9 research outputs found
Inhibitors and activity-based probes for β-D-glucuronidases, heparanases and β-L-arabinofuranosidases
Glycosidases (GHs) are enzymes responsible for the degradation of carbohydrates and play many roles in human health and pathophysiology. Often, abnormal levels of glycosidase activity are markedly linked to human pathologies. Example of this is the overexpression of heparanase (HPSE) in several cancer tissues. To date, the biomedical relevance of HPSE mostly pertains cancer treatment. This dissertation reports on the design, synthesis and biochemical evaluation of covalent mechanism-based inhibitors for heparanase, as well as the development of broad-spectrum activity-based probes (ABPs) for retaining exo- and endo-β-D-glucuronidases alike, including HPSE. The design of the novel inhibitors is supported by computational simulations, and the inhibition and selectivity of the newly synthesised compounds towards HPSE is demonstrated in vitro with the use of the newly developed ABPs. The thesis further builds on the concept of ABP-based profiling of GHs and discusses the development of inhibitors and probes targeting retaining β-L-arabinofuranosidases, a group of non-canonical glycosidases predominantly expressed by microorganisms of the human gut microbiome (HGM). As retaining β-L-arabinofuranosidases possess a contentious enzymatic mechanism, the novel chemical tools developed and presented in this thesis were decisive for unraveling β-L-arabinofuranosidases’ mechanism, and might serve in the future as probing tools for studies of the HGM.Bio-organic Synthesi
4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors.
Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with β-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over β-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.Medical BiochemistryBio-organic Synthesi
Design and experimental characterization of a NiTi-based, high-frequency, centripetal peristaltic actuator
Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.Bio-organic Synthesi
Sclerochoroidal calcifications associated with early-onset calcium pyrophosphate deposition disease
Non
Osteitis condensans ilii: prevalence and characteristics of a neglected mimic of sacroiliitis
Objectives: Osteitis condensans ilii (OCI) is a benign condition characterised by triangular sclerosis of the iliac bone which may mimic radiographic sacroiliitis. Prevalence is estimated between 0.9 and 2.5%, with female predominance, but the most recent article reporting original epidemiological data in the general population was published in 1971. The aim of our study is to contribute updated figures about prevalence of OCI in Italy. Method: A retrospective review of pelvic radiographs was conducted. Consecutive patients visiting the emergency department of our Institution between 1st January and 31st December 2020 were enrolled. Individuals with a past diagnosis of axial spondyloarthritis were excluded. Presence of OCI was evaluated by two musculoskeletal radiologists. Clinical and radiologic features such as osteoarthritis and insertional enthesopathy were also assessed. Results: We included 1047 individuals (61% female) with a median age of 74 years. OCI was present in 10 cases, accounting for a prevalence in the general population of 1.0% (95% CI 0.5–1.7). All patients with OCI were women and, in the female sample, prevalence was 1.6% (95% CI 0.7–2.8). Clinical characteristics and associated radiographic features were not different between patients with OCI and women without OCI. Conclusions: The prevalence of OCI observed in our study is consistent with previous literature, and we confirm that it is more frequently retrieved in women. Longitudinal research is warranted to elucidate the evolution, while knowledge about the disorder is needed to raise the awareness of rheumatologists and radiologists and to properly identify and report the condition.Key Points• OCI may mimic sacroiliitis and is a major differential diagnosis of radiographic axial spondyloarthritis.• Prevalence of OCI in our sample is 1.0%, in line with previous literature.• OCI predominantly affects women, and our study suggests that the disorder can be incidentally identified even after childbearing age.• Increased awareness of the characteristics of OCI can facilitate identification and reporting of the disorder
Study of pseudoelastic systems for the design of complex passive dampers: static analysis and modeling
I contesti storici e la societĂ del borgo sino al miracolo del 1522
Rapido excursus sulle vicende di Cannobio dall'Alto Medioevo sino al 1522, con particolare attenzione alla sua posizione chiave sulla via d'acqua da Pavia sino a Bellinzona e poi verso il centro Europa attraverso i passi del Lucomagno e in seguito del San Gottardo. Lo studio si inserisce nelle vicende della società cannobiese, da sempre attivissima nei commerci attraverso la Svizzera e la Germania. Il Miracolo avvenne durante le terribili guerre d'Italia, quando la Confederatio Helvetica mirava a conquistare l'intero bacino lacustre e la stessa Lombardia. In questi drammatici anni si registrò il prodigio del sangue uscito dal costato di Cristo
Levels and Factors Associated with Resilience in Italian Healthcare Professionals during the COVID-19 Pandemic: A Web-Based Survey
Background: Resilience is defined as the capacity to cope successfully with change or adversity. The aims of our study were to investigate levels of resilience in Italian healthcare professionals (HCPs) during the Coronavirus disease 2019 (COVID-19) pandemic and to identify potential predictors of resilience.
Methods: We performed a web-based survey of HCPs (n = 1009) working in Italian hospitals during the COVID-19 pandemic. The survey contained a 14-item resilience scale (RS14) and questionnaires to evaluate depression and anxiety symptoms. Non-HCP individuals (n = 375) from the general population were used for comparison.
Results: HCPs showed significantly lower resilience compared to the control group (p = 0.001). No significant differences were observed after stratification for geographical area, work setting, role, or suspected/confirmed diagnosis of COVID-19. In a linear regression analysis, RS14 was inversely correlated with depression (R2 = 0.227, p < 0.001) and anxiety (R2 = 0.117, p < 0.001) and directly correlated with age (R2 = 0.012, p < 0.001) but not with body mass index (BMI, R2 = 0.002, p = 0.213). In male HCPs, higher depression score (odds ratio (OR) 1.147, p < 0.001) or BMI (OR 1.136, p = 0.011) significantly predicted having low resilience. In female HCPs, higher depression score (OR 1.111, p < 0.0001) and working in a COVID-19 free setting (OR 2.308, p = 0.002) significantly predicted having low resilience. HCPs satisfied with personal protective equipment had higher levels of resilience (p < 0.010).
Conclusions: Our findings suggest that resilience was lower in Italian HCPs than in the general population after the first COVID-19 wave. Specific factors can be identified, and targeted interventions may have an important role to foster resilience of HCP