Archivio seminari dipartimentali 2022/23

26 luglio Vilma Petrikaite (Vilnius University, Lithuania), host Prof. Armando Genazzani

"Hypoxia-targeting nanoparticles for breast cancer treatment"

Il seminario si terrà mercoledì 26 luglio dalle 12:30 alle 13:20, aula A4, presso il Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/fdz-odvd-ewd

Solid tumors are often characterized by hypoxia, and it is considered as a prognostic marker of a poor clinical outcome. A membrane protein carbonic anhydrase IX (CAIX) is highly overexpressed in many types of cancers and is mostly absent in normal tissues. Thus it could be a possible target for tumor-targeted nanotherapeutics. In our studies we used a selective CA IX inhibitor with a Kd value of 0.05 nM. This
compound was used as a ligand in a hypoxia-targeting nanosystem based on porous silicon nanoparticles uploaded with doxorubicin. The prepared nanoparticles showed a pH responsive release at pH 5.0 and low premature release at pH 7.4. Cell viability results showed that MCF-7 cells were resistant to free doxorubicin in hypoxia conditions. However, the CA IX modified nanoparticles exhibited high activity in hypoxia conditions. In summary, the nanoplatform with CA IX inhibitor exhibited controlled drug release and improved anticancer effect, especially in fighting against hypoxia caused drug resistance.

12 luglio Silvia Pozzi (Universitè Laval Quebèc City), host Laura Tapella (DSF-UPO) 

"Amyotrophic Lateral Sclerosis: from biomarkers to therapeutic targets"

Il seminario si terrà mercoledì 13 luglio dalle 12:30 alle 13:20, aula A4, presso il Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/hcu-frxm-qhc

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons and leading to muscle paralysis. Ninety percent of cases of ALS are sporadic (sALS), while the remaining ten percent are due to familial inherited mutations (fALS). Presently very few biomarkers have been identified to distinguish the disease from other neuromuscular disorders and no effective cure is available for patients. Peptidyl-Prolyl Isomerase A (PPIA) is a ubiquitously expressed protein that has been identified as a translational biomarker for ALS, as it shows the same pattern of up-regulation in sporadic patient blood cells and SOD1G93A mice spinal cord and blood cells. PPIA has also been found highly released in the CSF of sporadic ALS patients and SOD1G93A animal models. Its involvement in SOD1G93A conditions has been deeply investigated finding that PPIA has beneficial effects inside the cells, due to its chaperone properties, and detrimental effects when it is found in the extracellular milieu. By binding to its receptor EMMPRIN (extracellular matrix metalloproteinase inducer), extracellular PPIA (ePPIA) induces a NF-kB-dependent pathway that finally leads to MMP-9 release and motor neuron death. So far, the effect of ePPIA has only been investigated in SOD1G93A mice, an animal model that recapitulates patients’ symptomatology but represents only the five percent of fALS cases. Our lab is presently interested in investigating the relevance of ePPIA as a therapeutic target for different forms of sporadic and familial ALS, and in deciphering the role of the PPIA/EMMPRIN/MMPs pathway on other cellular populations of the central and peripheral nervous system during the development of ALS. The overarching goal of our research line is to develop an antibody-based therapeutic approach that, by blocking the- PPIA/EMMPRIN interaction, will rescue motor neurons from degeneration. The obtained results and ongoing studies will be presented during the conference.

11 luglio Federico Facciolo (University of Minnesota), host Claudio Jommi (DSF-UPO) 

"Community pharmacies’ provision of enhanced services in the United States:  A mixed methods approach"

Il seminario si terrà martedì 11 luglio dalle 14:00 alle 16:00, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/qmi-aejm-tuq

The profession of pharmacy in the United States (U.S.) has evolved from medication product to patient-centered care focus. Community pharmacists in the U.S. are embracing this practice by providing enhanced services. Expanding on the discussion of the pharmacy profession in the U.S., research examining enhanced services and business strategies used at community pharmacies will be highlighted. Using a mixed methods research design, survey data of all independent pharmacies in Nebraska (N=193) and focus group interviews with pharmacy owners were collected and analyzed. Descriptive and inferential statistics and thematic development were utilized to determine the outcomes of enhanced services. Survey results showed that on average independent pharmacies provide 17.3 enhanced services and leverage relationships (38%), educate (53%), and establish collaborative practice agreements (50%) with providers to provide services. Interview themes included “profitability from enhanced services is key for sustainability of independent community pharmacies.

28 giugno Mariagrazia Grilli (Laboratory of Neuroplasticity, DSF-UPO) 

"OF NEURAL STEM CELLS, ASTROCYTES AND THEIR CROSS-TALK: A PHARMACOLOGIST’S PERSPECTIVE IN DOWN SYNDROME"

Il seminario si terrà mercoledì 28 giugno dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link    https://meet.google.com/igh-hdtp-mng

Traditionally, approaches primarily focused on neurons and their connectivity have been used to unravel mechanisms involved in the pathophysiology of neuropsychiatric and neurodegenerative disorders. Similarly, neurodevelopmental disorders have been mainly addressed with such a prevalent “neurocentric” view. Unfortunately most scientific programs based on neuronal cells as privileged targets in CNS disorders have resulted in a long series of drug discovery failures. Recent studies have drawn increased attention on the role of non neuronal cells, particularly neural stem/progenitor cells (NSPC) and glia in complex and undertreated CNS diseases. In the Laboratory of Neuroplasticity we have extensively studied NSPC cells and their communication with astrocytes and pursued the discovery of novel pathophysiological mechanisms and pharmacological targets
in neurodegenerative and psychiatric disorders. Now we will discuss how a less neurocentric view may also be applied for a better understanding of Down Syndrome (DS), a disorder which is both neurodevelopmental and neurodegenerative in nature. Particularly we will present cellular, molecular and pharmacological data pointing to novel signalling pathways that may disrupt NSPC functions, their cross-talk with astrocytes and potentially
contribute to intellectual disability and age-related neurodegeneration associated with DS. We will discuss how these findings may hold the potential to unravel novel non neuronal targets for pharmacological interventions not only in DS, but also in other brain disorders associated with NSPC and/or astrocyte dysfunction.

21 giugno Sara Boumya (Drug Innovation- DSF-UNIUPO)

"A SELECTIVE ALDH1A3 INHIBITOR IMPAIRS MESOTHELIOMA 3-D MULTICELLULAR SPHEROID GROWTH AND NEUTROPHIL RECRUITMENT"

Il seminario si terrà mercoledì 21 giugno dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/qrb-qdtm-esv

Aldehyde dehydrogenase 1A3 (ALDH1A3) has been associated with increased progression and drug resistance in various types of solid tumors. It has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and gener-ation of neutrophil extracellular traps (NETs). We demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumor microenvironment can open new fronts in the treatment of this cancer.

19 giugno Shimon Ben-Shabat (Ben-Gurion University of the Negev, ISRAEL), host Fausto Chiazza

"Role of Phytocannabinoids in Neuroinflammation, and Nanotechnological Approach for Transdermal Delivery and Intranasal-Direct Brain Targeting"

Il seminario si terrà lunedì 19 giugno dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/ait-igqw-dgt

Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative Disease. CBG, and CBDA, phytocannabinoids, have attracted significant pharmacological interest due to their non-psychotropic nature. We studied the effects of these compounds on microglial inflammation in vitro, followed by an in vivo study. CBG and CBDA attenuated the microglial production of NO in BV2 microglia and primary glial cells and reduced iNOS expression. TNF-a on the other hand was decreased by CBG but increased by CBDA. The same was found in MS in vivo model, experimental autoimmune encephalomyelitis (EAE). The clinical scores of EAE mice were attenuated and lumbar sections of EAE mice showed enhanced neuronal loss. Despite the potential activity, the delivery of phytocannabinoids to the periphery and to CNS remains challenging. We have developed a new particulate system capable of delivering phytocannabinoids into the periphery by transdermal delivery and to the brain via the intranasal route. In cultures of LPS-induced inflamed BV2 cells, the phytocannabinoid-loaded starch nanoparticles demonstrated low toxicity while effectively reducing NO production and IL-6 levels. Intranasal administration of CBD-loaded starch
nanoparticles resulted in higher levels of CBD in the brain than an identically administered CBD solution.

14 giugno Emiliano Biasini (Università di Trento)

"Protein Folding Pathways Across Physiology & Therapy"

Il seminario si terrà mercoledì 14 giugno dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link  meet.google.com/cio-drbh-fya

Recent computational advancements in the simulation of biochemical processes allow the reconstruction of protein folding pathways at an atomistic level of resolution. By coupling this innovative technology with experimental techniques we discovered the existence of non-native
metastable states transiently appearing along the folding process of several proteins. Inspired by such an unexpected biological paradigm, we designed a novel drug discovery approach to selectively suppress target proteins by impairing their folding process rather than targeting their
native conformations (named Pharmacological Protein Inactivation by Folding Intermediate Targeting, PPI-FIT). PPI-FIT was employed to identify a pharmacological degrader of the cellular prion protein (PrP), a surface glycoprotein playing a central role in transmissible neurodegenerative pathologies known as prion diseases. Our data reveal a previously unappreciated role for folding intermediates in the regulation of protein homeostasis and directly support the concept of modulating the expression of virtually any protein by acting on folding pathways.

7 giugno MHD Ouis Al Khatib (Drug Innovation-DSF UNIUPO)

 "Dissecting The Role of TRIM28 in Oncogenic Inflammation"

Il seminario si terrà mercoledì 7 giugno, in inglese,  dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/fkx-wzpz-iha

Colitis-associated cancer represents a prime example of the link between chronic inflammation and tumorigenesis. However, the molecular sensors connecting inflammatory signals to cell transformation are still unclear. Tripartite motif-containing 28 (TRIM28) is a pleiotropic protein that can modulate key cancer cell activities, such as proliferation, survival, genomic instability, epithelial-to-mesenchymal transition and stemness.  Accordingly, overexpression of TRIM28 in different types of cancer, including colorectal cancer (CRC), has been reportedly associated with a worse prognosis. Therefore, we investigate the role and the mechanisms linking TRIM28 in intestinal epithelial cells (IECs) to inflammation-driven colon cancer development. Tissue-specific ablation of TRIM28 in the intestinal epithelial cells inhibited colitis-induced but not chemically-induced colon carcinogenesis. In agreement, histological and immunohistochemical analysis of the colons showed that the lack of TRIM28 strongly reduced the tumor multiplicity, as well as its proliferative activity, estimated as Ki67-positive area. Of interest, these events were paralleled by increased neoformation of tertiary lymphoid aggregates. TRIM28 phosphorylation at Serine473 occurs in response to inflammatory stimuli (i.e. lipopolysaccharide) or in response to DNA damage (i.e. etoposide). After silencing of TRIM28, etoposide-treated MC38 cells exhibited slower kinetics of H2AX dephosphorylation and a pronounced arrest in the sub-G1 phase of the cell cycle, indicating a reduction in DNA repair and a greater commitment to apoptosis. Finally, we estimated the amount of cancer stem cells by the sphere formation test and found that silencing TRIM28 significantly reduced the percentage of stem cells, compared to the wild type counterpart. Overall, our results demonstrate that TRIM28 acts as tumor promoter, favoring cancer cell proliferation and resistance to apoptosis. Since phosphorylation of TRIM28 at Serine473 controls cell cycle progression, a necessary event for DNA damage repair, TRIM28 depletion appears to favor accumulation of mutations incompatible with cell life, favoring their apoptotic death. While this mechanistic hypothesis will require further confirmation, the tumor promoting role of TRIM28 is further supported by its ability to promote cancer cell stemness.

30 maggio Alexei Verkhratsky (University of Manchester), host Dmitry Lim

"Principles of gliopathology: rethinking astrocytic reactivity and challenging inflammaging"

Il seminario si terrà martedì 30 maggio dalle 12:30 alle 13:20 nell'Aula Magna del Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/rsu-aztf-etv

Alexei Verkhratsky is an internationally recognized scholar in the field of cellular neurophysiology. His research is concentrated on the mechanisms of inter‐ and intracellular signalling in the CNS, being especially focused on two main types of neural cells, on neurons and neuroglia. Among other contributions, he authored a pioneering hypothesis of astroglial atrophy and homeostatic failure as a mechanism of neurodegeneration, challenging the concept of «inflammaging».

24 maggio Marianna Moro (Drug Innovation- DSF-UNIUPO) 

"The involvement of eNAMPT in the angiogenic process: a spotlight on pericytes"

Il seminario si terrà mercoledì 24 maggio dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/cnf-ftua-bba

One of the hallmarks acquired by cancer cells during the multistep development of tumour is the induction of angiogenesis. Blood vessels are more than endothelial cells that line the vessel walls. Indeed, pericytes are mural cells that enwrap the endothelium to support the vessel wall and control the blood flow. The increase amount of pericyte coverage or their loosely attachment to the endothelial cells regulate tumour proliferation and metastatic invasion. Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein which exists in the cells in
two different forms. The extracellular form (eNAMPT) has cytokine-like properties, and it is released by different cell types including cancer cells. Breast cancer patients exhibit increased serum levels of eNAMPT as compared to controls which correlate with tumour progression and lymph node metastasis. Interestingly, tumour removal causes a significant decrease of eNAMPT levels. Although eNAMPT is reported to be a pro-angiogenic molecule for endothelial cells, the link between eNAMPT and tumour angiogenesis is wanting. Using a model of triple negative breast cancer cells (4T1) we have stably engineered them to release a massive amount of eNAMPT to monitor in vivo the involvement of eNAMPT in tumoural angiogenesis with a particular highlight on pericytes.

17 maggio Daniela Imperio (DSF-UNIUPO)

"Organocatalysis: new approaches to Catalytic Asymmetric Epoxidation"

Il seminario si terrà mercoledì 17 maggio dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link https://meet.google.com/eqt-dzuz-rxm

Organocatalysis is a useful tool for the asymmetric synthesis of biological or pharmaceutical compounds because it avoids harmful metals that are difficult to remove from target products. Furthermore, frequently, organocatalysis reactions can be carried out in benign solvents and do not
require anhydrous conditions. The use of simple organic biomolecules as catalysts has been a breakthrough in the chemical community, becoming a mainstay of modern organic chemistry culminating in the endowment of the Nobel Prize in Chemistry in 2021. Over the past three decades, other enantiopure natural compounds, such as carbohydrates, have been employed as organocatalysts. Carbohydrates are chiral, cheap, and biocompatible entities that have the potential utility of serving as suitable organocatalysts to enhance the selectivity of chemical
reactions. A new galactose-derived trifluoromethyl ketone has been shown to be an effective catalyst for the asymmetric epoxidation of a wide variety of trans- and tri-substituted olefins through the formation of reactive dioxirane species in situ.

10 maggio Marta Alberti (Drug Innovation- DSF-UNIUPO) 

"Exploring pyrimidine biosynthesis pathway as drug target of inhibitory agents of pharmaceutical interest"

Il seminario si terrà mercoledì 10 maggio dalle 12:30 alle 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/kby-nswt-rkt

Among de novo pyrimidine biosynthesis pathway (PBP), dihydroorotate dehydrogenase enzyme (DHODH) can be considered a versatile target in the treatment of several conditions because of its fundamental role in the nucleotide metabolism and in cellular homeostasis. Anchored to the inner mitochondrial membrane, human DHODH (hDHODH) is a validated target in different pathological conditions related to abnormal cellular proliferation, such as cancer and autoimmune disorders. With the aim to improve and enhance keys information about enzyme-inhibitor interactions, we solved the crystal structures of the enzyme in complex with different synthetic and natural compounds and the analysis of their binding poses helped us to redefine the optimal paradigm in the design of high potent hDHODH inhibitors. Since PBP is strictly conserved in several organisms and considering the interest of our laboratory in research related to poverty-related diseases, we selected DHODH from Mycobacterium tuberculosis (MtDHODH) and from Plamsodium falciparum parasite (PfDHODH) to be proposed as innovative therapeutic targets in more conventional pathogen-directed therapies and in innovative host-directed-therapies. In the present work, we built up the experimental framework for an early drug discovery pipeline aimed at interfering with the nucleotide metabolic pathway in different organisms. In particular, the biochemical and structural characterization of hDHODH, MtDHODH and PfDHODH will pave the way to the discovery of selective compounds of pharmaceutical interest.

26 aprile Giulia Dematteis (Drug Innovation- DSF-UNIUPO)

"Optimization of the ER-mitochondrial distances for Ca2+ transfer: patho-physiological implications"

Il seminario si terrà mercoledì 26 aprile dalle 12:30 to 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link https://meet.google.com/opy-esmd-rok

During last decades, alteration in mitochondria (Mit)-endoplasmic reticulum (ER) distances has been reported in different pathological condition, including Alzheimer disease (AD) models. One of the most important processes that takes place at the MIt- ER contact sites (MERCS) is the Ca2+ transfer from the ER to the mitochondria, where Ca2+ regulates bioenergetics and apoptosis. However, in the literature, the correlation between Mit-ER distances and calcium transfer deregulation is far from understanding. In other to define how, Mit-ER distance, can shape intracellular calcium signaling, and consequently cellular functions, we used different Mit-ER linkers to fine regulate the distance between the two organelles.
With this approach we identified, 20nm as the specific distance to promote ER-Mit calcium transfer, and we investigate the physio pathological implication of the crosstalk between Mit-ER distances and mitochondrial calcium uptake.

19 aprile Ambra Grolla (DSF-UNIUPO)

NAMPT: how a moonlighting protein can sustain cancer

Il seminario si terrà mercoledì 19 aprile dalle 12:30 to 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/ots-kohi-pbc

Tumoural cells have a remarkably different metabolism from that of the tissue from which they are derived. Several proteins cooperate to satisfy the request of cancer cells and recent evidences suggest a new vision of the protein arrangement of the cell, mainly in a tumour context. The traditional idea of one gene – one protein – one function has become too simple to fully explain the cellular complexity of protein function and interaction. It is now believed that when proteins appear in different subcellular locations, the cells surpass the expected activity of proteins given the same genomic information to satisfy complex biological behaviour. Although many proteins are now known to display multiple, independent functions beyond originally identified ones, and these multifunctional proteins are referred to as “moonlighting” proteins. Nicotinamide Phosphoribosyltransferase (NAMPT) might be represented by this category of proteins, indeed it exists in two different forms with three different localization. NAMPT is mainly known as intracellular key enzyme involved in NAD biosynthesis, which is localized mainly in the cytosol, but it translocates to the nucleus, where acquire new functions to sustain DNA damage mainly in tumoural cells. Moreover, NAMPT is also secreted in extracellular space, where it has been reported to act as a cytokine, with pro-inflammatory and pro-tumoural functions. For instance, in breast cancer, eNAMPT serum levels are proportional to TNM stage, tumour size, histological grade and correlate with a poor-prognosis and low overall-survival.

12 aprile Irene Preet Bhela (Drug Innovation- DSF-UNIUPO)

Store-Operated Calcium Entry (SOCE): our medchem contribution to the synthesis of negative modulators as a therapeutic approach against rare and common diseases

Il seminario si terrà mercoledì 12 aprile dalle 12:30 to 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link https://meet.google.com/eys-girs-roq

Store-Operated Calcium Entry (SOCE) is a complex machinery relying on two proteins, STIM and Orai, that contributes to the regulation of calcium homeostasis. Since it is involved in a wide range of cellular functions, such as inflammation, platelet activation and muscle contraction, an impairment of SOCE has been associated to several diseases. Among them, we have focused on acute pancreatitis, tubular aggregate myopathy and Duchenne muscular dystrophy, three diseases that still lack an effective medical treatment. During this talk, I will describe our medchem contribution to the design and synthesis of negative modulators of SOCE that has led to the identification of a preclinical candidate, in
collaboration with the start-up ChemICare, and its prodrugs. I will also describe the serendipitous discovery of a dual inhibitor of dihydroorotate dehydrogenase - involved in de novo pyrimidine biosynthesis - and SOCE as a novel modality to tackle autoimmune disorders.

22 marzo  Valerio Fasano (UNIMI), host Daniela Imperio

 New frontiers in boron chemistry: from migration to automation

Il seminario si terrà mercoledì 22 marzo dalle 12:30 to 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/jox-zvth-grh

The pinacol boronic ester (“Bpin” for short) is an important functional group in modern synthesis due to its accessibility, chemical stability, and synthetic versatility. In this talk, I will present new insights regarding the stereochemical properties of Bpin and how it could be exploited to access stereodefined fluoromethylated compounds. Finally, I will show how the merging of the unique chemistry of boron with the power of robotics can lead to automated organic syntheses.

8 marzo Angela De Simone (UNITO), host Erika Del Grosso

Multi-methodological approaches for pre-clinical drug characterization

Il seminario si terrà mercoledì 8 marzo dalle 12:30 to 13:20, aula A4, Dipartimento di Scienze del Farmaco (L.go Donegani 2, Novara) e in diretta streaming al link meet.google.com/qgv-pxbs-tja

The development of automated analytical techniques to screen and characterize new ligands for key targets, makes the hit selection of the drug discovery process faster and cheaper. The classical fluorimetric as well as luminometric or radiometric methods, usually adopted for the high throughput screening (HTS), are often related to some drawbacks such as false positive/negative results, high costs and health risks for operators. Advanced analytical methods based on the application of methodologies such as Immobilized Enzyme Reactors (IMERs); Ultra High Performance Liquid Chromatography (UHPLC); LC-Mass Spectrometry, Surface Plasmon Resonance (SPR) have demonstrated to be valid alternatives to the classical in vitro assays. Innovative assays aimed at characterizing inhibitors towards the main target involved in Alzheimer’s
Disease were developed. In particular, alternative assays were validated for the HTS of ligands addressed to BACE-1 and GSK-3β enzymes responsible for the production of β-amyloid peptide and the hyperphosphorylation of tau protein, respectively. Moreover, the use of different analytical techniques gave the opportunity of applying a multi-methodological approach to the structural characterization of proteins, investigation of ligand-target interaction and to the monitoring of β-amyloid aggregation process. Both the different and complementary information that can be obtained concerning the studied systems, through this approach, are extremely useful to the disclosure of small molecule mechanisms of action with the final aim to support the rational drug design process.

8 febbraio Sara Missaglia (Università Cattolica del Sacro Cuore- Milano), host: Giulia Pinton (UPO-DSF)

Malattie da accumulo di lipidi neutri; aspetti genetici, valutazioni biochimico-cliniche e analisi funzionali

Il seminario si terrà mercoledì 8 febbraio dalle 13:00 to 13:40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/wcb-booz-xsi

Le malattie da accumulo di lipidi neutri (NLSDs) sono un gruppo eterogeneo di malattie genetiche rare, a trasmissione autosomica recessiva, caratterizzate da un accumulo eccessivo, non lisosomiale, di lipidi neutri nei tessuti. Sono stati descritti due sottotipi di NLSDs, la malattia da accumulo di lipidi neutri con miopatia (NLSDM) e la malattia da accumulo di lipidi neutri con ittiosi (NLSDI), nota anche come sindrome di Chanarin-Dorfman. La NLSDM è causata da mutazioni nel gene PNPLA2, che codifica per la lipasi ATGL. Questo enzima è responsabile dell’idrolisi del primo acido grasso dei trigliceridi immagazzinati all’interno di organuli cellulari chiamati lipid droplets (LD). Mutazioni di ABHD5, un coattivatore di ATGL, sono associate all’insorgenza della NLSDI. Sebbene la patogenesi delle NLSDs sia ancora sconosciuta, è noto che l’attività di questi due enzimi è essenziale per il catabolismo dei trigliceridi allo scopo di fornire substrati per la produzione di energia nei mitocondri. Lo sviluppo di saggi biochimici e funzionali ha reso disponibile degli strumenti per lo studio più approfondito dell’effetto patogenetico delle diverse mutazioni identificate in PNPLA2 e ABHD5. Infine, la disponibilità di fibroblasti dermici e mioblasti ottenuti dai pazienti ha fornito
un modello cellulare unico per cercare di chiarire i meccanismi molecolari alla base dell’insorgenza delle NLSDs.

25 gennaio Simona Martinotti (UNIUPO-DISIT), host: Dmitry Lim (UPO-DSF)

Honey-triggered wound healing: a tale of H2O2 and Ca2+

Il seminario si terrà mercoledì 25 gennaio dalle 13:00 to 13:40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/egi-okqb-ano

Honey has a number of properties that are believed to facilitate the healing process. Its acidic pH, H2O2 production, high sugar content, and specific plant-derived chemicals serve to inhibit microbial growth. Indeed, since Biblical times, honey has been used in ‘folk medicine’, and empirical evidence established honey as a treatment for wounds and sores, and an extensive body of scientific literature on the wound healing capabilities of honey has confirmed its value. However, the cellular and molecular mechanisms involved in honey-promoted wound healing, was not completely understood. We observed that honey exposure induces a strong increase of some specific AQPs in keratinocytes, in particular AQP3. Therefore, we investigated the role of AQP3 upon honey exposure as a mediator of H2O2 signalling on wound healing mechanisms, because of its intrinsic H2O2 production in the extracellular space. This important entry of H2O2 influences Ca2+ dynamics. After honey exposure, we observed a rapid increase in [Ca2+]i, that was completely erased in absence of AQP3. The lack in Ca2+ signal determines a decrease in cell motility and wound closure rate. Finally, we pointed out the relationship between AQP3 expression, Ca2+ dynamics and wound healing upon honey exposure.

 

19 dicembre  Edoardo D'Imprima (EMBL Heidelberg), host: Giovanni Battista Giovenzana (UPO-DSF)

From proteins to whole cells: enabling structural discovery by cryo-electron microscopy

Il seminario si terrà lunedì 19 dicembre dalle 13:00 to 13:40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link https://meet.google.com/tgs-djjm-ghu

Cryo-electron microscopy (cryoEM) has developed into a technique for determining the structure of protein complexes at high resolution, at a rate that was difficult to imagine at the outset of the resolution revolution only a few years ago. One application, single particle cryoEM, allows the atomic resolution structure determination of isolated macromolecular complexes. Further, cryo-electron tomography (cryoET), can probe protein complexes directly in their native environment i.e. in-cell either by imaging the entire cell when it is smaller than a micron, like most bacteria. Conversely, focused ion beam (FIB) milling is required to access portions of larger mammalian cells at expense of the multicellular context. This can be instead preserved, by combining serial FIB sectioning and scanning electron microscopy (SEM) imaging. My talk will cover the current possibilities and challenges of single particle cryoEM, cryoET and FIB-SEM tomography for structural biology.

7 dicembre Oleksii Parniakov (Elea GmbH). Host:  Matteo Bordiga (UPO-DSF)

Industrial application of PEF (Pulsed Electric Field)

Il seminario si terrà mercoledì 7 dicembre dalle 13:00 to 13:40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/aiq-ukdh-oek 

The application of the Pulsed Electric Field (PEF) in the food industry is getting more and more attention. This emerging technology is one of the most implemented in the food industry. In the seminar the most common application of PEF in the food industry will be presented along with its economic and sustainable benefits.

5 dicembre Livija Deban (Prokarium). Host: Chiara Porta (UPO-DSF)

Overcoming The Suppressive Tumor Microenvironment With A Live Bacterial Immunotherapy

Il seminario si terrà lunedì 5 dicembre dalle 13:00 to 13:40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/kro-xtev-scd 

Recent advances in cancer immunotherapy have produced remarkable results in some cancer types. Unfortunately, efficacy is limited to patient subpopulations in certain indications. While the underlying reasons are many and not fully understood, tumor-infiltrating myeloid cells, a major immunosuppressive population, are one of the culprits. Tumor-infiltrating myeloid cells supress anti-tumor immunity within the tumor
microenvironment (TME) through direct and indirect inhibitory mechanisms. However, inherent myeloid plasticity offers the opportunity for treatments to reprogramme these cells. One class of agents with potential to reprogramme myeloid cells are bacteria and their products, which act locally on suppressive cell populations, but could also induce long-lasting systemic reprogramming of myeloid cells, a process termed trained immunity. Prokarium is developing a live attenuated Salmonella enterica serovar Typhi strain (ZH9) to be the next cancer immunotherapy and explored how Salmonella reprogrammes myeloid cells and enhances anti-tumor immune function.

30 novembre Simone Merlin (DISS-UNIUPO). Host: Giulia Pinton (UPO-DSF)

Cell and gene therapy of hemophilia A

Il seminario si terrà dalle 13:00 to 13:40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/zsg-guff-hix

Hemophilia A (HA) is an X-linked bleeding disorder due to mutations/deletions in FVIII gene. To date the treatment for preventing major bleeding episodes in HA is represented by replacement therapy with FVIII, a treatment with two major drawbacks: high costs and development of antibodies that neutralize FVIII activity (inhibitors) in ~30% of patients. As the current therapies based on frequent FVIII infusions are not a definitive cure, long-term expression of FVIII holds the promise of a one-time treatment. To this aim, we focused on the identification of cell-types able to synthesize and release FVIII and used them in cell therapy approaches. Additionally, in gene therapy approaches we expressed FVIII gene at the physiologic site of synthesis by the mean of transcriptional and post-transcriptional regulation to achieve a highly specific and stable transgene expression, while avoiding immune responses to FVIII. The combination of cell and gene therapy showed to be an additional and exploitable option for the treatment of HA. Overall, these approaches showed to have the potential of ameliorating the bleeding phenotype and provide the benefits of prophylaxis and reduce the need for frequent injections thus improving HA patients’ quality of life.

23 novembre  Fabio Cavaliere (Achucarro Basque Center for Neuroscience- Spain) 

The Marvellous Journey of a Skin Cell Who Wanna be a Brain

Il seminario si terrà dalle 11:30 to 12:10 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/ocg-udno-tqg

Most of current knowledge of brain physiopathology and pharmacological investigation on human brain is based on observational and functional studies on animal models. Nonetheless, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures and animal models cannot precisely replicate human brain physiopathology. Although essential in many fields of neurodegenerative disease investigation, animal models can not fill the gap with human biology. The development of cell reprogramming with the generation of human induced pluripotent stem cells (hiPSC) opened the door to bridge this gap giving the opportunity to culture patient’s neural cell in a dish. Here, we will show how the Basque biomodel platform for human research (BBioH) can model the brain physiology and the main pathological hallmark of neurodegenerative diseases, mainly Parkinson’s disease, using hiPScderived neural cells (astrocytes and neurons) and brain organoids. Especially, midbrain organoids recapitulate the cellular hallmarks of the actual human midbrain, with tyrosine hydroxylase positive neurons, astrocytes and oligodendrocytes. These organoids represent miniaturized and simplified versions of human midbrain converting them in patient’s avatars worth to study the progression of neurodegeneration.

16 novembre Daiana Mattoteia (The Armenise-Harvard Laboratory of Structural Biology-UNIPV)

An integrative structural biology approach to characterize the multifunctional PLODs family

Il seminario si terrà dalle 13.00 alle 13.40 presso la Sala Conferenze "Maurizio Pagani", Fondazione Novara Sviluppo (via Bovio 6, Novara) e in diretta streaming al link meet.google.com/qns-mxgk-tqi

Procollagen-lysine 2-oxoglutarate 5-dioxigenases (PLODs) are a three-member family of enzymes closely involved in the collagen maturation pathway and, consequently, in the homeostasis of the extracellular matrix (ECM). Alterations in expression or activity of PLODs greatly affect the ECM weaving and organisation, leading to some peculiar genetic disorders of connective tissues (ElhersDanlos and Bruck syndromes) or promoting metastasis of solid tumors. Although several studies have been carried out, much more work is needed to understand how LH enzymes are involved in ECM physiopathology. Moreover, since PLODs are a biomarker of poor prognosis (PLOD2 in particular), this family of multifunctional enzyme represent a very promising druggable target. Applying a multidisciplinary and integrative approach¬, our goals are solving structures of all PLOD isoforms and use them as templates for a rational structure-based campaign of drug design and discovery. The experience gained with the PLOD3 structure solution has strongly helped us to set and optimise a protocol for the PLOD1 and PLOD2 expression and production: having folded and stable proteins was the first step for their structural (nanoDSF, MALS, Negative staining, cryoEM) and functional (MS and luminescence assays) characterization. Furthermore, the druggability of PLODs was tested using PLOD3 structure as a template: these preliminary studies further highlighted how the catalytic activities of these multifunctional enzymes are challenging to regulate. Our results represent a significant milestone for a more comprehensive understanding of the PLODs role in collagen biosynthesis, ECM functions and, indirectly, in solid tumor metastasis.

19 ottobre Laura Morelli (UNIMI); host of the webinar: Daniela Imperio (UNIUPO)

 Synthetic epitopes common to Streptococcus pneumoniae 19F and 19A capsular polysaccharides

The webinar will be only streamed live on the link https://meet.google.com/tms-gfid-igk 

Pneumonia is a serious respiratory infection mainly caused by Streptococcus pneumoniae (Sp). Vaccination is known to be the most effective approach to prevent invasive pneumococcal disease. Nowadays 100 distinct Sp serotypes are known, differing in the chemical structures of the capsular polysaccharides (CPSs) that represent the outermost layer of the bacterial cell envelope. Since the Sp CPSs are key virulence factors, pneumococcal conjugate vaccines (PCVs) are made of bacterial CPS fragments conjugated to a carrier protein. PCVs are able to induce a
strong serotype-specific immune response and to establish a long-term immunological memory. The increasing number of infections caused by those serotypes not included in commercial PCVs is a serious concern. In this context, we envisage to identify novel saccharide antigens consisting of a common structure shared by Sp 19F and 19A serotypes, with the purpose of enabling cross-protective responses among different serotypes for a broader coverage.

5 ottobre 2022 Martín J. Riveira (Universidad Nacional de Rosario- Argentina), from 3:00 p.m. to 3:40 p.m

New Synthetic Applications of Conjugated Carbonyl Compounds

The seminar will be conducted exclusively via webcast at this link: https://meet.google.com/sdf-rtre-sbv

Throughout history, natural products have been and continue to be invaluable sources of solutions to humanity, particularly regarding treatments for human diseases. A comparative analysis of natural products and those drugs that are of neat synthetic origin reveals that the former feature a greater number of fused ring systems instead of isolated ones and therefore, the efficient preparation of such polycyclic systems plays a central role in the art of organic synthesis. Domino reactions of polyenic substrates outstand to provide access to structural complexity in simple and efficient ways. In this presentation domino processes of conjugated carbonyl substrates involving cyclization steps will be disclosed that have allowed the synthesis of cyclic and polycyclic systems of interest including natural products and analogues.