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Atrial fibrillation (AF), with its significant associated morbidity and mortality contributes to significant healthcare utilisation and expenditure. Given its progressively rising incidence, strategies to limit AF development and progression are urgently needed. Lifestyle modification is a potentially potent but underutilised weapon against the AF epidemic. The purpose of this article is to review the role of lifestyle factors as risk factors for AF, outline potential mechanisms of pathogenesis and examine the available evidence for lifestyle intervention in primary and secondary AF prevention. It will also highlight the need for investment by physicians, researchers, health services and governments in order to facilitate delivery of the comprehensive, multidisciplinary AF care that is required to manage this complex and multifactorial disease.
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Fibrilação Atrial , Estilo de Vida , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Fibrilação Atrial/terapia , Humanos , Fatores de RiscoRESUMO
Sleep deprivation (SD) is widely acknowledged as a significant risk factor for cognitive impairment. In this study, intraperitoneal caffeine administration significantly ameliorated the learning and memory (L/M) deficits induced by SD and reduced aggressive behaviors in adult zebrafish. SD led to a reduction in protein kinase A (PKA) phosphorylation, phosphorylated-cAMP response element-binding protein (p-CREB), and c-Fos expression in zebrafish brain. Notably, these alterations were effectively reversed by caffeine. In addition, caffeine mitigated neuroinflammation induced by SD, as evident from suppression of the SD-mediated increase in glial fibrillary acidic protein (GFAP) and nuclear factor-κB (NF-κB) activation. Caffeine restored normal O-GlcNAcylation and O-GlcNAc transferase (OGT) levels while reversing the increased expression of O-GlcNAcase (OGA) in zebrafish brain after SD. Intriguingly, rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, effectively mitigated cognitive deficits, restored p-CREB and c-Fos levels, and attenuated the increase in GFAP in brain induced by SD. In addition, rolipram reversed the decrease in O-GlcNAcylation and OGT expression as well as elevation of OGA expression following SD. Treatment with H89, a PKA inhibitor, significantly impaired the L/M functions of zebrafish compared with the control group, inducing a decrease in O-GlcNAcylation and OGT expression and, conversely, an increase in OGA expression. The H89-induced changes in O-GlcNAc cycling and L/M dysfunction were effectively reversed by glucosamine treatment. H89 suppressed, whereas caffeine and rolipram promoted O-GlcNAc cycling in Neuro2a cells. Our collective findings underscore the interplay between PKA signaling and O-GlcNAc cycling in the regulation of cognitive function in the brain, offering potential therapeutic targets for cognitive deficits associated with SD.NEW & NOTEWORTHY Our observation highlights the intricate interplay between cAMP/PKA signaling and O-GlcNAc cycling, unveiling a novel mechanism that potentially governs the regulation of learning and memory functions. The dynamic interplay between these two pathways provides a novel and nuanced perspective on the molecular foundation of learning and memory regulation. These insights open avenues for the development of targeted interventions to treat conditions that impact cognitive function, including SD.
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Disfunção Cognitiva , Isoquinolinas , Privação do Sono , Sulfonamidas , Animais , Privação do Sono/tratamento farmacológico , Peixe-Zebra/metabolismo , Cafeína/farmacologia , Rolipram , Acetilglucosamina/metabolismo , Processamento de Proteína Pós-Traducional , Cognição , Disfunção Cognitiva/tratamento farmacológico , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismoRESUMO
Human cytochrome P450 3A4 (CYP3A4) is a major drug-metabolizing enzyme that shows extreme substrate promiscuity. Moreover, its large and malleable active site can simultaneously accommodate several substrate molecules of the same or different nature, which may lead to cooperative binding and allosteric behavior. Due to difficulty of crystallization of CYP3A4-substrate complexes, it remains unknown how multiple substrates can arrange in the active site. We determined crystal structures of CYP3A4 bound to three and six molecules of caffeine, a psychoactive alkaloid serving as a substrate and modulator of CYP3A4. In the ternary complex, one caffeine binds to the active site suitably for C8-hydroxylation, most preferable for CYP3A4. In the senary complex, three caffeine molecules stack parallel to the heme with the proximal ligand poised for 3-N-demethylation. However, the caffeine stack forms extensive hydrophobic interactions that could preclude product dissociation and multiple turnovers. In both complexes, caffeine is also bound in the substrate channel and on the outer surface known as a peripheral site. At all sites, aromatic stacking with the caffeine ring(s) is likely a dominant interaction, while direct and water-mediated polar contacts provide additional stabilization for the substrate-bound complexes. Protein-ligand interactions via the active site R212, intrachannel T224, and peripheral F219 were experimentally confirmed, and the latter two residues were identified as important for caffeine association. Collectively, the structural, spectral, and mutagenesis data provide valuable insights on the ligand binding mechanism and help better understand how purine-based pharmaceuticals and other aromatic compounds could interact with CYP3A4 and mediate drug-drug interactions.
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Cafeína , Citocromo P-450 CYP3A , Humanos , Sítios de Ligação , Cafeína/química , Cafeína/metabolismo , Domínio Catalítico , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Ligantes , Especificidade por Substrato , Ligação Proteica , Regulação Alostérica , Cristalografia por Raios X , Cristalização , Desmetilação , Heme/metabolismo , Interações Hidrofóbicas e Hidrofílicas , MutaçãoRESUMO
The Drosophila neuropeptide, DPKQDFMRFamide, was previously shown to enhance excitatory junctional potentials (EJPs) and muscle contraction by both presynaptic and postsynaptic actions. Since the peptide acts on both sides of the synaptic cleft, it has been difficult to examine postsynaptic modulatory mechanisms, particularly when contractions are elicited by nerve stimulation. Here, postsynaptic actions are examined in 3rd instar larvae by applying peptide and the excitatory neurotransmitter, l-glutamate, in the bathing solution to elicit contractions after silencing motor output by removing the central nervous system (CNS). DPKQDFMRFamide enhanced glutamate-evoked contractions at low concentrations (EC50 1.3 nM), consistent with its role as a neurohormone, and the combined effect of both substances was supra-additive. Glutamate-evoked contractions were also enhanced when transmitter release was blocked in temperature-sensitive (Shibire) mutants, confirming the peptide's postsynaptic action. The peptide increased membrane depolarization in muscle when co-applied with glutamate, and its effects were blocked by nifedipine, an L-type channel blocker, indicating effects at the plasma membrane involving calcium influx. DPKQDFMRFamide also enhanced contractions induced by caffeine in the absence of extracellular calcium, suggesting increased calcium release from the sarcoplasmic reticulum (SR) or effects downstream of calcium release from the SR. The peptide's effects do not appear to involve calcium/calmodulin-dependent protein kinase II (CaMKII), previously shown to mediate presynaptic effects. The approach used here might be useful for examining postsynaptic effects of neurohormones and cotransmitters in other systems.NEW & NOTEWORTHY Distinguishing presynaptic and postsynaptic effects of neurohormones is a long-standing challenge in many model organisms. Here, postsynaptic actions of DPKQDFMRFamide are demonstrated by assessing its ability to potentiate contractions elicited by direct application of the neurotransmitter, glutamate, when axons are silent and when transmitter release is blocked. The peptide acts at multiple sites to increase contraction, increasing glutamate-induced depolarization at the cell membrane, acting on L-type channels, and acting downstream of calcium release from the sarcoplasmic reticulum.
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Drosophila , Neuropeptídeos , Animais , Drosophila/metabolismo , Junção Neuromuscular/fisiologia , Cálcio , Neuropeptídeos/farmacologia , Contração Muscular , Peptídeos/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Glutamatos , Neurotransmissores/farmacologiaRESUMO
Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.
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Esclerose Lateral Amiotrófica , Cafeína , Citocromo P-450 CYP1A2 , Progressão da Doença , Polimorfismo de Nucleotídeo Único , Receptor A2A de Adenosina , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Receptor A2A de Adenosina/genética , Citocromo P-450 CYP1A2/genética , Cognição/fisiologia , Cognição/efeitos dos fármacos , Estudos Prospectivos , Citocromo P-450 CYP1A1/genética , Receptores de Hidrocarboneto Arílico/genética , Adulto , Disfunção Cognitiva/genética , Riluzol/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
Epidemiological evidence regarding the relationship between coffee and tea consumption and the risk of ovarian cancer (OC) is inconsistent. Therefore, we aimed to quantitatively investigate this topic in a large prospective cohort study. This cohort study included 24,715 individuals recruited from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trials between 1993 and 2001. The data used for our analysis included the latest follow-up information collected up to 2015. Coffee intake of ≥4 cups/day (hazard ratio [HR], 0.586; 95% confidence interval [CI]: 0.356-0.966) or caffeine intake of 458.787 mg/day (HR, 0.607; 95% CI: 0.411-0.895) were associated with the lowest HR of incident OC in the fully adjusted model. Participants who consumed varying amounts of tea did not exhibit a statistically significant reduction in the risk of OC. Our findings suggest that a higher consumption of coffee or caffeine is associated with a reduced risk of OC. However, no statistically significant association was observed between tea consumption and the risk of OC.
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Café , Neoplasias Ovarianas , Chá , Humanos , Feminino , Neoplasias Ovarianas/epidemiologia , Estudos Prospectivos , Pessoa de Meia-Idade , Incidência , Idoso , Cafeína/administração & dosagem , Fatores de Risco , Modelos de Riscos ProporcionaisRESUMO
Mendelian randomization is an epidemiological technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.
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Caffeine, a widely consumed stimulant, is known for its effects on alertness and fatigue reduction by blockade of adenosine receptors. While it holds therapeutic potential, its diverse impacts pose risks, particularly in early development. This study explores the developmental effects of caffeine exposure using Caenorhabditis elegans (C. elegans) as a model organism. We investigated morphological and behavioral changes induced by caffeine exposure at the L1 stage and assessed their impact at the L4 stage, which roughly corresponds to human infancy and adolescence, respectively. Caffeine-exposed worms displayed increased body length, body bends, and pharyngeal pumping rates compared to control worms. These findings indicate heightened food-seeking behavior and greater food intake, leading to the observed morphological changes. While caffeine did not affect other locomotor behaviors, its stimulatory effect on growth and development highlights its significance. This study provides insights into the potential impact of early-life caffeine exposure on long-term health and development, offering a foundation for future research in vertebrates to uncover its implications on metabolism and other metrics of health.
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Proteínas de Caenorhabditis elegans , Cafeína , Animais , Humanos , Cafeína/farmacologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Receptores Purinérgicos P1RESUMO
INTRODUCTION: Caffeine and theophylline are methylxanthines and nonselective adenosine antagonists commonly used to treat apnea of prematurity. Both human and animal data suggest that xanthines also have clinically important long-term neuroprotective effects in the presence of inflammation in the perinatal period as seen following hypoxic-ischemic brain insults. Moreover, these protective effects appear to be more robust when administered shortly (<48 h) after preterm birth. METHOD: To evaluate the importance of the postdelivery therapeutic window, we collected and analyzed medical data from preterm infants meeting criteria (23-30 weeks' gestational age [GA]), born at the University of Connecticut Health Center (UCHC), and cared for at the UCHC/Connecticut Children's Medical Center (CCMC) NICU from 1991 to 2017 (n = 858). Eighteen-month follow-up data included cognitive and language scores from the Neonatal Neurodevelopmental Follow-Up Clinic records, with a retention of 81% of subjects (n = 696). Differences were analyzed via multivariate ANOVA and ANCOVA. RESULTS: Analyses showed that infants who received xanthine treatment within the first 48 h after preterm birth showed significantly better 18-month behavioral outcomes than those treated later than 48 h, despite a lack of a priori differences in GA, birth, or length of stay. The positive effect of early xanthine therapy was particularly robust for infants exposed prenatally to the inflammatory conditions of chorioamnionitis and/or preeclampsia. CONCLUSIONS: Current findings are consistent with human and animal data, showing that caffeine exerts protective effects, at least in part via attenuation of inflammation. Results add to the evidence supporting routine immediate prophylactic neuroprotective xanthine therapy (i.e., caffeine) in preterm infants. Findings also add important new evidence of the augmented value of caffeine for infants with inflammatory exposure due to mothers with preeclampsia or chorioamnionitis.
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BACKGROUND: Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism. METHODS: Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization. RESULTS: Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confidence interval (CI) CI: 0.95-0.98, p = 2.47 × 10-4), osteoarthrosis (OR = 0.97, 95% CI: 0.96-0.98, P=1.10 × 10-8) and osteoarthritis (OR: 0.97, 95% CI: 0.96 to 0.98, P = 1.09 × 10-6). Approximately one third of the protective effect of plasma caffeine on osteoarthritis risk was estimated to be mediated through lower bodyweight. Proteomic and metabolomic perturbations indicated lower chronic inflammation, improved lipid profiles, and altered protein and glycogen metabolism as potential biological mechanisms underlying these effects. CONCLUSIONS: We report novel evidence suggesting that long-term increases in circulating caffeine may reduce bodyweight and the risk of osteoarthrosis and osteoarthritis. We confirm prior genetic evidence of a protective effect of plasma caffeine on risk of overweight and obesity. Further clinical study is warranted to understand the translational relevance of these findings before clinical practice or lifestyle interventions related to caffeine consumption are introduced.
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Cafeína , Osteoartrite , Humanos , Proteoma/genética , Análise da Randomização Mendeliana , Proteômica , Obesidade/epidemiologia , Obesidade/genética , Metaboloma/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
PURPOSE: To propose a new method for quantitatively mapping the renal metabolic rate of oxygen (RMRO2) and to evaluate the proposed method using a caffeine challenge. THEORY AND METHODS: Pseudo-continuous arterial spin labeling (pCASL) and QSM sequences were used to obtain MR images in the kidney. Six healthy volunteers were scanned on caffeine and control days. The pCASL and QSM images were registered using DICOM information and rigid translation. The Fick principle was applied to estimate RMRO2. The results on caffeine and control days were compared to evaluate the capability of the proposed method to estimate renal oxygen consumption. A paired t-test was used to assess the statistical significance. RESULTS: Estimated renal blood flow (RBF), QSM, and RMRO2 maps were consistent with those reported in the literature. RMRO2 values were higher than the cerebral metabolic rate of oxygen (CMRO2) and were significantly reduced on the caffeine days compared to the control days, consistent with findings from non-MRI literature. CONCLUSION: The feasibility of measuring renal oxygen consumption using pCASL and QSM images was demonstrated. To the best of our knowledge, this work provides quantitative maps of renal oxygen consumption in humans for the first time. The results were consistent with the literature, including the statistically significant reduction in renal oxygen consumption with caffeine challenge. These findings suggest the potential utility of our technique in measuring renal oxygen consumption noninvasively, especially for patients with complications associated with contrast agents.
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Our hospital admitted a patient who had difficulty in coagulation even after blood replacement, and the patient had abused caffeine sodium benzoate (CSB) for more than 20 years. Hence, we aimed to explore whether CSB may cause dysfunction in vascular endothelial cells and its possible mechanism. Low, medium, and high concentrations of serum of long-term CSB intake patients were used to treat HUVECs, with LPS as the positive control. MTT and CCK8 were performed to verify CSB's damaging effect on HUVECs. The expression of ET-1, ICAM-1, VCAM-1, and E-selectin were measured by ELISA. TUNEL assay and Matrigel tube formation assay were carried out to detect apoptosis and angiogenesis of HUVECs. Flow cytometry was applied to analyze cell cycles and expression of CD11b, PDGF, and ICAM-1. Expression of PDGF-BB and PCNA were examined by western blot. The activation of MAPK signaling pathway was detected by qRT-PCR and western blot. Intracellular Ca2+ density was detected by fluorescent probes. CCK8 assay showed high concentration of CSB inhibited cell viability. Cell proliferation and angiogenesis were inhibited by CSB. ET-1, ICAM-1, VCAM-1, and E-selectin upregulated in CSB groups. CSB enhanced apoptosis of HUVECs. CD11b, ICAM-1 increased and PDGF reduced in CSB groups. The expression level and phosphorylation level of MEK, ERK, JUN, and p38 in MAPK pathway elevated in CSB groups. The expression of PCNA and PDGF-BB was suppressed by CSB. Intracellular Ca2+ intensity was increased by CSB. Abuse of CSB injured HUVECs and caused coagulation disorders.
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Selectina E , Molécula 1 de Adesão Intercelular , Humanos , Células Endoteliais da Veia Umbilical Humana , Células Cultivadas , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Selectina E/metabolismo , Benzoato de Sódio/metabolismo , Benzoato de Sódio/farmacologia , Becaplermina/farmacologia , Cafeína/metabolismo , Cafeína/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismoRESUMO
Caffeine is one of the most popular consumed psychostimulants that mitigates several neurodegenerative diseases. Nevertheless, the roles and molecular mechanisms of caffeine in HIV-associated neurocognitive disorders (HAND) remain largely unclear. Transactivator of transcription (Tat) is a major contributor to the neuropathogenesis of HAND in the central nervous system. In the present study, we determined that caffeine (100 µM) treatment significantly ameliorated Tat-induced decreased astrocytic viability, oxidative stress, inflammatory response and excessive glutamate and ATP release, thereby protecting neurons from apoptosis. Subsequently, SIRT3 was demonstrated to display neuroprotective effects against Tat during caffeine treatment. In addition, Tat downregulated SIRT3 expression via activation of EGR1 signaling, which was reversed by caffeine treatment in astrocytes. Overexpression of EGR1 entirely abolished the neuroprotective effects of caffeine against Tat. Furthermore, counteracting Tat or caffeine-induced differential expression of SIRT3 abrogated the neuroprotection of caffeine against Tat-triggered astrocytic dysfunction and neuronal apoptosis. Taken together, our study establishes that caffeine ameliorates astrocytes-mediated Tat neurotoxicity by targeting EGR1/SIRT3 signaling pathway. Our findings highlight the beneficial effects of caffeine on Tat-induced astrocytic dysfunction and neuronal death and propose that caffeine might be a novel therapeutic drug for relief of HAND.
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Apoptose , Astrócitos , Cafeína , Proteína 1 de Resposta de Crescimento Precoce , HIV-1 , Neurônios , Transdução de Sinais , Sirtuína 3 , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/virologia , Astrócitos/patologia , Sirtuína 3/genética , Sirtuína 3/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cafeína/farmacologia , Humanos , Apoptose/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia , Regulação para Cima/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/genética , Complexo AIDS Demência/metabolismo , Complexo AIDS Demência/patologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidadeRESUMO
OBJECTIVES: To explore the association between tea, coffee, and caffeine consumption and the risk of female infertility. METHODS: We analyzed data from 2099 females aged 18 to 44 years, participating in the National Health and Nutrition Examination Survey (NHANES) 2013-2018. We used generalized linear models (GLM) and generalized additive model (GAM) to investigate the dose-response relationship between the tea, coffee, and caffeine consumption and infertility, adjusting for potential confounders. RESULTS: A non-linear relationship was detected between tea consumption and infertility and the inflection point was 2 cups/day. On the right side of the inflection point, we did not detect a significant association. However, on the left side, we found a negative relationship between tea consumption and infertility (OR: 0.73; 95% CI: 0.57 to 0.93; P = 0.0122). Meanwhile, our study found no significant association between coffee (0.96, 0.81 to 1.13, P = 0.6189) or caffeine consumption (1.15, 0.93 to 1.42, P = 0.2148) and female infertility. CONCLUSIONS: Tea consumption was non-linearly associated with infertility, whereas no significant associations were found between coffee, caffeine consumption and infertility.
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Cafeína , Café , Infertilidade Feminina , Chá , Humanos , Feminino , Chá/efeitos adversos , Café/efeitos adversos , Cafeína/efeitos adversos , Cafeína/administração & dosagem , Adulto , Estudos Transversais , Infertilidade Feminina/epidemiologia , Adulto Jovem , Adolescente , Inquéritos Nutricionais , Fatores de RiscoRESUMO
The study investigates the association of coffee consumption and odds of osteoporosis/osteopenia among individuals older than 50 years in the United States. In NHANES 2005-2014, drinking ≤ 2 cups(16 oz) of coffee per day can reduce the risk of osteoporosis/osteopenia at the femoral neck and lumbar spine in US adults. Previous epidemiological studies revealed that daily coffee intake reduced the incidence of a cluster of metabolic diseases, however, the link between coffee consumption and prevalence of osteoporosis/osteopenia still remain inconclusive and awaits further confirmation. Based on data collection from 2005 to 2014 survey cycles, National Health and Nutrition Examination Survey (NHANES), a sample size of 8789 participants aged 50 and above completing two nonconsecutive 24-h dietary recalls were eventually enrolled for analysis. Associations between coffee intake and BMD were assessed. A lower odds of having femoral neck osteopenia/osteoporosis (FOO) was observed in participants with moderate intake of coffee (≤ 2 cups per day), rather than other beverages (OR 0.83; 95% CI, 0.72-0.95; p = 0.01). Moreover, significant associations existed between daily caffeine intake and both FOO and lumbar-spine osteopenia/osteoporosis (LOO). Even after adjusting for decaffeinated coffee, tea, sugar-sweetened beverages (SSBs), and coffee consumption, osteopenia and osteoporosis the odds remained lower at both femoral and neck levels. Our data suggest moderate habitual coffee intake (≤ 2 cups coffee/day) would have protective effects against osteoporosis/osteopenia of femoral neck and spine, among US adults over the age of 50.
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Doenças Ósseas Metabólicas , Osteoporose , Adulto , Pessoa de Meia-Idade , Humanos , Estados Unidos/epidemiologia , Idoso , Café/efeitos adversos , Inquéritos Nutricionais , Estudos Transversais , Osteoporose/epidemiologia , Doenças Ósseas Metabólicas/epidemiologia , Vértebras Lombares/metabolismoRESUMO
BACKGROUND: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. METHODS: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). RESULTS: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). DISCUSSION: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.
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OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) results in more years of potential life lost than any neurological condition with the exception of stroke. It is generally agreed that SUDEP happens due to some form of respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, the mechanistic cause of these perturbations is unclear. One possible explanation lies with adenosinergic signaling. Extracellular levels of the inhibitory neuromodulator adenosine rapidly rise during seizures, a countermeasure that is necessary for seizure termination. Previous evidence has suggested that excessive adenosinergic inhibition could increase the risk of SUDEP by silencing brain areas necessary for life, such as the respiratory nuclei of the brainstem. The goal of this investigation was to further clarify the role of adenosine in seizure-induced respiratory and electrocerebral dysfunction. METHODS: To determine the role of adenosine in postictal physiological dysregulation, we pharmacologically manipulated adenosine signaling prior to amygdala-kindled seizures in mice while recording electroencephalogram (EEG), electromyogram, and breathing using whole body plethysmography. The adenosinergic drugs used in this study included selective and nonselective adenosine receptor antagonists and inhibitors of adenosine metabolism. RESULTS: We found that high doses of adenosine receptor antagonists caused some seizures to result in seizure-induced death; however, counterintuitively, animals in these conditions that did not experience seizure-induced death had little or no postictal generalized EEG suppression. Inhibitors of adenosine metabolism had no effect on postictal breathing but did worsen some postictal electrocerebral outcomes. SIGNIFICANCE: The unexpected effect of high doses of adenosine antagonists on seizure-induced death observed in this study may be due to the increase in seizure severity, vasoconstriction, or phosphodiesterase inhibition caused by these drugs at high doses. These findings further clarify the role of adenosine in seizure-induced death and may have implications for the consumption of caffeine in epilepsy patients and the prevention of SUDEP.
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In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer that is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through the formation of hydrogen bonds. This will cause destabilization of the pharmaceutical products during processing or storage. Therefore, it is important to develop a mechanistic understanding of this transformation by monitoring each and every step of the reaction, employing a technique such as 1H nuclear magnetic resonance (NMR). In this study, an in situ monitoring of a coformer exchange reaction is carried out by 1H magic angle spinning (MAS) solid-state NMR (SSNMR) at a spinning frequency of 60 kHz. The changes in caffeine maleic acid cocrystals on addition of glutaric acid and caffeine glutaric cocrystals on addition of maleic acid were monitored. In all of the reactions, it has been observed that caffeine glutaric acid Form I is formed. When glutaric acid was added to 2:1 caffeine maleic acid, the formation of metastable 1:1 caffeine glutaric acid Form I was observed at the start of the experiment, indicating that the centrifugal pressure is enough for the formation. The difference in the end product of the reactions with a similar reaction pathway of 1:1 and 2:1 reactant stoichiometry indicates that a complete replacement of maleic acid has occurred only in the 1:1 stoichiometry of the reactants. The polymorphic transition of caffeine glutaric acid Form II to Form I at higher temperatures was a crucial reason that triggered the exchange of glutaric acid with maleic acid in the reaction of caffeine glutaric acid and maleic acid. Our results are novel since the new reaction pathways in competitive coformer exchange reactions enabled understanding the remarkable role of stoichiometry, polymorphism, temperature, and centrifugal pressure.
Assuntos
Cafeína , Glutaratos , Maleatos , Cafeína/química , Espectroscopia de Ressonância MagnéticaRESUMO
Caffeine is a widely used drug that broadly affects human cognition and brain function. Caffeine acts as an antagonist to the adenosine receptors in the brain. Previous anecdotal reports have also linked caffeine intake with changes in pupil diameter. By modifying the retinal irradiance, pupil diameter modulates all ocular light exposure relevant for visual (i.e., perception, detection and discrimination of visual stimuli) and non-visual (i.e., circadian) functions. To date, the extent of the influence of caffeine on pupillary outcomes, including pupil diameter, has not been examined in a systematic review. We implemented a systematic review laid out in a pre-registered protocol following PRISMA-P guidelines. We only included original research articles written in English reporting studies with human participants, in which caffeine was administered, and pupil diameter was measured using objective methods. Using broad search strategies, we consulted various databases (PsycINFO, Medline, Embase, Cochrane Library, bioRxiv and medRxiv) and used the Covidence platform to screen, review and extract data from studies. After importing studies identified through database search (n = 517 imported, n = 46 duplicates), we screened the title and abstracts (n = 471), finding 14 studies meeting our eligibility criteria. After full-text review, we excluded seven studies, leaving only a very modest number of included studies (n = 7). Extraction of information revealed that the existing literature on the effect of caffeine on pupil parameters is very heterogeneous, differing in pupil assessment methods, time of day of caffeine administration, dose, and protocol timing and design. The evidence available in the literature does not provide consistent results but studies rated as valid by quality assessment suggest a small effect of caffeine on pupil parameters. We summarize the numeric results as both differences in absolute pupil diameter and in terms of effect sizes. More studies are needed using modern pupil assessment methods, robust study design, and caffeine dose-response methodology.
Assuntos
Cafeína , Pupila , Humanos , Cafeína/farmacologia , Cafeína/administração & dosagem , Pupila/efeitos dos fármacos , Pupila/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagemRESUMO
Sirtuins, also called silent information regulator 2, are enzymes that rely on nicotinamide adenine dinucleotide (NAD+) to function as histone deacetylases. Further investigation is warranted to explore the advantageous impacts of Sirtuin 1 (SIRT1), a constituent of the sirtuin group, on lipid metabolism, in addition to its well-researched involvement in extending lifespan. The regulation of gene expression has been extensively linked to SIRT1. Sterol regulatory element-binding protein (SREBP) is a substrate of SIRT1 that has attracted significant interest due to its role in multiple cellular processes including cell cycle regulation, DNA damage repair, and metabolic functions. Hence, the objective of this analysis was to investigate and elucidate the correlation between SIRT1 and SREBPs, as well as assess the contribution of SIRT1/SREBPs in mitigating lipid metabolism dysfunction. The objective of this research was to investigate whether SIRT1 and SREBPs could be utilized as viable targets for therapeutic intervention in managing complications associated with diabetes.