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1.
Gene ; 738: 144483, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070750

RESUMO

TGFß signaling pathway is critical for the cell division, differentiation and apoptosis, the aberrant regulation of which will result in severe diseases including cancer. N6-methyl-adenosine (m6A) is one of the most abundant modifications on mRNA, it is unclear yet how m6A epitranscriptome response to stimulation of TGFß. Here, we found that cellular m6A level of RNA was elevated after TGFß treatment, which might be regulated by upregulation of WTAP and METTL3. MeRIP-Seq of mRNAs of MCF7 with or without treated by TGFß showed that mRNA with upregulated m6A modification level after TGFß treatment were enriched in TGFß signaling pathway. Phosphorylated level of SMAD2 or SMAD3 induced by TGFß was impaired when WTAP was silenced. Moreover, the m6A modification and mRNA level of JunB, which is known as a cell cycle inhibitor, both were increased after induction of TGFß and decreased after knockdown of WTAP. Intriguingly, growth inhibition caused by TGFß was rescued in WTAP-knockdown cells. Collectively, these results reveal the key role that m6A pathway playing in the cell cycle arrest induced by TGFß signaling, providing new mechanisms explanation for growth inhibition mediated by TGFß.


Assuntos
Adenosina/análogos & derivados , Ciclo Celular/genética , Fator de Crescimento Transformador beta/metabolismo , Adenosina/metabolismo , Adenosina/fisiologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Divisão Celular , Linhagem Celular Tumoral , Humanos , Células MCF-7 , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas Nucleares/genética , Fosforilação , RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , Transdução de Sinais/fisiologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
2.
Oncogene ; 38(33): 6123-6141, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285549

RESUMO

Most N6-methyladenosine (m6A) associated regulatory proteins (i.e., m6A writer, eraser, and reader proteins) are involved in the pathogenesis of various cancers, mostly in m6A-dependent manners. As a component in the m6A 'writers', KIAA1429 is reported to be an RNA-binding protein and involved in the m6A modification, mRNA splicing and processing. Till now, the functions of KIAA1429 in tumorigenesis and related mechanism have not been reported. In the present study, we found KIAA1429 was highly expressed in breast cancer tissues, but frequently down-regulated in non-cancerous breast tissues. The overall survival of breast cancer patients with high-expression KIAA1429 was significantly shorter than those with low-expression KIAA1429. Then, we demonstrated that KIAA1429 was associated with breast cancer proliferation and metastasis in vivo and in vitro. The potential targeting genes of KIAA1429 in breast cancer were identified by RNA immunoprecipitation sequencing. One of these genes is cyclin-dependent kinase 1 (CDK1), which plays an oncogenic role in cancers. Furthermore, we confirmed that KIAA1429 played its oncogenic role in breast cancer by regulating CDK1 by an m6A-independent manner. 5'-fluorouracil was found to be very effective in reducing the expression of KIAA1429 and CDK1 in breast cancer. These findings indicated that KIAA1429 could promote breast cancer progression and was correlated with pathogenesis. It may represent a promising therapeutic strategy on breast cancer, especially in combination with CDK1 treatment.


Assuntos
Adenosina/análogos & derivados , Neoplasias da Mama/genética , Proteína Quinase CDC2/genética , Oncogenes/fisiologia , Proteínas de Ligação a RNA/fisiologia , Adenosina/metabolismo , Adenosina/fisiologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína Quinase CDC2/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Proteínas de Ligação a RNA/genética , Células Tumorais Cultivadas
3.
PLoS Biol ; 17(4): e3000213, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951527

RESUMO

Adenosine modulation is considered both a paracrine signal coordinating different cells in a tissue and a stress signal. Both functions are ensured by 4 types of adenosine receptors (ARs), which have been studied individually. Mice with knockout of all ARs (quad-AR-KO) now allow enquiring the overall function of the adenosine modulation system. The observed "normal" physiology of quad-AR-KO mice indicates that ARs do not regulate homeostasis and are likely recruited to selectively control allostasis.


Assuntos
Alostase/fisiologia , Homeostase/fisiologia , Receptores Purinérgicos P1/metabolismo , Adenosina/fisiologia , Alostase/genética , Animais , Homeostase/genética , Camundongos , Camundongos Knockout , Receptores Purinérgicos P1/genética , Receptores Purinérgicos P1/fisiologia , Transdução de Sinais/fisiologia
4.
Mol Biol Rep ; 46(2): 2567-2575, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30911972

RESUMO

N6-methyladenosine (m6A) serves as a major RNA methylation modification and impacts the initiation and progression of various human cancers through diverse mechanisms. It has been reported that m6A RNA methylation is involved in different physiological and pathological processes, including stem cell differentiation and motility, immune response, cellular stress, tissue renewal and viral infection. In this review, the m6A modification and its regulatory functions in a few major cancers is introduced. The detection approaches for the m6A sites identification are discussed. Additionally, the potential of the RNA m6A modification in clinical application is discussed.


Assuntos
Adenosina/análogos & derivados , Neoplasias/genética , Adenosina/genética , Adenosina/metabolismo , Adenosina/fisiologia , Progressão da Doença , Humanos , Metilação , Metiltransferases/metabolismo , Neoplasias/metabolismo , RNA/genética , Processamento Pós-Transcricional do RNA/genética
5.
Biomed Pharmacother ; 112: 108613, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784918

RESUMO

N6-methyladenosine (m6A), the most abundant internal modification of RNA in eukaryotic cells, has gained increasing attention in recent years. The m6A modification affects multiple aspects of RNA metabolism, ranging from RNA processing, nuclear export, RNA translation to decay. Emerging evidence suggests that m6A methylation plays a critical role in cancer through various mechanisms. Moreover, m6A methylation has provided more possibilities for the early diagnosis and treatment of cancers. In this review, we focus on m6A-associated mechanisms and functions in several major malignancies and summarize the dual role of m6A methylation as well as its prospects in cancer.


Assuntos
Adenosina/análogos & derivados , Neoplasias/genética , Neoplasias/metabolismo , RNA/genética , RNA/metabolismo , Adenosina/fisiologia , Animais , Humanos , Metilação
6.
Brain ; 142(3): 700-718, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689733

RESUMO

Ectonucleotidase-mediated ATP catabolism provides a powerful mechanism to control the levels of extracellular adenosine. While increased adenosine A2A receptor (A2AR) signaling has been well-documented in both Parkinson's disease models and patients, the source of this enhanced adenosine signalling remains unclear. Here, we show that the ecto-5'-nucleotidase (CD73)-mediated adenosine formation provides an important input to activate A2AR, and upregulated CD73 and A2AR in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease models coordinatively contribute to the elevated adenosine signalling. Importantly, we demonstrate that CD73-derived adenosine-A2AR signalling modulates microglial immunoresponses and morphological dynamics. CD73 inactivation significantly attenuated lipopolysaccharide-induced pro-inflammatory responses in microglia, but enhanced microglia process extension, movement and morphological transformation in the laser injury and acute MPTP-induced Parkinson's disease models. Limiting CD73-derived adenosine substantially suppressed microglia-mediated neuroinflammation and improved the viability of dopaminergic neurons and motor behaviours in Parkinson's disease models. Moreover, CD73 inactivation suppressed A2AR induction and A2AR-mediated pro-inflammatory responses, whereas replenishment of adenosine analogues restored these effects, suggesting that CD73 produces a self-regulating feed-forward adenosine formation to activate A2AR and promote neuroinflammation. We further provide the first evidence that A2A enhanced inflammation by antagonizing dopamine-mediated anti-inflammation, suggesting that the homeostatic balance between adenosine and dopamine signalling is key to microglia immunoresponses. Our study thus reveals a novel role for CD73-mediated nucleotide metabolism in regulating neuroinflammation and provides the proof-of-principle that targeting nucleotide metabolic pathways to limit adenosine production and neuroinflammation in Parkinson's disease might be a promising therapeutic strategy.


Assuntos
5'-Nucleotidase/fisiologia , Adenosina/metabolismo , Dopamina/metabolismo , 5'-Nucleotidase/metabolismo , Adenosina/farmacologia , Adenosina/fisiologia , Animais , Modelos Animais de Doenças , Dopamina/fisiologia , Neurônios Dopaminérgicos/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/fisiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , Receptor A2A de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Artigo em Inglês | MEDLINE | ID: mdl-30594528

RESUMO

Icefishes characteristically lack the oxygen-binding protein haemoglobin and therefore are especially reliant on cardiovascular regulation to augment oxygen transport when oxygen demand increases, such as during activity and warming. Using both in vivo and in vitro experiments, we evaluated the roles for adrenaline and adenosine, two well-established cardio- and vasoactive molecules, in regulating the cardiovascular system of the blackfin icefish, Chaenocephalus aceratus. Despite increasing cardiac contractility (increasing twitch force and contraction kinetics in isometric myocardial strip preparations) and accelerating heart rate (ƒH), adrenaline (5 nmol kg-1 bolus intra-arterial injection) did not significantly increase cardiac output (Q̇) in vivo because it elicited a large decrease in vascular conductance (Gsys). In contrast, and despite preliminary data suggesting a direct negative inotropic effect of adenosine on isolated atria and little effect on isolated ventricle strips, adenosine (500 nmol kg-1) generated a large increase in Q̇ by increasing Gsys, a change reminiscent of that previously reported during both acute warming and invoked activity. Our data thus illustrate how Q̇ in C. aceratus may be much more dependent on peripheral control of vasomotor tone than direct regulation of the heart.


Assuntos
Adenosina/fisiologia , Débito Cardíaco , Fenômenos Fisiológicos Cardiovasculares , Epinefrina/fisiologia , Perciformes/fisiologia , Animais , Regiões Antárticas
8.
Neuroscientist ; 25(2): 113-125, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30047288

RESUMO

Restless legs syndrome (RLS) is a common sensorimotor disorder, whose basic components include a sensory experience, akathisia, and a sleep-related motor sign, periodic leg movements during sleep (PLMS), both associated with an enhancement of the individual's arousal state. The present review attempts to integrate the major clinical and experimental neurobiological findings into a heuristic pathogenetic model. The model also integrates the recent findings on RLS genetics indicating that RLS has aspects of a genetically moderated neurodevelopmental disorder involving mainly the cortico-striatal-thalamic-cortical circuits. Brain iron deficiency (BID) remains the key initial pathobiological factor and relates to alterations of iron acquisition by the brain, also moderated by genetic factors. Experimental evidence indicates that BID leads to a hyperdopaminergic and hyperglutamatergic states that determine the dysfunction of cortico-striatal-thalamic-cortical circuits in genetically vulnerable individuals. However, the enhanced arousal mechanisms critical to RLS are better explained by functional changes of the ascending arousal systems. Recent experimental and clinical studies suggest that a BID-induced hypoadenosinergic state provides the link for a putative unified pathophysiological mechanism for sensorimotor signs of RLS and the enhanced arousal state.


Assuntos
Encéfalo/fisiopatologia , Síndrome das Pernas Inquietas/genética , Síndrome das Pernas Inquietas/fisiopatologia , Adenosina/fisiologia , Animais , Encéfalo/metabolismo , Dopamina/fisiologia , Ácido Glutâmico/fisiologia , Homeostase , Humanos , Ferro/metabolismo , Neurônios/fisiologia , Síndrome das Pernas Inquietas/metabolismo , Medula Espinal/fisiopatologia
9.
Adv Exp Med Biol ; 1071: 43-50, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30357732

RESUMO

The mammalian carotid body (CB) is the main peripheral arterial chemoreceptor organ that is excited by decreases in blood PO2 (hypoxia) and increases in blood PCO2/H+. An increase in CB afferent carotid sinus nerve (CSN) discharge results in respiratory and cardiovascular reflex responses that help maintain homeostasis. The CB consists mainly of innervated clusters of the chemoreceptive type I (glomus) cells that are associated with the processes of glial-like type II cells. Extracellular ATP and adenosine (ADO) levels increase in response to acute hypoxia and there is evidence that during chronic sustained hypoxia ADO elevation plays a major role in regulating CB chemosensitivity and CSN discharge. We recently characterized the molecular identities of ectonucleotidase enzymes involved in regulating extracellular ATP hydrolysis to produce ADO in the rat CB. In the present study, we focus on a molecular characterization of the equilibrative nucleoside transporter (ENT) system that is known to regulate extracellular ADO concentrations in the rat CB based on pharmacological studies. Examination of ENT expression using quantitative PCR (qPCR) analysis revealed the expression of both ENT1 and ENT2 mRNAs in whole CB extracts from ~2-week-old juvenile rats. In dissociated rat CB cultures, both ENT1 and ENT2 immunoreactivity was localized to type I cell clusters. Furthermore, we show that ENT1 and ENT2 mRNA expression is downregulated in CBs isolated from rat pups exposed to chronic hypobaric hypoxia (~1 week). These findings reveal the molecular identities of the ENT system expressed in the rat CB and are consistent with the proposed shift to ADO signaling during chronic hypoxia.


Assuntos
Corpo Carotídeo/fisiologia , Hipóxia , Proteínas de Transporte de Nucleosídeos/fisiologia , Adenosina/fisiologia , Animais , Ratos
10.
Adv Exp Med Biol ; 1071: 89-93, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30357738

RESUMO

Adenosine is one of the key neurotransmitters involved in hypoxic signaling in the carotid body (CB), and it was recently found to have a modulatory role in mediating hypercapnic sensitivity in the CB. Herein we have investigated the contribution of adenosine to the hypercapnic response in the rat CB and studied the adenosine receptors responsible for this effect. Experiments were performed in Wistar rats. Adenosine release in normoxia (21% O2) and in response to hypercapnia (10% CO2) was quantified by HPLC. Carotid sinus nerve (CSN) chemosensory activity was evaluated in response to hypercapnia in the absence and presence of ZM241385 (300 nM), an A2 antagonist, and SCH58261 (20 nM), a selective A2A antagonist. Hypercapnia increased the extracellular concentrations of adenosine by 50.01%. Both, ZM241385 and SCH58261, did not modify significantly the basal frequency of discharges of the CSN. Also, ZM241385 and SCH58261 did not modify the latency time and the time to peak in CSN chemosensory activity. CSN activity evoked by hypercapnia decreased by 58.82 and 33.59% in response to ZM241385 and to SCH58261, respectively. In conclusion, the effect of adenosine in mediating the hypercapnic response in the rat CB involves an effect on A2A and A2B adenosine receptors.


Assuntos
Adenosina/fisiologia , Corpo Carotídeo/fisiologia , Hipercapnia/fisiopatologia , Hipóxia , Animais , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor A2A de Adenosina/fisiologia , Receptor A2B de Adenosina/fisiologia , Triazinas/farmacologia , Triazóis/farmacologia
11.
Sci Rep ; 8(1): 13827, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30218090

RESUMO

N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA. This modification has previously been shown to alter the export kinetics for mRNAs though the molecular details surrounding this phenomenon remain poorly understood. Recruitment of the TREX mRNA export complex to mRNA is driven by transcription, 5' capping and pre-mRNA splicing. Here we identify a fourth mechanism in human cells driving the association of TREX with mRNA involving the m6A methylase complex. We show that the m6A complex recruits TREX to m6A modified mRNAs and this process is essential for their efficient export. TREX also stimulates recruitment of the m6A reader protein YTHDC1 to the mRNA and the m6A complex influences the interaction of TREX with YTHDC1. Together our studies reveal a key role for TREX in the export of m6A modified mRNAs.


Assuntos
Adenosina/análogos & derivados , Exodesoxirribonucleases/metabolismo , Fosfoproteínas/metabolismo , Transporte de RNA/fisiologia , Transporte Ativo do Núcleo Celular , Adenosina/metabolismo , Adenosina/fisiologia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Exodesoxirribonucleases/fisiologia , Células HEK293 , Humanos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Fosfoproteínas/fisiologia , Processamento de RNA/fisiologia , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo
12.
Biomed Res Int ; 2018: 2749257, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228984

RESUMO

The vitreousness of glaucoma subjects contains elevated glutamate, and excessive extracellular glutamate is toxic to retinal neurons. Therefore, glutamate clearance is potentially impaired in the retina of glaucoma subjects. Müller cells play an important role in maintaining low extracellular levels of neurotransmitters, such as glutamate. A better understanding of the cross-talk between adenosine and glutamate may provide a better characterization of the regulatory network in Müller cells. Here, Müller cells were purified from the rat retina on postnatal day 5 using the papain digestion method. Application of increasing concentrations of glutamate (0-20 mmol/L) caused a dose-dependent decrease in the expression levels of Kir4.1, Kir2.1, GLAST, and GS. Exogenous adenosine regulated Kir channels and subsequently promoted GLAST and GS expression levels in Müller cells under exogenous glutamate stimulation. These effects were partly dependent on adenosine receptors.


Assuntos
Adenosina/fisiologia , Células Ependimogliais/fisiologia , Ácido Glutâmico/farmacologia , Antagonistas de Receptores Purinérgicos P1/metabolismo , Retina/metabolismo , Animais , Glaucoma , Neuroglia , Canais de Potássio Corretores do Fluxo de Internalização , Ratos , Ratos Sprague-Dawley
13.
Neurotoxicology ; 69: 17-22, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30157450

RESUMO

Ethanol is one of the most widely consumed drugs in the world, and the effects of ethanol during early development include morphological and cognitive problems. The regulation of adenosine levels is essential for the proper function of major neurotransmitter systems in the brain, particularly glutamate and dopamine; thus, the investigation of the relation of adenosine and memory after early ethanol exposure becomes relevant. Embryos of zebrafish were exposed to 1% ethanol during two distinct developmental stages: gastrula/segmentation or pharyngula. The evaluation of memory, morphology, and locomotor parameters was performed when fish were 3 months old. The effect of ecto-5'-nucleotidase and adenosine deaminase inhibition on the consequences of ethanol exposure with regard to memory formation was observed. Morphological evaluation showed decreases in body length and the relative telencephalic and cerebellar areas in ethanol exposed animals. The locomotor parameters evaluated were not affected by ethanol. In the inhibitory avoidance paradigm, ethanol exposure during the gastrula/segmentation and pharyngula stages decreased zebrafish memory retention. When ethanol was given in the pharyngula stage, the inhibition of ecto-5'-nucleotidase in the acquisition phase of memory tests was able to revert the effects of ethanol on the memory of adults. These findings suggest that the increased adenosine levels caused by ethanol could alter the neuromodulation of important components of memory formation, such as neurotransmitters. The adjustment of adenosine levels through ecto-5'-nucleotidase inhibition appears to be effective at restoring normal adenosine levels and the acquisition of memory in animals exposed to ethanol during the pharyngula stage.


Assuntos
Adenosina/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Etanol/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Memória/efeitos dos fármacos , Fatores Etários , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Desenvolvimento Embrionário/fisiologia , Etanol/administração & dosagem , Feminino , Masculino , Memória/fisiologia , Peixe-Zebra
14.
J Neurochem ; 147(2): 137-152, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29873074

RESUMO

Research over the past decade has provided strong support for the importance of various epigenetic mechanisms, including DNA and histone modifications in regulating activity-dependent gene expression in the mammalian central nervous system. More recently, the emerging field of epitranscriptomics revealed an equally important role of post-transcriptional RNA modifications in shaping the transcriptomic landscape of the brain. This review will focus on the methylation of the adenosine base at the N6 position, termed N6 methyladenosine (m6A), which is the most abundant internal modification that decorates eukaryotic messenger RNAs. Given its prevalence and dynamic regulation in the adult brain, the m6A-epitranscriptome provides an additional layer of regulation on RNA that can be controlled in a context- and stimulus-dependent manner. Conceptually, m6A serves as a molecular switch that regulates various aspects of RNA function, including splicing, stability, localization, or translational control. The versatility of m6A function is typically determined through interaction or disengagement with specific classes of m6A-interacting proteins. Here we review recent advances in the field and provide insights into the roles of m6A in regulating brain function, from development to synaptic plasticity, learning, and memory. We also discuss how aberrant m6A signaling may contribute to neurodevelopmental and neuropsychiatric disorders.


Assuntos
Adenosina/análogos & derivados , Encéfalo/crescimento & desenvolvimento , Epigenômica , Neurobiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Adenosina/genética , Adenosina/fisiologia , Animais , Humanos , Processamento de Proteína Pós-Traducional
15.
Pancreatology ; 18(6): 615-623, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29937364

RESUMO

Insulin, a key hormone produced by pancreatic beta cells precisely regulates glucose metabolism in vertebrates. In type 1 diabetes, the beta cell mass is destroyed, a process triggered by a combination of environmental and genetic factors. This ultimately results in absolute insulin deficiency and dysregulated glucose metabolism resulting in a number of detrimental pathophysiological effects. The traditional focus of treating type 1 diabetes has been to control blood sugar levels through the administration of exogenous insulin. Newer approaches aim to replace the beta cell mass through pancreatic or islet transplantation. Type 2 diabetes results from a relative insulin deficiency for the prevailing insulin resistance. Treatments are generally aimed at reducing insulin resistance and/or augmenting insulin secretion and the use of insulin itself is often required. It is increasingly being recognized that the beta cell mass is dynamic and increases insulin secretion in response to beta cell mitogens and stress signals to maintain glycemia within a very narrow physiological range. This review critically discusses the role of adrenergic, adenosine and opioid pathways and their interrelationship in insulin secretion, beta cell proliferation and regeneration.


Assuntos
Adenosina/fisiologia , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Receptores Opioides/fisiologia , Transdução de Sinais/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Proliferação de Células , Diabetes Mellitus/fisiopatologia , Humanos , Regeneração
16.
Pharmacol Rep ; 70(4): 661-667, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29909246

RESUMO

Although adenosine plays a key role in multiple motor, affective, and cognitive processes, it has received less attention in the neuroscience field compared to other neurotransmitters (e.g., dopamine). In this review, we highlight the role of adenosine in behavior as well as its interaction with other neurotransmitters, such as dopamine. We also discuss brain disorders impacted by alterations to adenosine, and how targeting adenosine can ameliorate Parkinson's disease motor symptoms. We also discuss the role of caffeine (as an adenosine antagonist) on cognition as well as a neuroprotective agent against Parkinson's disease (PD).


Assuntos
Adenosina/fisiologia , Encefalopatias/fisiopatologia , Doença de Parkinson/fisiopatologia , Adenosina/antagonistas & inibidores , Cafeína/uso terapêutico , Dopamina/fisiologia , Humanos , Doença de Parkinson/tratamento farmacológico
17.
Crit Rev Oncol Hematol ; 126: 24-31, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29759563

RESUMO

Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms. In this review, we focused on the multiple functions and related mechanisms of ADO signaling in CLL generation and progression.


Assuntos
Adenosina/fisiologia , Leucemia Linfocítica Crônica de Células B/terapia , Microambiente Tumoral/fisiologia , Adenosina/metabolismo , Adenosina/farmacologia , Carcinógenos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Progressão da Doença , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Transdução de Sinais/fisiologia
18.
Physiology (Bethesda) ; 33(3): 182-196, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29616880

RESUMO

This review compares two states that lower energy expenditure: non-rapid eye movement (NREM) sleep and torpor. Knowledge on mechanisms common to these states, and particularly on the role of adenosine in NREM sleep, may ultimately open the possibility of inducing a synthetic torpor-like state in humans for medical applications and long-term space travel. To achieve this goal, it will be important, in perspective, to extend the study to other hypometabolic states, which, unlike torpor, can also be experienced by humans.


Assuntos
Adenosina/fisiologia , Hibernação/fisiologia , Sono/fisiologia , Torpor/fisiologia , Animais , Humanos
19.
Naunyn Schmiedebergs Arch Pharmacol ; 391(5): 513-522, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29470593

RESUMO

Hypertension is a risk factor for cardiovascular diseases, which have been associated with dysfunction of sympathetic and purinergic neurotransmission. Therefore, herein, we evaluated whether modifications of adenosine receptor signaling may contribute to the cardiac dysfunction observed in hypertension. Isolated right atria from spontaneously hypertensive (SHR) or normotensive Wistar rats (NWR) were used to investigate the influence of adenosine receptor signaling cascade in the cardiac chronotropism. Our results showed that adenosine, the endogenous agonist of adenosine receptors, and CPA, a selective agonist of A1 receptor, decreased the atrial chronotropism of NWR and SHR in a concentration- and time-dependent manner, culminating in cardiac arrest (0 bpm). Interestingly, a 3-fold lower concentration of adenosine was required to induce the negative chronotropic effect in SHR atria. Pre-incubation of tissues from both strains with DPCPX, a selective A1 receptor antagonist, inhibited the negative chronotropic effect of CPA, while simultaneous inhibition of A2 and A3 receptors, with ZM241385 and MRS1523, did not change the adenosine chronotropic effects. Moreover, 1 µg/ml pertussis toxin, which inactivates the Gαi protein subunit, reduced by 80% the negative chronotropic effects of adenosine in the NWR atrium, with minor effects in SHR tissue. These data indicate that the negative chronotropic effect of adenosine in right atrium depends exclusively on the activation of A1 receptors. Moreover, the distinct responsiveness of NWR and SHR atria to pertussis toxin reveals that the enhanced negative chronotropic response of SHR right atrium is probably due to an increased activity of Gαi protein-mediated.


Assuntos
Adenosina/fisiologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Átrios do Coração/fisiopatologia , Hipertensão/fisiopatologia , Receptor A1 de Adenosina/fisiologia , Animais , Masculino , Ratos Endogâmicos SHR , Ratos Wistar , Transdução de Sinais
20.
Neuron ; 97(2): 313-325.e6, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29346752

RESUMO

N6-methyladenosine (m6A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m6A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m6A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m6A-CLIP mapping further reveals a dynamic m6A landscape in the adult DRG upon injury. Loss of either m6A methyltransferase complex component Mettl14 or m6A-binding protein Ythdf1 globally attenuates injury-induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system.


Assuntos
Adenosina/fisiologia , Axônios/fisiologia , Epigênese Genética/genética , Metiltransferases/fisiologia , Regeneração Nervosa/genética , Proteínas do Tecido Nervoso/fisiologia , Processamento Pós-Transcricional do RNA , Transcrição Genética , Adenosina/análogos & derivados , Animais , Gânglios Espinais/metabolismo , Ontologia Genética , Metiltransferases/deficiência , Camundongos Knockout , Compressão Nervosa , PTEN Fosfo-Hidrolase/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/fisiologia , Nervo Isquiático/lesões , Neuropatia Ciática/genética , Neuropatia Ciática/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Células Receptoras Sensoriais/ultraestrutura
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