Near-Infrared Spectroscopy with Supervised Machine Learning as a Screening Tool for Neutropenia.

The use of non-invasive tools in conjunction with artificial intelligence (AI) to detect diseases has the potential to revolutionize healthcare. Near-infrared spectroscopy (NIR) is a technology that can be used to analyze biological samples in a non-invasive manner. This study evaluated the use of NIR spectroscopy in the fingertip to detect neutropenia in solid-tumor oncologic patients. A total of 75 patients were enrolled in the study. Fingertip NIR spectra and complete blood counts were collected from each patient. The NIR spectra were pre-processed using Savitzky-Golay smoothing and outlier detection. The pre-processed data were split into training/validation and test sets using the Kennard-Stone method. A toolbox of supervised machine learning classification algorithms was applied to the training/validation set using a stratified 5-fold cross-validation regimen. The algorithms included linear discriminant analysis (LDA), logistic regression (LR), random forest (RF), multilayer perceptron (MLP), and support vector machines (SVMs). The SVM model performed best in the validation step, with 85% sensitivity, 89% negative predictive value (NPV), and 64% accuracy. The SVM model showed 67% sensitivity, 82% NPV, and 57% accuracy on the test set. These results suggest that NIR spectroscopy in the fingertip, combined with machine learning methods, can be used to detect neutropenia in solid-tumor oncology patients in a non-invasive and timely manner. This approach could help reduce exposure to invasive tests and prevent neutropenic patients from inadvertently undergoing chemotherapy.

Body fat estimated by equations based on anthropometric parameters correlates with bioelectrical impedance in patients undergoing bariatric surgery / Gordura corporal estimada por equações baseadas em parâmetros antropométricos correlaciona-se com a bioimpedância elétrica em pacientes submetidos à cirurgia bariátrica

Introduction: predictive equations to estimate body fat based on simple anthropometric parameters are easy to use in the clinical practice.Objective: to evaluate the relationship between predictive equations based on anthropometric parameters and bioelectrical impedance to estimate body fat in individuals undergoing bariatric surgery.Methods: a prospective and longitudinal study carried out with individuals undergoing bariatric surgery. Body weight, body mass index, waist circumference and body fat percentage estimated by anthropometric parameters and by impedance were evaluated at three moments, one month before, two and six months after surgery. Data were analyzed by one-way ANOVA for repeated measures with Holm-Sidak ́s post hoc or Friedman test with Tukey ́s post hoc, and Pearson or Spearman correlations, according to data distribution. Significance level adopted 5%.Results: twenty-five subjects composed the final sample. All anthropometric parameters reduced significantly over time (p<0.001). Except for Lean et al equation before surgery, the body fat percentage estimated by other formulas showed a strong correlation with impedance in all moments, with the highest correlation strength observed in Gómez-Ambrosi et al. equation.Conclusion: in the present study, the equations used showed a good correlation with bioelectrical impedance, and the Gómez-Ambrosi et al. equation as a better option to the use of bioimpedance to assess changes in body fat percentage of patients undergoing bariatric surgery for the treatment of severe obesity.

Introdução: Objetivos: analisar o consumo alimentar e os fatores associados ao estado nutricional de crianças menores de dois anos de vida.Método: Estudo de corte transversal realizado com uma amostra de 344 lactentes menores de dois anos de idade e suas respectivas mães, acompanhadas em Unidades de Saúde da Família. As variáveis sociodemográficas, antropométrica das mães e dos lactentes e o consumo alimentar dessas crianças foram avaliadas por meio de questionário estruturado. A força de associação entre as variáveis dependente e as independentes foi avaliada pelo odds ratio, tanto na análise univariada quanto na múltipla, com nível de significância de 5%.Resultados: A prevalência do estado nutricional inadequado foi de 38,08%. Observou que 29,09% das crianças menores de seis meses de idade não chegaram a receber leite materno de forma exclusiva ou o tempo de oferta foi inferior a 30 dias. Notou-se o consumo de alimentos ultraprocessados, principalmente, do suco industrializado no último mês [OR:1,96, IC 95%: 1,05-3,65], baixa ingestão de frutas e o hábito de comer assistindo televisão nos lactentes maiores de seis meses. Após ajuste para variáveis de confusão, permaneceram associadas ao estado nutricional: anemia gestacional [OR: 3,58 IC: 1,46-8,77] e trabalho materno [OR, 0,38, IC 95%: 0,18-0,80].Conclusão: A presença do estado nutricional inadequado, caracterizado pelo baixo ou excesso de peso, associou-se ao fato de a mãe trabalhar e à anemia gestacional. Ademais, constatou-se a participação precoce de alimentos ultraprocessados na alimentação das crianças menores de 24 meses de idade, substituindo alimentos considerados naturais e saudáveis, evidenciando assim práticas alimentares inadequadas frente às recomendações para a faixa etária.

Effect of Caffeine Ingestion on Indirect Markers of Exercise-Induced Muscle Damage: A Systematic Review of Human Trials.

The effect of caffeine on mitigating exercise-induced muscle damage (EIMD) is still poorly understood, but it was hypothesized that caffeine could contribute to decreasing delayed onset muscle soreness, attenuating temporary loss of strength, and reducing circulating levels of blood markers of muscle damage. However, evidence is not conclusive and beneficial effects of caffeine ingestion on EIMD are not always observed. Factors, such as the type of exercise that induces muscle damage, supplementation protocol, and type of marker analyzed contribute to the differences between the studies. To expand knowledge on the role of caffeine supplementation in EIMD, this systematic review aimed to investigate the effect of caffeine supplementation on different markers of muscle damage. Fourteen studies were included, evaluating the effect of caffeine on indirect muscle damage markers, including blood markers (nine studies), pain perception (six studies), and MVC maximal voluntary contraction force (four studies). It was observed in four studies that repeated administration of caffeine between 24 and 72 h after muscle damage can attenuate the perception of pain in magnitudes ranging from 3.9% to 26%. The use of a single dose of caffeine pre-exercise (five studies) or post-exercise (one study) did not alter the circulating blood levels of creatine kinase (CK). Caffeine supplementation appears to attenuate pain perception, but this does not appear to be related to an attenuation of EIMD, per se. Furthermore, the effect of caffeine supplementation after muscle damage on strength recovery remains inconclusive due to the low number of studies found (four studies) and controversial results for both dynamic and isometric strength tests.

Rapid diagnosis of COVID-19 using FT-IR ATR spectroscopy and machine learning.

Early diagnosis of COVID-19 in suspected patients is essential for contagion control and damage reduction strategies. We investigated the applicability of attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy associated with machine learning in oropharyngeal swab suspension fluid to predict COVID-19 positive samples. The study included samples of 243 patients from two Brazilian States. Samples were transported by using different viral transport mediums (liquid 1 or 2). Clinical COVID-19 diagnosis was performed by the RT-PCR. We built a classification model based on partial least squares (PLS) associated with cosine k-nearest neighbours (KNN). Our analysis led to 84% and 87% sensitivity, 66% and 64% specificity, and 76.9% and 78.4% accuracy for samples of liquids 1 and 2, respectively. Based on this proof-of-concept study, we believe this method could offer a simple, label-free, cost-effective solution for high-throughput screening of suspect patients for COVID-19 in health care centres and emergency departments.

High-volume endurance exercise training stimulates hematopoiesis by increasing ACE NH2-terminal activity.

One of the health benefits of endurance exercise training (ET) is the stimulation of hematopoiesis. However, the mechanisms underlying ET-induced hematopoietic adaptations are understudied. N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) inhibits proliferation of early hematopoietic progenitor cells. The angiotensin I-converting enzyme (ACE) NH2-terminal promotes hematopoiesis by inhibiting the anti-hematopoietic effect of Ac-SDKP. Here we demonstrate for the first time the role of ACE NH2-terminal in ET-induced hematopoietic adaptations. Wistar rats were subjected to 10 weeks of moderate-(T1) and high-(T2) volume swimming-training. Although both protocols induced classical ET-associated adaptations, only T2 increased plasma ACE NH2-domain activity (by 40%, P=0.0003) and reduced Ac-SDKP levels (by 50%, P<0.0001). T2 increased the number of hematopoietic stem cells (HSCs; ∼200%, P=0.0008), early erythroid progenitor colonies (∼300%, P<0.0001) and reticulocytes (∼500%, P=0.0007), and reduced erythrocyte lifespan (∼50%, P=0.022). Following, Wistar rats were subjected to T2 or T2 combined with ACE NH2-terminal inhibition (captopril (Cap) treatment: 10 mg.kg-1.day-1). T2 combined with ACE NH2-terminal inhibition prevented Ac-SDKP decrease and attenuated ET-induced hematopoietic adaptations. Altogether, our findings show that ET-induced hematopoiesis was at least partially associated with increased ACE NH2-terminal activity and reduction in the hematopoietic inhibitor Ac-SDKP.

Properties and Application of Cell-Free DNA as a Clinical Biomarker.

Biomarkers are valuable tools in clinical practice. In 2001, the National Institutes of Health (NIH) standardized the definition of a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. A biomarker has clinical relevance when it presents precision, standardization and reproducibility, suitability to the patient, straightforward interpretation by clinicians, and high sensitivity and/or specificity by the parameter it proposes to identify. Thus, serum biomarkers should have advantages related to the simplicity of the procedures and to the fact that venous blood collection is commonplace in clinical practice. We described the potentiality of cfDNA as a general clinical biomarker and focused on endothelial dysfunction. Circulating cell-free DNA (cfDNA) refers to extracellular DNA present in body fluid that may be derived from both normal and diseased cells. An increasing number of studies demonstrate the potential use of cfDNA as a noninvasive biomarker to determine physiologic and pathologic conditions. However, although still scarce, increasing evidence has been reported regarding using cfDNA in cardiovascular diseases. Here, we have reviewed the history of cfDNA, its source, molecular features, and release mechanism. We also show recent studies that have investigated cfDNA as a possible marker of endothelial damage in clinical settings. In the cardiovascular system, the studies are quite new, and although interesting, stronger evidence is still needed. However, some drawbacks in cfDNA methodologies should be overcome before its recommendation as a biomarker in the clinical setting.

COVID-19 hospitalization and death and relationship with social determinants of health and morbidities in Espírito Santo State, Brazil: a cross-sectional study. / Hospitalização e morte por COVID-19 e sua relação com determinantes sociais da saúde e morbidades no Espírito Santo: um estudo transversal.

OBJECTIVE: To analyze the association between social determinants and morbidities for the outcomes of hospitalization, intensive care unit admission and death by COVID-19 in Espírito Santo State, Brazil. METHODS: Cross-sectional study with secondary data from confirmed cases of COVID-19, reported in the Notifiable Diseases Information System. Poisson regression was used to estimate the prevalence ratios. RESULTS: 104,384 cases reported between February 28th and September 1st, 2020 were studied. The outcomes under study were more frequent among male, elderly, yellow, followed by black, uneducated and with multimorbidity. There was a higher risk of death among people over the age of 60 (PR=56.31 - 95%CI 34.24;92.61), multimorbidities (PR=3.63 - 95%CI 3.16;4.17), kidney disease (PR=3.42 - 95%CI 2.81;4.15) and neoplasms (PR=3.15 - 95%CI 2.41;4.13). CONCLUSION: The effect of social determinants and morbidities on hospitalization and deaths by COVID-19 is evident.

Ethereal Extract of Pepper: Preventing Atherosclerosis and Left Ventricle Remodeling in LDL Receptor Knockout Mice.

Cardiovascular diseases are the leading cause of mortality and morbidity worldwide. In this study we compared the effects of oral treatment with red pepper ethereal extracts or simvastatin on dyslipidemia, left ventricle remodeling, and atherosclerotic lesions of low-density lipoprotein (LDL) receptor knockout mice (LDLr-/-) fed a hyperlipidic diet. Forty 3-month-old male mice were distributed into four groups: control (C; animals fed a standard diet), HL (ani-mals fed a hyperlipidic diet), and HL+P or HL+S (animals fed a hyperlipidic diet plus red pepper ethereal extracts or simvastatin, respectively). After 60 days, treatment with both red pepper ethereal extracts and simvastatin prevented dyslipidemia, atherosclerotic lesion progression, and left ventricle hypertrophy. Our results suggest a cardioprotective effect of red pepper ethereal extracts in LDLr-/- mice, which is comparable to the well-known effects of simvastatin.

Diagnosis of Systemic Diseases Using Infrared Spectroscopy: Detection of Iron Overload in Plasma-Preliminary Study.

Despite the important role of iron in cellular homeostasis, iron overload (IO) is associated with systemic and tissue deposits which damage several organs. In order to reduce the impact caused by IO, invasive diagnosis exams (e.g., biopsies) and minimally invasive methods were developed including computed tomography and magnetic resonance imaging. However, current diagnostic methods are still time-consuming and expensive. A cost-effective solution is using Fourier-transform infrared spectroscopy (FTIR) for real-time and molecular-sensitive biofluid analysis during conventional laboratory exams. In this study, we performed the first evaluation of the accuracy of FTIR for IO diagnosis. The study was performed by collecting FTIR spectra of plasma samples of five rats intravenously injected with iron-dextran and five control rats. We developed a classification model based on principal component analysis and supervised methods including J48, random forest, multilayer perceptron, and radial basis function network. We achieved 100% accuracy for the classification of the IO status and provided a list of possible biomolecules related to the vibrational modes detected. In this preliminary study, we give a first step towards real-time diagnosis for acute IO or intoxication. Furthermore, we have expanded the literature knowledge regarding the pathophysiological changes induced by iron overload.

Hospitalização e morte por COVID-19 e sua relação com determinantes sociais da saúde e morbidades no Espírito Santo: um estudo transversal / Hospitalización y muerte por COVID-19 y su relación con los determinantes sociales de la salud y las morbilidades en Espírito Santo, Brasil: un estudio transversal / COVID-19 hospitalization and death and relationship with social determinants of health and morbidities in Espírito Santo State, Brazil: a cross-sectional study

Objetivo: Analisar a associação entre determinantes sociais e morbidades para os desfechos de internação, internação em unidade de terapia intensiva e óbito por COVID-19 no Espírito Santo, Brasil. Métodos: Estudo transversal, com dados secundários de casos confirmados de COVID-19 notificados no Sistema de Informação de Agravos de Notificação. Utilizou-se regressão de Poisson para estimar as razões de prevalências. Resultados: Foram estudados 104.384 casos, notificados entre 28 de fevereiro e 1º de setembro de 2020. Os desfechos em estudo foram mais frequentes entre indivíduos do sexo masculino, idosos, de raça/cor da pele amarela ou preta, sem escolaridade, com multimorbidade. Todas as morbidades associaram-se a maior risco de desfechos desfavoráveis. Observou-se maior risco de óbito entre pessoas com idade superior a 60 anos (RP=56,31 - IC95% 34,24;92,61), multimorbidades (RP=3,63 - IC95% 3,16;4,17), doença renal (RP=3,42 - IC95% 2,81;4,15) e neoplasias (RP=3,15 - IC95% 2,41;4,13). Conclusão: Evidencia-se o efeito dos determinantes sociais e morbidades em internação e óbitos por COVID-19.

Objetivo: Analizar la asociación entre determinantes sociales y morbilidad para los resultados de hospitalización, ingreso en unidad de cuidados intensivos y muerte por COVID-19 en el Estado de Espírito Santo, Brasil. Métodos: Estudio transversal con datos secundarios de casos confirmados de COVID-19, reportados en el Sistema de Información de Enfermedades Notificables. Se utilizó la regresión de Poisson para estimar las razones de prevalencia. Resultados: Se estudiaron 104.384 casos notificados entre el 28 de Febrero y el 1 de Septiembre de 2020. Los desenlaces en estudio fueron más frecuentes entre hombres, ancianos, amarillos, seguidos de negros, no educados y con multimorbilidad. Hubo un mayor riesgo de muerte entre las personas mayores de 60 años (RP=56,31 - IC95% 34,24;92,61), multimorbilidades (RP=3,63 - IC95% 3,16;4,17), enfermedad renal (RP=3,42 - IC95% 2,81;4,15) y neoplasias (RP=3,15 - IC95% 2,41;4,13). Conclusión: El efecto de los determinantes sociales y las morbilidades sobre la hospitalización y las muertes por COVID-19 es evidente.

Objective: To analyze the association between social determinants and morbidities for the outcomes of hospitalization, intensive care unit admission and death by COVID-19 in Espírito Santo State, Brazil. Methods: Cross-sectional study with secondary data from confirmed cases of COVID-19, reported in the Notifiable Diseases Information System. Poisson regression was used to estimate the prevalence ratios. Results: 104,384 cases reported between February 28th and September 1st, 2020 were studied. The outcomes under study were more frequent among male, elderly, yellow, followed by black, uneducated and with multimorbidity. There was a higher risk of death among people over the age of 60 (PR=56.31 - 95%CI 34.24;92.61), multimorbidities (PR=3.63 - 95%CI 3.16;4.17), kidney disease (PR=3.42 - 95%CI 2.81;4.15) and neoplasms (PR=3.15 - 95%CI 2.41;4.13). Conclusion: The effect of social determinants and morbidities on hospitalization and deaths by COVID-19 is evident.

Physiological and Biochemical Vascular Reactivity Parameters of Angiotensin II and the Action of Biased Agonist TRV023.

Vascular reactivity experiments using isolated aortic rings have been widely used as a model for physiological and pharmacological studies since the early sixties. Here, we suggest several parameters that the researcher should pay attention to when investigating angiotensin II in their experimental models. Angiotensin II is one of the active peptides of the renin-angiotensin system and exerts its effect through the AT1 and AT2 receptors. Some studies seek to understand the effects of angiotensin II receptors at the vascular level by using vascular reactivity experiments. However, because of the large number of variations, there are only a handful of reactivity studies that seek to use this method. Thus, the objective of this study was to standardize experimental methods with angiotensin II, through vascular reactivity protocols. For this, variables such as basal tension, concentration interval, single concentration, curve concentration response, and multiple experiments using the same aortic ring were developed using the technique of vascular reactivity in an organ bath. This is the first study that has standardized the vascular reactivity protocol. In addition, we demonstrated the effects of TRV023-biased ligand of the AT1R at vascular sites.

Early life stress and the programming of eating behavior and anxiety: Sex-specific relationships with serotonergic activity and hypothalamic neuropeptides.

Early life experiences have strong influences on brain programming and can affect eating behavior control and body weight later in life. However, there is no consensus about the relationship between neonatal stress and feeding behavior. We evaluated whether maternal deprivation (MD) and maternal separation (MS) alter body weight and appetite using standard rat chow consumption and palatable food. Also, we evaluated anxiety and the expression of the leptin receptor, neuropeptides POMC, CART, NPY in the hypothalamus, as well as the serotoninergic system in the amygdala and hypothalamus as possible modulators of these behaviors. We found a decrease in standard rat chow consumption in MD. However, both neonatal stress protocols increased the consumption of palatable food and led to anxiogenic behavior in male animals. MD led to decreased hypothalamic POMC levels in adult males. Serotonin in the hypothalamus was decreased by both stress models in males and females. In the amygdala, MS decreased serotonin levels while MD increased its metabolite levels. We observed that males are more vulnerable and females are more resilient to the effects of neonatal stress on anxiety-like behavior, as well as on food consumption and on the central changes observed. These data together add support to the concept that the early environment contributes to the development of eating disorders later in life.

Estrogen receptor α polymorphism is associated with dementia in a Brazilian cohort.

The growth of the elderly population is a worldwide phenomenon and it is associated with chronic diseases, including dementia. In this scenario, the present study aimed to evaluate a possible association of estrogen receptor α polymorphisms with dementia in a Brazilian cohort. The subject sample was divided into two groups, control (n = 105) and case (n = 73), according to analysis of two predictive dementia tests (MMSE and CDR). The genotyping for the ERα PvuII (c.454-397T>C, rs2234693) and XbaI (c.454-351A>G, rs9340799) polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. The ERα PvuII pp genotype was associated with higher odds ratio for dementia (OR = 3.42, 95% CI = 1.33-8.77, p = 0.01, in a model including covariates. A linear regression model identified significant associations of the ERα PvuII genotypes (independent variable) with CDR scale (dependent variable), ß = 0.26 and p = 0.001. In conclusion, estrogen receptor α PvuII polymorphism is associated with dementia in a Brazilian cohort. This finding may be useful for the identification of a possible set of significant genetic and clinical biomarkers for better understanding pathophysiology, early diagnosis and management of dementia.

Lipopolysaccharide exposure modulates the contractile and migratory phenotypes of vascular smooth muscle cells.

INTRODUCTION: Sepsis survivors are at higher risk for cardiovascular events. Lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4) in sepsis. Activation of TLR4 modulates vascular smooth muscle cells (VSMCs) phenotype and contributes to cardiovascular changes after sepsis. AIM: Investigate changes in VSMCs phenotype caused by LPS-induced TLR4 activation. METHODS: Rat VSMCs were incubated with LPS. Two incubation conditions were used in cell contraction and migration assays: acute stimulation - LPS stimulus was initiated at the beginning of the assay and maintained throughout; and preconditioning - LPS stimulation was applied prior to the assay then discontinued. Nitric oxide (NO) production, mRNA expression of cytokines and phenotype markers, and interleukin (IL)-6 production were evaluated. KEY FINDINGS: LPS increased gene expression of IL-1ß, IL-6, TNFα and MCP-1 (p < .001), of secretory phenotype markers collagen and vimentin (p < .0479) and of the contractile marker smooth muscle 22α (SM22α) (p = .0067). LPS exposure increased IL-6 secretion after 24 and 48 h (p < .0001), and NO at 8 and 24 h (p < .0249) via inducible nitric oxide synthase (iNOS), as demonstrated by a decrease in NO after incubation with aminoguanidine. Acute stimulation with LPS reduced migration and contraction in a NO-dependent manner, while preconditioning with LPS increased both in an IL-6-dependent manner. SIGNIFICANCE: LPS affects VSMCs by modulating their secretory, contractile and migratory phenotypes. LPS acute stimulation of VSMCs promoted a NO-dependent reduction in migration and contraction, while preconditioning with LPS promoted IL-6-dependent increases in migration and contraction, evidencing that VSMCs can present phenotype modifications that persist after sepsis, thereby contributing to postsepsis cardiovascular events.

Effects of direct high sodium exposure at endothelial cell migration.

The present study aimed to test the hypothesis that high sodium affects the migratory phenotype of endothelial cells (EC) and investigates mechanisms involved independently of hemodynamic factors. Cell migration was evaluated by Wound-Healing at conditions: High Sodium (HS; 160 mM) and Control (CT; 140 mM). O2- production was evaluated by DHE. NADPH oxidase activity was determined by chemiluminescence assay. Expression of adhesion molecules was analyzed by RT-PCR. Shear Stress was performed using a rhythmic shake. Nitric oxide production was measured by Griess reaction. HS-induced impairment in EC migration while both Candesartan and DPI prevented it. HS increased NADPH oxidase activity, which was blocked by Candesartan. Also, HS increased O2- production that was inhibited by Candesartan. HS decreased adhesion molecules expression via ROS (Integrin Alpha 5, Integrin Beta 1, Integrin Beta 3, VE-Cadherin and PECAM) and via AT1R (PECAM). The nitric oxide production induced by shear stress was decreased after EC exposure to HS while both Candesartan and DPI prevented it. Conclusion: This study demonstrated that HS reduced EC migration by AT1R and ROS derived from NADPH Oxidase and mitochondria. The HS reduction in adhesion molecules expression modulated by ROS and AT1R may help to explain the impairment in migration capacity. Also, HS affected EC functionality by reducing their nitric oxide production in response to shear stress.

Dipeptidyl peptidase-4 inhibition prevents vascular dysfunction induced by ß-adrenergic hyperactivity.

Chronic stimulation of the ß-adrenergic sympathetic system induces vascular dysfunction which is associated with increased inflammatory cytokines production. A recently proposed therapy to control vascular injury through inflammatory processes involves inhibition of the enzyme dipeptidyl peptidase-IV (DPP4). The present study investigates whether the inhibition of DPP4 prevents the increase in inflammatory markers induced by isoproterenol and restores endothelial function in vivo and in vitro. Male Wistar rats were divided into four groups: vehicle (VHC), an isoproterenol-treated group (ISO), a sitagliptin-treated group (SITA), and an isoproterenol and sitagliptin-treated group (ISO + SITA). The ISO group exhibited significantly increased contractile responses to phenylephrine associated with reduced endothelial participation, which was totally prevented by DPP4 inhibition. In vitro incubation with isoproterenol had no effect on vascular smooth muscle cells, however isoproterenol increased the activity of DPP4 and the expression of inflammatory cytokines in endothelial cells, while sitagliptin reduced the level of cytokines to basal level. In conclusion, we have shown that beta-adrenergic receptor activation can increase DPP4 activity, which was associated with vascular dysfunction and cytokine expression in endothelial cells. The important role of DPP4 was further supported by sitagliptin, which reversed vascular changes induced by isoproterenol in vivo and in vitro.

Cyclic stretch-induced Crp3 sensitizes vascular smooth muscle cells to apoptosis during vein arterialization remodeling.

Vein graft failure limits the long-term patency of the saphenous vein used as a conduit for coronary artery bypass graft. Early graft adaptation involves some degree of intima hyperplasia to sustain the hemodynamic stress, but the progress to occlusion in some veins remains unclear. We have demonstrated that stretch-induced up-regulation of cysteine and glycine-rich protein 3 (Crp3) in rat jugular vein and human saphenous vein in response to arterialization. Here, we developed a Crp3-KO rat to investigate the role of Crp3 in vascular remodeling. After 28 days jugular vein arterialization, the intima layer was 3-fold thicker in the Crp3-KO that showed comparable smooth muscle cells (SMC) proliferation but an absence of early apoptosis observed in the wild-type rat (WT). We then investigated the role of Crp3 in early integrin-mediated signaling apoptosis in isolated jugular SMC. Interestingly, under basal conditions, ceramide treatment failed to induce apoptosis in both WT and Crp3-KO SMC. Under stretch, Crp3 expression increased in WT SMC and ceramide induced apoptosis. Immunoblotting analysis indicated that ceramide stretch-induced apoptosis in SMC is accompanied by a decrease in the phosphorylation status of both Fak and Akt, leading to an increase in Bax expression and caspase-3 cleavage. In contrast, ceramide failed to decrease Fak and Akt phosphorylation in Crp3-KO SMC and, therefore, there was no downstream induction of Bax expression and effector caspase-3 cleavage. Taken together, we provide evidence that stretch-induced Crp3 modulates vein remodeling in response to arterialization by sensitizing SMC to apoptosis.

Effects of controlled doses of Oxyelite Pro on physical performance in rats.

BACKGROUND: OxyElite Pro (OEP) is a dietary supplement to increase metabolism which contains as key stimulant the ingredient 1,3-dimethylamylamine (DMAA). Serious adverse effects have been reported after OEP consumption however, these effects are related to poisoning or overdose. To our knowledge, no one studied the effects of OEP at controlled doses. Thus, the aim of this study was to evaluate acute and chronic OEP affects, at controlled doses in Wistar rats, on physical performance, metabolic parameters, liver injury markers and oxidative stress markers and mitochondrial biogenesis in skeletal muscle. METHODS: Rats were divided in control, 4.3 mg OEP/kg, 12.9 mg OEP/kg and 25.8 mg OEP/kg. All groups were submitted to supplementation with OEP for 4 weeks and the experimental protocols were performed 30 min after the first OEP administration (acute response) and 30 min after the last OEP administration at the end of the forth week (chronic response). RESULTS: Running distance and running time increased after acute administration of 12.9 mg OEP/kg (2.6-fold) and 25.8 mg OEP/kg (2.8-fold). Since no effect on the exercise tolerance test was observed at the lower OEP dose (4.3 mg OEP/kg), this group was removed from further analyzes. On other hand, running distance and running time decreased after daily supplementation for 4 weeks also in both groups (64% in 12.9 mg OEP/kg and 72% in 25.8 mg OEP/kg). Chronic supplementation at both 12.9 and 25.8 mg OEP/kg decreased TBARS levels in soleus muscle (36 and 31%) and liver (43 and 25%). AOPP was also decreased by both doses in the liver (39 and 45%). Chronic administration of the highest dose, 25.8 mg OEP/kg, was able to reduce mRNA expression of PGC-1α in soleus muscle (25%). No effect was found in other analyses such as spontaneous physical activity, body weight, food and water intake, hepatic toxicity, cardiac oxidative stress and mitochondrial DNA amount. CONCLUSION: Maximum and not recommended doses of OEP ingested acutely presented stimulating effect on the ability to exercise. However, its daily consumption for 4 weeks showed antioxidant effects in soleus muscle and liver which may have decreased the PGC-1α mRNA expression on soleus muscle and contributed to the impaired performance in the exercise tolerance test.

Epigenetic control of exercise training-induced cardiac hypertrophy by miR-208.

Aerobic exercise-induced cardiac hypertrophy (CH) is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: miR-208a, miR-208b and miR-499 are each encoded by a myosin gene and thus are also known as 'MyomiRs', regulating several mRNA targets that in turn regulate CH and metabolic pathways. To understand the role of myomiRs in the fine-tuning of cardiac myosin heavy chain (MHC) isoform expression by exercise training-induced physiological hypertrophy, Wistar rats were subjected to two different swim training protocols. We observed that high-volume swim training (T2), improved cardiac diastolic function, induced CH and decreased the expression of miR-208a and miR-208b Consequently, the increased expression of their targets, sex determining region y-related transcription factor 6 (Sox6), Med13, Purß, specificity proteins (Sp)/Krüppel-like transcription factor 3 (SP3) and HP1ß (heterochromatin protein 1ß) was more prominent in T2, thus converging to modulate cardiac metabolic and contractile adaptation by exercise training, with an improvement in the α-MHC/ß-MHC ratio, bypassing the increase in PPARß and histone deacetylase (HDAC) class I and II regulation. Altogether, we conclude that high-volume swim training finely assures physiological cardiac remodelling by epigenetic regulation of myomiRs, because inhibition of miR-208a and miR-208b increases the expression of their target proteins and stimulates the interaction among metabolic, contractile and epigenetic genes.