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1.
Acta Biomater ; 78: 178-188, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30076991

RESUMO

Protein/peptide fibrillation is an important challenge for biotechnological drug development. Salmon calcitonin (sCT) is currently used in the clinical treatment of bone-related diseases such as osteoporosis and hypercalcemia, but it still has the risk of immune responses. Although human calcitonin (hCT) would be a better choice in terms of immunogenicity, it has a strong tendency to irreversibly aggregate in aqueous solutions and form long amyloid fibrils, which significantly reduces its bioavailability and therapeutic potency. Here, we demonstrate that cucurbit[7]uril (CB[7]) can inhibit hCT fibrillation by supramolecular interaction with its aromatic groups (affinity: Phe16 > Tyr12 > Phe19 > Phe22). The hCT-CB[7] complex exhibits low cytotoxicity, even promotes osteoblast proliferation and osteogenic capacity of MC3T3 cells. Meanwhile the hCT-CB[7] complexes shows higher bioactivity compared to hCT in reducing blood calcium levels in rats, and also decreases the immunogenicity of hCT. These results suggest that CB[7] has the potential to improve the therapeutic potency of amyloidogenic protein/peptide drugs such as hCT.


Assuntos
Amiloide/antagonistas & inibidores , Materiais Biocompatíveis/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Calcitonina/antagonistas & inibidores , Imidazóis/farmacologia , Fosfatase Alcalina/metabolismo , Sequência de Aminoácidos , Animais , Calcitonina/química , Calcitonina/metabolismo , Cálcio/sangue , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imunoglobulina G/metabolismo , Cinética , Masculino , Camundongos Endogâmicos C57BL , Conformação Proteica , Ratos Sprague-Dawley
2.
Life Sci ; 198: 1-7, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29432759

RESUMO

Bisphenol A (BPA) (2,2,-bis (hydroxyphenyl) propane), a well-known endocrine disruptor (ED), is the exogenous chemical that mimic the natural endogenous hormone like oestrogen. Due to its extensive exposure to humans, BPA is considered to be a major toxicological agent for general population. Environmental exposure of BPA results in adverse health outcomes including bone loss. BPA disturbs the bone health by decreasing the plasma calcium level and inhibiting the calcitonin secretion. BPA also stimulated differentiation and induced apoptosis in human osteoblasts and osteoclasts. However, little is known about the underlying mechanisms of the untoward effect of BPA against bone metabolism. The present review gives an overview on the possible mechanisms of BPA towards bone loss. The previous literature shows that BPA exerts its toxic effect on bone cells by binding to the oestrogen related receptor-gamma (ERγ), reducing the bone morphogenic protein-2 (BMP-2) and alkaline phosphatase (ALP) activities. BPA interrupts the bone metabolism via RANKL, apoptosis and Wnt/ß-catenin signaling pathways. It is, however, still debated on the exact underlying mechanism of BPA against bone health. We summarised the molecular evidences with possible mechanisms of BPA, an old environmental culprit, in bone loss and enlightened the underlying understanding of adverse action of BPA in the society.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Osso e Ossos/efeitos dos fármacos , Fenóis/efeitos adversos , Fosfatase Alcalina/metabolismo , Animais , Apoptose , Proteína Morfogenética Óssea 2/metabolismo , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Calcitonina/antagonistas & inibidores , Cálcio/sangue , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/efeitos adversos , Humanos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
3.
Rev Neurol ; 61 Suppl 1: S3-7, 2015.
Artigo em Espanhol | MEDLINE | ID: mdl-26337644

RESUMO

Chronic migraine is a disease that affects 0.5-2.5% of the population, depending on the statistics that are analysed and the definition of chronic migraine that is used. It is extraordinarily disabling, since it does not allow the sufferer to carry out any of their scheduled personal, professional or social activities, and it has a great impact on the patients' quality of life, as measured on disability, quality of life and impact on daily activities scales. Yet, nowadays there are treatments that have proven to be effective in cases of chronic migraine, such as OnabotulinumtoxinA. It is a treatment that is well tolerated and with a high rate of efficacy. Yet it is not only a therapeutic tool, but in the world of headaches it has also opened up the doors to invasive treatments, to the learning of techniques and, in short, to placing headaches in referral units that are usually located in tertiary care hospitals. Furthermore, it has also helped to overcome the idea that patients with headache should be visited exclusively by primary care physicians or general neurologists. This is an opportunity to redefine the field of study and the care for headaches that must be seized. In the future, this is going to be complemented by novel treatments with neurostimulation and probably with monoclonal antibodies against the calcitonin gene-related peptide. A revolution has begun in our knowledge and capacity to act. It is our duty to give it the importance and usage it deserves both for our patients and for us as specialists.


Assuntos
Inibidores da Liberação da Acetilcolina/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Transtornos da Cefaleia/terapia , Unidades Hospitalares , Neurologia/organização & administração , Terapias em Estudo , Anticorpos Monoclonais/uso terapêutico , Calcitonina/antagonistas & inibidores , Cefaleia Histamínica/tratamento farmacológico , Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/prevenção & controle , Cefaleia Histamínica/terapia , Terapia por Estimulação Elétrica , Previsões , Frutose/análogos & derivados , Frutose/uso terapêutico , Transtornos da Cefaleia/tratamento farmacológico , Transtornos da Cefaleia/epidemiologia , Transtornos da Cefaleia/prevenção & controle , Unidades Hospitalares/provisão & distribução , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/prevenção & controle , Transtornos de Enxaqueca/terapia , Bloqueio Nervoso , Neuralgia/tratamento farmacológico , Neuralgia/epidemiologia , Neuralgia/prevenção & controle , Neuralgia/terapia , Prevalência , Precursores de Proteínas/antagonistas & inibidores , Espanha/epidemiologia , Topiramato , Estados Unidos/epidemiologia
4.
Neuropsychopharmacology ; 38(9): 1685-97, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23474592

RESUMO

The ability of amylin, a pancreatic ß-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward. Direct activation of VTA amylin receptors reduces the intake of chow and palatable sucrose solution in rats. This effect is mediated by reductions in meal size and is not due to nausea/malaise or prolonged suppression of locomotor activity. VTA amylin receptor activation also reduces sucrose self-administration on a progressive ratio schedule. Finally, antagonist studies provide novel evidence that VTA amylin receptor blockade increases food intake and attenuates the intake-suppressive effects of a peripherally administered amylin analog, suggesting that amylin receptor signaling in the VTA is physiologically relevant for food intake control and potentially clinically relevant for the treatment of obesity.


Assuntos
Ingestão de Alimentos/fisiologia , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/fisiologia , Área Tegmentar Ventral/fisiologia , Agonistas dos Receptores da Amilina , Animais , Calcitonina/administração & dosagem , Calcitonina/antagonistas & inibidores , Calcitonina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Náusea/induzido quimicamente , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/metabolismo , Ratos , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/antagonistas & inibidores , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Esquema de Reforço , Recompensa , Autoadministração , Sacarose/administração & dosagem , Sacarose/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos
5.
Bull Exp Biol Med ; 152(5): 553-9, 2012 Mar.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-22803131

RESUMO

We studied the effect of Russian preparation of porcine calcitonin (calcitrin, 1 U/100 g) and blockers of Ca(2+) channels nifedipine (1 mg/kg, blocker of chemosensitive Ca(2+) channels) and isoptin (5 mg/kg, blocker of voltage-dependent Ca(2+) channels) on glucose metabolism. Calcitonin produced a pronounced hyperglycemic effect in rats. A close negative correlation was found between glucose level and total calcium content. Injection of calcitonin reduced glucose tolerance in rats. Isoptin and nifedipine reduced plasma calcium level and did not affect significantly the blood glucose levels, did not change the pattern of alimentary hyperglycemia in response to glucose load, completely abolished the hyperglycemic effect of calcitonin, and prevented calcitonin-induced impairment of glucose tolerance.


Assuntos
Conservadores da Densidade Óssea/antagonistas & inibidores , Calcitonina/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hiperglicemia/prevenção & controle , Nifedipino/uso terapêutico , Verapamil/uso terapêutico , Animais , Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Cálcio/sangue , Bloqueadores dos Canais de Cálcio/farmacologia , Glucose/metabolismo , Teste de Tolerância a Glucose , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Masculino , Nifedipino/farmacologia , Ratos , Ratos Wistar , Suínos , Verapamil/farmacologia
6.
Nat Med ; 18(8): 1205-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22842475

RESUMO

Pressure-induced vasodilation (PIV) delays the decrease in cutaneous blood flow produced by local application of low pressure to the skin, a physiologically appropriate adjustment of local vasomotor function. Individuals without a normal PIV response have a high risk of ulceration. Here we demonstrate that acid-sensing ion channel 3 (Asic3) is an essential neuronal sensor for the vasodilation response to direct pressure in both humans and rodents and for protecting against pressure ulcers in mice.


Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Hiperemia/fisiopatologia , Mecanorreceptores/fisiologia , Lesão por Pressão/fisiopatologia , Pele/irrigação sanguínea , Vasodilatação/fisiologia , Canais Iônicos Sensíveis a Ácido/deficiência , Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Canais Iônicos Sensíveis a Ácido/genética , Adulto , Amilorida/farmacologia , Animais , Calcitonina/antagonistas & inibidores , Venenos de Cnidários/farmacologia , Diclofenaco/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Dedos/irrigação sanguínea , Humanos , Isquemia/etiologia , Isquemia/fisiopatologia , Masculino , Mecanorreceptores/efeitos dos fármacos , Camundongos , Camundongos Knockout , Pressão/efeitos adversos , Lesão por Pressão/etiologia , Lesão por Pressão/prevenção & controle , Precursores de Proteínas/antagonistas & inibidores , Distribuição Aleatória , Ratos , Ratos Wistar , Método Simples-Cego , Adulto Jovem
8.
Crit Care ; 14(6): 1007, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21138601

RESUMO

In inflammatory states, particularly in response to infectious stimuli, local procalcitonin (PCT) production rises, and because these tissues cannot further process PCT into calcitonin, serum levels increase. In the critical care setting, PCT should be considered a useful tool to help physicians in some specific, although frequent, situations. Serial measurements of PCT levels may indicate the effectiveness of medical decisions such as the appropriateness of antibiotic therapy, the detection of new infections, and the exclusion of a diagnosis of sepsis. PCT-guided algorithms may also help to decrease the duration of antimicrobial therapy. However, the role of PCT as a prognostic marker in critically ill patients is controversial. In a study by Karlsson and colleagues, PCT concentrations did not differ between hospital survivors and nonsurvivors, but the outcome was better in patients whose PCT concentrations decreased more than 50%. The study of PCT kinetics thus could offer an individual risk assessment in patients with severe sepsis.


Assuntos
Calcitonina/antagonistas & inibidores , Precursores de Proteínas/antagonistas & inibidores , Sepse/sangue , Sepse/diagnóstico , Peptídeo Relacionado com Gene de Calcitonina , Feminino , Humanos , Masculino
9.
Crit Care ; 14(6): R205, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21078153

RESUMO

INTRODUCTION: This prospective study investigated the predictive value of procalcitonin (PCT) for survival in 242 adult patients with severe sepsis and septic shock treated in intensive care. METHODS: PCT was analyzed from blood samples of all patients at baseline, and 155 patients 72 hours later. RESULTS: The median PCT serum concentration on day 0 was 5.0 ng/ml (interquartile range (IQR) 1.0 and 20.1 ng/ml) and 1.3 ng/ml (IQR 0.5 and 5.8 ng/ml) 72 hours later. Hospital mortality was 25.6% (62/242). Median PCT concentrations in patients with community-acquired infections were higher than with nosocomial infections (P = 0.001). Blood cultures were positive in 28.5% of patients (n = 69), and severe sepsis with positive blood cultures was associated with higher PCT levels than with negative cultures (P = < 0.001). Patients with septic shock had higher PCT concentrations than patients without (P = 0.02). PCT concentrations did not differ between hospital survivors and nonsurvivors (P = 0.64 and P = 0.99, respectively), but mortality was lower in patients whose PCT concentration decreased > 50% (by 72 hours) compared to those with a < 50% decrease (12.2% vs. 29.8%, P = 0.007). CONCLUSIONS: PCT concentrations were higher in more severe forms of severe sepsis, but a substantial concentration decrease was more important for survival than absolute values.


Assuntos
Calcitonina/antagonistas & inibidores , Precursores de Proteínas/antagonistas & inibidores , Sepse/sangue , Sepse/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina , Estudos de Coortes , Feminino , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Precursores de Proteínas/sangue , Sepse/mortalidade , Índice de Gravidade de Doença
10.
IDrugs ; 10(8): 566-74, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17665333

RESUMO

Olcegepant is the first potent and selective non-peptide antagonist of the calcitonin gene-related peptide 1 (CGRP1) receptor, a key modulator in neurogenic inflammatory pain. Under development by Boehringer Ingelheim GmbH, olcegepant is an intravenously formulated treatment for acute attacks of migraine. In preclinical studies, olcegepant attenuated arterial dilation induced by CGRP or electrical stimulation. In a phase II clinical trial, olcegepant reduced the severity of headache in 60% of migraine sufferers and met secondary endpoints including headache-free rate and rate of sustained response. Only mild-to-moderate transient adverse events were observed, with no adverse cardiovascular symptoms reported. The compound appears to be an effective anti-migraine medication that is well tolerated and does not display the vasoconstrictive effect that precludes the use of triptans and dihydroergotamine in certain patients. For a successful marketing of olcegepant, larger clinical trials and the development of an effective oral formulation will be necessary.


Assuntos
Calcitonina/antagonistas & inibidores , Dipeptídeos/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Precursores de Proteínas/antagonistas & inibidores , Quinazolinas/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Peptídeo Relacionado com Gene de Calcitonina , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Dipeptídeos/administração & dosagem , Dipeptídeos/química , Humanos , Injeções Intravenosas , Estrutura Molecular , Patentes como Assunto , Quinazolinas/administração & dosagem , Quinazolinas/química , Resultado do Tratamento
11.
Cancer Res ; 67(14): 6956-64, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17638907

RESUMO

The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented.


Assuntos
Antineoplásicos/farmacologia , Calcitonina/antagonistas & inibidores , Carbanilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/enzimologia , Animais , Calcitonina/metabolismo , Linhagem Celular Tumoral , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Transplante de Neoplasias , Fosforilação
12.
Crit Care ; 10(5): R125, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16956405

RESUMO

INTRODUCTION: This study sought to assess the prognostic value of the kinetics of procalcitonin (PCT), C-reactive protein (CRP) and clinical scores (clinical pulmonary infection score (CPIS), Sequential Organ Failure Assessment (SOFA)) in the outcome of ventilator-associated pneumonia (VAP) at an early time point, when adequacy of antimicrobial treatment is evaluated. METHODS: This prospective observational cohort study was conducted in a teaching hospital. The subjects were 75 patients consecutively admitted to the intensive care unit from October 2003 to August 2005 who developed VAP. Patients were followed for 28 days after the diagnosis, when they were considered survivors. Patients who died before the 28th day were non-survivors. There were no interventions. RESULTS: PCT, CRP and SOFA score were determined on day 0 and day 4. Variables included in the univariable logistic regression model for survival were age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, decreasing DeltaSOFA, decreasing DeltaPCT and decreasing DeltaCRP. Survival was directly related to decreasing DeltaPCT with odds ratio (OR) = 5.67 (95% confidence interval 1.78 to 18.03), decreasing DeltaCRP with OR = 3.78 (1.24 to 11.50), decreasing DeltaSOFA with OR = 3.08 (1.02 to 9.26) and APACHE II score with OR = 0.92 (0.86 to 0.99). In a multivariable logistic regression model for survival, only decreasing DeltaPCT with OR = 4.43 (1.08 to 18.18) and decreasing DeltaCRP with OR = 7.40 (1.58 to 34.73) remained significant. Decreasing DeltaCPIS was not related to survival (p = 0.59). There was a trend to correlate adequacy to survival. Fifty percent of the 20 patients treated with inadequate antibiotics and 65.5% of the 55 patients on adequate antibiotics survived (p = 0.29). CONCLUSION: Measurement of PCT and CRP at onset and on the fourth day of treatment can predict survival of VAP patients. A decrease in either one of these marker values predicts survival.


Assuntos
Proteína C-Reativa/antagonistas & inibidores , Calcitonina/antagonistas & inibidores , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/mortalidade , Precursores de Proteínas/antagonistas & inibidores , Ventiladores Mecânicos/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/biossíntese , Calcitonina/biossíntese , Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Precursores de Proteínas/biossíntese , Precursores de Proteínas/sangue , Respiração Artificial/mortalidade , Taxa de Sobrevida
13.
J Biol Chem ; 280(31): 28610-22, 2005 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-15929987

RESUMO

Fish-like calcitonins (CTs), such as salmon CT (sCT), are widely used clinically in the treatment of bone-related disorders; however, the molecular basis for CT binding to its receptor, a class II G protein-coupled receptor, is not well defined. In this study we have used photoaffinity labeling to identify proximity sites between CT and its receptor. Two analogues of the antagonist sCT(8-32) containing a single photolabile p-benzoyl-l-phenylalanine (Bpa) residue in position 8 or 19 were used. Both analogues retained high affinity for the CT receptor and potently inhibited agonist-induced cAMP production. The [Bpa(19)]sCT(8-32) analogue cross-linked to the receptor at or near the equivalent cross-linking site of the full-length peptide, within the fragment Cys(134)-Lys(141) (within the amino terminus of the receptor, adjacent to transmembrane 1) (Pham, V., Wade, J. D., Purdue, B. W., and Sexton, P. M. (2004) J. Biol. Chem. 279, 6720-6729). In contrast, proteolytic mapping and mutational analysis identified Met(49) as the cross-linking site for [Bpa(8)]sCT(8-32). This site differed from the previously identified cross-linking site of the agonist [Bpa(8)]human CT (Dong, M., Pinon, D. I., Cox, R. F., and Miller, L. J. (2004) J. Biol. Chem. 279, 31177-31182) and may provide evidence for conformational differences between interaction with active and inactive state receptors. Molecular modeling suggests that the difference in cross-linking between the two Bpa(8) analogues can be accounted for by a relatively small change in peptide orientation. The model was also consistent with cooperative interaction between the receptor amino terminus and the receptor core.


Assuntos
Calcitonina/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Receptores da Calcitonina/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Calcitonina/química , Chlorocebus aethiops , Humanos , Cinética , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Estrutura Secundária de Proteína , Receptores da Calcitonina/química , Receptores da Calcitonina/efeitos dos fármacos , Salmão , Transfecção
14.
Peptides ; 25(3): 365-91, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15134861

RESUMO

Over the past 20 years, receptor autoradiography has proven most useful to provide clues as to the role of various families of peptides expressed in the brain. Early on, we used this method to investigate the possible roles of various brain peptides. Natriuretic peptide (NP), neuropeptide Y (NPY) and calcitonin (CT) peptide families are widely distributed in the peripheral and central nervous system and induced multiple biological effects by activating plasma membrane receptor proteins. The NP family includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The NPY family is composed of at least three peptides NPY, peptide YY (PYY) and the pancreatic polypeptides (PPs). The CT family includes CT, calcitonin gene-related peptide (CGRP), amylin (AMY), adrenomedullin (AM) and two newly isolated peptides, intermedin and calcitonin receptor-stimulating peptide (CRSP). Using quantitative receptor autoradiography as well as selective agonists and antagonists for each peptide family, in vivo and in vitro assays revealed complex pharmacological responses and radioligand binding profile. The existence of heterogeneous populations of NP, NPY and CT/CGRP receptors has been confirmed by cloning. Three NP receptors have been cloned. One is a single-transmembrane clearance receptor (NPR-C) while the other two known as CG-A (or NPR-A) and CG-B (or NPR-B) are coupled to guanylate cyclase. Five NPY receptors have been cloned designated as Y(1), Y(2), Y(4), Y(5) and y(6). All NPY receptors belong to the seven-transmembrane G-protein coupled receptors family (GPCRs; subfamily type I). CGRP, AMY and AM receptors are complexes which include a GPCR (the CT receptor or CTR and calcitonin receptor-like receptor or CRLR) and a single-transmembrane domain protein known as receptor-activity-modifying-proteins (RAMPs) as well as an intracellular protein named receptor-component-protein (RCP). We review here tools that are currently available in order to target each NP, NPY and CT/CGRP receptor subtype and establish their respective pathophysiological relevance.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Peptídeos Natriuréticos/fisiologia , Neuropeptídeo Y/fisiologia , Receptores de Neuropeptídeos/análise , Animais , Sítios de Ligação , Calcitonina/agonistas , Calcitonina/antagonistas & inibidores , Calcitonina/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/agonistas , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Humanos , Peptídeos Natriuréticos/agonistas , Neuropeptídeo Y/agonistas , Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/fisiologia
15.
Eur J Pharmacol ; 483(2-3): 295-300, 2004 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-14729120

RESUMO

Calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide, is found in the central nervous system as well as in the heart. CGRP shows high sequence homology with amylin, salmon calcitonin, and adrenomedullin. This study aimed to investigate the effect of CGRP on atrial hemodynamics and atrial natriuretic peptide (ANP) release by using isolated perfused beating left atria and to identify its receptor subtypes. Rat alpha-CGRP (0.1, 1, 10, or 100 nM) increased atrial contractility and suppressed the release of ANP in a concentration-dependent manner. However, cys-CGRP (1 microM), a CGRP(2) receptor agonist, slightly decreased ANP release without positive inotropism. Human alpha-CGRP (1 nM) showed an effect on ANP release similar to that of rat alpha-CGRP with potent positive inotropism. However, salmon and rat calcitonin (1 microM) caused a slight decrease or no change in ANP release. Pretreatment with a receptor antagonist for CGRP(1) [rat alpha-CGRP-(8-37)] blocked rat alpha-CGRP-induced suppression of ANP release and positive inotropism, whereas the antagonists for salmon or amylin did not. Therefore, we suggest that rat alpha-CGRP causes a suppression of ANP release with positive inotropism through the receptor for CGRP(1) but not that for calcitonin and amylin.


Assuntos
Amiloide/farmacologia , Fator Natriurético Atrial/antagonistas & inibidores , Fator Natriurético Atrial/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Calcitonina/metabolismo , Calcitonina/farmacologia , Precursores de Proteínas/metabolismo , Animais , Calcitonina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , Precursores de Proteínas/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley
16.
Expert Opin Ther Targets ; 7(3): 377-83, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12783573

RESUMO

The primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. The associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP), but not other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment with administration of a 5-HT(1B/1D) agonist (triptan) results in alleviation of the headache and normalisation of the CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small-molecule CGRP antagonists, which are predicted to have fewer cardiovascular side effects in comparison to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reportedly efficacious in the relief of acute attacks of migraine.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Cefaleia/tratamento farmacológico , Adolescente , Adulto , Analgésicos não Entorpecentes/química , Analgésicos não Entorpecentes/uso terapêutico , Animais , Calcitonina/antagonistas & inibidores , Calcitonina/fisiologia , Criança , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Cefaleia/fisiopatologia , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Neurotransmissores , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Precursores de Proteínas/antagonistas & inibidores , Precursores de Proteínas/fisiologia , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Nervo Trigêmeo/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
17.
Horm Metab Res ; 34(5): 229-33, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12063634

RESUMO

Somatostatin (SRIH) analogs are commonly used to treat symptoms in medullary thyroid carcinoma (MTC), that expresses SRIH receptors (SSTR1 to SSTR5), as does the human MTC cell line TT. The aim of this work was to evaluate whether SRIH, SSTR2 and SSTR5-selective agonists influence calcitonin (CT) secretion and gene expression in the TT cell line. CT secretion was evaluated by chemiluminescence, and gene expression was analyzed by Northern blot. TT cell line proliferation was also assessed by [(3)H] thymidine ([(3)H]thy) incorporation and viable cell number count. SRIH significantly (p < 0.05) reduced [(3)H]thy incorporation (approx. 50 %), viable cell number (approx. 20 %), CT secretion (-30 %) and CT gene expression (approx. 2-fold). Exposure to the SSTR2-selective agonist, BIM-23 120, and to the SSTR5-selective agonist, BIM-23 206, did not modify CT secretion and mRNA levels in TT cells. Thus, SRIH inhibits DNA synthesis, cell proliferation, CT secretion and CT gene expression in the TT cell line, while SSTR2 and 5 selective agonists, although influencing DNA synthesis and cell proliferation, do not modify CT gene expression, suggesting that SRIH may influence gene expression acting through SSTRs other than subtypes 2 and 5. Furthermore, these findings may explain the erratic response of MTC patients in terms of CT plasma levels to treatment with SRIH analogs, like octreotide and lanreotide, which interact mainly with SSTR2 and 5.


Assuntos
Calcitonina/biossíntese , Calcitonina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptores de Somatostatina/agonistas , Somatostatina/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Northern Blotting , Calcitonina/antagonistas & inibidores , Contagem de Células , Divisão Celular/efeitos dos fármacos , DNA/biossíntese , DNA/genética , Humanos , Somatostatina/farmacologia , Células Tumorais Cultivadas
18.
Eur J Biochem ; 262(1): 95-101, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10231369

RESUMO

The calcitonin receptor is known to couple to Gs and Gq, activating adenylyl cyclase and phospholipase C, respectively. The observation of pertussis-toxin-sensitive responses to calcitonin suggests that the receptor is capable of coupling to Gi/o as well. However, the calcitonin-dependent activation of adenylyl cyclase in HEK-293 cells that stably express the cloned rabbit calcitonin receptor, as in many other cells that express calcitonin receptors, shows little pertussis toxin sensitivity. Calcitonin treatment of these cells stimulates protein kinase C, which is reported to antagonize the receptor-dependent activation of Gi. The possibility that protein kinase C could be antagonizing Galphai-adenylyl cyclase coupling was tested by examining the effects of protein kinase C inhibitors (chelerythrine chloride and sphingosine) or of chronic treatment with phorbol ester to deplete protein kinase C. All three treatments led to a reduction of calcitonin-induced adenylyl cyclase activity that was reversed by pertussis toxin. Inhibiting or depleting protein kinase C had no effect on the activation of adenylyl cyclase by cholera toxin, indicating that Gs and adenylyl cyclase were not affected by these treatments. Calcitonin treatment of HEK-293 cells, that stably express a myc-tagged rabbit calcitonin receptor, induced the formation of complexes of the receptor and Galphai subunits, confirming that the calcitonin receptor interacts with Gi. Thus, the calcitonin receptor can couple to Gi, but the inhibition of adenylyl cyclase by Galphai is negatively regulated by protein kinase C.


Assuntos
Toxina Adenilato Ciclase , Adenilil Ciclases/metabolismo , Toxina Pertussis , Proteína Quinase C/metabolismo , Receptores da Calcitonina/metabolismo , Fatores de Virulência de Bordetella/farmacologia , Sequência de Aminoácidos , Animais , Calcitonina/antagonistas & inibidores , Linhagem Celular , Ativação Enzimática , Humanos , Dados de Sequência Molecular , Ligação Proteica , Coelhos
19.
Therapie ; 54(5): 573-7, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10667092

RESUMO

The purpose of this study was to test the effect of calcitonin, when injected into the lateral ventricle, on conditioning behaviour and to see whether antidepressant drug treatment can antagonize calcitonin-induced impairment of this behaviour. Conditioned response by conditional stimulus (CS) was compared in control rat (CO) and in rats that received intraventricular perfusion of calcitonin (CA), acute antidepressant drug treatment (ADa), acute antidepressant drug treatment + calcitonin (ADa + CA), chronic antidepressant drug treatment (21 days) + calcitonin the day after (ADc + CA). Control rats acquired easily the conditioned response, the CA group and ADa + CA had problems in making the correlation between CS and unconditional stimulus (US), and consequently did not acquire a conditioned response, but in the ADc + CA group, rats exhibited more conditioned responses. The results indicate that calcitonin disrupts conditioning processes and chronic but not acute antidepressant drug treatment can reverse the effects of calcitonin.


Assuntos
Antidepressivos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Calcitonina/antagonistas & inibidores , Clomipramina/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Deficiências da Aprendizagem/prevenção & controle , Analgésicos/farmacologia , Animais , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Calcitonina/administração & dosagem , Calcitonina/farmacologia , Calcitonina/toxicidade , Clomipramina/administração & dosagem , Clomipramina/uso terapêutico , Eletrochoque , Injeções Intraperitoneais , Injeções Intraventriculares , Deficiências da Aprendizagem/induzido quimicamente , Masculino , Nociceptores/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Serotonina/fisiologia
20.
Neuroendocrinology ; 68(3): 220-8, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9734007

RESUMO

In this study we examined the possible interplay of amylin (AMY) and salmon calcitonin (sCT) in the central control of growth hormone (GH) and prolactin (PRL) secretion in male rats. For this purpose we first compared effects of central intracerebroventricular (i.c.v.) admininstration of various doses of AMY (2.5-2,500 ng/rat) and sCT (2.2-220 ng/rat) on beta-endorphin (beta-END, 0.5 microg/rat)-induced GH and PRL secretion. AMY and sCT dose-dependently inhibited beta-END-induced GH secretion, whereas only sCT was able to inhibit beta-END-induced PRL secretion. To examine whether the GH inhibitory effect of AMY was due to the possible cross-reactivity of AMY and sCT on the same receptors in the CNS, we pretreated some rats with the AMY antagonist (AMY8-37, 2. 5 microg/rat, i.c.v.). AMY8-37 significantly enhanced the GH-stimulatory action of beta-END. AMY8-37, administered prior to AMY and sCT, significantly removed the inhibitory effect of both AMY and sCT on beta-END-induced GH release, suggesting that both peptides mediate their response on GH through a common receptor. In vitro competition binding studies on rat hypothalamic membranes have shown that both AMY and sCT compete with [125I]rAMY binding with half inhibition (IC50) values of 3.6 x 10(-11) and 1.6 x 10(-10) M, respectively. Binding of [125I]sCT was inhibited by sCT with an IC50 of 1.09 x 10(-10) M and to a lesser extent by AMY with an IC50 of 1. 3 x 10(-6) M. Thus it is possible that the two peptides recognize a common hypothalamic receptor but with different affinities (sCT > AMY). Overall these data indicate that AMY behaves as a mimic of sCT in the central control of GH secretion. The failure of AMY, at variance with sCT, to modify the PRL-releasing activity of beta-END indicates that different receptor subtypes for sCT are involved in the endocrine effects of sCT and only those mediating the modulatory action of GH respond to AMY.


Assuntos
Amiloide/farmacologia , Calcitonina/farmacologia , Hormônio do Crescimento/metabolismo , Prolactina/metabolismo , beta-Endorfina/farmacologia , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Animais , Sítios de Ligação , Ligação Competitiva , Calcitonina/antagonistas & inibidores , Calcitonina/metabolismo , Membrana Celular/metabolismo , Hormônio do Crescimento/sangue , Hipotálamo/metabolismo , Injeções Intraventriculares , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , Fragmentos de Peptídeos/farmacologia , Prolactina/sangue , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
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