A5075877326- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- PARP inhibition in cancer therapy
- Calcium signaling and nucleotide metabolism
- Sirtuins and Resveratrol in Medicine
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Inhalation and Respiratory Drug Delivery
- Histone Deacetylase Inhibitors Research
- Asthma and respiratory diseases
- Lung Cancer Treatments and Mutations
- Phosphodiesterase function and regulation
- Microbial infections and disease research
- DNA Repair Mechanisms
- thermodynamics and calorimetric analyses
- Analytical Chemistry and Chromatography
- Respiratory and Cough-Related Research
- Liver Disease Diagnosis and Treatment
- Stress Responses and Cortisol
- Toxin Mechanisms and Immunotoxins
- Nuclear Physics and Applications
- Thermal Regulation in Medicine
- Tryptophan and brain disorders
- Neuroendocrine regulation and behavior
- Pulmonary Hypertension Research and Treatments
- Pharmacological Effects and Assays
Chiesi (Italy)
2013-2025
Azienda Ospedaliero Universitario Mater Domini
2019
University of Florence
2008-2013
During the last several years, evidence that various enzymes hydrolyze NAD into bioactive products prompted scientists to revisit or design strategies able increase intracellular availability of dinucleotide. However, plasma membrane permeability and mitochondrial origin dinucleotide still wait be clearly defined. Here, we report contents increased upon exposure cell lines primary cultures exogenous (eNAD). precursors could not reproduce effects eNAD, they were found in incubating medium...
Poly(ADP-ribose) polymerase-1 (PARP-1) is a NAD-consuming enzyme with an emerging key role in epigenetic regulation of gene transcription. Although PARP-1 expression characteristically restricted to the nucleus, few studies report mitochondrial localization and its ability regulate organelle functioning. Here, we show that, despite exclusive nuclear PARP-1, homeostasis compromised cell lines exposed pharmacological inhibitors or small interfering RNA. suppression reduces integrity DNA...
Therapeutic hypothermia is of relevance to treatment increased body temperature and brain injury, but drugs inducing selective, rapid, safe cooling in humans are not available. Here, we show that injections adenosine 5′-monophosphate (AMP), an endogenous nucleotide, promptly triggers mice by directly activating A1 receptors (A1R) within the preoptic area (POA) hypothalamus. Inhibition constitutive degradation extracellular AMP targeting ecto 5′-nucleotidase, also suffices prompt rodents....
ABSTRACT Tanimilast is an inhaled phosphodiesterase‐4 inhibitor in development for chronic obstructive pulmonary disease and asthma. We conducted two studies to evaluate tanimilast pharmacokinetics, one subjects with mild, moderate, or severe hepatic impairment matched healthy controls, renal controls. Both were single‐center, open‐label, parallel group; all a single 800 μg dose of tanimilast. The primary objective was systemic exposure impairment, subjects, terms maximum observed plasma...
Maintenance of poly(ADP-ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance PARG inhibitors still debated. Gallotannin, a complex mixture hydrolysable tannins from oak gall, inhibits but which its constituents responsible for inhibition whether pharmacodynamic properties are due to antioxidant properties, has not yet been established.A structure-activity relationship study was conducted on...
During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging (MALDI-IMS) has set new frontier for study distribution endogenous and exogenous molecules present within tissue. MALDI-IMS is surface sampling technique that allows not only detection multiple analytes but also gives spatial those analytes. Active compounds pulmonary disease need an optimal...
NAD biosynthesis is emerging as a key regulator of immune cell functions. Accordingly, inhibitors the NAD‐synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT) have anti‐inflammatory effects, counteract hematological malignancies and are being tested in clinical trials. Still, their effect on different types still waits to be fully investigated. Here we show that NAMPT inhibitor FK866 induces depletion various mouse organs but selectively causes dramatic atrophy spleen red pulp....
Aiming at the inhaled treatment of pulmonary diseases, optimization process previously reported MAPI compound 92a is herein described. The project was focused on overcoming chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats order to be confident clinical effect without having overdose one biological targets. strategy based fine-tuning substitution pattern muscarinic PDE4 structural portions dual pharmacology compounds, also making use analysis...
In the last several years, NAD+ supplementation has emerged as an innovative and safe therapeutic strategy for a wide spectrum of disorders, including diabetes neuropathy. However, critical questions remain to how its precursors are taken up by cells, well effects long-lasting intracellular (iNAD+) increases. Here, we investigated kinetics iNAD+ levels in different cell types challenged with prolonged exposure extracellular (eNAD+). Surprisingly, found that after initial increase, contents...
Idiopathic pulmonary fibrosis (IPF) is an irreversible disorder with a poor prognosis. The incomplete understanding of IPF pathogenesis and the lack accurate animal models limiting development effective treatments. Thus, selection clinically relevant endowed similarities human disease in terms lung anatomy, cell biology, pathways involved genetics essential. bleomycin (BLM) intratracheal murine model most commonly used preclinical assay to evaluate new potential therapies for IPF. Here, we...
In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for inhaled treatment pulmonary diseases. The identification was enabled by intuition that fusion a PDE4 scaffold derived from our CHF-6001 series with muscarinic through common linking ring could generate active versus both transmembrane receptor and intracellular enzyme. Two chemical characterized two different scaffolds were investigated. SAR optimization aimed at obtaining nanomolar affinity...
<b>Background:</b> Idiopathic Pulmonary Fibrosis (IPF), is a progressive lung disease characterized by basal and subpleural fibrosis associated with honeycomb changes. In experimental settings, single intratracheal (IT) administration of bleomycin (BLM) to rodents the most commonly used model. order more closely mimic human IPF, novel procedure two IT administrations BLM in rats described. <b>Aims objectives:</b> Histological biomolecular findings following double rat were compared....
ABSTRACT INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with poor prognosis. While pirfenidone nintedanib offer some benefits, they cannot cure IPF. Nintedanib inhibits various proliferative pathways has antifibrotic effects, but its molecular mechanisms impact on the transcriptome in vivo remain unclear. This study aims to evaluate nintedanib’s transcriptomic profile rat model of bleomycin-induced fibrosis. METHODOLOGY/PRINCIPAL FINDINGS Lung...
<b>Background & Objectives:</b> The aim of this study was to investigate the time-course molecular and histological changes induced by a double intratracheal (IT) administration bleomycin (BLM) on lung tissue. <b>Methods:</b> Male SD rats were injected with BLM (2 U/kg, IT) or saline day 0 4 sacrificed at 7, 14, 21, 28 56 after first dose. Several inflammatory fibrotic biomarkers assessed in lung, BALF plasma colorimetric immunometric assays. Histomorphometric analysis fibrosis performed...
<h3>Introduction</h3> Phenylketonuria (PKU MIM 261600) is a human metabolic disease caused by mutations in phenylalanine hydroxylase gene (PAH) and inherited an autosomal recessive Mendelian fashion. Phenylalanine (PAH also known as 4-monooxygenase EC 1,14,16,11) catalyzes the rate-limiting step L-Phenylalanine (L-Phe) catabolism liver, using tetrahydrobiopterin (BH<sub>4)</sub> dioxygen additional cosubstrates. Untreated PKU associated with abnormal phenotype which includes growth failure,...
<b>Introduction:</b> Bleomycin (BLM)-induced lung fibrosis is currently the main pre-clinical rodent model in use for screening of potential therapeutics Idiopathic Pulmonary Fibrosis (IPF). Typically, histological scoring observer-dependent and consequently subject to variability, precluding comparative studies between different laboratories. Thus, a reliable observer-independent quantification needed. <b>Aims Objectives:</b> We developed automated image Analysis Protocol Packages (APPs) by...
<b>Background:</b> A growing body of evidence suggests an altered role epigenetic regulators like histone deacetylases (HDACs) in IPF. Targeting the regulation by HDACs modulation could offer a promising approach to control and revert pulmonary fibrosis. Aims objectives. Test efficacy Panobinostat, FDA approved pan-HDAC inhibitor for treatment cancer, therapeutic Bleomycin (BLM) lung fibrosis rat model comparison reference drug IPF, Nintedanib (NINT). Methods. For pharmacokinetic (PK) target...