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1.
Molecules ; 24(17)2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31450691

RESUMO

The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1-2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to overcome the need for continuous infusion regimes. Multilamellar liposomes made of natural phosphatidylcholine were used for the incorporation of a mixture of somatostatin and sorbitol dissolved in citrate buffer at pH = 5. Lyophilization and reconstitution of the suspension were carried out, showing the flexibility of this preparation. Full characterization of this suspension was obtained as particle size, encapsulation efficiency and retarded release properties in aqueous medium and human plasma. Liposomal somatostatin incubated at 37 °C in the presence of Fe(II) and (III) salts were used as a biomimetic model of drug-cell membrane interaction, evidencing the free radical processes of peroxidation and isomerization that transform the unsaturated fatty acid moieties of the lipid vesicles. This study offers new insights into a liposomal delivery system and highlights molecular reactivity of sulfur-containing drugs with its carrier or biological membranes for pharmacological applications.


Assuntos
Lipossomos/química , Somatostatina/química , Somatostatina/farmacologia , Tampões (Química) , Cromatografia Líquida , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Radicais Livres/química , Humanos , Lipídeos/química , Espectrometria de Massas , Estrutura Molecular , Somatostatina/farmacocinética
2.
J Vet Pharmacol Ther ; 42(5): 541-547, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325161

RESUMO

Equine metabolic syndrome (EMS) is prevalent in the equine population, and somatostatin analogs might be useful for diagnosis and/or treatment of EMS in horses. The purpose of this study was to evaluate the glucose and insulin responses to subcutaneous and intravenous administration of somatostatin. Six healthy research horses were included in this prospective study. An initial pilot study was performed to assess several different doses (10-22 µg/kg [4.5-10 µg/lb]) in two horses, then a final dosage of 22 µg/kg (10 µg/lb) was administered to six horses IV and SQ in a two-period randomized cross-over study performed over a 3-month study period. Blood samples were collected for measurement of plasma insulin and glucose concentrations during a 24-hr study period. Both IV and SQ somatostatin resulted in decreased insulin and increased glucose concentrations. SQ somatostatin resulted in a longer clinical effect, with return to baseline insulin occurring at 1.5 hr postadministration, versus 45 min for IV. Both IV and SQ administration of somatostatin to normal horses resulted in decreased insulin and increased glucose concentrations, likely due to suppression of insulin secretion by somatostatin. A more prolonged effect was seen following SQ administration as compared to IV administration, and no adverse effects were noted at varying doses. This study provides additional information regarding the effect of somatostatin administration on insulin and glucose concentrations in clinically healthy horses.


Assuntos
Glicemia , Hormônios/farmacologia , Cavalos/sangue , Insulina/sangue , Somatostatina/farmacologia , Administração Intravenosa , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Hormônios/administração & dosagem , Injeções Subcutâneas , Somatostatina/administração & dosagem
3.
Amino Acids ; 51(9): 1247-1257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31350614

RESUMO

Somatostatin (SST) is an endogenous cyclic tetradecapeptide hormone that exerts multiple biological activities via a family of five receptors. BIM-23052 (DC-23-99) D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 is a linear SST analog with established in vitro GH-inhibitory activity and high affinity to sstr5, sstr3 and sstr2. The different SSTR subtypes are expressed in different tissues and in some tumor cells. Based on this finding, a series of new analogs of BIM-23052 with expected antitumor activity have been synthesized. The Thr at position 6 in BIM-23052 was replaced by the conformationally hindered Tle, Aib, Ac5c and Ac6c of the new analogs. The peptides were synthesized by standard solid-phase peptide chemistry methods, Fmoc strategy. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29, MDA-MB-23, Hep-G2, HeLa and the normal human diploid cell line Lep-3. All five somatostatin receptor subtypes were modeled and docking was performed to determine the binding affinity of the analogs. The new peptides exhibited different concentration-dependent antiproliferative effect on the tumor cell lines after 24 h of treatment. The compound 3B (Aib6) demonstrated the most pronounced antiproliferative effects on HepG-2 cells with the IC50 = 0.01349 nM. Docking confirmed that all compounds bind well to SST receptors with preference to sstr3 and sstr5, which is most probably the reason for the observed biological effects.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Somatostatina/análogos & derivados , Aminoácidos Cíclicos/química , Ácidos Aminoisobutíricos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ácidos Cicloexanocarboxílicos/química , Cicloleucina/química , Células HT29 , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Receptores de Somatostatina/química , Somatostatina/química , Somatostatina/farmacologia , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234481

RESUMO

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.


Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Animais , Antineoplásicos Hormonais/uso terapêutico , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Humanos , Tumores Neuroendócrinos/metabolismo , Octreotida/metabolismo , Octreotida/farmacologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Receptores de Somatostatina/metabolismo , Transdução de Sinais , Somatostatina/metabolismo , Somatostatina/farmacologia , Somatostatina/uso terapêutico
5.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212595

RESUMO

Pasireotide is a multi-receptor ligand somatostatin analogue approved for medical treatment of Cushing's disease and acromegaly. The liquid-phase total synthesis of pasireotide-a 18-membered cyclic hexapeptide-was achieved by the 3 + 2 + 1 strategy, and the Pro1-Phe6 peptide bond was selected as the final cyclization position. Two key fragments were simply synthesized using N,O-bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents, and processes of the two key fragments were simple without any chromatographic purification. The current synthesis method is easily scalable and produces the target peptide with an overall yield of 15%.


Assuntos
Somatostatina/análogos & derivados , Cromatografia Líquida de Alta Pressão , Humanos , Hidrólise , Espectrometria de Massas , Estrutura Molecular , Oligopeptídeos , Peptídeos Cíclicos , Somatostatina/síntese química , Somatostatina/química , Somatostatina/farmacologia
6.
PLoS One ; 14(6): e0218953, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237925

RESUMO

Somatostatin analogues (SSA) represent the standard of care for symptom control in patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In addition, SSA exert significant anti-proliferative effects in mid-gut and pancreatic NET (PanNET). In parallel, molecularly targeted therapies (MTT) have been shown to improve progression free survival (PFS) in patients with PanNET. However, due to either primary or acquired resistance to MTT, their impact on overall survival (OS) remains unclear. To date, various hypotheses exist to explain differences in patient responsiveness to SSA and MTT. However, data addressing one of the most pivotal questions, whether combining SSA with novel MTT will result in synergistic or additive efficacy compared to monotherapy, are lacking. The aim of this study is to characterize the interaction, optimal sequence and dosing of SSA-based and molecularly targeted therapies in PanNET. Somatostatin receptor subtypes 1-5 (SSTR) were evaluated in the neuroendocrine cell lines Bon1, QGP1 and Ins-1 via immunoblot and qRT-PCR. The impact of the SSA-analogue lanreotide alone or in combination with the MTT sunitinib, everolimus and regorafenib on intracellular signalling, hormone secretion and cell proliferation was determined in cell lysates and supernatants. In addition, synergistic effects of SSA and MTT in various sequential therapeutic approaches were investigated. SSTR were differently expressed in the examined neuroendocrine tumor cell lines. SSTR modulation via lanreotide moderately influenced proliferation, mainly via modulating AKT and ERK signalling, which was paralleled by decreased chromogranin A (CgA) expression and secretion. Interestingly, MTT treatment with regorafenib upregulated the expression of SSTR-2 and -5, while sunitinib and everolimus did not significantly alter SSTR expression. Cell viability was significantly reduced by all MTT, with regorafenib exerting the most significant effects. However, compared to the marked effects of MTT alone, synergistic effects of combined MTT and lanreotide treatment were only modest and time- and dose-dependent. SSTR are differentially expressed in various NEN cell lines. Their expression is influenced by MTT treatment. Various sequential or simultaneous combinations of lanreotide and MTT did not lead to significant synergistic effects.


Assuntos
Antineoplásicos/administração & dosagem , Terapia de Alvo Molecular/métodos , Tumores Neuroendócrinos/metabolismo , Peptídeos Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Somatostatina/análogos & derivados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Everolimo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Somatostatina/farmacologia , Sunitinibe/farmacologia , Resultado do Tratamento
7.
Invest Ophthalmol Vis Sci ; 60(6): 2257-2262, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31112610

RESUMO

Purpose: Structural retinal microvascular changes have been identified as risk markers of diabetic retinopathy (DR). In order to estimate the retinal response of neuroprotective eye drops, we aimed to evaluate the effect of topical retinal neuroprotection on retinal microvascular changes in early DR. Methods: Patients with type 2 diabetes with no or early DR were randomized 1:1:1 to topical treatment with placebo, brimonidine, or somatostatin in a 96-week prospective, phase II to III, European multicenter trial. Retinal vascular calibers were measured semiautomatically in digital fundus images by certified graders at baseline and follow-up and summarized as central retinal arteriolar and venular equivalent (CRAE and CRVE). Results: Of 449 patients originally included, 297 completed the study with gradable retinal images. Median age and duration of diabetes was 64.5 and 9.9 years, and 65.7% were male. At baseline, Early Treatment Diabetic Retinopathy Study levels were 10 (no DR, 42.8%), 20 (minimal DR, 28.3%), and 35 (mild DR, 29.0%), and CRAE and CRVE did not differ between groups. As opposed to patients with no or minimal DR at baseline, patients with mild DR in the active groups developed a larger retinal arteriolar (brimonidine: +6.2 µm, P = 0.006; somatostatin: +7.2 µm, P = 0.006) and venular (brimonidine: +13.9 µm, P = 0.01; somatostatin: +14.3 µm, P = 0.0001) caliber in contrast to those in the placebo group. Conclusions: Topical treatment with brimonidine and somatostatin causes retinal arteriolar and venular dilation in patients with type 2 diabetes and preexisting early DR. Upcoming studies should elaborate on the potential of these findings in arresting early DR.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Tartarato de Brimonidina , Retinopatia Diabética/tratamento farmacológico , Fármacos Neuroprotetores , Vasos Retinianos/efeitos dos fármacos , Somatostatina , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Adulto , Idoso , Tartarato de Brimonidina/farmacologia , Tartarato de Brimonidina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estudos Prospectivos , Somatostatina/farmacologia , Somatostatina/uso terapêutico
8.
Int J Mol Sci ; 20(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121844

RESUMO

"Small-for-size" livers arising in the context of liver resection and transplantation are vulnerable to the effects of increased portal flow in the immediate postoperative period. Increased portal flow is an essential stimulus for liver regeneration. If the rise in flow and stimulus for regeneration are excessive; however, liver failure and patient death may result. Somatostatin is an endogenous peptide hormone that may be administered exogenously to not only reduce portal blood flow but also offer direct protection to different cells in the liver. In this review article, we describe key changes that transpire in the liver following a relative size reduction occurring in the context of resection and transplantation and the largely beneficial effects that peri-operative somatostatin therapy may help achieve in this setting.


Assuntos
Hormônios/uso terapêutico , Fígado/efeitos dos fármacos , Somatostatina/uso terapêutico , Animais , Hepatectomia , Hormônios/metabolismo , Hormônios/farmacologia , Humanos , Fígado/fisiologia , Regeneração Hepática/efeitos dos fármacos , Transplante de Fígado , Tamanho do Órgão/efeitos dos fármacos , Somatostatina/metabolismo , Somatostatina/farmacologia
9.
Neurobiol Learn Mem ; 162: 9-14, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047997

RESUMO

Nociceptin/Orphanin FQ (N/OFQ) plays an important role in the regulation of spatial, fear and recognition memories. N/OFQ receptors are highly distributed in the perirhinal cortex, which is a key brain area involved in modulating novel object recognition (NOR) memory. However, the role of N/OFQ in NOR memory in the perirhinal cortex was still unknown. Moreover, the effects of N/OFQ on different stages of NOR memory were still unclear. In NOR task, we found that pre-training intracerebroventricular (icv) injection of N/OFQ (0.3 and 1 nmol) impaired long-term memory in a dose-dependent manner. However, icv infusion of N/OFQ immediately after training did not affect NOR memory consolidation even at a high dose of 3 nmol. Pre-test icv injection of N/OFQ (1 nmol) also did not influence NOR memory retrieval. These data indicate that N/OFQ negatively modulates long-term NOR memory during the acquisition phase. Furthermore, the amnesia effect of N/OFQ (1 nmol, icv) could be antagonist by pre-treatment with the selective N/OFQ receptor antagonist [Nphe1]N/OFQ(1-13)NH2 (10 nmol, icv), indicating pharmacological specificity. Then, we found that pre-training infusion of N/OFQ (0.1 and 0.3 nmol/side) into the bilateral perirhinal cortex impaired long-term NOR memory, suggesting the perirhinal cortex is a critical brain structure in mediating the amnesic effect of N/OFQ in NOR task. In conclusion, our data, for the first time, indicate that N/OFQ in the perirhinal cortex impairs NOR memory acquisition through the NOP receptors.


Assuntos
Memória de Longo Prazo/efeitos dos fármacos , Peptídeos Opioides/farmacologia , Córtex Perirrinal/efeitos dos fármacos , /efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Somatostatina/análogos & derivados , Somatostatina/farmacologia
10.
Neuroscience ; 408: 400-417, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981862

RESUMO

Intrinsically photosensitive retinal ganglion cells (ipRGCs) encode light intensity and trigger reflexive responses to changes in environmental illumination. In addition to functioning as photoreceptors, ipRGCs are post-synaptic neurons in the inner retina, and there is increasing evidence that their output can be influenced by retinal neuromodulators. Here we show that opioids can modulate light-evoked ipRGC signaling, and we demonstrate that the M1, M2 and M3 types of ipRGCs are immunoreactive for µ-opioid receptors (MORs) in both mouse and rat. In the rat retina, application of the MOR-selective agonist DAMGO attenuated light-evoked firing ipRGCs in a dose-dependent manner (IC50 < 40 nM), and this effect was reversed or prevented by co-application of the MOR-selective antagonists CTOP or CTAP. Recordings from solitary ipRGCs, enzymatically dissociated from retinas obtained from melanopsin-driven fluorescent reporter mice, confirmed that DAMGO exerts its effect directly through MORs expressed by ipRGCs. Reduced ipRGC excitability occurred via modulation of voltage-gated potassium and calcium currents. These findings suggest a potential new role for endogenous opioids in the mammalian retina and identify a novel site of action-MORs on ipRGCs-through which opioids might exert effects on reflexive responses to environmental light.


Assuntos
Receptores Opioides mu/antagonistas & inibidores , Células Ganglionares da Retina/metabolismo , Analgésicos Opioides/farmacologia , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos/farmacologia , Ratos , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Somatostatina/análogos & derivados , Somatostatina/farmacologia
11.
Exp Eye Res ; 184: 15-23, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30978347

RESUMO

PURPOSE: To assess the effect of somatostatin (SST) on the permeability of human retinal pigment epithelial cells. METHODS: We conducted two experiments, exposing cells from human-fetal retinal pigment epithelium (hfRPE) cultures to vascular endothelial growth factor (VEGF), with or without SST pretreatment, in one, and to hypoxic conditions, again with or without SST pretreatment, in the other. The paracellular permeability of hfRPE was assessed by measuring transepithelial electrical resistance (TER) and fluorescein isothiocyanate-sodium (FITC-sodium) flux. Immunochemistry analysis was used to assess the expression of occludin and Zonula occludens-1(ZO-1). RESULTS: Both VEGF and hypoxia increased permeability of the hfRPE, as measured by TER and tracer flux, and decreased occludin and ZO-1staining, as measured by immunochemistry. Pretreatment of cultures with SST partially counteracted these effects. CONCLUSIONS: Somatostatin may play a role in the regulation of permeability across retinal pigment epithelium. It may act as an anti-permeability factor in the retina through the enhancement of tight junction function.


Assuntos
Hormônios/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Somatostatina/farmacologia , Barreira Hematorretiniana/efeitos dos fármacos , Permeabilidade da Membrana Celular , Células Cultivadas , Impedância Elétrica , Fluoresceína/metabolismo , Humanos , Hipóxia/metabolismo , Imunoquímica , Ocludina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteína da Zônula de Oclusão-1/metabolismo
12.
Cell Physiol Biochem ; 52(3): 486-502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873823

RESUMO

BACKGROUND/AIMS: Cross-talk between different pancreatic islet cell types regulates islet function and somatostatin (SST) released from pancreatic delta cells inhibits insulin secretion from pancreatic beta cells. In other tissues SST exhibits both protective and pro-apoptotic properties in a tissue-specific manner, but little is known about the impact of the peptide on beta cell survival. Here we investigate the specific role of SST in the regulation of beta cell survival in response to physiologically relevant inducers of cellular stress including palmitate, cytokines and glucose. METHODS: Pancreatic MIN6 beta cells and primary mouse islet cells were pre-treated with SST with or without the Gi/o signalling inhibitor, pertussis toxin, and exposed to different cellular stress factors. Apoptosis and proliferation were assessed by measurement of caspase 3/7 activity, TUNEL and BrdU incorporation, respectively, and expression of target genes was measured by qPCR. RESULTS: SST partly alleviated upregulation of cellular stress markers (Hspa1a and Ddit3) and beta cell apoptosis in response to factors such as lipotoxicity (palmitate), pro-inflammatory cytokines (IL1ß and TNFα) and low glucose levels. This effect was mediated via a Gi/o protein-dependent pathway, but did not modify transcriptional upregulation of the specific NFκB-dependent genes, Nos2 and Ccl2, nor was it associated with transcriptional changes in SST receptor expression. CONCLUSION: Our results suggest an underlying protective effect of SST which modulates the beta cell response to ER stress and apoptosis induced by a range of cellular stressors associated with type 2 diabetes.


Assuntos
Proliferação de Células/efeitos dos fármacos , Glucose/antagonistas & inibidores , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Toxina Pertussis/antagonistas & inibidores , Somatostatina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Regulação da Expressão Gênica , Glucose/farmacologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/farmacologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Toxina Pertussis/farmacologia , Técnicas de Cultura de Tecidos , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia
13.
J Mol Neurosci ; 68(1): 120-134, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30879180

RESUMO

Somatostatin (SST) is a growth hormone inhibitory peptide involved in regulation of several physiological responses of cells including neurotransmission, cell migration, maturation, and neurite formation. In the present study, we examined the role of SST in all-trans retinoic acid (RA)-induced progression of neurite outgrowth in SH-SY5Y cells. We also determined the morphological and developmental changes in prominent intracellular markers of neurite growth including microtubule-associated protein 2 (MAP2), neuron-specific III ß-tubulin (TUJ1), and Tau. Here, we present evidence that SST is a molecular determinant in regulating the transition of SH-SY5Y cells from non-neuronal entity to neuronal phenotype in response to RA. The results from present study reveal that SST changes the distributional pattern of MAP2/Tau and TUJ1, and activates extracellular signal-regulated kinase (ERK1/2) signaling pathway through SST receptors (SSTRs). The expression of MAP2 and Tau remains elevated upon treatment with RA and SST alone or in combination. Importantly, we identified that the cells displaying strong co-expression of SST and TUJ1 are more likely to bear elongated neurite formation than cells devoid of such expression. These findings show that the site-specific expression of MAP2 and TUJ1 is an essential determinant of neurite outgrowth in SH-SY5Y cells in RA-mediated differentiation. Taken together, results presented here further substantiates the role of SST in the promotion of neurite formation and elongation in SH-SY5Y cells in combination with RA. Investigating how SST can improve neurite formation in neurodegenerative disease may help to develop new therapeutic approach in improving cognitive function and memory loss.


Assuntos
Proteínas Associadas aos Microtúbulos/metabolismo , Crescimento Neuronal , Somatostatina/farmacologia , Tretinoína/farmacologia , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Somatostatina/metabolismo , Tubulina (Proteína)/metabolismo
14.
Methods Mol Biol ; 1957: 271-289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30919360

RESUMO

Primary cilia (PC) are microtubule-based organelles that behave like a cellular antenna controlling key signaling pathways during development and tissue homeostasis. The ciliary membrane is highly enriched for G protein-coupled receptors (GPCRs), and PC are a crucial signaling compartment for this large receptor family. Downstream effectors of GPCR signaling are also present in cilia, and evidence obtained by our labs and others demonstrated that ß-arrestin (ßarr) family members are differentially recruited to PC and have investigated the role of GPCR activation in this process. In this chapter, we provide methods based on fluorescence microscopy on fixed or live cells suitable for investigating targeting and recruitment of ßarrs at PC.


Assuntos
Corpos Basais/metabolismo , Centrossomo/metabolismo , Cílios/metabolismo , Microscopia de Fluorescência/métodos , beta-Arrestina 2/metabolismo , Animais , Corpos Basais/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Centrossomo/efeitos dos fármacos , Cílios/efeitos dos fármacos , DNA/metabolismo , Recuperação de Fluorescência Após Fotodegradação , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Plasmídeos/metabolismo , Somatostatina/farmacologia
16.
Georgian Med News ; (286): 116-122, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30829602

RESUMO

Anterior cingulate cortex (ACC), which is activated by noxious stimuli, is involved in pain processing, the neural mechanisms of the ACC involvement in affective pain have yet to be elaborated. To study relation antinociceptive effects induced by non-steroidal anti-inflammatory drugs (NSAIDs) with endogenous opioid system we treated experimental rats with opioid receptor antagonists, naloxone and CTOP in the ACC pre- and post-following microinjections with NSAIDs. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds in rats' formalin test following microinjections of NSAIDs (diclofenac, ketoprofen, ketorolac and lornoxicam), saline or opioid receptor antagonists, naloxone and CTOP in the ACC. Five minutes following intraplantar formalin injection all animals showed a significant reduction in thermal paw withdrawal latency and mechanical withdrawal threshold compared to pre-baseline values. Fifteen minutes after formalin injection, diclofenac, ketoprofen, ketorolac and lornoxicam clearly showed antinociceptive effects of NSAIDs. When pretreated with naloxone and CTOP we found a significant reduction of analgesic effects of NSAIDs as well as post-treatment of these completely abolished NSAIDs-induced antinociception. We demonstrated that microinjection widely used non-opioid, NSAID analgesics, diclofenac, ketoprofen, ketorolac and lornoxicam injected into the rostral part of the ACC, induced antinociception in rats. The present findings support the concept that NSAIDs-evoked antinociception is mediated via descending endogenous opioid system.


Assuntos
Anti-Inflamatórios não Esteroides , Giro do Cíngulo , Naloxona , Somatostatina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Cetorolaco/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes , Percepção da Dor , Ratos , Ratos Wistar , Somatostatina/farmacologia
17.
Curr Radiopharm ; 12(2): 156-170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827276

RESUMO

BACKGROUND: Pancreatic Neuroendocrine Tumors (PNETs) are rare neoplasms, sporadic or familial, even being part of a syndrome. Their diagnosis is based on symptoms, hormonal disorders or may be fortuitous. The role of Nuclear Medicine is important, mainly because of the possibility of a theranostic strategy. This approach is allowed by the availability of biochemical agents, which may be labeled with radionuclides suitable for diagnostic or therapeutic purposes, showing almost identical pharmacokinetics. The major role for radiopharmaceuticals is connected with radiolabeled Somatostatin Analogues (SSA), since somatostatin receptors are highly expressed on some of the neoplastic cell types. DISCUSSION: Nowadays, in the category of radiolabeled SSA, although 111In-pentetreotide, firstly commercially proposed, is still used, the best choice for diagnosis is related to the so called DOTAPET radiotracers labeled with 68-Gallium (Ga), such as 68Ga-DOTATATE, 68Ga-DOTANOC, and 68Ga-DOTATOC. More recently, labeling with 64-Copper (Cu) (64Cu-DOTATATE) has also been proposed. In this review, we discuss the clinical interest of a SAA (Tektrotyd©) radiolabeled with 99mTc, a gamma emitter with better characteristics, with respect to 111Indium, radiolabeling Octreoscan ©. By comparing both pharmacokinetics and pharmacodynamics of Octreoscan©, Tektrotyd© and PET DOTA-peptides, on the basis of literature data and of our own experience, we tried to highlight these topics to stimulate further studies, individuating actual clinical indications for all of these radiotracers. CONCLUSION: In our opinion, Tektrotyd© could already find its applicative dimension in the daily practice of NETs, either pancreatic or not, at least in centers without a PET/CT or a 68Ga generator. Because of wider availability, a lower cost, and a longer decay, compared with respect to peptides labeled with 68Ga, it could be also proposed, in a theranostic context, for a dosimetry evaluation of patients undergoing Peptide Receptor Radionuclide Therapy (PRRT), and for non-oncologic indications of radiolabelled SSA. In this direction, and for a more rigorous cost/effective evaluation, more precisely individuating its clinical role, further studies are needed.


Assuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Peptídeos/química , Tomografia por Emissão de Pósitrons/instrumentação , Compostos Radiofarmacêuticos/farmacologia , Tecnécio/química , Animais , Raios gama , Humanos , Camundongos , Octreotida/análogos & derivados , Octreotida/farmacologia , Compostos Organometálicos/farmacologia , Compostos de Organotecnécio/farmacologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/instrumentação , Radioisótopos/farmacologia , Somatostatina/análogos & derivados , Somatostatina/farmacologia
18.
Am J Clin Nutr ; 109(2): 335-344, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722001

RESUMO

Background: Reduced appetite and weight loss are common after esophagectomy (ES), and this cohort demonstrates an exaggerated postprandial satiety gut hormone response. Satiety gut hormones modulate food reward, resulting in reduced energy intake. Objectives: This study aimed to determine the effect of satiety gut hormone modulation by measuring the effect of the somatostatin analog octreotide on appetitive behavior among patients after ES. Methods: In this randomized, double-blind, placebo-controlled crossover study, patients ≥1 y after ES and matched controls received either 1 mL 0.9% saline or 1 mL (100 µg) octreotide subcutaneously before completing a progressive ratio task. A measure of appetitive behavior, this task requires subjects to undertake progressively increasing amounts of work to obtain a sweet-fat reinforcer; the final completed increment (breakpoint) represents reinforcer reward value. Separate cohorts were studied in the fasted or 1-h postprandial states. Results: Thirty-six subjects (ES, n = 18; matched controls, n = 18) were studied. The ES subjects were 2.5 ± 0.3 y postoperation and had a weight loss of 14.6% ± 2.6% and elevated postprandial glucagon-like peptide 1 compared with controls (49.2 ± 13.4 compared with 20.2 ± 2.3 pM; P = 0.04). Octreotide did not alter the breakpoint among ES or control subjects when tested in a fasting condition (ES: 980 ± 371 compared with 1700 ± 584 clicks; P = 0.16; controls: 1056 ± 274 compared with 1124 ± 273 clicks; P = 0.81). When tested 1 h postprandially, octreotide was associated with an increased breakpoint compared with placebo among ES subjects (322 ± 143 compared with 246 ± 149 clicks; P = 0.04) but not controls (248 ± 119 compared with 247 ± 120 clicks; P = 0.97). Conclusions: Attenuation of the exaggerated postprandial satiety gut hormone response is associated with increased appetitive behavior toward a sweet-fat stimulus among patients post-ES. Suppression of satiety gut hormones may be a novel target to increase appetite, food intake, and body weight among patients after ES. This study was registered at clinicaltrials.gov as NCT02381249.


Assuntos
Apetite , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Esôfago/cirurgia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Resposta de Saciedade , Somatostatina/farmacologia , Adulto , Apetite/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Hormônios Gastrointestinais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Período Pós-Prandial , Saciação/efeitos dos fármacos , Resposta de Saciedade/efeitos dos fármacos , Somatostatina/análogos & derivados , Somatostatina/metabolismo
19.
PLoS One ; 14(2): e0206309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30807575

RESUMO

BACKGROUND: Signaling through mTOR and somatostatin pathway is implicated in thyroid cancer development. METHOD: We evaluated everolimus, an mTOR inhibitor and pasireotide, a multi receptor somatostatin analogue as potential therapy of thyroid cancer focusing on the in vitro and in vivo efficacy, as well as possible mechanism to explain any observed interaction. RESULTS: Both everolimus and pasireotide inhibit the growth of thyroid cancer cell lines in vitro with varied efficacy that correlates with tumor origin and somatostatin receptor (SSTR) expression profile of the cell lines. In vitro activity of everolimus show positive correlation with the expression of SSTR types 1, 4 and 5 (CC: 0.9; 0.85, 0.87) while pasireotide activity show negative correlation with SSTR2 (CC: -0.87). Although there is greater modulation of pS6 when pasireotide is combined with everolimus, there is no significant abrogation of the expected feedback upregulation of AKT induced by everolimus. Also, the combination is not significantly better than each agent alone in short and long term in vitro assays. Continuous administration of everolimus at a low dose as opposed to high intermittent dosing schedule has greater antitumor efficacy against thyroid cancer xenografts in vivo. Pasireotide LAR has modest in vivo efficacy and the combination of everolimus and pasireotide LAR achieve greater tumor growth inhibition than each agent alone in TPC-1 xenograft model of thyroid cancer (p = 0.048). CONCLUSION: Our findings provide support for the clinical evaluation of everolimus and pasireotide in thyroid cancer and other neuroendocrine tumors.


Assuntos
Antineoplásicos/farmacologia , Everolimo/farmacologia , Somatostatina/análogos & derivados , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos SCID , Tumores Neuroendócrinos/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Nus , Receptores de Somatostatina/metabolismo , Somatostatina/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
20.
Med Sci Monit ; 25: 1177-1186, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30757999

RESUMO

BACKGROUND This study investigated the effect and mechanism of notoginsenoside R1 (NGR1) on chronic atrophic gastritis (CAG) in a rat model. MATERIAL AND METHODS To perform our investigation, a rat model of CAG was established, and then rats were treated with various doses of NGR1. After treatment, hematoxylin-eosin (HE) staining was used for histopathological observation and further scoring. Enzyme-linked immunosorbent assay (ELISA) was used to determine the contents of gastrointestinal hormones, inflammatory factors, gastric mucosal destruction factors, and gastric mucosal-protective factors. Gene and protein expressions were measured using quantitative real-time PCR and Western blot assay, respectively. RESULTS Results indicated that NGR1 relieved rat CAG. NGR1 treatment significantly increased the levels of gastrin (GAS) and somatostatin (SS) and reduced motilin (MTL) in the serum of CAG rats. The serum levels of interleukin (IL)-1ß and IL-6 were significantly reduced by NGR1 treatment in CAG rats in a dose-dependent manner. Additionally, the increased levels of prostaglandin (PG)E2, nitric oxide synthase (NOS), and endothelin (ET) in CAG rats were significantly decreased by NGR1 administration. Moreover, the decreased level of secretory IgA (sIgA) and glutathione (GSH) in rats caused by MNNG was notably increased by NGR1 treatment. No significant changes were found in glutathione disulfide (GSSG) secretion. Finally, we found that the increased Bcl-2 expression and reduced Bax expression in the stomach tissues of rats caused by MNNG were eliminated by NGR1 treatment. CONCLUSIONS NGR1 exerts a protective effect on CAG, and it is a multi-target, multi-linked, comprehensive process.


Assuntos
Gastrite Atrófica/tratamento farmacológico , Ginsenosídeos/farmacologia , Animais , Doença Crônica/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Mucosa Gástrica/fisiopatologia , Gastrinas/farmacologia , Gastrite Atrófica/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Somatostatina/farmacologia
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