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[PMID]:27721576
[Au] Autor:Niewiarowska-Sendo A; Kozik A; Guevara-Lora I
[Ad] Endereço:Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
[Ti] Título:Kinin Peptides Enhance Inflammatory and Oxidative Responses Promoting Apoptosis in a Parkinson's Disease Cellular Model.
[So] Source:Mediators Inflamm;2016:4567343, 2016.
[Is] ISSN:1466-1861
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kinin peptides ubiquitously occur in nervous tissue and participate in inflammatory processes associated with distinct neurological disorders. These substances have also been demonstrated to promote the oxidative stress. On the other hand, the importance of oxidative stress and inflammation has been emphasized in disorders that involve the neurodegenerative processes such as Parkinson's disease (PD). A growing number of reports have demonstrated the increased expression of kinin receptors in neurodegenerative diseases. In this study, the effect of bradykinin and des-Arg -kallidin, two representative kinin peptides, was analyzed with respect to inflammatory response and induction of oxidative stress in a PD cellular model, obtained after stimulation of differentiated SK-N-SH cells with a neurotoxin, 1-methyl-4-phenylpyridinium. Kinin peptides caused an increased cytokine release and enhanced production of reactive oxygen species and NO by cells. These changes were accompanied by a loss of cell viability and a greater activation of caspases involved in apoptosis progression. Moreover, the neurotoxin and kinin peptides altered the dopamine receptor 2 expression. Kinin receptor expression was also changed by the neurotoxin. These results suggest a mediatory role of kinin peptides in the development of neurodegeneration and may offer new possibilities for its regulation by using specific antagonists of kinin receptors.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Cininas/farmacologia
Doença de Parkinson/metabolismo
[Mh] Termos MeSH secundário: 1-Metil-4-fenilpiridínio/metabolismo
Apoptose/genética
Bradicinina/farmacologia
Diferenciação Celular/efeitos dos fármacos
Diferenciação Celular/genética
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Citocinas/farmacologia
Seres Humanos
Calidina/análogos & derivados
Calidina/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Kinins); 0 (Reactive Oxygen Species); 342-10-9 (Kallidin); 71800-36-7 (kallidin, des-Arg(10)-); R865A5OY8J (1-Methyl-4-phenylpyridinium); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161011
[St] Status:MEDLINE


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[PMID]:26769916
[Au] Autor:Kilstein Y; Nowak W; Errasti AE; Feás AA; Armesto AR; Pelorosso FG; Rothlin RP
[Ad] Endereço:Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
[Ti] Título:Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins.
[So] Source:J Pharmacol Exp Ther;357(1):114-24, 2016 Apr.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The upregulated kinin B1 receptors exert a pivotal role in modulating inflammatory processes. In isolated human umbilical veins (HUVs), kinin B1 receptor is upregulated as a function of in vitro incubation time and proinflammatory stimuli. The aim of this study was to evaluate, using functional and biochemical methods, the involvement of extracellular signal-regulated kinase 5 (ERK5), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) on the kinin B1 receptor upregulation process in HUV. Real-time polymerase chain reaction analysis revealed for the first time that kinin B1 receptor mRNA expression closely parallels the functional sensitization to kinin B1 receptor selective agonist des-Arg(10)-kallidin (DAKD) in HUV. Moreover, the selective inhibition of ERK5, p38 MAPK, and JNK, but not ERK1/2, produced a dose-dependent rightward shift of the concentration-response curves to DAKD after 5-hour incubation and a reduction in kinin B1 receptor mRNA expression. Biochemical analyses showed that ERK5, p38 MAPK, and JNK phosphorylation is maximal during the first 2 hours postisolation, followed by a significant reduction in the last 3 hours. None of the treatments modified the responses to serotonin, an unrelated agonist, suggesting a specific effect on kinin B1 receptor upregulation. The present work provides for the first time pharmacologic evidence indicating that ERK5 plays a significant role on kinin B1 receptor upregulation. Furthermore, we confirm the relevance of p38 MAPK and JNK as well as the lack of effect of ERK1/2 in this process. This study may contribute to a better understanding of MAPK involvement in inflammatory and immunologic diseases.
[Mh] Termos MeSH primário: Proteína Quinase 7 Ativada por Mitógeno/metabolismo
Receptor B1 da Bradicinina/metabolismo
Veias Umbilicais/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Janus Quinases/metabolismo
Calidina/análogos & derivados
Calidina/farmacologia
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Contração Muscular/efeitos dos fármacos
Músculo Liso Vascular/efeitos dos fármacos
Gravidez
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
Serotonina/farmacologia
Veias Umbilicais/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
Proteínas Quinases p38 Ativadas por Mitógeno/genética
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Receptor, Bradykinin B1); 333DO1RDJY (Serotonin); 342-10-9 (Kallidin); 71800-36-7 (kallidin, des-Arg(10)-); EC 2.7.10.2 (Janus Kinases); EC 2.7.11.24 (MAPK7 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:160315
[Lr] Data última revisão:
160315
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160116
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.115.230169


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[PMID]:25327836
[Au] Autor:Ribeiro AS; Fernandes VS; Martínez MP; López-Oliva ME; Barahona MV; Recio P; Martínez AC; Blaha I; Orensanz LM; Bustamante S; García-Sacristán A; Prieto D; Hernández M
[Ad] Endereço:Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
[Ti] Título:Pre- and post-junctional bradykinin B2 receptors regulate smooth muscle tension to the pig intravesical ureter.
[So] Source:Neurourol Urodyn;35(1):115-21, 2016 Jan.
[Is] ISSN:1520-6777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: Neuronal and non-neuronal bradykinin (BK) receptors regulate the contractility of the bladder urine outflow region. The current study investigates the role of BK receptors in the regulation of the smooth muscle contractility of the pig intravesical ureter. METHODS: Western blot and immunohistochemistry were used to show the expression of BK B1 and B2 receptors and myographs for isometric force recordings. RESULTS: B2 receptor expression was consistently detected in the intravesical ureter urothelium and smooth muscle layer, B1 expression was not detected where a strong B2 immunoreactivity was observed within nerve fibers among smooth muscle bundles. On ureteral strips basal tone, BK induced concentration-dependent contractions, were potently reduced by extracellular Ca(2+) removal and by B2 receptor and voltage-gated Ca(2+) (VOC) channel blockade. BK contraction did not change as a consequence of urothelium mechanical removal or cyclooxygenase and Rho-associated protein kinase inhibition. On 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2α (U46619)-precontracted samples, under non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent NANC conditions, electrical field stimulation-elicited frequency-dependent relaxations which were reduced by B2 receptor blockade. Kallidin, a B1 receptor agonist, failed to increase preparation basal tension or to induce relaxation on U46619-induced tone. CONCLUSIONS: The present results suggest that BK produces contraction of pig intravesical ureter via smooth muscle B2 receptors coupled to extracellular Ca(2+) entry mainly via VOC (L-type) channels. Facilitatory neuronal B2 receptors modulating NO-dependent or independent NANC inhibitory neurotransmission are also demonstrated.
[Mh] Termos MeSH primário: Contração Muscular/fisiologia
Músculo Liso/metabolismo
Receptor B2 da Bradicinina/metabolismo
Ureter/metabolismo
[Mh] Termos MeSH secundário: Animais
Bradicinina/farmacologia
Feminino
Calidina/farmacologia
Masculino
Contração Muscular/efeitos dos fármacos
Relaxamento Muscular/efeitos dos fármacos
Relaxamento Muscular/fisiologia
Músculo Liso/efeitos dos fármacos
Receptor B1 da Bradicinina/metabolismo
Suínos
Ureter/efeitos dos fármacos
Urotélio/efeitos dos fármacos
Urotélio/metabolismo
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptor, Bradykinin B1); 0 (Receptor, Bradykinin B2); 0 (Vasodilator Agents); 342-10-9 (Kallidin); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141021
[St] Status:MEDLINE
[do] DOI:10.1002/nau.22685


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[PMID]:27655927
[Au] Autor:Liu Y; Liu J; Li M; Dai S; Liang J; Ji W
[Ad] Endereço:Postgraduate Institute, Southern Medical University, Guangzhou 510015, People's Republic of China Department of Anesthesiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 96 DongChuan Road, Guangzhou 510080, People's Republic of China.
[Ti] Título:The Effect of Kinin B1 Receptor on Chronic Itching Sensitization.
[So] Source:Mol Pain;11, 2015 01.
[Is] ISSN:1744-8069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Altered kallikrein-related peptidase activity and bradykinin are associated with skin disorders in humans and mice under chronic inflammation conditions. The bradykinin B1 receptor (B1R), also known as one of the G-protein-coupled receptor family and usually absent in intact tissues and upregulated during tissue injury, is responsible for vasodilation, capillary permeability, nociceptor sensitization, and pain; it is indispensable for physiopathological progress in chronic inflammation conditions, but its roles and effectors in the itching sensation of the allergic contact dermatitis model are poorly defined. RESULTS: We focused on incurable itching in a diphenylcyclopropenone (DCP) chronic inflammation experimental model. Preventive treatment with the B1R antagonist R892 significantly suppressed spontaneous scratching, while the B2R selective antagonist did not. B1R expression in the skin tissues of this model was detected using a quantitative, real-time polymerase chain reaction, Western blotting, and immunohistochemistry; B1R mRNA and protein levels were increased compared with a sham-treated control group. A higher B1R IHC staining signal was observed in the keratinocytes in DCP-treated mice compared with a vehicle-treated group, so we studied the B1R function when superimposed on a protease-activated receptor 2 (PAR2) background, establishing B1R as a pivotal mediator of PAR2 function in HaCaT cell lines. CONCLUSION: Our data provide evidence that B1R facilitates the chronic itching sensation related to keratinocytes in a DCP-treated chronic inflammation experimental model.
[Mh] Termos MeSH primário: Prurido/metabolismo
Prurido/patologia
Receptor B1 da Bradicinina/metabolismo
[Mh] Termos MeSH secundário: Animais
Bradicinina/análogos & derivados
Bradicinina/uso terapêutico
Antagonistas de Receptor B1 da Bradicinina/farmacologia
Antagonistas de Receptor B1 da Bradicinina/uso terapêutico
Linhagem Celular Transformada
Doença Crônica
Ciclopropanos/toxicidade
Modelos Animais de Doenças
Inibidores Enzimáticos/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Calidina/análogos & derivados
Calidina/farmacologia
Calidina/uso terapêutico
Queratinócitos/efeitos dos fármacos
Queratinócitos/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Oligopeptídeos/farmacologia
Prurido/induzido quimicamente
Prurido/prevenção & controle
Pirrolidinas/farmacologia
Receptor B1 da Bradicinina/genética
Transdução de Sinais/efeitos dos fármacos
Tiocarbamatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bradykinin B1 Receptor Antagonists); 0 (Cyclopropanes); 0 (Enzyme Inhibitors); 0 (JMV 1116); 0 (Oligopeptides); 0 (Pyrrolidines); 0 (Receptor, Bradykinin B1); 0 (Thiocarbamates); 0 (seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide); 25769-03-3 (pyrrolidine dithiocarbamic acid); 342-10-9 (Kallidin); 71800-36-7 (kallidin, des-Arg(10)-); I7G14NW5EC (diphenylcyclopropenone); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171127
[Lr] Data última revisão:
171127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE


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[PMID]:26338700
[Au] Autor:Mejia AJ; Matus CE; Pavicic F; Concha M; Ehrenfeld P; Figueroa CD
[Ad] Endereço:Laboratorio de Patologia Celular, Instituto de Anatomia, Histologia y Patologia, Universidad Austral de Chile, Isla Teja, PO Box 567, Valdivia, Chile.
[Ti] Título:Intracellular signaling pathways involved in the release of IL-4 and VEGF from human keratinocytes by activation of kinin B1 receptor: functional relevance to angiogenesis.
[So] Source:Arch Dermatol Res;307(9):803-17, 2015 Nov.
[Is] ISSN:1432-069X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The injured skin produces a number of mediators that directly or indirectly modulate cell chemotaxis, migration, proliferation, and angiogenesis. Components of the kinin pathway including the kinin B1 receptor (B1R) have been found to occur in the human skin, but information about its role on keratinocyte biology is still scarce. Our aim was to determine whether stimulation of B1R causes the secretion of IL-4 and/or VEGF from human keratinocytes and to evaluate the role of the B1R agonist Lys-des[Arg(9)]bradykinin and IL-4 on various stages of angiogenesis, such as cell migration, proliferation, and release of metalloproteases. By using ELISA and Western blotting, we showed that HaCaT keratinocytes stimulated with the B1R agonist release IL-4 and VEGF. Stimulation of B1R also caused transient c-JunN-terminal kinase phosphorylation and JunB nuclear translocation, transcription factor that regulates IL-4 expression. The 3D-angiogenesis assay, performed on spheroids of EA.hy923 endothelial cells embedded in a collagen matrix, showed that their cumulative sprout area increased significantly following stimulation with either IL-4 or B1R agonist. Furthermore, these ligands produced significant endothelial cell migration and release of metalloproteases 2 and 9, but did not increase endothelial cell proliferation as measured by 5-bromo-2'-deoxyuridine incorporation. Our results provide experimental evidence that establishes IL-4 and B1R agonist as important angiogenic factors of relevance for skin repair.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Interleucina-4/farmacologia
Interleucina-4/secreção
Queratinócitos/metabolismo
Neovascularização Fisiológica/fisiologia
Receptor B1 da Bradicinina/metabolismo
Fator A de Crescimento do Endotélio Vascular/secreção
[Mh] Termos MeSH secundário: Proteínas Angiogênicas/farmacologia
Linhagem Celular
Movimento Celular
Proliferação Celular
Meios de Cultivo Condicionados/farmacologia
Ativação Enzimática
Seres Humanos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Calidina/análogos & derivados
Calidina/farmacologia
Queratinócitos/secreção
Metaloproteinase 2 da Matriz/secreção
Metaloproteinase 9 da Matriz/secreção
Fosforilação
Proteínas Proto-Oncogênicas c-jun
Interferência de RNA
RNA Interferente Pequeno/genética
Receptor B1 da Bradicinina/agonistas
Receptor B1 da Bradicinina/genética
Transdução de Sinais/fisiologia
Pele/citologia
Pele/metabolismo
Esferoides Celulares
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Angiogenic Proteins); 0 (Culture Media, Conditioned); 0 (IL4 protein, human); 0 (Proto-Oncogene Proteins c-jun); 0 (RNA, Small Interfering); 0 (Receptor, Bradykinin B1); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 207137-56-2 (Interleukin-4); 342-10-9 (Kallidin); 71800-36-7 (kallidin, des-Arg(10)-); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 3.4.24.24 (MMP2 protein, human); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:151027
[Lr] Data última revisão:
151027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150905
[St] Status:MEDLINE
[do] DOI:10.1007/s00403-015-1595-6


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[PMID]:26101793
[Au] Autor:Amouroux G; Pan J; Jenni S; Zhang C; Zhang Z; Hundal-Jabal N; Colpo N; Liu Z; Bénard F; Lin KS
[Ad] Endereço:†Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
[Ti] Título:Imaging Bradykinin B1 Receptor with 68Ga-Labeled [des-Arg10]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake.
[So] Source:Mol Pharm;12(8):2879-88, 2015 Aug 03.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bradykinin B1 receptor (B1R) that is overexpressed in cancers but minimally expressed in normal healthy tissues represents an attractive biomarker for the development of cancer imaging agents. The goal of this study was to evaluate the effect of different linkers on the pharmacokinetics and tumor uptake of a B1R-targeting radio-peptide sequence, 68Ga-DOTA-linker-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu. Four peptides, SH01078, P03034, P04115, and P04168, with 6-aminohexanoic acid, 9-amino-4,7-dioxanonanoic acid, Gly-Gly, and 4-amino-(1-carboxymethyl)piperidine, respectively, as the linker were synthesized and evaluated. In vitro competition binding assays showed that the Ki values of SH01078, P03034, P04115, and P04168 were 27.8±4.9, 16.0±1.9, 11.4±2.5, and 3.6±0.2 nM, respectively. Imaging and biodistribution studies were performed in mice bearing both B1R-positive HEK293T::hB1R and B1R-negative HEK293T tumors. All tracers showed mainly renal excretion with excellent tumor visualization and minimal background activity except for kidneys and bladder. The average uptake of 68Ga-labeled SH01078, P03034, and P04115 in HEK293T::hB1R tumor was similar (1.96-2.17%ID/g) at 1 h postinjection. 68Ga-P04168 generated higher HEK293T::hB1R tumor uptake (4.15±1.13%ID/g) and lower background activity, leading to a >2-fold improvement in HEK293T::hB1R tumor-to-background (HEK293T tumor, blood, muscle, and liver) contrasts over those of 68Ga-labeled SH01078, P03034, and P04115. Our results indicate that the choice of linker affects binding affinity, pharmacokinetics, and tumor targeting. The use of the cationic 4-amino-(1-carboxymethyl)piperidine linker improved tumor visualization, and the resulting 68Ga-P04168 might be promising for clinical application for imaging B1R-expressing tumors with positron emission tomography.
[Mh] Termos MeSH primário: Radioisótopos de Gálio/farmacocinética
Calidina/análogos & derivados
Neoplasias/metabolismo
Neoplasias/patologia
Tomografia por Emissão de Pósitrons/métodos
Compostos Radiofarmacêuticos/farmacocinética
Receptor B1 da Bradicinina/metabolismo
[Mh] Termos MeSH secundário: Animais
Meios de Contraste/farmacocinética
Células HEK293
Seres Humanos
Processamento de Imagem Assistida por Computador
Calidina/química
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Neoplasias/diagnóstico por imagem
Fragmentos de Peptídeos/farmacocinética
Receptores de Interleucina-2/fisiologia
Distribuição Tecidual
Tomografia Computadorizada por Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Contrast Media); 0 (Gallium Radioisotopes); 0 (Peptide Fragments); 0 (Radiopharmaceuticals); 0 (Receptor, Bradykinin B1); 0 (Receptors, Interleukin-2); 342-10-9 (Kallidin); 71800-36-7 (kallidin, des-Arg(10)-)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150624
[St] Status:MEDLINE
[do] DOI:10.1021/acs.molpharmaceut.5b00070


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[PMID]:25745086
[Au] Autor:Lin KS; Amouroux G; Pan J; Zhang Z; Jenni S; Lau J; Liu Z; Hundal-Jabal N; Colpo N; Bénard F
[Ad] Endereço:Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada; and.
[Ti] Título:Comparative studies of three 68Ga-labeled [Des-Arg10]kallidin derivatives for imaging bradykinin B1 receptor expression with PET.
[So] Source:J Nucl Med;56(4):622-7, 2015 Apr.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Bradykinin B1 receptor (B1R) is a G-protein-coupled receptor that is overexpressed in a variety of cancers. B1R is not expressed in healthy tissues, making it an attractive cancer imaging marker. Previously, we reported selective uptake of (68)Ga-P03034 ((68)Ga-DOTA-dPEG2-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu) in B1R-positive (B1R+) HEK293T::hB1R tumor xenografts in mice. In this study, we compare (68)Ga-P03034 with (68)Ga-labeled P04158 ((68)Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic) and Z02090 ((68)Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg) derived from 2 potent B1R antagonists, B9858 and B9958, respectively, for imaging B1R expression with PET. METHODS: Peptide sequences were assembled on solid-phase. Cold standards were prepared by incubating DOTA-conjugated peptides with GaCl3. Binding affinity was measured via competition binding assays using hB1R-expressing Chinese hamster ovary-K1 cell membranes. (68)Ga labeling was performed in N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) buffer with microwave heating and purified by high-performance liquid chromatography. Imaging/biodistribution studies were performed in mice bearing wild-type HEK293T (B1R-) and B1R+ HEK293T::hB1R tumors. RESULTS: P03034, P04158, and Z02090 bound B1R with high affinity, with Ki values at 16.0 ± 2.9, 1.5 ± 1.9, and 1.1 ± 0.8 nM, respectively. (68)Ga-labeled P03034, P04159, and Z02090 were obtained in greater than 50% decay-corrected radiochemical yields with more than 99% radiochemical purity. Biodistribution studies showed that all three (68)Ga-labeled tracers cleared rapidly from the blood and normal tissues, with excretion mainly via the renal pathway. At 1 h after injection, only the kidneys, bladders, and B1R+ HEK293T::hB1R tumors were clearly visualized in PET images. Uptake values of (68)Ga-labeled P03034, P04158, and Z02090 in B1R+ tumors were 2.17 ± 0.49, 19.6 ± 4.50, and 14.4 ± 1.63 percentage injected dose per gram, respectively. Uptake ratios of B1R+ to B1R- tumor, blood, and muscle were 6.23 ± 1.69, 5.72 ± 2.20, and 25.5 ± 13.1 for (68)Ga-P03034; 34.5 ± 10.5, 19.2 ± 8.21, and 66.1 ± 17.0 for (68)Ga-P04158; and 29.3 ± 9.68, 29.9 ± 5.58, and 124 ± 28.1 for (68)Ga-Z02090, respectively. CONCLUSION: All three (68)Ga-labeled B1R-targeting peptides generated specific and high-contrasted images of B1R+ tumors xenografted in mice. With significantly higher tumor uptake and target-to-nontarget ratios, (68)Ga-labeled P04158 and Z02090 are superior to P03034 for imaging B1R expression with PET.
[Mh] Termos MeSH primário: Meios de Contraste
Radioisótopos de Gálio
Calidina/análogos & derivados
Tomografia por Emissão de Pósitrons/métodos
Receptor B1 da Bradicinina/metabolismo
[Mh] Termos MeSH secundário: Animais
Células CHO
Meios de Contraste/química
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Calidina/química
Masculino
Camundongos
Camundongos SCID
Transplante de Neoplasias
Peptídeos/química
Tomografia Computadorizada por Raios X
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Contrast Media); 0 (Gallium Radioisotopes); 0 (Peptides); 0 (Receptor, Bradykinin B1); 342-10-9 (Kallidin); 71800-36-7 (kallidin, des-Arg(10)-)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150307
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.114.152132


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[PMID]:25629412
[Au] Autor:Liu Z; Amouroux G; Zhang Z; Pan J; Hundal-Jabal N; Colpo N; Lau J; Perrin DM; Bénard F; Lin KS
[Ad] Endereço:Chemistry Department, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
[Ti] Título:(18)F-trifluoroborate derivatives of [des-arg(10)]kallidin for imaging bradykinin b1 receptor expression with positron emission tomography.
[So] Source:Mol Pharm;12(3):974-82, 2015 Mar 02.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bradykinin B1 receptor (B1R) is involved in pain and inflammation pathways and is upregulated in inflamed tissues and cancer. Due to its minimal expression in healthy tissues, B1R is an attractive target for the development of therapeutic agents to treat inflammation, chronic pain, and cancer. The goal of this study is to synthesize and compare two (18)F-labeled peptides derived from potent B1R antagonists B9858 and B9958 for imaging B1R expression with positron emission tomography (PET). Azidoacetyl-B9858 2 and azidoacetyl-B9958 3 were synthesized by a solid-phase approach and subsequently clicked to ammoniomethyl-trifluoroborate (AmBF3)-conjugated alkyne 1 to obtain AmBF3-B9858 and AmBF3-B9958, respectively. AmBF3-B9858 and AmBF3-B9958 bound B1R with high affinity, with Ki values at 0.09 ± 0.08 and 0.46 ± 0.03 nM, respectively, as measured by in vitro competition binding assays. (18)F labeling was performed via an (18)F-(19)F isotope exchange reaction. The radiofluorinated tracers were obtained within a synthesis time of 30 min and with 23-32% non-decay-corrected radiochemical yield, >99% radiochemical purity, and 43-87 GBq/µmol specific activity at the end of the synthesis. PET imaging and biodistribution studies were carried out in mice bearing both B1R-positive (B1R(+)) HEK293T::hB1R and B1R-negative (B1R(-)) HEK293T tumors. Both tracers cleared rapidly from most organs/tissues, mainly through the renal pathway. High uptake in B1R(+) tumors ((18)F-AmBF3-B9858: 3.94 ± 1.24% ID/g, tumor-to-muscle ratio 21.3 ± 4.33; (18)F-AmBF3-B9958: 4.20 ± 0.98% ID/g, tumor-to-muscle ratio 48.6 ± 10.7) was observed at 1 h postinjection. These results indicate that (18)F-AmBF3-B9858 and (18)F-AmBF3-B9958 are promising agents for the in vivo imaging of B1R expression with PET.
[Mh] Termos MeSH primário: Calidina/análogos & derivados
Receptor B1 da Bradicinina/metabolismo
[Mh] Termos MeSH secundário: Animais
Biofarmácia
Boratos
Bradicinina/análogos & derivados
Bradicinina/síntese química
Bradicinina/química
Antagonistas de Receptor B1 da Bradicinina/síntese química
Antagonistas de Receptor B1 da Bradicinina/química
Estabilidade de Medicamentos
Radioisótopos de Flúor
Células HEK293
Seres Humanos
Calidina/síntese química
Calidina/química
Masculino
Camundongos
Camundongos Knockout
Neoplasias Experimentais/diagnóstico por imagem
Tomografia por Emissão de Pósitrons
Compostos Radiofarmacêuticos
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (B 9858); 0 (Borates); 0 (Bradykinin B1 Receptor Antagonists); 0 (Fluorine Radioisotopes); 0 (Radiopharmaceuticals); 0 (Receptor, Bradykinin B1); 342-10-9 (Kallidin); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150129
[St] Status:MEDLINE
[do] DOI:10.1021/acs.molpharmaceut.5b00003


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[PMID]:25563717
[Au] Autor:Lizama AJ; Andrade Y; Colivoro P; Sarmiento J; Matus CE; Gonzalez CB; Bhoola KD; Ehrenfeld P; Figueroa CD
[Ad] Endereço:Laboratorio de Patologia Celular, Instituto de Anatomia, Histologia y Patologia, Universidad Austral de Chile, Valdivia, Chile.
[Ti] Título:Expression and bioregulation of the kallikrein-related peptidases family in the human neutrophil.
[So] Source:Innate Immun;21(6):575-86, 2015 Aug.
[Is] ISSN:1753-4267
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The family of kallikrein-related peptidases (KLKs) has been identified in a variety of immunolabeled human tissue sections, but no previous study has experimentally confirmed their presence in the human neutrophil. We have investigated the expression and bioregulation of particular KLKs in the human neutrophil and, in addition, examined whether stimulation by a kinin B(1) receptor (B1R) agonist or fMet-Leu-Phe (fMLP) induces their secretion. Western blot analysis of neutrophil homogenates indicated that the MM of the KLKs ranged from 27 to 50 kDa. RT-PCR showed that blood neutrophils expressed only KLK1, KLK4, KLK10, KLK13, KLK14 and KLK15 mRNAs, whereas the non-differentiated HL-60 cells expressed most of them, with exception of KLK3 and KLK7. Nevertheless, mRNAs for KLK2, KLK5, KLK6 and KLK9 that were previously undetectable appeared after challenging with a mixture of cytokines. Both kinin B(1)R agonist and fMLP induced secretion of KLK1, KLK6, KLK10, KLK13 and KLK14 into the culture medium in similar amounts, whereas the B(1)R agonist caused the release of lower amounts of KLK2, KLK4 and KLK5. When secreted, the differing proteolytic activity of KLKs provides the human neutrophil with a multifunctional enzymatic capacity supporting a new dimension for its role in human disorders of diverse etiology.
[Mh] Termos MeSH primário: Neutrófilos/metabolismo
Calicreínas Teciduais/metabolismo
[Mh] Termos MeSH secundário: Adulto
Linhagem Celular
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Calidina/análogos & derivados
Calidina/farmacologia
Masculino
Meia-Idade
N-Formilmetionina Leucil-Fenilalanina/farmacologia
Neutrófilos/efeitos dos fármacos
Neutrófilos/imunologia
Proteólise/efeitos dos fármacos
RNA Mensageiro/genética
Receptor B1 da Bradicinina/agonistas
Calicreínas Teciduais/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Receptor, Bradykinin B1); 342-10-9 (Kallidin); 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine); 71800-36-7 (kallidin, des-Arg(10)-); EC 3.4.21.35 (Tissue Kallikreins)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:150701
[Lr] Data última revisão:
150701
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150108
[St] Status:MEDLINE
[do] DOI:10.1177/1753425914566083


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[PMID]:24894913
[Au] Autor:Hallberg M
[Ad] Endereço:Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, Uppsala University, Biomedical Center, Uppsala, Sweden.
[Ti] Título:Neuropeptides: metabolism to bioactive fragments and the pharmacology of their receptors.
[So] Source:Med Res Rev;35(3):464-519, 2015 May.
[Is] ISSN:1098-1128
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.
[Mh] Termos MeSH primário: Neuropeptídeos/química
Peptidomiméticos/química
[Mh] Termos MeSH secundário: Analgésicos Opioides/química
Angiotensina II/metabolismo
Angiotensinas/metabolismo
Animais
Bradicinina/metabolismo
Seres Humanos
Calidina/metabolismo
Ligantes
Camundongos
Neuropeptídeo Y/metabolismo
Nociceptividade
Peptídeos Opioides/química
Fragmentos de Peptídeos
Peptídeos
Receptores de Neuropeptídeos/metabolismo
Receptores Opioides/metabolismo
Taquicininas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Angiotensins); 0 (Ligands); 0 (Neuropeptide Y); 0 (Neuropeptides); 0 (Opioid Peptides); 0 (Peptide Fragments); 0 (Peptides); 0 (Peptidomimetics); 0 (Receptors, Neuropeptide); 0 (Receptors, Opioid); 0 (Tachykinins); 11128-99-7 (Angiotensin II); 342-10-9 (Kallidin); 7AYI9N34FF (nociceptin); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140605
[St] Status:MEDLINE
[do] DOI:10.1002/med.21323



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