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Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal ß -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.
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Carnitina , Resistência à Insulina , Biomarcadores , Carnitina/análogos & derivados , Carnitina/química , Carnitina/metabolismo , Carnitina/uso terapêutico , Ácidos Graxos/metabolismo , Humanos , Resistência à Insulina/fisiologiaRESUMO
AIM: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity. METHODS: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRSLEAP2) using linear and logistic regression models. Sex-stratified analyses were also conducted. RESULTS: Five SNPs showed positive associations with obesity-related traits. rs57880964 was associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF-1 concentrations in both men and women. GRSLEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF-1 concentration in both sexes. CONCLUSIONS: These findings reveal sex-specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF-1 concentration.
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Bancos de Espécimes Biológicos , Índice de Massa Corporal , Predisposição Genética para Doença , Fator de Crescimento Insulin-Like I , Obesidade , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Masculino , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/análise , Reino Unido/epidemiologia , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/sangue , Relação Cintura-Quadril , Idoso , Adulto , Peptídeos Semelhantes à Insulina , Biobanco do Reino UnidoRESUMO
AIM: Liver-expressed antimicrobial peptide 2 (LEAP2) dynamics in human plasma and its association with feeding behaviour remain poorly understood. Therefore, this study aims: (a) to investigate fasting LEAP2 in participants with normal weight or with overweight or mild obesity (OW/OB); (b) to study the association between fasting LEAP2 and anthropometric and metabolic traits, feeding behaviour, LEAP2 genetic variants and blood cell DNA methylation status; and (c) to ascertain postprandial changes in LEAP2 after high protein intake and the association with feeding behaviour and food intake. METHODS: Anthropometric and behavioural measures, genotyping, methylation profiling, plasma glucose and LEAP2 concentrations were assessed in 327 females and males. A subgroup of 123 participants received an ad libitum high-protein meal, and postprandial LEAP2 concentration and behavioural measures were assessed. RESULTS: LEAP2 concentration was higher in participants with OW/OB (p < 0.001) and in females (p < 0.001), and was associated with LEAP2 single nucleotide polymorphisms rs765760 (p = 0.012) and rs803223 (p = 0.019), but not with LEAP2 methylation status. LEAP2 concentration was directly related to glycaemia (p = 0.001) and fullness (p = 0.003) in participants with normal weight, whereas it was associated with body mass index (p = 0.018), waist circumference (p = 0.014) and motor impulsivity in participants with OW/OB (p = 0.005). A negative association with reward responsiveness was observed in participants with OW/OB (p = 0.023). LEAP2 concentration was inversely associated with food intake (p = 0.034) and decreased after a high-protein meal (p < 0.001), particularly in women (p = 0.002). CONCLUSION: Increased LEAP2 in participants with OW/OB is associated with behavioural characteristics of obesity. Our results show sexual dimorphism in LEAP2 concentration before and after food intake and highlight the role of LEAP2 in feeding regulation.
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Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff. Circulatory biomarkers of acute brain injury may help in the management of patients with acute cerebrovascular events and prevent poor outcome and mortality. The purpose of this review is to provide an overview of the development of potential biomarkers of brain damage to increase diagnostic possibilities. For this purpose, we searched the PubMed database of studies on the diagnostic potential of brain injury biomarkers. We also accessed information from Clinicaltrials.gov to identify any clinical trials of biomarker measurements for the diagnosis of brain damage. In total, we present 41 proteins, enzymes and hormones that have been considered as biomarkers for brain injury, of which 20 have been studied in clinical trials. Several microRNAs have also emerged as potential clinical biomarkers for early diagnosis. Combining multiple biomarkers in a panel, along with other parameters, is yielding promising outcomes.
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Biomarcadores , Lesões Encefálicas , Isquemia Encefálica , Humanos , Biomarcadores/sangue , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/sangue , Isquemia Encefálica/diagnóstico , MicroRNAs/sangue , Animais , Imageamento por Ressonância Magnética/métodosRESUMO
PURPOSE: The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations. METHODS: We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB). RESULTS: Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (ß: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (ß: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (ß: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (ß: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner. CONCLUSIONS: LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans. TRIAL REGISTRATION: The study was retrospectively registered in clinicaltrials.gov (April 2023). CLINICALTRIALS: gov Identifier: NCT05815641.
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Grelina , Fome , Masculino , Feminino , Humanos , Fome/fisiologia , Hepcidinas , Apetite , Obesidade , SensaçãoRESUMO
Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue, depressive symptoms and cognitive impairment, are also key features of other psychiatric disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and major depressive disorder (MDD). However, clinically successful treatment strategies are still lacking and are often inspired by treatment options for diseases with similar clinical presentations, such as ME/CFS. Acetylcarnitine, the shortest metabolite of a class of fatty acid metabolites called acylcarnitines and one of the most abundant blood metabolites in humans can be used as a dietary/nutritional supplement with proven clinical efficacy in the treatment of MDD, ME/CFS and other neuropsychiatric disorders. Basic research in recent decades has established acylcarnitines in general, and acetylcarnitine in particular, as important regulators and indicators of mitochondrial function and other physiological processes such as neuroinflammation and energy production pathways. In this review, we will compare the clinical basis of neuropsychiatric long COVID with other fatigue-associated diseases. We will also review common molecular disease mechanisms associated with altered acetylcarnitine metabolism and the potential of acetylcarnitine to interfere with these as a therapeutic agent. Finally, we will review the current evidence for acetylcarnitine as a supplement in the treatment of fatigue-associated diseases and propose future research strategies to investigate the potential of acetylcarnitine as a treatment option for long COVID.
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The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.
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Bases de Dados Genéticas , Metaboloma/genética , Metabolômica/classificação , Humanos , Lipidômica/classificação , Espectrometria de Massas , Interface Usuário-ComputadorRESUMO
BACKGROUND: Subjective well-being (SWB) is associated with social support in cross-sectional studies. However, it remains unclear whether and how social support predicts SWB longitudinally, especially during the COVID-19 contingency. METHODS: By adopting a prospective design, the current work addressed this research question in a sample of 594 participants from the U.K. The data were collected via the online platform, Prolific, at two time points (June, 2020 and August, 2021) with a 14-month interval. Descriptive analysis and a moderated mediation model were conducted to test the proposed hypotheses. RESULTS: Baseline social support was a significant predictor of subjective well-being (SWB) 14 months later, even after controlling for baseline SWB and other covariates such as personality traits. Additionally, affect balance (i.e., the affective component of SWB) fully mediated the link between baseline social support and subsequent life satisfaction (i.e., the cognitive component of SWB). Moreover, household income moderated this relationship, indicating a stronger mediation for individuals with lower monthly household income. CONCLUSION: The present work sheds light on the underlying mechanism and boundary condition of the association between social support and different components of SWB during the COVID-19 pandemic.
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COVID-19 , Humanos , COVID-19/epidemiologia , Estudos Prospectivos , Estudos Transversais , Pandemias , Apoio SocialRESUMO
Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.
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Antineoplásicos , Neoplasias Encefálicas , Preparações Farmacêuticas , Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas , Humanos , Inibidores de ProteassomaRESUMO
The benefits of consuming fruits and vegetables are widely accepted. While previous studies suggest a protective role of fruits and vegetables against a variety of diseases such as dementia and depression, the biological mechanisms/effects remain unclear. Here we investigated the effect of fruit and vegetable consumption on brain structure. Particularly on grey matter (GM) and white matter (WM) volumes, regional GM volumes and subcortical volumes. Cross-sectional imaging data from UK Biobank cohort was used. A total of 9925 participants (Mean age 62.4 ± 7.5 years, 51.1 % men) were included in the present analysis. Measures included fruit and vegetable intake, other dietary patterns and a number of selected lifestyle factors and clinical data. Brain volumes were derived from structural brain magnetic resonance imaging. General linear model was used to study the associations between brain volumes and fruit/vegetable intakes. After adjusting for selected confounding factors, salad/raw vegetable intake showed a positive association with total white matter volume, fresh fruit intake showed a negative association with total grey matter (GM) volume. Regional GM analyses showed that higher fresh fruit intake was associated with larger GM volume in the left hippocampus, right temporal occipital fusiform cortex, left postcentral gyrus, right precentral gyrus, and right juxtapositional lobule cortex. We conclude that fruit and vegetable consumption seems to specifically modulate brain volumes. In particular, fresh fruit intake may have a protective role in specific cortical areas such as the hippocampus, areas robustly involved in the pathophysiology of dementia and depression.
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Demência , Substância Branca , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Frutas , Depressão/diagnóstico por imagem , Bancos de Espécimes Biológicos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imageamento por Ressonância Magnética/métodos , Reino Unido , Demência/diagnóstico por imagem , Demência/patologiaRESUMO
Recent studies have reported that Fusobacterium nucleatum (Fn) is associated with gastric cancer (GC). Cancer-derived exosomes contain key regulatory noncoding RNAs and are a crucial medium of intercellular communication. However, the function and regulatory mechanism of exosomes (Fn-GCEx) secreted from Fn-infected GC cells remains unclear. In this study, Fn-GCEx enhanced the proliferation, migration, and invasion capacity of GC cells in vitro, as well as tumor growth and metastasis in vivo. HOTTIP was also upregulated in GC cells treated with Fn-GCEx. Moreover, knockdown of HOTTIP weakened the effects of Fn-GCEx in recipient GC cells. Mechanistically, HOTTIP promoted EphB2 expression by sponging microRNA (miR)-885-3p, thus activating the PI3K/AKT pathway in Fn-GCEx treated GC cells. Overall, Fn infection induced the upregulation of exosomal HOTTIP from GC cells that subsequently promoted GC progression through the miR-885-3p/EphB2/PI3K/AKT axis. Herein, we identify a potential molecular pathway and therapeutic target for GC.
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MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fusobacterium nucleatum/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proliferação de Células/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
In brief: Ghrelin signals to the hypothalamus inhibit reproduction during times of food scarcity. In this study, we demonstrate that ghrelin impairs sperm quality in male mice. Abstract: Ghrelin (GHRL) is an orexigenic peptide that has been investigated as one of the signals responsible for the reproductive performance of mammals under fluctuating metabolic conditions. Central GHRL administration impairs spermatogenesis in mice by regulating the hypothalamic-pituitary-gonadal axis function. In the present study, the hypothalamus role as a mediator of GHRL effects on sperm fertilizing capacity and male sexual behavior was evaluated. After 42 days of hypothalamic GHRL infusion or artificial cerebrospinal fluid, in vitro and in vivo sperm fertilizing capacity, testicular α-tubulin, speriolin gene expression and spermatic α-tubulin protein were evaluated. Hypothalamic expression of genes Kiss1, Gpr54 and Gnrh was also studied. The second group of animals was infused with one time only GHRL or artificial cerebrospinal fluid into the hypothalamus to evaluate the effects on sexual behavior. Results demonstrated that chronic GHRL administration to male mice significantly increased the percentages of pre-implantation embryo loss and the number of post-implantation embryo loss. In relation to the gene expression, our results show a relative decrease of Kiss1, Gpr54 and Spatc1. Although no significant differences were observed in the quantitative expression of α-tubulin protein, qualitative changes in its expression pattern were observed. In addition, a dual effect on sexual behavior was observed: 40% of the treated animals showed a significant reduction in the number of mounts and intromissions, while a 60% showed a significant decrease in ejaculation latency vs control animals. In conclusion, our results provide evidence that central GHRL administration possibly induces failure in embryo development and/or implantation in the females mated with treated males, possibly because of a negative effect in the α-tubulin pattern.
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Aborto Espontâneo , Tubulina (Proteína) , Masculino , Camundongos , Animais , Feminino , Humanos , Gravidez , Perda do Embrião , Sêmen , Comportamento Sexual , Espermatozoides , MamíferosRESUMO
BACKGROUND: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls. METHODS: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume. RESULTS: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm3, 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm3, 95% CI [-7, 100]) and gray matter (mean difference: 49 mm3, 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm3, 95% CI [-7, 40]). CONCLUSION: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.
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Depressão , Transtornos de Enxaqueca , Humanos , Feminino , Depressão/epidemiologia , Bancos de Espécimes Biológicos , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/epidemiologia , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: Prolonged fasting is a major challenge for living organisms. An appropriate metabolic response to food deprivation requires the activation of the corticotropin-releasing factor-producing neurons of the hypothalamic paraventricular nucleus (PVHCRF neurons), which are a part of the hypothalamic-pituitary-adrenal axis (HPA), as well as the growth hormone secretagogue receptor (GHSR) signaling, whose activity is up- or down-regulated, respectively, by the hormones ghrelin and the liver-expressed antimicrobial peptide 2 (LEAP2). Since ghrelin treatment potently up-regulates the HPA axis, we studied the role of GHSR in mediating food deprivation-induced activation of the PVHCRF neurons in mice. METHODS: We estimated the activation of the PVHCRF neurons, using immuno-staining against CRF and the marker of neuronal activation c-Fos in brain sections, and assessed plasma levels of corticosterone and glucose in different pharmacologically or genetically manipulated mouse models exposed, or not, to a 2-day food deprivation protocol. In particular, we investigated ad libitum fed or food-deprived male mice that: (1) lacked GHSR gene expression, (2) had genetic deletion of the ghrelin gene, (3) displayed neurotoxic ablation of the hypothalamic arcuate nucleus, (4) were centrally treated with an anti-ghrelin antibody to block central ghrelin action, (5) were centrally treated with a GHSR ligand that blocks ghrelin-evoked and constitutive GHSR activities, or (6) received a continuous systemic infusion of LEAP2(1-12). RESULTS: We found that food deprivation results in the activation of the PVHCRF neurons and in a rise of the ghrelin/LEAP2 molar ratio. Food deprivation-induced activation of PVHCRF neurons required the presence and the signaling of GHSR at hypothalamic level, but not of ghrelin. Finally, we found that preventing the food deprivation-induced fall of LEAP2 reverses the activation of the PVHCRF neurons in food-deprived mice, although it has no effect on body weight or blood glucose. CONCLUSION: Food deprivation-induced activation of the PVHCRF neurons involves ghrelin-independent actions of GHSR at hypothalamic level and requires a decrease of plasma LEAP2 levels. We propose that the up-regulation of the actions of GHSR associated to the fall of plasma LEAP2 level are physiologically relevant neuroendocrine signals during a prolonged fasting.
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Peptídeos Catiônicos Antimicrobianos/metabolismo , Privação de Alimentos , Núcleo Hipotalâmico Paraventricular , Receptores de Grelina/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Ingestão de Alimentos , Grelina/metabolismo , Grelina/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Grelina/genéticaRESUMO
AIMS: Job satisfaction plays an important role for the life quality and health of working individuals. While studies have shown that self-reported mental health conditions such as stress, anxiety and depression are associated with job satisfaction, a large population-based study exploring and comparing self-reported physician posed diagnosed conditions and their association with job satisfaction and job tenure is missing. This study addresses the gap along with exploring the impact of the neurotic personality trait and other possible contributing factors. METHODS: Sixteen mental health disorders diagnosed by physicians, categorised into four major groups were investigated in relation to employment status (108,711 participants) and in relation to job satisfaction and job tenure (34,808 participants). Analyses were performed using linear regression adjusted for age, sex, townsend deprivation index, body mass index, education, physical activity, work hours and neuroticism. RESULTS: Neurotic and stress disorders, eating disorders and other mental health disorders were strongly associated with lower job satisfaction and shorter job tenure in both unadjusted and adjusted analyses. Neuroticism was strongly linked to job satisfaction but was not associated with job tenure. CONCLUSIONS: Study findings clarify the complex relationship of mental health with job satisfaction and job tenure, which is very important to understand in designing measures to improve working life participation of individuals with mental health issues.
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Satisfação no Emprego , Transtornos Mentais , Humanos , Saúde Mental , Estudos de Coortes , Bancos de Espécimes Biológicos , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Reino UnidoRESUMO
AIMS: General psychosocial stress and job strain have been related to blood pressure (BP) with conflicting results. This study sought to explore the contribution of several lifestyle factors in the relation between general psychosocial stress, job strain and BP. METHODS: This cross-sectional study investigated the association of general stress and job strain with systolic BP (SBP) and diastolic BP in a sample of 9441 employed individuals from the EpiHealth cohort. General stress was measured by the Perceived Stress Scale. Job strain was assessed with the Job Content Questionnaire, assessing two dimensions of job strain: psychological job demand and decision latitude. Linear regression and sensitivity analysis were performed. RESULTS: At the uncorrected model, general stress, job demand and decision latitude were all inversely associated with SBP. After further adjustment for lifestyle and health parameters, only general stress was associated with SPB (ß coefficient: -0.103; 95% confidence interval -0.182 to 0.023). CONCLUSIONS: General stress is associated with lower SBP independently of lifestyle in middle-aged adults. Our findings point towards a major contribution for job-unrelated stressors in determining SBP and support the pivotal role of lifestyle behaviours and health status in modulating the effect of stress on BP, calling for a careful selection of confounders.
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Estresse Psicológico , Adulto , Pessoa de Meia-Idade , Humanos , Pressão Sanguínea/fisiologia , Estudos Transversais , Suécia/epidemiologia , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologia , Inquéritos e QuestionáriosRESUMO
Every day, we are exposed to many environmental pollutants that can enter our body through different routes and cause adverse effects on our health. Epidemiological studies suggest that these pollutants are responsible for approximately nine million deaths per year. Acute lymphoblastic leukemia (ALL) represents one of the major cancers affecting children, and although substantial progress has been made in its treatment, relapses are frequent after initial treatment and are now one of the leading causes of cancer-related death in pediatric patients. Currently, relatively little attention is paid to pollutant exposure during drug treatment and this is not taken into account for dose setting or regulatory purposes. In this work, we investigated how bisphenol A (BPA), its derivative bisphenol A diglycidyl ether (BADGE), and perfluorooctanoic acid (PFOA) alter vincristine treatment in ALL when administered before or together with the drug. We found that these three pollutants at nanomolar concentrations, lower than those established by current regulations, can reduce the cytotoxic effects of vincristine on ALL cells. Interestingly, we found that this is only achieved when exposure to pollutants occurs prior to administration of the chemotherapeutic drug. Moreover, we found that this effect could be mediated by activation of the PI3K/AKT pathway and stabilization of microtubules. This work strengthens the idea of starting to take into account exposure to pollutants to improve the efficacy of chemotherapy treatments.
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Antineoplásicos , Poluentes Ambientais , Leucemia-Linfoma Linfoblástico de Células Precursoras , Vincristina , Criança , Humanos , Antineoplásicos/química , Antineoplásicos/toxicidade , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/análise , Poluentes Ambientais/química , Poluentes Ambientais/toxicidade , Compostos de Epóxi/toxicidade , Fosfatidilinositol 3-Quinases , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vincristina/química , Vincristina/toxicidadeRESUMO
The intake of macronutrients is crucial for the fitness of any animal and is mainly regulated by peripheral signals to the brain. How the brain receives and translates these peripheral signals or how these interactions lead to changes in feeding behavior is not well-understood. We discovered that 2 crustacean cardioactive peptide (CCAP)-expressing neurons in Drosophila adults regulate feeding behavior and metabolism. Notably, loss of CCAP, or knocking down the CCAP receptor (CCAP-R) in 2 dorsal median neurons, inhibits the release of neuropeptide F (NPF), which regulates feeding behavior. Furthermore, under starvation conditions, flies normally have an increased sensitivity to sugar; however, loss of CCAP, or CCAP-R in 2 dorsal median NPF neurons, inhibited sugar sensitivity in satiated and starved flies. Separate from its regulation of NPF signaling, the CCAP peptide also regulates triglyceride levels. Additionally, genetic and optogenetic studies demonstrate that CCAP signaling is necessary and sufficient to stimulate a reflexive feeding behavior, the proboscis extension reflex (PER), elicited when external food cues are interpreted as palatable. Dopaminergic signaling was also sufficient to induce a PER. On the other hand, although necessary, NPF neurons were not able to induce a PER. These data illustrate that the CCAP peptide is a central regulator of feeding behavior and metabolism in adult flies, and that NPF neurons have an important regulatory role within this system.
Assuntos
Comportamento Alimentar/fisiologia , Neuropeptídeos/metabolismo , Animais , Encéfalo/metabolismo , Ritmo Circadiano/fisiologia , Dopamina/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Neurônios/metabolismo , Neuropeptídeos/genética , Transdução de Sinais , Inanição/metabolismoRESUMO
BACKGROUND: Like most living organisms, the fruit fly Drosophila melanogaster exhibits strong and diverse behavioural reactions to light. Drosophila is a diurnal animal that displays both short- and long-term responses to light, important for, instance, in avoidance and light wavelength preference, regulation of eclosion, courtship, and activity, and provides an important model organism for understanding the regulation of circadian rhythms both at molecular and circuit levels. However, the assessment and comparison of light-based behaviours is still a challenge, mainly due to the lack of a standardised platform to measure behaviour and different protocols created across studies. Here, we describe the Drosophila Interactive System for Controlled Optical manipulations (DISCO), a low-cost, automated, high-throughput device that records the flies' activity using infrared beams while performing LED light manipulations. RESULTS: To demonstrate the effectiveness of this tool and validate its potential as a standard platform, we developed a number of distinct assays, including measuring the locomotor response of flies exposed to sudden darkness (lights-off) stimuli. Both white-eyed and red-eyed wild-type flies exhibit increased activity after the application of stimuli, while no changes can be observed in Fmr1 null allele flies, a model of fragile X syndrome. Next, to demonstrate the use of DISCO in long-term protocols, we monitored the circadian rhythm of the flies for 48 h while performing an alcohol preference test. We show that increased alcohol consumption happens intermittently throughout the day, especially in the dark phases. Finally, we developed a feedback-loop algorithm to implement a place preference test based on the flies' innate aversion to blue light and preference for green light. We show that both white-eyed and red-eyed wild-type flies were able to learn to avoid the blue-illuminated zones. CONCLUSIONS: Our results demonstrate the versatility of DISCO for a range of protocols, indicating that this platform can be used in a variety of ways to study light-dependent behaviours in flies.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Animais , Drosophila melanogaster/fisiologia , Ritmo Circadiano/fisiologia , Drosophila/fisiologia , Atividade Motora/fisiologia , Visão Ocular , Proteína do X Frágil da Deficiência IntelectualRESUMO
Nanoparticles are heterologous small composites that are usually between 1 and 100 nanometers in size. They are applied in many areas of medicine with one of them being drug delivery. Nanoparticles have a number of advantages as drug carriers which include reduced toxic effects, increased bioavailability, and their ability to be modified for specific tissues or cells. Due to the exciting development of nanotechnology concomitant with advances in biotechnology and medicine, the number of clinical trials devoted to nanoparticles for drug delivery is growing rapidly. Some nanoparticles, lipid-based types, in particular, played a crucial role in the developing and manufacturing of the two COVID-19 vaccines-Pfizer and Moderna-that are now being widely used. In this analysis, we provide a quantitative survey of clinical trials using nanoparticles during the period from 2002 to 2021 as well as the recent FDA-approved drugs (since 2016). A total of 486 clinical trials were identified using the clinicaltrials.gov database. The prevailing types of nanoparticles were liposomes (44%) and protein-based formulations (26%) during this period. The most commonly investigated content of the nanoparticles were paclitaxel (23%), metals (11%), doxorubicin (9%), bupivacaine and various vaccines (both were 8%). Among the FDA-approved nanoparticle drugs, polymeric (29%), liposomal (22%) and lipid-based (21%) drugs were the most common. In this analysis, we also discuss the differential development of the diverse groups of nanoparticles and their content, as well as the underlying factors behind the trends.