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The key DNA repair enzyme DNA-PKcs has several and important cellular functions. Loss of DNA-PKcs activity in mice has revealed essential roles in immune and nervous systems. In humans, DNA-PKcs is a critical factor for brain development and function since mutation of the prkdc gene causes severe neurological deficits such as microcephaly and seizures, predicting yet unknown roles of DNA-PKcs in neurons. Here we show that DNA-PKcs modulates synaptic plasticity. We demonstrate that DNA-PKcs localizes at synapses and phosphorylates PSD-95 at newly identified residues controlling PSD-95 protein stability. DNA-PKcs -/- mice are characterized by impaired Long-Term Potentiation (LTP), changes in neuronal morphology, and reduced levels of postsynaptic proteins. A PSD-95 mutant that is constitutively phosphorylated rescues LTP impairment when over-expressed in DNA-PKcs -/- mice. Our study identifies an emergent physiological function of DNA-PKcs in regulating neuronal plasticity, beyond genome stability.
Assuntos
Proteína Quinase Ativada por DNA , Proteína 4 Homóloga a Disks-Large , Potenciação de Longa Duração , Plasticidade Neuronal , Estabilidade Proteica , Animais , Fosforilação , Proteína Quinase Ativada por DNA/metabolismo , Proteína Quinase Ativada por DNA/genética , Camundongos , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteína 4 Homóloga a Disks-Large/genética , Neurônios/metabolismo , Camundongos Knockout , Humanos , Sinapses/metabolismo , Reparo do DNA , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas de Ligação a DNARESUMO
The functional interdependencies between the molecular components of a biological process demand for a network medicine platform that integrates systems biology and network science, to explore the interactions among biological components in health and disease. Access to large-scale omics datasets (genomics, transcriptomics, proteomics, metabolomics, metagenomics, phenomics, etc.) has significantly advanced our opportunity along this direction. Studies utilizing these techniques have begun to provide us with a deeper understanding of how the interaction between the intestinal microbes and their host affects the cardiovascular system in health and disease. Within the framework of a multiomics network approach, we highlight here how tryptophan metabolism may orchestrate the host-microbes interaction in cardiovascular diseases and the implications for precision medicine and therapeutics, including nutritional interventions.
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Doenças Cardiovasculares , Triptofano , Humanos , Genômica/métodos , Proteômica/métodos , Perfilação da Expressão Gênica/métodos , Metabolômica/métodosRESUMO
Widespread musculoskeletal pain characterizes fibromyalgia (FM), accompanied by sleep, fatigue, and mood problems. Chronic stress and depression play a crucial role in the etiology and pathophysiology of FM. They may contribute to a dysregulation of the central pain mechanisms together with the neuroendocrine and immune systems. Pharmacological treatments are the first-line therapy to reduce the symptoms of FM. The US Food and Drug Administration (FDA) indicated gabapentinoid, pregabalin, duloxetine, and milnacipran for adult patients. An alternative approach is widely used, based on therapies including interventions in patient education, behavioral therapy, exercise, pain management, and a healthy diet. A systematic search was performed on PubMed, MEDLINE, EMBASE, and Web of Science databases. The authors established the selection, inclusion, and exclusion criteria. We found a total of 908 articles. This systematic review will include ten articles selected after excluding duplicates and reading the abstracts and full texts. All studies related the effect of drugs to various symptoms caused by fibromyalgia patients with depression, such as insomnia/sleepiness, depression, suicide, difficulty walking/working, pain, fatigue, and nervousness. Although, we concluded that antidepressant drugs are effective in treating depression and pain in fibromyalgia, further studies are needed to understand the etiology of this disease and to find a combination of therapies to increase tolerability and adherence of the patient to the drug, decreasing the adverse effects.
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Fibromialgia , Dor Musculoesquelética , Adulto , Humanos , Fibromialgia/tratamento farmacológico , Antidepressivos/efeitos adversos , Fadiga/tratamento farmacológico , Dor Musculoesquelética/tratamento farmacológico , EmpregoRESUMO
Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are clinically diagnosed using neuropsychological and cognitive tests, expensive neuroimaging-based approaches (MRI and PET) and invasive and time-consuming lumbar puncture for cerebrospinal fluid (CSF) sample collection to detect biomarkers. Thus, a rapid, simple and cost-effective approach to more easily access fluids and tissues is in great need. Here, we exploit the chemical direct reprogramming of patient skin fibroblasts into neurons (chemically induced neurons, ciNs) as a novel strategy for the rapid detection of different pathological markers of neurodegenerative diseases. We found that FAD fibroblasts have a reduced efficiency of reprogramming, and converted ciNs show a less complex neuronal network. In addition, ciNs from patients show misfolded protein accumulation and mitochondria ultrastructural abnormalities, biomarkers commonly associated with neurodegeneration. Moreover, for the first time, we show that microfluidic technology, in combination with chemical reprogramming, enables on-chip examination of disease pathological processes and may have important applications in diagnosis. In conclusion, ciNs on microfluidic devices represent a small-scale, non-invasive and cost-effective high-throughput tool for protein misfolding disease diagnosis and may be useful for new biomarker discovery, disease mechanism studies and design of personalised therapies.
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Biomarcadores/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Dispositivos Lab-On-A-Chip , Masculino , Microfluídica/métodos , Pessoa de Meia-Idade , Neuroimagem/métodos , Testes Neuropsicológicos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologiaRESUMO
Oxidative stress induced post-translational protein modifications are associated with the development of inflammatory hypersensitivities. At least 90% of cellular reactive oxygen species (ROS) are produced in the mitochondria, where the mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), is located. MnSOD's ability to reduce ROS is enhanced by the mitochondrial NAD+-dependent deacetylase sirtuin (SIRT3). SIRT3 can reduce ROS levels by deacetylating MnSOD and enhancing its ability to neutralize ROS or by enhancing the transcription of MnSOD and other oxidative stress-responsive genes. SIRT3 can be post-translationally modified through carbonylation which results in loss of activity. The contribution of post-translational SIRT3 modifications in central sensitization is largely unexplored. Our results reveal that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with natural and synthetic antioxidants, prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD, and blocked the development of thermal hyperalgesia. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization.
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Analgésicos/farmacologia , Antioxidantes/farmacologia , Hiperalgesia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Animais , Linhagem Celular Tumoral , Humanos , Hiperalgesia/enzimologia , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Masculino , Metaloporfirinas/farmacologia , Carbonilação Proteica , Ratos Sprague-Dawley , Resveratrol/farmacologia , Transdução de Sinais , Sirtuínas/genética , Medula Espinal/fisiopatologia , Superóxido Dismutase/metabolismoRESUMO
(1) Background: Nicotine is implicated in the SARS-COV-2 infection through activation of the α7-nAChR and over-expression of ACE2. Our objective was to clarify the role of nicotine in SARS-CoV-2 infection exploring its molecular and cellular activity. (2) Methods: HBEpC or si-mRNA-α7-HBEpC were treated for 1 h, 48 h or continuously with 10-7 M nicotine, a concentration mimicking human exposure to a cigarette. Cell viability and proliferation were evaluated by trypan blue dye exclusion and cell counting, migration by cell migration assay, senescence by SA-ß-Gal activity, and anchorage-independent growth by cloning in soft agar. Expression of Ki67, p53/phospho-p53, VEGF, EGFR/pEGFR, phospho-p38, intracellular Ca2+, ATP and EMT were evaluated by ELISA and/or Western blotting. (3) Results: nicotine induced through α7-nAChR (i) increase in cell viability, (ii) cell proliferation, (iii) Ki67 over-expression, (iv) phospho-p38 up-regulation, (v) EGFR/pEGFR over-expression, (vi) increase in basal Ca2+ concentration, (vii) reduction of ATP production, (viii) decreased level of p53/phospho-p53, (ix) delayed senescence, (x) VEGF increase, (xi) EMT and consequent (xii) enhanced migration, and (xiii) ability to grow independently of the substrate. (4) Conclusions: Based on our results and on evidence showing that nicotine potentiates viral infection, it is likely that nicotine is involved in SARS-CoV-2 infection and severity.
Assuntos
COVID-19/patologia , Células Epiteliais/efeitos dos fármacos , Nicotina/efeitos adversos , Sistema Respiratório/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/virologia , Humanos , Receptores Nicotínicos/metabolismo , Sistema Respiratório/virologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Fumar/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. Objectives: We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. Methods: In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. Results: A significant association with functional outcomes, namely FEV1 (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. Conclusions: Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.
Assuntos
Corticosteroides/uso terapêutico , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Ligação a Tacrolimo/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/genética , Resultado do TratamentoRESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by long-term airflow limitation. Early-onset COPD in non-smoker subjects is ≥60 years and in the elderly is often associated with different comorbidities. Cognitive impairment is one of the most common feature in patients with COPD, and is associated with COPD severity and comorbidities. Cognitive impairment in COPD enhances the assistance requirement in different aspects of daily living, treatment adherence, and effectual self-management.This review describes various bioactive compounds of natural marine sources that modulate different targets shared by both COPD and cognitive impairment and hypothesizes a possible link between these two syndromes.
Assuntos
Organismos Aquáticos/química , Produtos Biológicos/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Idoso , Produtos Biológicos/isolamento & purificação , Biomarcadores/análise , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Comorbidade , Humanos , Incidência , Fármacos Neuroprotetores/isolamento & purificação , Fatores de RiscoRESUMO
The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons, and oligodendrocytes as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital components of the BBB able to preserve the brain homeostasis. These cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: (1) the presence of junction proteins and (2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. This review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders.
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Barreira Hematoencefálica/citologia , Proteínas de Membrana/metabolismo , Doenças Neurodegenerativas/metabolismo , Barreira Hematoencefálica/metabolismo , Comunicação Celular , Polaridade Celular , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Junções Intercelulares/metabolismoRESUMO
Sirtuins are conserved NAD+ -dependent deacylases. SIRT1 is a nuclear and cytoplasmic sirtuin involved in the control of histones a transcription factors function. SIRT3 is a mitochondrial protein, which regulates mitochondrial function. Although, both SIRT1 and SIRT3 have been implicated in resistance to cellular stress, the link between these two sirtuins has not been studied so far. Here we aimed to unravel: i) the role of SIRT1-SIRT3 axis for cellular response to oxidative stress and DNA damage; ii) how mammalian cells modulate such SIRT1-SIRT3 axis and which mechanisms are involved. Therefore, we analyzed the response to different stress stimuli in WT or SIRT1-silenced cell lines. Our results demonstrate that SIRT1-silenced cells are more resistant to H2 O2 and etoposide treatment showing decreased ROS accumulation, γ-H2AX phosphorylation, caspase-3 activation and PARP cleavage. Interestingly, we observed that SIRT1-silenced cells show an increased SIRT3 expression. To explore such a connection, we carried out luciferase assays on SIRT3 promoter demonstrating that SIRT1-silencing increases SIRT3 promoter activity and that such an effect depends on the presence of SP1 and ZF5 recognition sequences on SIRT3 promoter. Afterwards, we performed co-immunoprecipitation assays demonstrating that SIRT1 binds and deacetylates the transcription inhibitor ZF5 and that there is a decreased interaction between SP1 and ZF5 in SIRT1-silenced cells. Therefore, we speculate that acetylated ZF5 cannot bind and sequester SP1 that is free, then, to increase SIRT3 transcription. In conclusion, we demonstrate that cells with low SIRT1 levels can maintain their resistance and survival by increasing SIRT3 expression. J. Cell. Physiol. 232: 1835-1844, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Etoposídeo/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Acetilação/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Espaço Intracelular/metabolismo , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição Sp1/metabolismoRESUMO
Metabolic disorder has been frequently observed in chronic obstructive pulmonary disease (COPD) patients. However, the exact correlation between obesity, which is a complex metabolic disorder, and COPD remains controversial. The current study summarizes a variety of drugs from marine sources that have anti-obesity effects and proposed potential mechanisms by which lung function can be modulated with the anti-obesity activity. Considering the similar mechanism, such as inflammation, shared between obesity and COPD, the study suggests that marine derivatives that act on the adipose tissues to reduce inflammation may provide beneficial therapeutic effects in COPD subjects with high body mass index (BMI).
Assuntos
Organismos Aquáticos/química , Fatores Biológicos/química , Fatores Biológicos/farmacologia , Doenças Metabólicas/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , HumanosRESUMO
BACKGROUND: Oxidative and nitrosative stress are considered key events in the still unclear pathophysiology of migraine. METHODS: Studies comparing the level of biomarkers related to nitric oxide (NO) pathway/oxidative stress in the blood/urine of migraineurs vs. unaffected controls were extracted from the PubMed database. Summary estimates of mean ratios (MR) were carried out whenever a minimum of three papers were available. Nineteen studies were included in the meta-analyses, accounting for more than 1000 patients and controls, and compared with existing literature. RESULTS: Most studies measuring superoxide dismutase (SOD) showed lower activity in cases, although the meta-analysis in erythrocytes gave null results. On the contrary, plasma levels of thiobarbituric acid reactive substances (TBARS), an aspecific biomarker of oxidative damage, showed a meta-MR of 2.20 (95% CI: 1.65-2.93). As for NOs, no significant results were found in plasma, serum and urine. However, higher levels were shown during attacks, in patients with aura, and an effect of diet was found. The analysis of glutathione precursor homocysteine and asymmetric dimethylarginine (ADMA), an NO synthase inhibitor, gave inconclusive results. CONCLUSIONS: The role of the oxidative pathway in migraine is still uncertain. Interesting evidence emerged for TBARS and SOD, and concerning the possible role of diet in the control of NOx levels.
Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Estudos Transversais , HumanosRESUMO
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a restricted period of time. Currently, there is a translational research challenge into identifying the new effective drugs and their respective new therapeutic targets in AD and other neurodegenerative disorders. In this review, selected examples of marine-derived compounds in neurodegeneration, specifically in AD field are reported. The emphasis has been done on compounds and their possible relevant biological activities. The proposed drug development paradigm and current hypotheses should be accurately investigated in the future of AD therapy directions although taking into account successful examples of such approach represented by Cytarabine, Trabectedin, Eribulin and Ziconotide. We review a complexity of the translational research for such a development of new therapies for AD. Bryostatin is a prominent candidate for the therapy of AD and other types of dementia in humans.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Organismos Aquáticos/metabolismo , Briostatinas/química , Briostatinas/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Fármacos Neuroprotetores/química , Água do MarRESUMO
Despite the remarkable and progressive advances made in the prevention and management of cardiovascular diseases, the recurrence of cardiovascular events remains unacceptably elevated with a notable size of the residual risk. Indeed, in patients who suffered from myocardial infarction or who underwent percutaneous or surgical myocardial revascularization, life-style changes and optimized pharmacological therapy with antiplatelet drugs, lipid lowering agents, beta-blockers, renin angiotensin system inhibitors and antidiabetic drugs, when appropriate, are systematically prescribed but they might be insufficient to protect from further events. In such a context, an increasing body of evidence supports the benefits of cardiac rehabilitation (CR) in the setting of secondary cardiovascular prevention, consisting in the reduction of myocardial oxygen demands, in the inhibition of atherosclerotic plaque progression and in an improvement of exercise performance, quality of life and survival. However, prescription and implementation of CR programs is still not sufficiently considered.The aim of this position paper of the Italian Society of Cardiovascular Prevention (SIPREC) and of the Italian Heart Failure Association (ITAHFA) is to examine the reasons of the insufficient use of this strategy in clinical practice and to propose some feasible solutions to overcome this clinical gap.
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Background/Objectives: This study is based on data collected from a medical health record review to assess whether multidisciplinary intensive rehabilitation treatment in Parkinson's disease (PD) patients can improve global cognitive functioning and executive functions. Methods: The data related to PD patients were extrapolated from a clinical database called "NeuroRehab". A total of 104 PD patients (51 males; 53 females) performed 6 weeks of multidisciplinary intensive rehabilitation treatment in clinical practice from January 2019 to May 2023. This training program was characterized by three daily sessions of 60 min of activities (muscle relaxation and stretching exercises, moderate physical aerobic exercise, and occupational therapy). The patients were classified and stratified according to disease severity (according to the Hoehn and Yahr scale), postural instability and gait difficulty (PIGD) or tremor-dominant (TD) subtypes, disease duration (DD), and the presence of dyskinesias. The effect of multidisciplinary intensive rehabilitation treatment on cognitive and executive functions was evaluated through the administration of cognitive tests, such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery (FAB). All the parameters were evaluated at the baseline (T0) and at the end of the rehabilitation program (T1). Results: The multidisciplinary intensive rehabilitation treatment significantly improved cognitive performance. The MMSE, MoCA, and FAB test scores after the rehabilitation program (T1) were significantly higher compared to the scores obtained at the baseline (T0). Moreover, further analyses on subgroups of the patients who scored below the cut-off in the MMSE showed that at least 50% of patients overcame the cut-off score. Interestingly, the same analyses performed for the MoCA and FAB revealed a higher rate of improvement in cognitive functions, with normal scores in both tests after 6 weeks of multidisciplinary intensive rehabilitation treatment. Conclusions: This study revealed the potential effects of a 6-week multidisciplinary rehabilitation program in improving cognitive status in a PD inpatient cohort.
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AIMS: We evaluated the incidence and relative risk of major post-acute cardiovascular consequences of SARS-CoV-2 infection in a large real-world population from a primary care database in a region at moderate cardiovascular risk followed up in the period 2020-22. METHODS AND RESULTS: This is a retrospective cohort analysis using data from a cooperative of general practitioners in Italy. Individuals aged >18 affected by COVID-19 starting from January 2020 have been followed up for 3 years. Anonymized data from 228 266 patients in the period 2020-22 were considered for statistical analysis and included 31 764 subjects with a diagnosis of COVID-19. An equal group of subjects recorded in the same database in the period 2017-19 was used as propensity score-matched comparison as an unquestionable COVID-19-free population. Out of the 228 266 individuals included in the COMEGEN database during 2020-22, 31 764 (13.9%) were ascertained positive with SARS-CoV-2 infection by a molecular test reported to general practitioners. The proportion of individuals with a new diagnosis of major adverse cardiovascular and cerebrovascular events was higher in the 2020-22 COVID-19 group than in the 2017-19 COMEGEN propensity score-matched comparator, with an odds ratio of 1.73 (95% confidence interval: 1.53-1.94; P < 0.001). All major adverse cardiovascular and cerebrovascular events considered showed a significantly higher risk in COVID-19 individuals. Incidence calculated for each 6-month period after the diagnosis of COVID-19 in our population was the highest in the first year (1.39% and 1.45%, respectively), although it remained significantly higher than in the COVID-19-free patients throughout the 3 years. CONCLUSION: The increase of cardiovascular risk associated with COVID-19 might be extended for years and not limited to the acute phase of the infection. This should promote the planning of longer follow-up for COVID-19 patients to prevent and promptly manage the potential occurrence of major adverse cardiovascular and cerebrovascular events.
Assuntos
COVID-19 , Doenças Cardiovasculares , Transtornos Cerebrovasculares , Humanos , COVID-19/epidemiologia , COVID-19/diagnóstico , COVID-19/complicações , Masculino , Feminino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/virologia , Estudos Retrospectivos , Itália/epidemiologia , Pessoa de Meia-Idade , Idoso , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/diagnóstico , Incidência , Medição de Risco , SARS-CoV-2 , Fatores de Risco , Fatores de Tempo , Adulto , Bases de Dados Factuais , Idoso de 80 Anos ou maisRESUMO
The following study demonstrated that, in in vitro differentiated neurons, SIRT1 silencing induced an increase of IGF-1 protein expression and secretion and of IGF-1R protein levels which, in turn, prolonged neuronal cell survival in presence of an apoptotic insult. On the contrary, SIRT1 overexpression increased cell death. In particular, IGF-1 and IGF-1R expression levels were negatively regulated by SIRT1. In SIRT1 silenced cells, the increase in IGF-1 and IGF-1R expression was associated to an increase in AKT and ERK1/2 phosphorylation. Moreover, neuronal differentiation was reduced in SIRT1 overexpressing cells and increased in SIRT1 silenced cells. We conclude that SIRT1 silenced neurons appear more committed to differentiation and more resistant to cell death through the activation of IGF-1 survival pathway.
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Fator de Crescimento Insulin-Like I/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Animais , Morte Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Sobrevivência Celular , Regulação para Baixo/genética , Camundongos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores , RNA Interferente Pequeno/genética , Ratos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/genética , Regulação para Cima/genéticaRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder, characterized by motor and non-motor symptoms, that still lacks of a disease-modifying treatment. Consistent evidence proved the benefits of physical therapy on motor and non-motor symptoms in PD patients, leading the scientific community to propose physical activity as disease-modifying therapy for PD and suggesting the involvement of neurotrophic factors (NFs) as key mediators of neuroplasticity. However, the lack of standardized exercise training and methodological flaws of clinical trials have limited the evidence demonstrating the exercise-induced changes in serum and plasma neurotrophic factors concentration. A systematic search, covering 20 years of research in this field and including randomized and non-randomized controlled trials (RCTs and non-RCTs), which reported changes in serum and plasma NFs after a specific intervention, were reviewed. Pooled effect sizes (p-ESs) and 95% confidence intervals (95%CIs) were calculated using a random effects model with R software. A total of 18 articles, of which exercise programs of interventions were codified in terms of type, intensity and duration adopting a standardisation methodology, were included in the systematic review. Six papers, describing the effect of different training programs on BDNF and IGF-1 levels, were included and independently analysed in two meta-analyses. Quantitative analysis for BDNF indicated a statistically significant improvement in serum concentration of PD patients (MD: 5.99 ng/mL; 95%IC: 0.15 -11.83; I2 = 77%) performing physical activity compared with control conditions in RCTs. Preliminary evidence supported the hypothesis that a moderate intensity aerobic exercise (MIAE) would be necessary to induce the changes in NFs. However, sensitivity analysis of meta-analysis and the few studies included in subgroup analysis did not support these results. Alongside, meta-analysis followed by sensitivity analysis revealed a potential change in serum IGF-1 (MD: 33.47 ng/mL; 95%IC: 8.09-58.85) in PD patients performing physical activity with respect controls in RCT studies. Considering the limited evidence to support or refute the increase in NFs levels in PD patients performing physical activity, there is a need to develop a rigorous controlled randomized trial, with standardization for loading intensity of physical activity, greater sample size, and a correct stratification of PD patients to establish a well-defined correlation between physical activity and NFs levels.
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Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Fator de Crescimento Insulin-Like I , Fator Neurotrófico Derivado do Encéfalo , Exercício Físico , Plasticidade Neuronal , Qualidade de VidaRESUMO
BACKGROUND: Falls are a common cause of morbidity and functional impairment in the elderly and represent a significant health problem. General practitioners (GPs) are the first point of contact for health issues and may provide preventive services. The randomized clinical trial PREMIO was conducted by GPs to evaluate the effects of a multicomponent intervention for the prevention of falls in older adults aged ≥ 65 years at high risk of falling. METHODS: 117 GPs enrolled 1757 patients (1116 F, 641 M) and randomized them into 2 groups (intervention and control). The intervention group received medical and behavioral counseling, home risk-factor assessment, a physical-activity program and nutritional counseling. The control group received only the nutritional counseling. Both groups were followed for one year. The primary outcome was the rate of falls at home over 12 months. RESULTS: 1225 patients completed the study. Subjects receiving the intervention had, on average, fewer falls at home (percentage change -31.2%, p < 0.02) and fewer total falls (-26.0%, p < 0.02), although the reduction in the number of fallers was small (-3.9%, p = 0.05). Among the secondary endpoints, rates of general hospital or emergency-department admission and GP visits showed slight improvements (not statistically significant), while the risk of fractures was unexpectedly increased in the intervention group compared to the controls (odds ratio 2.39, p = 0.023). CONCLUSIONS: Future studies and public-health interventions to prevent domestic falls among community-dwelling older people at high risk of falling could benefit from a multicomponent approach including medication review, physical exercise and home risk assessment and should include assessment of risk factors for fractures.
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Advance assessment of the potential functional improvement of patients undergoing a rehabilitation program is crucial in developing precision medicine tools and patient-oriented rehabilitation programs, as well as in better allocating resources in hospitals. In this work, we propose a novel approach to this problem using machine learning algorithms focused on assessing the modified Barthel index (mBI) as an indicator of functional ability. We build four tree-based ensemble machine learning models and train them on a private training cohort of orthopedic (OP) and neurological (NP) hospital discharges. Moreover, we evaluate the models using a validation set for each category of patients using root mean squared error (RMSE) as an absolute error indicator between the predicted mBI and the actual values. The best results obtained from the study are an RMSE of 6.58 for OP patients and 8.66 for NP patients, which shows the potential of artificial intelligence in predicting the functional improvement of patients undergoing rehabilitation.