GABRIELA VENTURINI DA SILVA

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  • article 2 Citação(ões) na Scopus
    Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy
    (2022) OLIVEIRA, Theo G. M.; VENTURINI, Gabriela; ALVIM, Juliana M.; FEIJO, Larissa L.; DINARDO, Carla L.; SABINO, Ester C.; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.; KRIEGER, Jose E.; PEREIRA, Alexandre C.
    Chagas disease is a tropical zoonosis caused by Trypanosoma cruzi. After infection, the host present an acute phase, usually asymptomatic, in which an extensive parasite proliferation and intense innate immune activity occurs, followed by a chronic phase, characterized by low parasitemia and development of specific immunity. Most individuals in the chronic phase remain without symptoms or organ damage, a state called indeterminate IND form. However, 20 to 40% of individuals develop cardiac or gastrointestinal complications at any time in life. Cardiomyocytes have an important role in the development of Chronic Chagas Cardiomyopathy (CCC) due to transcriptional and metabolic alterations that are crucial for the parasite survival and replication. However, it still not clear why some infected individuals progress to a cardiomyopathy phase, while others remain asymptomatic. In this work, we used hiPSCs-derived cardiomyocytes (hiPSC-CM) to investigate patterns of infection, proliferation and transcriptional response in IND and CCC patients. Our data show that T. cruzi infection and proliferation efficiency do not differ significantly in PBMCs and hiPSC-CM from both groups. However, RNA-seq analysis in hiPSC-CM infected for 24 hours showed a significantly different transcriptional response to the parasite in cells from IND or CCC patients. Cardiomyocytes from IND showed significant differences in the expression of genes related to antigen processing and presentation, as well as, immune co-stimulatory molecules. Furthermore, the downregulation of collagen production genes and extracellular matrix components was significantly different in these cells. Cardiomyocytes from CCC, in turn, showed increased expression of mTORC1 pathway and unfolded protein response genes, both associated to increased intracellular ROS production. These data point to a differential pattern of response, determined by baseline genetic differences between groups, which may have an impact on the development of a chronic outcome with or without the presentation of cardiac symptoms.
  • article 7 Citação(ões) na Scopus
    Obstructive sleep apnoea is associated with myocardial injury in patients with refractory angina
    (2016) GEOVANINI, Glaucylara R.; PEREIRA, Alexandre C.; GOWDAK, Luis H. W.; DOURADO, Luciana Oliveira Cascaes; POPPI, Nilson T.; VENTURINI, Gabriela; DRAGER, Luciano F.; LORENZI-FILHO, Geraldo
    Objective To investigate the association between obstructive sleep apnoea (OSA) severity with markers of overnight myocardial injury in patients with refractory angina. Methods Patients with refractory angina were characterised clinically and they underwent ischaemia imaging stress tests by single-photon emission computed tomography (SPECT) and/or cardiac MRI. The patients were admitted to the hospital, remained under resting conditions for blood determination of high-sensitivity cardiac troponin T (hs-cTnT) at 14:00, 22:00 and after overnight polysomnography at 7:00. Results We studied 80 consecutive patients (age: 62 +/- 10 years; male: 66%; body mass index (BMI): 29.5 +/- 4 kg/m(2)) with well-established diagnosis of refractory angina. The mean apnoea-hypopnoea index (AHI) was 37 +/- 29 events/h and OSA (AHI >15 events/h) was present in 75% of the population. Morning detectable hs-cTnT and above 99th percentile was present in 88% and 36% of the population, respectively. Patients in the first to third quartiles of OSA severity did not have circadian variation of hs-cTnT. In contrast, patients in the fourth quartile (AHI >= 51 events/h) had a circadian variation of hs-cTnT with a morning peak of hs-cTnT that was two times higher than that in the remaining population (p = 0.02). The highest quartile of OSA severity remained associated with the highest quartile of hs-cTnT (p = 0.028) in multivariate analysis. Conclusion Very severe OSA is common and independently associated with overnight myocardial injury in patients with refractory angina.
  • article 42 Citação(ões) na Scopus
    Metabolomic and lipidomic profile in men with obstructive sleep apnoea: implications for diagnosis and biomarkers of cardiovascular risk
    (2018) LEBKUCHEN, Adriana; CARVALHO, Valdemir M.; VENTURINI, Gabriela; SALGUEIRO, Jessica S.; FREITAS, Lunara S.; DELLAVANCE, Alessandra; MARTINS, Franco C.; LORENZI-FILHO, Geraldo; CARDOZO, Karina H. M.; DRAGER, Luciano F.
    The use of metabolomic and lipidomic strategies for selecting potential biomarkers for obstructive sleep apnoea (OSA) has been little explored. We examined adult male patients with OSA (defined by an apnoea-hypopnoea index >= 15 events/hour), as well as age-, gender-, and fat-composition-matched volunteers without OSA. All subjects were subjected to clinical evaluation, sleep questionnaires for detecting the risk of OSA (Berlin and NoSAS score), metabolomic analysis by gas chromatography coupled to mass spectrometry and lipidomic analysis with liquid chromatography followed by detection by MALDI-MS. This study included 37 patients with OSA and 16 controls. From the 6 metabolites and 22 lipids initially selected, those with the best association with OSA were glutamic acid, deoxy sugar and arachidonic acid (metabolites), and glycerophosphoethanolamines, sphingomyelin and lysophosphocholines (lipids). For the questionnaires, the NoSAS score performed best with screening for OSA (area under the curve [AUC] = 0.724, p = 0.003). The combination of the NoSAS score with metabolites or lipids resulted in an AUC for detecting OSA of 0.911 and 0.951, respectively. In conclusion, metabolomic and lipidomic strategies suggested potential early biomarkers in OSA that could also be helpful in screening for this sleep disorder beyond traditional questionnaires.
  • article 16 Citação(ões) na Scopus
    Identification of bioactive peptides from a Brazilian kefir sample, and their anti-Alzheimer potential in Drosophila melanogaster
    (2022) MALTA, S. M.; BATISTA, L. L.; SILVA, H. C. G.; FRANCO, R. R.; SILVA, M. H.; RODRIGUES, T. S.; CORREIA, L. I. V.; MARTINS, M. M.; VENTURINI, G.; ESPINDOLA, F. S.; SILVA, M. V. da; UEIRA-VIEIRA, C.
    Alzheimer’s disease (AD) is the most common form of dementia in the elderly, affecting cognitive, intellectual, and motor functions. Different hypotheses explain AD’s mechanism, such as the amyloidogenic hypothesis. Moreover, this disease is multifactorial, and several studies have shown that gut dysbiosis and oxidative stress influence its pathogenesis. Knowing that kefir is a probiotic used in therapies to restore dysbiosis and that the bioactive peptides present in it have antioxidant properties, we explored its biotechnological potential as a source of molecules capable of modulating the amyloidogenic pathway and reducing oxidative stress, contributing to the treatment of AD. For that, we used Drosophila melanogaster model for AD (AD-like flies). Identification of bioactive peptides in the kefir sample was made by proteomic and peptidomic analyses, followed by in vitro evaluation of antioxidant and acetylcholinesterase inhibition potential. Flies were treated and their motor performance, brain morphology, and oxidative stress evaluated. Finally, we performed molecular docking between the peptides found and the main pathology-related proteins in the flies. The results showed that the fraction with the higher peptide concentration was positive for the parameters evaluated. In conclusion, these results revealed these kefir peptide-rich fractions have therapeutic potential for AD. © 2022, The Author(s).
  • article 2 Citação(ões) na Scopus
    Loss of mTORC2 Activity in Neutrophils Impairs Fusion of Granules and Affects Cellular Metabolism Favoring Increased Bacterial Burden in Sepsis
    (2021) BREDA, Cristiane Naffah de Souza; BREDA, Leandro Carvalho Dantas; CARVALHO, Larissa Anastacio da Costa; AMANO, Mariane Tami; TERRA, Fernanda Fernandes; SILVA, Reinaldo Correia; FRAGAS, Matheus Garcia; FORNI, Maria Fernanda; FONSECA, Monique Thais Costa; VENTURINI, Gabriela; FEITOSA, Amanda Campelo Melo; GHIROTTO, Bruno; CRUZ, Mario Costa; CUNHA, Flavia Franco; IGNACIO, Aline; LATANCIA, Marcela; CASTOLDI, Angela; ANDRADE-OLIVEIRA, Vinicius; SILVA, Eloisa Martins da; HIYANE, Meire Ioshie; PEREIRA, Alexandre da Costa; FESTUCCIA, William; MEOTTI, Flavia Carla; CAMARA, Niels Olsen Saraiva
    Sepsis is a complex infectious syndrome in which neutrophil participation is crucial for patient survival. Neutrophils quickly sense and eliminate the pathogen by using different effector mechanisms controlled by metabolic processes. The mammalian target of rapamycin (mTOR) pathway is an important route for metabolic regulation, and its role in neutrophil metabolism has not been fully understood yet, especially the importance of mTOR complex 2 (mTORC2) in the neutrophil effector functions. In this study, we observed that the loss of Rictor (mTORC2 scaffold protein) in primary mouse-derived neutrophils affects their chemotaxis by fMLF and their microbial killing capacity, but not the phagocytic capacity. We found that the microbicidal capacity was impaired in Rictor-deleted neutrophils because of an improper fusion of granules, reducing the hypochlorous acid production. The loss of Rictor also led to metabolic alterations in isolated neutrophils, increasing aerobic glycolysis. Finally, myeloid-Rictor-deleted mice (LysMRic Delta/Delta) also showed an impairment of the microbicidal capacity, increasing the bacterial burden in the Escherichia coli sepsis model. Overall, our results highlight the importance of proper mTORC2 activation for neutrophil effector functions and metabolism during sepsis.
  • article 4 Citação(ões) na Scopus
    Potential Biomarkers of the Turnover, Mineralization, and Volume Classification: Results Using NMR Metabolomics in Hemodialysis Patients
    (2020) BAPTISTA, A.L.; PADILHA, K.; MALAGRINO, P.A.; VENTURINI, G.; ZERI, A.C.M.; REIS, L.M. dos; MARTINS, J.S.; JORGETTI, V.; PEREIRA, A.C.; TITAN, S.M.; MOYSES, R.M.A.
    Bone biopsy is still the gold standard to assess bone turnover (T), mineralization (M), and volume (V) in CKD patients, and serum biomarkers are not able to replace histomorphometry. Recently, metabolomics has emerged as a new technique that could allow for the identification of new biomarkers useful for disease diagnosis or for the understanding of pathophysiologic mechanisms, but it has never been assessed in the chronic kidney disease–mineral and bone disorder (CKD–MBD) scenario. In this study, we investigated the association between serum metabolites and the bone TMV classification in patients with end-stage renal disease by using serum NMR spectroscopy and bone biopsy of 49 hemodialysis patients from a single center in Brazil. High T was identified in 21 patients and was associated with higher levels of dimethylsulfone, glycine, citrate, and N-acetylornithine. The receiver-operating characteristic curve for the combination of PTH and these metabolites provided an area under the receiver-operating characteristic curve (AUC) of 0.86 (0.76 to 0.97). Abnormal M was identified in 30 patients and was associated with lower ethanol. The AUC for age, diabetes mellitus, and ethanol was 0.83 (0.71 to 0.96). Low V was identified in 17 patients and was associated with lower carnitine. The association of age, phosphate, and carnitine provided an AUC of 0.83 (0.70 to 0.96). Although differences among the curves by adding selected metabolites to traditional models were not statistically significant, the accuracy of the diagnosis according to the TMV classification seemed to be improved. This is the first study to evaluate the TMV classification system in relation to the serum metabolome assessed by NMR spectroscopy, showing that selected metabolites may help in the evaluation of bone phenotypes in CKD–MBD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
  • article 58 Citação(ões) na Scopus
    Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats
    (2013) GIANNOCCO, Gisele; OLIVEIRA, Kelen C.; CRAJOINAS, Renato O.; VENTURINI, Gabriela; SALLES, Thiago A.; FONSECA-ALANIZ, Miriam H.; MACIEL, Rui M. B.; GIRARDI, Adriana C. C.
    The purpose of the current study was to test the hypothesis that the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which exerts anti-hyperglycemic and anti-hypertensive effects, upregulates GLUT4 translocation, protein levels, and/or mRNA expression in heart and skeletal muscle of spontaneously hypertensive rats (SHRs). Ten days of treatment with sitagliptin (40 mg/kg twice daily) decreased plasma DPPIV activity in both young (Y, 5-week-old) and adult (A, 20-week-old) SHRs to similar extents ( similar to 85%). However, DPPIV inhibition only lowered blood pressure in Y-SHRs (119 +/- 3 vs. 136 +/- 4 mmHg). GLUT4 translocation, total protein levels and mRNA expression were decreased in the heart, soleus and gastrocnemius muscle of SHRs compared to age-matched Wistar Kyoto (WKY) normotensive rats. These differences were much more pronounced between A-SHRs and A-WKY rats than between Y-SHRs and Y-WKY rats. In Y-SHRs, sitagliptin normalized GLUT4 expression in the heart, soleus and gastrocnemius. In A-SHRs, sitagliptin increased GLUT4 expression to levels that were even higher than those of A-WKY rats. Sitagliptin enhanced the circulating levels of the DPPIV substrate glucagon-like peptide-1 (GLP-1) in SHRs. In addition, stimulation of the GLP-1 receptor in cardiomyocytes isolated from SHRs increased the protein level of GLUT4 by 154 +/- 13%. Collectively, these results indicate that DPPIV inhibition upregulates GLUT4 in heart and skeletal muscle of SHRs. The underlying mechanism of sitagliptin-induced upregulation of GLUT4 in SHRs may be, at least partially, attributed to GLP-1.
  • article 27 Citação(ões) na Scopus
    Human cardiomyocytes for drug discovery
    (2018) BIAGI, Diogo Goncalves; GONCALVES, Jessica; CRUVINEL, Estela; DAMIANI, Renata; VALGODE, Flavia; MEDEIROS, Fabiana; MOREIRA, Camila G.; SANTOS, Evelyn; MARCON, Rodrigo; JOAO, Calixto; VENTURINI, Gabriela; PEREIRA, Alexandre; FERREIRA, Eden; MORTARA, Renato A.; VALADARES, Marcos C.
    Introduction: Cardiac drug discovery are based in old methods that use animals, animal cells or modified cells that do not faithfully represent human cardiac phenotypes. Objective: Here, we aimed to show that cardiomyocytes derived from human iPS cells represent a new tool for cardiac drug discovery and could contribute do reduce animal use in research. Method: Generation of human iPS cells derived cardiomyocytes and its use for cardiotoxicity evaluation and infection with T. cruzi for drug discovery. Results: Definition of robust protocol for human iPS cells reprogramming, maintenance and cardiac differentiation. Derivation of high purity cardiomyocytes from hiPSCs that presented toxicity to different doses of doxorubicin and were amenable to infection of T. cruzi. Conclusions: Human cardiomyocytes derived from human iPS cells can be a great tool for drug discovery and can replace several assays done in animals helping to reduce animal use in research.
  • article 1 Citação(ões) na Scopus
    Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature
    (2022) SABINO, Ester Cerdeira; FRANCO, Lucas Augusto Moyses; VENTURINI, Gabriela; RODRIGUES, Mariliza Velho; MARQUES, Emanuelle; SILVA, Lea Campos de Oliveira-da; MARTINS, Larissa Natany Almeida; FERREIRA, Ariela Mota; ALMEIDA, Paulo Emilio Clementino; SILVA, Felipe Dias Da; LEITE, Samara Fernandes; NUNES, Maria do Carmo Pereira; HAIKAL, Desiree Sant'Ana; OLIVEIRA, Claudia Di Lorenzo; CARDOSO, Clareci Silva; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.; CASAS, Juan P.; RIBEIRO, Antonio Luiz Pinho; KRIEGER, Jose E.; PEREIRA, Alexandre C.
    Background Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected. Methodology/Principal findings We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10(-9)) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302-5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis. Conclusions/Significance We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted.
  • article 1 Citação(ões) na Scopus
    High blood pressure induced by vitamin D deficiency is associated with renal overexpression and hyperphosphorylation of Na+-K+-2Cl-cotransporter type 2
    (2021) LUCHI, Weverton M.; CRAJOINAS, Renato O.; MARTINS, Flavia L.; CASTRO, Paulo de C.; VENTURINI, Gabriela; SEGURO, Antonio C.; GIRARDI, Adriana C. C.
    Objectives: Clinical and epidemiological studies have suggested a correlation between vitamin D deficiency (VDD) and high blood pressure (BP). This study aimed to test the hypothesis that high BP induced by VDD is associated with altered expression and covalent modification of apical sodium transporters along the nephron. The contributions of the intrarenal renin-angiotensin system (RAS) and oxidative stress were also investigated. Methods: Male Wistar rats were fed a vitamin D-free (n = 26) or standard diet (n = 25) for 30 days. BP was recorded using noninvasive and invasive procedures. The expression levels of total and phosphorylated apical sodium transporters in rat renal cortex and medulla were evaluated by immunoblotting. Intrarenal RAS components were assessed by immunoblotting and ELISA. Renal oxidative stress was analyzed by measuring the concentrations of thiobarbituric acid reactive substances and reduced glutathione. Results: Higher BP levels in VDD rats than controls were accompanied by overexpression and hyperphosphorylation of renal cortical and medullary Na+-K+-2Cl- cotransporter type 2, enhanced levels of phosphorylated Na+/H+ exchanger type 3, and reduced expression levels of total and phosphorylated Na+/Cl- cotransporter. Changes in intrarenal RAS induced by VDD vs. controls included the marked elevation of medullary renin expression, higher expression of cortical angiotensinogen, higher urinary angiotensinogen excretion, and higher cortical and medullary angiotensin II content. VDD rats displayed higher thiobarbituric acid reactive substances/glutathione ratios in the renal cortex and medulla than controls. Conclusion: These results suggest that the molecular mechanisms underlying the effects of VDD on BP may include the upregulation of Na+-K+-2Cl- cotransporter type 2 and activation of intrarenal RAS and oxidative stress.