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[PMID]:28892096
[Au] Autor:Loarca L; De Assuncao TM; Jalan-Sakrikar N; Bronk S; Krishnan A; Huang B; Morton L; Trussoni C; Bonilla LM; Krueger E; O'Hara S; Splinter P; Shi G; Pisarello MJL; Gores GJ; Huebert RC; LaRusso NF
[Ad] Endereço:Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
[Ti] Título:Development and characterization of cholangioids from normal and diseased human cholangiocytes as an in vitro model to study primary sclerosing cholangitis.
[So] Source:Lab Invest;97(11):1385-1396, 2017 Nov.
[Is] ISSN:1530-0307
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Primary sclerosing cholangitis (PSC) is an incurable, fibroinflammatory biliary disease for which there is no effective pharmacotherapy. We recently reported cholangiocyte senescence as an important phenotype in PSC while others showed that portal macrophages accumulate in PSC. Unfortunately, our ability to explore cholangiocyte senescence and macrophage accumulation has been hampered by limited in vitro models. Thus, our aim was to develop and characterize a three-dimensional (3D) model of normal and diseased bile ducts (cholangioids) starting with normal human cholangiocytes (NHC), senescent NHC (NHC-sen), and cholangiocytes from PSC patients. In 3D culture, NHCs formed spheroids of ~5000 cells with a central lumen of ~150 µm. By confocal microscopy and western blot, cholangioids retained expression of cholangiocyte proteins (cytokeratin 7/19) and markers of epithelial polarity (secretin receptor and GM130). Cholangioids are functionally active, and upon secretin stimulation, luminal size increased by ~80%. Cholangioids exposed to hydrogen peroxide exhibited cellular senescence and the senescence-associated secretory phenotype (SASP; increased IL-6, p21, SA-ß-Gal, yH2A.x and p16 expression). Furthermore, cholangioids derived from NHC-sen or PSC patients were smaller and had slower growth than the controls. When co-cultured with THP-1 macrophages, the number of macrophages associated with NHC-sen or PSC cholangioids was five- to seven-fold greater compared to co-culture with non-senescent NHC. We observed that NHC-sen and PSC cholangioids release greater number of extracellular vesicles (EVs) compared to controls. Moreover, conditioned media from NHC-sen cholangioids resulted in an ~2-fold increase in macrophage migration. In summary, we developed a method to generate normal and diseased cholangioids, characterized them morphologically and functionally, showed that they can be induced to senescence and SASP, and demonstrated both EV release and macrophage attraction. This novel model mimics several features of PSC, and thus will be useful for studying the pathogenesis of PSC and potentially identifying new therapeutic targets.
[Mh] Termos MeSH primário: Ductos Biliares/patologia
Colangite Esclerosante/patologia
Esferoides Celulares/patologia
[Mh] Termos MeSH secundário: Autoantígenos/metabolismo
Ductos Biliares/efeitos dos fármacos
Ductos Biliares/metabolismo
Ductos Biliares/ultraestrutura
Biomarcadores/metabolismo
Linhagem Celular
Células Cultivadas
Senescência Celular/efeitos dos fármacos
Colangite Esclerosante/imunologia
Colangite Esclerosante/metabolismo
Técnicas de Cocultura
Meios de Cultivo Condicionados
Vesículas Extracelulares/efeitos dos fármacos
Vesículas Extracelulares/metabolismo
Vesículas Extracelulares/patologia
Vesículas Extracelulares/ultraestrutura
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Peróxido de Hidrogênio/toxicidade
Queratina-19/metabolismo
Queratina-7/metabolismo
Ativação de Macrófagos
Macrófagos/citologia
Macrófagos/imunologia
Proteínas de Membrana/metabolismo
Microscopia Eletrônica de Transmissão
Corpos Multivesiculares/efeitos dos fármacos
Corpos Multivesiculares/metabolismo
Corpos Multivesiculares/patologia
Corpos Multivesiculares/ultraestrutura
Oxidantes/toxicidade
Receptores Acoplados a Proteínas-G/metabolismo
Receptores dos Hormônios Gastrointestinais/metabolismo
Esferoides Celulares/efeitos dos fármacos
Esferoides Celulares/metabolismo
Esferoides Celulares/ultraestrutura
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (Biomarkers); 0 (Culture Media, Conditioned); 0 (Golgin subfamily A member 2); 0 (KRT7 protein, human); 0 (Keratin-19); 0 (Keratin-7); 0 (Membrane Proteins); 0 (Oxidants); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Gastrointestinal Hormone); 0 (secretin receptor); BBX060AN9V (Hydrogen Peroxide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1038/labinvest.2017.63


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[PMID]:28667118
[Au] Autor:Asmar M; Asmar A; Simonsen L; Gasbjerg LS; Sparre-Ulrich AH; Rosenkilde MM; Hartmann B; Dela F; Holst JJ; Bülow J
[Ad] Endereço:Department of Endocrinology, Bispebjerg University Hospital, Copenhagen, Denmark masmar@sund.ku.dk.
[Ti] Título:The Gluco- and Liporegulatory and Vasodilatory Effects of Glucose-Dependent Insulinotropic Polypeptide (GIP) Are Abolished by an Antagonist of the Human GIP Receptor.
[So] Source:Diabetes;66(9):2363-2371, 2017 Sep.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A truncated form of human glucose-dependent insulinotropic polypeptide (GIP), GIP(3-30)NH , was recently identified as an antagonist of the human GIP receptor. This study examined the ability of GIP(3-30)NH to antagonize the physiological actions of GIP in glucose metabolism, subcutaneous abdominal adipose tissue blood flow (ATBF), and lipid metabolism in humans. Eight lean subjects were studied by measuring arteriovenous concentrations of metabolites and ATBF on three different occasions during hyperglycemic-hyperinsulinemic clamps with concomitant infusions of GIP, GIP(3-30)NH , or both GIP and GIP(3-30)NH During infusion of GIP(3-30)NH alone and in combination with GIP, insulin levels and the total glucose amount infused to maintain the clamp were lower than during GIP alone. In addition, ATBF remained constant during the antagonist and increased only slightly in combination with GIP, whereas it increased fivefold during GIP alone. Adipose tissue triacylglyceride (TAG) and glucose uptake decreased, and the free fatty acid/glycerol ratio increased during the antagonist alone and in combination with GIP. The changes in glucose infusion rates and plasma insulin levels demonstrate an inhibitory effect of the antagonist on the incretin effect of GIP. In addition, the antagonist inhibited GIP-induced increase in ATBF and decreased the adipose tissue TAG uptake, indicating that GIP also plays a crucial role in lipid metabolism.
[Mh] Termos MeSH primário: Polipeptídeo Inibidor Gástrico/metabolismo
Glucose/metabolismo
Metabolismo dos Lipídeos/efeitos dos fármacos
Receptores dos Hormônios Gastrointestinais/metabolismo
[Mh] Termos MeSH secundário: Tecido Adiposo/irrigação sanguínea
Adulto
Glicemia/efeitos dos fármacos
Estudos Cross-Over
Ácidos Graxos não Esterificados
Polipeptídeo Inibidor Gástrico/genética
Técnica Clamp de Glucose
Glicerol
Seres Humanos
Masculino
Fragmentos de Peptídeos
Triglicerídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Fatty Acids, Nonesterified); 0 (Peptide Fragments); 0 (Receptors, Gastrointestinal Hormone); 0 (Triglycerides); 0 (gastric inhibitory polypeptide (3-30)-amide); 0 (gastric inhibitory polypeptide receptor); 59392-49-3 (Gastric Inhibitory Polypeptide); IY9XDZ35W2 (Glucose); PDC6A3C0OX (Glycerol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE
[do] DOI:10.2337/db17-0480


  3 / 1505 MEDLINE  
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[PMID]:28592605
[Au] Autor:Li SX; Imamura F; Ye Z; Schulze MB; Zheng J; Ardanaz E; Arriola L; Boeing H; Dow C; Fagherazzi G; Franks PW; Agudo A; Grioni S; Kaaks R; Katzke VA; Key TJ; Khaw KT; Mancini FR; Navarro C; Nilsson PM; Onland-Moret NC; Overvad K; Palli D; Panico S; Quirós JR; Rolandsson O; Sacerdote C; Sánchez MJ; Slimani N; Sluijs I; Spijkerman AM; Tjonneland A; Tumino R; Sharp SJ; Riboli E; Langenberg C; Scott RA; Forouhi NG; Wareham NJ
[Ad] Endereço:Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
[Ti] Título:Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct.
[So] Source:Am J Clin Nutr;106(1):263-275, 2017 Jul.
[Is] ISSN:1938-3207
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study. We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study ( = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and -interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Thirteen observational studies met the eligibility criteria ( < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 ( ), gastric inhibitory polypeptide receptor ( ), caveolin 2 ( ), and peptidase D ( ) ( -interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.
[Mh] Termos MeSH primário: Diabetes Mellitus/etiologia
Dieta
Carboidratos da Dieta/farmacologia
Gorduras na Dieta/farmacologia
Fibras na Dieta/farmacologia
Comportamento Alimentar
Interação Gene-Ambiente
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Caveolina 2/genética
Diabetes Mellitus/genética
Dipeptidases/genética
Ingestão de Energia
Europa (Continente)
Feminino
Seres Humanos
Masculino
Meia-Idade
Modelos Biológicos
Receptores dos Hormônios Gastrointestinais/genética
Fatores de Risco
Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Caveolin 2); 0 (Dietary Carbohydrates); 0 (Dietary Fats); 0 (Dietary Fiber); 0 (Receptors, Gastrointestinal Hormone); 0 (TCF7L2 protein, human); 0 (Transcription Factor 7-Like 2 Protein); 0 (gastric inhibitory polypeptide receptor); EC 3.4.13.- (Dipeptidases); EC 3.4.13.9 (proline dipeptidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.3945/ajcn.116.150094


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[PMID]:28430907
[Au] Autor:Shimizu T; Sato T; Tsukiyama K; Fujita H; Kato S; Hoizumi M; Shirasawa H; Narita T; Terada Y; Seino Y; Yamada Y
[Ad] Endereço:Department of Endocrinology, Diabetes, and Geriatric Medicine, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
[Ti] Título:Food Intake Affects Sperm-Egg Fusion Through the GIP/PSG17 Axis in Mice.
[So] Source:Endocrinology;158(7):2134-2144, 2017 Jul 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In addition to overeating, starvation also reduces fecundity in mammals. However, little is known about the molecular mechanisms linking food intake to fertility, especially in males. Gastric inhibitory polypeptide (GIP), which is released from intestinal K-cells after meal ingestion, stimulates insulin secretion from pancreatic ß-cells through the action of incretin and has several extrapancreatic effects. Here, we identified GIP receptor (Gipr) expression in mouse spermatids. Microarray analysis revealed that pregnancy-specific glycoprotein 17 (Psg17), a potential CD9-binding partner, was significantly decreased in GIP receptor-knockout (Gipr-/-) testes. Glycosylphosphatidylinositol-anchored PSG17 was expressed on the surface of acrosome-reacted sperm, and Gipr-/- sperm led to a lower fertilization rate in vitro, compared with that of Gipr+/+ sperm, both in the absence and presence of the zona pellucida. Plasma GIP concentrations and Psg17 messenger RNA (mRNA) were immediately increased in the testis after a single meal, whereas ingestion of a chronic high-fat diet markedly decreased Gipr and Psg17 mRNA. These results suggest that reduced GIP signaling, by decreased GIP levels or the downregulation of Gipr, is associated with the reduction of fecundity due to starvation or overeating. Thus, proper regulation of GIP signaling in the testis could be a potential unique therapeutic target for male infertility in obese and diabetic individuals.
[Mh] Termos MeSH primário: Ingestão de Alimentos/fisiologia
Polipeptídeo Inibidor Gástrico/fisiologia
Glicoproteínas/fisiologia
Proteínas da Gravidez/fisiologia
Receptores dos Hormônios Gastrointestinais/fisiologia
Interações Espermatozoide-Óvulo/genética
[Mh] Termos MeSH secundário: Animais
Feminino
Fertilidade/genética
Polipeptídeo Inibidor Gástrico/genética
Glicoproteínas/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Análise em Microsséries
Proteínas da Gravidez/genética
Receptores dos Hormônios Gastrointestinais/genética
Transdução de Sinais/genética
Testículo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycoproteins); 0 (Pregnancy Proteins); 0 (Receptors, Gastrointestinal Hormone); 0 (gastric inhibitory polypeptide receptor); 0 (pregnancy-specific glycoprotein 17, mouse); 59392-49-3 (Gastric Inhibitory Polypeptide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1861


  5 / 1505 MEDLINE  
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[PMID]:28424368
[Au] Autor:Ward RJ; Pediani JD; Harikumar KG; Miller LJ; Milligan G
[Ad] Endereço:Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Wolfson Link Building 253, Glasgow G12 8QQ, U.K.
[Ti] Título:Spatial intensity distribution analysis quantifies the extent and regulation of homodimerization of the secretin receptor.
[So] Source:Biochem J;474(11):1879-1895, 2017 May 24.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Previous studies have indicated that the G-protein-coupled secretin receptor is present as a homodimer, organized through symmetrical contacts in transmembrane domain IV, and that receptor dimerization is critical for high-potency signalling by secretin. However, whether all of the receptor exists in the dimeric form or if this is regulated is unclear. We used measures of quantal brightness of the secretin receptor tagged with monomeric enhanced green fluorescent protein (mEGFP) and spatial intensity distribution analysis to assess this. Calibration using cells expressing plasma membrane-anchored forms of mEGFP initially allowed us to demonstrate that the epidermal growth factor receptor is predominantly monomeric in the absence of ligand and while wild-type receptor was rapidly converted into a dimeric form by ligand, a mutated form of this receptor remained monomeric. Equivalent studies showed that, at moderate expression levels, the secretin receptor exists as a mixture of monomeric and dimeric forms, with little evidence of higher-order complexity. However, sodium butyrate-induced up-regulation of the receptor resulted in a shift from monomeric towards oligomeric organization. In contrast, a form of the secretin receptor containing a pair of mutations on the lipid-facing side of transmembrane domain IV was almost entirely monomeric. Down-regulation of the secretin receptor-interacting G-protein Gα did not alter receptor organization, indicating that dimerization is defined specifically by direct protein-protein interactions between copies of the receptor polypeptide, while short-term treatment with secretin had no effect on organization of the wild-type receptor but increased the dimeric proportion of the mutated receptor variant.
[Mh] Termos MeSH primário: Receptores Acoplados a Proteínas-G/química
Receptores dos Hormônios Gastrointestinais/química
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetinae
Cricetulus
Proteínas de Fluorescência Verde/genética
Multimerização Proteica
Receptores Acoplados a Proteínas-G/genética
Receptores dos Hormônios Gastrointestinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Receptors, Gastrointestinal Hormone); 0 (enhanced green fluorescent protein); 0 (secretin receptor); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170184


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[PMID]:28366809
[Au] Autor:Verma MK; Goel R; Nandakumar K; Nemmani KVS
[Ad] Endereço:Department of Pharmacology, Novel Drug Discovery and Development, Lupin Limited (Research Park), Pune 412115, Maharashtra, India. Electronic address: mahipverma@lupin.com.
[Ti] Título:Effect of D-Ala GIP, a stable GIP receptor agonist on MPTP-induced neuronal impairments in mice.
[So] Source:Eur J Pharmacol;804:38-45, 2017 Jun 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The aim of the present study was to evaluate the ability of D-Ala GIP, a gastric inhibitory polypeptide (GIP) receptor agonist, to attenuate the behavioral phenotype of Parkinson's disease caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice. In the behavioral studies, MPTP administration led to spontaneous locomotor activity deficits, impaired rotarod performance, akinesia, muscular rigidity and increased tremor amplitude, which was attenuated by pretreatment with D-Ala GIP (50-100 nmol/kg, i.p.). This acute neuroprotective response by D-Ala GIP was found to be blocked by a selective GIP receptor antagonist, (Pro )GIP (50 nmol/kg, i.p.), indicating that the observed effects are mediated through GIP receptor mediated signaling pathway. Biochemical studies revealed that D-Ala GIP reduced the brain malondialdehyde levels and enhanced the brain glutathione levels, thereby mitigating the MPTP-induced oxidative stress. MPTP administration resulted in reduction of the striatal concentration of dopamine and its metabolites, homovanillic acid (HVA) and 3, 4-Dihydroxyphenylacetic acid (DOPAC). Pretreatment with D-Ala GIP attenuated the loss of striatal dopamine levels without affecting the normal dopamine catabolism. Thus, the observed effects in the MPTP-induced Parkinsonism model could be in part attributable to the antioxidant properties of D-Ala GIP and enhanced turnover of dopamine in the nigrostriatal pathways in mouse brain. These findings together suggest that GIP receptor could be a therapeutic target in the management of symptoms of Parkinson's disease.
[Mh] Termos MeSH primário: 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia
Polipeptídeo Inibidor Gástrico/farmacologia
Neurônios/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
Receptores dos Hormônios Gastrointestinais/agonistas
[Mh] Termos MeSH secundário: Ácido 3,4-Di-Hidroxifenilacético/metabolismo
Animais
Dopamina/metabolismo
Polipeptídeo Inibidor Gástrico/química
Polipeptídeo Inibidor Gástrico/uso terapêutico
Glutationa/metabolismo
Ácido Homovanílico/metabolismo
Locomoção/efeitos dos fármacos
Masculino
Malondialdeído/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Neostriado/efeitos dos fármacos
Neostriado/metabolismo
Neostriado/patologia
Neurônios/metabolismo
Fármacos Neuroprotetores/uso terapêutico
Tremor/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neuroprotective Agents); 0 (Receptors, Gastrointestinal Hormone); 0 (gastric inhibitory polypeptide receptor); 102-32-9 (3,4-Dihydroxyphenylacetic Acid); 4Y8F71G49Q (Malondialdehyde); 59392-49-3 (Gastric Inhibitory Polypeptide); 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine); GAN16C9B8O (Glutathione); VTD58H1Z2X (Dopamine); X77S6GMS36 (Homovanillic Acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE


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[PMID]:28250160
[Au] Autor:Mantelmacher FD; Fishman S; Cohen K; Pasmanik Chor M; Yamada Y; Zvibel I; Varol C
[Ad] Endereço:The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
[Ti] Título:Glucose-Dependent Insulinotropic Polypeptide Receptor Deficiency Leads to Impaired Bone Marrow Hematopoiesis.
[So] Source:J Immunol;198(8):3089-3098, 2017 Apr 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The bone marrow (BM) contains controlled specialized microenvironments, or niches, that regulate the quiescence, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPC). The glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone that mediates postprandial insulin secretion and has anabolic effects on adipose tissue. Previous studies demonstrated altered bone microarchitecture in mice deficient for GIP receptor ( ), as well as the expression of high-affinity GIP receptor by distinct cells constructing the BM HSPC niche. Nevertheless, the involvement of GIP in the process of BM hematopoiesis remains elusive. In this article, we show significantly reduced representation and proliferation of HSPC and myeloid progenitors in the BM of mice. This was further manifested by reduced levels of BM and circulating differentiated immune cells in young and old adult mice. Moreover, GIP signaling was required for the establishment of supportive BM HSPC niches during HSPC repopulation in radioablated BM chimera mice. Finally, molecular profiling of various factors involved in retention, survival, and expansion of HSPC revealed significantly lower expression of the Notch-receptor ligands Jagged 1 and Jagged 2 in osteoblast-enriched bone extracts from mice, which are important for HSPC expansion. In addition, there was increased expression of CXCL12, a factor important for HSPC retention and quiescence, in whole-BM extracts from mice. Collectively, our data suggest that the metabolic hormone GIP plays an important role in BM hematopoiesis.
[Mh] Termos MeSH primário: Medula Óssea/metabolismo
Polipeptídeo Inibidor Gástrico/metabolismo
Hematopoese/fisiologia
Células-Tronco Hematopoéticas/citologia
Células-Tronco Hematopoéticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Citometria de Fluxo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Análise de Sequência com Séries de Oligonucleotídeos
Reação em Cadeia da Polimerase em Tempo Real
Receptores dos Hormônios Gastrointestinais/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Gastrointestinal Hormone); 0 (gastric inhibitory polypeptide receptor); 59392-49-3 (Gastric Inhibitory Polypeptide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601441


  8 / 1505 MEDLINE  
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[PMID]:28242309
[Au] Autor:Kitazawa T; Yoshida M; Teraoka H; Kaiya H
[Ad] Endereço:School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan. Electronic address: tko-kita@rakuno.ac.jp.
[Ti] Título:Does motilin peptide regulate gastrointestinal motility of zebrafish? An in vitro study using isolated intestinal strips.
[So] Source:Gen Comp Endocrinol;249:15-23, 2017 Aug 01.
[Is] ISSN:1095-6840
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Motilin (MOT), a 22-amino-acid peptide hormone produced in the duodenal mucosa, stimulates gastrointestinal motility in mammals and birds, and it is a mediator of interdigestive motor complexes. Recently, expression of MOT-like peptide (MOTLP) and its receptor mRNAs was identified in zebrafish. The aim of the present study was to determine whether the zebrafish MOTLP (zfMOTLP, HIAFFSPKEMRELREKE) affects zebrafish gastrointestinal motility, with comparison to the effect of human MOT, in which five amino acids are identical to zfMOTLP at positions 5, 9, 15, 16, and 17. zfMOTLP caused small contractions of the rabbit duodenum and chicken ileum but, the sensitivity was about 3000-times lower than that of human MOT. zfMOTLP-induced contraction in the rabbit duodenum was decreased by pretreatment of the MOT receptor antagonist GM109, indicating that zfMOTLP could bind to the MOT receptor. zfMOTLP (3-100nM) increased the intracellular Ca concentration in zfMOT receptor-expressing HEK293 cells, but human MOT did not cause responses even at 100nM. In in vitro study using isolated zebrafish gastrointestinal strips, zfMOTLP caused only small contractions even at high doses (1-10µM). zfMOT receptor mRNA is detected in the gastrointestinal tract and brain to almost the same extent, and the expression level (40-70 copies/100ng total RNA) is much lower than that in the chicken gastrointestinal tract. These results suggest that the MOTLP/MOT receptor system is present in zebrafish, but its physiological role for regulation of gastrointestinal motility might be not significant due to the weak contractile activity and low expression level of the receptor.
[Mh] Termos MeSH primário: Motilidade Gastrointestinal/fisiologia
Intestinos/fisiologia
Motilina/farmacologia
[Mh] Termos MeSH secundário: Animais
Galinhas
Motilidade Gastrointestinal/efeitos dos fármacos
Células HEK293
Seres Humanos
Técnicas In Vitro
Intestinos/efeitos dos fármacos
Masculino
Camundongos
Contração Muscular/efeitos dos fármacos
Peptídeos Cíclicos/farmacologia
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Coelhos
Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores
Receptores dos Hormônios Gastrointestinais/genética
Receptores dos Hormônios Gastrointestinais/metabolismo
Receptores de Neuropeptídeos/antagonistas & inibidores
Receptores de Neuropeptídeos/genética
Receptores de Neuropeptídeos/metabolismo
Transfecção
Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GM 109); 0 (Peptides, Cyclic); 0 (RNA, Messenger); 0 (Receptors, Gastrointestinal Hormone); 0 (Receptors, Neuropeptide); 0 (motilin receptor); 52906-92-0 (Motilin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE


  9 / 1505 MEDLINE  
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[PMID]:28237651
[Au] Autor:Sparre-Ulrich AH; Gabe MN; Gasbjerg LS; Christiansen CB; Svendsen B; Hartmann B; Holst JJ; Rosenkilde MM
[Ad] Endereço:Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Denmark.
[Ti] Título:GIP(3-30)NH is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release.
[So] Source:Biochem Pharmacol;131:78-88, 2017 May 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Alternative processing of the precursor protein pro-GIP results in endogenously produced GIP(1-30)NH , that by DPP-4 cleavage in vivo results in the metabolite GIP(3-30)NH . We showed previously that GIP(3-30)NH is a high affinity antagonist of the human GIPR in vitro. Here we determine whether it is suitable for studies of GIP physiology in rats since effects of GIP agonists and antagonists are strictly species-dependent. Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation or assayed in competition binding using human I-GIP(1-42) as radioligand. In isolated perfused rat pancreata, insulin, glucagon, and somatostatin-releasing properties were evaluated. Competition binding demonstrated that on the rat GIP receptor (GIPR), rat GIP(3-30)NH bound with high affinity (K of 17nM), in contrast to human GIP(3-30)NH (K of 250nM). In cAMP studies, rat GIP(3-30)NH inhibited GIP(1-42)-induced rat GIPR activation and schild-plot analysis showed competitive antagonism with a pA of 13nM and a slope of 0.9±0.09. Alone, rat GIP(3-30)NH displayed weak, low-potent partial agonistic properties (EC >1µM) with an efficacy of 9.4% at 0.32µM compared to GIP(1-42). In perfused rat pancreata, rat GIP(3-30)NH efficiently antagonized rat GIP(1-42)-induced insulin, somatostatin, and glucagon secretion. In summary, rat GIP(3-30)NH is a high affinity competitive GIPR antagonist and effectively antagonizes GIP-mediated G protein-signaling as well as pancreatic hormone release, while human GIP(3-30)NH , despite a difference of only one amino acid between the two (arginine in position 18 in rat GIP(3-30)NH ; histidine in human), is unsuitable in the rat system. This underlines the importance of species differences in the GIP system, and the limitations of testing human peptides in rodent systems.
[Mh] Termos MeSH primário: Polipeptídeo Inibidor Gástrico/fisiologia
Glucagon/secreção
Insulina/secreção
Fragmentos de Peptídeos/farmacologia
Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores
Somatostatina/secreção
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Células COS
Cercopithecus aethiops
Polipeptídeo Inibidor Gástrico/química
Polipeptídeo Inibidor Gástrico/farmacologia
Seres Humanos
Masculino
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/fisiologia
Ratos
Ratos Wistar
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Peptide Fragments); 0 (Receptors, Gastrointestinal Hormone); 0 (gastric inhibitory polypeptide (1-42)); 0 (gastric inhibitory polypeptide (3-30)-amide); 0 (gastric inhibitory polypeptide receptor); 51110-01-1 (Somatostatin); 59392-49-3 (Gastric Inhibitory Polypeptide); 9007-92-5 (Glucagon)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170227
[St] Status:MEDLINE


  10 / 1505 MEDLINE  
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[PMID]:28179449
[Au] Autor:Regazzo D; Losa M; Albiger NM; Terreni MR; Vazza G; Ceccato F; Emanuelli E; Denaro L; Scaroni C; Occhi G
[Ad] Endereço:Endocrinology DivisionDepartment of Medicine, Hospital/University of Padova, Padova, Italy.
[Ti] Título:The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of somatotropinomas.
[So] Source:Eur J Endocrinol;176(5):543-553, 2017 May.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Glucose-dependent insulinotropic polypeptide receptor ( ) overexpression has been recently described in a proportion of somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load. DESIGN AND METHODS: This study was aimed at linking the GIP/GIPR pathway to GH secretion in 25 somatotropinomas-derived primary cultures and correlating molecular with clinical features in acromegalic patients. Given the impairment of the GIP/GIPR axis in acromegaly, an additional aim was to assess the effect of GH/IGF-1 stimulation on GIP expression in the enteroendocrine cell line STC-1. RESULTS: Nearly 80% of -expressing somatotropinomas, all of them negative for mutations, show increased GH secretion upon GIP stimulation, higher sensitivity to Forskolin but not to somatostatin analogs. Besides increased frequency of GH-PI, overexpression does not appear to affect acromegalic patients' clinical features. In STC-1 cells transfected with GIP promoter-driven luciferase vector, IGF-1 but not GH induced dose-dependent increase in luciferase activity. CONCLUSIONS: We demonstrate that mediates the GH-PI in a significant proportion of acromegalic patients. In these cases, the stimulatory effect of IGF-1 on GIP promoter support the hypothesis of a functional GH/IGF-1/GIP axis. Further studies based on larger cohorts and the development of a stable transgenic model with inducible GIPR overexpression targeted to pituitary somatotroph lineage will be mandatory to establish the real role of GIPR in the pathogenesis of somatotropinomas.
[Mh] Termos MeSH primário: Polipeptídeo Inibidor Gástrico/genética
Polipeptídeo Inibidor Gástrico/metabolismo
Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética
Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo
Hormônio do Crescimento Humano/metabolismo
Neoplasias Hipofisárias/genética
Neoplasias Hipofisárias/metabolismo
Receptores dos Hormônios Gastrointestinais/genética
Receptores dos Hormônios Gastrointestinais/metabolismo
[Mh] Termos MeSH secundário: Acromegalia/genética
Acromegalia/metabolismo
Adolescente
Adulto
Idoso
Linhagem Celular
Linhagem da Célula/genética
Colforsina/farmacologia
DNA/genética
Feminino
Seres Humanos
Fator de Crescimento Insulin-Like I/metabolismo
Masculino
Meia-Idade
Cultura Primária de Células
Regiões Promotoras Genéticas/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Gastrointestinal Hormone); 0 (gastric inhibitory polypeptide receptor); 12629-01-5 (Human Growth Hormone); 1F7A44V6OU (Colforsin); 59392-49-3 (Gastric Inhibitory Polypeptide); 67763-96-6 (Insulin-Like Growth Factor I); 9007-49-2 (DNA)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170320
[Lr] Data última revisão:
170320
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-16-0831



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