Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC 50 ≈ 50 μM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3′,5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3′,5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.

The expression of components present in the cartilaginous extracellular matrix is related to development, gender, and genotype, as well as to the biomechanical properties of each type of cartilage. In the present study, we analyzed small proteoglycans and glycosaminoglycans present in different cartilages of the chicken wing after extraction with guanidine hydrochloride or papain. Quantitative analysis of glycosaminoglycans showed a larger amount in humeral cartilage (around 200 mg/g tissue) than in articular cartilage of the radius and ulna, with 138 and 80 mg/g tissue, respectively. Non-collagenous proteins isolated were predominantly from cartilage in the proximal regions of the humerus and radius. D4 fractions obtained by ultracentrifugation were separated by DEAE-Sephacel and Octyl-Sepharose chromatography and analyzed by SDS-PAGE. Two bands of 57 and 70-90 kDa were observed for all samples treated with ß-mercaptoethanol. Immunoblotting of these proteins was positive for the small proteoglycans fibromodulin and decorin, respectively. Apparently, the 57-kDa protein is present in macromolecular complexes of 160 and 200 kDa. Chondroitin sulfate was detected in all regions. HPLC analysis of the products formed by chondroitinase AC and ABC digestion mainly revealed ß-D-glucuronic acid and N-acetyl ß-D-galactosamine residues. The 4-sulfation/6-sulfation ratio was close to 3, except for the proximal cartilage of the radius (2.5). These results suggest functional differences between the scapula-humerus, humerus-ulna, and humerus-radius joints of the chicken wing. This study contributes to the understanding of the physiology of cartilage and joints of birds under different types of mechanical stress.

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Objetivo: Verificar os impactos respiratórios provenientes da inalação de material particulado e de vapores durante o manejo e processamento do óleo de palma em trabalhadores da mesorregião do sul baiano. Métodos: Trata-se de um estudo quantitativo e observacional realizado com 43 indivíduos do sexo masculino. Foi aplicado um questionário aos participantes com variáveis sociodemográficas e de condições laborais como instrumento de coleta de dados. O questionário American Thoracic Society – Division of Lung Disease–1978-A foi utilizado para detecção de sinais e sintomas respiratórios. A medição do fluxo expiratório foi realizada por debitômetro adulto (Peak Flow Meter), no qual eram registradas a variação do fluxo de ar expirado entre 90 e 900 l/min. Resultados: Os sintomas mais frequentes foram dispneia, secretividade e tosse. Houve correlação moderada entre a variável tempo de serviço e o fluxo expiratório encontrado (p=0,006). Quanto maior foi o tempo de serviço da amostra, menor o pico de fluxo encontrado. O fluxo expiratório foi aquém do estimado em 97% dos trabalhadores (p<0,02). Conclusão: Nesta amostra, a poeira ocupacional combinada com a inalação dos vapores provenientes do processo de esterilização causou impacto no sistema respiratório dos trabalhadores, de acordo com os tipos e frequência dos sinais e sintomas apresentados.

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