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- Blueberry juice as a nutraceutical approach to prevent prediabetes progression in an animal model: focus on hepatic steatosisPublication . Nunes, Sara; Viana, Sofia; Rolo, Anabela; Palmeira, Carlos; André, Alexandra; Cavadas, Claudia; Pintado, Manuela; Reis, Flávio
- Crescent-like lesions as an early signature of nephropathy in a rat model of prediabetes induced by a hypercaloric dietPublication . Nunes, Sara; Alves, André; Preguiça, Inês; Barbosa, Adelaide; Vieira, Pedro; Mendes, Fernando; Martins, Diana; Viana, Sofia; Reis, FlávioDiabetic nephropathy (DN) is a major microvascular complication of diabetes. Obesity and hyperlipidemia, fueled by unhealthy food habits, are risk factors to glomerular filtration rate (GFR) decline and DN progression. Several studies recommend that diabetic patients should be screened early (in prediabetes) for kidney disease, in order to prevent advanced stages, for whom the current interventions are clearly inefficient. This ambition greatly depends on the existence of accurate early biomarkers and novel molecular targets, which only may arise with a more thorough knowledge of disease pathophysiology. We used a rat model of prediabetes induced by 23 weeks of high-sugar/high-fat (HSuHF) diet to characterize the phenotype of early renal dysfunction and injury. When compared with the control animals, HSuHF-treated rats displayed a metabolic phenotype compatible with obese prediabetes, displaying impaired glucose tolerance and insulin sensitivity, along with hypertriglyceridemia, and lipid peroxidation. Despite unchanged creatinine levels, the prediabetic animals presented glomerular crescent-like lesions, accompanied by increased kidney Oil-Red-O staining, triglycerides content and mRNA expression of IL-6 and iNOS. This model of HSuHF-induced prediabetes can be a useful tool to study early features of DN, namely crescent-like lesions, an early signature that deserves in-depth elucidation.
- A novel semi-solid pill for stress-free voluntary oral drug administration in experimental rodentsPublication . Viana, Sofia; Martins, B.; Nunes, S.; Palavra, F.; Preguiça, I.; Alves, A.; Nóbrega, C.; Fernandes, R.; Silva, S.; Barbosa Moreira, Zélia; Lima, D.L.D.; Fontes-Ribeiro, Carlos; Reis, FlávioDuring compound screening and drug development, long-term oral drug administration to experimental rodents is often required. Oral gavage, a straightforward drug dosing technique, is not suitable for extended treatments considering the recurrent traumatic complications (gastroesophageal injury) and physiological distress (corticosterone levels alterations) that frequently bias experimental design outcomes. These reasons create a challenge for preclinical drug assays and stress-free/metabolic-inert alternatives of oral drug administration are warranted. Herein, it is presented an innovative semi-solid pill optimized to overcome aforementioned drawbacks. After a brief training period, C57BL/6 mice submitted to a chronic oral administration protocol (50 days) displayed a high index of voluntary acceptance of emptyand drug- (e.g. sitagliptin) incorporated vehicle in both healthy and CNS-diseased states. This protocol operates in a pair-housed animal housing fashion, allowing animal socialization throughout entire protocol. At the end of experiments, a normal neurobehavioral phenotype (anxiolytic, memory, locomotion parameters) was recorded. Moreover, this new methodology proved to be safe, preserving serum metabolic (glucose, triglycerides, total cholesterol), hepatic (albumin, total proteins) and renal (urea, creatinine, uric acid) parameters along with normal ileum contractility. Remarkably, coherent sitagliptin ( 10 mg/ml) plasma levels were detected, along with a robust decrease ( 80%) on the activity of its target (dipeptidyl peptidase- 4), unequivocally proving in vivo drug efficacy. Overall, this innovative approach may enclose a breakthrough advance for translational studies in scientific and pharmaceutical fields, providing a reproducible, efficient, metabolic inert and stress-free alternative for voluntary oral drug administration, with expected improvement on the data feasibility.
- Emergent Biomarkers of Residual Cardiovascular Risk in Patients with Low HDL-c and/or High Triglycerides and Average LDL-c Concentrations: Focus on HDL Subpopulations, Oxidized LDL, Adiponectin, and Uric AcidPublication . Mascarenhas-Melo, Filipa; Palavra, Filipe; Marado, Daniela; Sereno, José; Teixeira-Lemos, Edite; Freitas, Isabel; Mendonça, Maria Isabel; Pinto, Rui; Teixeira, Frederico; F, ReisThis study intended to determine the impact of HDL-c and/or TGs levels on patients with average LDL-c concentration, focusing on lipidic, oxidative, inflammatory, and angiogenic profiles. Patients with cardiovascular risk factors (n = 169) were divided into 4 subgroups, combining normal and low HDL-c with normal and high TGs patients. The following data was analyzed: BP, BMI, waist circumference and serum glucose, Total-c, TGs, LDL-c, oxidized-LDL, total HDL-c and HDL subpopulations, paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF- α , adiponectin, VEGF, and iCAM1. The two populations with increased TGs levels, regardless of the normal or low HDL-c, presented obesity and higher waist circumference, Total-c, LDL-c, Ox-LDL, and uric acid. Adiponectin concentration was significantly lower and VEGF was higher in the population with cumulative low values of HDL-c and high values of TGs, while HDL quality was reduced in the populations with impaired values of HDL-c and/or TGs, viewed by reduced large and increased small HDL subfractions. In conclusion, in a population with cardiovascular risk factors, low HDL-c and/or high TGs concentrations seem to be associated with a poor cardiometabolic profile, despite average LDL-c levels. This condition, often called residual risk, is better evidenced by using both traditional and nontraditional CV biomarkers, including large and small HDL subfractions, Ox-LDL, adiponectin, VEGF, and uric acid.
- Determinação de GHB em Amostras BiológicasPublication . Castro, André Lobo; Reis, Flávio; Teixeira, HelenaApresentação dos parâmetros de Validação Analítica já estudados no desenvolvimento da técnica de determinação de GHB em amostras biológicas (sangue, urina, cabelo). Serão apresentados os estudos preliminares realizados para o desenvolvimento do método analítico e os resultados de validação obtidos até ao momento no estudo e desenvolvimento da técnica analítica, designadamente, extracção em fase sólida (SPE) e Cromatografia Gasosa acoplada a Espectrometria de Massa em tandem (GC/MS-MS).
- GHB Detection in biological samples by GC‐MS‐MS with forensic purposesPublication . Castro, André Lobo; Reis, Flávio; Teixeira, HelenaApresentação dos parâmetros de Validação Analítica já estudados no desenvolvimento da técnica de determinação de GHB em amostras biológicas (sangue, urina, cabelo). Serão apresentados os resultados de validação obtidos até ao momento no estudo e desenvolvimento da técnica analítica para amostras de sangue, designadamente, extração em fase sólida (SPE) e Cromatografia Gasosa acoplada a Espectrometria de Massa em tandem (GC/MS-MS). Serão também apresentados os resultados dos testes de extração efetuados para efeitos de desenvolvimento da técnica analítica para amostras de cabelo, designadamente, extração líquido-líquido e Cromatografia Gasosa acoplada a Espectrometria de Massa em tandem (GC/MS-MS).
- GHB – amostragem e armazenamento de amostras biológicas de interesse com fins forensesPublication . Castro, André Lobo; Dias, Mário; Reis, Flávio; Teixeira, HelenaO Ácido gama-hidroxibutírico (GHB) é um composto endógeno com um historial de utilização clínica desde os anos 1960’s. No entanto, devido aos seus efeitos secundários, foi classificado como uma substância controlada. É uma substância associada ao consumo ilícito para fins recreativos, para aumento forçado de massa muscular por parte de praticantes de culturismo e ainda ao abuso sexual facilitado por substâncias. A interpretação medico-legal de um resultado positivo para GHB está dependente do seu contexto endógeno e do comportamento post-mortem do composto. Neste pressuposto, serão discutidos os valores endógenos de GHB, quer in-vivo, quer post-mortem, e serão sugeridos alguns cuidados no que diz respeito à amostragem e armazenamento das diferentes amostras biológicas passíveis de ser utilizadas em contexto clínico e forense.
- Endogenous GHB concentrations in whole blood postmortem samples as a biomarker for post mortem interval estimation – A set of real cases analysisPublication . Castro, André Lobo; Tarelho, Sónia; Dias, Mário; Reis, Flávio; Teixeira, HelenaGamma-hydroxybutyric acid (GHB) is an endogenous compound which has a story of clinical use and illicit abuse since the 1960’s. Its postmortem behaviour, namely regarding degradation and metabolism, has been increasingly studied to be used as a putative biomarker for post-mortem interval (PMI) estimation. Thus, whole blood post-mortem GHB levels were obtained in thirty two real cases with previous information on death and autopsy data. The samples were treated through sample methanolic precipitation followed by GC-MS/MS analysis (LLOQ=0.1 mg/L). No differences were encountered for the other parameters evaluated, including age [under 44 years-old - 7.87 2.06 mg GHB/L (n=7), 45 to 60 years-old - 6.80 3.67 mg GHB/L (n=13) and over 61 years-old - 5.72 2.39 mg GHB/L (n=12), p0.05], gender [men - 7.79 5.04 mg GHB/L (n=23), women - 6.72 2.60 mg GHB/L (n=9), p=0.273], cause of death [accident - 7.96 ± 2.26 mg GHB/L (n=8), suicide - 6.75 ± 3.22 mg GHB/L (n=7) and unknown/natural death - 5.14 ± 2.96 mg GHB/L (n=17), p0.05] and presence or absence of substances [absence - 6.37 2.61 mg GHB/L, presence - 6.96 3.38 mg GHB/L, p=0.405]. On the other hand, the results obtained suggest that the PMI (until 5 days between death and sampling) influences GHB whole blood concentration, noticed namely between 48 and 72 hours (24 - 48 hours (p=0.893), 48 - 72 hours (p<0.05); 72 - 96 hours (p=0.123). This study brings additional data regarding the usefulness of GHB levels in forensic toxicology, which might be further strengthened with larger, but comparable, studies from other laboratories and institutions in the forensic toxicology context.
- Valores endógenos de GHB em amostras biológicas post-mortem – determinação analítica e avaliação estatísticaPublication . Castro, André Lobo; Tarelho, Sónia; Franco, João Miguel; Reis, Flávio; Teixeira, HelenaO Ácido gama-hidroxibutírico (GHB) é um composto endógeno com um historial de utilização clínica desde os anos 1960’s. No entanto, devido aos seus efeitos secundários, foi classificado como uma substância controlada. É uma substância associada ao consumo ilícito para fins recreativos, para induzir o aumento da massa muscular por parte de praticantes de culturismo e ainda ao abuso sexual facilitado por substâncias. No entanto, a interpretação médico-legal de um resultado positivo para GHB está dependente do seu contexto endógeno e do comportamento post-mortem do composto. Neste pressuposto, serão apresentados os valores de GHB determinados num conjunto de amostras post-mortem de sangue e cabelo, provenientes de casos sem qualquer suspeita de consumo de GHB. Estes valores foram estatisticamente analisados e comparados no sentido de se averiguar eventuais tendências de comportamento do composto em contexto post-mortem. Os resultados apresentados foram baseados no sexo dos indivíduos, faixa etária, diagnóstico diferencial médico-legal e intervalo post-mortem (intervalo entre a data da morte e a data da autópsia). A concentração média total de GHB em sangue foi de 6,7 g/L, com os valores a variarem entre 1,8 g/L e 15,7 g/L. Em termos de idade dos indivíduos, verificou-se uma descida da concentração do composto à medida que a idade aumenta, com uma média de 7,9 g/L para indivíduos com menos de 44 anos, 6,8 g/L para indivíduos com idades compreendidas entre 45 e 60 anos, e 5,7 g/L para o conjunto de indivíduos com idade superior a 60 anos. Relativamente ao diagnóstico diferencial médico-legal, os valores médios variaram entre 8,9 g/L e 5,1 g/L, consoante a causa de morte referenciada, nomeadamente acidente, causa natural ou suicídio. De notar que nenhum dos casos estudados constituía um contexto de homicídio. Finalmente, e considerando o intervalo post-mortem, foram encontrados valores médios que variaram entre 4,57 mg/L com 4 dias de PMI e 8,29 mg/L com 2 dias de PMI.
- Comparison of endogenous GHB concentrations in blood and hair in death cases with emphasis on the post mortem intervalPublication . Castro, André Lobo; Tarelho, Sónia; Dias, Mário; Reis, Flávio; Teixeira, Helena M.Gamma-hydroxybutyric acid (GHB) is an endogenous compound which has a story of clinical use and illicit abuse since the 1960’s. The possibility to use a multi-sample approach of GHB evaluation, including whole blood and hair, to better characterize a forensic toxicology case and evaluate a possible causal association with the death, is an exciting up-to-date issue. In addition, its post-mortem behaviour, namely regarding degradation and metabolism, has been increasingly investigated as a putative biomarker for post-mortem interval (PMI) estimation. Thus, In order to contribute to clarify this specific aspect, whole blood and hair post-mortem GHB levels were evaluated in thirty two real cases with previous information on death and autopsy data. The results obtained suggest that the PMI (until 5 days between death and sampling) influences GHB whole blood concentration, but not GHB levels in hair samples. No differences were encountered for the other parameters evaluated, including age, gender, cause of death and presence or absence of substances. This study brings new insights regarding the usefulness of GHB levels in forensic toxicology, which might be further strengthened with larger, but comparable, studies from other laboratories and institutions in the context of legal medicine.