2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents

2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents

Organ culture and Reflectance Confocal Microscopy as new integrated tools for barrier rescue studies in inflammatory skin diseases

Here we present a new integrated approach to understand skin barrier recovery after physical (tape stripping, TS) or chemical (SDS) injury by combining human skin organ culture and Reflectance Confocal Microscopy (RCM). TS in vitro produced a complete removal of stratum corneum and lipids, a drastic decrease of structural and adhesion proteins, and an increase in cell proliferation. Epidermal recovery with either proliferation or differentiation rescue was observed after 18 hours, with no apoptotic cell detection. On the other hand, when skin organ cultures were exposed to 2% SDS, cellular junctions were disrupted and the expression of late differentiation markers decreased. Junctions repair was detected 24 hours after treatment, with the restoration of epidermal integrity. Both models (TP or SDS) showed the induction of immune-inflammatory markers, such as psoriasin, keratin 16, and the increase in Langerhans cell number. RCM confirmed all the morphological and structural features presented by the organ cultures, thus making this technique fast and easily applicable in the context of dermatological research. These results indicate that combination of skin organ models and RCM can be successfully used for the study of barrier perturbation in skin diseases, for toxicology tests, and for evaluating novel therapies

Tongue cancer following hematopoietic cell transplantation for Fanconi anemia

Objectives: The aim of this retrospective study was to determine the incidence and the clinical outcome of tongue cancer (TC) in patients affected by Fanconi anemia (FA) who received an allogeneic hematopoietic cell transplantation (HCT). Materials and methods: The patient database from the Bone Marrow Transplant Center of Pescara was reviewed to enroll FA patients. Patients', donors', HCT's, and screening's data were collected as well to look for the incidence and the treatment of TC. Results: Twelve patients affected by FA were identified. Three patients died for transplant-related causes. Five of nine surviving patients were diagnosed with TC at a median of 21.7 years since transplantation and at a median age of 32.10 years. Interestingly, no patient manifested graft-versus-host-disease (GvHD). The 28-year cumulative incidence function of TC was 46.9% (95% CI, 36.9-56.9%). Two patients were treated with chemotherapy alone, two patients were treated with surgery alone, and one with surgery followed by chemotherapy. Overall, 4 patients with TC showed a clinical course characterized by a marked aggressiveness of the tumor disease which led to death due to cancer progression between 2 and 13 months. One patient is surviving 8 months after diagnosis of TC. Conclusions: Our study confirms the high incidence of tumors and in particular tongue tumors in allotransplanted FA patients. A careful screening has to be life-long maintained. Clinical relevance: Considering the rarity of FA and the frailty of FA patients, this study may add important information for the cancer management of these patients

2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa.

Funder: FP7 People: Marie-Curie Actions; Grant(s): 642620Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents

2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents

2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents.European Commission’s Horizon 2020 (Grant 642620), BBSRC (Grant BB/M019411/1 to M.W.), EPSRC (Grant EP/P020291/1 to D.R.S.). P.T. was supported by the Academy of Finland (Grant 277001) S.B. was supported by a Herchel Smith studentship

Discovery Of New Sigma-2 Receptor Agonist Endowed With Antiproliferative Activity

Sigma receptors (σR) have proved to be an attractive pharmacological target for the treatment of several pathologies. In particular, σ1 ligands have been considered to play an important role in the treatment of various neurological disorders, including depression, schizophrenia, neuropathic pain, Alzheimer's and Parkinson’s disease. Moreover, it has been found that σR are involved in the modulation of cellular proliferation and cell death and σ1 antagonists and σ2 agonists may represent useful tools as anticancer and tumor imaging agents. Recently, we reported that a properly substituted 1,3-dioxolane moiety could be employed as suitable scaffold for developing ligands for both σ1R and σ2R.1 In this work we explore a new set of structural related analogues obtained by combining different substituted spiro-heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified BS148 (1-(1,4-ditiaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperidne) as the most interesting compound of the series, displaying good affinity and selectivity for σ2R .The ability of BS148 to modulate the analgesic effect of the agonist morphine was evaluated in-vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Moreover, BS148 demonstrated to affect the growth (MTT test) of SK-MEL-28 and SK-MEL-2 melanoma cell lines in comparison to siramesine, suggesting an agonistic behavior at σ2R. The present work represents a new starting point for the design of potential therapeutically useful agents

The burden of atopic dermatitis in adults in Italy

Moderate-to-severe atopic dermatitis (AD) generates a considerable consumption of healthcare resources and significant economic consequences for the patients and their families, healthcare systems (NHS) and society. Several studies on the burden of AD in paediatric patients are available in literature, while data in adults is scant. The purpose of this study was to estimate the direct and indirect costs of moderate to severe AD in adult patients in Italy