Andrea Biserni

University of Milan, Milano, Lombardy, Italy

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Publications (16)47.49 Total impact

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    ABSTRACT: By the use of in vivo imaging, we investigated the dynamics of estrogen receptor (ER) activity in intact, ovariectomized, and hormone-replaced estrogen response element-luciferase reporter mice. The study revealed the existence of a long-paced, noncircadian oscillation of ER transcriptional activity. Among the ER-expressing organs, this oscillation was asynchronous and its amplitude and period were tissue dependent. Ovariectomy affected the amplitude but did not suppress ER oscillations, suggesting the presence of tissue endogenous oscillators. Long-term administration of raloxifene, bazedoxifene, combined estrogens alone or with basedoxifene to ovariectomized estrogen response element-luciferase mice showed that each treatment induced a distinct spatiotemporal profile of ER activity, demonstrating that the phasing of ER activity among tissues may be regulated by the chemical nature and the concentration of circulating estrogen. This points to the possibility of a hierarchical organization of the tissue-specific pacemakers. Conceivably, the rhythm of ER transcriptional activity translates locally into the activation of specific gene networks enabling ER to significantly change its physiological activity according to circulating estrogens. In reproductive and nonreproductive organs this hierarchical regulation may provide ER with the signaling plasticity necessary to drive the complex metabolic changes occurring at each female reproductive status. We propose that the tissue-specific oscillatory activity here described is an important component of ER signaling necessary for the full hormone action including the beneficial effects reported for nonreproductive organs. Thus, this mechanism needs to be taken in due consideration to develop novel, more efficacious, and safer hormone replacement therapies.
    Endocrinology 06/2011; 152(6):2256-65. · 4.72 Impact Factor
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    ABSTRACT: Prostate cancer (PC) develops in response to an abnormal activation of androgen receptor induced by circulating androgens and, in its initial stages, is pharmacologically controlled by androgen blockade. However, androgen ablation therapy often allows androgen-independent PC development, generally characterized by increased invasiveness. We previously reported that 5alpha-androstane-3beta,17beta-diol (3beta-Adiol) inhibits the migration of PC cell lines via the estrogen receptor beta (ERbeta) activation. Here, by combining in vitro assays and in vivo imaging approaches, we analyzed the effects of 3beta-Adiol on PC proliferation, migration, invasiveness, and metastasis in cultured cells and in xenografts using luciferase-labeled PC3 (PC3-Luc) cells. We found that 3beta-Adiol not only inhibits PC3-Luc cell migratory properties, but also induces a broader anti-tumor phenotype by decreasing the proliferation rate, increasing cell adhesion, and reducing invasive capabilities in vitro. All these 3beta-Adiol activities are mediated by ERbeta and cannot be reproduced by the physiological estrogen, 17beta-estradiol, suggesting the existence of different pathways activated by the two ERbeta ligands in PC3-Luc cells. In vivo, continuous administration of 3beta-Adiol reduces growth of established tumors and counteracts metastasis formation when PC3-Luc cells are engrafted s.c. in nude mice or are orthotopically injected into the prostate. Since 3beta-Adiol has no androgenic activity, and cannot be converted to androgenic compounds, the effects here described entail a novel potential application of this agent against human PC.
    Endocrine Related Cancer 09/2010; 17(3):731-42. · 5.26 Impact Factor
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    ABSTRACT: Using a mouse model engineered to measure estrogen receptor (ER) transcriptional activity in living organisms, we investigated the effect of long-term (21 d) hormone replacement on ER signaling by whole-body in vivo imaging. Estrogens and selective ER modulators were administered daily at doses equivalent to those used in humans as calculated by the allometric approach. As controls, ER activity was measured also in cycling and ovariectomized mice. The study demonstrated that ER-dependent transcriptional activity oscillated in time, and the frequency and amplitude of the transcription pulses was strictly associated with the target tissue and the estrogenic compound administered. Our results indicate that the spatiotemporal activity of selective ER modulators is predictive of their structure, demonstrating that the analysis of the effect of estrogenic compounds on a single surrogate marker of ER transcriptional activity is sufficient to classify families of compounds structurally and functionally related. For more than one century, the measure of drug structure-activity relationships has been based on mathematical equations describing the interaction of the drug with its biological receptor. The understanding of the multiplicity of biological responses induced by the drug-receptor interaction demonstrated the limits of current approach and the necessity to develop novel concepts for the quantitative analysis of drug action. Here, a systematic study of spatiotemporal effects is proposed as a measure of drug efficacy for the classification of pharmacologically active compounds. The application of this methodology is expected to simplify the identification of families of molecules functionally correlated and to speed up the process of drug discovery.
    Molecular Endocrinology 03/2010; 24(4):735-44. · 4.75 Impact Factor
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    ABSTRACT: Reporter mice associated to molecular imaging represent a major asset for the study of the spatio-temporal effects of drugs in living animals. The field is still relatively young and so far the number of animals genetically modified to express a given reporter gene ubiquitously and under the control of specific drugs is still limited. For a reporter animal the indispensable elements for the application to drug research and development are (i) the short life of the reporter enabling to have a clear view of the onset as well as the termination of drug effects, (ii) the generalized, drug-dependent activation of the reporter, and (iii) imaging modality suitable for high-throughput analysis. Because of its relative cheapness and ease to perform, in addition to all the above considerations, bioluminescence-based imaging is now regarded as the best imaging technology to be applied to the field of drug research. We show here the application of reporter mouse systems for drug screening in living animals in order to compare drug potency on target and specificity of action.
    Methods in molecular biology (Clifton, N.J.) 01/2010; 602:79-92. · 1.29 Impact Factor
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    ABSTRACT: We report here the finding of a new pharmacological activity of a well known antagonist of peroxisome proliferator-activated receptors (PPARs). PPARs belong to the family of nuclear receptors playing a relevant role in mammalian physiology and are currently believed to represent a major target for the development of innovative drugs for metabolic and inflammatory diseases. In the present study, the application of reporter animal technology was instrumental to obtain the global pharmacological profiling indispensable to unraveling 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)-selective PPAR modulator (SPPARM) activity not underlined by previous traditional, cell-based studies. The results of this study, demonstrating the usefulness of reporter mice, may open new avenues for the development of innovative drugs for cardiovascular, endocrine, neural, and skeletal systems characterized by limited side effects.
    Molecular pharmacology 06/2008; 73(5):1434-43. · 4.53 Impact Factor
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    ABSTRACT: The development of novel drugs is a lengthy process requiring years of preclinical research and many steps indispensable to ensure that the molecule of interest can be administered to humans with a minimal risk of toxic effects. Even a minimal reduction in the initial stages of drug development would result in a tremendous saving in time; therefore, pharmaceutical companies are eager to apply novel methodologies that shorten the time required for pharmacodynamic, pharmacokinetic and toxicological studies to be carried out in vitro and in animal systems. Currently, quantitative analysis of molecular events in living organisms is done with the combined application of imaging and genetic engineering technologies. In vivo imaging provides surrogate endpoints that can improve the identification of new drug candidates and speed up their research at preclinical stages. The integration of reporter systems in animal models of human diseases represents a reachable frontier that will dramatically advance drug development in terms of costs, time and efficacy. The present review outlines the applicability of imaging technologies for drug development and presents a panorama on the state of the art of currently available imaging technologies suitable for preclinical studies, with particular focus on bioluminescence and fluorescence as the methodologies of election.
    The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... 07/2007; 51(2):127-38. · 1.92 Impact Factor
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    ABSTRACT: There is a growing interest in peroxisome proliferator-activated receptors (PPARs) as major players in the regulation of lipid and carbohydrate metabolism. Drugs targeting PPARs were in fact shown to have major relevance for the treatment of diseases associated with aging, such as arteriosclerosis and diabetes. However, a variety of toxic effects associated with PPAR ligand administration has been documented, including hepatocarcinogenesis, which may severely limit its therapeutic use. A better comprehension of the multiplicity of PPAR physiological functions is therefore mandatory for the development of novel, safer drugs. We here describe the generation of a novel transgenic mouse for the detection of the generalized activities of PPARs, the PPAR responsive element-Luc reporter mouse. In this model luciferase expression is under the control of a PPAR-inducible promoter in all target organs. By optical imaging and ex vivo analysis, we were able to demonstrate the remarkable gender specificity of the PPAR transcriptional activity in liver. In fact, in the liver of female PPAR responsive element-Luc, the PPAR reporter transgene is more than one order of magnitude less expressed, thus leading to the conclusion that the signaling in females is much less activated than in males. Diet or hormonal manipulations as demonstrated here by treatments with high-fat diet or gonad removal and hormone replacement do not influence this low activation. The extent of the gender difference in PPAR transcriptional activity and the ineffectiveness of hormone treatments or diet to significantly elevate liver PPAR activity in females led us to hypothesize that gender-specific epigenetic events occurring during development may affect PPAR signaling in the liver. This study sets the ground for understanding the differential susceptibility of the two genders to metabolic disorders; furthermore, the model generated provides a novel opportunity for the molecular characterization of PPAR activity in pathophysiological conditions.
    Molecular Endocrinology 03/2007; 21(2):388-400. · 4.75 Impact Factor
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    ABSTRACT: Cancer is the result of a series of genetic and epigenetic mutations that evolve over years even decades and lead to the transformed phenotype. Paradoxically, most methods developed to study these changes are static and do not provide insights on the dynamics of the sequela of steps involved in tumorigenesis. This major shortcoming now can be overcome with the application of reporter genes and imaging technologies, which are providing tools to examine specific molecular events and their role in the carcinogenic process in single cells. In the last decade reporter-based biosensors were created to study gene transcription, protein/protein interactions, sub-cellular trafficking and protease activities; this wealth of systems enable to monitor intracellular signaling pathways at several key check points specifically involved in cancer cell development. The challenge is now to extend cell-based models to the generation of reporter mice, where non-invasive in vivo imaging technologies allow to follow single molecular events. When combined with murine models of cancer, these technologies will give an unprecedented opportunity to spatio-temporally investigate the molecular events resulting in neoplasia. The aim of the present review is to highlight the major changes occurring in this rapidly evolving field and their potential for increasing our knowledge in cancer biology and for the research of novel and more efficacious therapies.
    The International Journal of Biochemistry & Cell Biology 02/2007; 39(7-8):1288-96. · 4.15 Impact Factor
  • Breast. 01/2007; 16.
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    ABSTRACT: In the latest few years, the merging of imaging and animal engineering technologies has led to the generation of innovative tools that provide the opportunity to look into the dynamics of specific molecular events in living animals during their entire life under a completely renewed perspective. These tools will have a profound impact not only on basic research, but also on drug discovery and development allowing to depict the activity of any therapeutic agents in all their designed targets as well as in the organs where they may cause undesired effects. Along this research line, our laboratory has recently described the first animal model reporting the state of activity of estrogen receptors (ERs) in real time: the ERE-luc reporter mouse. The application of optical imaging to the ERE-luc has allowed an unprecedented in depth view of estrogen signaling in all of its target tissues. For example, the analysis of the state of activity of ERs in the physiological setting of the estrous cycle has provided compelling evidence that hormone-independent mechanisms are responsible for activating ERs in non-reproductive organs. This discovery may pave the way to a rational basis for the development of novel, more selective and effective treatments for menopause.
    Maturitas 08/2006; 54(4):315-20. · 2.84 Impact Factor
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    ABSTRACT: Non-invasive imaging of reporter gene expression using different imaging modalities is increasing its role for the in vivo assessment of molecular processes. Multimodality imaging protocols overcome limitations to a single imaging modality and provide a thorough view of specific processes, often allowing a quantitative measurement and direct visualization of the process in a specific target organ or tissue. The use of the right reporter gene for the development of animal models and the characterization of its expression in different conditions and tissues is fundamental for basic, translational and future pharmacological applications of a given model. This paper summarizes the major steps in the development and evaluation of a specific animal model for in vivo molecular imaging studies and describes the first example of an animal model designed for the in vivo assessment of a specific receptor activity and its possible evolution towards multimodality imaging analysis.
    Molecular and Cellular Endocrinology 03/2006; 246(1-2):69-75. · 4.04 Impact Factor
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    ABSTRACT: During the past decade remarkable progress in molecular genetics and the possibility of manipulating cells so that the expression of genes can directly 'report' on drug activity has produced major changes in drug development strategies. The recent description and pharmacological validation of reporter mice for in vivo analysis of hormone receptor activity opens new horizons for drug discovery. These novel animal models, in association with in vivo imaging technologies, provide a global view of the target tissues of drug action following acute and repeated drug treatment, thus enabling the prediction of potential side-effects in the early phase of preclinical studies. It is anticipated that further improvements of transgene architecture will lead to models that combine pharmacokinetic, pharmacodynamic and toxicological studies in a single step, which should provide a tremendous saving in time and, paradoxically, the number of animals to be sacrificed in the development of novel pharmacologically active molecules.
    Trends in Pharmacological Sciences 07/2004; 25(6):337-42. · 9.25 Impact Factor
  • Ernst Schering Research Foundation workshop 02/2004;
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    ABSTRACT: Wolbachia pipientis is an intracellular bacterial endosymbiont of arthropods and filarial nematodes. Six main supergroups of W. pipientis have been described: supergroups A, B, E, and F encompass arthropod wolbachiae; supergroups C and D encompass nematode wolbachiae. The description of these six supergroups has been based on the analysis of only two genes (ftsZ and 16S rDNA) and before decisions are taken on the taxonomic status of the six supergroups, analysis of further genes is required. In addition, the branching order of the six supergroups is still unresolved. Sequence information from other genes is also needed to allow phylogenesis to be addressed through the analysis of a higher number of characters. Here we report sequences from a portion of the gene coding for the DNAA protein of W pipientis, generated from the endosymbionts of 22 host species. Phylogenies based on dnaA gene sequences are congruent with the existence of at least six supergroups of W pipientis. In addition, subtrees generated for nematode wolbachiae in supergroups C and D were compared to the trees based on the already available gene sequences (ftsZ, 16S rDNA and wsp). The congruence observed among the trees based on the different genes agrees with the hypothesis that recombination does not occur in nematode wolbachiae.
    Parassitologia 04/2003; 45(1):13-8.
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