DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Advanced high performance vehicle frame design by means of topology optimization

Automotive chassis design, often based on the company know-how and the designer experience, usually leads to consolidated solutions that are poorly innovative and not necessarily altogether efficient. Optimization techniques are powerful means for systematic design that can make it possible to avoid this drawback. The present study proposes a methodology for automotive chassis design based on topology, topometry and size optimizations coupled with fem analyses. In particular, the methodology is applied to the design of a chassis suitable for a rear-central engine high performance car. A massive 3d fem model is conceived, in order to respect the geometrical requirements yet leaving maximum freedom to the topology optimization algorithm. Shell mod- els are employed for the subsequent topometry and size optimizations. The objective is the minimization of the chassis mass in fulfillment of a given set of structural performance constraints. The results demonstrate the general applicability of the method proposed

Advanced high performance vehicle frame design by means of topology optimization

Automotive chassis design, often based on the company know-how and the designer experience, usually leads to consolidated solutions that are poorly innovative and not necessarily altogether efficient. Optimization techniques are powerful means for systematic design that can make it possible to avoid this drawback. The present study proposes a methodology for automotive chassis design based on topology, topometry and size optimizations coupled with fem analyses. In particular, the methodology is applied to the design of a chassis suitable for a rear-central engine high performance car. A massive 3d fem model is conceived, in order to respect the geometrical requirements yet leaving maximum freedom to the topology optimization algorithm. Shell mod- els are employed for the subsequent topometry and size optimizations. The objective is the minimization of the chassis mass in fulfillment of a given set of structural performance constraints. The results demonstrate the general applicability of the method proposed

Impact of Spiramycin Treatment and Gestational Age on Maturation of Toxoplasma gondii Immunoglobulin G Avidity in Pregnant Women

The objective of the present study was to investigate the maturation of immunoglobulin G (IgG) avidity after Toxoplasma gondii seroconversion during pregnancy and the factors that affect IgG avidity over time. The study used 309 serum samples from 117 women and a multiple linear mixed regression analysis to show the patterns of variation of IgG avidity throughout gestation. The IgG avidity ratios and the patterns of their evolution with time were quite diverse among the women and were statistically heterogeneous (P = 0.011); however, the trend was toward a statistically significant increase (P < 0.0001). On average, a 1.0167-fold increase was observed for each additional gestational week after the putative date of infection. At 12 weeks after putative infection (the expected IgG avidity maturation time), the mean avidity ratio was 16.6% (95% confidence interval, 15.4 to 17.9%). At all times, the avidity ratio remained significantly heterogeneous among the women (P < 0.05); for 95% of them, that ratio ranged from 7.8 to 35.3% at 12 weeks after putative infection. Maternal age at the putative time of infection did not influence the maturation of IgG avidity. However, on average, a 1.009-fold decrease (P = 0.03) in that avidity was observed for each additional week of gestational age before infection and a 1.03-fold increase (P = 0.0003) was observed for each additional week of delay to the onset of spiramycin treatment. The rate of increase in the avidity ratio was lower if infection occurred late in pregnancy and higher if the delay to treatment was long. This information cannot allow accurate determination of the delay since the time of infection. The present results provide support for interpretation of the assay and caution against overinterpretation

Detection of interleukin-8 in the induced sputum of workers exposed to low airborne asbestos levels

The concentration of interleukin-8 (IL-8) in the induced sputum of 17 workers exposed to low airborne asbestos levels and of 10 controls was determined. IL-8 levels were statistically significantly increased in the asbestos exposed group compared to controls. This finding underlines the usefulness of the study of proinflammatory mediators as possible predictors of alveolar damage