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1.
Cell ; 184(3): 709-722.e13, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33482084

RESUMO

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca2+ dynamics and promoted NSC activation. We further discovered a Ca2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca2+ fluxes to mimic quiescent-state-like Ca2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.


Assuntos
Células-Tronco Adultas/metabolismo , Cálcio/metabolismo , Ritmo Circadiano , Espaço Intracelular/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Citosol/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Melatonina/metabolismo , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Optogenética , Transdução de Sinais/efeitos dos fármacos , Triptaminas/farmacologia
2.
Cell ; 162(6): 1212-4, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26359982

RESUMO

In this issue, Farez et al. report that the circadian hormone melatonin, whose levels vary with seasonal changes in night length, shifts the immune response toward an anti-inflammatory state that may explain the seasonal variability of multiple sclerosis disease activity.


Assuntos
Melatonina/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Animais , Feminino , Humanos , Masculino
3.
Cell ; 162(6): 1338-52, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26359987

RESUMO

Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.


Assuntos
Melatonina/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Luz , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Recidiva , Estações do Ano , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo
4.
Cell ; 159(1): 9-10, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25259913

RESUMO

Tosches et al. show that melatonin signaling regulates circadian swimming in annelid worms by rhythmically activating cholinergic neurons. This suggests an evolutionary connection between melatonin signaling in invertebrates and sleep regulation in vertebrates.


Assuntos
Melatonina/metabolismo , Células Fotorreceptoras de Invertebrados/metabolismo , Poliquetos/fisiologia , Animais
5.
Cell ; 159(1): 46-57, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25259919

RESUMO

Melatonin, the "hormone of darkness," is a key regulator of vertebrate circadian physiology and behavior. Despite its ubiquitous presence in Metazoa, the function of melatonin signaling outside vertebrates is poorly understood. Here, we investigate the effect of melatonin signaling on circadian swimming behavior in a zooplankton model, the marine annelid Platynereis dumerilii. We find that melatonin is produced in brain photoreceptors with a vertebrate-type opsin-based phototransduction cascade and a light-entrained clock. Melatonin released at night induces rhythmic burst firing of cholinergic neurons that innervate locomotor-ciliated cells. This establishes a nocturnal behavioral state by modulating the length and the frequency of ciliary arrests. Based on our findings, we propose that melatonin signaling plays a role in the circadian control of ciliary swimming to adjust the vertical position of zooplankton in response to ambient light.


Assuntos
Melatonina/metabolismo , Células Fotorreceptoras de Invertebrados/metabolismo , Poliquetos/fisiologia , Animais , Encéfalo/metabolismo , Cílios/fisiologia , Relógios Circadianos , Ritmo Circadiano , Regulação da Expressão Gênica , Larva/metabolismo , Dados de Sequência Molecular , Neurônios/metabolismo , Células Fotorreceptoras de Invertebrados/citologia , Poliquetos/citologia , Natação , Zooplâncton/citologia , Zooplâncton/fisiologia
6.
Proc Natl Acad Sci U S A ; 120(18): e2212685120, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37094145

RESUMO

Circadian rhythms influence physiology, metabolism, and molecular processes in the human body. Estimation of individual body time (circadian phase) is therefore highly relevant for individual optimization of behavior (sleep, meals, sports), diagnostic sampling, medical treatment, and for treatment of circadian rhythm disorders. Here, we provide a partial least squares regression (PLSR) machine learning approach that uses plasma-derived metabolomics data in one or more samples to estimate dim light melatonin onset (DLMO) as a proxy for circadian phase of the human body. For this purpose, our protocol was aimed to stay close to real-life conditions. We found that a metabolomics approach optimized for either women or men under entrained conditions performed equally well or better than existing approaches using more labor-intensive RNA sequencing-based methods. Although estimation of circadian body time using blood-targeted metabolomics requires further validation in shift work and other real-world conditions, it currently may offer a robust, feasible technique with relatively high accuracy to aid personalized optimization of behavior and clinical treatment after appropriate validation in patient populations.


Assuntos
Corpo Humano , Melatonina , Masculino , Humanos , Feminino , Luz , Ritmo Circadiano/fisiologia , Sono/fisiologia , Melatonina/metabolismo , Metabolômica
7.
Plant J ; 117(4): 1115-1129, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37966861

RESUMO

Nitrogen (N) is an essential nutrient for crop growth and development, significantly influencing both yield and quality. Melatonin (MT), a known enhancer of abiotic stress tolerance, has been extensively studied. However, its relationship with nutrient stress, particularly N deficiency, and the underlying regulatory mechanisms of MT on N absorption remain unclear. In this study, exogenous MT treatment was found to improve the tolerance of apple plants to N deficiency. Apple plants overexpressing the MT biosynthetic gene N-acetylserotonin methyltransferase 9 (MdASMT9) were used to further investigate the effects of endogenous MT on low-N stress. Overexpression of MdASMT9 improved the light harvesting and heat transfer capability of apple plants, thereby mitigating the detrimental effects of N deficiency on the photosynthetic system. Proteomic and physiological data analyses indicated that MdASMT9 overexpression enhanced the trichloroacetic acid cycle and positively modulated amino acid metabolism to counteract N-deficiency stress. Additionally, both exogenous and endogenous MT promoted the transcription of MdHY5, which in turn bound to the MdNRT2.1 and MdNRT2.4 promoters and activated their expression. Notably, MT-mediated promotion of MdNRT2.1 and MdNRT2.4 expression through regulating MdHY5, ultimately enhancing N absorption. Taken together, these findings shed light on the association between MdASMT9-mediated MT biosynthesis and N absorption in apple plants under N-deficiency conditions.


Assuntos
Malus , Melatonina , Melatonina/metabolismo , Malus/genética , Malus/metabolismo , Nitrogênio/metabolismo , Proteômica , Plantas Geneticamente Modificadas/genética
8.
PLoS Pathog ; 19(5): e1011406, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37200384

RESUMO

Influenza A virus (IAV) H1N1 infection is a constant threat to human health and it remains so due to the lack of an effective treatment. Since melatonin is a potent antioxidant and anti-inflammatory molecule with anti-viral action, in the present study we used melatonin to protect against H1N1 infection under in vitro and in vivo conditions. The death rate of the H1N1-infected mice was negatively associated with the nose and lung tissue local melatonin levels but not with serum melatonin concentrations. The H1N1-infected AANAT-/- melatonin-deficient mice had a significantly higher death rate than that of the WT mice and melatonin administration significantly reduced the death rate. All evidence confirmed the protective effects of melatonin against H1N1 infection. Further study identified that the mast cells were the primary targets of melatonin action, i.e., melatonin suppresses the mast cell activation caused by H1N1 infection. The molecular mechanisms involved melatonin down-regulation of gene expression for the HIF-1 pathway and inhibition of proinflammatory cytokine release from mast cells; this resulted in a reduction in the migration and activation of the macrophages and neutrophils in the lung tissue. This pathway was mediated by melatonin receptor 2 (MT2) since the MT2 specific antagonist 4P-PDOT significantly blocked the effects of melatonin on mast cell activation. Via targeting mast cells, melatonin suppressed apoptosis of alveolar epithelial cells and the lung injury caused by H1N1 infection. The findings provide a novel mechanism to protect against the H1N1-induced pulmonary injury, which may better facilitate the progress of new strategies to fight H1N1 infection or other IAV viral infections.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Lesão Pulmonar , Melatonina , Infecções por Orthomyxoviridae , Humanos , Animais , Camundongos , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Mastócitos/metabolismo , Melatonina/farmacologia , Melatonina/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Pulmão
9.
Am J Pathol ; 194(1): 85-100, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37918798

RESUMO

Sleep deficiency is associated with intestinal inflammatory conditions and is increasingly recognized as a public health concern worldwide. However, the effects of sleep deficiency on intestinal goblet cells (GCs), which play a major role in intestinal barrier formation, remain elusive. Herein, the effects of sleep deprivation on intestinal GCs were determined using a sleep-deprivation mouse model. Sleep deprivation impaired the intestinal mucosal barrier and decreased the expression of tight junction proteins. According to single-cell RNA sequencing and histologic assessments, sleep deprivation significantly reduced GC numbers and mucin protein levels in intestinal tissues. Furthermore, sleep deprivation initiated endoplasmic reticulum stress by activating transcription factor 6 and binding Ig protein. Treatment with melatonin, an endoplasmic reticulum stress regulator, significantly alleviated endoplasmic reticulum stress responses in intestinal GCs. In addition, melatonin increased the villus length, reduced the crypt depth, and restored intestinal barrier function in mice with sleep deprivation. Overall, the findings revealed that sleep deprivation could impair intestinal mucosal barrier integrity and GC function. Targeting endoplasmic reticulum stress could represent an ideal strategy for treating sleep deficiency-induced gastrointestinal disorders.


Assuntos
Enteropatias , Melatonina , Camundongos , Animais , Células Caliciformes/metabolismo , Privação do Sono/complicações , Privação do Sono/metabolismo , Privação do Sono/patologia , Melatonina/metabolismo , Melatonina/farmacologia , Mucosa Intestinal/metabolismo , Enteropatias/metabolismo , Estresse do Retículo Endoplasmático
10.
Plant Physiol ; 194(2): 1218-1232, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-37874769

RESUMO

Cassava common mosaic virus (CsCMV, genus Potexvirus) is a prevalent virus associated with cassava mosaic disease, so it is essential to elucidate the underlying molecular mechanisms of the coevolutionary arms race between viral pathogenesis and the cassava (Manihot esculenta Crantz) defense response. However, the molecular mechanism underlying CsCMV infection is largely unclear. Here, we revealed that coat protein (CP) acts as a major pathogenicity determinant of CsCMV via a mutant infectious clone. Moreover, we identified the target proteins of CP-related to abscisic acid insensitive3 (ABI3)/viviparous1 (VP1) (MeRAV1) and MeRAV2 transcription factors, which positively regulated disease resistance against CsCMV via transcriptional activation of melatonin biosynthetic genes (tryptophan decarboxylase 2 (MeTDC2), tryptamine 5-hydroxylase (MeT5H), N-aceylserotonin O-methyltransferase 1 (MeASMT1)) and MeCatalase6 (MeCAT6) and MeCAT7. Notably, the interaction between CP, MeRAV1, and MeRAV2 interfered with the protein phosphorylation of MeRAV1 and MeRAV2 individually at Ser45 and Ser44 by the protein kinase, thereby weakening the transcriptional activation activity of MeRAV1 and MeRAV2 on melatonin biosynthetic genes, MeCAT6 and MeCAT7 dependent on the protein phosphorylation of MeRAV1 and MeRAV2. Taken together, the identification of the CP-MeRAV1 and CP-MeRAV2 interaction module not only illustrates a molecular mechanism by which CsCMV orchestrates the host defense system to benefit its infection and development but also provides a gene network with potential value for the genetic improvement of cassava disease resistance.


Assuntos
Manihot , Melatonina , Vírus do Mosaico , Potexvirus , Resistência à Doença/genética , Manihot/genética , Manihot/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Potexvirus/genética , Melatonina/metabolismo , Doenças das Plantas/genética
11.
FASEB J ; 38(18): e70052, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39291773

RESUMO

Oogenesis involves two phases: initial volumetric growth driven by nutrient accumulation and subsequent nuclear maturation. While melatonin (MLT) has been employed as a supplement to enhance the quality of fully grown oocytes during nuclear maturation phase, its impact on oocyte growth remains poorly studied. Here, we provide in vivo evidence demonstrating that follicle-stimulating hormone increases MLT content in ovary. Administration of MLT improves oocyte growth and quality in mice and goats by enhancing nutrient reserves and mitochondrial function. Conversely, MLT-deficient mice have smaller oocytes and dysfunctional mitochondria. Exploring the clinical implications of MLT in promoting oocyte growth, we observe that a brief 2-day MLT treatment enhances oocyte quality and reproductive performance in older mice. These findings highlight the role of MLT in regulating oocyte growth and provide a specific treatment window for optimizing oocyte quality and reproductive performance in female animals.


Assuntos
Cabras , Melatonina , Mitocôndrias , Oócitos , Animais , Melatonina/farmacologia , Melatonina/metabolismo , Oócitos/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Camundongos , Feminino , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Oogênese/fisiologia , Hormônio Foliculoestimulante/metabolismo , Nutrientes/metabolismo , Camundongos Endogâmicos C57BL
12.
FASEB J ; 38(11): e23719, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38837828

RESUMO

Chronic disruption of circadian rhythms by night shift work is associated with an increased breast cancer risk. However, little is known about the impact of night shift on peripheral circadian genes (CGs) and circadian-controlled genes (CCGs) associated with breast cancer. Hence, we assessed central clock markers (melatonin and cortisol) in plasma, and peripheral CGs (PER1, PER2, PER3, and BMAL1) and CCGs (ESR1 and ESR2) in peripheral blood mononuclear cells (PBMCs). In day shift nurses (n = 12), 24-h rhythms of cortisol and melatonin were aligned with day shift-oriented light/dark schedules. The mRNA expression of PER2, PER3, BMAL1, and ESR2 showed 24-h rhythms with peak values in the morning. In contrast, night shift nurses (n = 10) lost 24-h rhythmicity of cortisol with a suppressed morning surge but retained normal rhythmic patterns of melatonin, leading to misalignment between cortisol and melatonin. Moreover, night shift nurses showed disruption of rhythmic expressions of PER2, PER3, BMAL1, and ESR2 genes, resulting in an impaired inverse correlation between PER2 and BMAL1 compared to day shift nurses. The observed trends of disrupted circadian markers were recapitulated in additional day (n = 20) and night (n = 19) shift nurses by measurement at early night and midnight time points. Taken together, this study demonstrated the misalignment of cortisol and melatonin, associated disruption of PER2 and ESR2 circadian expressions, and internal misalignment in peripheral circadian network in night shift nurses. Morning plasma cortisol and PER2, BMAL1, and ESR2 expressions in PBMCs may therefore be useful biomarkers of circadian disruption in shift workers.


Assuntos
Relógios Circadianos , Ritmo Circadiano , Hidrocortisona , Melatonina , Jornada de Trabalho em Turnos , Humanos , Feminino , Melatonina/metabolismo , Melatonina/sangue , Adulto , Jornada de Trabalho em Turnos/efeitos adversos , Relógios Circadianos/genética , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Ritmo Circadiano/fisiologia , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Enfermeiras e Enfermeiros , Leucócitos Mononucleares/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Tolerância ao Trabalho Programado/fisiologia , Condições de Trabalho
13.
Nature ; 569(7755): 289-292, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31019305

RESUMO

The human MT1 and MT2 melatonin receptors1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns3. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer3, and MT2 has also been implicated in type 2 diabetes4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H2085.46A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature7) and N862.50D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure8 of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [3H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.


Assuntos
Elétrons , Lasers , Modelos Moleculares , Receptor MT2 de Melatonina/química , Receptor MT2 de Melatonina/metabolismo , Cristalização , Diabetes Mellitus Tipo 2/genética , Humanos , Indenos/química , Indenos/metabolismo , Ligantes , Melatonina/análogos & derivados , Melatonina/química , Melatonina/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Receptor MT1 de Melatonina/química , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Relação Estrutura-Atividade , Especificidade por Substrato
14.
Cell Mol Life Sci ; 81(1): 61, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38279053

RESUMO

Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.


Assuntos
Melatonina , Glândula Pineal , Camundongos , Animais , Melatonina/metabolismo , Acetilserotonina O-Metiltransferasa/química , Acetilserotonina O-Metiltransferasa/metabolismo , alfa-Sinucleína/metabolismo , Glândula Pineal/metabolismo
15.
Genomics ; 116(3): 110844, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38608737

RESUMO

The study demonstrated that melatonin (MT) can induce the development of secondary hair follicles in Inner Mongolian cashmere goats through the Wnt10b gene, leading to secondary dehairing. However, the mechanisms underlying the expression and molecular function of Wnt10b in dermal papilla cells (DPC) remain unknown. This research aimed to investigate the impact of MT on DPC and the regulation of Wnt10b expression, function, and molecular mechanisms in DPC. The findings revealed that MT promotes DPC proliferation and enhances DPC activity. Co-culturing DPC with overexpressed Wnt10b and MT showed a significant growth promotion. Subsequent RNA sequencing (RNA-seq) of overexpressed Wnt10b and control groups unveiled the regulatory role of Wnt10b in DPC. Numerous genes and pathways, including developmental pathways such as Wnt and MAPK, as well as processes like hair follicle morphogenesis and hair cycle, were identified. These results suggest that Wnt10b promotes the growth of secondary hair follicles in Inner Mongolian cashmere goats by regulating crucial factors and pathways in DPC proliferation.


Assuntos
Proliferação de Células , Cabras , Folículo Piloso , Melatonina , Proteínas Wnt , Animais , Folículo Piloso/metabolismo , Folículo Piloso/citologia , Folículo Piloso/crescimento & desenvolvimento , Cabras/genética , Cabras/metabolismo , Melatonina/farmacologia , Melatonina/metabolismo , Proteínas Wnt/metabolismo , Proteínas Wnt/genética , Células Cultivadas
16.
Diabetologia ; 67(6): 1114-1121, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38413436

RESUMO

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.


Assuntos
Ritmo Circadiano , Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Melatonina , Células Ganglionares da Retina , Humanos , Melatonina/sangue , Melatonina/metabolismo , Retinopatia Diabética/metabolismo , Retinopatia Diabética/sangue , Retinopatia Diabética/fisiopatologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Idoso , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Sono/fisiologia , Adulto
17.
Mol Pharmacol ; 106(1): 3-12, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38811168

RESUMO

Melatonin N-acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biologic activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation, where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to different proteins such as calmodulin: a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence supporting that melatonin binds to calmodulin in presence of calcium, and we discuss the effects of this indolamine on the activity of calmodulin kinase II as an inhibitor and as stimulator of calmodulin-dependent protein kinase II activity. We also provide a literature review supporting the relevance of melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient, conserved mechanism. Finally, we highlight the importance of antioxidant effects of melatonin on calmodulin preservation. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of calmodulin kinase II, the possible mechanisms involved, and the relevance on regulation of circadian rhythms and neurodevelopment. Finally, we describe evidence supporting that the binding of melatonin to calmodulin hydrophobic pockets may prevent the oxidation of methionine species with a shielding effect that preserves the functionality of calmodulin.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Calmodulina , Ritmo Circadiano , Melatonina , Melatonina/metabolismo , Calmodulina/metabolismo , Humanos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ritmo Circadiano/fisiologia , Cálcio/metabolismo , Ligação Proteica
18.
J Cell Mol Med ; 28(7): e18160, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38506067

RESUMO

Apolipoprotein E4 (ApoE4) is involved in the stress-response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg-ApoEtm1Unc Cdh18Tg( GFAP-APOE i4)1Hol /J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4-induced depression. LPS treatment significantly aggravated depression-like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin-1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria-related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria-associated protein and mitophagy defects, including PGC-1α, TFAM, p-AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.


Assuntos
Apolipoproteína E4 , Melatonina , Camundongos , Animais , Apolipoproteína E4/metabolismo , Apolipoproteína E4/farmacologia , Depressão , Melatonina/farmacologia , Melatonina/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Proteômica , Mitocôndrias/metabolismo , Apolipoproteínas E/metabolismo , Camundongos Transgênicos , Proteínas Quinases Ativadas por AMP/metabolismo
19.
Eur J Neurosci ; 60(2): 3858-3890, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38816965

RESUMO

Patients with neurodevelopmental disorders, such as autism spectrum disorder, often display abnormal circadian rhythms. The role of the circadian system in these disorders has gained considerable attention over the last decades. Yet, it remains largely unknown how these disruptions occur and to what extent they contribute to the disorders' development. In this review, we examine circadian system dysregulation as observed in patients and animal models of neurodevelopmental disorders. Second, we explore whether circadian rhythm disruptions constitute a risk factor for neurodevelopmental disorders from studies in humans and model organisms. Lastly, we focus on the impact of psychiatric medications on circadian rhythms and the potential benefits of chronotherapy. The literature reveals that patients with neurodevelopmental disorders display altered sleep-wake cycles and melatonin rhythms/levels in a heterogeneous manner, and model organisms used to study these disorders appear to support that circadian dysfunction may be an inherent characteristic of neurodevelopmental disorders. Furthermore, the pre-clinical and clinical evidence indicates that circadian disruption at the environmental and genetic levels may contribute to the behavioural changes observed in these disorders. Finally, studies suggest that psychiatric medications, particularly those prescribed for attention-deficit/hyperactivity disorder and schizophrenia, can have direct effects on the circadian system and that chronotherapy may be leveraged to offset some of these side effects. This review highlights that circadian system dysfunction is likely a core pathological feature of neurodevelopmental disorders and that further research is required to elucidate this relationship.


Assuntos
Ritmo Circadiano , Transtornos do Neurodesenvolvimento , Humanos , Animais , Transtornos do Neurodesenvolvimento/fisiopatologia , Ritmo Circadiano/fisiologia , Transtornos Cronobiológicos/fisiopatologia , Melatonina/metabolismo
20.
Funct Integr Genomics ; 24(5): 169, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39313718

RESUMO

Melatonin (MLT), a main product of pineal gland, recently has attracted the attention of scientists due to its benefits in various diseases and also regulation of cellular homeostasis. Its receptor scares widely distributed indicating that it influences numerous organs. Programmed cell death (PCD), of which there several types, is a regulated by highly conserved mechanisms and important for development and function of different organs. Enhancement or inhibition of PCDs could be a useful technique for treatment of different diseases and MLT, due to its direct effects on these pathways, is a good candidate for this strategy. Many studies investigated the role of MLT on PCDs in different diseases and in this review, we summarized some of the most significant studies in this field to provide a better insight into the mechanisms of modulation of PCD by MLT modulation.


Assuntos
Apoptose , Melatonina , Melatonina/metabolismo , Melatonina/farmacologia , Humanos , Apoptose/efeitos dos fármacos , Animais
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