Role of histamine H4 receptor in the anti-inflammatory pathway of glucocorticoid-induced leucin zipper (GILZ) in a model of lung fibrosis.

INTRODUCTION: This study investigates the interactions between histaminergic system and glucocorticoid-induced leucin zipper (GILZ) in the inflammatory process and glucocorticoid modulation in lung fibrosis. METHODS: Wild-type (WT) and GILZ Knock-Out (KO) mice were treated with bleomycin (0.05 IU) or saline, delivered by intra-tracheal injection. After surgery, mice received a continuous infusion of JNJ7777120 (JNJ, 2 mg/kg b.wt.) or vehicle for 21 days. Lung function was studied by measuring airway resistance to air insufflation through the analysis of pressure at airway opening (PAO). Lung samples were collected to evaluate the expression of histamine H4R, Anx-A1, and p65-NF-kB, the activity of myeloperoxidase (MPO), and the production of pro-inflammatory cytokines. RESULTS: Airway fibrosis and remodeling were assessed by measuring TGF-ß production and α-SMA deposition. JNJ reduces PAO in WT but not in GILZ KO mice (from 22 ± 1 mm to 15 ± 0.5 and from 24 ± 1.5 to 19 ± 0.5 respectively), MPO activity (from 204 ± 3.13 pmol/mg to 73.88 ± 2.63 in WT and from 221 ± 4.46 pmol/mg to 107 ± 5.54 in GILZ KO), the inflammatory response, TGF-ß production, and α-SMA deposition in comparison to WT and GILZ KO vehicle groups. CONCLUSION: In conclusion, the role of H4R and GILZ in relation to glucocorticoids could pave the way for innovative therapies to counteract pulmonary fibrosis.

NCX 470 Exerts Retinal Cell Protection and Enhances Ophthalmic Artery Blood Flow After Ischemia/Reperfusion Injury of Optic Nerve Head and Retina.

Purpose: The purpose of this study was to assess the retinal protective activity and ocular hemodynamics after NCX 470 (0.1%) compared to bimatoprost administered as the US Food and Drug Administration (FDA)-approved drug (Lumigan - 0.01% ophthalmic solution, LUM) and at an equimolar dose (0.072%, BIM) to that released by NCX 470. Methods: Endothelin-1 (ET-1) induced ischemia/reperfusion injury model in rabbits was used. ET-1 was injected nearby the optic nerve head (ONH) twice/week for 6 weeks. Starting on week 3, the animals received vehicle (VEH), NCX 470, LUM, or BIM (30 µL/eye, twice daily, 6 days/week) until the end of ET-1 treatment. Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI), and electroretinogram (ERG) data were collected prior to dosing and at different time points postdosing. Reduced glutathione, 8-Hydroxy 2-deoxyguanosine, and Caspase-3 were determined in the retina of treated eyes. DNA fragmentation was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining. Results: ET-1 increased IOP (VEHIOP_Baseline = 20.5 ± 0.8 and VEHIOP_Week6 = 24.8 ± 0.3 mmHg) and OA-RI (VEHOA-RI_Baseline = 0.36 ± 0.02 and VEHOA-RI_Week6 = 0.55 ± 0.01) and reduced rod/cone responses over time. Oxidative stress, inflammation, and apoptotic markers increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6 = 18.1 ± 0.6 mmHg) and OA-RI changes (NCX 470OA-RI_Week6 = 0.33 ± 0.01) and restored ERG amplitude leaving unaltered the respective latency; these effects were only partially demonstrated by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation, and apoptosis in the retinas of treated eyes. BIM and LUM were numerically less effective on these parameters. Conclusions: NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction caused by ischemia/reperfusion via nitric oxide- and bimatoprost-mediated mechanisms. Translational Relevance: If confirmed in clinical setting our data may open new therapeutic opportunities to reduce visual field loss in glaucoma.

Adenosine A3 Receptor (A3AR) Agonist for the Treatment of Bleomycin-Induced Lung Fibrosis in Mice.

Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lacking an effective treatment. The present investigation explored the action of MRS5980, a new, highly potent and selective A3AR agonist, in an established murine model of lung fibrosis. The effects of either vehicle or MRS5980 were studied in mice following intratracheal bleomycin administration. We evaluated the role of the A3AR agonist on lung stiffness, studying the airway resistance to inflation, oxidative stress (8-OHdG and MDA), inflammation, pro- and anti-inflammatory marker levels (IL-1ß, IL-6, TNF-α, IL-10 and IL-17A) and fibrosis establishment, evaluating transforming growth factor (TGF)-ß expression and α-smooth muscle actin (α-SMA) deposition in lungs. Bleomycin administration increased lung stiffness, TGF-ß levels, α-SMA deposition, and inflammatory and oxidative stress markers. The treatment with MRS5980 attenuated all the analyzed functional, biochemical and histopathological markers in a dose-dependent manner. Our findings support the therapeutic potential of A3AR agonists in lung fibrosis by demonstrating reduced disease progression, as indicated by decreased inflammation, TGF-ß expression and fibrotic remodeling.

New Insight in Histamine Functions.

The first properties of histamine (HA) that were elucidated were vasodilation and contraction of smooth muscles in the gut after stimulating gastric acid secretion and constriction of the bronchial area during anaphylaxis [...].

Can We Barter Local Taxes for Maintaining Our Green? A Psychological Perspective.

Previous research highlighted that the desire for neighborhood improvement is an antecedent of the citizens' involvement in green urban areas maintenance. Nevertheless, the topic of civic participation in the maintenance of green areas is not yet well developed in the literature and a link with local legislation is missing. We investigate the intention of participation in such maintenance through a web-based experiment. We hypothesize that stimuli of poor (vs. good) maintenance will be associated with a higher intention of contributing to the upkeep of green areas following the administrative barter law. The administrative barter is a law approved in Italy, which gives citizens the possibility of a reduction of local taxes in exchange for their involvement in the improvement of the territory. One hundred ninety-six participants (M age = 33.81) were assigned randomly to good maintenance condition (n = 100) or poor maintenance condition (n = 96). The level of maintenance was manipulated through photographs of a neighborhood depicting good or poor maintenance of the urban green ornamentation. Results pointed out that people showed a greater willingness to engage in the improvement of green urban areas in the poor condition as compared to the good condition, according to the administrative barter law. This study suggests that local legislation may provide an incentive fostering citizens' involvement in green urban areas maintenance.

One-Pot Procedure for the Synthesis of Asymmetric Substituted Ureido Benzene Sulfonamides as Effective Inhibitors of Carbonic Anhydrase Enzymes.

We report a one-pot procedure for the synthesis of asymmetrical ureido-containing benzenesulfonamides based on in situ generation of the corresponding isocyanatobenezenesulfonamide species, which were trapped with the appropriate amines. A library of new compounds was generated and evaluated in vitro for their inhibition properties against a representative panel of the human (h) metalloenzymes carbonic anhydrases (EC 4.2.1.1), and the best performing compounds on the isozyme II (i.e., 7c, 9c, 11g, and 12c) were screened for their ability to reduce the intraocular pressure in glaucomatous rabbits. In addition, the binding modes of 7c, 11f, and 11g were assessed by means of X-ray crystallography.

The Histamine H4 Receptor Participates in the Anti-Neuropathic Effect of the Adenosine A3 Receptor Agonist IB-MECA: Role of CD4+ T Cells.

A3 adenosine receptor (A3AR) agonists have emerged as potent relievers of neuropathic pain by a T cell-mediated production of IL-10. The H4 histamine receptor (H4R), also implicated in pain modulation, is expressed on T cells playing a preeminent role in its activation and release of IL-10. To improve the therapeutic opportunities, this study aimed to verify the hypothesis of a possible cross-talk between A3AR and H4R in the resolution of neuropathic pain. In the mouse model of Chronic Constriction Injury (CCI), the acute intraperitoneal co-administration of the A3AR agonist IB-MECA (0.5 mg/kg) and the H4R agonist VUF 8430 (10 mg/kg), were additive in counteracting mechano-allodynia increasing IL-10 plasma levels. In H4R-/- mice, IB-MECA activity was reduced, lower pain relief and lower modulation of plasma IL-1ß, TNF-α, IL-6 and IL-10 were shown. The complete anti-allodynia effect of IB-MECA in H4R-/- mice was restored after intravenous administration of CD4+ T cells obtained from naïve wild type mice. In conclusion, a role of the histaminergic system in the mechanism of A3AR-mediated neuropathic pain relief was suggested highlighting the driving force evoked by CD4+ T cells throughout IL-10 up-regulation.

Novel Insight of Histamine and Its Receptor Ligands in Glaucoma and Retina Neuroprotection.

Glaucoma is a multifactorial neuropathy characterized by increased intraocular pressure (IOP), and it is the second leading cause of blindness worldwide after cataracts. Glaucoma combines a group of optic neuropathies characterized by the progressive degeneration of retinal ganglionic cells (RGCs). Increased IOP and short-term IOP fluctuation are two of the most critical risk factors in glaucoma progression. Histamine is a well-characterized neuromodulator that follows a circadian rhythm, regulates IOP and modulates retinal circuits and vision. This review summarizes findings from animal models on the role of histamine and its receptors in the eye, focusing on the effects of histamine H3 receptor antagonists for the future treatment of glaucomatous patients.

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

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.

NCX 667, a Novel Nitric Oxide Donor, Lowers Intraocular Pressure in Rabbits, Dogs, and Non-Human Primates and Enhances TGFß2-Induced Outflow in HTM/HSC Constructs.

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 (TGFß2) (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 TGFß2-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.

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

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 3, 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 PGE2 production, but not in modifying the platelet aggregation and the TXB2 production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound 3 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.

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

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 (TTI) 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 in silico 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.

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

The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e 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 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) 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 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.

Histamine H4 receptor stimulation in the locus coeruleus attenuates neuropathic pain by promoting the coeruleospinal noradrenergic inhibitory pathway.

The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α2-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 H4 receptor subtype in a mouse model of neuropathic pain. Intra LC administration of the H4 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 (H4 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 α2-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 H4 deficient mice. LC H4 receptors showed a ubiquitous distribution within LC, a neuronal localization and H4 immunostaining was detected on noradrenergic neurons expressing phosphorylated cAMP response element-binding protein (CREB), a marker of neuronal activation. Under pain pathological conditions H4 stimulation might promote the activation of the coeruleospinal noradrenergic neurons that exert an inhibitory control over spinal dorsal horn neuronal excitability. Thus, histamine H4 receptor stimulation may represent a perspective for neuropathic pain management.

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

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 in vitro 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 (5c) 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.

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.

Introduction: 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. Materials and Methods: Eighteen overweight/obese subjects (cases, BMI ≥25 kg/m2) and 18 normal weight controls (BMI 18.5-24.9 kg/m2) 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. Results: 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 rpoB 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. Discussion: 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. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03441802.

Effects of PARP-1 Deficiency and Histamine H4 Receptor Inhibition in an Inflammatory Model of Lung Fibrosis in Mice.

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 H4 receptors (H4Rs) have been recognized as a new target for inflammatory and immune diseases, and H4R ligands reduced inflammation and oxidative stress in lung tissue. The aim of the study was to evaluate the cross-talk between PARP-1 and H4R 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 H4R antagonist, or VUF8430, an H4R 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-1ß and TNF-α), regulatory (IL-10), and pro-fibrotic (TGF-ß) 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-1ß and TNF-α and a significant increase in IL-10 levels are observed in mice treated with H4R 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 H4R antagonist treatment also reduces TGF-ß 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 H4Rs 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 H4Rs together with non-toxic doses of selective PARP-1 inhibitors could have clinical relevance for the treatment of idiopathic pulmonary fibrosis.

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

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 (IOP60 change = -18.84 ± 4.85 mmHg, at 1%), remained stable until 120 min (IOP120 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 (8OHdG) 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.

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

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.

A Selective Histamine H4 Receptor Antagonist, JNJ7777120, Is Protective in a Rat Model of Transient Cerebral Ischemia.

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 H4 receptor (H4R) 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 H4R 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 H4R 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-1ß 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 H4R, JNJ, systemically and chronically administered after ischemia, reduces the ischemic brain damage, improves the neurological deficit and decreases blood pro-inflammatory cytokines, suggesting that H4R is a valuable pharmacological target after focal brain ischemia.