RESUMEN
INTRODUCTION: High-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations. The present study explores the safety of continuous high-dose inhaled (iNO) during EVLP for an extended period of 12 hours. METHODS: Lungs procured from Yorkshire pigs were randomized into control (standard ventilation) and treatment (standard ventilation + 200 ppm iNO) groups, then perfused with an acellular solution for 12 hours (n = 4/group). Lung physiology and biological markers were evaluated. RESULTS: After 12 hours of either standard EVLP or EVLP + 200 ppm iNO, we did not notice any significant physiologic difference between the groups: pulmonary oxygenation (P = .586), peak airway pressures (P = .998), and dynamic (P = .997) and static (P = .908) lung compliances. In addition, no significant differences were seen among proinflammatory cytokines measured in perfusate and lung tissue. Importantly, most common toxic compounds were kept at safe levels throughout the treatment course. CONCLUSIONS: High-dose inhaled NO delivered continuously over 12 hours appears to be safe without inducing any significant pulmonary inflammation or deterioration in lung function. These findings support further efficacy studies to explore the use of iNO for the treatment of infections in donor lungs during EVLP.
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Antiinfecciosos/administración & dosificación , Infecciones Bacterianas/prevención & control , Circulación Extracorporea , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Óxido Nítrico/administración & dosificación , Preservación de Órganos , Perfusión , Administración por Inhalación , Animales , Antiinfecciosos/toxicidad , Infecciones Bacterianas/microbiología , Burkholderia cepacia/efectos de los fármacos , Burkholderia cepacia/crecimiento & desarrollo , Circulación Extracorporea/efectos adversos , Estudios de Factibilidad , Pulmón/microbiología , Pulmón/cirugía , Masculino , Metahemoglobina/metabolismo , Modelos Animales , Óxido Nítrico/toxicidad , Preservación de Órganos/efectos adversos , Perfusión/efectos adversos , Neumonectomía , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Sus scrofaRESUMEN
Introduction: Air pollution is a risk factor for respiratory infections and asthma exacerbations. We previously reported impaired Type-I and Type-III interferons (IFN-ß/λ) from airway epithelial cells of preschool children with asthma and/or atopy. In this study we analyzed the association between rhinovirus-induced IFN-ß/λ epithelial expression and acute exposure to the principal outdoor air pollutants in the same cohort. Methods: We studied 34 children (17asthmatics/17non-asthmatics) undergoing fiberoptic bronchoscopy for clinical indications. Bronchial epithelial cells were harvested by brushing, cultured and experimentally infected with Rhinovirus Type 16 (RV16). RV16-induced IFN-ß and λ expression was measured by quantitative real time PCR, as was RV16vRNA. The association between IFNs and the mean exposure to PM10, SO2 and NO2 in the day preceding bronchoscopy was evaluated using a Generalized Linear Model (GLM) with Gamma distribution. Results: Acute exposure to PM10 and NO2 was negatively associated to RV16-induced IFNß mRNA. For each increase of 1ug/m3 of NO2 we found a significative decrease of 2.3x103 IFN-ß mRNA copies and for each increase of 1ug/m3 of PM10 a significative decrease of 1x103 IFN-ß mRNA copies. No significant associations were detected between IFN-λ mRNA and NO2 nor PM10. Increasing levels of NO2 (but not PM10) were found to be associated to increased RV16 replication. Conclusions: Short-term exposure to high levels of NO2 and PM10 is associated to a reduced IFN-ß expression by the airway epithelium, which may lead to increased viral replication. These findings suggest a potential mechanism underlying the link between air pollution, viral infections and asthma exacerbations.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Asma/metabolismo , Células Epiteliales/efectos de los fármacos , Interferón beta/metabolismo , Pulmón/efectos de los fármacos , Asma/diagnóstico , Asma/inmunología , Asma/virología , Estudios de Casos y Controles , Células Cultivadas , Niño , Preescolar , Resfriado Común/inmunología , Resfriado Común/metabolismo , Resfriado Común/virología , Progresión de la Enfermedad , Exposición a Riesgos Ambientales/efectos adversos , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Femenino , Interacciones Huésped-Patógeno , Humanos , Interferón beta/genética , Italia , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/virología , Masculino , Óxido Nítrico/toxicidad , Material Particulado/toxicidad , Rhinovirus/crecimiento & desarrollo , Rhinovirus/inmunología , Dióxido de Azufre/toxicidad , Replicación ViralRESUMEN
Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson's disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.
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Neuronas Dopaminérgicas/patología , Microglía/metabolismo , Degeneración Nerviosa/patología , Fagocitosis/fisiología , alfa-Sinucleína/metabolismo , Inmunidad Adaptativa/fisiología , Animales , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Encefalitis/metabolismo , Encefalitis/patología , Expresión Génica , Inmunidad Innata/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/patología , Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidad , Enfermedad de Parkinson/patología , Especies Reactivas de Oxígeno/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/patología , alfa-Sinucleína/genéticaRESUMEN
Bacterial response to nitric oxide (NO) is of major importance for bacterial survival. NO stress is a main actor of the eukaryotic immune response and several pathogenic bacteria have developed means for detoxification and repair of the damages caused by NO. However, bacterial mechanisms of NO resistance by Gram-positive bacteria are poorly described. In the opportunistic foodborne pathogen Bacillus cereus, genome sequence analyses did not identify homologs to known NO reductases and transcriptional regulators, such as NsrR, which orchestrate the response to NO of other pathogenic or non-pathogenic bacteria. Using a transcriptomic approach, we investigated the adaptation of B. cereus to NO stress. A cluster of 6 genes was identified to be strongly up-regulated in the early phase of the response. This cluster contains an iron-sulfur cluster repair enzyme, a nitrite reductase and three enzymes involved in siroheme biosynthesis. The expression pattern and close genetic localization suggest a functional link between these genes, which may play a pivotal role in the resistance of B. cereus to NO stress during infection.
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Bacillus cereus/metabolismo , Proteínas Bacterianas/metabolismo , Hemo/análogos & derivados , Hierro/metabolismo , Óxido Nítrico/toxicidad , Nitrito Reductasas/metabolismo , Estrés Oxidativo , Bacillus cereus/efectos de los fármacos , Bacillus cereus/genética , Bacillus cereus/crecimiento & desarrollo , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Hemo/biosíntesis , Transcripción GenéticaRESUMEN
We have created a novel glutathione S-transferase π1 (gstp1) knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis and response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, gstp1 KO larvae had higher expression of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) accompanied by a more reduced larval environment and a status consistent with reductive stress. Compared with wild type, various UPR markers were decreased in KO larvae, but treatment with drugs that induce ER stress caused greater toxicities and increased expression of Nrf2 and UPR markers in KO. Tunicamycin and 02-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl}1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/nitric oxide) activated inositol-requiring protein-1/X-box binding protein 1 pathways, whereas thapsigargin caused greater activation of protein kinase-like ER kinase/activating transcription factor 4/CHOP pathways. These results suggest that this teleost model is useful for predicting how GSTP regulates organismal management of oxidative/reductive stress and is a determinant of response to drug-induced ER stress and the UPR. SIGNIFICANCE STATEMENT: A new zebrafish model has been created to study the importance of glutathione S-transferase π1 in development, redox homeostasis, and response to drugs that enact cytotoxicity through endoplasmic reticulum stress and induction of the unfolded protein response.
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Gutatión-S-Transferasa pi/metabolismo , Respuesta de Proteína Desplegada , Ácido 4-Aminobenzoico/toxicidad , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Gutatión-S-Transferasa pi/genética , Homeostasis , Larva/efectos de los fármacos , Larva/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico/toxicidad , Oxidantes/toxicidad , Oxidación-Reducción , Transcriptoma , Tunicamicina/toxicidad , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The prevalence of periodontal disease poses a significant global health burden. Treatments for these diseases, primarily focused on removal and eradication of dental plaque biofilms, are challenging due to limited access to periodontal pockets where these oral pathogens reside. Herein, we report on the development and characterization of nitric oxide (NO)-releasing carboxymethylcellulose (CMC) derivatives and evaluate their in vitro bactericidal efficacy against planktonic Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, two prominent periodontopathogens. Bactericidal exposure assays revealed that three of the synthesized NO-releasing polymers were capable of reducing bacterial viability of both species by 99.9% in 2 hr at concentrations of 4 mg ml-1 or lower, reflecting NO's potent and rapid bactericidal action. The NO-releasing CMCs elicited minimal toxicity to human gingival fibroblasts at their bactericidal concentrations following 24-hr exposure.
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Aggregatibacter actinomycetemcomitans/efectos de los fármacos , Antibacterianos/farmacología , Compuestos Azo/farmacología , Carboximetilcelulosa de Sodio , Etanolaminas/farmacología , Óxido Nítrico/farmacología , Enfermedades Periodontales/microbiología , Poliaminas/farmacología , Porphyromonas gingivalis/efectos de los fármacos , Propilaminas/farmacología , Antibacterianos/administración & dosificación , Compuestos Azo/administración & dosificación , Compuestos Azo/química , Biopolímeros , Línea Celular , Diaminas/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Etanolaminas/administración & dosificación , Etanolaminas/química , Fibroblastos/efectos de los fármacos , Encía/citología , Humanos , Estructura Molecular , Óxido Nítrico/administración & dosificación , Óxido Nítrico/toxicidad , Poliaminas/administración & dosificación , Poliaminas/química , Propilaminas/administración & dosificación , Propilaminas/química , Especificidad de la Especie , ViscosidadRESUMEN
Data from epidemiological studies suggest that consumption of red and processed meat is a factor contributing to colorectal carcinogenesis. Red meat contains high amounts of heme, which in turn can be converted to its nitrosylated form, NO-heme, when adding nitrite-containing curing salt to meat. NO-heme might contribute to colorectal cancer formation by causing gene mutations and could thereby be responsible for the association of (processed) red meat consumption with intestinal cancer. Up to now, neither in vitro nor in vivo studies characterizing the mutagenic and cell transforming potential of NO-heme have been published due to the fact that the pure compound is not readily available. Therefore, in the present study, an already existing synthesis protocol was modified to yield, for the first time, purified NO-heme. Thereafter, newly synthesized NO-heme was chemically characterized and used in various in vitro approaches at dietary concentrations to determine whether it can lead to DNA damage and malignant cell transformation. While NO-heme led to a significant dose-dependent increase in the number of DNA strand breaks in the comet assay and was mutagenic in the HPRT assay, this compound tested negative in the Ames test and failed to induce malignant cell transformation in the BALB/c 3T3 cell transformation assay. Interestingly, the non-nitrosylated heme control showed similar effects, but was additionally able to induce malignant transformation in BALB/c 3T3 murine fibroblasts. Taken together, these results suggest that it is the heme molecule rather than the NO moiety which is involved in driving red meat-associated carcinogenesis.
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Transformación Celular Neoplásica/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Hemo/toxicidad , Neoplasias Intestinales/inducido químicamente , Óxido Nítrico/toxicidad , Animales , Células 3T3 BALB , Células CACO-2 , Carcinogénesis/inducido químicamente , Línea Celular , Ensayo Cometa , Cricetinae , Hemo/química , Humanos , Ratones , Mutagénesis , Mutación , Óxido Nítrico/química , Carne Roja/toxicidad , Factores de Riesgo , Análisis de la Célula IndividualRESUMEN
Nitric oxide (NO) release in the right medial prefrontal cortex (RmPFC) produces anxiogenesis. In the bed nucleus of the stria terminalis (BNST), a region that receives neuronal projections from the mPFC, NO provokes anxiety, an effect that is blocked by local injections of corticotrophin-releasing factor type 1 receptor (CRF1) or n-methyl-d-aspartate receptor (NMDAr) antagonist. Anxiety is also enhanced by social defeat stress, and chronic stress impairs and facilitates, respectively, PFC and BNST roles in modulating behavioral responses to aversive situations. This study investigated whether the (i) chronic social defeat stress (CSDS) increases NO signaling in the mPFC; and/or (ii) anxiogenic effects provoked by the intra-RmPFC injection of NOC-9 (an NO donor) or by CSDS are prevented by intra-BNST injections of AP-7 (0.05 nmol) or CP 376395 (3.0 nmol), respectively, NMDAr and CRF1 antagonists, in male Swiss-Webster mice exposed to the elevated plus-maze (EPM). Results showed that (a) CSDS increased anxiety (i.e., reduced open-arm exploration) and repeatedly activated nNOS-containing neurons, as measured by ΔFosB (a stable nonspecific marker of neural activity) + nNOS double-labeling, in the right (but not left) mPFC, (b) NOC-9 in the RmPFC also increased anxiety, and (c) both CSDS and NOC-9 effects were reversed by injections of AP-7 or CP 376395 into the BNST. These results suggest that NMDA and CRF1 receptors located in BNST play an important role in the modulation of anxiety provoked by NO in the RmPFC, as well as by chronic social defeat in mice.
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Ansiedad/metabolismo , Óxido Nítrico/metabolismo , Corteza Prefrontal/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septales/metabolismo , Derrota Social , Aminopiridinas/administración & dosificación , Animales , Ansiedad/inducido químicamente , Ansiedad/psicología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Microinyecciones , Óxido Nítrico/toxicidad , Corteza Prefrontal/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Núcleos Septales/efectos de los fármacos , Triazenos/administración & dosificaciónAsunto(s)
Cefaleas Secundarias/etiología , Óxido Nítrico/toxicidad , Trastornos Relacionados con Sustancias/complicaciones , Cefalea/inducido químicamente , Cefalea/metabolismo , Cefaleas Secundarias/inducido químicamente , Cefaleas Secundarias/metabolismo , Humanos , Canal de Sodio Activado por Voltaje NAV1.9/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.9/metabolismo , Óxido Nítrico/farmacología , Medicamentos bajo Prescripción/efectos adversos , Transducción de Señal/efectos de los fármacos , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
BACKGROUND: Racial/ethnic disparities in blood pressure and hypertension have been evident in previous studies, as were associations between race/ethnicity with ambient air pollution and those between air pollution with hypertension. The role of air pollution exposure to racial/ethnic differences in hypertension has not been explored. OBJECTIVE: To assess the potential mediating effects of ambient air pollution on the association between race/ethnicity and blood pressure levels. METHODS: We studied 6,463 White, Black, Hispanic and Chinese adults enrolled across 6 US cities. Systolic (SBP) and diastolic blood pressure (DBP) were measured at Exam 1 (2000-2002) and Exam 2 (2002-2004). Household-level annual average concentrations of fine particulate matter (PM2.5), oxides of nitrogen (NOX), and ozone (O3) for the year 2000 were estimated for participants. RESULTS: The difference in SBP levels by race/ethnicity that was related to higher PM2.5 concentrations compared with White men ("indirect associations") was 0.3 (95% CI: 0.1, 0.6) mmHg for Black men, 0.3 (95% CI: 0.1, 0.6) mmHg for Hispanic men and 1.0 (95% CI: 0.2, 1.8) mmHg for Chinese men. Findings were similar although not statistically significant for women. PM2.5 did not mediate racial/ethnic differences in DBP. Indirect associations were significant for O3 for SBP among women and men and for DBP among men. In contrast, racial/ethnic disparities were attenuated due to exposure to NOX. CONCLUSION: Racial disparities in blood pressure were reduced after accounting for PM2.5 and ozone while increased after accounting for NOX.
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Contaminantes Atmosféricos , Contaminación del Aire , Aterosclerosis , Presión Sanguínea , Adulto , Contaminantes Atmosféricos/toxicidad , Aterosclerosis/inducido químicamente , Aterosclerosis/etnología , Presión Sanguínea/efectos de los fármacos , Exposición a Riesgos Ambientales , Etnicidad , Femenino , Humanos , Masculino , Óxido Nítrico/toxicidad , Ozono/toxicidad , Material ParticuladoRESUMEN
Elevated H2 O2 is implicated in many cardiovascular diseases. We previously demonstrated that H2 O2 -induced endothelial nitric oxide synthase (eNOS) activation and excessive NO production contribute to vascular cell injury and increases in microvessel permeability. However, the mechanisms of excessive NO-mediated vascular injury and hyperpermeability remain unknown. This study aims to examine the functional role of NO-derived peroxynitrite (ONOO- ) in H2 O2 -induced vascular barrier dysfunction by elucidating the interrelationships between H2 O2 -induced NO, superoxide, ONOO- , and changes in endothelial [Ca2+ ]i and microvessel permeability. Experiments were conducted on intact rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). Endothelial [Ca2+ ]i , NO, and O2- were assessed with fluorescence imaging. Perfusion of vessels with H2 O2 (10 µmol/L) induced marked productions of NO and O2- , resulting in extensive protein tyrosine nitration, a biomarker of ONOO- . The formation of ONOO- was abolished by inhibition of NOS with NG -Methyl-L-arginine. Blocking NO production or scavenging ONOO- by uric acid prevented H2 O2 -induced increases in endothelial [Ca2+ ]i and Lp. Additionally, the application of exogenous ONOO- to microvessels induced delayed and progressive increases in endothelial [Ca2+ ]i and microvessel Lp, a pattern similar to that observed in H2 O2 -perfused vessels. Importantly, ONOO- caused further activation of eNOS with amplified NO production. We conclude that the augmentation of NO-derived ONOO- is essential for H2 O2 -induced endothelial Ca2+ overload and progressively increased microvessel permeability, which is achieved by self-promoted amplifications of NO-dependent signaling cascades. This novel mechanism provides new insight into the reactive oxygen and/or reactive nitrogen species-mediated vascular dysfunction in cardiovascular diseases.
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Permeabilidad Capilar/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Especies Reactivas de Oxígeno/toxicidad , Animales , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Peróxido de Hidrógeno/metabolismo , Microvasos/efectos de los fármacos , Microvasos/metabolismo , Óxido Nítrico/toxicidad , Ácido Peroxinitroso/toxicidad , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Iron (Fe) is essential for life, but in excess can cause oxidative cytotoxicity through the generation of Fe-catalyzed reactive oxygen species. It is yet unknown which genes and mechanisms can provide Fe-toxicity tolerance. Here, we identify S-nitrosoglutathione-reductase (GSNOR) variants underlying a major quantitative locus for root tolerance to Fe-toxicity in Arabidopsis using genome-wide association studies and allelic complementation. These variants act largely through transcript level regulation. We further show that the elevated nitric oxide is essential for Fe-dependent redox toxicity. GSNOR maintains root meristem activity and prevents cell death via inhibiting Fe-dependent nitrosative and oxidative cytotoxicity. GSNOR is also required for root tolerance to Fe-toxicity throughout higher plants such as legumes and monocots, which exposes an opportunity to address crop production under high-Fe conditions using natural GSNOR variants. Overall, this study shows that genetic or chemical modulation of the nitric oxide pathway can broadly modify Fe-toxicity tolerance.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/embriología , Arabidopsis/metabolismo , Tolerancia a Medicamentos/fisiología , Glutatión Reductasa/metabolismo , Hierro/metabolismo , Hierro/toxicidad , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Muerte Celular , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Glutatión Reductasa/genética , Haplotipos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/toxicidad , Meristema/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidad , Nitrosación , Estrés Oxidativo , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Plantas Modificadas GenéticamenteRESUMEN
Detrimental microbes caused the evolution of a great diversity of antimicrobial defenses in plants and animals. Insects developing underground seem particularly threatened. Here we show that the eggs of a solitary digger wasp, the European beewolf Philanthus triangulum, emit large amounts of gaseous nitric oxide (NOâ ) to protect themselves and their provisions, paralyzed honeybees, against mold fungi. We provide evidence that a NO-synthase (NOS) is involved in the generation of the extraordinary concentrations of nitrogen radicals in brood cells (~1500 ppm NOâ and its oxidation product NO2â ). Sequencing of the beewolf NOS gene revealed no conspicuous differences to related species. However, due to alternative splicing, the NOS-mRNA in beewolf eggs lacks an exon near the regulatory domain. This preventive external application of high doses of NOâ by wasp eggs represents an evolutionary key innovation that adds a remarkable novel facet to the array of functions of the important biological effector NOâ .
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Radicales Libres/metabolismo , Hongos/crecimiento & desarrollo , Óxido Nítrico/metabolismo , Óvulo/metabolismo , Avispas/metabolismo , Animales , Antiinfecciosos/metabolismo , Antiinfecciosos/toxicidad , Aspergillus flavus/efectos de los fármacos , Aspergillus flavus/crecimiento & desarrollo , Aspergillus flavus/fisiología , Radicales Libres/toxicidad , Hongos/efectos de los fármacos , Hongos/fisiología , Óxido Nítrico/toxicidad , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Simbiosis/efectos de los fármacos , Avispas/genética , Avispas/microbiologíaRESUMEN
For effective foraging, many insect pollinators rely on the ability to learn and recall floral odours, behaviours that are associated with a complex suite of cellular processes. Here, we investigated how acute exposure to a high-dose of diesel exhaust (containing 19.8 and 17.5 ppm of NO and NO2, respectively) affected associative learning behaviour of honey bees (Apis mellifera) and expression of a ubiquitous heat shock protein, HSP70, in their central nervous system (CNS). To determine whether exposure to diesel exhaust would alter their tolerance to a subsequent abiotic stress, we further subjected individuals to heat stress. Diesel exhaust exposure decreased honey bees' ability to learn and recall a conditioned odour stimulus. Whilst there was no significant difference in CNS HSP70 expression between honey bees exposed to either diesel exhaust or clean air across the entire duration of the experiment (3.5 h), there was a significant effect of time and a significant interaction between exposure treatment and time. This interaction was investigated using correlation analyses, which demonstrated that only in the diesel exhaust exposed honey bees was there a significant positive correlation between HSP70 expression and time. Furthermore, there was a 44% reduction in honey bee individuals that were able to recall the odour 72 h after diesel exposure compared with clean air control individuals. Moreover, diesel exhaust affected A. mellifera in a way that reduced their ability to survive a second subsequent stressor. Such negative effects of air pollution on learning, recall, and stress tolerance has potential to reduce foraging efficiency and pollination success of individual honey bees.
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Abejas/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Memoria , Emisiones de Vehículos/toxicidad , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiología , Proteínas del Choque Térmico HSP72/genética , Proteínas del Choque Térmico HSP72/metabolismo , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Óxido Nítrico/toxicidad , Dióxido de Nitrógeno/toxicidad , Estrés FisiológicoRESUMEN
CO2, SO2, and NO are the main components of flue gas and can cause serious environmental issues. Utilization of these compounds in oleaginous microalgae cultivation not only could reduce air pollution but could also produce feedstock for biodiesel production. However, the continuous input of SO2 and NO inhibits microalgal growth. In this study, the toxicity of simulated flue gas (15% CO2, 0.03% SO2, and 0.03% NO, balanced with N2) was reduced through automatic pH feedback control. Integrated lipid production and CO2 fixation with the removal of SO2 and NO was achieved. Using this technique, a lipid content of 38.0% DW was achieved in Chlorella pyrenoidosa XQ-20044. The lipid composition and fatty acid profile indicated that lipid production by C. pyrenoidosa XQ-20044 cultured with flue gas is suitable as a biodiesel feedstock; 81.2% of the total lipids were neutral lipids and 99.5% of the total fatty acids were C16 and C18. The ratio of saturated fatty acids to monounsaturated fatty acids in the microalgal lipid content was 74.5%. In addition, CO2, SO2, and NO from the simulated flue gas were fixed and converted to biomass and lipids with a removal efficiency of 95.9%, 100%, and 84.2%, respectively. Furthermore, the utilization efficiencies of CO2, SO2, and NO were equal to or very close to their removal efficiencies. These results provide a novel strategy for combining biodiesel production with biofixation of flue gas.
Asunto(s)
Biotecnología/métodos , Chlorella/efectos de los fármacos , Chlorella/metabolismo , Lípidos/biosíntesis , Contaminantes Atmosféricos/química , Contaminantes Atmosféricos/aislamiento & purificación , Contaminantes Atmosféricos/toxicidad , Biocombustibles , Biomasa , Biotecnología/instrumentación , Dióxido de Carbono/aislamiento & purificación , Dióxido de Carbono/toxicidad , Chlorella/crecimiento & desarrollo , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Concentración de Iones de Hidrógeno , Microalgas/efectos de los fármacos , Microalgas/crecimiento & desarrollo , Microalgas/metabolismo , Óxido Nítrico/aislamiento & purificación , Óxido Nítrico/toxicidad , Dióxido de Azufre/aislamiento & purificación , Dióxido de Azufre/toxicidadRESUMEN
Effective use of medical device implants is often hindered by infection, which may cause the device to be rejected from the body and seriously endanger health. Such infections are often a result of biofilm formation or microbial colonies collecting on a surface. Therefore, a challenge in the medical field is to mitigate the impact of biofilm formation in order to save thousands of lives and millions of healthcare dollars annually. The proposed strategy is to target the attachment phase of the biofilm lifecycle to try to prevent the formation of antimicrobial resistant biofilms. Prevention of bacterial attachment may be induced through the introduction of nitric oxide (NO), a small biological signaling molecule known for its antibacterial properties. NO may be delivered via release from a donating molecule incorporated in the polymer composing the medical device. The NO donor S-nitrosoglutathione (GSNO) was utilized in this study because it is a relatively stable small molecule that naturally exists in the body, therefore negating possible adverse reactions when it is introduced to the body. Tygon®, a polymer commonly found in Food and Drug Administration approved medical devices such as catheters, was utilized as a platform for the inhibition of biofilms. To study the necessary amount of released NO needed to cause a reduction in attachment across varying strains, different concentrations of GSNO were applied. Two Gram-negative (Pseudomonas aeruginosa and Acinetobacter baumannii) and two Gram-positive species (Staphylococcus aureus and Methicillin Resistant Staphylococcus aureus), all strong biofilm formers listed as urgent threats by the Center for Disease Control, illustrated different responses to NO. Gram-positive species showed a decrease in viability over 80% with an average total NO release of 2.01 ± 2.11 × 10 - 4 µmols, while Gram-negative response was less, with viability decreasing to 38% (P. aeruginosa) and 71% (A. baumannii) with 1.25 ± 1.63 × 10-4 µmols NO. Further studies utilizing glutathione surface roughness controls highlight that increasing the surface roughness of the polymer platform produces no statistically significant difference in viability compared to the Tygon-only negative control in all strains except P. aeruginosa. Developing a quantitative understanding of how NO release and platform surface roughness impact biofilm attachment across Gram strains is key to reducing the incidence and impact of medical device associated infections.
Asunto(s)
Antibacterianos/toxicidad , Biopelículas/efectos de los fármacos , Microbiología Ambiental , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Óxido Nítrico/toxicidad , Propiedades de Superficie , Biopelículas/crecimiento & desarrollo , Equipos y Suministros/microbiología , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/crecimiento & desarrollo , Viabilidad Microbiana/efectos de los fármacos , S-Nitrosoglutatión/toxicidadRESUMEN
Senescence is a regulated process of tissue degeneration that can affect any plant organ and consists of the degradation and remobilization of molecules to other growing tissues. Senescent organs display changes at the microscopic level as well as modifications to internal cellular structure and differential gene expression. A large number of factors influencing senescence have been described including age, nutrient supply, and environmental interactions. Internal factors such as phytohormones also affect the timing of leaf senescence. A link between the senescence process and the production of nitric oxide (NO) in senescing tissues has been known for many years. Remarkably, this link can be either a positive or a negative correlation depending upon the organ. NO can be both a signaling or a toxic molecule and is known to have multiple roles in plants; this review considers the duality of NO roles in the senescence process of two different plant organs, namely the leaves and root nodules.
Asunto(s)
Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidad , Hojas de la Planta/fisiología , Fenómenos Fisiológicos de las Plantas , Nódulos de las Raíces de las Plantas/fisiología , Transducción de SeñalRESUMEN
Ligustilide (LIG) is the main lipophilic component of the Umbelliferae family of pharmaceutical plants, including Radix angelicae sinensis and Ligusticum chuanxiong. LIG shows various pharmacological properties associated with anti-inflammation and anti-apoptosis in several kinds of cell lines. However, the therapeutic effects of LIG on chondrocyte apoptosis remain unknown. In this study, we investigated whether LIG had an anti-apoptotic activity in sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis and could delay cartilage degeneration in a surgically induced rat OA model, and elucidated the potential mechanisms. In vitro studies revealed that LIG significantly suppressed chondrocyte apoptosis and cytoskeletal remodelling, which maintained the nuclear morphology and increased the mitochondrial membrane potential. In terms of SNP, LIG treatment considerably reduced the expression levels of cleaved caspase-3, Bax and inducible nitric oxide synthase and increased the expression level of Bcl-2 in a dose-dependent manner. The LIG-treated groups presented a significantly suppressed expression of activating transcription factor 2 and phosphorylation of Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The inhibitory effect of LIG was enhanced by the p38 MAPK inhibitor SB203580 or the JNK inhibitor SP600125 and offset by the agonist anisomycin. In vivo studies demonstrated that LIG attenuated osteoarthritic cartilage destruction by inhibiting the cartilage chondrocyte apoptosis and suppressing the phosphorylation levels of activating transcription factor 2, JNK and p38 MAPK. This result was confirmed by histological analyses, micro-CT, TUNEL assay and immunohistochemical analyses. Collectively, our studies indicated that LIG protected chondrocytes against SNP-induced apoptosis and delayed articular cartilage degeneration by suppressing JNK and p38 MAPK pathways.
Asunto(s)
4-Butirolactona/análogos & derivados , Apoptosis/efectos de los fármacos , Cartílago Articular/patología , Condrocitos/enzimología , Condrocitos/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Óxido Nítrico/toxicidad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , 4-Butirolactona/química , 4-Butirolactona/farmacología , Animales , Forma del Núcleo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Inyecciones Intraarticulares , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Nitroprusiato/farmacología , Osteoartritis/patología , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Early-life air pollution exposure is associated with lung function in children and adolescents. However, whether the association of prenatal and early postnatal exposure to air pollution with lung function continues into adulthood remains unclear. OBJECTIVE: To investigate the associations of early exposure to air pollution with lung function at ~17.5â¯years in a non-western developed setting with more concentrated air pollutants. METHODS: We examined the associations of exposure to particular matter with an aerodynamic diameter of <10⯵m (PM10), nitrogen dioxides (NO2), nitric oxide (NO), sulfur dioxide (SO2) in standard deviations (SD)) at different early life stages with lung function (indicated by forced vital capacity (FVC), forced expiratory volume in 1â¯s (FEV1) and forced expiratory flow at 25%-75% of the pulmonary volume (FEF25%-75%)) in SD at ~17.5â¯years, personal history of wheezing and asthma in the population-representative Hong Kong Chinese birth cohort "Children of 1997"(nâ¯=â¯2942). RESULTS: Higher in utero and infancy and toddlerhood NO2 were associated with lower FEV1 (-0.022, 95% confidence interval (CI) -0.029 to -0.015 andâ¯-â¯0.026, 95% CI -0.033 to -0.019), FEV1/FVC (-0.035, 95% CI -0.050 to -0.021 and -0.052, 95% CI -0.066 to -0.038) and FEF25%-75% (-0.031, 95% CI -0.040 to -0.022 and -0.043, 95% CI -0.051 to -0.035). A similar association was observed for NO. Weak associations of NO2 and NO with FVC were observed (-0.011, 95% CI -0.018 to -0.003 and -0.010, 95% CI -0.020 to -0.001). NOx was associated with higher risk of wheezing (1.08, 95% CI 1.03 to 1.14) but not asthma (1.02, 95% CI 0.94 to 1.11). SO2 and PM10 were not clearly associated with lung function, wheezing or asthma. CONCLUSION: Our findings suggest that early exposure to air pollution from NO2 may have long-term effects on lung function, which could affect respiratory health throughout life.