(2-Aminobenzothiazole)-Methyl-1,1-bisphosphonic acids: Targeting matrix metalloproteinase 13 inhibition to the bone

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group

Chemical and protein structural basis for biological crosstalk between PPARα and COX enzymes

We have previously validated a probabilistic framework that combined computational approaches for predicting the biological activities of small molecule drugs. Molecule comparison methods included molecular structural similarity metrics and similarity computed from lexical analysis of text in drug package inserts. Here we present an analysis of novel drug/target predictions, focusing on those that were not obvious based on known pharmacological crosstalk. Considering those cases where the predicted target was an enzyme with known 3D structure allowed incorporation of information from molecular docking and protein binding pocket similarity in addition to ligand-based comparisons. Taken together, the combination of orthogonal information sources led to investigation of a surprising predicted relationship between a transcription factor and an enzyme, specifically, PPARα and the cyclooxygenase enzymes. These predictions were confirmed by direct biochemical experiments which validate the approach and show for the first time that PPARα agonists are cyclooxygenase inhibitors

Professionalità esperte per l'insegnamento. Considerazioni e proposte

Gli autori del presente contributo hanno coordinato il Secondo tavolo di discussione della VI Conferenza sulla ricerca educativa e pedagogica - svoltasi a Bergamo il 6 e 7 dicembre 2021 - di cui riportano in questa sede alcune delle questioni e delle proposte emerse durante il confronto

Prefazione

Si tratta della prefazione agli atti del convegno internazionale su "Donne tra arte, tradizione e cultura. Mediterraneo e oltre" che si è svolto presso l'Università di Foggia sotto l'alto patronato della Presidenza della Repubblica italiana e con il patrocinio del Ministero delle Pari opportunità, del Presidente della Giunta della Regione Puglia, della Provincia e del Comune di Foggia. Il convegno è stato un punto di incontro tra saperi, culture, lingue differenti sulla dimensione di genere e sui temi più cruciali della contemporaneità: il tema dei diritti e della democrazia, della pace e del dialogo intercultural

Introduzione

Nell'Introduzione, a doppia firma, vengono analizzati i nuclei concettuali centrali poi ripresi nei saggi che compongono il volume; in particolare si problematizza il costrutto di genere tra identità e alterità, sottolineandone la valenza pedagogica ai fini della costruzione di una cultura alla creatività di genere

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow of myeloma patients. These data provide rationale for selectively inhibiting MMP-2 activity as a multiple myeloma treatment strategy. Given that MMP-2 is systemically expressed, we used novel “bone-seeking” bisphosphonate based MMP-2 specific inhibitors (BMMPIs) to target the skeletal tissue thereby circumventing potential off-target effects of MMP-2 inhibition outside the bone marrow-tumor microenvironment. Using in vivo models of multiple myeloma (5TGM1, U266), we examined the impact of MMP-2 inhibition on disease progression using BMMPIs. Our data demonstrate that BMMPIs can decrease multiple myeloma burden and protect against cancer-induced osteolysis. Additionally, we have shown that MMP-2 can be specifically inhibited in the multiple myeloma-bone microenvironment, underscoring the feasibility of developing targeted and tissue selective MMP inhibitors. Given the well-tolerated nature of bisphosphonates in humans, we anticipate that BMMPIs could be rapidly translated to the clinical setting for the treatment of multiple myeloma