Cis-trimethoxystilbene, exhibits higher genotoxic and antiproliferative effects than its isomer trans-trimethoxystilbene in MCF-7 and MCF-10A cell lines.

Stilbenes are a class of natural compounds with a wide variety of biological effects, such as antitumor activity. The best-known stilbene is resveratrol, whose clinical application is limited due to its low bioavailability. Methoxylated derivatives of this stilbene, including cis-trimethoxystilbene (cis-TMS) and trans-trimethoxystilbene (trans-TMS) have demonstrated more pronounced cytotoxic and anti-proliferative effects than resveratrol. Thus, the objective of this study is to evaluate and compare the cytotoxicity and antiproliferative effects of cis- and trans-TMS in MCF-7 and its normal counterpart MCF-10A. Both compounds were cytotoxic, genotoxic, and induced G2-M accumulation and cell death in the two cell lines. These results suggested that the genotoxicity of cis- and trans-TMS is involved in the reduction of cellular proliferation of MCF-7 and MCF-10A cells, but notably, such antiproliferative effects are more pronounced for cis- than trans-TMS.

Water-Soluble Glutamic Acid Derivatives Produced in Culture by Penicillium solitum IS1-A from King George Island, Maritime Antarctica.

A new method of screening was developed to generate 770 organic and water-soluble fractions from extracts of nine species of marine sponges, from the growth media of 18 species of marine-derived fungi, and from the growth media of 13 species of endophytic fungi. The screening results indicated that water-soluble fractions displayed significant bioactivity in cytotoxic, antibiotic, anti-Leishmania, anti-Trypanosoma cruzi, and inhibition of proteasome assays. Purification of water-soluble fractions from the growth medium of Penicillium solitum IS1-A provided the new glutamic acid derivatives solitumine A (1), solitumine B (2), and solitumidines A-D (3-6). The structures of compounds 1-6 have been established by analysis of spectroscopic data, chemical derivatizations, and vibrational circular dichroism calculations. Although no biological activity could be observed for compounds 1-6, the new structures reported for 1-6 indicate that the investigation of water-soluble natural products represents a relevant strategy in finding new secondary metabolites.

Licochalcone A induces morphological and biochemical alterations in Schistosoma mansoni adult worms.

This paper is the first report on the in vitro effects of licochalcone A, a chalcone isolated from Glycyrrhiza inflate Batalin (Leguminosae), on Schistosoma mansoni adult worms. In vitro, licochalcone A afforded lethal concentrations for 50% of parasites (LC50) of 9.12±1.1 and 9.52±0.9µM against female and male adult worms, respectively, at 24h. Additionally, the compound reduced the total number of S. mansoni eggs and affected the development of eggs produced by S. mansoni adult worms. Together, the results achieved after 24h showed that licochalcone A was 55.7- and 53.3-fold more toxic to S. mansoni female and male adult worms than to Chinese hamster ovary fibroblasts cells, respectively. Treatment with licochalcone A elicited drastic changes in the tegument of S. mansoni adult worms, as well as mitochondrial alteration and chromatin condensation. Licochalcone A also increased the superoxide anion level and decreased the superoxide dismutase activity in S. mansoni adult worms. Overall, our results indicated that licochalcone A displays in vitro schistosomicidal activity. This effect may result from increased production of reactive oxygen species (ROS) induced by the action of licochalcone A. The resulting ROS could act on the S. mansoni tegument and membranes and help induce the death of S. mansoni adult worms.

Cytotoxicity and genotoxicity of stilbene derivatives in CHO-K1 and HepG2 cell lines

Abstract The cytotoxicity and genotoxicity of the stilbenes (E)-methyl-4-(3-5-dimethoxystyryl)benzoate (ester), (E)-4-(3-5-dimethoxystyryl)aniline (amino), (Z)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (cis-TMS) and (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (trans-TMS) were investigated in this work. Structural modifications of resveratrol, a naturally occurring stilbene, have been previously performed, including the replacement of hydroxyl by different functional groups. Such modifications resulted in significant improvement of target-specific effects on cell death and antiproliferative responses. The parameters were evaluated using XTT assay, clonogenic survival assay and the cytokinesis-block micronucleus assay in CHO-K1 and HepG2 cell lines. The results showed that cis-TMS is approximately 250-fold more cytotoxic than the amino and ester, and 128-fold more cytotoxic than trans-TMS. When genotoxicity was evaluated, only the trans-TMS did not significantly increase the frequency of micronucleus (MN). While the cis-TMS induced a mean of 5.2 and 5.9 MN/100 cells at 0.5 μM in CHO-K1 and HepG2, respectively, the amino and ester induced 3.1 and 3.6 MN/100 cells at 10 μM in CHO-K1, respectively, and 3.5 and 3.8 in HepG2. Trans-TMS is genotoxic only in HepG2 cells. Based on these results, the cis-TMS was the most cytotoxic and genotoxic compound in both cell lines.

Cytotoxicity and genotoxicity of stilbene derivatives in CHO-K1 and HepG2 cell lines.

The cytotoxicity and genotoxicity of the stilbenes (E)-methyl-4-(3-5-dimethoxystyryl)benzoate (ester), (E)-4-(3-5-dimethoxystyryl)aniline (amino), (Z)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (cis-TMS) and (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (trans-TMS) were investigated in this work. Structural modifications of resveratrol, a naturally occurring stilbene, have been previously performed, including the replacement of hydroxyl by different functional groups. Such modifications resulted in significant improvement of target-specific effects on cell death and antiproliferative responses. The parameters were evaluated using XTT assay, clonogenic survival assay and the cytokinesis-block micronucleus assay in CHO-K1 and HepG2 cell lines. The results showed that cis-TMS is approximately 250-fold more cytotoxic than the amino and ester, and 128-fold more cytotoxic than trans-TMS. When genotoxicity was evaluated, only the trans-TMS did not significantly increase the frequency of micronucleus (MN). While the cis-TMS induced a mean of 5.2 and 5.9 MN/100 cells at 0.5 µM in CHO-K1 and HepG2, respectively, the amino and ester induced 3.1 and 3.6 MN/100 cells at 10 µM in CHO-K1, respectively, and 3.5 and 3.8 in HepG2. Trans-TMS is genotoxic only in HepG2 cells. Based on these results, the cis-TMS was the most cytotoxic and genotoxic compound in both cell lines.

Effect of diterpenoid kaurenoic acid on genotoxicity and cell cycle progression in gastric cancer cell lines.

The goal of our study was to evaluate the effect of kaurenoic acid, obtained from copaiba oil resin, in gastric cancer (GC) and a normal mucosa of stomach (MNP01) cell lines. The compound was tested at concentrations of 2.5, 5, 10, 30 and 60µg/mL. Comet and micronucleus assays were used to access its potential genotoxicity in vitro. Moreover, we evaluated the effect of kaurenoic acid in cell cycle progression and in the transcription of genes involved in the control of the cell cycle: MYC, CCND1, BCL2, CASP3, ATM, CHK2 and TP53. Kaurenoic acid induced an increase on cell DNA damage or micronucleus frequencies on GC cell lines in a dose-dependent manner. The GC and MNP01 cell lines entering DNA synthesis and mitosis decreased significantly with kaurenoic acid treatment, and had an increased growth phase compared with non-treated cells. The treatment induced apoptosis (or necrosis) even at a concentration of 2.5µg/mL in relation to non-treated cells. GC cell lines presented reduced MYC, CCND1, BCL2 and CASP3 transcription while ATM, CHK2 and TP53 increased in transcription in relation to non-treated cells, especially at a concentration above 10µg/mL. The gene transcription in the MNP01 (non-treated non-cancer cell line) was designated as a calibrator for all the GC cell lines. In conclusion, our results showed that kaurenoic acid obtained from Copaifera induces DNA damage and increases the micronuclei frequency in a dose-dependent manner in GC cells, with a significant genotoxicity observed above the concentration of 5µg/mL. Moreover, this compound seems to be able to induce cell cycle arrest and apoptosis in GC cells.

Increased frequency of micronuclei in the lymphocytes of patients chronically infected with hepatitis B or hepatitis C virus.

In this study, we analysed the frequency of micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) and evaluated mutagen-induced sensitivity in the lymphocytes of patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In total, 49 patients with chronic viral hepatitis (28 HBV-infected and 21 HCV-infected patients) and 33 healthy, non-infected blood donor controls were investigated. The frequencies (‰) of MN, NPBs and NBUDs in the controls were 4.41 ± 2.15, 1.15 ± 0.97 and 2.98 ± 1.31, respectively. The frequencies of MN and NPBs were significantly increased (p < 0.0001) in the patient group (7.01 ± 3.23 and 2.76 ± 2.08, respectively) compared with the control group. When considered separately, the HBV-infected patients (7.18 ± 3.57) and HCV-infected patients (3.27 ± 2.40) each had greater numbers of MN than did the controls (p < 0.0001). The HCV-infected patients displayed high numbers of NPBs (2.09 ± 1.33) and NBUDs (4.38 ± 3.28), but only the HBV-infected patients exhibited a significant difference (NPBs = 3.27 ± 2.40, p < 0.0001 and NBUDs = 4.71 ± 2.79, p = 0.03) in comparison with the controls. Similar results were obtained for males, but not for females, when all patients or the HBV-infected group was compared with the controls. The lymphocytes of the infected patients did not exhibit sensitivity to mutagen in comparison with the lymphocytes of the controls (p = 0.06). These results showed that the lymphocytes of patients who were chronically infected with HBV or HCV presented greater chromosomal instability.

Increased frequency of micronuclei in the lymphocytes of patients chronically infected with hepatitis B or hepatitis C virus

In this study, we analysed the frequency of micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) and evaluated mutagen-induced sensitivity in the lymphocytes of patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In total, 49 patients with chronic viral hepatitis (28 HBV-infected and 21 HCV-infected patients) and 33 healthy, non-infected blood donor controls were investigated. The frequencies (‰) of MN, NPBs and NBUDs in the controls were 4.41 ± 2.15, 1.15 ± 0.97 and 2.98 ± 1.31, respectively. The frequencies of MN and NPBs were significantly increased (p < 0.0001) in the patient group (7.01 ± 3.23 and 2.76 ± 2.08, respectively) compared with the control group. When considered separately, the HBV-infected patients (7.18 ± 3.57) and HCV-infected patients (3.27 ± 2.40) each had greater numbers of MN than did the controls (p < 0.0001). The HCV-infected patients displayed high numbers of NPBs (2.09 ± 1.33) and NBUDs (4.38 ± 3.28), but only the HBV-infected patients exhibited a significant difference (NPBs = 3.27 ± 2.40, p < 0.0001 and NBUDs = 4.71 ± 2.79, p = 0.03) in comparison with the controls. Similar results were obtained for males, but not for females, when all patients or the HBV-infected group was compared with the controls. The lymphocytes of the infected patients did not exhibit sensitivity to mutagen in comparison with the lymphocytes of the controls (p = 0.06). These results showed that the lymphocytes of patients who were chronically infected with HBV or HCV presented greater chromosomal instability.

Anticlastogenic and antigenotoxic effects of selenomethionine on doxorubicin-induced damage in vitro in human lymphocytes.

The use of antioxidants during chemotherapy has been shown to reduce or prevent the undesirable effects experienced by healthy cells. Micronutrient selenium is well known for its antioxidant properties; however, selenium exhibits a bimodal nature in that both its beneficial and toxic properties lie within a limited and narrow dose range. The present study investigated the possible protective effects of selenomethionine (SM) on the cytotoxicity, genotoxicity and clastogenicity of the chemotherapic doxorubicin (DXR), a key chemotherapic used in cancer treatment. Human peripheral lymphocytes were treated in vitro with varying concentrations of SM (0.25 microM, 0.5 microM, 1.0 microM and 2.0 microM), tested in combination with DXR (0.15 microg/mL). SM alone was not cytotoxic and when combined with DXR treatment, reduced the DNA damage index significantly, the frequency of chromosomal aberrations, the number of aberrant metaphases and the frequency of apoptotic cells. The mechanism of chemoprotection of SM may be related to its antioxidant properties as well as its ability to interfere with DNA repair pathways. Therefore this study showed that SM is effective in reducing the genetic damage induced by the antitumoral agent DXR.

Protection of doxorubicin-induced DNA damage by sodium selenite and selenomethionine in Wistar rats.

The importance of selenium in human nutrition is well recognized. It is an important micronutrient involved in antioxidant defense and is of fundamental importance in the maintenance of genomic stability. However, questions relating to the appropriate chemical form of selenium used for supplementation and its beneficial dose is still being debated. Therefore, the present study investigated the ability of 2 selenium compounds-sodium selenite (SS) and selenomethionine (SM)-to protect DNA against the damage induced by doxorubicin (DXR). Wistar rats were supplemented orally for 10 consecutive days with SS or SM (1 and 2 mg/kg bw); 24 hours before euthanasia a single dose of DXR (90 mg/kg bw) was injected intraperitoneally. DNA lesions were assessed by the comet assay and micronucleus test; the concentrations of thiobarbituric acid reactive substances, vitamin E, and reduced glutathione were determined by using liver homogenates. The results obtained showed that SS and SM prevented the induction of DNA damage by DXR. It was also observed that these 2 selenium compounds increased the hepatic concentration of glutathione, maintained the thiobarbituric acid reactive substances, and allowed for the maintenance of hepatic concentrations of vitamin E even after DXR treatment, confirming the antioxidant properties of selenium compounds. Sodium selenite and SM supplementation exhibited very similar patterns of protection. In conclusion, SS and SM supplementation was effective in protecting DNA against DXR-induced DNA damage in Wistar rats, probably because of their antioxidant properties.

Fototeste: proposta para o exame teórico de habilitação de motoristas

Apresenta um novo exame teórico sobre sinalização e legislação de trânsito, na forma de perguntas sobre o comportamento desejado do motorista diante de uma situação real de trânsito, utilizando-se de fotografias. Os Ss são 1109 indivíduos divididos em 5 grupos experimentais. Busca a estimativa da fidedignidade dos itens propostos (experimento 1), seleção dos melhores itens (experimento 2), estimativa da fidedignidade dos itens selecionados e a comparação com o critério existente (experimento 3), estimativa da validade simultânea do teste através de um grupo de bons motoristas (experimento 4) e uma comparação temporal dos resultados com aplicações seqüenciais em uma mesma amostra (experimento 5). Utiliza 3 métodos para a verificação da fidedignidade e consistência interna: a correlação de Pearson entre item-teste, o método de Kuder-Richardson e o Método das Metades, os quais mostram um alto índice de consistência interna. Conclui sugerindo a adoção do teste pelo órgão oficial, uma vez que o teste utilizado atualmente não inclui situações reais e o critério de reprovação utilizado, incluindo erros de ortografia, não fornece uma medida real do conhecimento teórico de trânsito (AU)

Analise psicofisica do espaco visual - teoria e pesquisa: tributo a S.S. Stevens

O presente trabalho consistiu numa analise psicofisica de duas dimensoes inter-relacionadas do espaco visual: tamanho e distancia. Ele constituiu-se de tres partes. Na primeira foi realizada uma revisao da literatura experimental e teorica concernente a aplicacao dos metodos escalares na psicofisica e percepcao. Constatou-se que estes procedimentos produzem uma funcao-potencia (R=K.En), que relaciona a magnitude subjetiva a magnitude fisica. O expoente, n, e o parametro mais importante. As modalidades perceptivas de tamanho e distancia foram consideradas com mais detalhes. Na segunda parte foram realizados cinco experimentos diferentes, em que se procurou verificar quais variaveis afetam o valor do expoente. os resultados mostraram, de um lado, que a presenca do estimulo-padrao, o valor do modulo e o tipo de observacao sao variaveis que nao afetam o valor do expoente. De outro, o tipo de julgamento e a amplitude de distancias parecem afetar significativamente o valor do expoente para escalas de distancia aparente em grandes espacos. O expoente medio, combinando-se os resultados de todos os experimentos, foi 0,97 + 0,07, valor que esta dentro do intervalo predito em funcao da revisao da literatura.

Origem e desenvolvimento da percepcao de tamanho e distancia

Neste artigo realizamos uma revisao dos estudos concernentes a duas dimensoes interelacionadas da percepcao espacial: tamanho e distancia. Os seguintes topicos referentes a origem e evolucao da percepcao de tamanho e distancia foram enfatizados: 1) discriminacao do tamanho do objeto, 2) discriminacao da distancia do objeto, 3) constancia de tamanho em infantes, 4) evolucao da percepcao de tamanho e 5) evolucao da percepcao de distancia em criancas capazes de estimativas verbais.