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1.
Anim Sci J ; 91(1): e13420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32618083

RESUMO

This study aimed to evaluate the effect of miR-10b on growth hormone (GH) in pituitary cells of Yanbian yellow cattle. According to analysis of GH and somatostatin receptor 2 (SSTR2) mRNA and protein expression levels, we found that miR-10b targeted 3'UTR of SSTR2. Compared with the negative control (NC) group, GH mRNA transcription and protein expression in pituitary cells of Yanbian yellow cattle were significantly increased by adding miR-10b mimics (p < .01), while these were significantly decreased by adding miR-10b inhibitor (p < .05); compared with the NC group, SSTR2 mRNA transcription and protein expression were significantly inhibited by the addition of miR-10b mimics (p < .01), while these were significantly increased by the addition of miR-10b inhibitor compared with the iNC group (p < .05). This study suggested that miR-10b could regulate GH level by regulating SSTR2 gene expression in pituitary cells of Yanbian yellow cattle.


Assuntos
Bovinos/genética , Bovinos/metabolismo , Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , MicroRNAs/genética , MicroRNAs/fisiologia , Hipófise/citologia , Hipófise/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Somatostatina/metabolismo , Transfecção , Animais , Células Cultivadas , MicroRNAs/metabolismo
2.
Clin Nucl Med ; 45(9): e422-e424, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657867

RESUMO

Primary neuroendocrine tumor of the mediastinum is a relatively rare entity. In metastatic/inoperable disease, therapeutic options are limited to cytotoxic chemotherapy in poorly differentiated tumors and peptide receptor radionuclide therapy in case of well-differentiated tumors. We present the case of a 52-year-old man with mediastinal atypical carcinoid (grade II) neuroendocrine tumor showing mild somatostatin receptor expression and intense FDG avidity with progressive disease on chemotherapy. Chemokine receptor targeted PET/CT with CXCR4 (Ga-CXCR4) showed tracer avidity in tumor sites higher than the physiological sites, which may pave the way for CXCR4-targeted radionuclide therapy in this subgroup of patients.


Assuntos
Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/metabolismo , Receptores CXCR4/metabolismo , Tumor Carcinoide/diagnóstico por imagem , Tumor Carcinoide/patologia , Fluordesoxiglucose F18 , Humanos , Masculino , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Receptores de Somatostatina/metabolismo
3.
Clin Nucl Med ; 45(8): e363-e364, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32558717

RESUMO

We present a 48-year-old woman with an olfactory neuroblastoma who was referred for accurate staging using PET/CT. The Ga-DOTATATE PET/CT showed a 51 × 32-mm mass with an SUVmax of 7.59 in the sphenoidal sinuses, whereas radiotracer uptake on F-FDG PET/CT was similar to that of brain tissue. Ga-DOTATATE PET/CT might be especially useful in regions with difficult tumor visualization resulting from high background, such as brain tissue. The results of this case may suggest that somatostatin receptor imaging in patients with esthesioneuroblastoma may facilitate the potential application of radiotheranostic agents for the treatment of this aggressive subtype of tumors.


Assuntos
Estesioneuroblastoma Olfatório/diagnóstico por imagem , Fluordesoxiglucose F18 , Cavidade Nasal/diagnóstico por imagem , Neoplasias Nasais/diagnóstico por imagem , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estesioneuroblastoma Olfatório/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Nasais/metabolismo , Receptores de Somatostatina/metabolismo
5.
Clin Nucl Med ; 45(7): 563-565, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32433163

RESUMO

After dedicated CT and MRI, Ga-DOTATATE PET/CT was performed in a patient with a temporal bone mass with primary diagnostic considerations of an endolymphatic sac tumor versus a glomus jugulotympanicum paraganglioma. The Ga-DOTATATE PET showed mild radiotracer uptake in the mass (SUVmax, 10.9). After surgical resection, pathology revealed an endolymphatic sac tumor. Immunohistochemical staining demonstrated somatostatin receptor type 2A expression in the vasculature of the mass, but not in the tumor cells.


Assuntos
Neoplasias da Orelha/diagnóstico por imagem , Neoplasias da Orelha/patologia , Saco Endolinfático/diagnóstico por imagem , Saco Endolinfático/patologia , Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Idoso , Diagnóstico Diferencial , Neoplasias da Orelha/metabolismo , Saco Endolinfático/metabolismo , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico , Receptores de Somatostatina/metabolismo
6.
Clin Imaging ; 66: 18-22, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32442855

RESUMO

Meningiomas are the most common non-malignant primary intracranial tumors, accounting for nearly 40% of all primary brain tumors, usually expressing high levels of somatostatin receptors (SSTR), particularly SSTR2. Because 68Ga-DOTATATE targets SSTR2, it is increasingly used clinically for meningioma evaluation. While previous apparent lack of SSTR expression in meningiomas has been reported in isolated cases, these prior studies utilized Indium-111 (111In) Octreotide, which is of lesser diagnostic accuracy compared to 68Ga-DOTATATE, as well as Technetium-99m (99mTc)-DTPA scintigraphy, which necessitates an intact blood-tumor-permeability barrier. This paper presents a histopathologic proven atypical meningioma, WHO Grade II, with low level avidity on 68Ga-DOTATATE PET/MRI, subsequently proven to be SSTR2-negative by immunohistochemistry, with a review and discussion of the current literature and imaging implications.


Assuntos
Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Receptores de Somatostatina/metabolismo , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Radioisótopos de Índio , Masculino , Pessoa de Meia-Idade , Octreotida , Compostos Organometálicos , Cintilografia , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X
7.
Life Sci ; 253: 117726, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32348837

RESUMO

AIMS: Vascular smooth muscle cell (VSMC) proliferation plays a significant role in the development of various vascular disorders. However, the effect of cortistatin (CST) on VSMC proliferation remains unclear. Therefore, the purpose of our research aimed to study whether CST protected VSMCs from angiotensin II (Ang II)-induced proliferation and which mechanisms participated in the process. MAIN METHODS: Cultured rat VSMCs were treated with Ang II with or without CST for 24 h. Cell proliferation rate was measured by cell counting kit-8 (CCK8) assay. The expressions of CST and its receptors were assessed by quantitative real-time PCR (qRT-PCR). The protein expression levels were analyzed by western blots. Immunofluorescence and transmission electron microscopy (TEM) were used to observe autophagy. KEY FINDINGS: Our results showed that different concentrations of CST alleviated the Ang II-induced VSMC proliferation. The autophagy and reactive oxygen species (ROS) stimulated by Ang II were attenuated by CST. Furthermore, when the autophagy inhibitor 3-methyladenine (3-MA) was added, it exerted similar inhibition effects like CST, but didn't augment the protective role of CST on Ang II-induced VSMC autophagy and proliferation. Moreover, blocking somatostatin receptor 3 and 5 (SSTR3 and SSTR5) partially abrogated the suppressive effect of CST on Ang II-stimulated VSMC proliferation and autophagy. SIGNIFICANCE: This study indicated that CST could ameliorate Ang II-stimulated VSMC proliferation by inhibiting autophagy partially through its receptors SSTR3 and SSTR5, providing a reasonable evidence for CST as a novel perspective therapeutic target of vascular diseases.


Assuntos
Angiotensina II/administração & dosagem , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neuropeptídeos/farmacologia , Animais , Células Cultivadas , Masculino , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de Somatostatina/metabolismo
8.
Nat Commun ; 11(1): 1896, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312960

RESUMO

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Exocitose/fisiologia , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Imagem Óptica , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo
9.
Clin Nucl Med ; 45(6): e279-e280, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32332303

RESUMO

DOTA-D-Phe-Tyr-octreotide labeled with Ga (Ga-DOTATOC) is the commonly used PET tracer for imaging meningioma because of its high affinity to somatostatin receptor subtype 2 (SSTR2) and an established imaging modality for planning radiation and radionuclide therapy. However, SSTR2 is not an exclusive marker for meningioma, and not all meningiomas express high levels of SSTR2. The SSTR2 expression has been reported in other intracranial tumors, for example, glioma, pituitary adenoma, medullablastoma, primitive neuroectodermal tumors, and hemangioblastoma leading to a significant risk of misinterpretation of PET/CT findings. We present 2 cases with similar Ga-DOTATOC uptakes in 2 distinct etiologies, for example, cerebral lymphoma and meningioma.


Assuntos
Interpretação de Imagem Assistida por Computador , Octreotida/análogos & derivados , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Feminino , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/metabolismo , Meningioma/diagnóstico por imagem , Meningioma/metabolismo , Pessoa de Meia-Idade , Octreotida/metabolismo , Compostos Organometálicos/metabolismo , Receptores de Somatostatina/metabolismo
10.
Clin Nucl Med ; 45(5): e232-e235, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32209879

RESUMO

Radiolabeled somatostatin analogs for somatostatin receptor (SSTR)-targeted imaging and peptide receptor radionuclide therapy (PRRT) have demonstrated remarkable success in the management of SSTR-expressing neuroendocrine neoplasms. Primary neuroendocrine breast carcinoma is rare. Heterogeneous SSTR overexpression has also been documented in breast cancer, in both human breast cancer specimens and clinical studies. We report here a case of a 69-year-old woman who had both breast invasive ductal carcinoma and primary large-cell neuroendocrine breast carcinoma (Ki-67 proliferation index of 20%), with disseminated bone and lymph node metastases, demonstrating exceptional tracer uptake on Ga-DOTATOC PET/CT, and remarkably partial remission after Lu-DOTATOC PRRT.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Receptores de Somatostatina/metabolismo , Idoso , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Metástase Linfática , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Octreotida/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Resultado do Tratamento
11.
Sci Rep ; 10(1): 1982, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029751

RESUMO

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring. In situ hybridisation revealed that polyI:C offspring had: (1) SST mRNA reductions in the cingulate cortex and nucleus accumbens shell, regardless of MIA timing; (2) SSTR2 mRNA reductions in the cortex and striatum of GD19, but not GD10, MIA; (3) no alterations in cortical or striatal GAD1 mRNA of polyI:C offspring, but an expected reduction of PVALB mRNA in the infralimbic cortex, and; (4) no alterations in inhibitory markers in hippocampus. Maternal IL-6 response negatively correlated with adult offspring SST mRNA in cortex and striatum, but not hippocampus. These results show lasting inhibitory-related deficits in cortex and striatum in adult offspring from MIA. SST downregulation in specific cortical and striatal subregions, with additional deficits in somatostatin-related signalling through SSTR2, may contribute to some of the adult behavioural changes resulting from MIA and its timing.


Assuntos
Inibição Neural/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Esquizofrenia/imunologia , Animais , Comportamento Animal , Biomarcadores/análise , Biomarcadores/metabolismo , Córtex Cerebral/patologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Glutamato Descarboxilase/análise , Glutamato Descarboxilase/metabolismo , Hipocampo/patologia , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Interneurônios/imunologia , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Poli I-C/imunologia , Gravidez , Ratos , Receptores de Somatostatina/análise , Receptores de Somatostatina/metabolismo , Esquizofrenia/patologia , Fatores Sexuais , Transdução de Sinais/imunologia , Somatostatina/análise , Somatostatina/metabolismo , Fatores de Tempo
12.
Radiologe ; 60(5): 413-420, 2020 May.
Artigo em Alemão | MEDLINE | ID: mdl-32052116

RESUMO

CLINICAL/METHODICAL ISSUE: Conventional imaging tests like computed tomography (CT) cannot visualize somatostatin receptor (SSTR) expression on the tumor cell surface. STANDARD RADIOLOGICAL METHODS: For imaging of SSTR-expressing tumors conventional morphological imaging tests such as CT or magnetic resonance imaging (MRI) are employed. METHODICAL INNOVATIONS: Molecular imaging of SSTR expression on the tumor cell surface, in particular by using (whole body) single photon emission computed tomography (SPECT) and positron emission tomography (PET), are considered the current standard of care. Only the use of CT enables for exact localization of putative sites of disease (hybrid imaging). PERFORMANCE: Hybrid SPECT/CT and PET/CT are of utmost importance for staging and monitoring of treatment efficacy. SSTR-PET is superior to SPECT and the PET radiotracer 68Ga-DOTATATE has been approved in multiple countries. In addition, SSTR positivity revealed by SPECT or PET pave the way for a peptide receptor radionuclide therapy (PRRT). Such a theranostic approach enables for systemic or locoregional radiation with ß­emitting radionuclides, which are linked to the identical amino acid peptide used for PET or SPECT imaging. The prospective, randomized Netter­1 trial has shown significant benefit for patients receiving PRRT. ACHIEVEMENTS: A combined use of conventional and functional imaging tests is superior to conventional imaging alone and allows for identification of suitable candidates for a theranostic approach. PRACTICAL RECOMMENDATIONS: In case of clinical suspicion or after having obtained histological evidence, hybrid SSTR-SPECT/CT or -PET/CT should be performed, preferably in a dedicated molecular imaging center.


Assuntos
Imagem Multimodal , Neoplasias/diagnóstico por imagem , Receptores de Somatostatina/metabolismo , Nanomedicina Teranóstica , Humanos , Neoplasias/química , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ensaios Clínicos Controlados Aleatórios como Assunto , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
13.
Sci Rep ; 10(1): 371, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941913

RESUMO

Acute myeloid leukemia (AML) is characterized by relapse and treatment resistance in a major fraction of patients, underlining the need of innovative AML targeting therapies. Here we analysed the therapeutic potential of an innovative biohybrid consisting of the tumor-associated peptide somatostatin and the photosensitizer ruthenium in AML cell lines and primary AML patient samples. Selective toxicity was analyzed by using CD34 enriched cord blood cells as control. Treatment of OCI AML3, HL60 and THP1 resulted in a 92, and 99 and 97% decrease in clonogenic growth compared to the controls. Primary AML cells demonstrated a major response with a 74 to 99% reduction in clonogenicity in 5 of 6 patient samples. In contrast, treatment of CD34+ CB cells resulted in substantially less reduction in colony numbers. Subcellular localization assays of RU-SST in OCI-AML3 cells confirmed strong co-localization of RU-SST in the lysosomes compared to the other cellular organelles. Our data demonstrate that conjugation of a Ruthenium complex with somatostatin is efficiently eradicating LSC candidates of patients with AML. This indicates that receptor mediated lysosomal accumulation of photodynamic metal complexes is a highly attractive approach for targeting AML cells.


Assuntos
Leucemia Mieloide Aguda/terapia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Receptores de Somatostatina/metabolismo , Rutênio/uso terapêutico , Somatostatina/uso terapêutico , Adulto , Idoso , Apoptose , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Feminino , Sangue Fetal/metabolismo , Humanos , Lisossomos/metabolismo , Masculino , Pessoa de Meia-Idade , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo
14.
BMC Cancer ; 20(1): 27, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924180

RESUMO

BACKGROUND: High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. METHOD: Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier's method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5-30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1-30%), and abnormal when negative (0%) or strongly positive (> 30%). RESULTS: In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. CONCLUSION: Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.


Assuntos
Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Cromogranina A/metabolismo , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Neuroendócrino/etiologia , Carcinoma Neuroendócrino/mortalidade , Linhagem Celular Tumoral , Feminino , Seguimentos , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
15.
Surgery ; 167(1): 189-196, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629542

RESUMO

BACKGROUND: Neuroendocrine tumors are found throughout the body, including the pancreas. These tumors are phenotypically and genetically heterogeneous and can be difficult to accurately image using current imaging standards. However, positron emission tomography/computed tomography with radiolabeled somatostatin analogs has shown clinical success because many neuroendocrine tumors overexpress somatostatin receptor subtype 2. Unfortunately, patients with poorly differentiated neuroendocrine tumors often have a diminished level of somatostatin receptor subtype 2. We found that histone deacetylase inhibitors can upregulate the functional expression of somatostatin receptor subtype 2. METHODS: We evaluated the effect of histone deacetylase inhibitors on somatostatin receptor subtype 2 expression at the mRNA and protein level in neuroendocrine tumor cell lines. The effect of histone deacetylase inhibitors on surface somatostatin receptor subtype 2 was also investigated by fluorescence-activated cell sorting analysis. Changes in somatostatin receptor subtype 2 expression in neuroendocrine tumor xenografts after treatment were imaged using Ga68-DOTATATE positron emission tomography/computed tomography. RESULTS: The functional increase of somatostatin receptor subtype 2 in neuroendocrine tumors after histone deacetylase inhibitor treatment was confirmed through in vitro experiments and small animal Ga68-DOTATATE positron emission tomography/computed tomography imaging. Histone deacetylase inhibitors increased somatostatin receptor subtype 2 transcription and protein expression in neuroendocrine tumor cell lines. Small animal Ga68-DOTATATE positron emission tomography/computed tomography imaging confirmed the enhancement of radiopeptide uptake after histone deacetylase inhibitor administration. CONCLUSION: This study demonstrates a new method to potentially improve imaging and treatments that target somatostatin receptor subtype 2 in neuroendocrine tumors.


Assuntos
Inibidores de Histona Desacetilases/administração & dosagem , Imagem Molecular/métodos , Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Receptores de Somatostatina/metabolismo , Animais , Linhagem Celular Tumoral , Separação Celular , Depsipeptídeos/administração & dosagem , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Tumores Neuroendócrinos/patologia , Compostos Organometálicos/administração & dosagem , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Análise Serial de Tecidos , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Talanta ; 208: 120286, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816809

RESUMO

Tumor markers play an important role in the early diagnosis and therapeutic effect monitoring of tumors. An electrochemical biosensor was developed based on multi-branched gold nanoshells (BGSs) and octreotide (OCT) functionalized Pt nano-flakes (PtNFs) modified electrodes, which was used for detection of tumor-specific markers to evaluate tumor cells. Sandwich-type nano-hybrid materials were prepared by layer-by-layer modification. First, reduced graphene oxide (RGO) and BGSs were modified as electronic materials onto glassy carbon electrodes (GCE). This modified electrode has strong electron transfer capability and large electrode surface area. The OCT was then anchored to the surface of BGSs to sensitively detect Somatostatin receptors (SSTRs) on the surface of HeLa cells. In addition, PtNFs were synthesized using a dual-template method, and OCT template on the surface of PtNFs, as an adsorption bioprobe, was used to reduce the H2O2 and amplify the electrochemical signal of biosensor. The proposed biosensor can be applied to the quantitative broad linear range of HeLa cells covering from 10 to 1 × 106 cells mL-1 (R2 = 0.9998) and the limit of detection (LOD) was 2 cells mL-1. The experimental results also show that the sensor has good stability, biocompatibility and high selectivity, which has great potential for clinical application.


Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Nanopartículas Metálicas/química , Octreotida/administração & dosagem , Platina/química , Receptores de Somatostatina/metabolismo , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/química , Eletrodos , Ouro/química , Células HeLa , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Octreotida/química
17.
Brain Struct Funct ; 225(1): 387-401, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31873798

RESUMO

Inhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80-90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.


Assuntos
Interneurônios/química , Receptores de Somatostatina/análise , Córtex Somatossensorial/química , Animais , Interneurônios/citologia , Interneurônios/metabolismo , Masculino , Camundongos Transgênicos , Parvalbuminas/análise , Receptores de Somatostatina/metabolismo , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Somatostatina/análise , Peptídeo Intestinal Vasoativo/análise
18.
J Cell Biol ; 219(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31825461

RESUMO

The surfacing of the glucose transporter GLUT4 driven by insulin receptor activation provides the prototypic example of a homeostasis response dependent on mobilization of an intracellular storage compartment. Here, we generalize this concept to a G protein-coupled receptor, somatostatin receptor subtype 2 (SSTR2), in pituitary cells. Following internalization in corticotropes, SSTR2 moves to a juxtanuclear syntaxin-6-positive compartment, where it remains until the corticotropes are stimulated with corticotropin releasing factor (CRF), whereupon SSTR2 exits the compartment on syntaxin-6-positive vesicular/tubular carriers that depend on Rab10 for their fusion with the plasma membrane. As SSTR2 activation antagonizes CRF-mediated hormone release, this storage/resurfacing mechanism may allow for a physiological homeostatic feedback system. In fact, we find that SSTR2 moves from an intracellular compartment to the cell surface in pituitary gland somatotropes, concomitant with increasing levels of serum growth hormone (GH) during natural GH cycles. Our data thus provide a mechanism by which signaling-mediated plasma membrane resurfacing of SSTR2 can fine-tune pituitary hormone release.


Assuntos
Corticotrofos/metabolismo , Hormônio do Crescimento Humano/metabolismo , Hipófise/metabolismo , Proteínas Qa-SNARE/metabolismo , Receptores de Somatostatina/metabolismo , Proteínas rab de Ligação ao GTP/fisiologia , Animais , Hormônio Liberador da Corticotropina , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipófise/citologia , Proteínas Qa-SNARE/genética , Receptores de Somatostatina/genética , Transdução de Sinais
19.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835716

RESUMO

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.


Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Somatostatina/agonistas , Administração Oral , Analgésicos/química , Animais , Células CHO , Doença Crônica , Cricetinae , Cricetulus , Diterpenos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Inflamação/patologia , Ligantes , Masculino , Camundongos , Simulação de Dinâmica Molecular , Neuralgia/complicações , Neuralgia/patologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/química , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores de Somatostatina/metabolismo
20.
Neuropeptides ; 78: 101976, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668651

RESUMO

Itch is a somatosensory sensation that informs the organism about the presence of potentially harmful substances or parasites, and initiates scratching to remove the threat. Itch-inducing (pruritogenic) substances activate primary afferent neurons in the skin through interactions with specific receptors that converts the stimulus into an electrical signal. These signals are conveyed to the dorsal horn of the spinal cord through the release of neurotransmitters such as natriuretic polypeptide b and somatostatin, leading to an integrated response within a complex spinal interneuronal network. A large sub-population of somatostatin-expressing spinal interneurons also carry the Neuropeptide Y (NPY) Y1 receptor, indicating that NPY and somatostatin partly regulate the same neuronal pathway. This review focuses on recent findings regarding the role of the NPY/Y1 and somatostatin/SST2A receptor in itch, and also presents data integrating the two neurotransmitter systems.


Assuntos
Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Prurido/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Medula Espinal/metabolismo , Animais , Humanos , Vias Neurais/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo
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