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1.
Nature ; 574(7779): 559-564, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645735

RESUMO

Although glucose-sensing neurons were identified more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here we identify a pair of glucose-sensing neurons with bifurcated axons in the brain of Drosophila. One axon branch projects to insulin-producing cells to trigger the release of Drosophila insulin-like peptide 2 (dilp2) and the other extends to adipokinetic hormone (AKH)-producing cells to inhibit secretion of AKH, the fly analogue of glucagon. These axonal branches undergo synaptic remodelling in response to changes in their internal energy status. Silencing of these glucose-sensing neurons largely disabled the response of insulin-producing cells to glucose and dilp2 secretion, disinhibited AKH secretion in corpora cardiaca and caused hyperglycaemia, a hallmark feature of diabetes mellitus. We propose that these glucose-sensing neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when haemolymph glucose levels are high.


Assuntos
Encéfalo/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Animais , Axônios/metabolismo , Encéfalo/anatomia & histologia , Drosophila melanogaster/anatomia & histologia , Glucose/análise , Hormônios de Inseto/metabolismo , Masculino , Inibição Neural , Vias Neurais , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Neurotransmissores/metabolismo , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo
2.
Bol. latinoam. Caribe plantas med. aromát ; 18(5): 459-479, sept. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-1008268

RESUMO

Neuronal cell damage is often caused by prolonged misuse of Methylphenidate (MPH). Topiramate (TPM) carries neuroprotective properties but its assumed mechanism remains unclear. The present study evaluates in vivo role of various doses of TPM and its mechanism against MPH-induced motor activity and related behavior disorder. Thus, we used domoic acid (DOM), bicuculline (BIC), Ketamine (KET), Yohimibine (YOH) and Haloperidole (HAL) as AMPA/kainite, GABAA, NMDA, ɑ2 adrenergic and D2 of dopamine receptor antagonists respectively. Open Field Test (OFT), Elevated Plus Maze (EPM) and Forced Swim Test (FST) were used to study motor activity, anxiety and depression level. TPM (100 and 120 mg/kg) reduced MPH-induced rise and inhibited MPH-induced promotion in motor activity disturbance, anxiety and depression. Pretreatment of animals with KET, HAL, YOH and BIC inhibited TPM- improves anxiety and depression through the interacting with Dopaminergic, GABAA, NMDA and ɑ2-adrenergic receptors.


El daño a las células neuronales a menudo es causado por el uso prolongado de metilfenidato (MPH). El topiramato (TPM) tiene propiedades neuroprotectoras, pero su mecanismo de acción no es claro. El presente estudio evalúa el papel in vivo de varias dosis de TPM y su mecanismo contra la actividad motora inducida por MPH y el trastorno de comportamiento relacionado. Utilizamos ácido domoico (DOM), bicuculina (BIC), ketamina (KET), yohimbina (YOH) y haloperidol (HAL), así como antagonistas AMPA/kainato, GABAA, NMDA, ɑ2-adrenérgico y D2 dopaminérgicos, respectivamente. Se utilizaron las pruebas de campo abierto (OFT), elevación de laberinto (EPM) y natación forzada (FST) para estudiar la actividad motora, la ansiedad y el nivel de depresión. El TPM (100 y 120 mg/kg) redujo el aumento inducido por MPH e inhibió la promoción inducida por MPH en la alteración de la actividad motora, la ansiedad y la depresión. El tratamiento previo de animales con KET, HAL, YOH y BIC inhibió el TPM, mejora la ansiedad y la depresión a través de la interacción con los receptores dopaminérgicos, GABAA, NMDA y ɑ2-adrenérgico.


Assuntos
Animais , Masculino , Ratos , Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , /farmacologia , Transtornos Mentais/prevenção & controle , Metilfenidato/efeitos adversos , Ratos Wistar , Neurotransmissores/metabolismo , Transtornos Mentais/induzido quimicamente , Atividade Motora/efeitos dos fármacos
3.
Environ Pollut ; 254(Pt B): 113029, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454584

RESUMO

Neurotransmission plays an essential role during the central nervous system (CNS) development. During the last years, several studies based on the changes produced in neurotransmitters of aquatic organisms caused by pharmaceuticals have been reported. Daphnia magna, the aquatic ecotoxicological model organism, shares several of the neurotransmitters targeted by antidepressant and other neuro-active drugs with vertebrates. Therefore, a method based on liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) has been applied for the first time to study the levels of 41 neurotransmitters in Daphnia magna under the effect of four different neuro-active pharmaceuticals (sertraline, venlafaxine, duloxetine and fluoxetine). In addition, the performance of LC-HRMS was studied in terms of linearity, sensitivity, intra- and inter-day precision, and overall robustness. The developed analytical method using LC-HRMS is a new tool for neurotoxicology research using the Daphnia magna model. As a result, general differences on the concentrations of those neurotransmitters exposed to the mentioned pharmaceuticals were observed.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Daphnia/química , Cloridrato de Duloxetina/toxicidade , Fluoxetina/toxicidade , Espectrometria de Massas/métodos , Neurotransmissores/química , Sertralina/toxicidade , Cloridrato de Venlafaxina/toxicidade , Animais , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/crescimento & desenvolvimento , Organismos Aquáticos/metabolismo , Daphnia/efeitos dos fármacos , Daphnia/metabolismo , Cloridrato de Duloxetina/análise , Fluoxetina/análise , Modelos Animais , Neurotransmissores/metabolismo , Sertralina/análise , Cloridrato de Venlafaxina/análise , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
4.
Chemosphere ; 235: 383-390, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31271998

RESUMO

The sensory-motor function in larval zebrafish (Danio rerio) following exposure to low water pH was investigated. The results suggested that acid exposure (pH 4.0-5.0; control: pH 7.4) significantly reduced the touch-evoked escape response of larval zebrafish at 3 days post fertilization (dpf). A significant number of pH 4.0-exposed larvae also exhibited a lack of escape response. Treatment with neurotransmitters showed that serotonin or acetylcholine, but not dopamine, reduced the adverse effects of acid exposure on the escape response of larvae. Co-exposure to serotonin and acetylcholine did not further improve the escape response of acid-exposed larvae, suggesting no additive effect by these neurotransmitters. Interestingly, the negative effects of acid exposure on the escape response could be completely rescued by elevating the water levels of Ca2+, but not NaCl. Collectively, these results suggested that acid-induced disruption in Ca2+ balance suppressed the serotonin- and acetylcholine-mediated neuronal signaling, thereby affecting the sensory-motor function and escape response of larval zebrafish. Findings from the present study may have important implication for the survival (e.g., escape from adverse conditions) of larval fish in acid-impacted environments, particularly during early development when they are still incapable of spontaneous swimming.


Assuntos
Atividade Motora/fisiologia , Neurotransmissores/metabolismo , Água/química , Acidose , Animais , Concentração de Íons de Hidrogênio , Larva/efeitos dos fármacos , Serotonina , Natação , Peixe-Zebra/crescimento & desenvolvimento
5.
Nat Commun ; 10(1): 2998, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278365

RESUMO

At the Drosophila neuromuscular junction, inhibition of postsynaptic glutamate receptors activates retrograde signaling that precisely increases presynaptic neurotransmitter release to restore baseline synaptic strength. However, the nature of the underlying postsynaptic induction process remains enigmatic. Here, we design a forward genetic screen to discover factors in the postsynaptic compartment necessary to generate retrograde homeostatic signaling. This approach identified insomniac (inc), a putative adaptor for the Cullin-3 (Cul3) ubiquitin ligase complex, which together with Cul3 is essential for normal sleep regulation. Interestingly, we find that Inc and Cul3 rapidly accumulate at postsynaptic compartments following acute receptor inhibition and are required for a local increase in mono-ubiquitination. Finally, we show that Peflin, a Ca2+-regulated Cul3 co-adaptor, is necessary for homeostatic communication, suggesting a relationship between Ca2+ signaling and control of Cul3/Inc activity in the postsynaptic compartment. Our study suggests that Cul3/Inc-dependent mono-ubiquitination, compartmentalized at postsynaptic densities, gates retrograde signaling and provides an intriguing molecular link between the control of sleep and homeostatic plasticity at synapses.


Assuntos
Proteínas Culina/metabolismo , Proteínas de Drosophila/metabolismo , Somação de Potenciais Pós-Sinápticos/fisiologia , Terminações Pré-Sinápticas/metabolismo , Sono/fisiologia , Animais , Drosophila melanogaster , Feminino , Homeostase/fisiologia , Masculino , Modelos Animais , Junção Neuromuscular/metabolismo , Neurotransmissores/metabolismo , Ubiquitinação/fisiologia
6.
Aquat Toxicol ; 214: 105233, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301545

RESUMO

The water bodies are greatly influenced by heavy metal contamination and global increasing temperature. Arsenic (As) is one of the most dangerous widespread pollutants that pose health threats to human, animals and fishes. Considering the above, the study has been carried out to delineate 96 h median lethal concentration of arsenic alone and in combination with high temperature (As-T, 34 °C) by conducting static non-renewable bio-assay acute toxicity in Pangasianodon hypophthalmus (average weight 6.25 ±â€¯0.69 g, length 5.32 cm). Effect of definitive doses such as 25, 26, 27, 28, 29 and 30 mg/L of As alone and in combination with high temperature (As-T) were evaluated on stress biomarkers and cellular metabolism of P. hypophthalmus. The lethal concentration (96 h LC50) of As alone and in combination with high temperature was found to be 28.16 mg/L and 26.88 mg/L, respectively. The stress biomarkers in terms of catalase, superoxide dismutase (SOD) and glutathione-s-transferase (GST) in liver, gill, brain and kidney, blood glucose and NBT were remarkable higher (p < 0.01) in comparison to unexposed group (control group). Brain neurotransmitter enzyme, AChE, immunological status (blood glucose and NBT) and cellular metabolic enzymes (lactate dehydrogenase LDH, malate dehydrogenase MDH, aspartate aminotransferase AST, and alanine aminotransferase ALT, glucose-6-phosphate dehydrogenase G6PDH and ATPase) were noticeably (p < 0.01) altered by As and As-T exposure. The histopathological study exhibited devastating changes with exposure to As and As-T such as bile stagnation, hepatocyte with irregular nucleus, eosinophilic granules in the cytoplasm, necrosis, and nuclear hypertrophy in liver and curling of secondary lamellae, hypertrophy of lamellar epithelium, blood congestion, incomplete fusion of secondary lamellae, complete fusion of several lamellae and aneurysm in gill. Overall results clearly indicate that acute exposure of As and high temperature led to pronounced deleterious alterations on stress biomarkers and cellular and metabolic activities of P. hypophthalmus.


Assuntos
Arsênico/toxicidade , Biomarcadores/metabolismo , Peixes-Gato/imunologia , Peixes-Gato/metabolismo , Temperatura Alta , Estresse Oxidativo , Estresse Fisiológico/efeitos dos fármacos , Testes de Toxicidade Aguda , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Catalase/metabolismo , Brânquias/metabolismo , Glutationa Transferase/metabolismo , Glicólise/efeitos dos fármacos , Dose Letal Mediana , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Metais Pesados/metabolismo , Neurotransmissores/metabolismo , Superóxido Dismutase/metabolismo , Poluentes Químicos da Água/toxicidade
7.
Endocrinology ; 160(10): 2230-2242, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265059

RESUMO

Polycystic ovary syndrome (PCOS) is a prevalent and distressing disorder of largely unknown etiology. Although PCOS defined by ovarian dysfunction, accumulating evidence supports a critical role for the brain in the ontogeny and pathophysiology of PCOS. A critical pathological feature of PCOS is impaired gonadal steroid hormone negative feedback to the GnRH neuronal network in the brain that regulates fertility. This impairment is associated with androgen excess, a cardinal feature of PCOS. Impaired steroid hormone feedback to GnRH neurons is thought to drive hyperactivity of the neuroendocrine axis controlling fertility, leading to a vicious cycle of androgen excess and reproductive dysfunction. Decades of clinical research have been unable to uncover the mechanisms underlying this impairment, because of the extreme difficulty in studying the brain in humans. It is only recently, with the development of preclinical models of PCOS, that we have begun to unravel the role of the brain in the development and progression of PCOS. Here, we provide a succinct overview of what is known about alterations in the steroid hormone-sensitive GnRH neuronal network that may underlie the neuroendocrine defects in clinical PCOS, with a particular focus on those that may contribute to impaired progesterone negative feedback, and the likely role of androgens in driving this impairment.


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Sistemas Neurossecretores/fisiopatologia , Neurotransmissores/metabolismo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Animais , Feminino , Humanos
8.
Nat Commun ; 10(1): 2413, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160571

RESUMO

Synapotagmin-1 (Syt1) interacts with both SNARE proteins and lipid membranes to synchronize neurotransmitter release to calcium (Ca2+) influx. Here we report the cryo-electron microscopy structure of the Syt1-SNARE complex on anionic-lipid containing membranes. Under resting conditions, the Syt1 C2 domains bind the membrane with a magnesium (Mg2+)-mediated partial insertion of the aliphatic loops, alongside weak interactions with the anionic lipid headgroups. The C2B domain concurrently interacts the SNARE bundle via the 'primary' interface and is positioned between the SNAREpins and the membrane. In this configuration, Syt1 is projected to sterically delay the complete assembly of the associated SNAREpins and thus, contribute to clamping fusion. This Syt1-SNARE organization is disrupted upon Ca2+-influx as Syt1 reorients into the membrane, likely displacing the attached SNAREpins and reversing the fusion clamp. We thus conclude that the cation (Mg2+/Ca2+) dependent membrane interaction is a key determinant of the dual clamp/activator function of Synaptotagmin-1.


Assuntos
Membrana Celular/ultraestrutura , Lipídeos de Membrana/metabolismo , Proteínas SNARE/ultraestrutura , Sinaptotagmina I/ultraestrutura , Animais , Cálcio/metabolismo , Membrana Celular/metabolismo , Microscopia Crioeletrônica , Magnésio/metabolismo , Fusão de Membrana , Neurotransmissores/metabolismo , Ligação Proteica , Ratos , Proteínas SNARE/metabolismo , Transmissão Sináptica , Sinaptotagmina I/metabolismo
9.
Int J Mol Sci ; 20(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174279

RESUMO

Stress exposure is considered to be the main environmental cause associated with the development of depression. Due to the limitations of currently available antidepressants, a search for new pharmacological targets for treatment of depression is required. Recent studies suggest that adenosine triphosphate (ATP)-mediated signaling through the P2X7 receptor (P2X7R) might play a prominent role in regulating depression-related pathology, such as synaptic plasticity, neuronal degeneration, as well as changes in cognitive and behavioral functions. P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling. P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate. Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD. Importantly, blockade of P2X7R leads to antidepressant-like effects in different animal models, which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans. This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.


Assuntos
Depressão/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais , Estresse Psicológico/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurotransmissores/metabolismo
10.
Biochim Biophys Acta Rev Cancer ; 1872(1): 66-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152820

RESUMO

Increasing studies have demonstrated that neuroendocrine system is involved in the development and progression of cholangiocarcinoma. The neuroendocrine hormones, neurotransmitters and neuropeptides regulate cholangiocarcinoma via affecting pathophysiology of tumor cells. The developing interaction and interplay between neuroendocrine-associated factors and tumor cells provide novel insights into neural control of tumorigenesis and reveal potential therapeutic effect on patients with cholangiocarcinoma. Herein we reviewed the latest findings and achievements which demonstrate the close interactions between neuroendocrine regulation and progression of cholangiocarcinoma. Also, future therapeutic approaches targeting neuroendocrine-associated factors are discussed which may help improve management and treatment of cholangiocarcinoma.


Assuntos
Colangiocarcinoma/genética , Neoplasias Hepáticas/genética , Sistemas Neurossecretores/metabolismo , Colangiocarcinoma/patologia , Humanos , Neoplasias Hepáticas/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Sistemas Neurossecretores/patologia , Neurotransmissores/genética , Neurotransmissores/metabolismo
11.
Neuron ; 103(3): 459-472.e4, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204083

RESUMO

Vocalizations are fundamental to mammalian communication, but the underlying neural circuits await detailed characterization. Here, we used an intersectional genetic method to label and manipulate neurons in the midbrain periaqueductal gray (PAG) that are transiently active in male mice when they produce ultrasonic courtship vocalizations (USVs). Genetic silencing of PAG-USV neurons rendered males unable to produce USVs and impaired their ability to attract females. Conversely, activating PAG-USV neurons selectively triggered USV production, even in the absence of any female cues. Optogenetic stimulation combined with axonal tracing indicates that PAG-USV neurons gate downstream vocal-patterning circuits. Indeed, activating PAG neurons that innervate the nucleus retroambiguus, but not those innervating the parabrachial nucleus, elicited USVs in both male and female mice. These experiments establish that a dedicated population of PAG neurons gives rise to a descending circuit necessary and sufficient for USV production while also demonstrating the communicative salience of male USVs. VIDEO ABSTRACT.


Assuntos
Corte , Rede Nervosa/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Vocalização Animal/fisiologia , Animais , Sinais (Psicologia) , Vias Eferentes/fisiologia , Feminino , Genes Reporter , Vetores Genéticos/genética , Lentivirus/genética , Masculino , Camundongos , Neurônios/fisiologia , Neurotransmissores/metabolismo , Optogenética , Centro Respiratório/fisiologia
12.
Rev Assoc Med Bras (1992) ; 65(5): 706-713, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31166449

RESUMO

The term meditation can be used in many different ways, according to the technique to which it refers. Transcendental Meditation (MT) is one of these techniques. TM could serve as a model for research on spiritual meditation, unlike the meditation techniques based on secular knowledge. The purpose of the present study is to conduct a bibliographic review to organize scientific evidence on the effects of TM on neurophysiology, neurochemistry, and cognitive and behavioral aspects of its practitioners. To conduct this critical narrative review of the literature, we searched for scientific papers on the PubMed database of the National Center for Biotechnology Information. The keywords used in the search were Transcendental Meditation, Neuroscience of meditation e Meditation and behavior. We selected 21 papers that analyzed different aspects that could be altered through meditation practice. We concluded that TM has positive and significant documentable neurochemical, neurophysiological, and cognitive-behavioral effects. Among the main effects are the reduction of anxiety and stress (due to the reduction of cortisol and norepinephrine levels), increase of the feeling of pleasure and well-being (due to the increase of the synthesis and release of dopamine and serotonin), and influence on memory recall and possible consolidation. Further studies are needed using creative and innovative methodological designs that analyze different neural circuitry and verify the clinical impact on practitioners.


Assuntos
Cognição/fisiologia , Meditação/psicologia , Fenômenos Fisiológicos do Sistema Nervoso , Sistema Nervoso/química , Humanos , Neurotransmissores/análise , Neurotransmissores/metabolismo
13.
Int J Biol Macromol ; 133: 1090-1101, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31054300

RESUMO

The aim of this study is to probe new functions of a polysaccharide from Spirulina platensis (PSP) on constipation and intestinal microbiota in mice. Diphenoxylate-induced constipation in mice was treated with different doses of PSP, followed by examining the defecation patterns, levels of acetyl cholinesterase (AchE), nitric oxide (NO), and tissue section histopathology. The composition of intestinal microbiota was determined by genome sequencing analysis of the 16S rDNA. This study found that the average molecular weight of PSP was 29, 600 Da, and mainly monosaccharides of PSP were rhamnose (24.7%), glucose (16.15%) and galactose (13.32%). The beneficial effects of PSP treatment include defecation improvement, increase of AchE activity, reduction of NO concentration, renovation of the damaged intestinal villus and affection on the expression of some related genes in the constipated mice. In addition, PSP had significant effects on the gut microbiota, showing the enhancement in abundance of beneficial bacteria including Akkermansia, Lactobacillus, Butyricimonas, Candidatus Arthromitus and Prevotella, and the reduction in abundance of harmful bacteria such as Clostridium and Dorea. The present s uncovered a new function of PSP, indicating that PSP could be used in constipation therapies.


Assuntos
Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Difenoxilato/efeitos adversos , Polissacarídeos Bacterianos/farmacologia , Spirulina/química , Animais , Vilosidades Coriônicas/efeitos dos fármacos , Vilosidades Coriônicas/metabolismo , Constipação Intestinal/metabolismo , Constipação Intestinal/fisiopatologia , Defecação/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurotransmissores/metabolismo , Polissacarídeos Bacterianos/uso terapêutico , Água/metabolismo
14.
Neuron ; 103(1): 66-79.e12, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31104951

RESUMO

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1+47 persistently displayed higher mobility within nanodomains. Synaptic accumulation of CaV2.1 was accomplished by optogenetic clustering, but only CaV2.1+47 increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of CaV2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.


Assuntos
Canais de Cálcio/genética , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Canais de Cálcio/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Células HEK293 , Humanos , Luz , Neurotransmissores/metabolismo , Optogenética , Gravidez , Isoformas de Proteínas/genética , Ratos , Vesículas Sinápticas/fisiologia
15.
Food Funct ; 10(5): 2926-2934, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31070611

RESUMO

Weaning stress in piglets can lead to poor health outcomes and reduced production. We investigated the effects of probiotics, one potential antibiotic alternative, on the growth performance, serum biochemical parameters, intestinal morphology, mucosal immunity, hypothalamic neurotransmitters, and colonic microflora in weaned piglets. Thirty-six weaned piglets were fed a basal diet, a diet supplemented with colistin sulphate antibiotic, or a diet supplemented with probiotics including Clostridium butyricum, Bacillus subtilis, and B. licheniformis. Probiotics significantly increased the feed : gain ratio, improved the average day gain from day 1 to day 28, and decreased the diarrhoea index. Probiotics also lowered the serum concentrations of AST, ALT, and ALP on day 14 and lowered the serum concentration of ALT on day 28 compared with the control. Probiotic supplementation caused fewer ileal apoptotic cells. The serum and ileal concentrations of TNF-α and IL-1ß on day 28 were significantly lowered, and the serum concentrations of IL-6 were significantly lowered on days 14 and 28. Probiotic-fed piglets exhibited higher contents of hypothalamic serotonin and dopamine as well as serum γ-aminobutyric acid along with higher colonic concentrations of butyrate and valerate on day 28. High-throughput sequencing showed 972 core operational taxonomic units among all groups, of which 48 were unique to the probiotic-treated group. The relative abundance of genus Bacillus and species Bacillus velezensis was enriched in probiotic piglets; the phylogenetic investigation of communities by the reconstruction of unobserved states indicated that amino acid metabolism, DNA repair, replication and recombination proteins, and secretion systems were enriched with probiotics. In conclusion, the Clostridium butyricum-based probiotics improved growth performance, enhanced intestinal morphology, changed hypothalamic neurotransmitters and modulated colonic microflora in weaned piglets.


Assuntos
Clostridium butyricum/fisiologia , Colo/microbiologia , Diarreia/veterinária , Hipotálamo/metabolismo , Intestinos/imunologia , Neurotransmissores/metabolismo , Probióticos/administração & dosagem , Doenças dos Suínos/tratamento farmacológico , Ração Animal/análise , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Diarreia/tratamento farmacológico , Diarreia/imunologia , Diarreia/microbiologia , Suplementos Nutricionais/análise , Microbioma Gastrointestinal , Intestinos/microbiologia , Filogenia , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/metabolismo , Doenças dos Suínos/microbiologia , Desmame
16.
Cell Tissue Res ; 377(1): 73-79, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31076872

RESUMO

Most growth factors are synthesized as precursors and biologically active forms are generated by proteolytic cleavage of the pro-domain. However, the biological functions of pro-domains are ill-defined. New roles were recently reported for the pro-domain of brain-derived neurotrophic factor (BDNF), a well-known growth factor in the brain. Interestingly, the pro-domain of BDNF (BDNF pro-peptide) is localized at presynaptic termini, where it facilitates long-term depression (LTD) in hippocampal slices, implicating it as a novel synaptic modulator. BDNF binds its pro-peptide with high affinity in a pH-dependent manner and when bound to BDNF, the BDNF pro-peptide cannot facilitate hippocampal LTD, representing a new mechanism of regulation. The BDNF pro-peptide is present in human cerebrospinal fluid (CSF) and levels were significantly lower in patients with major depressive disorder (MDD) than in controls. Notably, male MDD patients exhibit significantly lower levels of CSF pro-peptide than females. These findings demonstrate that the BDNF pro-peptide is a biologically important synaptic modulator and is associated with MDD, particularly in males.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Neurotransmissores/metabolismo , Terminações Pré-Sinápticas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Camundongos , Precursores de Proteínas/líquido cefalorraquidiano , Precursores de Proteínas/metabolismo , Ratos , Transmissão Sináptica
17.
Expert Opin Pharmacother ; 20(11): 1351-1363, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31120798

RESUMO

INTRODUCTION: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it predates PD diagnosis in about 30% of patients. Between 20% and 60% of depressed patients with PD are either without recognition or treatment of their depression. AREAS COVERED: The pathophysiology of depression in PD is unclear. There are several structural changes seen in depressed patients with PD that are also seen in patients with depression. In addition, the neurotransmitters dopamine, serotonin, and norepinephrine are all depleted in PD. This article covers the pharmacological treatment of depression in PD; this involves standard antidepressant treatment such as selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. As with depression not associated with PD, most treatment is partially successful. Non-pharmacological approaches are also touched upon. EXPERT OPINION: Most antidepressant therapy shows partial efficacy in patients with PD. However, there is a need for better study design as well as more comparative studies for the treatment of depression in PD. Biomarkers will help identify patients with PD and depression earlier in the future.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Doença de Parkinson/patologia , Biomarcadores/metabolismo , Citocinas/metabolismo , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/etiologia , Exercício , Humanos , Inibidores da Monoaminoxidase/uso terapêutico , Neurotransmissores/metabolismo , Doença de Parkinson/complicações , Inibidores de Captação de Serotonina/uso terapêutico
18.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 53-62, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078153

RESUMO

Thyroid hormones regulate the development and maturation of the brain by maintaining levels of neurotransmitters and their related metabolites. The present work emphasizes the neural dysfunction in the brain caused by hypothyroidism and the potential role of Hordeum vulgare (water soluble barley, (B)) in ameliorating these effects. The study was conducted on euothyroid and hypothyroid adult female rats. The induction of hypothyroidism was conducted by oral-administration of neo-mercazole (5.0 mg.kg-1) daily for thirty days prior the study and terminated at the end of the study. The groups were assigned as; euthyroid (EU) and hypothyroid (H) groups and other two groups were treated with 100 mg.kg-1 water soluble barley; daily for one month and assigned as (EU+B) and (H+B) groups. Compared with EU and EU+B groups, a reduction in fT4, and ERK1/2 levels and elevation in TSH in brain tissue, Moreover, a  significant elevation in 8-OH deoxyguanosine and caspase-3 levels, confirmed with increase percentage DNA-damage in the brain and thyroid tissues in hypothyroid control rats. Furthermore, a significant decrease in all monoamines levels in different brain areas and downregulation of dopamine and 5-hydroxytreptamin receptors transcription, with a significant increase in excitatory amino acids and no significant change in the levels inhibitory amino acids were recorded in control hypothyroid group. Treatment of hypothyroid group with Hordeum vulgare improved the above-mentioned adverse impact by ameliorating the thyroid hormone levels with depleting the DNA-degradation and elaborating the levels of neurotransmitters with related receptors and amino acids in brain areas.  Water soluble Hordeum vulgare as a phytonutrient, is safe and efficient agent in ameliorating the neural dysfunction resulting from hypothyroidism status in adult female rats.


Assuntos
Monoaminas Biogênicas/metabolismo , Hordeum/química , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/fisiopatologia , Sistema Nervoso/fisiopatologia , Extratos Vegetais/uso terapêutico , Glândula Tireoide/fisiopatologia , Aminoácidos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Caspase 3/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Sistema Nervoso/efeitos dos fármacos , Neurotransmissores/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo
19.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934777

RESUMO

Lignans from Schisandra chinensis (Turcz.) Baill can ameliorate cognitive impairment in animals with Alzheimer's disease (AD). However, the metabolism of absorbed ingredients and the potential targets of the lignans from S. chinensis in animals with AD have not been systematically investigated. Therefore, for the first time, we performed an in-vivo ingredient analysis and implemented a target-network pharmacology strategy to assess the effects of lignans from S. chinensis in rats with AD. Ten absorbed prototype constituents and 39 metabolites were identified or tentatively characterized in the plasma of dosed rats with AD using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Based on the results of analysis of the effective constituents in vivo, the potential therapeutic mechanism of the effective constituents in the rats with AD was investigated using a target-network pharmacology approach and independent experimental validation. The results showed that the treatment effects of lignans from S. chinensis on cognitive impairment might involve the regulation of amyloid precursor protein metabolism, neurofibrillary tangles, neurotransmitter metabolism, inflammatory response, and antioxidant system. Overall, we identified the effective components of lignans in S. chinensis that can improve the cognitive impairment induced by AD and proposed potential therapeutic metabolic pathways. The results might serve as the basis for a fundamental strategy to explore effective therapeutic drugs to treat AD.


Assuntos
Cromatografia Líquida de Alta Pressão , Lignanas/química , Lignanas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Schisandra/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Biomarcadores , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Redes e Vias Metabólicas , Estrutura Molecular , Neurônios/metabolismo , Neurotransmissores/metabolismo , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Ratos
20.
Nat Commun ; 10(1): 1651, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971693

RESUMO

Functional interfaces between electronics and biological matter are essential to diverse fields including health sciences and bio-engineering. Here, we report the discovery of spontaneous (no external energy input) hydrogen transfer from biological glucose reactions into SmNiO3, an archetypal perovskite quantum material. The enzymatic oxidation of glucose is monitored down to ~5 × 10-16 M concentration via hydrogen transfer to the nickelate lattice. The hydrogen atoms donate electrons to the Ni d orbital and induce electron localization through strong electron correlations. By enzyme specific modification, spontaneous transfer of hydrogen from the neurotransmitter dopamine can be monitored in physiological media. We then directly interface an acute mouse brain slice onto the nickelate devices and demonstrate measurement of neurotransmitter release upon electrical stimulation of the striatum region. These results open up avenues for use of emergent physics present in quantum materials in trace detection and conveyance of bio-matter, bio-chemical sciences, and brain-machine interfaces.


Assuntos
Bioengenharia/instrumentação , Técnicas Biossensoriais/instrumentação , Compostos de Cálcio/química , Glucose Oxidase/metabolismo , Óxidos/química , Titânio/química , Animais , Interfaces Cérebro-Computador , Corpo Estriado/metabolismo , Estimulação Elétrica/instrumentação , Eletrodos , Eletrônica , Elétrons , Glucose/química , Glucose/metabolismo , Hidrogênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Neurotransmissores/metabolismo , Oxirredução
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