SEMINARI

I seminari dipartimentali, edizione 2021/22, si svolgeranno sempre di mercoledì, dalle 13:00 alle 13:40 in un'aula indicata di volta in volta, presso il Dipartimento di Scienze del Farmaco, L.go Donegani 2 a Novara.  

Chi volesse aggiungere in automatico le date al proprio calendario, può farlo tramite il seguente link: https://goo.gl/jtddhG

In allegato il calendario dei seminari.

27 ottobre 2021 Fausto Chiazza (UNIUPO - DSF)

La dieta e il suo ruolo nella neuroplasticità ippocampale

Uno stile di vita caratterizzato da una dieta equilibrata è essenziale per l'omeostasi dell'organismo e ancor più rilevante per il sistema nervoso centrale (SNC), influenzando direttamente funzioni cognitive ed emotive soprattutto ad età particolarmente vulnerabili come l’adolescenza. Nel SNC, memoria e umore sono regolati principalmente dall'ippocampo: qui avviene un processo di neuroplasticità noto come "postnatal hippocampal neurogenesis" (hNG) che consente a nuovi neuroni di formarsi e integrarsi nei circuiti ippocampali. Numerosi studi hanno dimostrato che riduzioni nelle performance cognitive e sviluppo di depressione possono essere conseguenza di una disfunzione nell’hNG. Molte evidenze suggeriscono inoltre che un eccessivo consumo di cibo possa influenzare l’hNG anche prima di un significativo aumento di peso corporeo e quindi indipendentemente dallo sviluppo di conclamate patologie metaboliche come obesità e diabete. In questo progetto sono stati quindi analizzati gli effetti di un breve apporto di una dieta ipercalorica sulla neuroplasticità ippocampale ed in particolare su un’importante popolazione di neuroni immaturi (doublecortin+) in topi adolescenti o adulti.

*progetto finanziato dal Bando Ricerca Locale

3 novembre 2021 Federica Grosso (Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo)

Clinical, molecular and genetic features and new treatment options for malignant pleural mesothelioma

Il mesotelioma, pur essendo un tumore raro, è il tumore primitivo più frequente della pleura: ogni anno in Italia si verificano circa 2000 nuovi casi. La patogenesi è legata alla esposizione all’amianto e i modelli di previsione di mortalità indicano che il picco durerà almeno fino al 2025 e si assisterà successivamente ad un lento decremento.
Recentemente, l’immunoterapia ha mostrato un impatto prognostico rilevante dopo quasi due decadi in cui non si assisteva ad alcun miglioramento e si appresta a diventare un nuovo standard terapeutico.
Molti altri quesiti rimangono però ancora aperti circa la biologia di questo tumore: diversi nuovi approcci sono in valutazione per giungere alla definizione di approcci più personalizzati, anche se la strada per questo è ancora lunga.

17 novembre 2021 Zhou Wang (Aston University- Birmingham)

Tranglutaminas in Human Diseases

Transglutaminase 2 (TG2) is a multifunctional enzyme involved in various physiological and pathological processes. Physiologically, TG2 plays an important role in wound healing and angiogenesis via mediating cell adhesion, migration and survival and in matrix deposition and assembly. Pathologically, TG2 has been shown to be involved in cancer progression, fibrosis and neurodegenerative diseases. Research in our group has focused on understanding the role of TG2 in these processes in particular its role in fibrosis, cancer progression and pathological angiogenesis. Importantly, we have been working on developing therapeutic agents that specifically target TG2, such as small molecule inhibitors, for the treatment of these different human diseases, such as cardiac fibrosis, lung fibrosis, cystic fibrosis and colorectal cancer. In this seminar, I will present a summary of the recent research progress in the TG2 research field and recent updates on the research in our group.

1 dicembre 2021 Elena Petricci (UNISI-DBCF)

Synthetic approaches to the development of new Antibody-Drug Conjugates charged with unconventional payloads

With more than 50 Antibody Drug Conjugates (ADCs) in clinical trials for cancer treatment, the ADC approach opens a new era of chemotherapy. ADCs activity is strictly related to the chemical properties of both linker and payload, while the conjugation methodologies impact their homogeneity. Here we report our experience in the development of novel ADCs that can deliver to human tumors Hystone DeACetylase (HDAC) inhibitors and other payloads (i.e. Smo inhibitors) with low cytotoxicity. Different payloads were prepared using both cleavable and noncleavable linkers and conjugated to Cetuximab and Trastuzumab resulting in ADCs exhibiting unmodified ability to recognize EGFR and efficient internalization into tumor cells. Animal models of human solid tumors showed high anti-tumor efficacy of the conjugates without the toxicity of traditional ADCs charged with highly potent cytotoxic drugs. These new bioconjugates proved to be suitable for targeted epigenetic modulation possibly extending the ADC strategy to therapeutic applications beyond cancer.

15 dicembre 2021  Marco Ferrero (UNIUPO-DSF)

Ultra Fast Silicon Detector in Medical Physics application

The Ultra-Fast Silicon Detectors (UFSDs) are innovative solid state detectors initially developed for high energy physics applications, now gaining interest in medicine. The elements sensitive to ionizing radiation are thin silicon layers with internal gain, able to generate large and fast signals. The time of arrival of a particle can be measured with a precision of tens of picoseconds. Thanks to their performance, UFSDs are currently being considered for ion beam characterization and monitoring in radiobiological and clinical irradiations. They can overcome the limits of the currently used ionization chambers. Recent developments in two therapy applications will be discussed: (i) counting the particles delivered at high rate (100 MHz) to a patient in a therapeutic beam; (ii) measuring the beam particle energy using the time-of-flight method.

12 gennaio 2022  Daniele Passarella (UNIMI- Dipartimento di Chimica)

Sostanze Naturali: Scaffold e Lead in Sintesi Organica

La diversità strutturale, le peculiari reattività e le singolari attività biologiche fanno dei prodotti naturali un immenso tesoro che da sempre caratterizza la vita sulla terra stimolando l’interesse della scienza volta ad individuarne la biogenesi, i meccanismi di azione e le loro possibili applicazioni, tra cui spicca la difesa della salute dell’uomo. Nel nostro gruppo di ricerca i prodotti naturali vengono utilizzati come “building block”, come “lead” per l’ottenimento di analoghi o come “target” per studiare nuove vie sintetiche. Verranno quindi presentati 4 diversi progetti ad esemplificare questi 3 modi diversi di utilizzare i composti naturali con applicazioni volte a due grandi problematiche come il cancro e la neurodegenerazione. I 4 diversi progetti vedranno come attori principali withaferin A, maytansine, cannabidiolo e gli epotiloni.

19 gennaio 2022 David Jeruzalmi (City University of New York)

Convergent Evolution in Two Bacterial Helicase Loaders

Dedicated loader proteins play essential roles in bacterial DNA replication by opening ring-shaped DnaB-family helicases and chaperoning ssDNA into a central motor chamber as a prelude to DNA unwinding. Although unrelated in sequence, the E. coli DnaC and bacteriophage λ P loaders feature a similar overall architecture: a globular domain linked to an extended lasso/grappling hook element, located at their amino and carboxy termini, respectively. Both loaders remodel a closed DnaB ring into nearly identical right-handed open conformations. The sole element shared by the loaders is a single alpha helix, which binds to the same site on the helicase. Physical features of the loaders establish that DnaC and λ P evolved independently to converge, through molecular mimicry, on a common helicase opening mechanism.

9 febbraio 2022 Heather Bondi (UNIUPO-DSF)

La plasticità astrogliale in risposta all'ambiente e all'invecchiamento: un nuovo target per terapie?

Per lungo tempo il neurone è stato considerato l’unità fondamentale del sistema nervoso centrale (SNC), confinando le altre cellule ad un ruolo marginale. Tuttavia, le recenti evidenze scientifiche hanno dimostrato che anche le altre popolazioni neurali svolgono ruoli chiave nella funzionalità cerebrale, superando così la visione neurocentrica del cervello. Gli astrociti, ad esempio, oltre a fornire supporto trofico e metabolico ai neuroni, partecipano alla regolazione dell’omeostasi dei neurotrasmettitori, regolano la barriera ematoencefalica e sono coinvolti attivamente nei processi di plasticità cerebrale. Gli astrociti sono estremamente plastici, capaci di rimodellare la propria forma, modificare l’espressione genica e adattare le proprie funzioni a seguito di stimoli endogeni ed esogeni. Attraverso un approccio morfometrico, abbiamo studiato il rimodellamento strutturale degli astrociti in risposta all’invecchiamento e ad uno stimolo ambientale, lo stress cronico, osservando cambiamenti specifici della complessità astrocitaria, soprattutto a livello delle aree cerebrali maggiormente coinvolte nelle malattie neurodegenerative e neuropsichiatriche. La regolazione della plasticità astrogliale, quindi, apre la possibilità di individuare nuovi approcci terapeutici per il trattamento delle patologie del SNC.

23 febbraio 2022 Elia Bari (UNIUPO-DSF)

Tecnologie per la formulazione di vescicole extracellulari e secretomi: nuove sfide per la medicina rigenerativa e il drug delivery

Tutte le cellule eucariote hanno un’attività secretoria più o meno spiccata e il loro secreto, chiamato anche secretoma, è costituito da fattori solubili di varia natura e da una componente corpuscolata costituita da vescicole extracellulari micro/nanostrutturate.
Negli ultimi anni il secretoma ha destato un grande interessa da parte della comunità scientifica per il suo potenziale impiego sia in campo diagnostico, in quanto marker di cellule con specifiche funzioni, sia in campo terapeutico. In particolare, l’uso di secretoma delle cellule staminali mesenchimali (MSC) è stato proposto in sostituzione delle cellule madri in medicina rigenerativa, oppure la sua componente vescicolare può essere impiegato come sistema di drug delivery. Tuttavia, per traslare con successo la ricerca sul secretoma delle MSC alla clinica, è necessaria la sua conversione in un prodotto medicinale di qualità, sicuro ed efficace. Il seminario descriverà quindi la “farmaceuticalizzazione” del secretoma delle MSC in una polvere liofilizzata stabile e standardizzata, detta liosecretoma. Verranno trattate alcune delle potenziali applicazioni terapeutiche del liosecretoma, in particolare nell’ambito di patologie polmonari, del wound healing e della rigenerazione ossea, come anche nella terapia veterinaria di patologie muscoloscheletriche, e, infine, nella veicolazione e direzionamento di principi attivi o nanoparticelle a cellule/tessuti target.

9 marzo 2022 Tracey Pirali  (UNIUPO-DSF)

Precision deuteration in medicinal chemistry: are we moving towards heavy drugs?

Deuterium incorporation is definitely entering the medicinal chemist’s toolbox. Despite being the smallest structural change that can be made in a molecule, precision deuteration might afford great advantages in many respects and lead to superior therapeutics.
By relying on the so-called Deuterium Kinetic Isotope Effect (DKIE), H-D isosterism slows down oxidative metabolism when including a rate-limiting C-H cleavage step and is perfectly suited to those soft spots in the molecule that do not tolerate changes in terms of steric hindrance or electronic properties. Deuterium incorporation might eventually lead to longer half-life, higher exposure, and in turn lower and/or less frequent dosage. Yet, the potential advantages of deuterium incorporation go beyond the simple amelioration of the pharmacokinetic profile: to name a few, H-D isosterism might reduce toxicity, minimize drug-drug interactions and interpatient variability, be responsible for biological activity, and stabilize otherwise unstable chiral centers. As a consequence, deutetrabenazine was approved in 2017 and at least other 15 deuterated candidates have entered clinical trials so far. Most of them are the result of a deuterium switching approach i.e. incorporation of deuterium in marketed drugs. While deuterium switching seems to be near to an ending, mainly due to intellectual property concerns, deuterium is becoming increasingly used since the early stages of drug discovery, as exemplified by deucravacitinib. In this seminar, case studies that exemplify the power of deuterium in medicinal chemistry will be provided, together with an analysis of the potential pitfalls that might be encountered when dealing with this isotope in drug R&D.

23 marzo 2022 Concettina La Motta (UNIPI)

"AMP-activated protein kinase: a therapeutic target in inflammatory diseases"

AMP-activated protein kinase (APMK) is a serine/threonine kinase commonly acknowledged as a master regulator of intracellular energy homeostasis. It promotes energy conservation in response to environmental stimuli by both inhibiting anabolic processes and stimulating catabolic pathways. In addition, it is increasingly clear that AMPK contributes also to the modulation of immune/inflammatory cell functions such as cytokine production, chemotaxis, cytotoxicity, apoptosis and proliferation. Indeed, a reduced AMPK expression and/or activity plays a key role in the pathophysiology of immune-mediated inflammatory disorders characterized by abnormal immune cell functions, such as psoriasis, inflammatory bowel diseases, rheumatoid arthritis, atherosclerosis and some neurodegenerative diseases. Therefore, AMPK can be considered a relevant molecular target for this kind of pathologies and the obtainment of effective AMPK activators a promising approach for their treatment. In this regards, we developed a novel class of AMPK activators as a useful tool to manage inflammatory bowel diseases.

6 aprile 2022 Francesco Moccia (UNIPV)

"SOCE and TRPV1: two interacting partners to stimulate therapeutic angiogenesis in cardiovascular disorders"

It has long been known that an increase in endothelial Ca2+ concentration is crucial to finely regulate sprouting angiogenesis, and recent evidence confirmed that intracellular Ca2+ signalling drive the angiogenic behaviour also in circulating endothelial progenitor cells (EPCs). During this talk, I will describe how storeoperated Ca2+ entry can be activated by multiple pro-angiogenic cues to induce EPC proliferation, migration and tube formation, whereas endogenous TRPV1 can be stimulate by geneless optical excitation of organic semiconductors. I will conclude by describing how SOCE can be engaged by TRPV1-mediated Ca2+ entry and how this signalling cascade has the potential to promote therapeutic neovascularization in cardiovascular disorders.

20 aprile 2022 Mattia Mori (Università di Siena)

"Nature-inspired discovery of anticancer leads targeting DNA G-quadruplexes"

G-quadruplexes (G4s) are non-canonical four-stranded structural motifs of nucleic acids formed by guanine-rich sequences, which play a wide range of biological functions in human and non-human genomes. Human G4s are related to genetic disorders, hereditary diseases and cancers, and are considered as profitable targets for pharmacological intervention. Natural compounds are appealing candidates for targeting G4s due to their high structural diversity of their scaffolds. In the search for novel G4s-targeting chemotypes, we screened in silico an in-house library of plant-derived natural products. By combining molecular docking with G4-CPG experimental screening assay, we identified five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Chelidonine and Rotenone emerged as the most active compounds of this series against cancer cells.

27 aprile 2022 Mara Zilocchi (University of Regina- Canada)

"Deciphering C6orf47 role in bipolar disorder: behind-the-scenes of mitochondria and glutamate metabolism"

Bipolar Disorder (BD) type I is a complex, highly heritable mood disorder characterized by alternating episodes of mania and depression, affecting millions globally. Although the etiology of this disorder is still poorly understood, a confluence of evidence suggests mitochondrial (mt) dysfunctions and glutamatergic alterations contribute to BD susceptibility due to decreased electron transport chain (ETC) activity and increased glutamate/glutamine ratio levels in the brain cortex of BD subjects. In this research project, we elucidated the mt dysfunctions characterizing BD patients through whole exome sequencing and biochemical fractionation coupled with mass spectrometry. After dissecting the mt protein interaction of BD vs healthy subjects, we found C6orf47, an uncharacterized protein, forming complexes with members of the ETC and glutamate metabolism in healthy subjects, while BD patients were characterized by the loss of these protein interactions. By applying targeted approaches in iPSC-derived neural progenitor cells and cortical neurons, we found C6orf47 playing a fundamental role in OXPHOS and glutamate metabolism regulation.

4 maggio 2022 Andrea Marcantoni (UNITO)

"Dysregulation of calcium released from ryanodine receptors and related synaptic impairments during Alzheimer's disease onset"

Synaptic dysfunction is one of the earliest hallmarks of Alzheimer’s Disease (AD). It is known that the oligomeric form of amyloid beta protein Abeta42 contributes to the development of synaptic abnormalities and cognitive impairments associated with AD. We have already reported that Abeta42 increases intracellular calcium concentration released through calcium-permeable ryanodine receptors (RyRs) and opposite effects have been described on AMPA and NMDA-dependent glutamatergic synapses. In particular, we have observed that, while the former is inhibited, the latter is potentiated. To date, there is an impressive lack of information on how Abeta42 affects the elementary parameters regulating inhibitory GABAergic synaptic function. Here the potentiating effects of Abeta42 on GABAergic synapses are examined. We further tested whether ryanodine receptors (RyRs) contributed to exacerbate the synaptic impairments observed by stabilizing the interaction between RyRs and the accessory protein calstabin. We observed that the RyRs-calstabin interaction stabilizer S107 restored the GABAergic synaptic parameters. In conclusion, our findings clarify the mechanisms of potentiation of GABAergic synapses induced by Abeta42 and suggest that RyRs are involved in the control of synaptic activity during the early stages of AD onset. Their stabilization rather than inhibition could represent a new therapeutical approach for AD treatment.

18 maggio 2022 Gian Cesare Tron (UNIUPO-DSF) 

"Old dog, new tricks. Isocyanides: from strategic hubs for novel multicomponent reactions to innovative pharmacophoric groups in medicinal chemistry"

This seminar is divided in two parts. In the first one, the most relevant isocyanide-based multicomponent reactions recently discovered in my lab will be discussed (e.g. chloroximes-isocyanides, TosMic-aryl azides). In that period, we only considered isocyanides as reactive functional groups pivotal for the success in multicomponent transformations. However, after synthesizing and using dozens of isocyanides, we began to ponder their potential use as innovative pharmacophoric groups in medicinal chemistry. The second part of this presentation is focused on this neglected aspect of isocyanides, focusing on their metabolism and applications in med chem.

25 maggio 2022  Loris Rizzello (UNIMI)

"Polymersomes eradicating intracellular pathogens"

Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional phagocytes can be parasitized by intracellular bacteria, turning them from housekeepers to hiding places and favoring chronic and/or disseminated infection. One of the most infamous is the bacteria that cause tuberculosis (TB), which is the most pandemic and one of the deadliest diseases, with one-third of the world’s population infected and an average of 1.8 million deaths/year worldwide. Here we demonstrate the effective targeting and intracellular delivery of antibiotics to infected macrophages both in vitro and in vivo, using pH-sensitive nanoscopic polymersomes made of PMPC–PDPA block copolymer. Polymersomes showed the ability to significantly enhance the efficacy of the antibiotics killing Mycobacterium bovis, Mycobacterium tuberculosis, and another established intracellular pathogen, Staphylococcus aureus. Moreover, they demonstrated to easily access TB-like granuloma tissues—one of the harshest environments to penetrate—in zebrafish models. We thus successfully exploited this targeting for the effective eradication of several intracellular bacteria. Moving on from the standard antibiotic-based therapy, we are also taking inspiration from the solutions provided by Nature and exploited the bacterial-restricted lytic properties of bacteriophages to develop an effective nanomedicinebased therapy. All known phages, with no exceptions detected so far, own a very specific set of lytic proteins, namely the endolysin (or lysin). They are highly efficient enzymes binding a very specific substrate, able to swindle cell wall integrity, and, finally, induce the death of the bacteria. Interestingly, mycobacteriophages encode for a second lysin, known as endolysin B (LysB). Contrary to other endolysin, LysB not only bears in its N-terminal the domain responsible for the binding to its target but also recognizes a different substrate represented by the outer layer (i.e., mycolic acids) of the waxy mycobacterial cell wall. This prompted us to hypothesize that the binding properties of lysins, such as LysB, might represent a high-affinity and specific tool that we can exploit to develop a selective antimycobacterial therapy. Therefore, we undertook a comprehensive study aiming to identify the minimal aminoacidic consensus sequence required for LysB binding to the mycomembrane, to create a precise targeting tool against intracellular bacteria. We believe this new bacteriophages-inspired therapy, coupled with the unique tools of by nanoparticles delivery, will provide an unprecedent therapeutic approach to Mtb infection and treatment, while also avoiding the rise in antimicrobial resistance.