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The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a pos-itive-sense, single stranded RNA virus, responsible for the pandemic outbreak called COVID-19. The pandemic, still ongoing, had presented unprecedented challenges in terms of finding appropriate pharmacological treatments. Methods: Starting from the recent literature that demonstrates how ALKBH5 inhibitors could be used as a new strategy to reduce SARS-CoV-2 replication, we decided to repurpose our newly dis-covered ALKBH5 inhibitor MV1035, previously tested and proved effective against glioblastoma, for its putative antiviral activity against SARS-CoV-2. We demonstrated a reduction in SARS-CoV-2-induced CPE after 72 h incubation using MV1035 (50 µM), for SARS-CoV-2 wild type (Wuhan strain) and South African variant. Results: The results show how MV1035 seems to be able to reduce SARS-CoV-2 replication through an indirect mechanism of action, which might involve an interaction with the host cell rather than with a virus protein. Conclusion: This may be particularly interesting as it lays the foundation for the rational design of molecules in principle not subject to drug resistance, as host cell proteins are not affected by virus mutations.

Bortezomib (BTZ), è un inibitore del proteasoma, approvato nel 2003 dalla Food and Drug Administration per il trattamento del mieloma multiplo. Attualmente, BTZ è utilizzato per il trattamento del mieloma multiplo e del linfoma mantellare. Tuttavia, la neuropatia periferica indotta da BTZ (BIPN) si verifica in circa il 30-40% dei pazienti ed è caratterizzata da sintomi sensoriali e dolore neuropatico (BIPN). Secondo le linee guida pubblicate nel 2014 e confermate nel 2019 dall'American Society of Clinical Oncology, non esistono terapie altamente raccomandate per la prevenzione o il trattamento della neuropatia periferica indotta da chemioterapici (CIPN). Solo il farmaco duloxetina è stato raccomandato nel 2020. Grazie alle nanotecnologie è possibile la progettazione di particelle di piccole dimensioni e versatili. In campo farmaceutico, le nanostrutture caricate con farmaci sono più selettive verso il tessuto bersaglio. I materiali in silice sono classificati dalla FDA come “Generally Recognized as Safe” e sono stati utilizzati come additivo alimentare e nei cosmetici. Le nanoparticelle di silice mesoporosa (MSN) (diametro di 50-300 nm) sono importanti nelle applicazioni mediche perché hanno caratteristiche molto interessanti: assenza di tossicità (<100 microg/m2), dimensione dei pori regolabile (2–50 nm), elevata superficie (700–1000 m2/g), elevata capacità di caricamento e rilascio graduale del farmaco, buona biocompatibilità e bassi costi di produzione. In questo progetto, con l'obiettivo di aumentare l'efficacia e la selettività del BTZ per il mieloma multiplo e di conseguenza ridurre la tossicità del BTZ (in particolare la neurotossicità), nanoparticelle FOL-MSN-BTZ sintetizzate dal Dipartimento di Ingegneria Ambientale dell’Università della Calabria sono state indagate. Le nanoparticelle FOL-MSN-BTZ hanno due caratteristiche molto importanti: a) rilascio del farmaco pH dipendente. Questa caratteristica è finalizzata al rilascio pr, Bortezomib (BTZ), a first-generation proteasome inhibitor, was approved by the Food and Drug Administration (FDA) in 2003 for the treatment of multiple myeloma. At present, BTZ is frequently used for treatment of multiple myeloma and mantle cell lymphoma. However, bortezomib-induced peripheral neuropathy (BIPN) occurs in approximately 30%–40% of patients and it is characterized by sensory symptoms (hypoesthesia, paresthesias and numbness) and/or neuropathic pain. According to clinical practice guidelines released by the American Society of Clinical Oncology (ASCO) in 2014, also confirmed in 2019, there are no highly recommended therapies for the prevention or treatment of chemotherapy-induced peripheral neuropathy (CIPN), including BIPN. only one drug (duloxetine) was added to the latest guidelines released in 2020. Therefore, novel therapeutic strategies are highly desirable to prevent and manage CIPN symptoms. Nanotechnologies provide the design of small and flexible structures. In the pharmaceutical field, hosting old drugs in nanostructures allows the drugs to selectively recognize the target tissue. Silica materials are classified by FDA as “Generally Recognized as Safe (GRAS)” and they have been used, for a long time, as a food-additive and in cosmetics. Mesoporous Silica Nanoparticles (MSNs) (diameter of 50-300 nm) are very interesting in medical applications due to their no toxicity (<100microg/m), tunable pore size (2–50 nm), high surface area (700–1000 m2/g), high capacity of drug loading and gradual release, good biocompatibility, and low production costs. In this project, with the aim of increasing the efficacy and target selectivity of BTZ and consequently reducing the toxicity of BTZ (in particular BTZ neurotoxicity), FOL-MSN-BTZ designed, synthetized and characterized by the Department of Environmental Engineering University of Calabria have been investigated. FOL-MSN-BTZ have two very important characteristics: a) drug release depends on pH. This cha

Simple Summary AMPK is an enzyme that plays a role in cellular energy mechanisms and controls many metabolic and physiological processes. AMPK is dysregulated in different diseases, making it a potential therapeutic target. AMPK can be activated in a direct or indirect way. In this review, we discuss different AMPK activating compounds and especially focus our attention on those compounds that imitate physiological mechanisms of AMPK activation. 5 '-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that regulates cellular energy homeostasis, glucose, fatty acid uptake, and oxidation at low cellular ATP levels. AMPK plays an important role in several molecular mechanisms and physiological conditions. It has been shown that AMPK can be dysregulated in different chronic diseases, such as inflammation, diabetes, obesity, and cancer. Due to its fundamental role in physiological and pathological cellular processes, AMPK is considered one of the most important targets for treating different diseases. Over decades, different AMPK targeting compounds have been discovered, starting from those that activate AMPK indirectly by altering intracellular AMP:ATP ratio to compounds that activate AMPK directly by binding to its activation sites. However, indirect altering of intracellular AMP:ATP ratio influences different cellular processes and induces side effects. Direct AMPK activators showed more promising results in eliminating side effects as well as the possibility to engineer drugs for specific AMPK isoforms activation. In this review, we discuss AMPK targeting drugs, especially concentrating on those compounds that activate AMPK by mimicking AMP. These compounds are poorly described in the literature and still, a lot of questions remain unanswered about the exact mechanism of AMP regulation. Future investigation of the mechanism of AMP binding will make it possible to develop new compounds that, in combination with others, can activate AMPK in a syne

We report the rational design, synthesis, and in vitro preliminary evaluation of a new small library of non-peptide ligands of Gastrin Releasing Peptide Receptor (GRP-R), able to antagonize its natural ligand bombesin (BN) in the nanomolar range of concentration. GRP-R is a transmembrane G-protein coupled receptor promoting the stimulation of cancer cell proliferation. Being overexpressed on the surface of different human cancer cell lines, GRP-R is ideal for the selective delivery to tumor cells of both anticancer drug and diagnostic devices. What makes very challenging the design of non-peptide BN analogues is that the 3D structure of the GRP-R is not available, which is the case for many membrane-bound receptors. Thus, the design of GRP-R ligands has to be based on the structure of its natural ligands, BN and GRP. We recently mapped the BN binding epitope by NMR and here we exploited the same spectroscopy, combined with MD, to define BN conformation in proximity of biological membranes, where the interaction with GRP-R takes place. The gained structural information was used to identify a rigid C-galactosidic scaffold able to support pharmacophore groups mimicking the BN key residues’ side chains in a suitable manner for binding to GRP-R. Our BN antagonists represent hit compounds for the rational design and synthesis of new ligands and modulators of GRP-R. The further optimization of the pharmacophore groups will allow to increase the biological activity. Due to their favorable chemical properties and stability, they could be employed for the active receptor-mediated targeting of GRP-R positive tumors.

We report the NMR characterization of the molecular interaction between Gastrin Releasing Peptide Receptor (GRP-R) and its natural ligand bombesin (BN). GRP-R is a transmembrane G-protein coupled receptor promoting the stimulation of cancer cell proliferation; in addition, being overexpressed on the surface of different human cancer cell lines, it is ideal for the development of new strategies for the selective targeted delivery of anticancer drugs and diagnostic devices to tumor cells. However, the design of new GRPR binders requires structural information on receptor interaction with its natural ligands. The experimental protocol presented herein, based on on-cell STD NMR techniques, is a powerful tool for the screening and the epitope mapping of GRP-R ligands aimed at the development of new anticancer and diagnostic tools. Notably, the study can be carried out in a physiological environment, at the surface of tumoral cells overespressing GRP-R. Moreover, to the best of our knowledge, this is the first example of an NMR experiment able to detect and investigate the structural determinants of BN/GRP-R interaction.

Objectives: To explore whether facial emotion recognition (FER), impaired in both schizophrenia and alcohol and substance use disorders (AUDs/SUDs), is additionally compromised among comorbid subjects, also considering the role of catechol‐O‐methyltransferase (COMT) Val158Met. Methods: We conducted a cross‐sectional study, randomly recruiting 67 subjects with a DSM‐IV‐TR diagnosis of schizophrenia, and rigorously assessing AUDs/SUDs and COMT Val158Met polymorphism. FER was assessed using the Ekman 60 Faces Test‐ EK‐60F. Results: As a whole, the sample scored significantly lower than normative data on EK‐60F. However, subjects with comorbid AUDs/SUDs did not perform worse on EK‐60F than those without, who had a better performance on EK‐60F if they carried the COMT Val/Met variant. Conclusions: This study is the first to date examining the impact of AUDs/SUDs and COMT variants on FER in an epidemiologically representative sample of subjects with schizophrenia. Our findings do not suggest an additional impairment from comorbid AUDs/SUDs on FER among subjects with schizophrenia, whilst COMT Val158Met, though based on a limited sample, might have a role just among those without AUDs/SUDs. Based on our results, additional research is needed also exploring differential roles of various substances.

Background: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis. Methods: To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored. Results: Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype. Conclusions: This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD.