Produção de biotensoativos a partir de resíduos de óleos e gorduras

O presente trabalho visou a seleção de microrganismos com capacidade de produzir biotensoativos a partir de resíduos de óleos e gorduras gerados em restaurantes e indústrias alimentícias. Borra de soja, gordura de frango, gordura vegetal hidrogenada e óleo de soja usado em frituras foram estudados como fonte de carbono. Os isolados LMI 6c e LMI 7a, ambos pertencentes ao gênero Pseudomonas, foram selecionados como potenciais produtores de biotensoativos. Dentre os resíduos propostos, a borra de soja foi considerada o melhor substrato, gerando 9,69 g.L-1 de ramnolipídios e uma tensão superficial de 31 mN/m.

Inflamação e má resposta ao uso de eritropoetina na doença renal crônica

ResumoA prevalência da doença renal crônica (DRC) tem aumentado nos últimos anos e vários fatores estão associados à instalação e progressão da DRC, tais como obesidade, hipertensão arterial e diabetes mellitus. Uma das complicações da DRC é a anemia causada principalmente pela deficiência de ferro e de eritropoetina (EPO). Um dos tratamentos para este tipo de anemia é uso de eritropoetina exógena. O paciente com DRC submetido à diálise apresenta um estado inflamatório crônico, provocando uma situação de má resposta à ação medular da EPO, causando anemia, desnutrição, agravamento da aterosclerose e aumento da mortalidade. O objetivo deste artigo foi revisar as evidências científicas referentes à associação da má resposta clínica ao uso de EPO e a presença de inflamação na DRC.

Temperaturas para germinação de sementes de Poecilanthe parviflora Bentham (Fabaceae - Faboideae)

Poecilanthe parviflora (coração-de-negro) é uma planta arbórea com potencial para uso em áreas degradadas e no paisagismo. Este trabalho teve por objetivo avaliar condições de temperatura para condução do teste de germinação para as sementes de P. parviflora. Foram realizados dois experimentos paralelos. No experimento 1 foi utilizado o lote denominado de JABOTICABAL que foi submetido à germinação em diferentes temperaturas constantes (10, 15, 20, 25, 30, 35 e 40 ºC) e alternadas (20-30, 25-35 e 20-35 ºC), totalizando 10 tratamentos. No experimento 2 foram utilizados os lotes denominados de USM, SEMEX e JABOTICABAL que foram submetidos à germinação a 25ºC e a 20-30ºC com fotoperíodo de 12 horas, totalizando seis tratamentos. Em cada experimento, foram utilizadas quatro repetições de 25 sementes por tratamento. A protrusão da raiz primária (> 0,5 cm) foi adotada como critério para considerar a semente germinada. Foram analisados os seguintes parâmetros: porcentagem de germinação e de plântulas normais, índice de velocidade de germinação, comprimento de plântulas, matéria fresca e seca de plântulas. O delineamento estatístico utilizado foi o inteiramente casualizado e as médias foram comparadas pelo teste de Scott-Knott a 5% de probabilidade. Concluiu-se que o teste de germinação pode ser conduzido a 25 e a 25-35 ºC, com fotoperíodo de 12 horas, por 21 dias.

Recueil de lettres et de pièces originales, et de copies de pièces indiquées comme telles dans le dépouillement qui suit.

Contient : 1 Lettre de « HENRY [D'ALBRET, roi de Navarre]... à mon cousin monseigneur le grant mestre » ; 2 Lettre, en italien, de « MAXIMILIANO [SFORZA, duc de Milan]... al' illustrissimo... signor gran maestro... Cremonae, XIII junii M.D.XXX » ; 3 Lettre de « P. DE VILLERS L'YLE ADAM,... à monseigneur le mareschal de Montmorency, mon nepveu... De Romme, le XIX septembre 1523 » ; 4 Lettre, en italien, de « THEODORO TRIVULTIO,... al re [François Ier]... De Genova, alli XXX di aprile M.D.XXVIII » ; 5 Lettre, en italien, d'«HANIBALLE GONZAGA,... al christianissimo re... Da Novelara, alli XIIII dijuglio M.D.XXVIII » ; 6 Lettre de « PEDRO NAVARRO,... à monseigneur... le grant maistre, mareschal de France... Escript en gallere, au port de Savonne, le premier jour de janvier » ; 7 Lettre, en italien, d'«il vescovo di Lodi... à monseigneur... gran metre... Di Murano in Venetia, alli XV di agosto M.D.XXIX » ; 8 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grant maistre... Escript à Lyon, le IIe de juin » ; 9 Lettre, en italien, de « FRANCISCUS [SFORZA, duc de Milan]... reverendissimo... domino Gaspari, equiti Landriano, consiliario et oratori nostro dilectissimo... Cremone, XVIIIa 9bris 1526 ». Copie ; 10 « Copia di lettere venute da Granata, di 9 di ottobre 1526 » ; 11 Lettre, en italien, d'«ANTONIO DORIA,... allo illustrissimo... monsignor lo gran maestro... Da Marsegia, a li XV de agosto M.D.XXVIIII » ; 12 Lettre, en italien, de « GUIDO RANGONE,... al' illustrissimo... monsignor lo gran maestro di Franza... Di Carignano, a li 14 octobre 1536 » ; 13 Lettre, en italien, de « GUIDO RANGONE,... al' illustrissimo... monseigneur lo maestro di Franza, luocotenente di S. Mta... Di Carignano, a li 15 d'ottobre 1536 » ; 14 Lettre, en italien, de « GUIDO RANGONE,... al' illustrissimo... monseigneur il gran maestro di Franza... Di Carignano, il XIII octobre 1536 » ; 15 Lettre, en italien, d'«ALESANDRO DI PEPULI, PHILIPPO DI PEPULI, HIERONYMO DI PEPULI,... allo illustrissimo... monsignor il gran mestro del re christianissimo... De Bologna, alli 20 de ottobre M.D.XXVIII » ; 16 Lettre de « POMPONIO TRIVULTIO,... à monseigneur le grant maistre... Escript à Lyon, le XVIIe jour de janvyer » ; 17 Lettre, en italien, de « GREGORIO CASALE,... Da Roma, alli 24 di marzo 1531 » ; 18 Lettre, en italien, de « GREGORIO CASALE,... Da Roma, alli 24 di marzo M.D.XXXI » ; 19 Lettre, en italien, de « GUIDO RANGONE,... al' illustrissimo... monseigneur lo gran maestro di Franza... De Venetia, l'ottavo de zugno 1530 » ; 20 Lettre, en espagnol, de « los consellers de Barcelona » à « lo señor... capita de Lengadoc... De Barcelona, a XXXI de juliol any mil D.XXVI » ; 21 Lettre, en italien, adressée à « l'illustrissimo... D. Julio de Sancto Severino, regio capitaneo et consiliario... In Gisies, a li XIIII di agosto M.D.XXVI » ; 22 Lettre, en italien, de « JANUS LASCARIS,... In Vicenza, a di XIIII de agosto M.D.XXII » ; 23 Lettre, en italien, d'«el datario... a monsignor... el gran maestro... Da Roma, alli XIX de juio M.D.XXVI » ; 24 Lettre, en italien, de « JOVANNE CLEMENTE STANGHA,... allo illustrissimo... monsignore el gran maestro... Data in Paris, alli 22 aprile del 1531 » ; 25 Lettre, en italien, d'«el datario... a monsignor... el gran mastro... Da Roma, alli XXI di aprile M.D.XXVI » ; 26 Lettre, en espagnol, de « l'obispo de Ciguença... al muy noble señor, museñor de Clermunt, teniente de governador de Llenguadoc... De Monçon, a X de junio de M.D.XXVIII° » ; 27 Lettre, en italien, de « THEODORO TRIVULTIO,... a monsignor... il gran maestro de Franza... Da Alexandria, allo ultimo de febraro M.D.XXVIIII » ; 28 Lettre de « THEODORO TRIVULTIO,... à monseigneur... le grant maistre... De Lyon, ce XIXe de mars » ; 29 Lettre de « POMPONIO TRIVULTIO,... au roy... Escript à Lyon, le XXIIme jour de mars » ; 30 Lettre d'«UGO DI PEPOLI,... à monseigneur... de Monmorancy, mareschal de France... De Olege, ce dernier jour de janvier » ; 31 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grant maistre... Escript à Lyon, ce XVIIme jour [de] janvyer » ; 32 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grant maistre... Escript à Lyon, ce IIe de may » ; 33 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grant maistre... Escript à Lyon, ce XXIIIe may » ; 34 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grant maistre... Escript à Lyon, ce XVIIe may » ; 35 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grant maistre... Escript à Lyon, ce XIe jour d'apvril » ; 36 Lettre de « POMPONIO TRIVULTIO,... à monseigneur... le grantmaistre... Escript à Lyon, le cinquiesme du moys de may » ; 37 Fragment, en italien, sur la république de Venise et le duché de Barri ; 38 Lettre, en italien, de « PIRRHO GONZAGA,... al re [François Ier]... Da Orivieto, al' ultimo di Xbre M.D.XXVII » ; 39 Lettre, en italien, d'«ANTONIO DORIA,... a lo illustrissimo... el signor... gran maestro [di] Franza... Da Genova, al primo d'agosto M.D.XXVIII » ; 40 Lettre, en italien, d'«ANSALDO DE GRIM[A]LDO,... allo illustrissimo... monsignor gran maistro de Franza... Scritta in Orvietto, a di II junio M.D.XXVIII » ; 41 Lettre, en italien, de « GALEATIO VESCONTE,... al' illustrissimo signor Pomponio Trivultio, governador de Lione... Dal Campo a Loesa, al primo de settembre 1528 » ; 42 Lettre, en italien, avec chiffre, de « BILIA,... al signor JO. Francesco Zaberna, oratore de lo... duca de Milano... De Burgos, XXII novembre M.D.XXVII » ; 43 Lettre, en italien et en chiffre, de « JO. ANTONIO BILIA,... al' illustrissimo signore... el signore duca de Milano... De Burgos, XXII novembris 1527 » ; 44 Lettre, en italien, de « JOACHIN [DE VAULX]... allo illustrissimo... signor [gran maestro] di Francia... Scritta de Viterbo, el XVI d'agosto 1528 » ; 45 Lettre, en latin, de « JOHANNES DIESBACH, locumtenens illustrissimi domini marescalli de Momoransi, capitaney generalis exercitus Helveciorum et alii capitaney totius lige Elveciorum de presente in exercitu regio existentes... illustrissimo principi, domino duci Veneciarum et magnificis dominis senatoribus venetis... In felicibus castris regiis apud Abietem Grassum, die primo martii 1524 » ; 46 Lettre, en italien, de « JOACHIN [DE VAULX]... allo illustrissimo... signor gran maestro di Francia... Da Cales, el XVIIII genaro 1530 » ; 47 Lettre, en italien, de « JOAN BAPTISTA DA PONT,... à monseigneur... le grant maestre de France... In Lode, a li 23 de zugno 1529 » ; 48 Lettre, en italien, de « BALDASSARTE » et de « CARDUCCI,... [all'] illustrissimo... signore monsignor il gran mastro di Francia... D'Angulem, il giorno XXXI julii M.D.XXX » ; 49 Lettre, en italien, de « SIMONE DE THEBALDI,... allo illustrissimo... signore monsignor de Momoransi, gran mastro de Francia... In Barletta, a di XVIII de mayo 1529 » ; 50 Lettre, en italien, de « JOACHIN [DE VAULX]... al' illusfrissimo... signor gran maestro de Francia... Da Londra, XXIIII ottobre M.D.XXX » ; 51 Lettre, en italien, de « JOACHIN [DE VAULX]... al' illustrissimo... signor gran maestro de Francia... D'Amptoncort, lo VIII ottobre M.D.XXX » ; 52 Lettre, en italien, de « PETRO BIRAGO,... al' illustrissimo... monsignor maresial de Memoransi,... In Ferara, octavi junii 1525 » ; 53 Lettre, en italién, de « LODOVICO CATO,... al magnifico... signor... de Sormano,... A Bordeos, alli V di junio M.D.XXX » ; 54 Lettre, en italien, de « GALEATIO VESCONTE,... In Lione, a li XXIIII octobre » ; 55 Lettre, en italien, de « GALEATIO VESCONTE,... à monseigneur... le grant maistre de France... Dato in Alexandria, a li XX de aprile » ; 56 Lettre, en italien, de « GALEATIO VESCONTE,... allo illustrissimo signore gran maestro... In Lyon, alli 29 settembris » ; 57 Lettre, en italien, de « OTTAVIANO GRIMALDO,... al' illustrissimo... signor maresial de Montmoranci,... Scritta in Venetia, a di XXVIIIImo zenaro » ; 58 Lettre, en italien, de « MAXIMILIANO [SFORZA, duc de Milan]... à monseigneur le grant mestre de France » ; 59 « Extratto di cyfra... De Lodi, XIX avost ». Copie ; 60 Lettre d'«el secretario veneto... allo illustrissimo... mons. el gran maestro... Da Bles, alli 2 octobre 1526 » ; 61 « Extraict de la lettre cinquiesme du seigneur OCTAVYAN GRIMALDO, ordonnée lui expedier par messeigneurs les commissaires ». Copie ; 62 Lettre de « MICHEL ANTHOINE DE SALLUCES,... au roy [François Ier]... A Sainct Pierre, le Vme jour d'octobre... V.C.XXIIII ». Copie ; 63 Lettre de « RENZO DE CERE,... à monseigneur le grand maistre de France... De Ligerne, ce VIIIme jour de fevrier » ; 64 Nouvelles d'Italie, lettre écrite « de Lodi, 13 marzo 1529 ». Copie ; 65 Lettre, en italien, de « JOACHIN [DE VAULX]... al' illustrissimo... signor gran maestro de Francia... Fatta et X novembre M.D.XXX » ; 66 Lettre, en italien, de « JOACHIN [DE VAULX]... all' illustrissimo [signor gran maestro de Fran]cia... Da Vinetia, el XV luglio 1529 » ; 67 Lettre, en italien, de « JACOBO NOMISCHIO,... Da Napoli, a 21 magio 1529... Copia... intercetta in Puglia » ; 68 Lettre de « JOANNA... DE GONZAGA,... allo illustrissimo... mons. di Momoransi,... In Bozolo, al XII de febraro del 1528 » ; 69 Lettre de « GLAUDE DE DURRE,... au roy... Escript en vostre ville de Marseille, ce XVIIIe de decembre »

Género e Domesticidade na Indonésia : A Nova Ordem

Mulheres que garantam uma vida familiar calma e feliz e, sobretudo, proveitosa para as actividades do marido. Este foi um ideal acalentado por Jan Pieterszoon Coen, considerado como o fundador da autoridade holandesa no arquipélago de Insulíndia. Coen desempenhava papéis-chave na VOC2 no início do século XVII, altura em que os holandeses sucediam aos portugueses como potência europeia com mais influência no arquipélago. A presença portuguesa, entretanto, ficou limitada a poucas regiões, tais como Macaçar e a zona de Timor. Jan Pieterszoon Coen, já antes de ascender ao mais alto cargo, o de Governador Geral, delineou uma política de colonização para os postos holandeses, nomeadamente Batávia (actualmente Jacarta) como a sede da VOC na Ásia. Nesta política, o factor feminino tinha lugar de destaque. Segundo Coen, para contrariar os excessos e as bebedeiras, em suma a vida desordeira levada pelos homens europeus ao serviço da VOC, que prejudicava bastante o seu funcionamento, eles precisavam de uma relação estável com uma mulher, ou seja, de uma vida matrimonial.3 Os projectos demográficos de Coen e as iniciativas mal sucedidas, como o transporte de mulheres e em particular de meninas órfãs da Holanda, neste texto não serão abordados.4 Mas é significante que um dos primeiros protagonistas da expansão europeia no país agora chamado Indonésia dava tanta importância à responsabilidade das mulheres por uma vida doméstica serena e um marido contente. Neste artigo, que foca a situação das mulheres na Indonésia, nomeadamente nos anos 70 e 80 do século XX, serão abordadas várias influências normativas. Entre essas contam-se as ideias dos ocidentais que, durante os três séculos depois do governo de Coen, iriam aumentar o seu poder no arquipélago. No entanto, houve muitos outros factores, entre os quais a singularidade das culturas indígenas, descritas desde o início do século XVI por portugueses tais como Tomé Pires e António Galvão.

Antitumour activity of [1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride in xenografted Ehrlich's ascites tumour

The effects of a new titanocene compound with an ansa ligand in the cyclopentadienyl rings, the 1,2-di(cyclopentadienyl)-1,2-di(p-NNdimethylaminophenyl)-ethanediyl] titanium dichloride (TITANOCENE X), on the growth and differentiation of granulocyte-macrophage progenitor cells [colony-forming unit-granulocyte-macrophage (CFU-GM)] and Natural killer (NK) cell activity in Ehrlich's ascites tumour (EAT)-bearing mice were studied. Myelosuppression concomitant with increased numbers of spleen CFU-GM was observed in tumour-bearing mice. Treatment of these animals with TITANOCENE X (2.5-50mg/kg/day) produced an increase in myelopoicsis, in a dose-dependent manner, and reduced spleen colony formation. In addition, the treatment of EAT-bearing mice with 3 doses of 20 or 50 mg/kg TITANOCENE X restored to normal values the reduced Natural killer cell function observed during tumour growth. In parallel, TITANOCENE X prolonged, in a dose-dependent manner, the survival of mice inoculated with Ehrlich's ascites tumour. The highest dose of 50 mg/kg prolonged in 50% the survival time of EAT-bearing mice, compared to non-treated tumour-bearing controls. In comparison with previous results from our laboratory addressing the effects of titanocenes on haematopoiesis, we observed with TITANOCENE X a similar effective profile as for bis(cyclopentadienyl) dithiocyanate titanium(IV), being both less effective than di(cyclopentadienyl) dichloro titanium(IV), since the latter not only prolonged, but also increased the rate of survival. These differences in efficacy may be due to the nature of the ansa-cyclopentadienyl ligand used in TITANOCENE X, since the C, bridge between the two cyclopentadienyl groups will increase the hydrolytic stability by an organometallic chelate effect. Also, the introduction of two dimethylamino substituents increases the water solubility of TITANOCENE X when compared to titanocene dichloride itself (c) 2006 Elsevier B.V. All rights reserved.

Role of Halogen Bonds in Thyroid Hormone Receptor Selectivity: Pharmacophore-Based 3D-QSSR Studies

Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TR alpha and TR beta. Several pharmacological effects mediated by TR beta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TR beta activation may elicit these effects while maintaining an acceptable safety profile, To understand the molecular determinants of affinity and subtype selectivity of TR ligands, we have successfully employed a ligand- and structure-guided pharmacophore-based approach to obtain the molecular alignment of a large series of thyromimetics. Statistically reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models were obtained using the comparative molecular field analysis (CoMFA) method, and the visual analyses of the contour maps drew attention to a number of possible opportunities for the development of analogs with improved affinity and selectivity. Furthermore, the 3D-QSSR analysis allowed the identification of a novel and previously unmentioned halogen bond, bringing new insights to the mechanism of activity and selectivity of thyromimetics.

Ligand induced interaction of thyroid hormone receptor beta with its coregulators

Thyroid hormones exert most of their physiological effects through two thyroid hormone receptor (TR) subtypes, TR alpha and TR beta, which associate with many transcriptional coregulators to mediate activation or repression of target genes. The search for selective TR beta ligands has been stimulated by the finding that several pharmacological actions mediated by TR beta might be beneficial in medical conditions such as obesity, hypercholesterolemia and diabetes. Here, we present a new methodology which employs surface plasmon resonance to investigate the interactions between TR beta ligand binding domain (LBD) complexes and peptides derived from the nuclear receptor interaction motifs of two of its coregulators, SRC2 and DAX1. The effect of several TR beta ligands, including the TR beta selective agonist GC-I and the TR beta selective antagonist NH-3, were investigated. We also determined the kinetic rate constants for the interaction of TR beta-T3 with both coregulators, and accessed the thermodynamic parameters for the interaction with DAX1. Our findings Suggest that flexibility plays an important role in the interaction between the receptor and its coregulators. and point out important aspects of experimental design that should be addressed when using TR beta LBD and its agonists. Furthermore, the methodology described here may be useful for the identification of new TR beta ligands. (C) 2008 Elsevier Ltd. All rights reserved.

Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example

Alzheimer`s disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r (2) = 0.88, q (2) = 0.69 and r (pred) (2) = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology.

Trypanosoma cruzi maxicircle heterogeneity in Chagas disease patients from Brazil

The majority of individuals in the chronic phase of Chagas disease are asymptomatic (indeterminate form, IF). Each year, similar to 3% of them develop lesions in the heart or gastrointestinal tract. Cardiomyopathy (CCHD) is the most severe manifestation of Chagas disease. The factors that determine the outcome of the infection are unknown, but certainly depend on complex interactions amongst the genetic make-up of the parasite, the host immunogenetic background and environment. In a previous study we verified that the maxicircle gene NADH dehydrogenase (mitochondrial complex 1) subunit 7 (ND7) from IF isolates had a 455 bp deletion compared with the wild type (WT) ND7 gene from CCHD strains. We proposed that ND7 could constitute a valuable target for PCR assays in the differential diagnosis of the infective strain. In the present study we evaluated this hypothesis by examination of ND7 structure in parasites from 75 patients with defined pathologies, from Southeast Brazil. We also analysed the structure of additional mitochondrial genes (ND4/CR4, COIII and COII) since the maxicircle is used for clustering Trypanosoma cruzi strains into three clades/haplogroups. We conclude that maxicircle genes do not discriminate parasite populations which induce IF or CCHD forms. Interestingly, the great majority of the analysed isolates belong to T cruzi 11 (discrete typing unit, (DTU) IIb) genotype. This scenario is at variance with the prevalence of hybrid (DTU IId) human isolates in Bolivia, Chile and Argentina. The distribution of WT and deleted ND7 and ND4 genes in T cruzi strains suggests that mutations in the two genes occurred in different ancestrals in the T cruzi 11 cluster, allowing the identification of at least three mitochondrial sub-lineages within this group. The observation that T. cruzi strains accumulate mutations in several genes coding for complex I subunits favours the hypothesis that complex I may have a limited activity in this parasite. (C) 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Chlorella vulgaris up-modulation of myelossupression induced by lead: The role of stromal cells

In this study, Chlorella vulgaris (CV) was examined for its chelating effects on the ability of bone marrow stromal cell layer to display myeloid progenitor cells in vitro in lead-exposed mice, using the long-term bone marrow culture (LTBMC). In addition, the levels of interleukin (IL)-6, an important hematopoietic stimulator, as well as the numbers of adherent and non-adherent cells were also investigated. Mice were gavage treated daily with a single 50 mg/kg dose of CV for 10 days, concomitant to continuous offering of 1300 ppm lead acetate in drinking water. We found that CV up-modulates the reduced ability of stromal cell layer to display myeloid progenitor cells in vitro in lead-exposed mice and restores both the reduced number of non-adherent cells and the ability of stromal cells from these mice to produce IL-6. Monitoring of lead poisoning demonstrated that CV treatment significantly reduced lead levels in blood and tissues, completely restored the normal hepatic ALA levels, decreased the abnormally high plasma ALA and partly recovered the liver capacity to produce porphyrins. These findings provide evidence for a beneficial use of CV for combination or alternative chelating therapy to protect the host from the damage induced by lead poisoning. (C) 2008 Elsevier Ltd. All rights reserved.

Cytotoxicity and antiangiogenic activity of grandisin

Objectives The antitumoural properties of grandisin, a tetrahydrofuran neolignan from Piper solmsianum, were investigated by in-vitro and in-vivo assays using the Ehrlich ascites tumoural (EAT) model. Methods Viability of the tumour cells was evaluated by Trypan blue exclusion and MTT methods, after incubation with grandisin (0.017-2.3 mu M). The effects of grandisin on the activity of caspase-3, -6, -8, and -9 were also investigated using colorimetric protease kits. In-vivo studies were performed in EAT-bearing mice treated intraperitoneally with 2.5, 5 or 10 mg/kg grandisin for 10 days. Key findings Grandisin inhibited the growth of EAT cells, by both methods, with IC50 values less than 0.25 mu M. The results showed that the activity of all the caspases studied increased in grandisin-treated cells, when compared with control, non-treated cells. Administering grandisin to EAT-bearing mice increased survival of the animals, in a dose-dependent manner. Simultaneously, we detected a 66.35% reduction of intraperitoneal tumour cell burden in the animals treated with 10 mg/kg grandisin. Additionally, in these animals, the marked increase of vascular endothelial growth factor (VEGF) levels, induced by EAT development, was decreased with treatment with grandisin, resulting in a reduction of 32.1% of VEGF levels in the peritoneal washing supernatant, when compared with the control. Conclusions The results demonstrated that grandisin induced in-vitro cytotoxicity and antiangiogenic effects in mice while it acted against tumour evolution, prolonging host survival.

In vitro basal cytotoxicity assay applied to estimate acute oral systemic toxicity of grandisin and its major metabolite

Preclinical investigations can start with preliminary in vitro studies before using animal models. Following this approach, the number of animals used in preclinical acute toxicity testing can be reduced. In this study, we employed an in-house validated in vitro cytotoxicity test based on the Spielmann approach for toxicity evaluation of the lignan grandisin, a candidate anticancer agent, and its major metabolite. the 4-O-demethylgrandisin, by neutral red uptake (NRU) assay, on mouse fibroblasts Balb/c 3T3 cell line. Using different concentrations of grandisin and its major metabolite (2.31; 1.16; 0.58; 0.29; 0.14; 0.07; 0.04; 0.002 mu M) in Balb/c 3T3-A31 NRU cytotoxicity assay, after incubation for 48 h, we obtained IC(50) values for grandisin and its metabolite of 0.078 and 0.043 mu M, respectively. The computed LD(50) of grandisin and 4-O-demethylgrandisin were 617.72 and 429.95 mg/kg, respectively. Both were classified under the Globally Harmonized System as category 4. Since pharmacological and toxicological data are crucial in the developmental stages of drug discovery, using an in vitro assay we demonstrated that grandisin and its metabolite exhibit distinct toxicity profiles. Furthermore, results presented in this work can contribute to reduce the number of animals required in subsequent pharmacological/toxicological studies. (C) 2010 Elsevier GmbH. All rights reserved.

Bcl-2 expression and apoptosis induction in human HL60 leukaemic cells treated with a novel organotellurium(IV) compound RT-04

Organotellurium(]V) compounds have been reported to have multiple biological activities including cysteine protease-inhibitory activity, mainly cathepsin B. As cathepsin B is a highly predictive indicator for prognosis and diagnosis of cancer, a possible antitumor potential for these new compounds is expected. In this work, it was investigated the effectiveness of organotellurium(IV) RT-04 to produce lethal effects in the human promyelocytic leukaemia cell line HL60. Using the MTT tetrazolium reduction test, and trypan blue exclusion assay, the IC50 for the compound after 24 h incubation was 6.8 and 0.35 mu M, respectively. Moreover, the compound was found to trigger apoptosis in HL60 cells, inducing DNA fragmentation and caspase-3, -6, and -9 activations. The apoptsosis-induced by RT-04 is probably related to the diminished Bcl-2 expression, observed by RT-PCR, in HL60-treated cells. In vivo studies demonstrated that the RT-04 treatment (2.76 mg/kg given for three consecutive days) produces no significant toxic effects for bone marrow and spleen CFU-GM. However, higher doses (5.0 and 10 mg/kg) produced a dose-dependent reduction in the number of CFU-GM of RT-04-treated mice. These results suggest that RT-04 is able to induce apoptosis in HL60 cells by Bcl-2 expression down-modulation. Further studies are necessary to better clarify the effects of this compound on bone marrow normal cells. (C) 2008 Elsevier Ltd. All rights reserved.