المؤلفون: Maria Claudia Costa, Claudia Angelini, Monica Franzese, Concetta Iside, Marco Salvatore, Luigi Laezza, Francesco Napolitano, Michele Ceccarelli

المصدر: Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-19 (2024)

مصطلحات موضوعية: OA, Cartilage, Consensus signature, Network, Risk score, Drug prediction, Medicine

الوصف: Abstract Background Osteoarthritis (OA) is a multifactorial, hypertrophic, and degenerative condition involving the whole joint and affecting a high percentage of middle-aged people. It is due to a combination of factors, although the pivotal mechanisms underlying the disease are still obscure. Moreover, current treatments are still poorly effective, and patients experience a painful and degenerative disease course. Methods We used an integrative approach that led us to extract a consensus signature from a meta-analysis of three different OA cohorts. We performed a network-based drug prioritization to detect the most relevant drugs targeting these genes and validated in vitro the most promising candidates. We also proposed a risk score based on a minimal set of genes to predict the OA clinical stage from RNA-Seq data. Results We derived a consensus signature of 44 genes that we validated on an independent dataset. Using network analysis, we identified Resveratrol, Tenoxicam, Benzbromarone, Pirinixic Acid, and Mesalazine as putative drugs of interest for therapeutics in OA for anti-inflammatory properties. We also derived a list of seven gene-targets validated with functional RT-qPCR assays, confirming the in silico predictions. Finally, we identified a predictive subset of genes composed of DNER, TNFSF11, THBS3, LOXL3, TSPAN2, DYSF, ASPN and HTRA1 to compute the patient’s risk score. We validated this risk score on an independent dataset with a high AUC (0.875) and compared it with the same approach computed using the entire consensus signature (AUC 0.922). Conclusions The consensus signature highlights crucial mechanisms for disease progression. Moreover, these genes were associated with several candidate drugs that could represent potential innovative therapeutics. Furthermore, the patient’s risk scores can be used in clinical settings.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1479-5876Test

الوصول الحر: https://doaj.org/article/a1029b4b319b40b9a751143efea7d602Test

المؤلفون: Maria Fortunata Lofiego, Francesca Piazzini, Francesca Pia Caruso, Francesco Marzani, Laura Solmonese, Emma Bello, Fabrizio Celesti, Maria Claudia Costa, Teresa Noviello, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Sandra Coral, Anna Maria Di Giacomo, Michele Maio, Alessia Covre, The EPigenetic Immune-oncology Consortium Airc (EPICA) investigators

المصدر: Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-13 (2024)

مصطلحات موضوعية: Glioblastoma, Brain metastases, Immunotherapy, DNA hypomethylating agent, Melanoma, Medicine

الوصف: Abstract Background Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM. Methods Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients’ cohort. Results The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways. Conclusions Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1479-5876Test

الوصول الحر: https://doaj.org/article/de9304cb7f1e45d7b01e1059c5afd11bTest

المؤلفون: Teresa Maria Rosaria Noviello, Anna Maria Di Giacomo, Francesca Pia Caruso, Alessia Covre, Roberta Mortarini, Giovanni Scala, Maria Claudia Costa, Sandra Coral, Wolf H. Fridman, Catherine Sautès-Fridman, Silvia Brich, Giancarlo Pruneri, Elena Simonetti, Maria Fortunata Lofiego, Rossella Tufano, Davide Bedognetti, Andrea Anichini, Michele Maio, Michele Ceccarelli

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-18 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/05375b66e651420298a4c3d815f3dee9Test

المؤلفون: Maiquel Bueno Cortes, Raphael Silveira Nunes da Silva, Patrícia Caetano de Oliveira, Diego Silveira da Silva, Maria Claudia Costa Irigoyen, Gustavo Waclawovsky, Maximiliano Isoppo Schaun

المصدر: Scientific Reports, Vol 13, Iss 1, Pp 1-15 (2023)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract The objective of this systematic review was to examine the effects of exercise training on endothelial function in individuals with overweight and obesity. Our review study included only randomized controlled trials (RCTs) involving adults (≥ 18 years of age) with body mass index (BMI) ≥ 25.0 kg/m2. Our search was conducted in the electronic bases MEDLINE (PubMed), Cochrane, LILACS and EMBASE and in the gray literature. We performed random-effects analyses for effect estimates and used 95% prediction intervals (95% PI) for estimating the uncertainty of the study results. There were selected 10 RCTs involving 14 groups (n = 400). The quality assessment of studies using Cochrane risk-of-bias 2 (RoB 2) tool identified some concerns. Exercise training resulted in improved flow-mediated dilation (FMD) in individuals with overweight and obesity (p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/5d88bbfd5e7c42e58d16701738f8a012Test

المؤلفون: Gustavo Waclawovsky, Liliana Fortini Cavalheiro Boll, Salvador Gomes Neto, Maria Claudia Costa Irigoyen, Alexandre M. Lehnen

المصدر: Trials, Vol 22, Iss 1, Pp 1-11 (2021)

مصطلحات موضوعية: Endothelium, Autonomic nervous system, Aerobic exercise, Resistance exercise, Systemic arterial hypertension, Randomized clinical trial, Medicine (General), R5-920

الوصف: Abstract Background Arterial hypertension has a direct association with endothelial dysfunction and major cardiovascular events. There is evidence showing the benefits of aerobic exercise on flow-mediated dilation (FMD) in hypertensive individuals but little is known about the effect of autonomic nervous system (ANS) activation on FMD of the brachial artery in response to different types of exercise in this specific population. This study aims to examine the effects of ANS activation on FMD of the brachial artery in response to exercise in hypertensive individuals following a session of different types of exercise including aerobic exercise (AE), resistance exercise (RE), or combined exercise (CE). Methods Thirty-nine hypertensive volunteers aged 35 to 55 years will be randomly assigned to two exercise sessions: AE (40 min on a cycle ergometer at 60% of HR reserve), RE (4 lower limb sets with 12 repetitions at 60% 1-RM for 40 min), or CE (RE for 20 min + AE for 20 min). Each exercise group will be randomized to receive either an α1-adrenergic blocker (doxazosin 0.05 mg/kg−1) or placebo. Ultrasound measurement of FMD is performed 10 min before and 10, 40, and 70 min after exercise. ANS activation is monitored using a Finometer and measurements are taken during 10 min before each FMD assessment. Arterial stiffness is assessed by pulse wave velocity (PWV) analysis using a Complior device. Discussion We expect to demonstrate the effect of ANS activation on FMD of the brachial artery in hypertensive individuals in response to different types of exercise. This study may give some insight on how to improve exercise prescription for hypertension management. Trial registration https://clinicaltrials.govTest and ID "NCT04371757". Registered on May 1, 2020.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1745-6215Test

الوصول الحر: https://doaj.org/article/31fb16e549b948dda7fce78bbfa50223Test

المؤلفون: Ana Jessica Pinto, Tiago Peçanha, Kamila Meireles, Fabiana Braga Benatti, Karina Bonfiglioli, Ana Lúcia de Sá Pinto, Fernanda Rodrigues Lima, Rosa Maria Rodrigues Pereira, Maria Claudia Costa Irigoyen, James Edward Turner, John P. Kirwan, Neville Owen, David W. Dunstan, Hamilton Roschel, Bruno Gualano

المصدر: Trials, Vol 21, Iss 1, Pp 1-13 (2020)

مصطلحات موضوعية: Sitting, Light-intensity physical activity, Rheumatic arthritis, Medicine (General), R5-920

الوصف: Abstract Background Patients with rheumatoid arthritis spend most of their daily hours in sedentary behavior (sitting), a predisposing factor to poor health-related outcomes and all-cause mortality. Interventions focused on reducing sedentary time could be of novel therapeutic relevance. However, studies addressing this topic remain scarce. We aim to investigate the feasibility and efficacy of a newly developed intervention focused on reducing sedentary time, and potential clinical, physiological, metabolic and molecular effects in rheumatoid arthritis. Methods The Take a STAND for Health study is a 4-month, parallel-group, randomized controlled trial, in which postmenopausal patients with rheumatoid arthritis will set individually tailored, progressive goals to replace their sedentary time with standing and light-intensity activities. Patients will be recruited from the Clinical Hospital (School of Medicine, University of Sao Paulo) and will be assessed at baseline and after a 4-month follow up. Outcomes will include objectively measured sedentary behavior (primary outcome) and physical activity levels, clinical parameters, anthropometric parameters and body composition; aerobic fitness, muscle function, blood pressure, cardiovascular autonomic function, vascular function and structure, health-related quality of life, and food intake. Blood and muscle samples will be collected for assessing potential mechanisms, through targeted and non-targeted approaches. Discussion Findings will be of scientific and clinical relevance with the potential to inform new prescriptions focused on reducing sedentary behavior, a modifiable risk factor that thus far has been overlooked in patients with rheumatoid arthritis. Trial registration ClinicalTrials.gov, NCT03186924. Registered on 14 June 2017.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1745-6215Test

الوصول الحر: https://doaj.org/article/0bf7c01c87d44f13a7fe648a95832859Test

المؤلفون: Rodrigo Schmidt, Clarissa Garcia Rodrigues, Kelen Heinrich Schmidt, Maria Claudia Costa Irigoyen

المصدر: ESC Heart Failure, Vol 7, Iss 1, Pp 3-14 (2020)

مصطلحات موضوعية: Baroreflex activation therapy, Heart failure, Rapid review, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Abstract To retrieve and assess the available data in the literature about the safety and efficacy of baroreflex activation therapy (BAT) in heart failure with reduced ejection fraction (HFrEF) patients, through a rapid systematic review of clinical studies. Rapid systematic review of literature. Searched electronic databases included PubMed, EMBASE, CENTRAL, Scopus, and Web of Science using Mesh and free terms for heart failure and BAT. No language restriction was used for the searches. We included full peer reviewed publications of clinical studies (randomized or not), including patients with HFrEF undergoing BAT, with or without control group, assessing safety and efficacy outcomes. One reviewer conducted the analysis of the selected abstracts and the full‐text articles, performed data extraction, and evaluated the methodological quality of the selected articles. The methodological quality was assessed according to the Cochrane Collaboration instruments. A descriptive summary of the results is provided. Of the 441 citations screened, 10 publications were included (three were only conference abstracts), reporting data from three studies. Only one study was a randomized clinical trial. Two studies reported a 6 month following, and the other study analysed outcomes up to 41 months. The procedure seems to be safe when performed by a well‐trained multi‐professional team. An 86% rate of system and procedure‐related complication‐free was reported, with no cranial nerve injuries. Improvements in New York Heart Association class of heart failure, quality of life, 6 min walk test, and hospitalization rates, as well as in muscle sympathetic nerve activity. No meta‐analysis was conducted because of the lack of homogeneity across studies; the results from each study are reported individually. BAT procedure seems to be safe if appropriate training is provided. Improvements in clinical outcomes were described in all included studies. However, several limitations do not allow us to make conclusive statements on the efficacy of BAT for HFrEF. New well‐designed trials are still needed.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2055-5822Test

الوصول الحر: https://doaj.org/article/cb73c60923b04927b902096d88febf6cTest

المؤلفون: Diego Lopes Mendes Barretti, Everton Crivoi do Carmo, Kaleizu Teodoro Rosa, Maria Claudia Costa Irigoyen, Edilamar Menezes de Oliveira

المصدر: Revista Brasileira de Educação Física e Esporte : RBEFE, Vol 25, Iss 4, Pp 593-605 (2011)

مصطلحات موضوعية: Obesidade, Cardiopatias, Treinamento físico aeróbio, Ratos Zucker, Obesity, Cardiac disease, Aerobic exercise training, Zucker rats, Sports, GV557-1198.995

الوصف: A obesidade é uma patologia diretamente relacionada com o desenvolvimento de doenças cardiovasculares. Por outro lado, o treinamento físico aeróbio atenua o desenvolvimento da obesidade e promove benefícios cardíacos em obesos. Dessa forma, nosso objetivo foi investigar se a obesidade altera a função cardíaca e se sua associação com o treinamento físico aeróbio promove melhora na função cardíaca em ratos Zucker obesos. Os ratos Zucker foram divididos da seguinte forma: grupo magro (GM), grupo obeso (GO), grupo magro treinado (GMTR) e grupo obeso treinado (GOTR). O protocolo de treinamento aeróbio de natação foi realizado por um período de 10 semanas com cinco sessões semanais de 60 minutos de duração. A frequência cardíaca de repouso, a pressão arterial sistólica, a hipertrofia e função cardíaca foram avaliadas no final do período de treinamento físico. Ambos os grupos treinados apresentaram uma queda de 12% da frequência cardíaca de repouso, quando comparado com seus respectivos controles. Ainda, nossos resultados demonstraram que o treinamento aeróbio reduziu o aumento da massa cardíaca em 13% e melhorou a função diastólica na obesidade em 43%. Em conclusão, nossos dados demonstraram que o treinamento físico aeróbio reverteu os prejuízos cardíacos causados pela obesidade.Obesity is profoundly involved in cardiovascular diseases. On the other hand, aerobic exercise training (EXT) attenuates obesity and promotes cardiac benefits in obese individuals. Therefore, the aim of this study was to investigate if obesity alters the cardiac function and whether its association with exercise training can improve cardiac function in an obese Zucker rat strain. The rats were divided in the following groups: Lean Zucker rats (LZR); lean Zucker rats plus exercise training (LZR+EXT); obese Zucker rat (OZR) and obese Zucker rat plus exercise training (OZR+EXT). EXT consisted of 10 weeks swimming sessions of 60 min, 5 days/week. At the end of the training protocol we evaluated heart rate (HR), systolic blood pressure (SBP), cardiac hypertrophy (CH) and function. The trained groups LZR+EXT and OZR+EXT showed a 12% lower resting HR when compared with theirs respective controls. In addition, our results showed that exercise training reduced the cardiac mass by 13% and improved the diastolic function by 43% in the obese trained group when compared with the obese untrained. In conclusion, aerobic exercise training reverts the cardiac injuries in obese Zucker rats.

وصف الملف: electronic resource

العلاقة: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-55092011000400005Test; https://doaj.org/toc/1807-5509Test; https://doaj.org/toc/1981-4690Test

الوصول الحر: https://doaj.org/article/e3dea36e8cc544729a4b643b4005519eTest

المؤلفون: Cortes, Maiquel Bueno, da Silva, Raphael Silveira Nunes, de Oliveira, Patrícia Caetano, da Silva, Diego Silveira, Irigoyen, Maria Claudia Costa, Waclawovsky, Gustavo, Schaun, Maximiliano Isoppo

المساهمون: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

المصدر: Scientific Reports ; volume 13, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: The objective of this systematic review was to examine the effects of exercise training on endothelial function in individuals with overweight and obesity. Our review study included only randomized controlled trials (RCTs) involving adults (≥ 18 years of age) with body mass index (BMI) ≥ 25.0 kg/m 2 . Our search was conducted in the electronic bases MEDLINE (PubMed), Cochrane, LILACS and EMBASE and in the gray literature. We performed random-effects analyses for effect estimates and used 95% prediction intervals (95% PI) for estimating the uncertainty of the study results. There were selected 10 RCTs involving 14 groups (n = 400). The quality assessment of studies using Cochrane risk-of-bias 2 (RoB 2) tool identified some concerns. Exercise training resulted in improved flow-mediated dilation (FMD) in individuals with overweight and obesity (p < 0.001) compared to the no-exercise control group. This effect of training modalities on FMD was seen for aerobic training (p < 0.001) but not for resistance training (p = 0.051). There was no difference in FMD in response to exercise training by BMI classification (overweight, obesity, overweight + obesity), p = 0.793. The present results are consistent with the notion that aerobic exercise training elicits favorable adaptations in endothelial function in individuals with overweight and obesity. Our findings should be interpreted with caution because of the small number of studies included in this review.

الإتاحة: https://doi.org/10.1038/s41598-023-38603-xTest
https://www.nature.com/articles/s41598-023-38603-x.pdfTest
https://www.nature.com/articles/s41598-023-38603-xTest

المؤلفون: Parletta, Aline Cristina, Cerri, Gabriela Cavazza, Gasparini, Claudia Ribeiro Borba, Panico, Karine, Vieira-Junior, Denival Nascimento, Zacarias-Rodrigues, Larissa Maria, Senger, Nathalia, de Almeida Silva, Amanda, Fevereiro, Marina, Diniz, Gabriela Placoná, Irigoyen, Maria Cláudia Costa, Barreto-Chaves, Maria Luiza Morais

المصدر: Pflugers Arch ; ISSN:1432-2013 ; Volume:476 ; Issue:7

مصطلحات موضوعية: Cardiac hypertrophy, Caspase-1, IL-1β, NLRP3 inflammasome, Thyroid hormone

الوصف: Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1β production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8-12 weeks, by triiodothyronine (7 μg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice.

العلاقة: https://doi.org/10.1007/s00424-024-02965-6Test; https://pubmed.ncbi.nlm.nih.gov/38679646Test

الإتاحة: https://doi.org/10.1007/s00424-024-02965-6Test
https://pubmed.ncbi.nlm.nih.gov/38679646Test