RESUMO
Melatonin (MEL) is a pleiotropic indolamine that reaches multiple intracellular targets. Among these, MEL binds to calmodulin (CaM) with high affinity. In presence of Ca2+, CaM binds to CaM-dependent kinase II (CaMKII). The Ca2+-CaM/CaMKII pathway regulates a myriad of brain functions in different cellular compartments. Evidence showing the regulation of this cellular pathway by MEL is scarce. Thus, our main objective was to study the interaction of MEL with CaM and its effects on CaMKII activity in two microenvironments (aqueous and lipidic) naturally occurring within the cell. In addition, colocalization of MEL with CaM in vivo was explored in mice brain hippocampus. In vitro CaM-MEL interaction and the structural conformations of CaM in the presence of this indoleamine were assessed through electrophoretic mobility and isoelectric point. The functional consequence of this interaction was evaluated by measuring CaMKII activity. Ca2+-CaM-MEL increased the activity of CaMKII in aqueous buffer but reduced the kinase activity in lipid buffer. Importantly, MEL colocalizes in vivo with Ca2+-CaM in the hippocampus. Our evidence suggests that MEL regulates the key cellular Ca2+-CaM/CaMKII pathway and might explain why physiological MEL concentrations reduce CaMKII activity in some experimental conditions, while in others it drives biological processes through activation of this kinase.
Assuntos
Calmodulina , Melatonina , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Melatonina/farmacologia , Camundongos , FosforilaçãoRESUMO
Sleep has a major role in learning, memory consolidation, and metabolic function. Although it is known that sleep restriction increases the accumulation of amyloid ß peptide (Aß) and the risk to develop Alzheimer's disease (AD), the mechanism behind these effects remains unknown. In this review, we discuss how chronic sleep restriction induces metabolic and cognitive impairments that could result in the development of AD in late life. Here, we integrate evidence regarding mechanisms whereby metabolic signaling becomes disturbed after short or chronic sleep restriction in the context of cognitive impairment, particularly in the accumulation of Aß in the brain. We also discuss the role of the blood-brain barrier in sleep restriction with an emphasis on the transport of metabolic signals into the brain and Aß clearance. This review presents the unexplored possibility that the alteration of peripheral metabolic signals induced by sleep restriction, especially insulin resistance, is responsible for cognitive deficit and, subsequently, implicated in AD development.
RESUMO
The coronavirus disease (COVID-19) that broke out in China in December 2019 rapidly became a worldwide pandemic. In Mexico, the conditions requiring the declaration of a sanitary emergency were reached by the last week of March 2020, and health authorities' limited mobility and imposed social isolation were the main strategies to keep the virus from spreading. Thus, daily living conditions changed drastically in a few days, generating a stressful situation characterized by an almost complete lack of mobility, social isolation, and forced full-time interactions with family members. Soon, complaints of sleep disturbances, anxiety, and symptoms of depression were reported. The present study reports the results of an online survey performed during the first two months of isolation. Questionnaires exploring sleep disturbances, anxiety, and depression were sent to people who responded to an open invitation. A total of 1230 participants filled out the sleep questionnaire, 812 responded to the anxiety questionnaire, and 814 responded to the depression questionnaire. Both men and women reported poor sleep quality, but women showed a higher proportion (79%) than men (60%); young women were more likely to be affected by social isolation. Concerning anxiety and depression, both sexes reported high similar symptoms. These data suggest that stressful conditions related to social isolation and the economic uncertainty caused by the pandemic may induce mental health disturbances, which may become worse with sleep restriction.
Assuntos
COVID-19 , Coronavirus , Ansiedade/epidemiologia , China/epidemiologia , Depressão/epidemiologia , Feminino , Humanos , Masculino , Saúde Mental , México/epidemiologia , Pandemias , SARS-CoV-2 , Sono , Isolamento SocialRESUMO
Homeless people face stressful circumstances influencing drug consumption, mental health, and sleep disorders. We performed an interdisciplinary study involving psychometric, polysomnographic, and ethnographic records to relate stress, psychiatric disorders, drug consumption, and sleep in ten people (four women, M = 32 y/o) living on the streets of Mexico City. Toluene-based inhalant dependence and suicidality were the more common psychiatric disorders among participants. They also presented sleep fragmentation; some manifested insomnia or sleep restriction, whereas others displayed extended rapid-eye movement sleep latencies associated with depression or inhalant consumption. Inhalants are used to improve mood, strengthen social bonds, and induce either sleep or alertness during the night. Inter-individual distinctions may be related to differential levels of intoxication, stress perception, backgrounds, and abilities to live and sleep on the street. Sleep restriction seems to be the more common factor, which may enhance the negative consequences of street situation.
Assuntos
Pessoas Mal Alojadas/psicologia , Abuso de Inalantes/psicologia , Transtornos Mentais/psicologia , Sono , Estresse Psicológico/psicologia , Adulto , Feminino , Pessoas Mal Alojadas/estatística & dados numéricos , Humanos , Masculino , México , Distúrbios do Início e da Manutenção do Sono/psicologia , Fatores de TempoRESUMO
Sleep loss increases blood-brain barrier permeability. As the blood-brain barrier and the blood-tissue barriers in the reproductive tract (blood-testis and blood-epididymis barriers) share common characteristics, we hypothesized that sleep restriction may also modify their barrier function. Previous reports showed that sleep loss decreased sperm viability and progressive fast mobility, which may be a consequence of altered blood-testis and blood-epididymis barrier. Therefore, we quantified changes in blood-testis and blood-epididymis barrier after sleep loss and related them to male fertility. Adult male Wistar rats were sleep restricted using the multiple-platform technique in a protocol of 20 hr daily sleep deprivation plus 4 hr of sleep recovery in the home-cage. At the 10th day, barrier permeability assays were performed with Na-fluorescein, 10 kDa Cascade blue-dextrans and Evans blue, and the expression of tight junction proteins, actin and androgen receptor was quantified. At the 10th day of sleep restriction and after sleep recovery days 1-7, males were placed with sexually receptive females, sexual behaviour was tested, and the percentage of pregnancies was calculated. Sleep restriction increased the barrier permeability to low- and high-molecular-weight tracers, and decreased the expression of tight junction proteins, actin and androgen receptor. Concomitantly, sleep restriction reduced the percentage of ejaculating males and the number of pregnancies. Sleep recovery for 2-3 days progressively re-established fertility, as indicated by a higher percentage of ejaculating males and impregnated females. In conclusion, chronic sleep loss alters fertility concomitantly with the disruption of the blood-tissue barriers at the reproductive tract, the mechanism involves androgen signalling.
Assuntos
Barreira Hematoencefálica/fisiopatologia , Epididimo/fisiopatologia , Fertilidade/fisiologia , Microscopia Confocal/métodos , Distúrbios do Início e da Manutenção do Sono/complicações , Animais , Doença Crônica , Humanos , Masculino , Ratos , Ratos Wistar , Privação do Sono/fisiopatologia , Testículo/fisiopatologiaRESUMO
Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and increased blood-brain barrier permeability.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Receptor A2A de Adenosina/química , Privação do Sono/fisiopatologia , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Masculino , Ratos , Ratos WistarRESUMO
Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed.
Assuntos
Resistência à Doença , Imunidade , Infecções/etiologia , Sono , Animais , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/fisiologia , Infecções/metabolismoRESUMO
Obstructive sleep apnea (OSA) has been related to elevation of inflammatory cytokines and development of insulin resistance in morbidly obese (MO) subjects. However, it is still unclear whether the systemic concentration of anti-inflammatory mediators is also affected in MO subjects directly related to the severity of OSA and level of insulin resistance. Normal weight and MO subjects were subjected to overnight polysomnography in order to establish the severity of OSA, according to the apnea-hypopnea index (AHI). Blood samples were obtained for estimation of total cholesterol and triglycerides, insulin, glucose, insulin resistance, tumor necrosis factor alpha (TNF-α), interleukin 12 (IL12), and interleukin 10 (IL-10). Serum levels of IL-10 were significantly lower in MO subjects with OSA than in MO and control individuals without OSA. Besides being inversely associated with serum TNF-α and IL-12, decreased IL-10 levels were significantly related to increased AHI, hyperinsulinemia, and insulin resistance. Serum IL-10 is significantly reduced in morbidly obese subjects with severe OSA while also showing a clear relationship with a state of hyperinsulinemia and insulin resistance probably regardless of obesity in the present sample. It may be of potential clinical interest to identify the stimulatory mechanisms of IL-10 in obese individuals with OSA.
Assuntos
Regulação da Expressão Gênica , Resistência à Insulina , Interleucina-10/sangue , Obesidade Mórbida/imunologia , Apneia Obstrutiva do Sono/metabolismo , Adulto , Antropometria , Índice de Massa Corporal , Estudos de Casos e Controles , Colesterol/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Hiperinsulinismo , Insulina/metabolismo , Interleucina-10/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Polissonografia , Síndromes da Apneia do Sono/metabolismo , Inquéritos e Questionários , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
INTRODUCTION: The multiple partner choice arena (MPCA) is an experimental setup in which male rats display a significant shortening of ejaculation latency, which is the main characteristic of premature ejaculation (PE) in men. Thus, the MPCA is a potential animal model for PE. AIM: In this study, we further analyze whether the features of the MPCA satisfy the validity criteria for it to be considered an animal model as well as the possible participation of the serotoninergic system in the faster ejaculation exhibited by male rats in the MPCA. METHODS: In Experiment 1, male rats were tested in a standard arena to assess their sexual behavior, then were assessed 1 week later in the MPCA. Another group was first tested in the MPCA, then in a standard arena. In Experiment 2, male rats divided into two groups were treated daily with WAY-100635 (5-HT(1A) antagonist) or vehicle for 15 days. In each group, half of the subjects were tested in a standard arena and half were tested in the MPCA on days 1, 8, and 15 of treatment. MAIN OUTCOME MEASURES: Number of intromissions and intromission and ejaculation latencies were the main outcome measures. RESULTS: In Experiment 1, males tested in the MPCA ejaculated significantly faster, regardless of the order in which they were evaluated in both arenas. In Experiment 2, the administration of WAY-100635 increased intromission and ejaculation latencies, and the number of intromissions in the MPCA. CONCLUSIONS: The results obtained in the MPCA support its use as an animal model for PE evaluation.