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Background Current literature suggests that anywhere from 2.9-27% of renal transplant recipients (RTR) will develop recurrent urinary tract infections (UTIs) (≥2 UTIs over six months or ≥3 UTIs over 12 months). Recurrent UTIs are of particular importance to RTR given its increased risk for allograft fibrosis and overall patient survival. Alternative solutions are needed for the management of recurrent UTIs, especially given the vulnerability of RTR to UTIs. We hypothesize that bladder washout (BW) reduces the incidence and recurrence of UTIs in RTR. Methods This is a retrospective study evaluating the utility of BW procedures on RTR diagnosed with recurrent UTIs between December 2013 and July 2021 at a single center. Results A total of 106 patients were included in the study with a total of 118 BW performed. 69% of patients were successfully treated with BW, meaning they no longer met the criteria for recurrent UTIs (<1 UTI) in the six-month post-BW period. The mean number of UTIs was 2.76 (range 2-7) before the BW and 1.16 (range 0-5) after the BW. On average, there were 1.60 fewer UTIs in the post-BW period compared to the pre-BW period (p<0.0001). There is no statistically significant difference in success rates stratified by bacterial class (p=1) or antimicrobial resistance class (p=0.6937). Conclusion BW decreased the incidence of UTIs in the six-month post-operative period as nearly 70% of patients did not have UTI recurrence. This data provides evidence that BW may have utility in transplant recipients with recurrent UTIs. We hope this will stimulate further prospective randomized studies in this area.
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Climate change is one of the major challenges societies round the world face at present. Apart from efforts to achieve a reduction of emissions of greenhouse gases so as to mitigate the problem, there is a perceived need for adaptation initiatives urgently. Ecosystems are known to play an important role in climate change adaptation processes, since some of the services they provide, may reduce the impacts of extreme events and disturbance, such as wildfires, floods, and droughts. This role is especially important in regions vulnerable to climate change such as the African continent, whose adaptation capacity is limited by many geographic and socio-economic constraints. In Africa, interventions aimed at enhancing ecosystem services may play a key role in supporting climate change adaptation efforts. In order to shed some light on this aspect, this paper reviews the role of ecosystems services and investigates how they are being influenced by climate change in Africa. It contains a set of case studies from a sample of African countries, which serve the purpose to demonstrate the damages incurred, and how such damages disrupt ecosystem services. Based on the data gathered, some measures which may assist in fostering the cause of ecosystems services are listed, so as to cater for a better protection of some of the endangered Africa ecosystems, and the services they provide.
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The immobilization of proteins on carbon nanotubes (CNTs) has been widely reported mainly for the preparation of sensors while the conjugation of enzymes for therapeutic purposes has scarcely been considered. Herein we report, to the best of our knowledge, the first example of intracellular delivery of a therapeutic enzyme by means of CNTs, retaining its activity. Mucopolysaccharidosis I is a rare genetic disease characterized by the deficiency or absence of the activity of the α-l-iduronidase (IDUA) enzyme. We evaluated the capacity of the recombinant form of the human IDUA enzyme, laronidase (Aldurazyme®), conjugated with CNTs to be internalized by fibroblasts from subjects affected with Mucopolysaccharidosis type I and the capacity of the enzyme to retain its activity after internalization. The enzyme was successfully delivered into the lysosomal space and the enzymatic activity of the conjugate was preserved after internalization up to 48 hours. This paves the way towards the use of such a kind of construct for therapeutic applications.
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Portadores de Fármacos , Iduronidasa/administración & dosificación , Mucopolisacaridosis I/tratamiento farmacológico , Nanotubos de Carbono , Células Cultivadas , Fibroblastos/efectos de los fármacos , Humanos , Proteínas Recombinantes/administración & dosificación , Piel/citologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Drypetes klainei Pierre ex Pax is used in Cameroon by Baka Pygmies in the wound healing process and for the treatment of burns. AIM OF THE STUDY: To validate the traditional use of D. klainei Pierre ex Pax stem bark extracts through the evaluation of their antimicrobial properties and their ability to improve wound healing process in fibroblast cell cultures. MATERIALS AND METHODS: The antimicrobial properties of D. klainei extracts were evaluated against Staphylococcus aureus ATCC 6538, Streptococcus pyogenes ATCC 19615, Escherichia coli ATCC 10536, Candida albicans ATCC 10231, on the basis of the minimum inhibitory concentration (MIC) and the minimum bactericidal-fungicidal concentration (MBC-MFC) by the macrodilution method. The extracts abilities to accelerate wound healing were studied on murine and human fibroblasts in terms of cell viability and migration (scratch wound-healing assay). RESULTS: All the extracts were non-toxic against the selected microorganisms at the tested concentrations, and significantly improve wound healing process in vitro, compared to untreated controls. However, the defatted methanol extract was active at lower concentrations, compared to the water extract. CONCLUSIONS: The ability of both water and defatted methanol extracts to accelerate scratch wound closure in fibroblast cultures may support the traditional use of D. klainei stem bark in the treatment of skin lesions (such as burns) even if no antimicrobial activity was evidenced.
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Fibroblastos/efectos de los fármacos , Magnoliopsida , Extractos Vegetales/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Línea Celular , Células Cultivadas , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Corteza de la Planta , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/crecimiento & desarrolloRESUMEN
Atrial natriuretic peptide (ANP) is a cardiac hormone playing a crucial role in cardiovascular homeostasis mainly through blood volume and pressure regulation. In the last years, the new property ascribed to ANP of inhibiting tumor growth both in vitro and in vivo has made this peptide an attractive candidate for anticancer therapy. The molecular mechanism underlying the anti-proliferative effect of ANP has been mainly related to its interaction with the specific receptors NPRs, through which this natriuretic hormone inhibits some metabolic targets critical for cancer development, including the Ras-MEK1/2-ERK1/2 kinase cascade, functioning as a multikinase inhibitor. In this review we summarize the current knowledge on this topic, focusing on our recent data demonstrating that the antitumor activity of this natriuretic hormone is also mediated by a concomitant effect on the Wnt/ß-catenin pathway and on the pH regulation ability of cancer cells, through a Frizzled-related mechanism. This peculiarity of simultaneously targeting two processes crucial for neoplastic transformation and solid tumor survival reinforces the utility of ANP for the development of both preventive and therapeutic strategies.
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Antineoplásicos/farmacología , Factor Natriurético Atrial/farmacología , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Vía de Señalización Wnt/efectos de los fármacos , Antineoplásicos/uso terapéutico , Factor Natriurético Atrial/uso terapéutico , Humanos , Concentración de Iones de Hidrógeno/efectos de los fármacosRESUMEN
During hemodialysis, amino acids (AA) are lost in the ultrafiltrate with consequent modification of their plasma profile. The aim of this cross-sectional study was to evaluate intradialytic changes of plasma AA levels during a single session of hemodiafiltration with endogenous reinfusion (HFR) versus acetate-free biofiltration (AFB). 48 patients chronically treated with HFR or AFB were matched 1:1 for age, gender, Kt/V and diabetes. Blood samples were collected at the beginning and the end of dialysis. Baseline plasma levels (µmol/l) of total AA (3,176 ± 722), essential AA (889 ± 221), and branched chain AA (459 ± 140) levels in HFR were similar to those in AFB (3,399 ± 621, 938 ± 277, and 463 ± 71, respectively). Plasma intradialytic AA levels did not change in HFR, while in AFB there was a reduction by about 25%. In conclusion, as compared with AFB, HFR has a sparing effect on AA loss due to the lack of adsorption by cartridge and to their complete reinfusion in blood.
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Aminoácidos/sangre , Hemodiafiltración , Diálisis Renal , Anciano , Estudios Transversales , Soluciones para Hemodiálisis/administración & dosificación , Humanos , Persona de Mediana EdadRESUMEN
Melanoma development is a multi-step process arising from a series of genetic and epigenetic events. Although the sequential stages involved in progression from melanocytes to malignant melanoma are clearly defined, our current understanding of the mechanisms leading to melanoma onset is still incomplete. Growing evidence show that the activation of endogenous retroviral sequences might be involved in transformation of melanocytes as well as in the increased ability of melanoma cells to escape immune surveillance. Here we show that human melanoma cells in vitro undergo a transition from adherent to a more malignant, non-adherent phenotype when exposed to stress conditions. Melanoma-derived non-adherent cells are characterized by an increased proliferative potential and a decreased expression of both HLA class I molecules and Melan-A/MART-1 antigen, similarly to highly malignant cells. These phenotypic and functional modifications are accompanied by the activation of human endogenous retrovirus K expression (HERV-K) and massive production of viral-like particles. Down-regulation of HERV-K expression by RNA interference prevents the transition from the adherent to the non-adherent growth phenotype in low serum. These results implicate HERV-K in at least some critical steps of melanoma progression.
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Transformación Celular Viral , Retrovirus Endógenos/fisiología , Melanoma/virología , Activación Viral/fisiología , Células CACO-2 , Proliferación Celular , Transformación Celular Viral/genética , Células Cultivadas , Células Clonales/virología , Progresión de la Enfermedad , Retrovirus Endógenos/genética , Humanos , Células Jurkat , Células K562 , Melanocitos/patología , Melanocitos/ultraestructura , Melanocitos/virología , Melanoma/etiología , Melanoma/genética , Melanoma/patología , Modelos Biológicos , ARN Viral/aislamiento & purificación , Virión/crecimiento & desarrollo , Activación Viral/genéticaRESUMEN
Airway smooth muscle (ASM) plays a key role in bronchomotor tone, as well as in structural remodeling of the bronchial wall. Therefore, ASM contraction and proliferation significantly participate in the development and progression of asthma. Many contractile agonists also behave as mitogenic stimuli, thus contributing to frame a hyperresponsive and hyperplastic ASM phenotype. In this review, the molecular mechanisms and signaling pathways involved in excitation-contraction coupling and ASM cell growth will be outlined. Indeed, the recent advances in understanding the basic aspects of ASM biology are disclosing important cellular targets, currently explored for the implementation of new, more effective anti-asthma therapies.
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Asma/fisiopatología , Contracción Muscular , Músculo Liso/fisiopatología , Sistema Respiratorio/fisiopatología , Asma/patología , Broncoconstricción , Calcio/fisiología , Proliferación Celular , Citocinas/fisiología , Humanos , Músculo Liso/patología , Sistema Respiratorio/patología , Transducción de SeñalRESUMEN
A novel approach to the study of RBCs based on the collection of three-dimensional high-resolution AFM images and on the measure of the surface roughness of their plasma membrane is presented. The dependence of the roughness from several parameters of the imaging was investigated and a general rule for a trustful analysis and comparison has been suggested. The roughness of RBCs is a morphology-related parameter which has been shown to be characteristic of the single cells composing a sample, but independent of the overall geometric shape (discocyte or spherocyte) of the erythrocytes, thus providing extra-information with respect to a conventional morphology study. The use of the average roughness value as a label of a whole sample was tested on different kinds of samples. Analyzed data revealed that the quantitative roughness value does not change after treatment of RBCs with various commonly used fixation and staining methods while a drastic decrease occurs when studying cells with membrane-skeletal alteration both naturally occurring or artificially induced by chemical treatments. The present method provides a quantitative and powerful tool for a novel approach to the study of erythrocytes structure through an ultrastructural morphological analysis with the potential to give information, in a non-invasive way, on the RBCs function.
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Membrana Celular/ultraestructura , Eritrocitos/ultraestructura , Microscopía de Fuerza Atómica , Humanos , Esferocitosis Hereditaria , Propiedades de SuperficieRESUMEN
Transforming growth factor-beta1 (TGF-beta1) is crucially involved in the fibrotic events characterizing interstitial lung diseases (ILDs), as well as in the airway remodeling process typical of asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal and fibrotic human lung fibroblasts (HLFs), the effects of TGF-beta1 on mitogen-activated protein kinase (MAPK) phosphorylation, cell proliferation, and production of interleukins 6 (IL-6) and 11 (IL-11), in the presence or absence of a pretreatment with budesonide (BUD). MAPK phosphorylation was detected by Western blotting, cell viability and proliferation were evaluated using Trypan blue staining and [(3)H]-thymidine incorporation assay, respectively, and the release of IL-6 and IL-11 into cell culture supernatants was assessed by ELISA. TGF-beta1 (10 ng/ml) significantly stimulated MAPK phosphorylation (P < 0.01), and also enhanced cell proliferation as well as the secretion of both IL-6 and IL-11, which reached the highest increases at the 72nd h of cell exposure to this growth factor. All such effects were prevented by BUD (10(-8) M) and, with the exception of IL-6 release, also by a mixture of MAPK inhibitors. Therefore, our findings suggest that the fibrotic action exerted by TGF-beta1 in the lung is mediated at least in part by MAPK activation and by an increased synthesis of the profibrogenic cytokines IL-6 and IL-11; all these effects appear to be prevented by corticosteroids via inhibition of MAPK phosphorylation.
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Fibroblastos/metabolismo , Glucocorticoides/farmacología , Interleucinas/metabolismo , Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Factor de Crecimiento Transformador beta1/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Inhibidores Enzimáticos/farmacología , Fibroblastos/efectos de los fármacos , Humanos , Interleucina-11/metabolismo , Interleucina-6/metabolismo , Pulmón/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
A review is presented of the literature data concerning the effects induced by carbon nanoparticles on the biological environment and the importance of these effects in human and animal health. The discovery in 1985 of fullerenes, a novel carbon allotrope with a polygonal structure made up solely by 60 carbon atoms, and in 1991 of carbon nanotubes, thin carbon filaments (1-3 microm in length and 1-3 nm in diameter) with extraordinary mechanical properties, opened a wide field of activity in carbon research. During the last few years, practical applications of fullerenes as biological as well as pharmacological agents have been investigated. Various fullerene-based compounds were tested for biological activity, including antiviral, antioxidant, and chemiotactic activities. Nanotubes consist of carbon atoms arranged spirally to form concentric cylinders, that are perfect crystals and thinner than graphite whiskers. They are stronger than steel but very flexible and lightweight and transfer heat better than any other known material. These characteristics make them suitable for various potential applications such as super strong cables and tips for scanning probe microscopes, as well as biomedical devices for drug delivery, medical diagnostic, and therapeutic applications. The effects induced by these nanostructures on rat lung tissues, as well as on human skin and human macrophage and keratinocyte cells are presented.
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Materiales Biocompatibles/efectos adversos , Reacción a Cuerpo Extraño/etiología , Enfermedades Pulmonares/etiología , Nanotubos de Carbono/efectos adversos , Medición de Riesgo/métodos , Enfermedades de la Piel/etiología , Animales , Reacción a Cuerpo Extraño/prevención & control , Humanos , Factores de RiesgoRESUMEN
The involvement of bronchial vasculature in the airway remodelling occurring in symptomatic smokers with normal lung function and with chronic obstructive pulmonary disease (COPD) has been poorly investigated. An immunohistochemical study was performed on bronchial biopsies taken from 8 non-smokers and 18 smokers divided, according to global health initiative on obstructive lung diseases (GOLD) classification of COPD, into two groups, GOLD 0 and GOLD 2, each of 9 subjects. The number of vessels and the percentage of vascular area in the lamina propria were evaluated by mAb anti-collagen IV. Cellular expression of VEGF and vascular expression of alphavbeta3 integrin were evaluated by the specific monoclonal antibodies. An image processing and analysis system was used to quantify the immunohistochemical data. The number of vessels, the vascular area, the cellular expression of VEGF, the number and percentage of alphavbeta3 positive vessels were significantly higher in GOLD 0 and in GOLD 2 smokers than in non-smokers. The comparison between GOLD 0 and GOLD 2 smokers did show a weak but significantly lower number of vessels in GOLD 2, while the vascular area and the percentage of alphavbeta3 positive vessels did not differ between the two groups. A higher cellular VEGF expression was detected in the GOLD 2 than in the GOLD 0 group. Angiogenesis of bronchial vessels is a component of the airway remodelling occurring in symptomatic smokers with normal lung function and with COPD, it seems independent by the development of airway obstruction and not related to its severity.
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Bronquios/patología , Neovascularización Patológica/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/patología , Fumar/patología , Biopsia , Bronquios/irrigación sanguínea , Bronquios/metabolismo , Femenino , Volumen Espiratorio Forzado , Humanos , Integrina alfaVbeta3/metabolismo , Masculino , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Mucosa Respiratoria/metabolismo , Fumar/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Capacidad VitalRESUMEN
Respiratory tract infections caused by both viruses and/or atypical bacteria are involved in the pathogenesis of asthma. In particular, several viruses such as respiratory syncytial virus, rhinovirus and influenza/parainfluenza viruses may favour the expression of the asthmatic phenotype, being also implicated in the induction of disease exacerbations. Within this pathological context, a significant role can also be played by airway bacterial colonizations and infections due to Chlamydiae and Mycoplasms. All these microbial agents probably interfere with complex immunological pathways, thus contributing to induce and exacerbate asthma in genetically predisposed individuals.
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Asma/microbiología , Infecciones del Sistema Respiratorio/microbiología , Adolescente , Adulto , Asma/genética , Asma/virología , Infecciones Bacterianas/microbiología , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/virología , Virosis/virologíaRESUMEN
COPD is a widespread inflammatory respiratory disorder characterized by a progressive, poorly reversible airflow limitation. Currently available therapies are mostly based on those used to treat asthma. However, such compounds are not able to effectively reduce the gradual functional deterioration, as well as the ongoing airway and lung inflammation occurring in COPD patients. Therefore, there is an urgent need to improve the efficacy of the existing drug classes and to develop new treatments, targeting the main cellular and molecular mechanisms underlying disease pathogenesis. These therapeutic strategies will be highlighted in the present review.
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Diseño de Fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Quimiocinas/antagonistas & inhibidores , Quimiocinas/farmacología , Quimiocinas/uso terapéutico , Citocinas/farmacología , Citocinas/uso terapéutico , Humanos , Italia , Preparaciones Farmacéuticas/clasificación , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Transducción de Señal/efectos de los fármacosRESUMEN
Endothelin-1 (ET-1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET-1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET-1 in the presence or absence of an overnight pre-treatment with either ET(A) or ET(B) selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen-activated protein kinases (MAPK). ET-1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL-6/IL-11 release into cell culture supernatants. All these effects were inhibited by the selective ET(A) antagonist BQ-123, but not by the specific ET(B) antagonist BQ-788. The stimulatory influence of ET-1 on IL-11, but not on IL-6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET-1 exerts a profibrogenic action via an ET(A) receptor-dependent, MAPK-mediated induction of IL-11 release and cell proliferation.
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Endotelina-1/farmacología , Fibroblastos/citología , Fibroblastos/metabolismo , Interleucina-11/metabolismo , Pulmón/citología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptor de Endotelina A/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Antagonistas de los Receptores de la Endotelina A , Antagonistas de los Receptores de la Endotelina B , Endotelina-1/metabolismo , Fibroblastos/efectos de los fármacos , Humanos , Interleucina-6/metabolismo , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Factores de TiempoRESUMEN
We examined the morphological, biochemical and molecular outcome of a nonspecific sulfhydryl reduction in cells, obtained by supplementation of N-acetyl-L-cysteine (NAC) in a 0.1-10 mM concentration range. In human normal primary keratinocytes and in colon and ovary carcinoma cells we obtained evidences for: (i) a dose-dependent inhibition of proliferation without toxicity or apoptosis; (ii) a transition from a proliferative mesenchymal morphology to cell-specific differentiated structures; (iii) a noticeable increase in cell-cell and cell-substratum junctions; (iv) a relocation of the oncogenic beta-catenin at the cell-cell junctions; (v) inhibition of microtubules aggregation; (vi) upregulation of differentiation-related genes including p53, heat shock protein 27 gene, N-myc downstream-regulated gene 1, E-cadherin, and downregulation of cyclooxygenase-2; (vii) inhibition of c-Src tyrosine kinase. In conclusion, a thiol reduction devoid of toxicity as that operated by NAC apparently leads to terminal differentiation of normal and cancer cells through a pleiade of converging mechanisms, many of which are targets of the recently developed differentiation therapy.
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Diferenciación Celular/fisiología , Neoplasias del Colon/patología , Neoplasias Ováricas/patología , Compuestos de Sulfhidrilo/metabolismo , Acetilcisteína/farmacología , Proteína Tirosina Quinasa CSK , Cadherinas/metabolismo , Adhesión Celular/efectos de los fármacos , Adhesión Celular/fisiología , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Proteínas del Citoesqueleto/metabolismo , Femenino , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Neoplasias Ováricas/metabolismo , Fosfotransferasas/antagonistas & inhibidores , Fosfotransferasas/metabolismo , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Timidina/metabolismo , Transactivadores , beta Catenina , Familia-src QuinasasRESUMEN
We previously demonstrated that exogenously administered neurokinin A and neurokinin B, but not substance P, increased the sensitivity of cultured cerebellar granule neurons (CGNs) to glutamate. In the present study, the presence of tachykinin neuropeptides in CGNs was tested by confocal-based immunofluorescence. We found that neurokinin A and neurokinin B are present in CGNs but absent in astrocytes while substance P is abundant in astrocytes but absent in CGNs. It is postulated that the different localization of tachykinin neuropeptides in CGNs and astroglial cells has a physiological role in the modulation of excitatory transmission.
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Cerebelo/química , Neuronas/química , Neuropéptidos/análisis , Taquicininas/análisis , Animales , Especificidad de Anticuerpos , Astrocitos/química , Astrocitos/citología , Astrocitos/metabolismo , Células Cultivadas , Cerebelo/citología , Cerebelo/metabolismo , Gránulos Citoplasmáticos , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Microscopía Confocal , Neuroquinina A/análisis , Neuroquinina A/biosíntesis , Neuroquinina B/análisis , Neuroquinina B/biosíntesis , Neuronas/citología , Neuronas/metabolismo , Neuropéptidos/biosíntesis , Ratas , Sustancia P/análisis , Sustancia P/biosíntesis , Taquicininas/biosíntesisRESUMEN
Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes which play a key role in signal transduction mediated by cytokines, growth factors, neurotransmitters and various types of environmental stresses. In the airways, these extracellular stimuli elicit complex inflammatory and structural changes leading to the typical features of asthma including T cell activation, eosinophil and mast cell infiltration, as well as bronchial hyperresponsiveness and airway remodelling. Because MAPKs represent an important point of convergence for several different signalling pathways, they affect multiple aspects of normal airway function and also significantly contribute to asthma pathophysiology. Therefore, this review focuses on the crucial involvement of MAPKs in asthma pathogenesis, thus also discussing their emerging role as molecular targets for anti-asthma drugs.
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Asma/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Corticoesteroides/farmacología , Antiasmáticos/química , Antiasmáticos/metabolismo , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Bronquios/anatomía & histología , Bronquios/inmunología , Activación Enzimática , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Humanos , Sistema Inmunológico/fisiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Estructura MolecularRESUMEN
Interferon-alpha (IFNalpha) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumors, and melanoma. IFNalpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumor cell growth is directly suppressed by IFNalpha is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will review the consolidate signal transducer and activator of transcription (STAT)-dependent mechanism of action of IFNalpha. We will discuss data obtained by us and others on the triggering of the stress-dependent kinase pathway induced by IFNalpha and its correlations with the apoptotic process. The regulation of the expression of proteins involved in apoptosis occurrence will be also described. In this regard, IFNalpha is emerging as a post-translational controller of the intracellular levels of the apoptosis-related protein tissue transglutaminase (tTG). This new way of regulation of tTG occurs through the modulation of their proteasome-dependent degradation induced by the cytokine. Until today, inconsistent data have been obtained regarding the clinical effectiveness of IFNalpha in the therapy of solid tumors. In fact, the benefit of IFNalpha treatment is limited to some neoplasms while others are completely or partially resistant. The mechanisms of tumor resistance to IFNalpha have been studied in vitro. The alteration of JAK-STAT components of the IFNalpha-induced signaling, can be indeed a mechanism of resistance to IFN. However, we have recently described a reactive mechanism of protection of tumor cells from the apoptosis induced by IFNalpha dependent on the epidermal growth factor (EGF)-mediated Ras/extracellular signal regulated kinase (Erk) signaling. The involvement of the Ras-->Erk pathway in the protection of tumor cells from the apoptosis induced by IFNalpha is further demonstrated by both Ras inactivation by RASN17 transfection and mitogen extracellular signal regulated kinase 1 (Mek-1) inhibition by exposure to PD098059. These data strongly suggest that the specific disruption of the latter could be a useful approach to potentiate the antitumour activity of IFNalpha against human tumors based on the new mechanistic insights achieved in the last years.
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Interferón-alfa/farmacología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis , División Celular/efectos de los fármacos , Humanos , Interferón-alfa/genética , Familia de Multigenes , Neoplasias/patología , Neoplasias/fisiopatología , Inhibidores de la Síntesis de la Proteína/farmacología , Proteínas Recombinantes/farmacologíaRESUMEN
Genetic factors play a key role in determining the widely heterogeneous response to pharmacological treatment detectable among asthmatics. In particular, polymorphisms of the genes encoding relevant anti-asthma drug targets contribute significantly to such a variability. Therefore, it is very important to characterize asthmatic patient's genotypes and the related phenotypic patterns, in order to predict the individual therapeutic outcome. This pharmacogenetic approach will eventually help clinicians to optimize and personalize anti-asthma treatment, and will also provide useful information with regard to pre- and post-marketing evaluation of both effectiveness and side effects of newly introduced drugs.