In vitro and in vivo efficacy of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on human melanoma

6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is a powerful inhibitor of the glutathione transferase P1-1 (GSTP1-1) and causes the disruption of the complex between GSTP1-1 and c-Jun N-terminal Kinase (JNK). This induces JNK activation and apoptosis in tumour cells. in the present work we assess the in vitro and in vivo effectiveness of NBDHEX on two human melanoma cell lines, Me501 and A375. NBDHEX shows IC50 values in the low micromolar range (IC50 of 1.2 +/- 0.1 mu M and 2.0 +/- 0.2 mu M for Me501 and A375, respectively) and is over 100 times more cytotoxic to these cell lines than temozolomide. Apoptosis is observed in Me501 cells within 3 h of the addition of NBDHEX, while in A375 cells the apoptotic event is rather late, and is preceded by a G2/M phase arrest. In both melanoma cell lines, INK activity is required for the ability of NBDHEX to trigger apoptosis, confirming that the JNK pathway is an important therapeutic target for this tumour. NBDHEX is also both effective and well tolerated in in vivo tumour models. A tumour inhibition of 70% is observed in vivo against Me501 human melanoma and a similar result is obtained on A375 model, with 63% of turnout inhibition. These findings indicate that the activation of the JNK pathway, through a selective GSTP1-1 targeting, could prove to be a promising new strategy for treating melanoma, which responds poorly to conventional therapies. (C) 2009 Elsevier Ltd. All rights reserved

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the proteinquality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. Methods: We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. Conclusions: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders

Comparison Of Methods For Estimating Heights From Complete Stem Analysis Data For Pinus taeda

O objetivo do presente trabalho foi comparar os valores reais das alturas dos an\ue9is de crescimento anual com os estimados por meio da t\ue9cnica de an\ue1lise de tronco pelos m\ue9todos de Graves (1906), Carmean (1972), Lenhart (1972), Newberry (1978), Propor\ue7\uf5es e Gr\ue1fico e identificar o mais acurado para \ue1rvores de Pinus taeda do sul do Brasil. Para isso, foram usadas seis \ue1rvores de regenera\ue7\ue3o natural com idade m\uednima de 11 anos. Coletaram-se discos de 5 cm de espessura nas alturas 0,1m, 0,7m, 1,30m e a cada 1 m at\ue9 o fim do tronco. Os valores reais das alturas em cada ano foram medidos diretamente nos troncos, rachando-se as se\ue7\uf5es entre discos ao longo da medula e procurando pelo ponto exato em que cada idade terminava. As an\ue1lises de precis\ue3o foram baseadas nos res\uedduos entre os valores reais das alturas em cada ano e os valores estimados para cada m\ue9todo. Para esse fim, foram calculados o desvio m\ue9dio relativo (D%), desvio m\ue9dio relativo dos valores em m\uf3dulo (AbsD%), desvio-padr\ue3o (Sd) e soma de quadrado dos desvios relativos (SSRR). Essas quatro estat\uedsticas avaliadas em conjunto, permitiram identificar o m\ue9todo mais preciso para cada ano. Complementarmente foi aplicado o teste de t0.05 para dados n\ue3o pareados, para avaliar se, no geral, os desvios foram significantes ou n\ue3o. Os resultados das an\ue1lises indicaram que os m\ue9todos de Carmean (1972) e Lenhart (1972) tiveram desempenho id\ueantico, em fun\ue7\ue3o de estimarem a mesma altura quando h\ue1 apenas um anel de crescimento terminando numa mesma se\ue7\ue3o. Isso ocorreu na maioria das vezes. Concluiu-se que esses dois m\ue9todos foram os melhores por terem gerado desvios n\ue3o significativos para a maioria das \ue1rvores estudadas.The objective of this research was to compare actual heights at known ages with those estimated by the methods proposed by Graves (1906), Carmean (1972), Lenhart (1972), Newberry (1978), and the Ratio and Graphic methods, in order to identify the most accurate one for Pinus taeda from Southern Brazil. That way, six trees aged at least 11 years were used. Cross-sections with 5 cm thickness were collected at heights of 0.10 meters, 0.70 meters, 1.30 meters and so on at every 1 meter along the bole. True height growth for a given age was measured on the section itself by dividing it in two parts along the pith and looking for the exact point where the true annual height growth took place. The accuracy analyses were based on residuals between true heights and those estimated by the tested methods for each age. For this analysis, the relative mean deviation (D%), relative mean absolute deviation (AbsD%), standard deviation of differences (Sd) and sum of squared relative residuals (SSRR) were calculated. These 4 statistics evaluated together, allowed for the identification of the most accurate method for every age. Complementarily, the non paired t0.05 test for data was applied to evaluate whether the residuals from each method were significant or not. The results of the analysis indicated that Carmean (1972) and Lenhart (1972) were identical owing to the fact that they estimated the same height value for sections where there was only one growth ring finishing in the same section. This situation occurred for most of the results in this current study. It was concluded that Carmean (1972) and Lenhart (1972) were the best methods for estimating height growth because both produced nonsignificant residuals for the majority of the trees studied