Evidence for a Role of Oxidative Stress in the Carcinogenicity of Ochratoxin A

The in vitro and in vivo evidence compatible with a role for oxidative stress in OTA carcinogenicity has been collected and described. Several potential oxido-reduction mechanisms have been identified in the past. More recently, the possibility of a reduction of cellular antioxidant defense has been raised as an indirect source of oxidative stress. Consequences resulting from the production of oxidative stress are observed at different levels. First, OTA exposure has been associated with increased levels of oxidative DNA, lipid, and protein damage. Second, various biological processes known to be mobilized under oxidative stress were shown to be altered by OTA. These effects have been observed in both in vitro and in vivo test systems. In vivo, active doses were often within doses documented to induce renal tumors in rats. In conclusion, the evidence for the induction of an oxidative stress response resulting from OTA exposure can be considered strong. Because the contribution of the oxidative stress response in the development of cancers is well established, a role in OTA carcinogenicity is plausible. Altogether, the data reviewed above support the application of a threshold-based approach to establish safe level of dietary human exposure to OTA

Synthesis and vibrational spectroscopy of Fe-57-labeled models of [NiFe] hydrogenase: first direct observation of a nickel-iron interaction

A new route to iron carbonyls has enabled synthesis of 57Fe-​labeled [NiFe] hydrogenase mimic (OC)​357Fe(pdt)​Ni(dppe) (pdt = 1,​3-​propanedithiolate)​. Its study by nuclear resonance vibrational spectroscopy revealed Ni-​57Fe vibrations, as confirmed by calcns. The modes are absent for [(OC)​357Fe(pdt)​Ni(dppe)​]​+, which lacks Ni-​57Fe bonding, underscoring the utility of the analyses in identifying metal-​metal interactions

Fatores afetando o consumo e utilização de forrageiras de baixa qualidade por ruminantes - revisão.

A quantidade máxima de alimento capaz de ser consumida por um ruminante e de grande importância para o produtor. De um modo geral, quanto maior for o consumo, menor será a quantidade de alimento necessário por unidade de produção. Este fato e que caracteriza a eficiência produtiva de um animal. A conseqüência econômica seria que maiores lucros estariam dependentes da capacidade dos ruminantes em digerir alimentos fibrosos mais baratos e disponíveis em maiores quantidades. O Maximo consumo de uma forragem pelo ruminante depende, primariamente, das taxas de escoamento do rúmen da celulose e hemicelulose. Estas taxas, por sua vez, depende de vários fatores que interferem na atividade da flora microbiana do rúmen, quais sejam: evolução do processo de lignificação com o estágio de maturação das forrageiras, parcial ausência de nutrientes para a microflora como nitrogênio ou minerais e a presença em excesso de agentes bacteriostáticos. Dada a sua importância econômica e cientifica, este assunto vem sendo estudado extensivamente por nutricionistas e fisiologistas em varias partes do mundo, gerando uma enorme gama de conceitos relacionados ao binômio animal-planta, parte dos quais foram reunidos no presente trabalho de revisão.bitstream/item/131377/1/fatores-afetando-o-consumo.pd

A Toxicogenomics Approach to Identify New Plausible Epigenetic Mechanisms of Ochratoxin A Carcinogenicity in Rat

Ochratoxin A (OTA) is a mycotoxin occurring naturally in a wide range of food commodities. In animals, it has been shown to cause a variety of adverse effects, nephrocarcinogenicity being the most prominent. Because of its high toxic potency and the continuous exposure of the human population, OTA has raised public health concerns. There is significant debate on how to use the rat carcinogenicity data to assess the potential risk to humans. In this context, the question of the mechanism of action of OTA appears of key importance and was studied through the application of a toxicogenomics approach. Male Fischer rats were fed OTA for up to 2 years. Renal tumors were discovered during the last 6 months of the study. The total tumor incidence reached 25% at the end of the study. Gene expression profile was analyzed in groups of animals taken in intervals from 7 days to 12 months. Tissue-specific responses were observed in kidney versus liver. For selected genes, microarray data were confirmed at both mRNA and protein levels. In kidney, several genes known as markers of kidney injury and cell regeneration were significantly modulated by OTA. The expression of genes known to be involved in DNA synthesis and repair, or genes induced as a result of DNA damage, was only marginally modulated. Very little or no effect was found amongst genes associated with apoptosis. Alterations of gene expression indicating effects on calcium homeostasis and a disruption of pathways regulated by the transcription factors hepatocyte nuclear factor 4 alpha (HNF4α) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but not in the liver. Previous data have suggested that a reduction in HNF4α may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney. The inhibition of defense mechanism appears as a highly plausible new mechanism, which could contribute to OTA carcinogenicit

Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR).

Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR), inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk

The mediating effect of task presentation on collaboration and children's acquisition of scientific reasoning

There has been considerable research concerning peer interaction and the acquisition of children's scientific reasoning. This study investigated differences in collaborative activity between pairs of children working around a computer with pairs of children working with physical apparatus and related any differences to the development of children's scientific reasoning. Children aged between 9 and 10 years old (48 boys and 48 girls) were placed into either same ability or mixed ability pairs according to their individual, pre-test performance on a scientific reasoning task. These pairs then worked on either a computer version or a physical version of Inhelder and Piaget's (1958) chemical combination task. Type of presentation was found to mediate the nature and type of collaborative activity. The mixed-ability pairs working around the computer talked proportionally more about the task and management of the task; had proportionally more transactive discussions and used the record more productively than children working with the physical apparatus. Type of presentation was also found to mediated children's learning. Children in same ability pairs who worked with the physical apparatus improved significantly more than same ability pairs who worked around the computer. These findings were partially predicted from a socio-cultural theory and show the importance of tools for mediating collaborative activity and collaborative learning

Matrix Modulation of the Bioactivation of Estragole by Constituents of Different Alkenylbenzene-containing Herbs and Spices and Physiologically Based Biokinetic Modeling of Possible In Vivo Effects

The alkenylbenzene estragole is a constituent of several herbs and spices. It induces hepatomas in rodents at high doses following bioactivation by cytochrome P450s and sulfotransferases (SULTs) giving rise to the ultimate carcinogenic metabolite 1'-sulfooxyestragole which forms DNA adducts. Methanolic extracts from different alkenylbenzene-containing herbs and spices were able to inhibit SULT activity. Flavonoids including quercetin, kaempferol, myricetin, apigenin, and nevadensin were the major constituents responsible for this inhibition with Ki values in the nano to micromolar range. In human HepG2 cells exposed to the proximate carcinogen 1ʹ-hydroxyestragole, the various flavonoids were able to inhibit estragole DNA adduct formation and shift metabolism in favor of glucuronidation which is a detoxification pathway for 1ʹ-hydroxyestragole. In a next step, the kinetics for SULT inhibition were incorporated in physiologically based biokinetic (PBBK) models for estragole in rat and human to predict the effect of co-exposure to estragole and (mixtures of) the different flavonoids on the bioactivation in vivo. The PBBK-model-based predictions indicate that the reduction of estragole bioactivation in rat and human by co-administration of the flavonoids is dependent on whether the intracellular liver concentrations of the flavonoids can reach their Ki values. It is expected that this is most easily achieved for nevadensin which has a Ki value in the nanomolar range and is, due to its methyl ation, more metabolically stable than the other flavonoid

Coffee bean extracts rich and poor in kahweol both give rise to elevation of liver enzymes in healthy volunteers

BACKGROUND: Coffee oil potently raises serum cholesterol levels in humans. The diterpenes cafestol and kahweol are responsible for this elevation. Coffee oil also causes elevation of liver enzyme levels in serum. It has been suggested that cafestol is mainly responsible for the effect on serum cholesterol levels and that kahweol is mainly responsible for the effect on liver enzyme levels. The objective of this study was to investigate whether coffee oil that only contains a minute amount of kahweol indeed does not cause elevation of liver enzyme levels. METHODS: The response of serum alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) to Robusta coffee oil (62 mg/day cafestol, 1.6 mg/day kahweol) was measured in 18 healthy volunteers. RESULTS: After nine days one subject was taken off Robusta oil treatment due to an ALAT level of 3.6 times the upper limit of normal (ULN). Another two subjects stopped treatment due to other reasons. After 16 days another two subjects were taken off Robusta oil treatment. One of those subjects had levels of 5.8 ULN for ALAT and 2.0 ULN for ASAT; the other subject had an ALAT level of 12.4 ULN and an ASAT level of 4.7 ULN. It was then decided to terminate the study. The median response of subjects to Robusta oil after 16 days was 0.27 ULN (n = 15, 25(th),75(th )percentile: 0.09;0.53) for ALAT and 0.06 ULN (25(th),75(th )percentile -0.06;0.22) for ASAT. CONCLUSIONS: We conclude that the effect on liver enzyme levels of coffee oil containing hardly any kahweol is similar to that of coffee oil containing high amounts of kahweol. Therefore it is unlikely that kahweol is the component of coffee oil that is responsible for the effect. Furthermore, we conclude that otherwise unexplained elevation of liver enzyme levels observed in patients might be caused by a switch from consumption of filtered coffee to unfiltered coffee

Midbrain-Hindbrain Involvement in Septo-Optic Dysplasia

BACKGROUND AND PURPOSE: Midbrain-hindbrain involvement in septo-optic dysplasia has not been well described, despite reported mutations of genes regulating brain stem patterning. We aimed to describe midbrain-hindbrain involvement in patients with septo-optic dysplasia and to identify possible clinical-neuroimaging correlations. MATERIALS AND METHODS: Using MR imaging, we categorized 38 patients (21 males) based on the presence (group A, 21 patients) or absence (group B, 17 patients) of visible brain stem anomalies. We measured height and anteroposterior diameter of midbrain, pons, and medulla, anteroposterior midbrain/pons diameter (M/P ratio), vermian height, and tegmento-vermian angle, and compared the results with 114 healthy age-matched controls. Furthermore, patients were subdivided based on the type of midline anomalies. The associations between clinical and neuroradiological features were investigated. Post hoc tests were corrected according to Bonferroni adjustment (pB). RESULTS: Patients with brain stem abnormalities had smaller anteroposterior pons diameter than controls (pB CONCLUSION: Midbrain-hindbrain abnormalities are a significant, albeit underrecognized, component of the septo-optic dysplasia spectrum, and are significantly associated with developmental delay in affected patients

Targeting of Pseudorabies Virus Structural Proteins to Axons Requires Association of the Viral Us9 Protein with Lipid Rafts

The pseudorabies virus (PRV) Us9 protein plays a central role in targeting viral capsids and glycoproteins to axons of dissociated sympathetic neurons. As a result, Us9 null mutants are defective in anterograde transmission of infection in vivo. However, it is unclear how Us9 promotes axonal sorting of so many viral proteins. It is known that the glycoproteins gB, gC, gD and gE are associated with lipid raft microdomains on the surface of infected swine kidney cells and monocytes, and are directed into the axon in a Us9-dependent manner. In this report, we determined that Us9 is associated with lipid rafts, and that this association is critical to Us9-mediated sorting of viral structural proteins. We used infected non-polarized and polarized PC12 cells, a rat pheochromocytoma cell line that acquires many of the characteristics of sympathetic neurons in the presence of nerve growth factor (NGF). In these cells, Us9 is highly enriched in detergent-resistant membranes (DRMs). Moreover, reducing the affinity of Us9 for lipid rafts inhibited anterograde transmission of infection from sympathetic neurons to epithelial cells in vitro. We conclude that association of Us9 with lipid rafts is key for efficient targeting of structural proteins to axons and, as a consequence, for directional spread of PRV from pre-synaptic to post-synaptic neurons and cells of the mammalian nervous system