Cancer risk evaluation: Preliminary analysis of inflammatory biomarkers in farmers exposed to zoonotic agents

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Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

It has been confirmed that multidrug resistant (MDR) human melanoma cells are more sensitive than their wild-type counterparts to H(2)O(2) and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. The metabolites formed by BSAO and spermine are more toxic than exogenous H(2)O(2) and acrolein, even thou-h their concentration is lower during the initial phase of incubation due to their more gradual release than the exogenous products. Both wild-type and MDR cells, after pre-treatment with MDL 72527, an inactivator of polyamine oxidase and a lysosomotropic compound, show to be sensitized to subsequent exposure to BSAO/spermine. Evidence of ultrastructural aberrations and acridine orange release from lysosomes is presented in this work that is in favor of the permeabilization of the lysosomal membrane as the major cause of sensitization by MDL 72527. Owing to its lysosomotropic effect, pre-treatment with MDL 72527 amplifies the ability of the metabolites formed from spermine by oxidative deamination to induce cell death. Since it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumor cells, it is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting

Anticancer drugs and hyperthermia enhance cytotoxicity induced by polyamine enzymatic oxidation products

A correlation between regulation of cell proliferation and polyamine metabolism is described. The latter can enter protein synthesis through the modification of eukaryotic initiation factor 5A (eIF5A) and the formation of the peculiar amino acid hypusine. Specific inhibitors of hypusine formation induce apoptosis that can be potentiated by the combination with cytokines such as interferon alpha (IFN alpha) that itself decreases hypusine synthesis. We have also demonstrated that the concomitant treatment of cancer cells with IFNa and the protein synthesis inhibitor fusion protein TGF alpha/Pseudomonas Aeruginosa toxin synergize in inducing cancer cell growth inhibition. Another way used by polyamines to induce apoptosis is the generation of intracellular oxidative stress through the interaction with bovine serum amine oxidase (BSAO). This enzyme used simultaneously to spermine induces apoptosis, necrosis, inhibition of cell proliferation and inhibition of DNA and protein synthesis in several cell types. The enzymatic oxidation products of polyamine, H2O2 and aldehyde(s) cause these effects. We have recently found that the cytotoxicity of anti-cancer agents, either etoposide or docetaxel, in cancer cells is potentiated in the presence of BSAO/Spermine. In conclusion, polyamine metabolites could be useful in the design of new therapeutic strategies

2 years-long monitoring of <i>Codium elisabethae</i> population dynamics in the Azorian reef ecosystem (Faial Island) with seabed imagery

In the Site of Community Interest (Natura, 2000) of Monte-da-Guia (Faial, Azores), two sites were delimited in order to investigate particularly the links between habitat characteristics, population structure, distribution and dynamics of the green alga Codium elisabethae. The first site is a large protected rocky seafloor of an ancient volcano crater (20m deep) and classified as no-go reserve. It shows very high density stands of Codium elisabethae (up to 105 ind.m-2), representing the main vegetal biomass. At similar depth but distant of about two kilometers, the second site is in a more exposed area, where a sparse population (about 13 ind.m-2) occupies rocky tables and boulders emerging from shallow sandy deposits. These contrasting densities reflect different population dynamic equilibrium resulting from the particular environmental pressures of each site. A two year population survey started in August 2003, aiming principally at building submarine image mosaics of each site on a seasonal basis. Further, a computer assisted detection is run on the images to derive valuable information about the studied macroalgae. This technique allows to study a comparatively large zone regarding to the diving time invested so as to integrate spatial patchiness and to focus on the temporal evolution of well identified individuals. The imagery methodology was validated with in situ measurements, confirming the adequacy of the 1cm precision size histograms produced, when considering individuals larger than 5cm diameter. Seasonal fluctuations of growth rate (from 0.5 to 3cm.month-1) and primary production (from 1 to 15kg.m-².month-1) could be described. For both sites studied, density, biomass and cover rate seemed affected by a seasonal variation with reduction starting in end summer early autumn. In both sites, the reduction was sharp in the fall 2003 and population density didn’t recover completely in spring and summer 2004. During the following year, population of the protected site could maintain density and biomass, while population of the exposed site dropped continuously all year. Last processing step will search to relate statistically these different population evolutions to the benthic environmental constraints measured in both sites during the year 2004-2005 (temperature, currents, turbidity, photosynthetic active radiation, nutrients). Differences in hydrodynamic exposure of both sites could be part of the answer, but observed differences in the reproduction intensity of these two populations is an important factor, and remains unexplained

Effect of peroxides on spermine transport in rat brain and liver mitochondria.

The polyamine spermine is transported into the matrix of various types of mitochondria by a specific uniporter system identified as a protein channel. This mechanism is regulated by the membrane potential; other regulatory effectors are unknown. This study analyzes the transport of spermine in the presence of peroxides in both isolated rat liver and brain mitochondria, in order to evaluate the involvement of the redox state in this mechanism, and to compare its effect in both types of mitochondria. In liver mitochondria peroxides are able to inhibit spermine transport. This effect is indicative of redox regulation by the transporter, probably due to the presence of critical thiol groups along the transport pathway, or in close association with it, with different accessibility for the peroxides and performing different functions. In brain mitochondria, peroxides have several effects, supporting the hypothesis of a different regulation of spermine transport. The fact that peroxovanadate can inhibit tyrosine phosphatases in brain mitochondria suggests that mitochondrial spermine transport is regulated by tyrosine phosphorylation in this organ. In this regard, the evaluation of spermine transport in the presence of Src inhibitors suggests the involvement of Src family kinases in this process. It is possible that phosphorylation sites for Src kinases are present in the channel pathway and have an inhibitory effect on spermine transport under regulation by Src kinases. The results of this study suggest that the activity of the spermine transporter probably depends on the redox and/or tyrosine phosphorylation state of mitochondria, and that its regulation may be different in distinct organs

Anticancer drugs and hyperthermia enhance cytotoxicity induced by polyamine enzymatic oxidation products Review Article

Summary. A correlation between regulation of cell proliferation and polyamine metabolism is described. The latter can enter protein synthesis through the modification of eukaryotic initiation factor 5A (eIF5A) and the formation of the peculiar amino acid hypusine. Specific inhibitors of hypusine formation induce apoptosis that can be potentiated by the combination with cytokines such as interferona (IFNa) that itself decreases hypusine synthesis. We have also demonstrated that the concomitant treatment of cancer cells with IFNa and the protein synthesis inhibitor fusion protein TGFa=Pseudomonas Aeruginosa toxin synergize in inducing cancer cell growth inhibition. Another way used by polyamines to induce apoptosis is the generation of intracellular oxidative stress through the interaction with bovine serum amine oxidase (BSAO). This enzyme used simultaneously to spermine induces apoptosis, necrosis, inhibition of cell proliferation and inhibition of DNA and protein synthesis in several cell types. The enzymatic oxidation products of polyamine, H 2 O 2 and aldehyde(s) cause these effects. We have recently found that the cytotoxicity of anti-cancer agents, either etoposide or docetaxel, in cancer cells is potentiated in the presence of BSAO=Spermine. In conclusion, polyamine metabolites could be useful in the design of new therapeutic strategies

PARP-1 modulates amyloid beta peptide-induced neuronal damage.

Amyloid beta peptide (A beta) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with A beta(25-35) fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. A beta(25-35) induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following A beta(25-35) exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that A beta(25-35) induces DNA damage which in turn activates PARP-1. Challenge with A beta(25-35) is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, A beta(25-35) via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by A beta and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed