[Possible use of microRNAs as biomarkers for monitoring of workers exposed to asbestos]. / Possibile impiego di microRNA come biomarcatori nel monitoraggio dei lavoratori professionalmente esposti ad amianto.

Exposure to asbestos is the predominant cause of pleural mesothelioma (PM). The PM is a tumor difficult to diagnose, chemoresistant, and with rising Incidence. The long latency periods and the lack of preventive and therapeutic strategies for the MP, suggest that asbestos will be a social and health issue in the near future. Therefore, this overview focuses on current knowledge of epigenetic alterations and on the key role of microRNAs, small RNAs that negatively regulate gene expression, as biomarkers in PM development. Dysregulated microRNA expression pattern is specific for different cancers, including MP. MicroRNA expression analysis is a promising tool for diagnosis, typing of MP than normal tissue and other lung tumors and monitoring of new therapies. However, a better knowledge of miRNA signatures in PM is still necessary to verify the contribution of specific miRNAs as diagnostic biomarkers, also compared to different asbestos forms, exposure and subject work history.

[Epigenetics and environmental exposure to xenobiotics]. / Epigenetica ed esposizione ambientale a xenobiotici.

Environmental pollution, together with predisposing genetic factors, plays a key role in determining short and long-term adverse effects on human health. In the industrialized countries the identification of etiology related to diseases of environmental origin has then become a research of priority interest. With regard to this, it has been widely demonstrated that different chemical compounds, such as endocrine disruptors, are able to modify the epigenetic characteristics of a human being. According to recent studies, the paradigm "genotype is strongly correlated with a phenotype" is changing in favor of the concept that a phenotype is defined by a "genotype and by an epigenome". Thus, there is a genotype identical for all cells associated to the epigenome that causes changes in gene expression without modifying the nucleotide sequence of the genome, through alterations in DNA methylation, histone modifications and the pathway of small non-coding RNAs. The epigenome is easily affected by different factors, such as aberrations of normal epigenetic processes that can be caused by environmental factors as exposure to xenobiotics, social behavior and nutritional deficiencies. Epigenetic changes are thus a biological response to environmental stress factors and may be transmitted to the offspring. As the elimination of the environmental factor determines the possible reversion of epigenetic modifications, it seems not to play a role in the natural selection process. However, epigenetic aberrations affect gene expression by interfering with the stability and survival of cells and with the inactivation of onco-suppressor genes. Thus, it is of considerable interest to investigate about the possible elements of induction of epigenetic processes in order to implement prevention protocols. Moreover, the gene expression screening through high through-put techniques like microarray, represent a new tool for the identification of new epigenetic indicators in order to monitor the early biological effects on the population exposed to xenobiotics.

[Gene expression and environmental exposure to xenobiotics: overview and applications]. / Espressione genica ed esposizione ambientale a xenobiotici: overview e applicazioni.

Industrial chemicals, pesticides, pharmaceuticals, foods, heavy metals, air pollutants, and naturally occurring substances, are an integral part of our daily lives. Environmental exposure can induce changes in gene regulation associated with human diseases. A new discipline of toxicology is "predictive toxicology" that defines the relationship between the structure and activity of the genome and the adverse biological effects of exogenous agents. Toxicogenomic technologies allow complete assessment of the functional activity of biochemical pathways, and of the structural genetic (sequence) differences among individuals (polymorphisms), that were previously unattainable. Microarray technology provides the means to study multiple pathways and mechanisms at concurrent times. Gene expression is a sensitive indicator of toxicant exposure, disease state, and cellular metabolism and thus represents a way of characterising how cells and organisms adapt to changes in the external environment. The application of these technologies to toxicology can lead us into a new era when genotypes and toxicant-induced genome expression, proteins, and metabolite patterns can be used to screen compounds for hazard identification, to monitor individual exposure to toxicants, to track cellular responses to different doses, to assess mechanisms of action, and to predict individual variability in sensitivity to toxicants and potential ways to improve risk assessment.

Interferon gamma stimulates cell-mediated transmission of HIV type 1 from abortively infected endothelial cells.

Human umbilical vein endothelial cells (HUVEC) can be abortively infected with HIV-1, but virus production is rescued by T cells. The influence of interferon gamma (IFN-gamma) in this experimental system has been investigated. HUVEC either untreated or treated with IFN-gamma were infected with HIV-1 and cocultivated with rescuer T cells. Virus yield was subsequently assessed as antigen or infectivity present in the cocultures supernatants. Viral DNA in HUVEC was detected by polymerase chain reaction. Transmission electron microscopy was used to establish direct interactions between HUVEC and T cells. Intercellular adhesion molecule (ICAM)-1 expression by HUVEC was measured by enzyme-linked immunoassay. Monoclonal antibodies (MAbs) to adhesion molecules were used to block the rescue of infection by T cells. Treatment of HUVEC with IFN-gamma caused a dose-dependent enhancement of HIV-1 yield in cocultures of HUVEC with either lymphoblastoid or normal T cells. IFN-gamma was effective also when administered to HUVEC 1 day after infection. Neither HIV-1 adsorption nor virus reverse transcription was stimulated by IFN. Physical contact between HIV-1-infected HUVEC and rescuer T cells was observed, and discrete tracts of discontinuity between the juxtaposed membranes were detected, being more frequent when HUVEC had been treated with IFN-gamma. Treatment with IFN determined an increase of ICAM-1 expression by HUVEC, and anti ICAM-1 MAbs inhibited HIV-1 rescue, being more effective when HUVEC had been exposed to IFN-gamma. Treatment of T cells with anti-LFA-1 Mab also inhibited HIV-1 rescue. The enhancing effect of IFN-gamma could be the result of stimulated transfer of HIV-1 infection from HUVEC to T cells, possibly mediated by enhanced expression of ICAM-1 by HUVEC, that could, in turn, enhance the efficiency of membrane interaction with T cells. Since in HIV-1-infected patients circulating IFN-gamma is enhanced, our results can have pathogenetic implications.

HIV type 1 grown on interferon gamma-treated U937 cells shows selective increase in virion-associated intercellular adhesion molecule 1 and HLA-DR and enhanced infectivity for CD4-negative cells.

Cellular adhesion molecules, such as ICAM-1, -2, and -3; LFA-1; and HLA class I and II are incorporated into HIV-1 virions during budding from infected cells. These virion-associated molecules can be involved in the adsorption to susceptible cells displaying the corresponding counterligands. A number of cytokines have been shown to upregulate the cellular expression of adhesion molecules, such as ICAM-1 and HLA-DR. In this study we investigated the effects of IFN-gamma on the incorporation of ICAM-1, LFA-1, and HLA-DR into mature HIV-1 progeny from chronically infected cells. The ability of such virus progeny to infect either CD4-positive or -negative cells was also investigated. The results indicate that IFN-gamma stimulates the expression of ICAM-1 and of HLA-DR on HIV-1-infected cells, whereas LFA-1 expression is unaffected. The same modifications were also observed on virus progeny, because specific MAbs to ICAM-1 and HLA-DR captured infectious HIV-1 from IFN-treated cells with higher efficiency as compared to virus from control cells, whereas virus binding to anti LFA-1 MAb was unchanged. Moreover, the HIV-1 progeny released from IFN-treated cells showed an increased ability to bind to and to infect CD4-negative cells, whereas the infectivity was basically unchanged for CD4-positive cells. Our results suggest that cytokines, as well as other soluble factors, may expand the host cell range of HIV-1, possibly through modifications of the cell-derived surface molecules on the virions.(ABSTRACT TRUNCATED AT 250 WORDS)