I seminari dipartimentali si svolgeranno secondo il seguente calendario, due volte al mese, dalle 13:00 alle 13:40 in aula seminari al II piano di largo Donegani 2 (ex Wild), a Novara.
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1) Pharmacogenetics and genetics of migraine: our contribution to the field
03 ottobre 2018; Sarah Cargnin (UNIUPO - DSF)
Episodic migraine is a disabling neurovascular disease that affects around 10% of the worldwide adult population. Despite triptans are now considered as the gold-standard acute treatment for migraine, their use is limited by at least two main drawbacks: first, a consistent proportion of migraineurs do not benefit from these medications; second, it has been shown that the overuse of triptans per se is, paradoxically, one of the major causes of migraine chronification into Medication Overuse Headache (MOH). In the last years we conducted several studies aimed at identifying single neuclotide polymorphisms as genetic predictors of the clinical response to triptans or of the risk of developing MOH. We herein propose the use of a polygenic risk score approach as an adequate tool to unravel the genetic/pharmacogenetic basis of migraine and its chronification.
2) Role of the epigenetic modulators KDM6B and EZH2 in malignant mesothelioma
17 ottobre 2018; Giulia Pinton (UNIUPO – DSF)
Mesothelioma is a type of cancer that forms on the thin protective lining that cover the lungs and other internal organs, often associated with exposure to asbestos. For patients with relapsed or refractory mesothelioma, there are currently no approved treatment options.
Tazemetostat, a first-in-class EZH2 (Enhancer of Zeste homology 2) inhibitor, is currently being studied as a monotherapy in ongoing Phase 1 and 2 programs. EZH2 is a methyltransferase that trimethylates histone H3 lysine 27 (H3K27me3) on chromatin. This repressive mark is removed by the lysine demethylase KDM6B. We assessed the role of EZH2 and KDM6B in mesothelioma derived cells, cultured as monolayer or as spheroids.
3) From mass spectrometry to biochemistry: in vitro and in vivo applications
07 novembre 2018; Marcello Manfredi (UNIUPO – IRCAD)
Today, mass spectrometry methods are utilized in an increasing number of molecular and biology studies that aim for a better understanding of the biochemistry of living organisms. Biological processes, pathways and biomarkers are only some of the information that can be obtained through mass spectrometry. A selection of these studies will be presented: firstly, using a multi-omics approach we will show the specific behavior of serum proteins, metabolites and lipids during sport activity. The second case research is related to the use of proteomics to study the effect of a drug and its possible targets. The third case study will show the use of a multi-omics approach to analyze the content and the effect of platelet rich plasma.
4) MORPHEUS: an automated tool for unbiased and reproducible cell morphometry
21 novembre 2018; Federico Ruffinatti (UNIUPO – DSF)
Cell morphometry can be defined as the quantitative description of cell shape for the inference of important information about cell functionality and/or its correlation with certain biological process of interest, such as proliferation, differentiation, migration, motility, growth dynamics or adhesion to particular substrates. In recent years, a plethora of shape descriptors has been proposed to virtually capture every geometrical feature of a cell, or subcellular compartment. However, the simultaneous use of multiple descriptors rapidly raises the level of complexity, making the analysis multivariate and highly redundant. Moreover, the visual inspection of the whole dataset of images for manual cell selection, together with the lack of standardized protocols of analysis, is likely to introduce a heavy operator-dependent bias into the procedure, thus impairing its reproducibility. In order to solve most of these problems, we developed a new plug-in for ImageJ called MORPHEUS, that combines within a single pipeline the evaluation of the most relevant cell-shape descriptors, the extraction of nucleus features and an advanced analysis of orientation. Morpheus is a first proposal for the standardization of cell morphometric analysis in which the automation descending from the adaptative nature of the algorithm eliminates the user-bias factor and translates into a reproducibility-oriented approach to cell morphometry.
5) Relazioni struttura-attività del diterpene antitumorale EBC-46
05 dicembre 2018; Giovanni Battista Appendino (UNIUPO – DSF)
The diterpene ester tiglianol tigliate (EBC-46) occurs in high concentration in the unpalatable seeds of Fontainea picrosperma C.T. White (blushwood), a subcanopy euphorbiaceous tree endemic to a restricted (ca. 20 Km2) area of the Queensland rainforest. Tiglianol tigliate is remarkably efficacious in the treatment of localized tumors, and has successfully completed Phase III clinical development for veterinarian use and Phase I human clinical studies. Intra-tumor injection of EBC46 triggers a triad of responses (massive destruction of tumor vasculature, tumor hemorrhagic necrosis, stimulation of wound healing) sensitive to PKC pan-inhibitors, suggesting that modulation of PKC is part of its mechanism of action. The PKC isoform activation of EBC-6 is significantly different from the one of tetradecanoyl phorbol acetate (PMA) and ingenol mebutate, and studies aimed at clarifying the role of PKC in the mechanism of action of EBC-46 by systematically modifying the functional groups of the natural product will be presented.
6) Nucleotide Excision Repair and direct DNA damage reversal in Mycobacterium tuberculosis: a biochemical and structural perspective
19 dicembre 2018; Riccardo Miggiano (UNIUPO – DSF)
Mycobacterium tuberculosis (MTB) is a human pathogen that during its complex life cycle is continuously exposed to a variety of DNA-damaging stresses. The mutagenic effects of O6-alkylated guanine in DNA is counteracted by the action of the suicidal O6-methylguanine methyltransferase protein (OGT). I will present the crystal structure of wild-type MTB OGT in complex with a modified dsDNA, gaining structural insights into the OGT cooperative DNA-binding mechanism. The MTB DNA repair toolbox includes also multi-enzymatic DNA repair systems such as the Nucleotide Excision Repair (NER). The first steps in NER are carried out by the coordinated action of the UvrA, UvrB and UvrC proteins. We analyzed the hydrodynamic properties and the oligomeric state of the MTB UvrB showing that the protein forms dimers in solution, which are characterized by an elongated shape, as determined by SAXS analysis. Moreover, we analyzed the UvrA/UvrB lesion sensing/tracking complex by adopting a SEC-based approach followed by SAXS-and cryo-EM-based structural analysis, revealing that the two proteins interact in solution, in the absence of ligands, with an A2B2 stoichiometry. Surface plasmon resonance analysis showed that the dissociation constant of the complex falls in the low micromolar range that could represent the basis for a fine modulation of the complex architecture. Finally, the characterization of such complexes in terms of thermodynamics and stoichiometry provides an experimental framework to screen molecules for their capability to interfere with the DNA-lesion searching response in mycobacterial NER.
7) Real World Evidence: quanto è davvero reale?
09 gennaio 2019; Francesco Barone Adesi (UNIUPO – DSF)
According to the British Academy of Medical Sciences, Real-World Evidence (RWE) is the evidence generated from clinically relevant data collected outside of the context of conventional Randomized Controlled Trials (RCT). This includes data available through electronic health records, medical claims, drug and disease registries, patient lifestyle-related activities and health-monitoring devices. RWE studies are regarded as complementary to RCT in the generation of scientific evidence. For example, results of RWE studies have usually a larger generalizability, because they often involve subjects that would not be recruited in RCT. However, several methodological challenges should be considered when interpreting findings based on RWE studies. In particular, the observational design of these studies makes them more vulnerable to bias and confounding than RCT. The seminar illustrates some limitations in the evaluation of drug safety and effectiveness through RWE studies and proposes possible solutions to mitigate them.
8) A new possibility on acute myelogenous leukemia (AML): targeting myeloid differentiation using potent and innovative human dihydroorotate dehydrogenase (hDHODH) inhibitors
16 gennaio 2019; Marco Lolli (UNITO)
Acute myelogenous leukemia (AML) is a clinically most devastating disease with dismal prognosis and survival rate. Efforts to identify new therapeutic targets to overcome myeloid differentiation blockade were largely unsuccessful until the breakthrough study in 2016 by Sykes et al. who demonstrated that inhibition of dihydroorotate dehydrogenase (hDHODH) enables myeloid differentiation in both human and mouse AML models. The development of potent and optimized hDHODH inhibitors has become a potential new strategy for the treatment of AML. After several series of optimization in the development of hDHODH inhibitors using state-of-the-art designing paradigms, including synthesis, structure-activity relationships (SAR), crystallographic and molecular modelling studies, biological assays (cell viability, proliferation, cytotoxicity, immunosuppression and myeloid differentiation), and physicochemical characterization, we have recently discovered a novel small molecule, representative of a novel class of hDHODH inhibitors based on a hydroxylpyrazole-pyridine scaffold, that is able to restore the myeloid differentiation in leukemia cell lines at a 1-log lower concentration compared to the lead brequinar. To our knowledge, it is one of the most potent hDHODH inhibitor, with a safety profile, so far discovered.
9) Lipotoxicity-mediated disruption of adult hypothalamic neural progenitor cells as a potential contributor in Metabolic Syndrome
06 febbraio 2019; Heather Bondi (UNIUPO – DSF)
Metabolic syndrome (MetS) represents a risk factor for the onset of type 2 diabetes (T2D) and other chronic diseases, including neurodegenerative disorders. The hypothalamus (Hyt) is the brain region that plays a key role in regulation of food intake and energy expenditure. In mice, high-fat diet (HFD) induces an increase of circulating and brain free fatty acids (FFA), which, in turn, can exert toxic effects (lipotoxicity) and potentially compromise Hyt functions. Adult neurogenesis (aNG) is a key form of neuroplasticity which also occurs in Hyt (aHytNG) and is impaired in mice exposed to HFD. This observation has generated the hypothesis that lack of remodelling in the Hyt network as a consequence of disrupted NG may potentially contribute to MetS. Little is currently known about the direct effects of lipotoxicity on aHytNG. The present project aims at understanding the in vitro effects of a FFA-enriched microenvironment on adult Hyt neural progenitor cells (aHytNPC), using an innovative and highly throughput image-based approach, namely High Content Analysis (HCA). We will use Palmitic acid (PA) to reproduce lipotoxicity and its potential underlying cellular and molecular effects on aHytNPC. Moreover, we want: i) to assess whether aHytNPC impairment by PA may be pharmacologically counteractable; ii) to identify novel drugs with protective properties against lipotoxicity. Our results may shed light on novel pathophysiological mechanisms that link MetS and brain dysfunction.
10) Regulation of neuronal protein expression and function by astroglial calcineurin
20 febbraio 2019; Laura Tapella (UNIUPO – DSF)
Astrocytes play fundamental homeostatic functions in the brain. Calcineurin (CaN) is a Ca2+-activated phosphatase that, in astrocytes, is known to trigger reactive gliosis and neuroinflammation. Surprisingly, nothing is known about a role of astroglial CaN in brain physiology. For that reason, we have generated a conditional CaN KO mouse model specific in astroglial cells, (ACN-KO). ACN-KO mice grew normal in terms of body and brain weight but starting from 2 month of age develop memory impairment and later on spontaneous tonic-clonic seizures. In this seminar, I will present data on: 1) the role of astroglial CaN in neuronal excitability through the modulation of Na+/K+ ATPase (NKA) activity; 2) preliminary results of proteomic analysis on ACN-KO mice. In summary, our data suggest that astroglial CaN controls phenotype and function of neurons in term of protein expression and excitability.
11) Italian pigmented rice varieties: an overview on the phenolic composition, nutraceutical potentiality and technological aspects
06 marzo 2019 Monica Locatelli (UNIUPO – DSF)
Pigmented rice is characterized by the presence in the pericarp (the bran part of the caryopsis) of pigments that confer to it different colors, mainly red, purple or black. Red and black rice are valuable sources of fiber, minerals and phytochemicals, including various phenolic compounds; for these reasons, pigmented rice can be considered as "functional food", and can also be used for nutraceutical applications. Moreover, due to its high anthocyanin content, black rice could be used as source of pigments useful to replace artificial colorants in food applications.
In this seminar the composition of various Italian pigmented rice cultivars (Oryza sativa) will be presented, particularly focusing on the polyphenolic profile. Black and red rice varieties, in fact, show a similar proximate composition, but a quali/quantitative different profile of polyphenols (anthocyanins, phenolic acids and flavonoids). Based on its peculiar characteristics, black rice was then subjected to different cooking methods in order to evaluate their impact on the phenolic composition. In addition, some black rice by-products (husk, straw and broken rice) were further characterized and considered for potential nutraceutical applications, such as the production of anthocyanin-rich extracts, useful for the formulation of functional foods or dietary supplements.
12) The importance of being a bitter natural compound
20 marzo 2019 Federica Pollastro (UNIUPO – DSF)
Bitter taste is a peculiar and emblematic perception that could act as defence, medicinal and gastronomic purpose. Bitter natural compounds are involved in this perception with different biological activity. A significant example is the consumption of wild bitter herbs, an important trait of the Mediterranean diet, to flavour alcoholic beverages and prepare herbal infusions whose value extends to traditional medicine too. Plants from the genus Artemisia exemplify this use, and their properties on appetite and digestion have been traditionally related to their bitter constituents.
The popularity of alpine bitter herbs had fostered studies aimed at the isolation of their bitter principles and the identification of their receptors (hTAS2Rs). Bitter taste receptors were originally defined on the base of their role in type-2 taste cells of the tongue, in which they serve to detect bitter chemicals like sesquiterpene lactones, a major class of bitter compounds. Further interest originated from the discovery that bitter taste receptors are expressed in extra oral tissue, especially in the gastrointestinal tract and in the respiratory system, where they are involved, respectively in glucose regulation, appetite regulation, weight management, and bronchodilation.
The study of hTAS2Rs in broncho-epithelial cells is a potential therapeutic target for inflammatory diseases of respiratory tract and highlight the relevance of bitter agonists as drug lead structures.
13) Macrophage plasticity in inflammatory diseases and cancers
03 aprile 2019 Chiara Porta (UNIUPO – DSF)
Macrophage plasticity, namely the ability of macrophages to respond to microenvironmental changes with the expression of different functional programs of activation, is essential for host defense and tissue homeostasis, but it may also promotes the development of different diseases. Exploring the molecular mechanisms driving macrophage polarized activation in infectious diseases and established cancers we identified that p50 NF-κB is a key molecule for the expression of an M2-skewed phenotype. Accordingly, we have recently demonstrated that p50 NF-κB supports colorectal cancer development and progression through its commitment to the tumor-promoting (M2-like) activation of macrophages. Therefore p50 NF-κB represents both a new prognostic indicator and an attractive target for therapeutic interventions. Strategies aimed to “re-educate” tumor associated macrophages (TAM) in “M1” effector cells have recently entered clinical trials. Malignant pleura mesothelioma (MPM) is an aggressive cancer with dismal prognosis. We are now investigating whether the combination of TAM reprograming with Tazemetostat, an inhibitor of the histone methyltransferase EZH2, could represent a new therapeutic option for MPM. Our preliminary results indicate that M1-polarized monocytes can kill MPM cells enhancing the anti-tumor effect of Tazemetostat. These findings prompt us to go insight the study of potential synergistic effects of epigenetic rewiring in association with macrophage-based immunotherapy.
14) PARP inhibitor sensitization by deregulated PARP1 turnover
05 aprile 2019 Marco Gatti (Università di Zurigo)
Poly(ADP-ribose) polymerase 1 (PARP1, ARTD1) has multiple important roles in metabolism, stress signaling, chromatin dynamics, transcription and DNA repair, and it is the target of PARP inhibitors (PARPi) used as therapy for BRCA-mutated ovarian and breast tumors. The cytotoxicity of PARPi is in part caused by the ability of PARPi to lock PARP1 in an inactive conformation and thereby stabilize potentially toxic PARP1-DNA complexes, a mechanism that is referred to as PARP trapping. A hypothesis based on the PARP trapping model is that PARPi might work best in cancer cells expressing high levels of PARP1, with consequentially increased cytotoxic PARP1 trapping. PARP1 is indeed upregulated in various cancers and PARP1 expression may have prognostic value for PARPi-based cancer treatment. A relatively novel and still insufficiently explored aspect of PARP biology is the interplay between PARylation and ubiquitin-dependent protein turnover. In order to identify components of the ubiquitin-proteasome machinery with hitherto uncharacterized roles in the regulation of PARP1 steady-state levels, we employed a targeted siRNA approach in conjunction with high-throughput single cell imaging and found that posttranslational regulation of PARP1 turnover indeed impacts cellular sensitivity to PARPi. Our current work is aimed at dissecting the molecular details of ubiquitin-dependent PARP1 turnover and to study its implications for PARPi responses, both in BRCA-deficient and in BRCA-proficient settings.
15) Mono- and multi species biofilm infections on medical devices: prevention and eradication strategies by microbial biosurfactants
17 aprile 2019 Chiara Ceresa (UNIUPO – DSF)
L’impiego di dispositivi medici impiantabili è significativamente correlato all’insorgenza di infezioni microbiche causate dalla formazione di complesse strutture tridimensionali dette biofilm. Gli organismi che vivono in questa forma sono per lo più refrattari sia alla terapia farmacologica che alla risposta immunitaria dell'ospite. In particolare, la presenza di biofilm multi-specie è stata associata ad infezioni più aggressive a causa delle interazioni sinergiche che si vengono a creare tra i microorganismi coinvolti che potenziano la virulenza, la biomassa e la resistenza ai trattamenti antimicrobici della comunità stessa. I biosurfattanti (BS) sono recentemente emersi come una nuova generazione di agenti antiadesivi e antimicrobici per lo sviluppo di biomateriali ad alta biocompatibilità.
L'efficacia inibitoria dei BS nei confronti della formazione di biofilm da parte di specie microbiche clinicamente rilevanti è stata studiata seguendo un approccio multidisciplinare. I risultati ottenuti pongono le basi per lo sviluppo di strategie innovative comprendenti molecole naturali per la prevenzione della colonizzazione microbica su dispositivi medici.
16) ADME properties as an useful tool in development of new bioactive substances: applications and perspectives
08 maggio 2019 Silvio Aprile (UNIUPO – DSF)
17) Microencapsulation: principles and practice
22 maggio 2019 Andrea Foglio Bonda (UNIUPO – APTsol)
18) The hidden world of minor cannabinoids: our contribution to the synthesis and discovery of novel bioactive derivatives
05 giugno 2019 Diego Caprioglio (UNIUPO – DSF)
19) Fighting diseases with protein structures
19 giugno 2019 Davide Ferraris (UNIUPO – DSF)
20) Boron Neutron Capture Therapy: the renaissance of an old anticancer treatment
03 luglio 2019 Daniela Imperio (UNIUPO – DSF)
21) Targeting aldehyde dehydrogenase 1A3 in gliomas by using curcumin-based probes