, with two antiparallel β-strands stabilized by three disulfide bridges. The loop region linking the β-strands (loop 4) presents residue 24 in a configuration where it could bind to the proposed free cysteine of the channel (Cys-910, rat NaV1.2 numbering; at site 8). The structure-activity study shows that three residues (Lys-12, Arg-14, and Tyr-16) located in loop 2 and spatially close to residue 24 were also important for functional activity. We propose that the interaction of μO§-GVIIJ with the channel depends on not only disulfide tethering via Cys-24 to a free cysteine at site 8 on the channel but also the participation of key residues of μO§-GVIIJ on a distinct surface of the peptide.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 5
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    Posttranslational Processing of Human and Mouse Urocortin 2: Characterization and Bioactivity of Gene Products (2013)
    Oxford University Press
    Details
    Publication Date: 2013-03-23
    Description: Mouse (m) and human (h) urocortin 2 (Ucn 2) were identified by molecular cloning strategies and the primary sequence of their mature forms postulated by analogy to closely related members of the corticotropin-releasing factor (CRF) neuropeptide family. Because of the paucity of Ucn 2 proteins in native tissues, skin, muscle, and pancreatic cell lines were transduced with lentiviral constructs and secretion media were used to isolate and characterize Ucn 2 products and study processing. Primary structures were assigned using a combination of Edman degradation sequencing and mass spectrometry. For mUcn 2, transduced cells secreted a 39 amino acid peptide and the glycosylated prohormone lacking signal peptide; both forms were C-terminally amidated and highly potent to activate the type 2 CRF receptor. Chromatographic profiles of murine tissue extracts were consistent with cleavage of mUcn 2 prohormone to a peptidic form. By contrast to mUcn 2, mammalian cell lines transduced with hUcn 2 constructs secreted significant amounts of an 88 amino acid glycosylated hUcn 2 prohormone but were unable to further process this molecule. Similarly, WM-266-4 melanoma cells that express endogenous hUcn 2 secreted only the glycosylated prohormone lacking the signal peptide and unmodified at the C terminus. Although not amidated, hUcn 2 prohormone purified from overexpressing lines activated CRF receptor 2. Hypoxia and glycosylation, paradigms that might influence secretion or processing of gene products, did not significantly impact hUcn 2 prohormone cleavage. Our findings identify probable Ucn 2 processing products and should expedite the characterization of these proteins in mammalian tissues.
    Print ISSN: 0013-7227
    Topics: Medicine
    Published by Oxford University Press on behalf of The Endocrine Society.
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  • 6
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    Key Role of CRF in the Skin Stress Response System (2013)
    The Endocrine Society
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    Publication Date: 2013-12-07
    Description: The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1α receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF-〉pro-opiomelanocortin-〉ACTH, MSH, and β-endorphin. Expression of these peptides and of CRFR-1α is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis.
    Print ISSN: 0163-769X
    Electronic ISSN: 1945-7189
    Topics: Medicine
    Published by The Endocrine Society
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  • 7
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    Comparison of Somatostatin Receptor Agonist and Antagonist for Peptide Receptor Radionuclide Therapy: A Pilot Study (2014)
    The Society of Nuclear Medicine (SNM)
    Details
    Publication Date: 2014-08-02
    Description: Preclinical and clinical studies have indicated that somatostatin receptor (sst)–expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In 4 consecutive patients with advanced neuroendocrine tumors, we evaluated whether treatment with 177 Lu-labeled sst antagonists is feasible. Methods: After injection of approximately 1 GBq of 177 Lu-DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH 2 ] ( 177 Lu-DOTA-JR11) and 177 Lu-DOTATATE, 3-dimensional voxel dosimetry analysis based on SPECT/CT was performed. A higher tumor-to-organ dose ratio for 177 Lu-DOTA-JR11 than for 177 Lu-DOTATATE was the prerequisite for treatment with 177 Lu-DOTA-JR11. Results: Reversible minor adverse effects of 177 Lu-DOTA-JR11 were observed. 177 Lu-DOTA-JR11 showed a 1.7–10.6 times higher tumor dose than 177 Lu-DOTATATE. At the same time, the tumor-to-kidney and tumor–to–bone marrow dose ratio was 1.1–7.2 times higher. All 4 patients were treated with 177 Lu-DOTA-JR11, resulting in partial remission in 2 patients, stable disease in 1 patient, and mixed response in the other patient. Conclusion: Treatment of neuroendocrine tumors with radiolabeled sst antagonists is clinically feasible and may have a significant impact on peptide receptor radionuclide therapy.
    Print ISSN: 0022-3123
    Topics: Medicine
    Published by The Society of Nuclear Medicine (SNM)
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  • 8
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    Highly Increased 125I-JR11 Antagonist Binding In Vitro Reveals Novel Indications for sst2 Targeting in Human Cancers (2017)
    The Society of Nuclear Medicine (SNM)
    Details
    Publication Date: 2017-02-02
    Description: There is recent in vitro and in vivo evidence that somatostatin receptor subtype 2 (sst 2 ) antagonists are better tools to target neuroendocrine tumors (NETs) than sst 2 agonists. Indeed, antagonists bind to a greater number of sst 2 sites than agonists. Whether sst 2 antagonists could be used successfully to target non-NETs, expressing low sst 2 density, is unknown. Here, we compare quantitatively 125 I-JR11 sst 2 antagonist binding in vitro with that of the sst 2 agonist 125 I-Tyr 3 -octreotide in large varieties of non-NET and NET. Methods: In vitro receptor autoradiography was performed with 125 I-JR11 and 125 I-Tyr 3 -octreotide in cancers from prostate, breast, colon, kidney, thyroid, and lymphoid tissues as well as NETs as reference. Results: In general, 125 I-JR11 binds to many more sst 2 sites than 125 I-Tyr 3 -octreotide. In 13 breast cancers, 8 had a low binding (mean density, 844 ± 168 dpm/mg of tissue) with the agonist whereas 12 had a high binding (mean density, 4,447 ± 1,128 dpm/mg of tissue) with the antagonist. All 12 renal cell cancers showed a low binding of sst 2 with the agonist (mean density, 348 ± 49 dpm/mg of tissue) whereas all cases had a high sst 2 binding with the antagonist (mean density, 3,777 ± 582 dpm/mg of tissue). One of 5 medullary thyroid cancers was positive with the agonist, whereas 5 of 5 were positive with the antagonist. In 15 non-Hodgkin lymphomas, many more sst 2 sites were labeled with the antagonist than with the agonist. In 14 prostate cancers, none had sst 2 binding with the agonist and only 4 had a weak binding with the antagonist. None of 17 colon cancers showed sst 2 sites with the agonist, and only 3 cases were weakly positive with the antagonist. In the various tumor types, adjacent sst 2 -expressing tissues such as vessels, lymphocytes, nerves, mucosa, or stroma were more strongly labeled with the antagonist than with the agonist. The reference NET cases, incubated with a smaller amount of tracer, were also found to have many more sst 2 sites measured with the antagonist. Conclusion: All renal cell cancers and most breast cancers, non-Hodgkin lymphomas, and medullary thyroid cancers represent novel indications for the in vivo radiopeptide targeting of sst 2 by sst 2 antagonists, comparable to NET radiotargeting with sst 2 agonists.
    Print ISSN: 0022-3123
    Topics: Medicine
    Published by The Society of Nuclear Medicine (SNM)
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  • 9
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    Phyllotaxis: a non-conventional crystalline solution to packing efficiency in situations with radial symmetry (2012)
    Wiley-Blackwell
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    Publication Date: 2012-06-20
    Description: Phyllotaxis, the search for the most homogeneous and dense organizations of small discs inside a large circular domain, was first developed to analyse arrangements of leaves or florets in plants. It has since become an object of study not only in botany, but also in mathematics, computer simulations and physics. Although the mathematical solution is now well known, an algorithm setting out the centres of the small discs on a Fermat spiral, the very nature of this organization and its properties of symmetry remain to be examined. The purpose of this paper is to describe a phyllotactic organization of points through its Voronoi cells and Delaunay triangulation and to refer to the concept of defects developed in condensed matter physics. The topological constraint of circular symmetry introduces an original inflation–deflation symmetry taking the place of the translational and rotational symmetries of classical crystallography.
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Published by Wiley-Blackwell on behalf of International Union of Crystallography (IUCr).
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  • 10
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    Unexpected Sensitivity of sst2 Antagonists to N-Terminal Radiometal Modifications (2012)
    The Society of Nuclear Medicine (SNM)
    Details
    Publication Date: 2012-09-07
    Description: Chelated somatostatin agonists have been shown to be sensitive to N-terminal radiometal modifications, with Ga-DOTA agonists having significantly higher binding affinity than their Lu-, In-, and Y-DOTA correlates. Recently, somatostatin antagonists have been successfully developed as alternative tracers to agonists. The aim of this study was to evaluate whether chelated somatostatin antagonists are also sensitive to radiometal modifications and how. We have synthesized 3 different somatostatin antagonists, DOTA- p -NO 2 -Phe-c[ d -Cys-Tyr- d -Aph(Cbm)-Lys-Thr-Cys]- d -Tyr-NH 2 , DOTA-Cpa-c[ d -Cys-Aph(Hor)- d -Aph(Cbm)-Lys-Thr-Cys]- d -Tyr-NH 2 (DOTA-JR11), and DOTA- p -Cl-Phe-c[ d -Cys-Tyr- d -Aph(Cbm)-Lys-Thr-Cys]- d -Tyr-NH 2 , and added various radiometals including In(III), Y(III), Lu(III), Cu(II), and Ga(III). We also replaced DOTA with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and added Ga(III). The binding affinity of somatostatin receptors 1 through 5 was evaluated in all cases. In all 3 resulting antagonists, the Ga-DOTA analogs were the lowest-affinity radioligands, with a somatostatin receptor 2 binding affinity up to 60 times lower than the respective Y-DOTA, Lu-DOTA, or In-DOTA compounds. Interestingly, however, substitution of DOTA by the NODAGA chelator was able to increase massively its binding affinity in contrast to the Ga-DOTA analog. The 3 NODAGA analogs are antagonists in functional tests. In vivo biodistribution studies comparing 68 Ga-DOTATATE agonist with 68 Ga-DOTA-JR11 and 68 Ga-NODAGA-JR11 showed not only that the JR11 antagonist radioligands were superior to the agonist ligands but also that 68 Ga-NODAGA-JR11 was the tracer of choice and preferable to 68 Ga-DOTA-JR11 in transplantable HEK293-hsst 2 tumors in mice. One may therefore generalize that somatostatin receptor 2 antagonists are sensitive to radiometal modifications and may preferably be coupled with a 68 Ga-NODAGA chelator–radiometal complex.
    Print ISSN: 0022-3123
    Topics: Medicine
    Published by The Society of Nuclear Medicine (SNM)
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