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1.
Inflamm Res ; 72(10-11): 2037-2052, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37815550

RESUMEN

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.


Asunto(s)
Glucocorticoides , Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Histamina , Factores de Transcripción/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Receptores Histamínicos , Factor de Crecimiento Transformador beta/metabolismo
2.
Int J Mol Sci ; 23(21)2022 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-36362112

RESUMEN

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.


Asunto(s)
Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Bleomicina/farmacología , Ratones Endogámicos C57BL , Pulmón/patología , Factor de Crecimiento Transformador beta/metabolismo , Fibroblastos/metabolismo , Fibrosis , Inflamación/patología , Receptores Purinérgicos P1/metabolismo , Adenosina/metabolismo
3.
Int J Mol Sci ; 20(4)2019 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-30813468

RESUMEN

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.


Asunto(s)
Glaucoma/tratamiento farmacológico , Glaucoma/fisiopatología , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Presión Intraocular , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/fisiopatología , Animales , Coroides/efectos de los fármacos , Coroides/metabolismo , Coroides/patología , Modelos Animales de Enfermedad , Glaucoma/genética , Antagonistas de los Receptores Histamínicos H3/farmacología , Imidazoles/farmacología , Imidazoles/uso terapéutico , Presión Intraocular/efectos de los fármacos , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Modelos Biológicos , Hipertensión Ocular/genética , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Conejos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Factores de Tiempo
4.
Environ Manage ; 63(3): 322-337, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30448998

RESUMEN

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.


Asunto(s)
Renta , Urbanización , Ciudades , Europa (Continente) , Europa Oriental , Población Urbana
5.
Eur Addict Res ; 24(1): 9-18, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29393208

RESUMEN

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.


Asunto(s)
Analgésicos Opioides/uso terapéutico , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Metadona/sangre , Tratamiento de Sustitución de Opiáceos/métodos , Factores de Tiempo , Resultado del Tratamiento
6.
J Enzyme Inhib Med Chem ; 33(1): 234-240, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29251173

RESUMEN

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.


Asunto(s)
Biomarcadores de Tumor , Anhidrasa Carbónica IX/sangre , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/diagnóstico , Anciano , Western Blotting , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Carcinoma de Células Renales/enzimología , Caspasa 3/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia Arriba
7.
Environ Manage ; 61(1): 116-131, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29071552

RESUMEN

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.


Asunto(s)
Agricultura/economía , Remodelación Urbana/economía , Bosques , Geografía , Italia , Factores Socioeconómicos , Desarrollo Sostenible/economía , Urbanización
8.
J Cell Mol Med ; 21(2): 324-335, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27704718

RESUMEN

Idiopathic pulmonary fibrosis is a severe disease characterized by excessive myofibroblast proliferation, extracellular matrix and fibrils deposition, remodelling of lung parenchyma and pulmonary insufficiency. Drugs able to reduce disease progression are available, but therapeutic results are unsatisfactory; new and safe treatments are urgently needed. Poly(ADP-ribose) polymerases-1 (PARP-1) is an abundant nuclear enzyme involved in key biological processes: DNA repair, gene expression control, and cell survival or death. In liver and heart, PARP-1 activity facilitates oxidative damage, collagen deposition and fibrosis development. In this study, we investigated the effects of HYDAMTIQ, a potent PARP-1 inhibitor, in a murine model of lung fibrosis. We evaluated the role of PARP on transforming growth factor-ß (TGF-ß) expression and TGF-ß/SMAD signalling pathway in lungs. Mice were intratracheally injected with bleomycin and then treated with either vehicle or different doses of HYDAMTIQ for 21 days. Airway resistance to inflation and lung static compliance, markers of lung stiffness, were assayed. Histochemical and biochemical parameters to evaluate TGF-ß/SMAD signalling pathway with alpha-smooth muscle actin (αSMA) deposition and the levels of a number of inflammatory markers (tumour necrosis factor-α, interleukin-1ß, iNOS and COX-2) were performed. Bleomycin administration increased lung stiffness. It also increased lung PARP activity, TGF-ß levels, pSMAD3 expression, αSMA deposition and content of inflammatory markers. HYDAMTIQ attenuated all the above-mentioned physiological, biochemical and histopathological markers. Our findings support the proposal that PARP inhibitors could have a therapeutic potential in reducing the progression of signs and symptoms of the disease by decreasing TGF-ß expression and the TGF-ß/SMAD transduction pathway.


Asunto(s)
Isoquinolinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/enzimología , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Tiofenos/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , Actinas/metabolismo , Animales , Biomarcadores/metabolismo , Bleomicina , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Hidroxiprolina/metabolismo , Mediadores de Inflamación/metabolismo , Isoquinolinas/farmacología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Fibrosis Pulmonar/inducido químicamente , Tiofenos/farmacología
9.
J Biol Chem ; 291(28): 14803-14, 2016 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-27226579

RESUMEN

Histamine, a major mediator in allergic diseases, differentially regulates the polarizing ability of dendritic cells after Toll-like receptor (TLR) stimulation, by not completely explained mechanisms. In this study we investigated the effects of histamine on innate immune reaction during the response of human monocyte-derived DCs (mDCs) to different TLR stimuli: LPS, specific for TLR4, and Pam3Cys, specific for heterodimer molecule TLR1/TLR2. We investigated actin remodeling induced by histamine together with mDCs phenotype, cytokine production, and the stimulatory and polarizing ability of Th0. By confocal microscopy and RT-PCR expression of Rac1/CdC42 Rho GTPases, responsible for actin remodeling, we show that histamine selectively modifies actin cytoskeleton organization induced by TLR4, but not TLR2 and this correlates with increased IL4 production and decreased IFNγ by primed T cells. We also demonstrate that histamine-induced cytoskeleton organization is at least in part mediated by down-regulation of small Rho GTPase CdC42 and the protein target PAK1, but not by down-regulation of Rac1. The presence and relative expression of histamine receptors HR1-4 and TLRs were determined as well. Independently of actin remodeling, histamine down-regulates IL12p70 and CXCL10 production in mDCs after TLR2 and TLR4 stimulation. We also observed a trend of IL10 up-regulation that, despite previous reports, did not reach statistical significance.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/metabolismo , Histamina/metabolismo , Monocitos/metabolismo , Receptor Toll-Like 4/metabolismo , Linfocitos T CD4-Positivos/citología , Diferenciación Celular , Células Cultivadas , Humanos , Prueba de Cultivo Mixto de Linfocitos , Monocitos/citología
10.
Bioorg Med Chem Lett ; 27(3): 479-483, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28027869

RESUMEN

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.


Asunto(s)
Oxadiazoles/química , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Modelos Animales de Enfermedad , Glaucoma/tratamiento farmacológico , Presión Intraocular/efectos de los fármacos , Óxido Nítrico/metabolismo , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/patología , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Conejos , Solubilidad , Timolol/farmacología , Timolol/uso terapéutico
11.
Bioorg Med Chem ; 25(17): 4560-4565, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28728897

RESUMEN

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.


Asunto(s)
Anhidrasa Carbónica II/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/química , Oxazoles/química , Animales , Sitios de Unión , Anhidrasa Carbónica II/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Cristalografía por Rayos X , Humanos , Presión Intraocular/efectos de los fármacos , Masculino , Conformación Molecular , Simulación de Dinámica Molecular , Hipertensión Ocular/tratamiento farmacológico , Oxazoles/farmacología , Oxazoles/uso terapéutico , Estructura Terciaria de Proteína , Conejos
12.
J Pharmacol Exp Ther ; 357(3): 451-8, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27048661

RESUMEN

Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD), which is characterized by airway remodeling, lung inflammation and fibrosis, emphysema, and respiratory failure. The current therapies can improve COPD management but cannot arrest its progression and reduce mortality. Hence, there is a major interest in identifying molecules susceptible of development into new drugs to prevent or reduce CS-induced lung injury. Serelaxin (RLX), or recombinant human relaxin-2, is a promising candidate because of its anti-inflammatory and antifibrotic properties highlighted in lung disease models. Here, we used a guinea pig model of CS-induced lung inflammation, and remodeling reproducing some of the hallmarks of COPD. Animals exposed chronically to CS (8 weeks) were treated with vehicle or RLX, delivered by osmotic pumps (1 or 10 µg/day) or aerosol (10 µg/ml/day) during CS treatment. Controls were nonsmoking animals. RLX maintained airway compliance to a control-like pattern, likely because of its capability to counteract lung inflammation and bronchial remodeling. In fact, treatment of CS-exposed animals with RLX reduced the inflammatory recruitment of leukocytes, accompanied by a significant reduction of the release of proinflammatory cytokines (tumor necrosis factor α and interleukin-1ß). Moreover, RLX was able to counteract the adverse bronchial remodeling and emphysema induced by CS exposure by reducing goblet cell hyperplasia, smooth muscle thickening, and fibrosis. Of note, RLX delivered by aerosol has shown a comparable efficacy to systemic administration in reducing CS-induced lung dysfunction and damage. In conclusion, RLX emerges as a new molecule to counteract CS-induced inflammatory lung diseases.


Asunto(s)
Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Nicotiana/química , Relaxina/farmacología , Humo/efectos adversos , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Cobayas , Pulmón/patología , Masculino , Relaxina/sangre , Respiración/efectos de los fármacos
13.
Pharmacol Res ; 111: 740-748, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27475884

RESUMEN

Fibrosis of lung tissue is a disease where a chronic inflammatory process determines a pathological remodelling of lung parenchyma. The animal model obtained by intra-tracheal administration of bleomycin in C57BL/6 mice is one of the most validated murine model. Bleomycin stimulates oxidative stress and the production of pro-inflammatory mediators. Histamine H4R have recently been implicated in inflammation and immune diseases. This study was focused to investigate the effects of H4R ligands in the modulation of inflammation and in the reduction of lung fibrosis in C57BL/6 mice treated with bleomycin. C57BL/6 mice were treated with vehicle, JNJ7777120 (JNJ, selective H4R antagonist) or ST-1006 (partial H4R agonist), ST-994 (H4R neutral antagonist) and ST-1012 (inverse H4R agonist) at equimolar doses, released by micro-osmotic pumps for 21days. Airway resistance to inflation was assayed and lung samples were processed to measure malondialdehyde (TBARS); 8-hydroxy-2'-deoxyguanosine (8OHdG); myeloperoxidase (MPO); COX-2 expression and activity as markers of oxidative stress and inflammation. Fibrosis and airway remodelling were evaluated throughout transforming growth factor-ß (TGF-ß), percentage of positive Goblet cells, smooth muscle layer thickness determination. Our results indicated that JNJ, ST-994 and ST-1012 decreased inflammation and oxidative stress markers, i.e. the number of infiltrating leukocytes evaluated as lung tissue MPO, COX-2 expression and activity, TBARS and 8OHdG production. They also reduced the level of TGF-ß, a pro-fibrotic cytokine, collagen deposition, thickness of smooth muscle layer, Goblet cells hyperplasia; resulting in a decrease of airway functional impairment. The results here reported clearly demonstrated that H4R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H4R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases.


Asunto(s)
Antiinflamatorios/farmacología , Bleomicina , Antagonistas de los Receptores Histamínicos/farmacología , Indoles/farmacología , Pulmón/efectos de los fármacos , Piperazinas/farmacología , Fibrosis Pulmonar/prevención & control , Pirimidinas/farmacología , Receptores Histamínicos H4/antagonistas & inhibidores , Animales , Biomarcadores/metabolismo , Colágeno/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Agonismo Parcial de Drogas , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patología , Hiperplasia , Mediadores de Inflamación/metabolismo , Ligandos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Neumonía/inducido químicamente , Neumonía/metabolismo , Neumonía/prevención & control , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Receptores Histamínicos H4/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo
14.
Bioorg Med Chem ; 23(18): 6223-7, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26319622

RESUMEN

Two new sulfonamides incorporating arylsulfonylureido moieties were complexed with gamma cyclodextrin (γ-CD), hydroxypropyl-gamma cyclodextrin (HPγ-CD), hydroxypropyl-beta cyclodextrin (HPß-CD) and hydroxyethyl-beta cyclodextrin (HEß-CD) in order to obtain drug formulations with effective topical intraocular pressure (IOP) lowering effects, in an animal model of glaucoma. The HPγ-CD was the best solubilizing agent for the two sulfonamides and its complexes were characterized in detail and administered to rabbits with eye hypertension of 45-50 mmHg. The peak IOP lowering was observed after 1h post-administration and was of 36-37 mmHg. A low IOP pressure (of around-35 mmHg) was then maintained for the next 24h post-administration, which has not been observed before with any IOP lowering drug.


Asunto(s)
Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Ciclodextrinas/química , Sulfonamidas/química , Administración Tópica , Animales , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Anhidrasas Carbónicas/metabolismo , Química Farmacéutica , Modelos Animales de Enfermedad , Glaucoma/tratamiento farmacológico , Humanos , Presión Intraocular/efectos de los fármacos , Masculino , Conejos , Solubilidad , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Bencenosulfonamidas
15.
Bioorg Med Chem ; 23(10): 2368-76, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25846066

RESUMEN

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide.


Asunto(s)
Antihipertensivos/síntesis química , Inhibidores de Anhidrasa Carbónica/síntesis química , Anhidrasas Carbónicas/química , Glaucoma/tratamiento farmacológico , Tiocarbamatos/síntesis química , Animales , Antihipertensivos/farmacología , Disulfuro de Carbono/química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Modelos Animales de Enfermedad , Glaucoma/fisiopatología , Humanos , Presión Intraocular/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Morfolinas/química , Piperazinas/química , Piperidinas/química , Quinuclidinas/química , Conejos , Relación Estructura-Actividad , Especificidad por Sustrato , Sulfonamidas/farmacología , Tiocarbamatos/farmacología , Tiofenos/farmacología
16.
J Cell Mol Med ; 18(3): 468-79, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24444146

RESUMEN

Activation of poly(ADP-ribose) polymerases (PARPs) is considered a key event in the molecular and cellular processes leading from acute asthma attacks to bronchial hyper-reactivity, leucocyte recruitment, chronic inflammation, airway remodelling and lung damage. The present investigation has been carried out to investigate the action of hydroxyl-dimethylaminomethyl-thieno[2,3-c]isoquinolin-5(4H)-one (HYDAMTIQ), a new potent PARP inhibitor, in the process leading from asthma-like events to airway damage. Ovalbumin-sensitized guinea pigs exposed two times to allergen inhalation were treated for 8 days with vehicle or HYDAMTIQ. Asthma-like signs, bronchial hyper-reactivity to methacholine, cytokine production, histamine release from mast cells, airway remodelling, collagen deposition and lung damage were evaluated. Repeated HYDAMTIQ administration (1-10 mg/kg/day i.p.) reduced lung PARP activity, delayed the appearance and reduced the severity of allergen-induced cough and dyspnoea and dampened the increased bronchial responses to methacholine. HYDAMTIQ-treated animals presented reduced bronchial or alveolar abnormalities, lower number of eosinophils and other leucocytes in the lung and decreased smooth muscle or goblet cell hyperplasia. The treatment also reduced lung oxidative stress markers, such as malondialdehyde or 8-hydroxy-2'-deoxyguanosine and the lung content of pro-inflammatory cytokines (TNF-α, interleukin (IL)-1ß, IL-5, IL-6 and IL-18). Finally, mast cells isolated from the peritoneal or pleural cavities of sensitized, HYDAMTIQ-treated animals had a reduced ability to release histamine when exposed to ovalbumin in vitro. Our findings support the proposal that PARP inhibitors could have a therapeutic potential to reduce chronic lung inflammation, airway damage and remodelling in severe unresponsive asthmatic patients.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Alérgenos/inmunología , Asma/tratamiento farmacológico , Asma/fisiopatología , Hiperreactividad Bronquial/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Tiofenos/uso terapéutico , Animales , Asma/inmunología , Asma/patología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Cobayas , Liberación de Histamina , Inflamación/patología , Isoquinolinas/farmacología , Leucocitos/efectos de los fármacos , Leucocitos/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ovalbúmina/inmunología , Estrés Oxidativo/efectos de los fármacos , Poli Adenosina Difosfato Ribosa/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Tiofenos/farmacología
17.
J Pharmacol Exp Ther ; 351(2): 308-16, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25185215

RESUMEN

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-ß, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.


Asunto(s)
Bleomicina/efectos adversos , Indoles/farmacología , Naproxeno/farmacología , Piperazinas/farmacología , Neumonía/prevención & control , Fibrosis Pulmonar/prevención & control , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Antiinflamatorios/farmacología , Colágeno/metabolismo , Ciclooxigenasa 2/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animales de Enfermedad , Células Caliciformes/metabolismo , Células Caliciformes/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Ratones , Músculo Liso/patología , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Neumonía/inducido químicamente , Neumonía/metabolismo , Neumonía/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
18.
Pediatr Res ; 76(4): 378-85, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25029260

RESUMEN

BACKGROUND: Oral propranolol, a nonselective ß-blocker, is able to reduce the progression of retinopathy of prematurity in newborns, but it appeared unsafe. This study aimed to find, in rabbits, a propranolol eye drop concentration able to induce lower plasma but higher retinal concentrations than those obtained after oral administration. METHODS: Male New Zealand white rabbits were treated with oral propranolol (0.25 mg/kg/6 h) for 5 d, and propranolol concentrations were measured after 1, 2, 3, and 6 h in plasma, aqueous humor, vitreous humor, and retina. These concentrations were compared with those obtained after the administration of one drop of 25 µl of propranolol 0.1% prepared in saline, applied every 6 h to both eyes for 5 d. A Draize eye test and histological analyses were performed to assess eye drop tolerability. RESULTS: The administration of eye drops produced retinal concentrations similar to, but plasma concentrations significantly lower than, those measured after oral administration. The local tolerability profile was excellent. CONCLUSION: Propranolol eye drops are able to ensure high retinal and low plasma concentrations of propranolol, and this finding opens the perspective of possible topical treatment with propranolol in newborns with retinopathy of prematurity.


Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Propranolol/administración & dosificación , Administración Oftálmica , Antagonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacocinética , Animales , Recuento de Colonia Microbiana , Masculino , Propranolol/efectos adversos , Propranolol/farmacocinética , Conejos
19.
Bioorg Med Chem ; 22(15): 3913-21, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25022971

RESUMEN

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.


Asunto(s)
Antineoplásicos/química , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Oxadiazoles/química , Sulfonamidas/química , Resinas Acrílicas/toxicidad , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Anhidrasas Carbónicas/metabolismo , Modelos Animales de Enfermedad , Glaucoma/inducido químicamente , Glaucoma/tratamiento farmacológico , Humanos , Masculino , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Conejos , Sulfonamidas/síntesis química , Sulfonamidas/uso terapéutico
20.
Dig Dis Sci ; 59(5): 949-57, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24357184

RESUMEN

BACKGROUND: Gastroesophageal reflux (GER) causes injury of the esophageal squamous epithelium, a condition called reflux esophagitis. The sequence reflux-esophagitis-intestinal metaplasia-dysplasia-invasive cancer is widely accepted as the main adenocarcinogenetic pathway in the esophagus; however, the mechanisms of this progression need to be better defined. AIMS: We evaluated COX-2 expression and activity in biopsies from patients affected with GER, and these parameters have been correlated with the stage of the disease, ceramide expression, apoptotic process, and angiogenesis. The effects of celecoxib on bile acid- and EGF-induced mucosal proliferation, apoptosis and angiogenesis have been also investigated. METHODS: Four groups of patients were distinguished: non esophagitis, non erosive esophagitis, erosive esophagitis, and Barrett's esophagus. COX-2 expression, basal PGE2 levels, proliferative activity, VEGF expression and apoptosis were evaluated in esophageal biopsies. RESULTS: COX-2 expression, basal PGE2 levels, proliferative activity, VEGF expression and apoptosis progressively increase from non esophagitis patients to patients with non erosive and erosive esophagitis, to those with BE. Incubation of the cells with DCA/EGF increases PGE2 production, proliferative activity and VEGF production, effects prevented by celecoxib pretreatment. Ceramide expression increased from non esophagitis patients to patients with non erosive and erosive esophagitis, and decreased in BE; caspase-3 activity progressively decreased from non esophagitis to BE patients, suggesting an impairment of the apoptotic process with disease progression. CONCLUSION: These results stand for a close relationship between progression of initial steps of gastroesophageal reflux disease (GERD) and COX-2, proliferative activity and EGF/VEGF expression and could have implications in GERD treatment in order to prevent its neoplastic evolution.


Asunto(s)
Esófago de Barrett/patología , Ciclooxigenasa 2/metabolismo , Esófago/patología , Reflujo Gastroesofágico/patología , Inflamación/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/metabolismo , Biopsia , Caspasa 3/genética , Caspasa 3/metabolismo , Ceramidas/genética , Ceramidas/metabolismo , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Dinoprostona/genética , Dinoprostona/metabolismo , Femenino , Reflujo Gastroesofágico/metabolismo , Regulación Enzimológica de la Expresión Génica , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto Joven
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