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1.
Cancer Lett ; 524: 232-244, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34637845

RESUMO

Increasingly common, neuroendocrine tumors (NETs) are regarded nowadays as neoplasms potentially causing debilitating symptoms and life-threatening medical conditions. Pheochromocytoma is a NET that develops from chromaffin cells of the adrenal medulla, and is responsible for an excessive secretion of catecholamines. Consequently, patients have an increased risk for clinical symptoms such as hypertension, elevated stroke risk and various cardiovascular complications. Somatostatin analogues are among the main anti-secretory medical drugs used in current clinical practice in patients with NETs. However, their impact on pheochromocytoma-associated catecholamine hypersecretion remains incompletely explored. This study investigated the potential efficacy of octreotide and pasireotide (SOM230) on human tumor cells directly cultured from freshly resected pheochromocytomas using an implemented catecholamine secretion measurement by carbon fiber amperometry. SOM230 treatment efficiently inhibited nicotine-induced catecholamine secretion both in bovine chromaffin cells and in human tumor cells whereas octreotide had no effect. Moreover, SOM230 specifically decreased the number of exocytic events by impairing the stimulation-evoked calcium influx as well as the nicotinic receptor-activated inward current in human pheochromocytoma cells. Altogether, our findings indicate that SOM230 acts as an inhibitor of catecholamine secretion through a mechanism involving the nicotinic receptor and might be considered as a potential anti-secretory treatment for patients with pheochromocytoma.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Feocromocitoma/tratamento farmacológico , Somatostatina/análogos & derivados , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Catecolaminas/biossíntese , Catecolaminas/metabolismo , Linhagem Celular Tumoral , Humanos , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Octreotida/farmacologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Somatostatina/farmacologia
2.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119146, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599984

RESUMO

Gaba-ergic neurons are a diverse cell class with extensive influence over cortical processing, but their role in experience-dependent plasticity is not completely understood. Here we addressed the role of cortical somatostatin- (SOM-INs) and vasoactive intestinal polypeptide- (VIP-INs) containing interneurons in a Pavlovian conditioning where stimulation of the vibrissae is used as a conditioned stimulus and tail shock as unconditioned one. This procedure induces a plastic change observed as an enlargement of the cortical functional representation of vibrissae activated during conditioning. Using layer-targeted, cell-selective DREADD transductions, we examined the involvement of SOM-INs and VIP-INs activity in learning-related plastic changes. Under optical recordings, we injected DREADD-expressing vectors into layer IV (L4) barrels or layer II/III (L2/3) areas corresponding to the activated vibrissae. The activity of the interneurons was modulated during all conditioning sessions, and functional 2-deoxyglucose (2DG) maps were obtained 24 h after the last session. In mice with L4 but not L2/3 SOM-INs suppressed during conditioning, the plastic change of whisker representation was absent. The behavioral effect of conditioning was disturbed. Both L4 SOM-INs excitation and L2/3 VIP-INs inhibition during conditioning did not affect the plasticity or the conditioned response. We found the activity of L4 SOM-INs is indispensable in the formation of learning-induced plastic change. We propose that L4 SOM-INs may provide disinhibition by blocking L4 parvalbumin interneurons, allowing a flow of information into upper cortical layers during learning.


Assuntos
Interneurônios/fisiologia , Aprendizagem , Inibição Neural , Plasticidade Neuronal , Córtex Somatossensorial/fisiologia , Animais , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Moduladores de Transporte de Membrana/farmacologia , Camundongos , Córtex Somatossensorial/citologia , Somatostatina/genética , Somatostatina/metabolismo , Vibrissas/inervação , Vibrissas/fisiologia
3.
Medicina (Kaunas) ; 57(12)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34946232

RESUMO

Background and Objectives: Long-acting somatostatin analogues (SSA) (octreotide LAR and lanreotide Autogel) are recommended as first line treatment of locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs) with a good expression of somatostatin receptor (SSTR). Both of these SSAs are usually administered via injections repeated every 4 weeks. The purpose of the study was to compare the route of SSA administration (injection performed by professional medical staff and self-administration of the drug) with progression-free survival. Materials and methods: 88 patients in 2019 and 96 patients in 2020 with locally advanced or metastatic well-differentiated NETs were included in the study. All patients had a good expression of SSTR type 2 and had been treated for at least 3 months with a stable dose of long-acting somatostatin analogue every 4 weeks. All of them had received training on drug self-injections from professional NET nurses at the beginning of the COVID-19 epidemic. Results: The rate of NET progression in the study group in 2020 was higher than in 2019 29.1% vs. 18.1% (28 vs. 16 cases), p = 0.081. Conclusions: The method of administration of long-acting SSA injection performed by professional medical staff vs. self-injection of the drug may significantly affect the risk of NET progression. The unequivocal confirmation of such a relationship requires further observation.


Assuntos
Tumores Neuroendócrinos , Octreotida/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Autoadministração , Somatostatina/análogos & derivados , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Somatostatina/administração & dosagem , Resultado do Tratamento
4.
Rev Med Chil ; 149(6): 888-898, 2021 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-34751348

RESUMO

Neuroendocrine Tumors (NETs) encompass a wide variety of tumors arising from neuroendocrine cells, which produce bioactive substances. The incidence of NETs increased significantly lately, becoming one of the most common tumors of the digestive tract. Their clinical presentation is as diverse as their capacity for hormone production. Carcinoid syndrome is the most common hormonal syndrome produced by NETs and is characterized by diarrhea, flushing and cardiac valvular lesions. New research brought multiple changes in the classification of these neoplasms and a new understanding about their diagnosis and treatment, promoting a multidisciplinary approach. Somatostatin analogues, radiation, biological, and cytotoxic drugs have improved the prognosis of these patients, which entails a great challenge for healthcare providers.


Assuntos
Antineoplásicos , Tumores Neuroendócrinos , Antineoplásicos/uso terapêutico , Diarreia , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Somatostatina/uso terapêutico
5.
Molecules ; 26(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34641586

RESUMO

We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is 177Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.


Assuntos
Antineoplásicos/uso terapêutico , Citotoxinas/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Imunoconjugados/uso terapêutico , Neoplasias/terapia , Peptídeos/uso terapêutico , Radioterapia/métodos , Portadores de Fármacos/química , Desenho de Fármacos , Humanos , Melfalan/análogos & derivados , Melfalan/uso terapêutico , Peptídeos/química , Preparações Farmacêuticas/química , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Somatostatina/uso terapêutico
7.
Clin Adv Hematol Oncol ; 19(9): 582-593, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34495022

RESUMO

Neuroendocrine tumors (NETs) are a heterogeneous group of epithelial neoplasms with predominantly neural and endocrine differentiation that have the ability to produce peptide hormones and other biologically active substances. The histologic characterization of NETs based on differentiation and grading is crucial to determining prognosis and treatment. Surgery still offers the best chance of cure for patients with NETs, and tumor resection is the preferred approach when possible. For locally advanced or metastatic disease, approaches to treatment can vary widely depending on the extent of disease and goals of therapy. A better understanding of the biology of NETs acquired over the last decade has facilitated the development of targeted therapies, such as everolimus and a variety of tyrosine kinase inhibitors. Furthermore, the field of theranostics has led to dramatic improvements in our diagnostic and treatment abilities. Chemotherapy has a role in the treatment of NETs, evidenced by the benefit shown with the combination of temozolomide and capecitabine to treat pancreatic NETs. Somatostatin analogues are a mainstay of treatment because they reduce secretory products and have antiproliferative effects on NET cells. In this work, we aim to review the landscape for the diagnosis and treatment of well-differentiated NETs.


Assuntos
Antineoplásicos , Tumores Neuroendócrinos , Antineoplásicos/uso terapêutico , Capecitabina/uso terapêutico , Everolimo/uso terapêutico , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas , Somatostatina/uso terapêutico
8.
FASEB J ; 35(10): e21944, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34569087

RESUMO

Information represented by principal neurons in anterior piriform cortex (APC) is regulated by local, recurrent excitation and inhibition, but the circuit mechanisms remain elusive. Two types of layer 2 (L2) principal neurons, semilunar (SL), and superficial pyramidal (SP) cells, are parallel output channels, and the control of their activity gates the output of APC. Here, we examined the hypothesis that recurrent inhibition differentially regulates SL and SP cells. Patterned optogenetic stimulation revealed that the strength of recurrent inhibition is target- and layer-specific: L1 > L3 for SL cells, but L3 > L1 for SP cells. This target- and layer-specific inhibition was largely attributable to the parvalbumin (PV), but not somatostatin, interneurons. Intriguingly, olfactory experience selectively modulated the PV to SP microcircuit while maintaining the overall target and laminar specificity of inhibition. Together, these results indicate the importance of target-specific inhibitory wiring for odor processing, implicating these mechanisms in gating the output of piriform cortex.


Assuntos
Inibição Neural , Vias Neurais , Córtex Piriforme/citologia , Córtex Piriforme/metabolismo , Animais , Feminino , Interneurônios/metabolismo , Masculino , Camundongos , Nariz , Odorantes/análise , Percepção Olfatória/fisiologia , Parvalbuminas/metabolismo , Olfato/fisiologia , Somatostatina , Transmissão Sináptica
9.
Lancet Gastroenterol Hepatol ; 6(11): 922-932, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34508668

RESUMO

BACKGROUND: Gastrointestinal angiodysplasias are vascular malformations that often cause red blood cell transfusion-dependent anaemia. Several studies suggest that somatostatin analogues might decrease rebleeding rates, but the true effect size is unknown. We therefore aimed to investigate the efficacy of somatostatin analogues on red blood cell transfusion requirements of patients with gastrointestinal angiodysplasias and to identify subgroups that might benefit the most from somatostatin analogue therapy. METHODS: We did a systematic review and individual patient data meta-analysis. We searched MEDLINE, Embase, and Cochrane on Jan 15, 2016, with an updated search on April 25, 2021. All published randomised controlled trials and cohort studies that reported on somatostatin analogue therapy in patients with gastrointestinal angiodysplasias were eligible for screening. We excluded studies without original patient data, single case reports, small case series (ie, <10 participants), studies in which patients had a specific aetiology of gastrointestinal angiodysplasias, and studies in which somatostatin analogue therapy was initiated simultaneously with other treatment modalities. Authors of eligible studies were invited to share individual patient data. Aggregated data was used if individual patient data were not provided. The primary outcome was the mean reduction in the number of red blood cell transfusions during somatostatin analogue therapy, compared with baseline, expressed as the incidence rate ratio (IRR) and absolute mean decrease. We defined patients as either good responders (≥50% reduction in the number of red blood cell transfusions) or poor responders (<50% reduction). A mixed-effects negative binomial regression was used to account for clustering of patients and skewness in data. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42020213985. FINDINGS: We identified 11 eligible studies (one randomised controlled trial and ten cohort studies) of moderate-to-high quality and obtained individual patient data from the authors of nine (82%) studies. The remaining two (18%) studies provided sufficient information in the published manuscript to extract individual patient data. In total, we analysed data from 212 patients. Somatostatin analogues reduced the number of red blood cell transfusions with an IRR of 0·18 (95% CI 0·14-0·24; p<0·0001) during a median treatment duration of 12 months (IQR 6·0-12·0) and follow-up period of 12 months (12·0-12·0), correlating with a mean absolute decrease in the number of red blood cell transfusions from 12·8 (95% CI 10·4-15·8) during baseline to 2·3 (1·9-2·9) during follow-up-ie, a reduction of 10·5 red blood cell transfusions (p<0·0001). 177 (83%) of 212 patients had a good response to somatostatin analogue therapy (defined as at least a 50% reduction in the number of red blood cell transfusions). Heterogeneity across studies was moderate (I2=53%; p=0·02). Location of gastrointestinal angiodysplasias in the stomach compared with angiodysplasias in the small bowel and colon (IRR interaction 1·92 [95% CI 1·13-3·26]; p=0·02) was associated with worse treatment response. Octreotide was associated with a better treatment response than lanreotide therapy (IRR interaction 2·13 [95% CI 1·12-4·04]; p=0·02). The certainty of evidence was high for the randomised controlled trial and low for the ten cohort studies. Adverse events occurred in 38 (18%) of 212 patients receiving somatostatin analogue therapy, with ten (5%) discontinuing this therapy because of adverse events. The most common adverse events were loose stools (seven [3%] of 212), cholelithiasis (five [2%]), flatulence (four [2%]), and administration site reactions (erythema, five [2%]). INTERPRETATION: Somatostatin analogue therapy is safe and effective in most patients with red blood cell transfusion-dependent bleeding due to gastrointestinal angiodysplasias. Somatostatin analogue therapy is more effective in patients with angiodysplasias located in the small bowel and colon, and octreotide therapy seems to be more effective than lanreotide therapy. FUNDING: The Netherlands Organisation for Health Research and Development and the Radboud University Medical Center.


Assuntos
Angiodisplasia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Angiodisplasia/complicações , Transfusão de Eritrócitos/estatística & dados numéricos , Gastroenteropatias/complicações , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Humanos , Somatostatina/uso terapêutico , Resultado do Tratamento
10.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502208

RESUMO

In the mammalian brain, cortical interneurons (INs) are a highly diverse group of cells. A key neurophysiological question concerns how each class of INs contributes to cortical circuit function and whether specific roles can be attributed to a selective cell type. To address this question, researchers are integrating knowledge derived from transcriptomic, histological, electrophysiological, developmental, and functional experiments to extensively characterise the different classes of INs. Our hope is that such knowledge permits the selective targeting of cell types for therapeutic endeavours. This review will focus on two of the main types of INs, namely the parvalbumin (PV+) or somatostatin (SOM+)-containing cells, and summarise the research to date on these classes.


Assuntos
Morte Celular , Córtex Cerebral/patologia , Interneurônios/patologia , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Animais , Córtex Cerebral/metabolismo , Humanos , Interneurônios/metabolismo
11.
eNeuro ; 8(5)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34518366

RESUMO

Forming long-term memories is crucial for adaptive behavior and survival in changing environments. The molecular consolidation processes which underlie the formation of these long-term memories are dependent on protein synthesis in excitatory and SST-expressing neurons. A centrally important, parallel process to this involves the removal of the memory constraint quinone reductase 2 (QR2), which has been recently shown to enhance memory consolidation for novel experiences in the cortex and hippocampus, via redox modulation. However, it is unknown within which cell type in the cortex removal of QR2 occurs, nor how this affects neuronal function. Here, we use novel taste learning in the mouse anterior insular cortex (aIC) to show that similarly to mRNA translation, QR2 removal occurs in excitatory and SST-expressing neurons. Interestingly, both novel taste and QR2 inhibition reduce excitability specifically within SST, but not excitatory neurons. Furthermore, reducing QR2 expression in SST, but not in PV or excitatory neurons, is sufficient to enhance taste memory. Thus, QR2 mediated intrinsic property changes of SST interneurons in the aIC is a central removable factor to allow novel taste memory formation. This previously unknown involvement of QR2 and SST interneurons in resetting aIC activity hours following learning, describes a molecular mechanism to define cell circuits for novel information. Therefore, the QR2 pathway in SST interneurons provides a fresh new avenue by which to tackle age-related cognitive deficits, while shedding new light onto the functional machinations of long-term memory formation for novel information.


Assuntos
Somatostatina , Paladar , Animais , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Camundongos , Somatostatina/metabolismo
12.
J Neurosci ; 41(42): 8761-8778, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34493543

RESUMO

Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). However, under certain conditions, neurons can respond reliably with highly precise responses to the same visual stimuli from trial to trial. This suggests that there exists intrinsic neural circuit mechanisms that dynamically modulate the intertrial variability of visual cortical neurons. Here, we sought to elucidate the role of different inhibitory interneurons (INs) in reliable coding in mouse V1. To study the interactions between somatostatin-expressing interneurons (SST-INs) and parvalbumin-expressing interneurons (PV-INs), we used a dual-color calcium imaging technique that allowed us to simultaneously monitor these two neural ensembles while awake mice, of both sexes, passively viewed natural movies. SST neurons were more active during epochs of reliable pyramidal neuron firing, whereas PV neurons were more active during epochs of unreliable firing. SST neuron activity lagged that of PV neurons, consistent with a feedback inhibitory SST→PV circuit. To dissect the role of this circuit in pyramidal neuron activity, we used temporally limited optogenetic activation and inactivation of SST and PV interneurons during periods of reliable and unreliable pyramidal cell firing. Transient firing of SST neurons increased pyramidal neuron reliability by actively suppressing PV neurons, a proposal that was supported by a rate-based model of V1 neurons. These results identify a cooperative functional role for the SST→PV circuit in modulating the reliability of pyramidal neuron activity.SIGNIFICANCE STATEMENT Cortical neurons often respond to identical sensory stimuli with large variability. However, under certain conditions, the same neurons can also respond highly reliably. The circuit mechanisms that contribute to this modulation remain unknown. Here, we used novel dual-wavelength calcium imaging and temporally selective optical perturbation to identify an inhibitory neural circuit in visual cortex that can modulate the reliability of pyramidal neurons to naturalistic visual stimuli. Our results, supported by computational models, suggest that somatostatin interneurons increase pyramidal neuron reliability by suppressing parvalbumin interneurons via the inhibitory SST→PV circuit. These findings reveal a novel role of the SST→PV circuit in modulating the fidelity of neural coding critical for visual perception.


Assuntos
Interneurônios/metabolismo , Parvalbuminas/metabolismo , Percepção/fisiologia , Somatostatina/metabolismo , Córtex Visual/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parvalbuminas/genética , Somatostatina/genética , Córtex Visual/citologia
13.
Eur J Endocrinol ; 185(4): R93-R101, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370694

RESUMO

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.


Assuntos
Hormônios Peptídicos/fisiologia , Animais , Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/genética , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/genética , Humanos , Hipertensão/genética , Hipertensão/terapia , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Obesidade/genética , Obesidade/terapia , Hormônios Peptídicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Somatostatina/química , Somatostatina/farmacologia , Somatostatina/fisiologia
14.
eNeuro ; 8(5)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34400470

RESUMO

Excitatory synaptic inputs arriving at the dendrites of a neuron can engage active mechanisms that nonlinearly amplify the depolarizing currents. This supralinear synaptic integration is subject to modulation by inhibition. However, the specific rules by which different subtypes of interneurons affect the modulation have remained largely elusive. To examine how inhibition influences active synaptic integration, we optogenetically manipulated the activity of the following two subtypes of interneurons: dendrite-targeting somatostatin-expressing (SST) interneurons; and perisomatic-targeting parvalbumin-expressing (PV) interneurons. In acute slices of mouse primary visual cortex, electrical stimulation evoked nonlinear synaptic integration that depended on NMDA receptors. Optogenetic activation of SST interneurons in conjunction with electrical stimulation resulted in predominantly divisive inhibitory gain control, reducing the magnitude of the supralinear response without affecting its threshold. PV interneuron activation, on the other hand, had a minimal effect on the supralinear response. Together, these results delineate the roles for SST and PV neurons in active synaptic integration. Differential effects of inhibition by SST and PV interneurons likely increase the computational capacity of the pyramidal neurons in modulating the nonlinear integration of synaptic output.


Assuntos
Neocórtex , Animais , Interneurônios/metabolismo , Camundongos , Neocórtex/metabolismo , Parvalbuminas/metabolismo , Células Piramidais/metabolismo , Somatostatina/metabolismo
15.
Nutrients ; 13(8)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34444986

RESUMO

Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH.


Assuntos
Pressão Sanguínea , Polipeptídeo Inibidor Gástrico/sangue , Fármacos Gastrointestinais/farmacologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Hipotensão , Período Pós-Prandial , Somatostatina/sangue , Acarbose/farmacologia , Acarbose/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Fármacos Gastrointestinais/uso terapêutico , Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/sangue , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/fisiopatologia , Insulina/sangue , Peptídeos , Circulação Esplâncnica
16.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445147

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-ß peptide (Aß) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer's disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aß and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aß peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer's disease pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Somatostatina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Proteínas tau/metabolismo
17.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1866(11): 159018, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34332074

RESUMO

Neuronostatin is a peptide hormone encoded by the somatostatin gene. Biological effects of neuronostatin are mediated through activation of GPR107. There is evidence indicating that neuronostatin modulates energy homeostasis by suppressing food intake and insulin secretion, while stimulating glucagon secretion. While it was found that neuronostatin receptor is expressed in white adipose tissue, the role of neuronostatin in controlling adipose tissue formation is unknown. The aim of this study is to investigate the effects of neuronostatin on proliferation and differentiation of rat primary preadipocytes and 3T3-L1 cells. We found that neuronostatin receptor GPR107 is expressed in rat preadipocytes and 3T3-L1 cells. Neuronostatin promotes proliferation of preadipocytes via AKT activation. Downregulation of GPR107 mRNA expression and protein production results in an attenuation of neuronostatin-induced stimulation of preadipocyte proliferation. Moreover, neuronostatin reduces intracellular lipid content and the expression of adipogenesis-modulating genes C/ebpα, C/ebpß, Pparγ, and Fabp4. In summary, these results show that neuronostatin, AKT-dependently, stimulates the proliferation of preadipocytes via GPR107. In contrast, neuronostatin inhibits the differentiation of preadipocytes into mature adipocytes.


Assuntos
Adipócitos/metabolismo , Fragmentos de Peptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Somatostatina/metabolismo , Células 3T3-L1 , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
18.
Nat Commun ; 12(1): 4610, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326331

RESUMO

Integration of multi-frequency sounds into a unified perceptual object is critical for recognizing syllables in speech. This "feature binding" relies on the precise synchrony of each component's onset timing, but little is known regarding its neural correlates. We find that multi-frequency sounds prevalent in vocalizations, specifically harmonics, preferentially activate the mouse secondary auditory cortex (A2), whose response deteriorates with shifts in component onset timings. The temporal window for harmonics integration in A2 was broadened by inactivation of somatostatin-expressing interneurons (SOM cells), but not parvalbumin-expressing interneurons (PV cells). Importantly, A2 has functionally connected subnetworks of neurons preferentially encoding harmonic over inharmonic sounds. These subnetworks are stable across days and exist prior to experimental harmonics exposure, suggesting their formation during development. Furthermore, A2 inactivation impairs performance in a discrimination task for coincident harmonics. Together, we propose A2 as a locus for multi-frequency integration, which may form the circuit basis for vocal processing.


Assuntos
Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Potenciais Evocados Auditivos/fisiologia , Interneurônios/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Som
19.
Poult Sci ; 100(8): 101285, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34229215

RESUMO

Melatonin (MEL) plays an important role in regulating growth and development of organisms and the cellular metabolism. This study was conducted to explore the role of MEL in mediating monochromatic light-induced secretion of somatostatin (SST) in the hypothalamus and pituitary in chicks. Pinealectomy models of newly hatched broilers were exposed to white (WL), red (RL), green (GL), and blue (BL) lights. The results showed that SST immunoreactive neurons and fibers were distributed in the hypothalamus. SST and SST receptor 2 (SSTR2) mRNA and protein levels in the hypothalamus and pituitary were higher in chicks exposed to RL than in chicks exposed to GL and BL. However, after pinealectomy, the mRNA and protein levels of SST and SSTR2 in the hypothalamus and pituitary in the different light groups were increased, and the differences between the groups disapeared. The expression trend of SSTR5 mRNA in the pituitary was the idential to that of SSTR2 mRNA in the pituitary. In vitro, exogenous SST inhibited growth hormone (GH) secretion, and selective antogonists of SSTR2 and SSTR5 promoted GH secretion. Selective antogonists of the melatonin receptor 1b (Mel1b) and Mel1c increased the relative concentrations of SST in the adenohypophysis cells. These results indicated that monochromatic light affects the expression of SST in chick hypothalamus and pituitary. MEL, via Mel1b and Mel1c, decreased SST secretion under GL, which was associated with the inhibition of SST, SSTR2, and SSTR5 in adenohypophysis cells.


Assuntos
Melatonina , Animais , Galinhas/metabolismo , Hipotálamo/metabolismo , Receptores de Melatonina/genética , Receptores de Melatonina/metabolismo , Somatostatina
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