Publications by authors named "Emanuela Masini"

121 Publications

D-Tagatose Feeding Reduces the Risk of Sugar-Induced Exacerbation of Myocardial I/R Injury When Compared to Its Isomer Fructose.

Front Mol Biosci 2021 13;8:650962. Epub 2021 Apr 13.

Department of Drug Science and Technology, University of Turin, Turin, Italy.

It is known that fructose may contribute to myocardial vulnerability to ischemia/reperfusion (I/R) injury. D-tagatose is a fructose isomer with less caloric value and used as low-calorie sweetener. Here we compared the metabolic impact of fructose or D-tagatose enriched diets on potential exacerbation of myocardial I/R injury. Wistar rats were randomizedly allocated in the experimental groups and fed with one of the following diets: control (CTRL), 30% fructose-enriched (FRU 30%) or 30% D-tagatose-enriched (TAG 30%). After 24 weeks of dietary manipulation, rats underwent myocardial injury caused by 30 min ligature of the left anterior descending (LAD) coronary artery followed by 24 h' reperfusion. Fructose consumption resulted in body weight increase (49%) as well as altered glucose, insulin and lipid profiles. These effects were associated with increased I/R-induced myocardial damage, oxidative stress (36.5%) and inflammation marker expression. TAG 30%-fed rats showed lower oxidative stress (21%) and inflammation in comparison with FRU-fed rats. Besides, TAG diet significantly reduced plasmatic inflammatory cytokines and GDF8 expression (50%), while increased myocardial endothelial nitric oxide synthase (eNOS) expression (59%). Overall, we demonstrated that D-tagatose represents an interesting sugar alternative when compared to its isomer fructose with reduced deleterious impact not only on the metabolic profile but also on the related heart susceptibility to I/R injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2021.650962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076855PMC
April 2021

NCX 667, a Novel Nitric Oxide Donor, Lowers Intraocular Pressure in Rabbits, Dogs, and Non-Human Primates and Enhances TGFβ2-Induced Outflow in HTM/HSC Constructs.

Invest Ophthalmol Vis Sci 2021 Mar;62(3):17

Nicox Research Institute, Milan, Italy.

Purpose: NCX 667, a novel nitric oxide (NO) donor with an isomannide core, was characterized for its IOP-lowering ability in animal models of ocular hypertension and glaucoma. Bioengineered human trabecular meshwork/Schlemm's canal (HTM/HSC) constructs were used to explore the mode of action.

Methods: Ocular normotensive New Zealand white (NZW) rabbits (ONT-rabbits), spontaneously ocular hypertensive pigmented Dutch-belted rabbits (sOHT-rabbits), hypertonic saline (5%)-induced transient ocular hypertensive NZW rabbits (tOHT-rabbits), ocular normotensive Beagle dogs (ONT-dogs), and laser-induced ocular hypertensive cynomolgus monkeys (OHT-monkeys) were used. NCX 667 or vehicle (30 µL) was instilled in a crossover, masked fashion and intraocular pressure (IOP) measured before dosing (baseline) and for several hours thereafter. The ONT-rabbits were used for cyclic guanosine monophosphate (cGMP) determination in ocular tissues after ocular dosing with NCX 667. Transforming growth factor-beta2 (TGFβ2) (2.5 ng/mL, six days)-treated HTM/HSC constructs were used to address changes in outflow facility.

Results: NCX 667 resulted in robust and dose-dependent IOP decrease in all models used. Maximal IOP-lowering efficacy at 1% was -4.1 ± 0.6, -12.2 ± 2.7, -10.5 ± 2.0, -5.3 ± 0.8, and -6.6 ± 1.9 mmHg, respectively, in ONT-dogs, sOHT-rabbits, tOHT-rabbits, ONT-rabbits, and OHT-monkeys. In ONT-rabbits NCX 667 (1%) increased cGMP in aqueous humor (AH) but not in retina and iris/ciliary body. NCX 667 concentration-dependently increased outflow facility in TGFβ2-treated HTM/HSC constructs (outflow facility, 0.10 ± 0.06 and 0.30 ± 0.10 µL/min/mmHg/mm2, respectively, in vehicle- and NCX 667-treated constructs).

Conclusions: NCX 667 leads to robust IOP lowering in several animal models. Evidence in HTM/HSC constructs indicate that the IOP reduction likely results from NO-mediated increase of the conventional outflow pathway. Other mechanisms including changes in AH production and episcleral vein pressure may not be excluded at this time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.62.3.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960798PMC
March 2021

Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis.

Biomolecules 2020 09 10;10(9). Epub 2020 Sep 10.

Department of NEUROFARBA, Pharmaceutical Science Section, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.

Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. The pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. The activity of compound , one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. The hybrid compounds showed a higher potency in inhibiting PGE production, but not in modifying the platelet aggregation and the TXB production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. In conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10091307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564963PMC
September 2020

Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.

J Med Chem 2020 07 22;63(13):7422-7444. Epub 2020 Jun 22.

Department NEUROFARBA - Pharmaceutical and nutraceutical section, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence Italy.

The "tail approach" has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic division of hCAs active site, several subpockets have been identified at the middle/outer active sites rim, which could be targeted to increase the CAI isoform selectivity. This postulate is explored here by three-tailed benzenesulfonamide CAIs () to fully exploit such amino acid differences among hCAs. In this proof-of-concept study, an extensive structure-activity relationship (SAR) study was carried out with 32 such benzenesulfonamides differing in tails combination that were assayed for hCAs I, II, IV, and XII inhibition. A structural study was undertaken by X-ray crystallography and tools to assess the ligand/target interaction mode. The most active and selective inhibitors against isoforms implicated in glaucoma were assessed in a rabbit model of the disease achieving an intraocular pressure-lowering action comparable to the clinically used dorzolamide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008423PMC
July 2020

Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action.

J Med Chem 2020 03 20;63(6):3317-3326. Epub 2020 Feb 20.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.

The design of three dual-tailed sulfonamide series , , and as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma ( in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (, , and ) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds - and were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. and showed significant efficacy when compared to the clinically used drug dorzolamide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b02090DOI Listing
March 2020

Histamine H receptor stimulation in the locus coeruleus attenuates neuropathic pain by promoting the coeruleospinal noradrenergic inhibitory pathway.

Eur J Pharmacol 2020 Feb 14;868:172859. Epub 2019 Dec 14.

Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy. Electronic address:

The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α-adrenoceptors. Histaminergic innervation from the tuberomammillary nucleus of the LC increases firing of noradrenergic neurons and might contribute to pain control. Here we evaluated the contribution of LC histaminergic innervation in descending modulation of neuropathic hypersensitivity, by investigating the role of the histamine H receptor subtype in a mouse model of neuropathic pain. Intra LC administration of the H agonist VUF 8430 attenuated mechanical and thermal allodynia of mice that underwent spared nerve injury (SNI). Similarly, histamine in the LC showed mechanical and thermal anti-hypersensitivity. Pretreatment of LC with JNJ 10191584 (H antagonist) prevented the beneficial effect of VUF 8430 and histamine on nociceptive behaviour. Comparable results were obtained after intrathecal administration of drugs. The intrathecal administration of the α-adrenoceptor agonist clonidine ameliorated mechanical and thermal allodynia in SNI mice. The clonidine-induced anti-hypersensitivity effect was prevented by intra LC pretreatment with JNJ 10191584. In addition, clonidine failed to suppress neuropathic pain in H deficient mice. LC H receptors showed a ubiquitous distribution within LC, a neuronal localization and H immunostaining was detected on noradrenergic neurons expressing phosphorylated cAMP response element-binding protein (CREB), a marker of neuronal activation. Under pain pathological conditions H stimulation might promote the activation of the coeruleospinal noradrenergic neurons that exert an inhibitory control over spinal dorsal horn neuronal excitability. Thus, histamine H receptor stimulation may represent a perspective for neuropathic pain management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2019.172859DOI Listing
February 2020

Effect of Mediterranean Diet Enriched in High Quality Extra Virgin Olive Oil on Oxidative Stress, Inflammation and Gut Microbiota in Obese and Normal Weight Adult Subjects.

Front Pharmacol 2019 15;10:1366. Epub 2019 Nov 15.

Department of Agriculture, Food, Environment and Forestry (DAGRI), University of Florence, Florence, Italy.

The Mediterranean Diet (MD) is useful in the prevention of overweight, obesity and metabolic disease. High Quality-Extra Virgin Olive Oil (HQ-EVOO), an essential component of this diet, exerts protective effects against chronic diseases. Gut Microbiota (GM), recognized as a key factor in driving metabolic activities, is involved in the regulation of host immunity. Lactic Acid Bacteria (LAB) and their probio-active cellular substances produce beneficial effects in the gastrointestinal tract. Eighteen overweight/obese subjects (cases, BMI ≥25 kg/m) and 18 normal weight controls (BMI 18.5-24.9 kg/m) were fed with MD enriched with 40 g/die HQ-EVOO for three months. Feces and blood samples were collected at time 0 (T0) and after three months (T1) for LAB composition, oxidative stress, metabolic and inflammation parameter determinations. Myeloperoxidase and 8-hydroxy-2-deoxyguanosine, markers of inflammation and oxidative stress, were significantly decreased after MD rich in HQ-EVOO both in controls and in cases. Proinflammatory cytokines levels were significantly decreased in cases in comparison to controls, while IL-10 and adiponectin were significantly increased in cases. LAB's B copies/ng of DNA increased 55.6 folds in cases compared to their baseline after MD rich in HQ-EVOO. MD rich in HQ-EVOO increased adiponectin and IL-10 concentration in overweight/obese subjects and decreased oxidative stress and inflammation parameters and at the same time, increased LAB number in GM. Our results indicate that MD rich in HQ-EVOO induces an increase of LAB in GM and could have a potential role in the prevention of inflammation. www.ClinicalTrials.gov, identifier NCT03441802.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.01366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872540PMC
November 2019

Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug-Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis.

J Med Chem 2020 03 15;63(5):2325-2342. Epub 2019 Nov 15.

Section of Pharmaceutical and Nutraceutical Sciences, Department of NEUROFARBA, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.

Multitarget nonsteroidal anti-inflammatory drug (NSAID)-carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending on the NSAID portion. A selection of derivatives were assayed to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated that the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative () showed major antihyperalgesic action compared with the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multitarget compounds, which induce markedly improved pain relief compared with the parent NSAIDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b01130DOI Listing
March 2020

Effects of PARP-1 Deficiency and Histamine H Receptor Inhibition in an Inflammatory Model of Lung Fibrosis in Mice.

Front Pharmacol 2019 16;10:525. Epub 2019 May 16.

Section of Pharmacology, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.

Pulmonary fibrosis is the most frequent form of interstitial lung disease. Effective therapies are not yet available; novel therapeutic approaches are needed for counteracting fibrosis. Poly(ADP-ribose) polymerases are enzymes, involved in DNA repair and cell apoptosis. PARP-1 deficient mice exhibited reduced lung fibrosis in response to bleomycin treatment compared to wild-type controls. Histamine H receptors (HRs) have been recognized as a new target for inflammatory and immune diseases, and HR ligands reduced inflammation and oxidative stress in lung tissue. The aim of the study was to evaluate the cross-talk between PARP-1 and HR in a model of bleomycin-induced lung fibrosis in PARP-1 and WT mice. Animals were treated with bleomycin or saline by intra-tracheal injection. JNJ7777120, an HR antagonist, or VUF8430, an HR agonist, were administered i.p for 21 days. Airway resistance to inflation was evaluated, and lung tissues were processed for PARylated protein content, oxidative stress evaluation, and histology of small bronchi. The levels of pro-inflammatory (IL-1β and TNF-α), regulatory (IL-10), and pro-fibrotic (TGF-β) cytokines were evaluated. The deposition of αSMA was determined by immunofluorescence analysis. The results indicate that JNJ7777120 reduces PARylated protein production, decreases oxidative stress damage, and MPO, a marker for leukocyte tissue infiltration, in PARP-1 mice. A significant decrease in the production of both IL-1β and TNF-α and a significant increase in IL-10 levels are observed in mice treated with HR antagonist, suggesting a crucial anti-inflammatory activity of JNJ7777120. The smooth muscle layer thickness, the goblet cell relative number, and collagen deposition decreased following JNJ7777120 administration. The HR antagonist treatment also reduces TGF-β production and αSMA deposition, suggesting an important role of JNJ7777120 in airway remodeling. Our results show that PARylation is essential for the pathogenesis of pulmonary fibrosis and propose that PARP-1 and HRs are both involved in inflammatory and fibrotic responses. JNJ7777120 treatment, in a condition of PARP-1 inhibition, exerts anti-inflammatory and anti-fibrotic effects, reducing airway remodeling and bronchoconstriction. Therefore, selective inhibition of HRs together with non-toxic doses of selective PARP-1 inhibitors could have clinical relevance for the treatment of idiopathic pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535496PMC
May 2019

Role of Histamine H₃ Receptor Antagonists on Intraocular Pressure Reduction in Rabbit Models of Transient Ocular Hypertension and Glaucoma.

Int J Mol Sci 2019 Feb 24;20(4). Epub 2019 Feb 24.

Department of Neuroscience, Psychiatry, Drug Area and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50130 Florence, Italy.

Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term IOP fluctuation and glaucoma progression; however, it has not yet been determined whether histamine plays a role in IOP fluctuations. The aim of this research was to establish the distribution of the histamine receptor proteins and respective mRNAs in the eye by western blot, immunohistochemistry and RT-PCR in New Zealand rabbits. Furthermore, we used a transient ocular hypertension (OHT) model induced by injection of 50 µL of 5% hypertonic saline into the vitreous and a stable OHT model (100 µL 0.1% carbomer in the anterior chamber) to address the potential IOP-lowering ability of H₃ receptor (H₃R) antagonists (ciproxifan, DL76 and GSK189254). IOPs were performed with a Tono-Pen at baseline and 60, 120 and 240 min post treatment after transient OHT induction and, every day for 12 days in the stable OHT model. All histamine receptor subtypes were localized in the rabbit retina and ciliary body/trabecular meshwork. All the treatments lowered IOP in a dose-dependent fashion between 0.3% and 1%. More specifically, the effects were maximal with ciproxifan at 60 min post-dose (IOP change = -18.84 ± 4.85 mmHg, at 1%), remained stable until 120 min (IOP change = -16.38 ± 3.8 mmHg, at 1%) and decayed thereafter to reach baseline values at 240 min. These effects were highly specific and dependent on histamine release as pre-treatment with imetit (H₃R agonist, 1%) or pyrilamine (H₁R antagonist, 1%) largely blocked ciproxifan-mediated effects. Color Doppler ultrasound examination was performed to evaluate changes in ophtalmic artery resistivity index (RI) before and after repeated dosing with DL 76, GSK189254, ciproxifan and timolol. Chronic treatments with H₃R antagonists and timolol improved the vascular performance of ophthalmic arteries and reduced retinal ganglion cell death. Oxidative stress was also reduced and measured 8-Hydroxy-2'-deoxyguanosine (8OHG) expression, and by dihidroethydium (DHE) staining. These results demonstrated that the histamine system participates in IOP regulation and that H₃R antagonists could represent a future promising therapy for glaucoma. Further studies should be focused on the long-term IOP circadian fluctuations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20040981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412827PMC
February 2019

Urban Growth, Land-use Efficiency and Local Socioeconomic Context: A Comparative Analysis of 417 Metropolitan Regions in Europe.

Environ Manage 2019 03 17;63(3):322-337. Epub 2018 Nov 17.

Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria (CREA), Research Centre for Forestry and Wood, Viale S. Margherita 80, Arezzo, 52100, Italy.

The present study presents a multidimensional analysis of land-use efficiency in terms of per-capita built-up area over 417 metropolitan regions from 27 European countries. The study period encompasses two urban phases including economic expansion (2000-2007) and crisis (2008-2015). Multiple geographical gradients were identified as relevant predictors of land-use efficiency across Europe. The socioeconomic variables most associated with high land-use efficiency were per-capita disposable income (in Western, Atlantic and Central Europe) and income growth during 2000-2007 (in Eastern Europe), indicating that wealthier cities are characterized by higher land-use efficiency. Land-use efficiency increased in contexts with diversified urban landscapes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00267-018-1119-1DOI Listing
March 2019

A Selective Histamine H Receptor Antagonist, JNJ7777120, Is Protective in a Rat Model of Transient Cerebral Ischemia.

Front Pharmacol 2018 29;9:1231. Epub 2018 Oct 29.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.

Cerebral ischemia is a multifactorial pathology characterized by different events evolving in time. The acute injury, characterized by excitoxicity, is followed by a secondary brain injury that develops from hours to days after ischemia. Extracellular levels of histamine increase in the ischemic area after focal cerebral ischemia induced by occlusion of the middle cerebral artery (MCAo). The histamine H receptor (HR) is predominantly expressed in cell types of immune system where is involved in the regulation of immunological and inflammatory responses, and in numerous area of the Central Nervous System (CNS) including cortex and striatum. Our aim was to assess the putative neuroprotective effects of the potent and selective HR antagonist, JNJ7777120 (JNJ), chronically administered (1 mg/kg, i.p., twice/day for 7 days) on damage parameters in a rat model of focal ischemia induced by transient MCAo (tMCAo). Chronic treatment with the HR antagonist JNJ, significantly protected from the neurological deficit and from body weight loss after tMCAo. Seven days after the ischemic insult, JNJ reduced the volume of the ischemic cortical and striatal damage, the number of activated microglia and astrocytes in the ischemic cortex and striatum and decreased the plasma levels of IL-1β and TNF-α, while increased the levels of IL-10. Two days after ischemia, JNJ has reduced granulocyte infiltration in the ischemic area. Results demonstrate that the selective antagonist of HR, JNJ, systemically and chronically administered after ischemia, reduces the ischemic brain damage, improves the neurological deficit and decreases blood pro-inflammatory cytokines, suggesting that HR is a valuable pharmacological target after focal brain ischemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.01231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215858PMC
October 2018

Reduced Susceptibility to Sugar-Induced Metabolic Derangements and Impairments of Myocardial Redox Signaling in Mice Chronically Fed with D-Tagatose when Compared to Fructose.

Oxid Med Cell Longev 2018 19;2018:5042428. Epub 2018 Sep 19.

Department of Drug Science and Technology, University of Turin, Italy.

Background: D-tagatose is an isomer of fructose and is ~90% as sweet as sucrose with less caloric value. Nowadays, D-tagatose is used as a nutritive or low-calorie sweetener. Despite clinical findings suggesting that D-tagatose could be beneficial in subjects with type 2 diabetes, there are no experimental data comparing D-tagatose with fructose, in terms of metabolic derangements and related molecular mechanisms evoked by chronic exposure to these two monosaccharides.

Materials And Methods: C57Bl/6j mice were fed with a control diet plus water (CD), a control diet plus 30% fructose syrup (L-Fr), a 30% fructose solid diet plus water (S-Fr), a control diet plus 30% D-tagatose syrup (L-Tg), or a 30% D-tagatose solid diet plus water (S-Tg), during 24 weeks.

Results: Both solid and liquid fructose feeding led to increased body weight, abnormal systemic glucose homeostasis, and an altered lipid profile. These effects were associated with vigorous increase in oxidative markers. None of these metabolic abnormalities were detected when mice were fed with both the solid and liquid D-tagatose diets, either at the systemic or at the local level. Interestingly, both fructose formulations led to significant Advanced Glycation End Products (AGEs) accumulation in mouse hearts, as well as a robust increase in both myocardial AGE receptor (RAGE) expression and NF-B activation. In contrast, no toxicological effects were shown in hearts of mice chronically exposed to liquid or solid D-tagatose.

Conclusion: Our results clearly suggest that chronic overconsumption of D-tagatose in both formulations, liquid or solid, does not exert the same deleterious metabolic derangements evoked by fructose administration, due to differences in carbohydrate interference with selective proinflammatory and oxidative stress cascades.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/5042428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169220PMC
December 2018

Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit.

J Med Chem 2018 09 4;61(17):7902-7916. Epub 2018 Sep 4.

Dipartimento di Scienze degli Alimenti e del Farmaco , Università degli Studi di Parma , Parco Area delle Scienze 27/A I-43124 Parma , Italy.

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT/MT agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00893DOI Listing
September 2018

Targeting Serotonin 2A and Adrenergic α Receptors for Ocular Antihypertensive Agents: Discovery of 3,4-Dihydropyrazino[1,2-b]indazol-1(2H)-one Derivatives.

ChemMedChem 2018 08 9;13(15):1597-1607. Epub 2018 Jul 9.

Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A., Piazzale della stazione snc, 00071, S. Palomba-Pomezia (Rome), Italy.

Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α ) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201800199DOI Listing
August 2018

Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy.

J Med Chem 2018 06 13;61(12):5380-5394. Epub 2018 Jun 13.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences , University of Florence, Polo Scientifico , Via U. Schiff 6 , 50019 Sesto Fiorentino , Firenze Italy.

The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β- and β-ARs. X-ray crystallography studies provided rationale for the observed hCA inhibition. The best dual-agents decreased IOP more effectively than clinically used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucoma therapy with an innovative mechanism of action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00625DOI Listing
June 2018

2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents.

Eur J Med Chem 2018 May 3;151:363-375. Epub 2018 Apr 3.

University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy. Electronic address:

Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2018.04.002DOI Listing
May 2018

Fructose liquid and solid formulations differently affect gut integrity, microbiota composition and related liver toxicity: a comparative in vivo study.

J Nutr Biochem 2018 05 13;55:185-199. Epub 2018 Feb 13.

Dept. of Drug Science and Technology, University of Turin, Italy. Electronic address:

Despite clinical findings suggesting that the form (liquid versus solid) of the sugars may significantly affect the development of metabolic diseases, no experimental data are available on the impact of their formulations on gut microbiota, integrity and hepatic outcomes. In the present sudy, C57Bl/6j mice were fed a standard diet plus water (SD), a standard diet plus 60% fructose syrup (L-Fr) or a 60% fructose solid diet plus water (S-Fr) for 12 weeks. Gut microbiota was characterized through 16S rRNA phylogenetic profiling and shotgun sequencing of microbial genes in ileum content and related volatilome profiling. Fructose feeding led to alterations of the gut microbiota depending on the fructose formulation, with increased colonization by Clostridium, Oscillospira and Clostridiales phyla in the S-Fr group and Bacteroides, Lactobacillus, Lachnospiraceae and Dorea in the L-Fr. S-Fr evoked the highest accumulation of advanced glycation end products and barrier injury in the ileum intestinal mucosa. These effects were associated to a stronger activation of the lipopolysaccharide-dependent proinflammatory TLR4/NLRP3 inflammasome pathway in the liver of S-Fr mice than of L-Fr mice. In contrast, L-Fr intake induced higher levels of hepatosteatosis and markers of fibrosis than S-Fr. Fructose-induced ex novo lipogenesis with production of SCFA and MCFA was confirmed by metagenomic analysis. These results suggest that consumption of fructose under different forms, liquid or solid, may differently affect gut microbiota, thus leading to impairment in intestinal mucosa integrity and liver homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jnutbio.2018.02.003DOI Listing
May 2018

ERRATUM.

Oncol Res 2018 Mar;26(2):333-334

Department of Health Sciences, University of Florence, Florence, Italy.

The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3727/096504018X15187172557369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844681PMC
March 2018

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial.

Eur Addict Res 2018 31;24(1):9-18. Epub 2018 Jan 31.

Department of NEUROFARBA, Pharmacology Section, University of Florence, Florence, Italy.

Aims: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a "target" plasma R-methadone level (80-250 ng/mL).

Methods: A multicenter randomized controlled trial was organized.

Results: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the "target range" at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. -Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000485029DOI Listing
September 2018

Plasmatic carbonic anhydrase IX as a diagnostic marker for clear cell renal cell carcinoma.

J Enzyme Inhib Med Chem 2018 Dec;33(1):234-240

a Department of Neuroscience, Psychiatry and Drug Area and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology and Section of Pharmaceutical Sciences , University of Florence , Florence , Italy.

Carbonic anhydrase (CA, EC 4.2.1.1) IX is regarded as a tumour hypoxia marker and CA inhibitors have been proposed as a new class of antitumor agents, with one such agent in Phase II clinical trials. The expression of some CAs, in particular the isoforms CA IX and CA XII, has been correlated with tumour aggressiveness and progression in several cancers. The aim of this study was to evaluate the possibility that CA IX could represent a marker related to clear cell Renal Cell Carcinoma (ccRCC). Bcl-2 and Bax, and the activity of caspase-3, evaluated in tissue biopsies from patients, were congruent with resistance to apoptosis in ccRCCs with respect to healthy controls, respectively. In the same samples, the CA IX and pro-angiogenic factor VEGF expressions revealed that both these hypoxia responsive proteins were strongly increased in ccRCC with respect to controls. CA IX plasma concentration and CA activity were assessed in healthy volunteers and patients with benign kidney tumours and ccRCCs. CA IX expression levels were found strongly increased only in plasma from ccRCC subjects, whereas, CA activity was found similarly increased both in plasma from ccRCC and benign tumour patients, compared to healthy volunteers. These results show that the plasmatic level of CA IX, but not the CA total activity, can be considered a diagnostic marker of ccRCCs. Furthermore, as many reports exist relating CA IX inhibition to a better outcome to anticancer therapy in ccRCC, plasma levels of CA IX could be also predictive for response to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2017.1411350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011953PMC
December 2018

Activation of ERK/CREB pathway in noradrenergic neurons contributes to hypernociceptive phenotype in H4 receptor knockout mice after nerve injury.

Neuropharmacology 2018 Jan 28;128:340-350. Epub 2017 Oct 28.

Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, 50139 Florence, Italy.

G-protein coupled receptor H4 (H4R) is a histamine receptor subtype that is involved in a condition of pathological chronic pain, but its pathophysiological function is unknown. Here, we investigate the role of H4R in a model of traumatic nerve injury. H4R knockout (H4R/) mice exposed to spared nerve injury (SNI) developed a more prominent mechanical and thermal hypersensitivity than wild type mice. Western blotting and immunofluorescence were used to characterize the cellular mechanisms. Nerve injury increased phosphorylated pERK MAPK expression in the spinal cord that was further promoted in H4R/ genotype. Additionally, the increase in the phosphorylated cAMP response element-binding protein (CREB) was significantly enhanced in neuropathic H4R/ mice. In the same way, after SNI a remarkable increase of dopamine beta-hydroxylase (DβH) immunoreactive neurons was detected in spinal cord of H4R/ mice. The number of injured DRG neurons after SNI of H4R/ mice, identified by activating transcription factor 3 (ATF3) staining was comparable to that of wild type littermates. Similarly the density of intraepidermal nerve fibres in plantar skin after SNI was reduced with the same degree in H4R/ mice and with wild type mice. We conclude that the phenotype of H4R/ mice leads to increased neuropathic pain hypersensitivity promoting an overactivation of spinal ERK-CREB pathway in DβH expressing neurons without modifying the innervation of the hind paw skin and integrity of the primary sensory neurons. In summary, our results provide H4R as a potential new target for the clinical management of chronic neuropathic pain conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2017.10.025DOI Listing
January 2018

Paths to Change: Bio-Economic Factors, Geographical Gradients and the Land-Use Structure of Italy.

Environ Manage 2018 01 25;61(1):116-131. Epub 2017 Oct 25.

Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria (CREA), Research Centre for Forestry and Wood, Viale S. Margherita 80, Arezzo, 52100, Italy.

This study introduces a bio-economic approach to evaluate the influence of local socioeconomic contexts on complex processes of landscape transformation (urbanization, withdrawal of farming with woodland creation and loss in crop mosaics) in a sustainable development perspective. Land-use and socioeconomic indicators (including shares of agriculture, industry and services in total product, per-worker value added, productivity by economic sector, distance from central cities, latitude and elevation) at the local district scale in Italy have been considered together in an exploratory approach based on multivariate statistics. The combined use of land-use and socioeconomic indicators was preferred to more traditional approaches based on single-variable analysis and allows identifying latent factors of landscape transformation at the local scale. Our approach sheds light in the intimate relationship between regional economic structures and land-use change in districts with varying socio-environmental attributes across Italy. Urban-rural divides, coastal-inland dichotomy and the elevation gradient were relevant factors shaping urbanization-driven landscape transformations at the country scale. Indicators of economic structure (and especially industrial production and per-worker productivity of industry and services) were also documented to influence greatly entity and direction of change in the use of land. Discontinuous and dispersed urbanization has been demonstrated to be spatially-decoupled from consolidated (continuous and compact) urbanization, expanding into undeveloped rural areas progressively far away from central cities and being spatially associated with forest land.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00267-017-0950-0DOI Listing
January 2018

-Dinitroalkyl Benzenes: A Novel Class of IOP-Lowering Agents for the Treatment of Ocular Hypertension.

ACS Med Chem Lett 2017 Oct 13;8(10):1054-1059. Epub 2017 Sep 13.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Turin, Italy.

Primary open angle glaucoma is the second most common cause of blindness worldwide. Nitric oxide has recently received particular attention as a potential antiglaucoma agent. In this work, -dinitroalkyl benzenes are evaluated for their capability to act as a new class of IOP lowering agents. These derivatives have been endowed with a variety of NO-release capacities and found to relax contracted rat aorta strips in a concentration-dependent manner. They have been studied for their IOP-lowering activity in a transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compounds - and , whose activity was similar to that of Molsidomine 120 min after administration. Compounds and were selected for evaluation using carbomer-induced glaucoma as the chronic model of IOP. They cause a significant reduction in IOP in the first 24 h, and their activity is maintained over 5 days, displaying a Molsidomine-like profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.7b00264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641960PMC
October 2017

1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X-ray crystallography of two leads.

Bioorg Med Chem 2017 09 11;25(17):4560-4565. Epub 2017 Jul 11.

Institute of Chemistry, Saint Petersburg State University, Peterhof 198504, Russian Federation. Electronic address:

Two lead 1,3-oxazole-based carbonic anhydrase inhibitors (CAIs) earlier identified as selective, picomolar inhibitors of hCA II (a cytosolic target for treatment of glaucoma) have been investigated further. Firstly, they were found to be conveniently synthesized on multigram scale, which enables further development. These compounds were found to be comparable in efficacy to dorzolamide eye drops when applied in the eye drop form as well. Finally, the reasons for unusually high potency of these compounds became understood from their high-resolution X-ray crystallography structures. These data significantly expand our understanding of heterocycle-based primary sulfonamides, many of which have recently emerged from our labs - particularly, from the corneal permeability standpoint.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2017.06.054DOI Listing
September 2017

The Inhibitory Effects of HYDAMTIQ, a Novel PARP Inhibitor, on Growth in Human Tumor Cell Lines With Defective DNA Damage Response Pathways.

Oncol Res 2017 Nov 20;25(9):1441-1451. Epub 2017 Apr 20.

The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3727/096504017X14926854178616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841208PMC
November 2017

New furoxan derivatives for the treatment of ocular hypertension.

Bioorg Med Chem Lett 2017 02 18;27(3):479-483. Epub 2016 Dec 18.

Dipartimento di Scienza e Tecnologia del Farmaco - Università degli Studi di Torino, Via P. Giuria 9, 10125 Turin, Italy.

A small series of water-soluble NO-donor furoxans bearing a basic center at the 4-position, having a wide lipophilic-hydrophilic balance range, and endowed with different NO-release capacities, were synthesized and characterized. Selected members were studied for their IOP-lowering activity in the transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compounds 3 and 7, whose activity 60min after administration was similar to that of Timolol. Notably, 7 was characterized by a long-lasting action. The IOP-lowering activity in this series of products appeared to be modulated by the lipophilic-hydrophilic balance rather than by the NO-donor capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.12.041DOI Listing
February 2017

Benzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering Investigations.

J Med Chem 2016 12 21;59(23):10692-10704. Epub 2016 Nov 21.

Università degli Studi di Firenze , Neurofarba Department., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.

Herein we report the synthesis of two series of benzenesulfonamide containing compounds that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section of the molecules with the intent to confer additional flexibility. All obtained compounds were screened in vitro as inhibitors of the physiologically relevant human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors, whereas they did not potently inhibit hCA I. Computational and X-ray crystallographic studies of the enzyme-inhibitor adducts helped us to rationalize the obtained results. Some of the sulfonamides reported here showed significant intraocular pressure lowering activity in an animal model of glaucoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.6b01389DOI Listing
December 2016

Behavioural phenotype of histamine H receptor knockout mice: Focus on central neuronal functions.

Neuropharmacology 2017 03 27;114:48-57. Epub 2016 Nov 27.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy. Electronic address:

The functional expression of H receptors (HR) within neurons of the central nervous system has been recently reported, but their role is poorly understood. The present study aims to elucidate the role of neuronal HR by providing the first description of the behavioural phenotype of HR-deficient (HR knockout, HR-KO) mice. Mice lacking HR underwent behavioural studies to evaluate locomotor activity, pain perception, anxiety, depression, memory and feeding behaviour. HR-KO mice showed a significant increase in ambulation in an open field as well as in exploratory activity in the absence of any modification of motor coordination. The sensitivity of mutant mice to a thermal or a mechanical stimulus was identical to that of the wild type mice, but HR-KO showed sensory hypersensitivity toward a condition of neuropathic pain. The lack of HR is associated with the promotion of anxiety in the light-dark box test. HR-KO mice showed an increased immobility time in the tail suspension test, experimental procedure used to evaluate the response of HR deficient mice to a behavioural despair paradigm. Cognitive function parameters of HR deficient mice, examined using the passive avoidance and the novel object recognition tests, were unaltered showing the lack of influence of HR on working and recognition memory. Finally, HR-deficient mice showed an orectic phenotype. These results illustrate that HR modulates various neurophysiological functions such as locomotor activity, anxiety, nociception and feeding behaviour, confirming the importance of the integrity and functionality of neuronal HR in the histaminergic regulation of neuronal functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2016.11.023DOI Listing
March 2017

Histamine H receptor agonist-induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress.

Br J Pharmacol 2017 01 18;174(1):28-40. Epub 2016 Nov 18.

Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.

Background And Purpose: Neuropathic pain is under-treated, with a detrimental effect on quality of life, partly because of low treatment efficacy, but also because pathophysiological mechanisms are not fully elucidated. To clarify the pathobiology of neuropathic pain, we studied the contribution of neuroinflammation and oxidative stress in a model of peripheral neuropathy. We also assessed an innovative treatment for neuropathic pain by investigating the effects of histamine H receptor ligands in this model.

Experimental Approach: A peripheral mononeuropathy was induced in mice, by spared nerve injury (SNI). Neuroinflammation and oxidative stress parameters were evaluated by spectrophotometry. The mechanical (von Frey test) and thermal (plantar test) nociceptive thresholds were evaluated.

Key Results: SNI mice showed increased expression of the pro-inflammatory cytokines IL-1ß and TNF-α, decreased antioxidant enzyme Mn-containing SOD (MnSOD), increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of oxidative DNA damage, and of PARP, nuclear enzyme activated upon DNA damage. Intrathecal administration of VUF 8430 (H receptor agonist) reversed the mechanical and thermal allodynia and was associated with decreased expression of IL-1ß, TNF-α, 8-OHdG and PARP and with restoration of MnSOD activity in the spinal cord and sciatic nerve. These effects were prevented by JNJ 10191584 (H receptor antagonist).

Conclusion And Implications: In the SNI mouse model of neuropathic pain, neuronal H receptor stimulation counteracts hyperalgesia and reduces neuroinflammation and oxidative stress in the spinal cord and sciatic nerve. Targeting both oxidative stress and pro-neuroinflammatory pathways through H receptor-mediated mechanisms could have promising therapeutic potential for neuropathic pain management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.13644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341487PMC
January 2017