Publications by authors named "Alessandra Pulliero"

50 Publications

Prevention of Covid-19 Infection and Related Complications by Ozonized Oils.

J Pers Med 2021 Mar 22;11(3). Epub 2021 Mar 22.

Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.

Background: The COVID-19 pandemic continues to ravage the human population; therefore, multiple prevention and intervention protocols are being rapidly developed. The aim of our study was to develop a new chemo-prophylactic/-therapeutic strategy that effectively prevents COVID-19 and related complications.

Methods: In in vitro studies, COVID-19 infection-sensitive cells were incubated with human oropharyngeal fluids containing high SARS-CoV-2 loads. Levels of infection were determined via intra-cellular virus loads using quantitative PCR (qPCR). Efficacies for infection prevention were determined using several antiviral treatments: lipid-encapsulated ozonized oil (HOO), water-soluble HOO (HOOws), UV, and hydrogen peroxide. In in vivo studies, safety and efficacy of HOO in fighting COVID-19 infection was evaluated in human subjects.

Results: HOO in combination with HOOws was the only treatment able to fully neutralize SARS-CoV-2 as well as its capacity to penetrate and reproduce inside sensitive cells. Accordingly, the feasibility of using HOO/HOOws was tested in vivo. Analysis of expired gas in healthy subjects indicates that HOO administration increases oxygen availability in the lung. For our human studies, HOO/HOOws was administered to 52 cancer patients and 21 healthy subjects at high risk for COVID-19 infection, and all of them showed clinical safety. None of them developed COVID-19 infection, although an incidence of at least 11 cases was expected. Efficacy of HOO/HOOws was tested in four COVID-19 patients obtaining recovery and qPCR negativization in less than 10 days.

Conclusions: Based on our experience, the HOO/HOOws treatment can be administered at standard doses (three pills per day) for chemo-prophylactic purposes to healthy subjects for COVID-19 prevention and at high doses (up to eight pills per day) for therapeutic purposes to infected patients. This combined prevention strategy can provide a novel protocol to fight the COVID-19 pandemic.
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http://dx.doi.org/10.3390/jpm11030226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004285PMC
March 2021

Relationship between the miRNA Profiles and Oncogene Mutations in Non-Smoker Lung Cancer. Relevance for Lung Cancer Personalized Screenings and Treatments.

J Pers Med 2021 Mar 5;11(3). Epub 2021 Mar 5.

Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy.

Oncogene mutations may be drivers of the carcinogenesis process. MicroRNA (miRNA) alterations may be adaptive or pathogenic and can have consequences only when mutation in the controlled oncogenes occurs. The aim of this research was to analyze the interplay between miRNA expression and oncogene mutation. A total of 2549 miRNAs were analyzed in cancer tissue-in surrounding normal lung tissue collected from 64 non-smoking patients and in blood plasma. Mutations in 92 hotspots of 22 oncogenes were tested in the lung cancer tissue. MicroRNA alterations were related to the mutations occurring in cancer patients. Conversely, the frequency of mutation occurrence was variable and spanned from the k-ras and p53 mutation detected in 30% of patients to 20% of patients in which no mutation was detected. The prediction of survival at a 3-year follow up did not occur for mutation analysis but was, conversely, well evident for miRNA analysis highlighting a pattern of miRNA distinguishing between survivors and death in patients 3 years before this clinical onset. A signature of six lung cancer specific miRNAs occurring both in the lungs and blood was identified. The obtained results provide evidence that the analysis of both miRNA and oncogene mutations was more informative than the oncogene mutation analysis currently performed in clinical practice.
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http://dx.doi.org/10.3390/jpm11030182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999775PMC
March 2021

Precision Medicine and Public Health: New Challenges for Effective and Sustainable Health.

J Pers Med 2021 Feb 16;11(2). Epub 2021 Feb 16.

Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

The development of high-throughput omics technologies represents an unmissable opportunity for evidence-based prevention of adverse effects on human health. However, the applicability and access to multi-omics tests are limited. In Italy, this is due to the rapid increase of knowledge and the high levels of skill and economic investment initially necessary. The fields of human genetics and public health have highlighted the relevance of an implementation strategy at a national level in Italy, including integration in sanitary regulations and governance instruments. In this review, the emerging field of public health genomics is discussed, including the polygenic scores approach, epigenetic modulation, nutrigenomics, and microbiomes implications. Moreover, the Italian state of implementation is presented. The omics sciences have important implications for the prevention of both communicable and noncommunicable diseases, especially because they can be used to assess the health status during the whole course of life. An effective population health gain is possible if omics tools are implemented for each person after a preliminary assessment of effectiveness in the medium to long term.
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http://dx.doi.org/10.3390/jpm11020135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920275PMC
February 2021

Potential Role of miRNAs in the Acquisition of Chemoresistance in Neuroblastoma.

J Pers Med 2021 Feb 7;11(2). Epub 2021 Feb 7.

Department of Experimental Medicine, University of Genova, 16100 Genova, Italy.

Neuroblastoma (NB) accounts for about 8-10% of pediatric cancers, and the main causes of death are the presence of metastases and the acquisition of chemoresistance. Metastatic NB is characterized by amplification that correlates with changes in the expression of miRNAs, which are small non-coding RNA sequences, playing a crucial role in NB development and chemoresistance. In the present study, miRNA expression was analyzed in two human -amplified NB cell lines, one sensitive (HTLA-230) and one resistant to Etoposide (ER-HTLA), by microarray and RT-qPCR techniques. These analyses showed that miRNA-15a, -16-1, -19b, -218, and -338 were down-regulated in ER-HTLA cells. In order to validate the presence of this down-regulation in vivo, the expression of these miRNAs was analyzed in primary tumors, metastases, and bone marrow of therapy responder and non-responder pediatric patients. Principal component analysis data showed that the expression of miRNA-19b, -218, and -338 influenced metastases, and that the expression levels of all miRNAs analyzed were higher in therapy responders in respect to non-responders. Collectively, these findings suggest that these miRNAs might be involved in the regulation of the drug response, and could be employed for therapeutic purposes.
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http://dx.doi.org/10.3390/jpm11020107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916079PMC
February 2021

The Molecular Mechanisms of Adaptive Response Related to Environmental Stress.

Int J Mol Sci 2020 Sep 25;21(19). Epub 2020 Sep 25.

Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine, 14220 Prague, Czech Republic.

The exposure of living organisms to environmental stress triggers defensive responses resulting in the activation of protective processes. Whenever the exposure occurs at low doses, defensive effects overwhelm the adverse effects of the exposure; this adaptive situation is referred to as "hormesis". Environmental, physical, and nutritional hormetins lead to the stimulation and strengthening of the maintenance and repair systems in cells and tissues. Exercise, heat, and irradiation are examples of physical hormetins, which activate heat shock-, DNA repair-, and anti-oxidative-stress responses. The health promoting effect of many bio-actives in fruits and vegetables can be seen as the effect of mildly toxic compounds triggering this adaptive stimulus. Numerous studies indicate that living organisms possess the ability to adapt to adverse environmental conditions, as exemplified by the fact that DNA damage and gene expression profiling in populations living in the environment with high levels of air pollution do not correspond to the concentrations of pollutants. The molecular mechanisms of the hormetic response include modulation of (a) transcription factor Nrf2 activating the synthesis of glutathione and the subsequent protection of the cell; (b) DNA methylation; and (c) microRNA. These findings provide evidence that hormesis is a toxicological event, occurring at low exposure doses to environmental stressors, having the benefit for the maintenance of a healthy status.
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http://dx.doi.org/10.3390/ijms21197053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582272PMC
September 2020

Anticancer effect of physical activity is mediated by modulation of extracellular microRNA in blood.

Oncotarget 2020 Jun 2;11(22):2106-2119. Epub 2020 Jun 2.

Department of Experimental Medicine, University of Genoa, Genoa, Italy.

Epidemiological studies provide evidence that physical activity reduces the risk of cancer, particularly of breast cancer. However, little is known about the underlying molecular mechanisms as related to microRNAs. The goal of the herein presented study is to explore the involvement of miRNAs in beneficial effects exerted by physical activity in breast cancer prevention. Thirty subjects (mean age: 57.1 ± 14.7 years) underwent 45 minutes of treadmill walking under standardized conditions. The levels of extracellular miRNAs were evaluated in blood plasma before and after structured exercise by means of microarray analysis of 1,900 miRNAs identifying mostly modulated miRNAs. Structured exercise has been found to modulate the expression of 14 miRNAs involved in pathways relevant to cancer. The different expression of two miRNAs involved in breast cancer progression, i. e. up-regulation of miR-206 and down-regulation of anti-miR-30c, were the most striking effects induced by exercise. The biological effects of these miRNAs were investigated in MCF-7 human breast cancer cells. miR-206 transfection and anti-miR-30c silencing, inhibited cell growth and increased apoptosis of MCF-7 cells. Moreover, the combined use of the two miRNAs further enhanced apoptosis and induced growth arrest in the G1/S phase of cell cycle. Our results support that physical activity effectively change the expression of extracellular miRNAs. Specifically, miR-206 up-regulation and anti-miR-30c down-regulation act as suppressors in breast cancer cells. The evaluation of these miRNAs in blood can be used as non-invasive biomarkers for breast cancer prevention.
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http://dx.doi.org/10.18632/oncotarget.27609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275780PMC
June 2020

Radon Biomonitoring and microRNA in Lung Cancer.

Int J Mol Sci 2020 Mar 20;21(6). Epub 2020 Mar 20.

Department of Experimental Medicine, University of Genoa, I-16132 Genoa, Italy.

Radon is the number one cause of lung cancer in non-smokers. microRNA expression in human bronchial epithelium cells is altered by radon, with particular reference to upregulation of miR-16, miR-15, miR-23, miR-19, miR-125, and downregulation of let-7, miR-194, miR-373, miR-124, miR-146, miR-369, and miR-652. These alterations alter cell cycle, oxidative stress, inflammation, oncogene suppression, and malignant transformation. Also DNA methylation is altered as a consequence of miR-29 modification induced by radon. Indeed miR-29 targets DNA methyltransferases causing inhibition of CpG sites methylation. Massive microRNA dysregulation occurs in the lung due to radon expose and is functionally related with the resulting lung damage. However, in humans this massive lung microRNA alterations only barely reflect onto blood microRNAs. Indeed, blood miR-19 was not found altered in radon-exposed subjects. Thus, microRNAs are massively dysregulated in experimental models of radon lung carcinogenesis. In humans these events are initially adaptive being aimed at inhibiting neoplastic transformation. Only in case of long-term exposure to radon, microRNA alterations lead towards cancer development. Accordingly, it is difficult in human to establish a microRNA signature reflecting radon exposure. Additional studies are required to understand the role of microRNAs in pathogenesis of radon-induced lung cancer.
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http://dx.doi.org/10.3390/ijms21062154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139524PMC
March 2020

miRNA Regulation of Glutathione Homeostasis in Cancer Initiation, Progression and Therapy Resistance.

Microrna 2020 ;9(3):187-197

Department of Experimental Medicine, University of Genoa, Genoa, Italy.

Glutathione (GSH) is the most abundant antioxidant that contributes to regulating the cellular production of Reactive Oxygen Species (ROS) which, maintained at physiological levels, can exert a function of second messengers in living organisms. In fact, it has been demonstrated that moderate amounts of ROS can activate the signaling pathways involved in cell growth and proliferation, while high levels of ROS induce DNA damage leading to cancer development. Therefore, GSH is a crucial player in the maintenance of redox homeostasis and its metabolism has a role in tumor initiation, progression, and therapy resistance. Our recent studies demonstrated that neuroblastoma cells resistant to etoposide, a common chemotherapeutic drug, show a partial monoallelic deletion of the locus coding for miRNA 15a and 16-1 leading to a loss of these miRNAs and the activation of GSH-dependent responses. Therefore, the aim of this review is to highlight the role of specific miRNAs in the modulation of intracellular GSH levels in order to take into consideration the use of modulators of miRNA expression as a useful strategy to better sensitize tumors to current therapies.
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http://dx.doi.org/10.2174/2211536609666191218103220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366003PMC
January 2020

Human Papillomavirus Infections, Cervical Cancer and MicroRNAs: An Overview and Implications for Public Health.

Microrna 2020 ;9(3):174-186

Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy.

Human Papillomavirus (HPV) is among the most common sexually transmitted infections in both females and males across the world that generally do not cause symptoms and are characterized by high rates of clearance. Persistent infections due at least to twelve well-recognized High-Risk (HR) or oncogenic genotypes, although less frequent, can occur, leading to diseases and malignancies, principally cervical cancer. Three vaccination strategies are currently available for preventing certain HR HPVs-associated diseases, infections due to HPV6 and HPV11 low-risk types, as well as for providing cross-protection against non-vaccine genotypes. Nevertheless, the limited vaccine coverage hampers reducing the burden of HPV-related diseases globally. For HR HPV types, especially HPV16 and HPV18, the E6 and E7 oncoproteins are needed for cancer development. As for other tumors, even in cervical cancer, non-coding microRNAs (miRNAs) are involved in posttranscriptional regulation, resulting in aberrant expression profiles. In this study, we provide a summary of the epidemiological background for HPV occurrence and available immunization programs. In addition, we present an overview of the most relevant evidence of miRNAs deregulation in cervical cancer, underlining that targeting these biomolecules could lead to wide translational perspectives, allowing better diagnosis, prognosis and therapeutics, and with valuable applications in the field of prevention. The literature on this topic is rapidly growing, but advanced investigations are required to achieve more consistent findings on the up-regulated and down-regulated miRNAs in cervical carcinogenesis. Because the expression of miRNAs is heterogeneously reported, it may be valuable to assess factors and risks related to individual susceptibility.
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http://dx.doi.org/10.2174/2211536608666191026115045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366004PMC
January 2020

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor.

Carcinogenesis 2020 03;41(1):91-99

Department of Health Sciences, University of Genoa, Genoa, Italy.

Chronic inflammation plays a crucial role in the carcinogenesis process and, in particular, in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods.
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http://dx.doi.org/10.1093/carcin/bgz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456342PMC
March 2020

Human primary endothelial cells are impaired in nucleotide excision repair and sensitive to benzo[a]pyrene compared with smooth muscle cells and pericytes.

Sci Rep 2019 09 24;9(1):13800. Epub 2019 Sep 24.

Institute of Toxicology, University Medical Center, Mainz, 55131, Germany.

The endothelium represents the inner cell layer of blood vessels and is supported by smooth muscle cells and pericytes, which form the vessel structure. The endothelium is involved in the pathogenesis of many diseases, including the development of atherosclerosis. Due to direct blood contact, the blood vessel endothelium is inevitably exposed to genotoxic substances that are systemically taken up by the body, including benzo[a]pyrene, which is a major genotoxic component in cigarette smoke and a common environmental mutagen and human carcinogen. Here, we evaluated the impact of benzo[a]pyrene diol epoxide (BPDE), which is the reactive metabolite of benzo[a]pyrene, on the three innermost vessel cell types. Primary human endothelial cells (HUVEC), primary human smooth muscle cells (HUASMC) and primary human pericytes (HPC) were treated with BPDE, and analyses of cytotoxicity, cellular senescence and genotoxic effects were then performed. The results showed that HUVEC were more sensitive to the cytotoxic activity of BPDE than HUASMC and HPC. We further show that HUVEC display a detraction in the repair of BPDE-induced adducts, as determined through the comet assay and the quantification of BPDE adducts in post-labelling experiments. A screening for DNA repair factors revealed that the nucleotide excision repair (NER) proteins ERCC1, XPF and ligase I were expressed at lower levels in HUVEC compared with HUASMC and HPC, which corresponds with the impaired NER-mediated removal of BPDE adducts from DNA. Taken together, the data revealed that HUVEC exhibit an unexpected DNA repair-impaired phenotype, which has implications on the response of the endothelium to genotoxicants that induce bulky DNA lesions, including the development of vascular diseases resulting from smoking and environmental pollution.
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http://dx.doi.org/10.1038/s41598-019-49953-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760230PMC
September 2019

A Global MicroRNA Profile in Fanconi Anemia: A Pilot Study.

Metab Syndr Relat Disord 2019 02 30;17(1):53-59. Epub 2018 Oct 30.

1 Mutagenesis and Preventive Oncology, Ospedale Policlinico San Martino, Genova, Italy.

Purpose: Fanconi anemia (FA) is a complex tumor-prone disease defined by an entangled genotype and phenotype. Despite enormous efforts in the last 20 years, a comprehensive and integrated view of the disease is still missing. The aim of this pilot study was to establish whether a global microRNA (miRNA) analysis approach could be helpful in defining aspects in FA phenotype, which might deserve future attention with the perspective to develop miRNA-based therapies.

Methods: miRNA array were employed to characterize the global miRNA (miRNoma) profile of FA RNA samples with respect to normal samples.

Results: We report and compare miRNA profile from two FA established cell lines and three FA patients. This analysis reveals that 36 and 64 miRNAs, respectively, are found differentially expressed (>2-fold variation and P < 0.05) in the samples from FA cell lines and FA patients. Overlap of these data results in 24 miRNAs as shared in the two sample populations. Available bioinformatics methods were used to predict target genes for the differentially expressed miRNAs and to perform pathway enrichment analysis.

Conclusions: Seven pathway results associated with the FA phenotype. It is interesting to note that some of these pathways were previously unrelated to FA phenotype. It might be important to focus on these pathways not previously emerged as dysfunctional in FA to better define the pathophysiological context of this disease. This is the first report of a global miRNA analysis in FA.
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http://dx.doi.org/10.1089/met.2018.0085DOI Listing
February 2019

Modulation of genomic and epigenetic end-points by celecoxib.

Oncotarget 2018 Sep 14;9(72):33656-33681. Epub 2018 Sep 14.

Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.

Celecoxib, a nonsteroidal anti-inflammatory drug that selectively targets cyclooxygenase-2, is a promising cancer chemopreventive agent. However, safety concerns have been raised in clinical trials evaluating its ability to prevent colorectal adenomas. The rationale for the herein reported studies was to analyze genomic and epigenetic end-points aimed at investigating both the chemopreventive properties of celecoxib towards cigarette smoke-associated molecular alterations and its possible adverse effects. We carried out three consecutive studies in mice treated with either smoke and/or celecoxib. investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations (expression of 1,135 microRNAs) in lung and blood of Swiss H mice; evaluated the formation of DNA adducts in lung, liver, and heart; and evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice. Surprisingly, the oral administration of celecoxib to smoke-free mice resulted in the formation of DNA adducts in both lung and heart and in dysregulation of microRNAs in mouse organs and body fluids. On the other hand, celecoxib attenuated smoke-related DNA damage and dysregulation of microRNA expression. In conclusion, celecoxib showed pleiotropic properties and multiple mechanisms by counteracting the molecular damage produced by smoke in a variety of organs and body fluids. However, administration of celecoxib to non-smoking mice resulted in evident molecular alterations, also including DNA and RNA alterations in the heart, which may bear relevance in the pathogenesis of the cardiovascular adverse effects of this drug.
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http://dx.doi.org/10.18632/oncotarget.26062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154745PMC
September 2018

Etoposide-resistance in a neuroblastoma model cell line is associated with 13q14.3 mono-allelic deletion and miRNA-15a/16-1 down-regulation.

Sci Rep 2018 09 13;8(1):13762. Epub 2018 Sep 13.

Department of Experimental Medicine, General Pathology Section, University of Genova, Genova, Italy.

Drug resistance is the major obstacle in successfully treating high-risk neuroblastoma. The aim of this study was to investigate the basis of etoposide-resistance in neuroblastoma. To this end, a MYCN-amplified neuroblastoma cell line (HTLA-230) was treated with increasing etoposide concentrations and an etoposide-resistant cell line (HTLA-ER) was obtained. HTLA-ER cells, following etoposide exposure, evaded apoptosis by altering Bax/Bcl2 ratio. While both cell populations shared a homozygous TP53 mutation encoding a partially-functioning protein, a mono-allelic deletion of 13q14.3 locus, where the P53 inducible miRNAs 15a/16-1 are located, and the consequent miRNA down-regulation were detected only in HTLA-ER cells. This event correlated with BMI-1 oncoprotein up-regulation which caused a decrease in p16 tumor suppressor content and a metabolic adaptation of HTLA-ER cells. These results, taken collectively, highlight the role of miRNAs 15a/16-1 as markers of chemoresistance.
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http://dx.doi.org/10.1038/s41598-018-32195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137223PMC
September 2018

Inherent and toxicant-provoked reduction in DNA repair capacity: A key mechanism for personalized risk assessment, cancer prevention and intervention, and response to therapy.

Int J Hyg Environ Health 2018 08 21;221(7):993-1006. Epub 2018 Jul 21.

Shantou University Medical College, Shantou, China; University of Medicine and Pharmacy, Tirgu Mures, Romania; University of Texas Medical Branch, Galveston, TX, USA. Electronic address:

Genomic investigations reveal novel evidence which indicates that genetic predisposition and inherent drug response are key factors for development of cancer and for poor response to therapy. However, mechanisms for these outcomes and interactions with environmental factors have not been well-characterized. Therefore, cancer risk, prevention, intervention and prognosis determinations have still mainly been based on population, rather than on individualized, evaluations. The objective of this review was to demonstrate that a key mechanism which contributes to the determination is inherent and/or toxicant-provoked reduction in DNA repair capacity. In addition, functional and quantitative determination of DNA repair capacity on an individual basis would dramatically change the evaluation and management of health problems from a population to a personalized basis. In this review, justifications for the scenario were delineated. Topics to be presented include assays for detection of functional DNA repair deficiency, mechanisms for DNA repair defects, toxicant-perturbed DNA repair capacity, epigenetic mechanisms (methylation and miRNA expression) for alteration of DNA repair function, and bioinformatics approach to analyze large amount of genomic data. Information from these topics has recently been and will be used for better understanding of cancer causation and of response to therapeutic interventions. Consequently, innovative genomic- and mechanism-based evidence can be increasingly used to develop more precise cancer risk assessment, and target-specific and personalized medicine.
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http://dx.doi.org/10.1016/j.ijheh.2018.07.003DOI Listing
August 2018

A novel calix[4]pyrrole derivative as a potential anticancer agent that forms genotoxic adducts with DNA.

Sci Rep 2018 07 23;8(1):11075. Epub 2018 Jul 23.

Department of Health Sciences, University of Genova, Genova, Italy.

meso-(p-acetamidophenyl)-calix[4]pyrrole 3 was found to exhibit remarkable cytotoxicity towards A549 cancer cells. A comparative study including the isomer of 3 meso-(m-acetamidophenyl)-calix[4]pyrrole 5, as well as molecules containing 'fragments' of these structures, demonstrated that both the calix[4]pyrrole and the acetamidophenyl units are essential for high cytotoxicity. Although calix[4]pyrroles and other anion-complexing ionophores have recently been reported to induce apoptosis by perturbing cellular chloride concentrations, in our study an alternative mechanism has emerged, as proven by the isolation of covalent DNA adducts revealed by the P postlabelling technique. Preliminary pharmacokinetic studies indicate that 3 is able to cross the Blood-Brain-Barrier, therefore being a potential drug that could kill primary and brain metastatic cancer cells simultaneously.
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http://dx.doi.org/10.1038/s41598-018-29314-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056420PMC
July 2018

Brain microglia activation induced by intracranial administration of oligonucleotides and its pharmacological modulation.

Drug Deliv Transl Res 2018 10;8(5):1345-1354

Department of Health Sciences, University of Genoa, via A. Pastore, 1, 16132, Genoa, Italy.

Oligonucleotide overloading results in type I interferonopathies such as the Aicardi-Goutiéres Syndrome, a progressive encephalopathy determined by an immune response against endogenous DNA/RNA molecules. No therapy targeting pathogenic mechanisms is available for affected patients. Accordingly, we set up an in vitro/in vivo experimental model aimed at reproducing the pathogenic mechanisms of type I interferonopathies, in order to develop an effective pharmacological modulation and toxicological alterations caused by intracranial delivery of encapsulated CpG. The in vitro model used Aicardi-Goutiéres Syndrome immortalized lymphocytes activated by interferon I and co-cultured with human astrocytes; lymphocyte neurotoxicity was attenuated by the calcineurin-inhibitor Tacrolimus and by the anti-interferon monoclonal antibody Sifalimumab. The in vivo model was set up in mice by subcutaneous injection of encapsulated CpG oligonucleotides; the immune-stimulating activity was demonstrated by cytometric analysis in the spleen. To mime pathogenesis of type I interferonopathies in the central nervous system, CpG oligonucleotides were administered intracranially in mice. In the brain, CpG overload induced a rapid activation of macrophage-like microglial cells and focal accumulation mononuclear cells. The subcutaneous administration of Tacrolimus and, more potently, Sifalimumab attenuated CpG-induced brain alterations. These findings shed light on molecular mechanisms triggered by oligonucleotides to induce brain damage. Monoclonal antibodies inhibiting interferon seem a promising therapeutic strategy to protect brain in type I interferonopathies.
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http://dx.doi.org/10.1007/s13346-018-0535-3DOI Listing
October 2018

miR-19 in blood plasma reflects lung cancer occurrence but is not specifically associated with radon exposure.

Oncol Lett 2018 Jun 30;15(6):8816-8824. Epub 2018 Mar 30.

Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana, Akmola 010008, Kazakhstan.

Radon is one of the most powerful carcinogens, particularly in terms of lung cancer onset and development. miRNAs may be considered not only as markers of the ongoing tumorigenesis but also as a hallmark of exposure to radiation, including radon and its progeny. Therefore, the purpose of the present study was to estimate the value of plasma miR-19b-3p level as the prospective marker of the response to radon exposure in lung cancer pathogenesis. A total of 136 subjects were examined, including 49 radon-exposed patients with lung cancer, 37 patients with lung cancer without radon exposure and 50 age/sex matched healthy controls. Total RNA from blood samples was extracted and used to detect miR-19b-3p expression via reverse transcription quantitative-polymerase chain reaction. The 2 method was used to quantify the amount of relative miRNA. The plasma level of p53 protein was determined using a Human p53 ELISA kit. Plasma miR-19b-3p level was significantly higher in the patients with lung cancer groups, compared with the healthy control group (P<0.0001). No other statistically significant differences were determined in the expression level of plasma miR-19b-3p between patients diagnosed with lung cancer exposed to radon and not exposed to radon. The expression level of free circulating miR-19b-3p was higher in the group of non-smoking patients with lung cancer, compared with smokers with lung cancer. The miR-19b-3p was 1.4-fold higher in non-smokers than in smokers (P<0.05). No association between plasma levels of p53 protein and miR-19b-3p freely circulating in patients with lung cancer was observed. No other statistically significant differences were determined in the plasma p53 protein level between patients diagnosed with lung cancer exposed and not exposed to radon. These results indicated that detection of miR-19b-3p levels in plasma potentially could be exploited as a noninvasive method for the lung cancer diagnostics. However, this miRNA is not suitable as the precise marker for radon impact.
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http://dx.doi.org/10.3892/ol.2018.8392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950512PMC
June 2018

Release of MicroRNAs into Body Fluids from Ten Organs of Mice Exposed to Cigarette Smoke.

Theranostics 2018 8;8(8):2147-2160. Epub 2018 Mar 8.

Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.

: MicroRNAs are small non-coding RNAs that regulate gene expression, thereby playing a role in a variety of physiological and pathophysiological states. Exposure to cigarette smoke extensively downregulates microRNA expression in pulmonary cells of mice, rats, and humans. Cellular microRNAs are released into body fluids, but a poor parallelism was previously observed between lung microRNAs and circulating microRNAs. The purpose of the present study was to validate the application of this epigenetic biomarker by using less invasive collection procedures. : Using microarray analyses, we measured 1135 microRNAs in 10 organs and 3 body fluids of mice that were either unexposed or exposed to mainstream cigarette smoke for up to 8 weeks. The results obtained with selected miRNAs were validated by qPCR. : The lung was the main target affected by smoke (190 dysregulated miRNAs), followed by skeletal muscle (180), liver (138), blood serum (109), kidney (96), spleen (89), stomach (36), heart (33), bronchoalveolar lavage fluid (32), urine (27), urinary bladder (12), colon (5), and brain (0). Skeletal muscle, kidney, and lung were the most important sources of smoke-altered microRNAs in blood serum, urine, and bronchoalveolar lavage fluid, respectively. : microRNA expression analysis was able to identify target organs after just 8 weeks of exposure to smoke, well before the occurrence of any detectable histopathological alteration. The present translational study validates the use of body fluid microRNAs as biomarkers applicable to human biomonitoring for mechanistic studies, diagnostic purposes, preventive medicine, and therapeutic strategies.
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http://dx.doi.org/10.7150/thno.22726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928877PMC
April 2019

Early and late effects of aspirin and naproxen on microRNAs in the lung and blood of mice, either unexposed or exposed to cigarette smoke.

Oncotarget 2017 Oct 24;8(49):85716-85748. Epub 2017 Aug 24.

Department of Health Sciences, University of Genoa, Genoa, Italy.

We recently showed that nonsteroidal anti-inflammatory drugs (NSAIDs) are able to inhibit the lung tumors induced by cigarette smoke, either mainstream (MCS) or environmental (ECS), in female mice. We used subsets of mice to analyze the expression of 1135 microRNAs in both lung and blood serum, as related to the whole-body exposure to smoke and/or oral administration of either aspirin or naproxen. In a first study, we evaluated early microRNA alterations in A/J mice exposed to ECS for 10 weeks, starting at birth, and/or treated with NSAIDs for 6 weeks, starting after weaning. At that time, when no histopathological change were apparent, ECS caused a considerable downregulation of pulmonary microRNAs affecting both adaptive mechanisms and disease-related pathways. Aspirin and naproxen modulated, with intergender differences, the expression of microRNAs having a variety of functions, also including regulation of cyclooxygenases and inflammation. In a second study, we evaluated late microRNA alterations in Swiss H mice exposed to MCS during the first 4 months of life and treated with NSAIDs after weaning until 7.5 months of life, when tumors were detected in mouse lung. Modulation of pulmonary microRNAs by the two NSAIDs was correlated with their ability to prevent preneoplastic lesions (microadenomas) and adenomas in the lung. In both studies, exposure to smoke and/or treatment with NSAIDs also modulated microRNA profiles in the blood serum. However, their levels were poorly correlated with those of pulmonary microRNAs, presumably because circulating microRNAs reflect the contributions from multiple organs and not only from lung.
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http://dx.doi.org/10.18632/oncotarget.20464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689642PMC
October 2017

Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators.

Am J Cancer Res 2017 1;7(6):1350-1371. Epub 2017 Jun 1.

Department of Health Sciences, University of GenoaItaly.

Chemo-resistance, which is the main obstacle in cancer therapy, is caused by the onset of drug-resistant cells in the heterogeneous cell population in cancer tissues. MicroRNAs regulate gene expression at the post-transcriptional level, and they are involved in many different biological processes, including cell proliferation, differentiation, metabolism, stress response, and apoptosis. The aberrant expression of microRNAs plays a major pathogenic role from the early stages of the carcinogenesis process. Recently, microRNAs have been reported to play an important role in inducing resistance to anti-cancer drugs. Specific microRNA alterations occur selectively in cancer cells, rendering these cells resistant to various chemotherapeutic agents. For example, resistance to 5-fluorouracil is mediated by alterations in miR-21, miR-27a/b, and miR-155; the sensitivity to Docetaxel is influenced by miR-98, miR-192, miR-194, miR-200b, miR-212, and miR-424; and the resistance to Cisplatin is mediated by miR-let-7, miR-15, miR-16 miR-21 and miR-214. Chemo-resistant cancer cells are characterized by altered functions in enzymes that are involved in microRNA maturation, primarily including Dicer, as demonstrated in ovarian cancer, oral squamous cell carcinoma, breast cancer and cervical cancer. Based on the evidence reviewed in this paper, various strategies have been developed to artificially re-establish microRNA expression in resistant cells, thus restoring chemo-sensitivity. These strategies employ synthetic analogs, anti-microRNA oligonucleotides, locked nucleic acid, microRNA sponges, drugs that inhibit DNA methylation or histone deacetylation, and the introduction of microRNA mimics. The ability to modulate microRNA expression is a promising strategy for overcoming the problem of drug resistance in cancer treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489783PMC
June 2017

Regulation of oncogenic genes by MicroRNAs and pseudogenes in human lung cancer.

Biomed Pharmacother 2016 Oct 20;83:1182-1190. Epub 2016 Aug 20.

Department of Health Sciences, University of Genoa, Italy; Mutagenesis Unit, IRCCS University Hospital San Martino-IST, National Institute for Cancer Research, Genoa, Italy.

Lung cancer is one of the most common mortal cancer types both for men and women. Several different biomarkers have been analyzed to reveal lung cancer prognosis pathways for developing efficient therapeutics and diagnostic agents. microRNAs (miRNAs) and pseudogenes are critical biomarkers in lung cancer and alteration of their expression levels has been identified in each step of lung cancer tumorigenesis. miRNAs and pseudogenes are crucial gene regulators in normal cells as well as in lung cancer cells, and they have both oncogenic and tumor-suppressive roles in lung cancer tumorigenesis. In this study, we have determined the relationship between lung cancer related oncogenes and miRNAs along with pseudogenes in lung cancer, and the results indicate their potential as biological markers for diagnostic and therapeutic purposes.
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http://dx.doi.org/10.1016/j.biopha.2016.08.043DOI Listing
October 2016

Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice.

Oncotarget 2016 Dec;7(51):84758-84774

Department of Health Sciences, University of Genoa, Genoa, Italy.

Cigarette smoke (CS) is known to dysregulate microRNA expression profiles in the lungs of mice, rats, and humans, thereby modulating several pathways involved in lung carcinogenesis and other CS-related diseases. We designed a study aimed at evaluating (a) the expression of 1135 microRNAs in the lung of Swiss H mice exposed to mainstream CS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months, (b) the relationship between lung microRNA profiles and histopathological alterations in the lung, (c) intergender differences in microRNA expression, and (d) the comparison with microRNA profiles in blood serum. CS caused multiple histopathological alterations in the lung, which were almost absent in sham-exposed mice. An extensive microRNA dysregulation was detected in the lung of CS-exposed mice. Modulation of microRNA profiles was specifically related to the histopathological picture, no effect being detected in lung fragments with non-neoplastic lung diseases (emphysema or alveolar epithelial hyperplasia), whereas a close association occurred with the presence and multiplicity of preneoplastic lesions (microadenomas) and benign lung tumors (adenomas). Three microRNAs regulating estrogen and HER2-dependent mechanisms were modulated in the lung of adenoma-bearing female mice. Blood microRNAs were also modulated in mice affected by early neoplastic lesions. However, there was a poor association between lung microRNAs and circulating microRNAs, which can be ascribed to an impaired release of mature microRNAs from the damaged lung. Studies in progress are evaluating the feasibility of analyzing blood microRNAs as a molecular tool for lung cancer secondary prevention.
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http://dx.doi.org/10.18632/oncotarget.12475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341294PMC
December 2016

Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma.

Oncotarget 2016 Oct;7(43):70715-70737

Department of Experimental Medicine, University of Genova, Genova, Italy.

Neuroblastoma, a paediatric malignant tumor, is initially sensitive to etoposide, a drug to which many patients develop chemoresistance. In order to investigate the molecular mechanisms responsible for etoposide chemoresistance, HTLA-230, a human MYCN-amplified neuroblastoma cell line, was chronically treated with etoposide at a concentration that in vitro mimics the clinically-used dose. The selected cells (HTLA-Chr) acquire multi-drug resistance (MDR), becoming less sensitive than parental cells to high doses of etoposide or doxorubicin. MDR is due to several mechanisms that together contribute to maintaining non-toxic levels of H2O2. In fact, HTLA-Chr cells, while having an efficient aerobic metabolism, are also characterized by an up-regulation of catalase activity and higher levels of reduced glutathione (GSH), a thiol antioxidant compound. The combination of such mechanisms contributes to prevent membrane lipoperoxidation and cell death. Treatment of HTLA-Chr cells with L-Buthionine-sulfoximine, an inhibitor of GSH biosynthesis, markedly reduces their tumorigenic potential that is instead enhanced by the exposure to N-Acetylcysteine, able to promote GSH synthesis.Collectively, these results demonstrate that GSH and GSH-related responses play a crucial role in the acquisition of MDR and suggest that GSH level monitoring is an efficient strategy to early identify the onset of drug resistance and to control the patient's response to therapy.
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http://dx.doi.org/10.18632/oncotarget.12209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342585PMC
October 2016

Extracellular MicroRNA in liquid biopsy: applicability in cancer diagnosis and prevention.

Am J Cancer Res 2016 1;6(7):1461-93. Epub 2016 Jul 1.

Department of General Biology and Genomics, Inst. of Cell Biology and Biotechnology, L.N. Gumyliov Eurasian National University Astana, Kazakhstan.

One of the goals of contemporary cancer research is the development of new markers that facilitate earlier and non-invasive diagnosis. MicroRNAs are non-coding RNA molecules that regulate gene expression; studies have shown that their expression levels are altered in cancer. Recently, extra-cellular microRNAs have been detected in biological fluids and studied as possible cancer markers that can be detected by noninvasive procedures. In this review, we analyze the current understanding of extracellular miRNAs based on clinical studies to establish their possible use for the prevention of the most common tumors. Despite discrepancies among different studies of the same cancers, panels of specific extracellular microRNAs are emerging as a new tool for the secondary (selection of high-risk individuals to undergo screening) and tertiary (relapse) prevention of cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969398PMC
August 2016

Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal irradiation.

Oncotarget 2015 Nov;6(34):36098-112

Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.

The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.
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http://dx.doi.org/10.18632/oncotarget.5553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742164PMC
November 2015

Genetic and Epigenetic Effects of Environmental Mutagens and Carcinogens.

Biomed Res Int 2015 4;2015:608054. Epub 2015 Aug 4.

Laboratory of Toxicology UT-BIORAD, ENEA, CR Casaccia, Via Anguillarese 301, 00123 Rome, Italy.

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http://dx.doi.org/10.1155/2015/608054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539433PMC
June 2016

Effect of Environmental Chemical Stress on Nuclear Noncoding RNA Involved in Epigenetic Control.

Biomed Res Int 2015 3;2015:761703. Epub 2015 Aug 3.

Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.

In the last decade the role of noncoding RNAs (ncRNAs) emerges not only as key elements of posttranscriptional gene silencing, but also as important players of epigenetic regulation. New kind and new functions of ncRNAs are continuously discovered and one of their most important roles is the mediation of environmental signals, both physical and chemical. The activity of cytoplasmic short ncRNA is extensively studied, in spite of the fact that their function and role in the nuclear compartment are not yet completely unraveled. Cellular nucleus contains a multiplicity of long and short ncRNAs controlling at different levels transcriptional and epigenetic processes. In addition, some ncRNAs are involved in RNA editing and quality control. In this paper we review the existing knowledge dealing with how chemical stressors can influence the functionality of short nuclear ncRNAs. Furthermore, we perform bioinformatics analyses indicating that chemical environmental stressors not only induce DNA damage but also influence the mechanism of ncRNAs production and control.
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http://dx.doi.org/10.1155/2015/761703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538421PMC
May 2016

Biological monitoring of Italian soldiers deployed in Iraq. Results of the SIGNUM project.

Int J Hyg Environ Health 2016 Jan 4;219(1):24-32. Epub 2015 Aug 4.

IRCCS AUO San Martino-IST Istituto Nazionale Ricerca sul Cancro, Genoa, Italy; Department of Health Sciences, University of Genoa, Genova, Italy.

Background: Leukemia/lymphoma cases reported in 2001 among United Nation soldiers or peacekeepers deployed to the Balkans aroused alert on the exposure to depleted uranium. Recent epidemiological studies carried out in different European countries among peacekeepers who served in the Balkans failed to demonstrate a higher than expected risk of all cancers but, mostly due to their limitations in size and follow up time, leave open the debate on health risk of depleted uranium. The aim of SIGNUM (Study of the Genotoxic Impact in Military Units) was to identify potential genotoxic risk associated with the exposure to depleted uranium or other pollutants in the Italian Army military personnel deployed in Iraq.

Methods: Blood and urine samples were collected before and after the deployment from 981 Italian soldiers operating in Iraq in 2004-2005. As, Cd, Mo, Ni, Pb, U, V, W, and Zr were determined in urine and serum. DNA-adducts, 8-hydroxy-2'-deoxyguanine and micronuclei frequency were evaluated in blood lymphocytes. Three different genetic polymorphisms, GSTM1, XRCC1, OGG1 were analyzed.

Results: Significant T0-T1 reduction in the total concentration of uranium, increases for Cd, Mo, Ni, Zr, and decreases for As, Pb, W, and V in urine and plasma were observed. Increases in oxidative alterations and in micronuclei frequency, included in the range of values of non-occupationally exposed populations, were observed at the end of the period of employment.

Conclusions: Our results did not detect any toxicologically relevant variation of DNA-damage biomarkers related to the deployment in the operational theater.
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http://dx.doi.org/10.1016/j.ijheh.2015.08.001DOI Listing
January 2016

MicroRNAs and Physical Activity.

Microrna 2015 ;4(2):74-85

Department of Health Sciences, Faculty of Medicine and Surgery, University of Genoa, via Pastore 1, 16132 Genoa, Italy.

Micro-RNAs (miRNAs) are responsible for important and evolutionary-conserved regulatory functions in several cellular processes such as apoptosis, signalling, differentiation and proliferation. There is a growing interest in understanding more clearly the mechanisms regulating activation and suppression of miRNAs expression in benefit of health prevention advancement. It is now acknowledged that physical activity represents one of the most effective preventive agents in chronic degenerative diseases. Indeed, a regular exercise exerts a great influence on several parameters and biological pathways, both at genomic and post-genomic levels. Recent works have highlighted the effects of structured physical activity on miRNAs modulation. Modulation of MiRNAs, regulated by exercise in human skeletal muscle, depends on type, duration and intensity of an exercise performed. The aim of this review is to provide a comprehensive overview of scientific evidence concerning the effects of physical activity on miRNAs and its relevance for chronic-degenerative diseases prevention.
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http://dx.doi.org/10.2174/2211536604666150813152450DOI Listing
July 2016