New Intracellular Peptide Derived from Hemoglobin Alpha Chain Induces Glucose Uptake and Reduces Blood Glycemia.

Intracellular peptides were shown to derive from proteasomal degradation of proteins from mammalian and yeast cells, being suggested to play distinctive roles both inside and outside these cells. Here, the role of intracellular peptides previously identified from skeletal muscle and adipose tissues of C57BL6/N wild type (WT) and neurolysin knockout mice were investigated. In differentiated C2C12 mouse skeletal muscle cells, some of these intracellular peptides like insulin activated the expression of several genes related to muscle contraction and gluconeogenesis. One of these peptides, LASVSTVLTSKYR (Ric4; 600 µg/kg), administrated either intraperitoneally or orally in WT mice, decreased glycemia. Neither insulin (10 nM) nor Ric4 (100 µM) induced glucose uptake in adipose tissue explants obtained from conditional knockout mice depleted of insulin receptor. Ric4 (100 µM) similarly to insulin (100 nM) induced Glut4 translocation to the plasma membrane of C2C12 differentiated cells, and increased GLUT4 mRNA levels in epididymal adipose tissue of WT mice. Ric4 (100 µM) increased both Erk and Akt phosphorylation in C2C12, as well as in epididymal adipose tissue from WT mice; Erk, but not Akt phosphorylation was activated by Ric4 in tibial skeletal muscle from WT mice. Ric4 is rapidly degraded in vitro by WT liver and kidney crude extracts, such a response that is largely reduced by structural modifications such as N-terminal acetylation, C-terminal amidation, and substitution of Leu8 for DLeu8 (Ac-LASVSTV[DLeu]TSKYR-NH2; Ric4-16). Ric4-16, among several Ric4 derivatives, efficiently induced glucose uptake in differentiated C2C12 cells. Among six Ric4-derivatives evaluated in vivo, Ac-LASVSTVLTSKYR-NH2 (Ric4-2; 600 µg/kg) and Ac-LASVSTV[DLeu]TSKYR (Ric4-15; 600 µg/kg) administrated orally efficiently reduced glycemia in a glucose tolerance test in WT mice. The potential clinical application of Ric4 and Ric4-derivatives deserves further attention.

Criteria for eligibility to cisplatin in the curative treatment of head and neck cancer: Consensus opinion from a panel of experts.

Squamous-cell carcinoma of the head and neck (SCCHN) is an important problem in Brazil, where epidemiological and socioeconomic features often create barriers to the implementation of combined modalities with curative potential. Cisplatin improves the efficacy of radiotherapy in the adjuvant treatment of localized SCCHN and in the definitive therapy of locally advanced disease. However, the addition of high-dose cisplatin to radiotherapy increases treatment toxicity and is not always warranted. A panel of experts convened in Sao Paulo, Brazil, for discussions and recommendations regarding the use of high-dose cisplatin in combination with radiotherapy in SCCHN. In addition to discussing their professional experience, panel members used the current literature to provide evidence-based, practical recommendations regarding sociodemographic or medical criteria that may preclude safe administration of cisplatin. It is hoped that the application of these recommendations in clinical practice may improve therapeutic results in Brazil and other countries with similar health-care environments.

Social choice functions: A tool for ranking variables involved in action plans against road noise.

Traffic noise is gaining importance in planning and operation of roads in developing countries, and particularly in Europe and Latin America. Many variables with different degrees of importance influence the perception of noise from roads. Thus, the problem of prioritizing road stretches for action against such noise is an important issue in environmental noise management. For example, it can be addressed using multicriteria methods. However, these methodologies require criteria or suitable variables to be ranked according to their relative importance. In the present study, for this ranking, a list of nine variables involved in the decision-making process (called "road stretch priority variables") was presented in the form of questionnaires to high-level experts from Andalusia, southern Spain. These experts ranked the variables by relevance. Using the same data, seven social choice functions (Plurality, Raynaud, Kemeny-Young, Copeland, Simpson, Schulze, and Borda) were used in order to rank the variables. The results indicate that the most important variables were those that take into account the parameters of greatest exposure for the citizens, followed by variables related to the intensity of the problem analyzed. The results show that a combination of the use of social choice functions on aggregated information from expert panels can provide a consensus for ranking priority variables related to road stretches.

PPARγ activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1α and D2.

Here, we investigated whether pharmacological PPARγ activation modulates key early events in brown adipose tissue (BAT) recruitment induced by acute cold exposure with the aim of unraveling the interrelationships between sympathetic and PPARγ signaling. Sprague-Dawley rats treated or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1), 7 days) were kept at 23°C or exposed to cold (5°C) for 24 h and evaluated for BAT gene expression, sympathetic activity, thyroid status, and adrenergic signaling. Rosiglitazone did not affect the reduction in body weight gain and the increase in feed efficiency, Vo(2), and BAT sympathetic activity induced by 24-h cold exposure. Rosiglitazone strongly attenuated the increase in serum total and free T4 and T3 levels and BAT iodothyronine deiodinase type 2 (D2) and PGC-1α mRNA levels and potentiated the reduction in BAT thyroid hormone receptor (THR) ß mRNA levels induced by cold. Administration of T3 to rosiglitazone-treated rats exacerbated the cold-induced increase in energy expenditure but did not restore a proper activation of D2 and PGC-1α, nor further increased uncoupling protein 1 expression. Regarding adrenergic signaling, rosiglitazone did not affect the changes in BAT cAMP content and PKA activity induced by cold. Rosiglitazone alone or in combination with cold increased CREB binding to DNA, but it markedly reduced the expression of one of its major coactivators, CREB binding protein. In conclusion, pharmacological PPARγ activation impairs short-term cold elicitation of BAT adrenergic and thyroid signaling, which may result in abnormal tissue recruitment and thermogenic activity.