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1.
Sci Rep ; 10(1): 7581, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371888

RESUMO

Biomineralization is the process by which living organisms acquired the capacity to accumulate minerals in tissues. Shells are the biomineralized exoskeleton of marine molluscs produced by the mantle but factors that regulate mantle shell building are still enigmatic. This study sought to identify candidate regulatory factors of molluscan shell mineralization and targeted family B G-protein coupled receptors (GPCRs) and ligands that include calcium regulatory factors in vertebrates, such as calcitonin (CALC). In molluscs, CALC receptor (CALCR) number was variable and arose through lineage and species-specific duplications. The Mediterranean mussel (Mytilus galloprovincialis) mantle transcriptome expresses six CALCR-like and two CALC-precursors encoding four putative mature peptides. Mussel CALCR-like are activated in vitro by vertebrate CALC but only receptor CALCRIIc is activated by the mussel CALCIIa peptide (EC50 = 2.6 ×10-5 M). Ex-vivo incubations of mantle edge tissue and mantle cells with CALCIIa revealed they accumulated significantly more calcium than untreated tissue and cells. Mussel CALCIIa also significantly decreased mantle acid phosphatase activity, which is associated with shell remodelling. Our data indicate the CALC-like system as candidate regulatory factors of shell mineralization. The identification of the CALC system from molluscs to vertebrates suggests it is an ancient and conserved calcium regulatory system of mineralization.


Assuntos
Biomineralização , Calcitonina/metabolismo , Sequência de Aminoácidos , Animais , Evolução Biológica , Transporte Biológico , Biomineralização/genética , Bivalves , Calcificação Fisiológica , Calcitonina/genética , Cálcio/metabolismo , Biologia Computacional/métodos , Sequência Conservada , Ativação Enzimática , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo , Receptores Acoplados a Proteínas-G/classificação , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo
2.
J Clin Ultrasound ; 48(4): 227-230, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045024

RESUMO

Metastases to the submandibular gland are extremely rare; a literature search retuned only three previously reported cases from a thyroid gland primary site. Herein, we report two cases of metastatic thyroid carcinoma to the submandibular gland in a 64-year-old woman with PTC and a 70-year-old-woman with medullary thyroid carcinoma (MTC). The metastases were identified on CT and PET/CT in one case and on CT in the other case, but both were diagnosed with ultrasound-guided fine-needle aspiration. Our cases highlight that while rare, both PTC and MTC can metastasize to the submandibular gland.


Assuntos
Carcinoma Neuroendócrino/secundário , Neoplasias da Glândula Submandibular/secundário , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Idoso , Biópsia por Agulha Fina , Calcitonina/metabolismo , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Submandibular/diagnóstico por imagem , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/secundário , Tireoidectomia , Tomografia Computadorizada por Raios X , Ultrassonografia
3.
J Phys Chem B ; 123(48): 10171-10180, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31692350

RESUMO

The most common obstacles to the development of therapeutic polypeptides are peptide stability and aggregation. Human calcitonin (hCT) is a 32-residue hormone polypeptide secreted from the C-cells of the thyroid gland and is responsible for calcium and phosphate regulation in the blood. hCT reduces calcium levels by inhibiting the activity of osteoclasts, which are bone cells that are mainly responsible for breaking down the bone tissue or decreasing the resorption of calcium from the kidneys. Thus, calcitonin injection has been used to treat osteoporosis and Paget's disease of bone. hCT is an aggregation-prone peptide with a high tendency to form amyloid fibrils. As a result, salmon calcitonin (sCT), which is different from hCT at 16-residue positions and has a lower propensity to aggregate, has been chosen as a clinical substitute for hCT. However, significant side effects, including immune reactions, have been shown with the use of sCT injection. In this study, we found that two residues, Tyr-12 and Asn-17, play key roles in inducing the fibrillization of hCT. Double mutation of hCT at these two crucial sites could greatly enhance its resistance to aggregation and provide a peptide-based inhibitor to prevent amyloid formation by hCT. Double-mutated hCT retains its ability to interact with its receptor in vivo. These findings suggest that this variant of hCT would serve as a valuable therapeutic alternative to sCT.


Assuntos
Amiloide/química , Calcitonina/química , Cálcio/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Agregados Proteicos/genética , Sequência de Aminoácidos , Amiloide/antagonistas & inibidores , Amiloide/genética , Amiloide/metabolismo , Animais , Calcitonina/genética , Calcitonina/metabolismo , Cálcio/metabolismo , AMP Cíclico/química , AMP Cíclico/metabolismo , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Células MCF-7 , Mutação , Fosfatos/química , Fosfatos/metabolismo , Conformação Proteica em alfa-Hélice , Salmão , Alinhamento de Sequência , Trifluoretanol/química , Trifluoretanol/metabolismo
4.
Thyroid ; 29(11): 1704-1707, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31650892

RESUMO

Medullary thyroid carcinoma (MTC) is most commonly associated with RET gene mutations. ALK fusions have rarely been described, although not previously in pediatrics and not previously partnered with CCDC6 in MTC or any other cancer. A 10-year-old boy with progressive stridor was found to have metastatic MTC, including lung, lymph node, and adrenal metastases. Baseline calcitonin was 6703 pg/mL. While molecular testing was pending, he was treated empirically with the investigational selective RET inhibitor, LOXO-292, without improvement. Molecular testing revealed a novel CCDC6-ALK fusion. His therapy was changed to crizotinib and then to alectinib for improved tolerability. Calcitonin decreased to 663 pg/mL after 6 days of ALK inhibition. He remains on alectinib with ongoing response. A novel CCDC6-ALK fusion has now been implicated in a pediatric case of metastatic MTC. This fusion has profound clinical sensitivity to ALK inhibitors. This report expands the spectrum of ALK fusions seen in MTC, including the first pediatric case of ALK translocated MTC. This novel fusion with CCDC6 has not previously been reported in other human cancers. Given the dramatic response to ALK inhibition in this case, identifying patients with ALK fusion MTC has important therapeutic implications.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Neuroendócrino/genética , Fusão Gênica/genética , Neoplasias da Glândula Tireoide/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Calcitonina/metabolismo , Carbazóis/uso terapêutico , Criança , Proteínas do Citoesqueleto/genética , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Metástase Neoplásica , Piperidinas/uso terapêutico , Resultado do Tratamento
5.
BMC Endocr Disord ; 19(1): 103, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619220

RESUMO

BACKGROUND: Medullary thyroid carcinoma is a malignant uncommon and aggressive tumour of the parafollicular C cells. In about 75% of cases it is sporadic while, in case of RET mutation, it is associated to multiple endocrine neoplasia type 2 (25% of cases). The biochemical features of medullary thyroid carcinoma include the production of calcitonin and carcinoembryogenic antigen. The above-mentioned features are useful in the diagnostic process as well as in the follow up and in the prognostication of the disease. Even if calcitonin elevation is strongly associated to MTC, it can also be found increased in many pathological different conditions as pregnancy, lactation, C-cells hyperplasia, autoimmune thyroiditis, end stage renal disease, lung and prostate cancer and several neuroendocrine tumours. Major medullary thyroid tumours are usually connected to high doses of circulating calcitonin, in fact non-secretory variants have hardly been described. CASE PRESENTATION: We herein report the case of a 59 years old male, who had undergone total thyroidectomy for multinodular goiter with negative preoperative calcitonin, showing medullary thyroid carcinoma at definitive pathology. To the best of our knowledge, this is the first case documenting a non-secretory medullary thyroid carcinoma, with double negative markers at the time of diagnosis and at the relapse. CONCLUSION: A Literature review underlining pathological hypothesis, differential diagnosis and alternative and innovative biomarkers to identify non-secretory medullary thyroid carcinoma was carried out.


Assuntos
Biomarcadores Tumorais/metabolismo , Calcitonina/metabolismo , Antígeno Carcinoembrionário/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/cirurgia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia
6.
Endocr Relat Cancer ; 26(11): 815-828, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31561211

RESUMO

Stem cell-like-cancer cells are key drivers of tumor growth, metastasis, and relapse of cancer following remission. Prostate stem cell-like cancer cells isolated from human prostate cancer (PC) biopsies express CD44+/α2ß1 hi/CD133+ cell surface markers and can self-renew in vitro. Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in PCs and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. We investigated whether CT-CTR autocrine axis induces stem cell-like phenotype in two PC cell lines. CT-CTR axis in these cell lines was activated by enforced expression of CTR. The cells were then examined for the changes in the expression of CD44 and CD133, collagen adherence, tumorigenic, metastatic and repopulating characteristics. The activation of CT-CTR axis led to a large increase in adherence to collagen and a remarkable increase of CD44 and CD133 in PC-3 and LNCaP cells. This was accompanied by a strong increase in tumorigenic, metastatic and repopulation properties of PC cells. However, the mutation of CTR-C PDZ-binding site in CTR almost abolished CTR-mediated increases in stem cell-like characteristics of PC cells. These results support an important role for CT-CTR axis in the progression of PC from localized cancer to an aggressive form, and a majority of proinvasive CTR actions may be mediated through its interaction with its partner protein at the PDZ-binding site. These results suggest that CT/CTR can serve as a valuable target to prevent the generation of stem-like PC cells.


Assuntos
Calcitonina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/metabolismo , Antígeno AC133 , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colágeno/metabolismo , Humanos , Receptores de Hialuronatos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Fenótipo , Neoplasias da Próstata/patologia , Receptores da Calcitonina/metabolismo , Cicatrização
7.
Thyroid ; 29(10): 1447-1456, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31364476

RESUMO

Background: Inherited medullary thyroid carcinoma (MTC) is primarily caused by RET mutations that are commonly localized in exons 5, 8, 10, 11, and 13-16. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the RET proto-oncogene. Methods: Targeted sequencing was used to diagnose four apparently sporadic MTC index cases carrying the germline RET S409Y (c.1226 C>A) variant. Subsequently, 27 relatives of these individuals underwent clinical and genetic assessments and/or thyroid surgery. Furthermore, in silico analyses and in vitro assays were performed to predict or verify the potential oncogenic activity of the S409Y variant. Results: Overall, 15 of 31 participants were found to carry the RET S409Y variant. Of these, 6 presented with isolated MTC (mean age 50.2 years; range 41-75 years), of which 3 presented with neck lymph node metastases and 2 presented with distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age 56 years; range 41-76 years) had elevated serum calcium-stimulated calcitonin (sCtn) or concurrent marginally elevated serum calcitonin (Ctn) levels, whereas the other 6 (mean age 37.5 years; range 14-52 years) exhibited typical Ctn/sCtn levels (p < 0.05). None of the 15 carriers in these 4 families presented clinical evidence of pheochromocytoma, hyperparathyroidism, or Hirschsprung's disease. In silico analyses revealed that S409Y was a "possibly damaging" mutation that could affect the RET protein inter-domain interface. An in vitro assay revealed that the phosphorylation level of RET tyrosine 905 was relatively higher in the RET S409Y mutant than in wild-type (WT) RET. Moreover, transfection of HEK 293 cells with S409Y enhanced the phosphorylation activity of AKT, ERK pathways, and it increased cell proliferation compared with WT RET, but to a lesser degree than that for the RET C618Y and C634Y mutations. Conclusions: This study demonstrates that the novel germline RET S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations. Individuals with S409Y should be managed using a personalized approach, and additionally, "at-risk" family members should be evaluated. Additional studies are needed to elucidate the correlation between the S409Y mutation and multiple endocrine neoplasia type 2-specific tumors.


Assuntos
Carcinoma Neuroendócrino/genética , Mutação em Linhagem Germinativa , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Calcitonina/metabolismo , Carcinoma Neuroendócrino/metabolismo , Proliferação de Células/genética , Simulação por Computador , Feminino , Humanos , Técnicas In Vitro , Metástase Linfática , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
8.
Hormones (Athens) ; 18(3): 289-295, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292912

RESUMO

The biologic and clinical significance of reactive C cell hyperplasia (CCH), adjacent to differentiated thyroid cancers, remains unknown. Our aim was to investigate the presence of CCH in thyroidectomy specimens with papillary thyroid carcinomas (PTC) and discuss its epidemiology and histology. In total, 413 patients were prospectively included in the study (189 benign goiters, 224 PTC). Reactive CCH was observed in 9.8% of PTC cases (32% males, 68% females, mean age 48.3 ± 16.4 years) and usually ipsilateral to the primary tumor (91%). Histologically, CCH was either focal (91%) or diffuse (9%) and almost always (92%) found in the middle or upper thirds of the thyroid lobes. Patients with PTC/CCH were generally younger than patients with benign goiters (0.027). On the other hand, patients with PTC and with PTC/CCH did not differ in terms of age, gender, basal calcitonin levels, primary tumor size, multifocality, extrathyroidal invasion, or lymph node metastasis. Thyroiditis, however, was more frequent in cases with PTC/CCH compared to PTC alone. Reactive CCH is considered a physiological response of the C cells to various stimuli, differentiated thyroid cancer among others. It bears no malignant potential and requires no additional treatment, following thyroidectomy.


Assuntos
Câncer Papilífero da Tireoide/cirurgia , Células Epiteliais da Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Calcitonina/metabolismo , Estudos de Coortes , Comorbidade , Feminino , Humanos , Hiperplasia/diagnóstico , Hiperplasia/epidemiologia , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Câncer Papilífero da Tireoide/complicações , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/epidemiologia , Células Epiteliais da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/epidemiologia , Tireoidectomia , Adulto Jovem
9.
J Physiol Sci ; 69(5): 749-756, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270742

RESUMO

The effects of the pharyngeal non-noxious mechanical stimulation on the secretion of immunoreactive thyroxin (iT4), immunoreactive calcitonin (iCT), and immunoreactive parathyroid hormone (iPTH) into thyroid venous blood were examined in anesthetized rats. Secretion rates of iT4, iCT, and iPTH were calculated from their concentration in thyroid venous plasma and the plasma flow rate. A mechanical stimulation was delivered to the pharynx by a rubber balloon placed on the tongue that was intermittently pushed into the pharyngeal cavity. Pharyngeal stimulation increased iT4 and iCT secretion, but iPTH secretion was unchanged. The secretion responses were abolished by transecting the superior laryngeal nerves (SLNs) bilaterally. The activities of the thyroid parasympathetic efferent nerves and the afferent nerves in the SLN increased significantly during pharyngeal stimulation. These results indicate that pharyngeal mechanical stimulation promotes thyroxin and calcitonin secretion from the thyroid gland by a reflex increase in SLN parasympathetic efferent activity, triggered by excitation of SLN mechanoreceptive afferents.


Assuntos
Calcitonina/metabolismo , Faringe/metabolismo , Glândula Tireoide/metabolismo , Tiroxina/metabolismo , Vias Aferentes/metabolismo , Animais , Estimulação Elétrica/métodos , Nervos Laríngeos/metabolismo , Masculino , Hormônio Paratireóideo/metabolismo , Ratos , Ratos Sprague-Dawley , Reflexo/fisiologia
10.
J Pineal Res ; 67(3): e12594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286565

RESUMO

Astronauts experience osteoporosis-like loss of bone mass because of microgravity conditions during space flight. To prevent bone loss, they need a riskless and antiresorptive drug. Melatonin is reported to suppress osteoclast function. However, no studies have examined the effects of melatonin on bone metabolism under microgravity conditions. We used goldfish scales as a bone model of coexisting osteoclasts and osteoblasts and demonstrated that mRNA expression level of acetylserotonin O-methyltransferase, an enzyme essential for melatonin synthesis, decreased significantly under microgravity. During space flight, microgravity stimulated osteoclastic activity and significantly increased gene expression for osteoclast differentiation and activation. Melatonin treatment significantly stimulated Calcitonin (an osteoclast-inhibiting hormone) mRNA expression and decreased the mRNA expression of receptor activator of nuclear factor κB ligand (a promoter of osteoclastogenesis), which coincided with suppressed gene expression levels for osteoclast functions. This is the first study to report the inhibitory effect of melatonin on osteoclastic activation by microgravity. We also observed a novel action pathway of melatonin on osteoclasts via an increase in CALCITONIN secretion. Melatonin could be the source of a potential novel drug to prevent bone loss during space flight.


Assuntos
Reabsorção Óssea/prevenção & controle , Melatonina/uso terapêutico , Voo Espacial , Animais , Densidade Óssea/efeitos dos fármacos , Calcitonina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Carpa Dourada , Imuno-Histoquímica , NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Ausência de Peso/efeitos adversos
11.
Clin Nucl Med ; 44(9): e546-e547, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31283604

RESUMO

Neuroendocrine tumors (NETs) of the thyroid gland are generally considered to be derived from parafollicular endocrine or C cells and are known as medullary thyroid carcinomas. Non-calcitonin-producing NETs of the thyroid are extremely rare in occurrence and pose a significant diagnostic dilemma for the physician and pathologist. We describe a case of a 58-year-old woman who was diagnosed as having primary NET thyroid with normal calcitonin levels and Ga DOTANOC PET-CT scan findings which were done for initial extent evaluation of the disease.


Assuntos
Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Calcitonina/metabolismo , Carcinoma Neuroendócrino/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias da Glândula Tireoide/patologia
12.
Sci Rep ; 9(1): 8447, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186439

RESUMO

A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.


Assuntos
Calcitonina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Animais , Fármacos Antiobesidade/metabolismo , Fármacos Antiobesidade/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Calcitonina/genética , Calcitonina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Masculino , Obesidade/metabolismo , Obesidade/patologia , Ratos , Receptores de Glucagon/genética
13.
J Exp Biol ; 222(Pt 13)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31221740

RESUMO

In Protostoma, the diuretic hormone 31 (DH31) signalling system was long considered as the orthologue of the chordate calcitonin (CT) signalling system. Using the Pacific oyster (Crassostrea gigas) transcriptomic database GigaTON, we characterized seven G-protein-coupled receptors (GPCRs) named Cragi-CTR1-7 and phylogenetically related to chordate CT receptors (CTRs) and to protostome DH31 receptors. Two CT precursors (Cragi-CTP1 and Cragi-CTP2) containing two CT-type peptides and encoded by two distinct genes with a similar organization were also characterized. These oyster neuropeptides (Cragi-CT1/2) exhibit the two N-terminal paired cysteine residues and, except CTP2-derived peptide (Cragi-CTP2dp), show the C-terminal proline-amide motif typical of deuterostome CT-type peptides. All mature Cragi-CTs except Cragi-CTP2dp were detected in visceral ganglion extracts using mass spectrometry. Cell-based assays revealed that the previously characterized oyster receptors Cg-CT-R and Cragi-CTR2 were specifically activated by Cragi-CT1b and Cragi-CT2, respectively. This activation does not require the co-expression of receptor activity-modifying proteins (RAMPs). Thus, oyster CT signalling appears functionally more closely related to vertebrate CT/CTR signalling than to calcitonin gene-related peptide/calcitonin receptor-like receptor (CGRP/CLR) signalling. Gene expression profiles in different adult tissues and in oysters acclimated to brackish water suggest the potential implication of both Cg-CT-R/Cragi-CT1b and Cragi-CTR2/Cragi-CT2 in water and ionic regulations, although with apparently opposite effects. The present study represents the first comprehensive characterization of a functional CT-type signalling system in a protostome and provides evidence for its evolutionarily ancient origin and its early role in osmotic homeostasis.


Assuntos
Calcitonina/metabolismo , Crassostrea/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Sequência de Aminoácidos , Animais , Sequência de Bases , Evolução Biológica , Crassostrea/metabolismo , Filogenia , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Alinhamento de Sequência
14.
J Pediatr Endocrinol Metab ; 32(6): 585-595, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31150358

RESUMO

Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.


Assuntos
Biomarcadores/análise , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Recidiva Local de Neoplasia/cirurgia , Complicações Pós-Operatórias , Tireoidectomia/métodos , Adolescente , Calcitonina/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Mutação em Linhagem Germinativa , Humanos , Japão/epidemiologia , Masculino , Neoplasia Endócrina Múltipla Tipo 2a/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Estudos Retrospectivos , Inquéritos e Questionários , Fatores de Tempo
15.
J Colloid Interface Sci ; 552: 186-195, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125829

RESUMO

Advances in pharmaceutical technology have promoted the development of colon-targeted delivery system for oral administration of bioactive peptides or proteins to enhance their bioavailability. In this study, a multi-unit nanofiber mat was fabricated by coaxial electrospinning and its feasibility as the colon-targeted delivery system for a bioactive peptide, salmon calcitonin (sCT), was investigated. Sodium alginate and sCT-loaded liposome coated with pectin served as the shell layer and core layer, respectively. An in vitro study demonstrated that the encapsulated sCT was released in a sustained and colon-targeted way. Analysis using different mathematical models showed that release followed a complex mechanism. In addition, greater amounts of sCT were released from the core-shell nanofiber mat into simulated colon fluid (SCF) than was released from a uniaxial nanofiber mat (65.2% vs. 47.8%). The use of a core-shell nanofiber mat further alleviated the burst release of sCT into simulated gastric and intestinal fluid (SGF and SIF), demonstrating the superiority of a multi-unit vehicle for colon-targeted delivery of sCT. Furthermore, 88% of the bioactivity of encapsulated sCT was retained. This multi-unit vehicle offers a better-designed vehicle for the colon-targeted sustained release of bioactive peptides or proteins and, thus, should improve oral bioavailability.


Assuntos
Calcitonina/metabolismo , Colo/metabolismo , Nanofibras/química , Pectinas/metabolismo , Administração Oral , Alginatos/administração & dosagem , Alginatos/química , Alginatos/metabolismo , Disponibilidade Biológica , Calcitonina/administração & dosagem , Calcitonina/química , Colo/química , Sistemas de Liberação de Medicamentos , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/metabolismo , Nanofibras/administração & dosagem , Tamanho da Partícula , Pectinas/administração & dosagem , Pectinas/química , Propriedades de Superfície
16.
Endocrinology ; 160(7): 1590-1599, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127815

RESUMO

Human calcitonin release is promoted by elevated extracellular Ca2+ (Ca2+o) concentration acting, at least in part, via the calcium-sensing receptor (CaSR). The CaSR is positively modulated by L-amino acids, including the aromatic amino acids L-phenylalanine (Phe) and L-tryptophan (Trp). To investigate the effect of L-amino acids on human calcitonin secretion, we selected thyroid TT cells and exposed them to various Ca2+o concentrations in the absence or presence of L-Phe, plasma-like mixtures of L-amino acids, or the clinically effective positive modulator (calcimimetic) cinacalcet. In the presence of L-Phe or plasma-like mixtures of amino acids, TT cells exhibited enhanced Ca2+o sensitivity in assays of calcitonin release and intracellular Ca2+ mobilization. Furthermore, the effect of elevated Ca2+o and L-Phe on calcitonin release was markedly suppressed by the calcilytic NPS-2143. These effects were dependent on CaSR-mediated activation of Gq/11 as revealed by the specific inhibitor YM-254890. The findings support the hypothesis that calcitonin release is stimulated by increases in plasma L-amino acid levels as well as elevated Ca2+o concentration. They also demonstrate that stimulated calcitonin release as well as basal levels of calcitonin secretion are mediated by a CaSR:Gq/11 signaling mechanism.


Assuntos
Cálcio/farmacologia , Fenilalanina/farmacologia , Receptores de Detecção de Cálcio/metabolismo , Transdução de Sinais/fisiologia , Células Epiteliais da Tireoide/metabolismo , Triptofano/farmacologia , Calcitonina/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Células Epiteliais da Tireoide/efeitos dos fármacos
17.
J Endocrinol ; 242(2): 13-23, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31042672

RESUMO

Many studies have investigated the actions of melatonin on osteoblasts and osteoclasts. However, the underlying mechanisms, especially regarding osteocyte function, remain largely unknown. Therefore, this study aimed to clarify the underlying mechanisms of melatonin action on bone tissue via osteocyte function. Chick calvariae were employed as a model. In ovo injection of melatonin (5, 50 and 500 µg) dose-dependently decreased the mRNA expression levels of cathepsin K and matrix metalloproteinase 9 (MMP9) in chick calvariae without affecting the expression levels of receptor activator of NF-κB ligand or osteoprotegerin. Surprisingly enough, the expression of calcitonin mRNA in chick calvariae was significantly raised. After 3 days of in vitro treatment of melatonin (10-7 and 10-5 M) on newly hatched chick calvariae, both calcitonin mRNA expression in calvariae and the concentration of calcitonin in cultured medium were augmented in a dose-dependent manner, coincident with the decreased mRNA expression levels of cathepsin K and MMP9. Immunohistochemical analyses revealed expression of melatonin receptors and calcitonin by osteocytes buried in bone matrix. Moreover, the mRNA expression levels of melatonin receptors, calcitonin and sclerostin (a marker of osteocyte), were strongly and positively correlated. In conclusion, we demonstrated the expression of melatonin receptors and calcitonin expression in osteocytes for the first time and suggest a new mechanism underlying the suppressive effect of melatonin on osteoclasts via upregulation of calcitonin secretion by osteocytes.


Assuntos
Calcitonina/metabolismo , Melatonina/farmacologia , Osteoclastos/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Calcitonina/genética , Células Cultivadas , Embrião de Galinha , Galinhas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Melatonina/administração & dosagem , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteócitos/citologia , Osteócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Melatonina/genética , Receptores de Melatonina/metabolismo , Crânio/citologia , Crânio/efeitos dos fármacos , Crânio/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
J Inorg Biochem ; 196: 110686, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31003065

RESUMO

Irreversible aggregation can extremely limit the bioavailability and therapeutic activity of peptide-based drugs. Thus, peptide fibrillation is an excellent challenge for biotechnological drug development. Human calcitonin (hCT) is such a peptide hormone known for its hypocalcaemic effect but has limited pharmaceutical potential due to a high tendency to aggregate. hCT is therefore not widely used preparation in clinical practice. Nonetheless, hCT seems to be still an ideal target for clinical therapy when fibrillation is effectively inhibited, because the alternatives of hCT can stimulate undesirable immune responses in patients and cause side effects. Interestingly, heme is an essential component for many livings and has been shown a strong inhibitory effect on some amyloidogenic peptides aggregation. Here we demonstrate that it may be a most suitable, safe, biocompatible small molecule inhibitor on hCT aggregation, and thereby improving its activity when guiding the drug peptide in clinical therapeutics. In this work, we found that heme was able to reversibly bind with hCT to form a heme-hCT complex with a moderate binding constant (9.17 × 106 M-1) and significantly suppress the aggregation of hCT probably accomplished by heme binding to it, blocking the ß-sheet structure assembly which is essential in hCT fibril aggregation. Meanwhile, the heme-hCT complexes showed enhanced bioactivity compared to hCT itself after a 24 h incubation time in reducing blood calcium levels in mice. This study may develop a new strategy to reuse the wild-type hCT in clinical therapeutics.


Assuntos
Calcitonina/química , Calcitonina/metabolismo , Heme/química , Heme/uso terapêutico , Hipocalcemia/tratamento farmacológico , Hipocalcemia/metabolismo , Animais , Calorimetria , Dicroísmo Circular , Feminino , Humanos , Camundongos , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência
19.
PLoS One ; 14(4): e0214222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31013271

RESUMO

BACKGROUND: Procalcitonin is a biomarker that supports clinical decision-making on when to initiate and discontinue antibiotic therapy. Several cost (-effectiveness) analyses have been conducted on Procalcitonin-guided antibiotic stewardship, but none mainly based on US originated data. OBJECTIVE: To compare effectiveness and costs of a Procalcitonin-algorithm versus standard care to guide antibiotic prescription for patients hospitalized with a diagnosis of suspected sepsis or lower respiratory tract infection in the US. METHODS: A previously published health economic decision model was used to compare the costs and effects of Procalcitonin-guided care. The analysis considered the societal and hospital perspective with a time horizon covering the length of hospital stay. The main outcomes were total costs per patient, including treatment costs and productivity losses, the number of patients with antibiotic resistance or C.difficile infections, and costs per antibiotic day avoided. RESULTS: Procalcitonin -guided care for hospitalized patients with suspected sepsis and lower respiratory tract infection is associated with a reduction in antibiotic days, a shorter length of stay on the regular ward and the intensive care unit, shorter duration of mechanical ventilation, and fewer patients at risk for antibiotic resistant or C.difficile infection. Total costs in the Procalcitonin-group compared to standard care were reduced by 26.0% in sepsis and 17.7% in lower respiratory tract infection (total incremental costs of -$11,311 per patient and -$2,867 per patient respectively). CONCLUSIONS: Using a Procalcitonin-algorithm to guide antibiotic use in sepsis and hospitalised lower respiratory tract infection patients is expected to generate cost-savings to the hospital and lower rates of antibiotic resistance and C.difficile infections.


Assuntos
Gestão de Antimicrobianos/economia , Calcitonina/metabolismo , Custos e Análise de Custo , Economia Médica , Hospitalização/economia , Modelos Econômicos , Infecções Respiratórias/tratamento farmacológico , Sepse/tratamento farmacológico , Humanos , Infecções Respiratórias/economia , Sepse/economia , Resultado do Tratamento , Estados Unidos
20.
J Diabetes Res ; 2019: 9426014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918901

RESUMO

Objective: Diabetic polyneuropathy (DPN) is one of the most prevalent diabetic complications. We previously demonstrated that exendin-4 (Ex4), a glucagon-like peptide-1 receptor agonist (GLP-1RA), has beneficial effects in animal models of DPN. We hypothesized that GLP-1 signaling would protect neurons of the peripheral nervous system from oxidative insult in DPN. Here, the therapeutic potential of GLP-1RAs on DPN was investigated in depth using the cellular oxidative insult model applied to the dorsal root ganglion (DRG) neuronal cell line. Research Design and Methods: Immortalized DRG neuronal 50B11 cells were cultured with and without hydrogen peroxide in the presence or absence of Ex4 or GLP-1(7-37). Cytotoxicity and viability were determined using a lactate dehydrogenase assay and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt), respectively. Antioxidant enzyme activity was evaluated using a superoxide dismutase assay. Alteration of neuronal characteristics of 50B11 cells induced by GLP-1RAs was evaluated with immunocytochemistry utilizing antibodies for transient receptor potential vanilloid subfamily member 1, substance P, and calcitonin gene-related peptide. Cell proliferation and apoptosis were also examined by ethynyl deoxyuridine incorporation assay and APOPercentage dye, respectively. The neurite projection ratio induced by treatment with GLP-1RAs was counted. Intracellular activation of adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling was also quantified after treatment with GLP-1RAs. Results: Neither Ex4 nor GLP-1(7-37) demonstrated cytotoxicity in the cells. An MTS assay revealed that GLP-1RAs amended impaired cell viability induced by oxidative insult in 50B11 cells. GLP-1RAs activated superoxide dismutase. GLP-1RAs induced no alteration of the distribution pattern in neuronal markers. Ex4 rescued the cells from oxidative insult-induced apoptosis. GLP-1RAs suppressed proliferation and promoted neurite projections. No GLP-1RAs induced an accumulation of cAMP. Conclusions: Our findings indicate that GLP-1RAs have neuroprotective potential which is achieved by their direct actions on DRG neurons. Beneficial effects of GLP-1RAs on DPN could be related to these direct actions on DRG neurons.


Assuntos
Apoptose , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Calcitonina/metabolismo , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , AMP Cíclico/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Ratos , Substância P/metabolismo , Superóxido Dismutase/metabolismo
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