Scielo RSS <![CDATA[Brazilian Journal of Medical and Biological Research]]> http://www.scielo.br/rss.php?pid=0100-879X20160012&lang=es vol. 49 num. 12 lang. es <![CDATA[SciELO Logo]]> http://www.scielo.br/img/en/fbpelogp.gif http://www.scielo.br <![CDATA[Lithium carbonate and coenzyme Q10 reduce cell death in a cell model of Machado-Joseph disease]]> http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200601&lng=es&nrm=iso&tlng=es Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials. <![CDATA[Glucagon-like peptide 1 improves insulin resistance <em>in vitro</em> through anti-inflammation of macrophages]]> http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200602&lng=es&nrm=iso&tlng=es Glucagon-like peptide 1 (GLP-1), a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D). Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4) not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS)-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D. <![CDATA[ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia]]> http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200603&lng=es&nrm=iso&tlng=es This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life &gt;60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development. <![CDATA[Different methods of calculating ankle-brachial index in mid-elderly men and women: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)]]> http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200701&lng=es&nrm=iso&tlng=es The ankle-brachial index (ABI) is a marker of subclinical atherosclerosis related to health-adverse outcomes. ABI is inexpensive compared to other indexes, such as coronary calcium score and determination of carotid artery intima-media thickness (IMT). Our objective was to identify how the ABI can be applied to primary care. Three different methods of calculating the ABI were compared among 13,921 men and women aged 35 to 74 years who were free of cardiovascular diseases and enrolled in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). The ABI ratio had the same denominator for the three categories created (the highest value for arm systolic blood pressure), and the numerator was based on the four readings for leg systolic blood pressure: the highest (ABI-HIGH), the mean (ABI-MEAN), and the lowest (ABI-LOW). The cut-off for analysis was ABI&lt;1.0. All determinations of blood pressure were done with an oscillometric device. The prevalence of ABI&lt;1% was 0.5, 0.9, and 2.7 for the categories HIGH, MEAN and LOW, respectively. All methods were associated with a high burden of cardiovascular risk factors. The association with IMT was stronger for ABI-HIGH than for the other categories. The proportion of participants with a 10-year Framingham Risk Score of coronary heart disease &gt;20% without the inclusion of ABI&lt;1.0 was 4.9%. For ABI-HIGH, ABI-MEAN and ABI-LOW, the increase in percentage points was 0.3, 0.7, and 2.3%, respectively, and the relative increment was 6.1, 14.3, and 46.9%. In conclusion, all methods were acceptable, but ABI-LOW was more suitable for prevention purposes.