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1.
Pharmaceutics ; 16(6)2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38931823

RESUMEN

Malaria poses a global threat to human health, with millions of cases and thousands of deaths each year, mainly affecting developing countries in tropical and subtropical regions. Malaria's causative agent is Plasmodium species, generally transmitted in the hematophagous act of female Anopheles sp. mosquitoes. The main approaches to fighting malaria are eliminating the parasite through drug treatments and preventing transmission with vector control. However, vector and parasite resistance to current strategies set a challenge. In response to the loss of drug efficacy and the environmental impact of pesticides, the focus shifted to the search for biocompatible products that could be antimalarial. Plant derivatives have a millennial application in traditional medicine, including the treatment of malaria, and show toxic effects towards the parasite and the mosquito, aside from being accessible and affordable. Its disadvantage lies in the type of administration because green chemical compounds rapidly degrade. The nanoformulation of these compounds can improve bioavailability, solubility, and efficacy. Thus, the nanotechnology-based development of plant products represents a relevant tool in the fight against malaria. We aim to review the effects of nanoparticles synthesized with plant extracts on Anopheles and Plasmodium while outlining the nanotechnology green synthesis and current malaria prevention strategies.

2.
J Leukoc Biol ; 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38727078

RESUMEN

Listeriosis, caused by Listeria monocytogenes (L.m.), poses a significant public health concern as one of the most severe foodborne diseases. The pathogenesis of L.m. involves critical steps such as phagosome rupture and escape upon internalization. Throughout infection, L.m. influences various host processes, including lipid metabolism pathways, yet the role of lipid droplets (LDs) remains unclear. Here, we reported a rapid, time-dependent increase in LD formation in macrophages induced by L.m. LD biogenesis was found to be dependent on L.m. viability and virulence genes, particularly on the activity of the pore-forming protein listeriolysin O (LLO). The prevention of LD formation by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) and cytosolic phospholipase A2 (cPLA2) significantly reduced intracellular bacterial survival, impaired prostaglandin E2 (PGE2) synthesis, and decreased IL-10 production. Additionally, inhibiting LD formation led to increased levels of TNF-α and IFN-ß. Collectively, our data suggest a role for LDs in promoting L.m. cell survival and evasion within macrophages.

3.
Mol Omics ; 20(1): 27-36, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-37751172

RESUMEN

Cancer is one of the deadliest diseases in humans and dogs. Nevertheless, most tumor types spread faster in canines, and early cancer detection methods are necessary to enhance animal survival. Here, cerumen (earwax) was tested as a source of potential biomarkers for cancer evaluation in dogs. Earwax samples from dogs were collected from tumor-bearing and clinically healthy dogs, followed by Headspace/Gas Chromatography-Mass Spectrometry (HS/GC-MS) analyses and multivariate statistical workflow. An evolutionary-based multivariate algorithm selected 18 out of 128 volatile metabolites as a potential cancer biomarker panel in dogs. The candidate biomarkers showed a full discrimination pattern between tumor-bearing dogs and cancer-free canines with high accuracy in the test dataset: an accuracy of 95.0% (75.1-99.9), and sensitivity and specificity of 100.0% and 92.9%, respectively. In summary, this work raises a new perspective on cancer diagnosis in dogs, being carried out painlessly and non-invasive, facilitating sample collection and periodic application in a veterinary routine.


Asunto(s)
Neoplasias , Compuestos Orgánicos Volátiles , Humanos , Perros , Animales , Cerumen/química , Cerumen/metabolismo , Compuestos Orgánicos Volátiles/análisis , Compuestos Orgánicos Volátiles/química , Compuestos Orgánicos Volátiles/metabolismo , Neoplasias/diagnóstico , Neoplasias/veterinaria , Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Cromatografía de Gases y Espectrometría de Masas/métodos
4.
Oxid Med Cell Longev ; 2022: 9966750, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36111166

RESUMEN

Plant preparations have been used to treat various diseases and discussed for centuries. Research has advanced to discover and identify the plant components with beneficial effects and reveal their underlying mechanisms. Flavonoids are phytoconstituents with anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial properties. Herein, we listed and contextualized various aspects of the protective effects of the flavonols quercetin, isoquercetin, kaempferol, and myricetin and the flavones luteolin, apigenin, 3',4'-dihydroxyflavone, baicalein, scutellarein, lucenin-2, vicenin-2, diosmetin, nobiletin, tangeretin, and 5-O-methyl-scutellarein. We presented their structural characteristics and subclasses, importance, occurrence, and food sources. The bioactive compounds present in our diet, such as fruits and vegetables, may affect the health and disease state. Therefore, we discussed the role of these compounds in inflammation, oxidative mechanisms, and bacterial metabolism; moreover, we discussed their synergism with antibiotics for better disease outcomes. Indiscriminate use of antibiotics allows the emergence of multidrug-resistant bacterial strains; thus, bioactive compounds may be used for adjuvant treatment of infectious diseases caused by resistant and opportunistic bacteria via direct and indirect mechanisms. We also focused on the reported mechanisms and intracellular targets of flavonols and flavones, which support their therapeutic role in inflammatory and infectious diseases.


Asunto(s)
Antiinfecciosos , Flavonas , Antibacterianos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Apigenina , Flavonas/farmacología , Flavonoides/farmacología , Flavonoles/farmacología , Quempferoles , Luteolina , Preparaciones de Plantas , Quercetina
5.
Int J Mol Sci ; 23(9)2022 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-35563317

RESUMEN

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, leaving the inflammation process without a proper resolution, leading to tissue damage and possibly sequelae. The central nervous system (CNS) is one of the first regions affected by the peripheral inflammation caused by sepsis, exposing the neurons to an environment of oxidative stress, triggering neuronal dysfunction and apoptosis. Sepsis-associated encephalopathy (SAE) is the most frequent sepsis-associated organ dysfunction, with symptoms such as deliriums, seizures, and coma, linked to increased mortality, morbidity, and cognitive disability. However, the current therapy does not avoid those patients' symptoms, evidencing the search for a more optimal approach. Herein we focus on microglia as a prominent therapeutic target due to its multiple functions maintaining CNS homeostasis and its polarizing capabilities, stimulating and resolving neuroinflammation depending on the stimuli. Microglia polarization is a target of multiple studies involving nerve cell preservation in diseases caused or aggravated by neuroinflammation, but in sepsis, its therapeutic potential is overlooked. We highlight the peroxisome proliferator-activated receptor gamma (PPARγ) neuroprotective properties, its role in microglia polarization and inflammation resolution, and the interaction with nuclear factor-κB (NF-κB) and mitogen-activated kinases (MAPK), making PPARγ a molecular target for sepsis-related studies to come.


Asunto(s)
Microglía , Sepsis , Humanos , Inflamación , Microglía/citología , Microglía/metabolismo , Insuficiencia Multiorgánica , PPAR gamma/uso terapéutico , Sepsis/metabolismo , Sepsis/terapia
6.
J Int Dev ; 34(4): 803-822, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35465459

RESUMEN

Workers' remittances declined sharply as the COVID-19 pandemic spread in the first half of 2020, rebounding in the second half. This paper analyses the impact of containment and economic support measures on remittances sent to Latin America during 2019-2020 using a gravity model estimated with the Poisson pseudo-maximum likelihood estimator (PPML). Results show that containment measures in receiving countries mainly explain the fall in remittance flows, whereas the effect of economic support measures is not robust. Among the traditional explanatory factors, the business cycle and the real exchange rate in receiving countries explain the subsequent recovery of remittances.

7.
Methods Mol Biol ; 2409: 245-255, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34709647

RESUMEN

Dengue is an infectious disease caused by Dengue Virus, mainly transmitted by Aedes aegypti mosquitoes. Severe dengue is a potentially fatal syndrome in consequence of overwhelmed inflammation, in which thrombocytopenia and increased vascular permeability are frequently observed. Several experimental evidences point to the participation of both microvesicles (MVs) and circulating lipoproteins in inflammatory amplification in dengue pathogenesis. On this regard, many protocols for isolating plasma MVs have shown lipoproteins as the main contaminant. This is a limitation to studies aiming at the functional characterization of MVs, since both MVs and lipoproteins can modulate inflammatory responses. Here, we describe a biphasic density-based gradient ultracentrifugation as a tool for concomitant isolation of MVs and lipoproteins without cross-contamination. Flow cytometry for MVs quantification and western blot for detection of apoB100 may be used to confirm the isolation and purity of the MVs.


Asunto(s)
Micropartículas Derivadas de Células , Animales , Dengue , Citometría de Flujo , Lipoproteínas
8.
PLoS One ; 16(2): e0246891, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33577592

RESUMEN

BACKGROUND: During pneumonia, normal alveolar areas coexist adjacently with consolidated areas, and high inspiratory efforts may predispose to lung damage. To date, no study has evaluated different degrees of effort during Biphasic positive airway pressure (BIVENT) on lung and diaphragm damage in experimental pneumonia, though largely used in clinical setting. We aimed to evaluate lung damage, genes associated with ventilator-induced lung injury (VILI) and diaphragmatic injury, and blood bacteria in pressure-support ventilation (PSV), BIVENT with low and high inspiratory efforts in experimental pneumonia. MATERIAL AND METHODS: Twenty-eight male Wistar rats (mean ± SD weight, 333±78g) were submitted Pseudomonas aeruginosa-induced pneumonia. After 24-h, animals were ventilated for 1h in: 1) PSV; 2) BIVENT with low (BIVENTLow-Effort); and 3) BIVENT with high inspiratory effort (BIVENTHigh-Effort). BIVENT was set at Phigh to achieve VT = 6 ml/kg and Plow at 5 cmH2O (n = 7/group). High- and low-effort conditions were obtained through anaesthetic infusion modulation based on neuromuscular drive (P0.1). Lung mechanics, histological damage score, blood bacteria, and expression of genes related to VILI in lung tissue, and inflammation in diaphragm tissue. RESULTS: Transpulmonary peak pressure and histological damage score were higher in BIVENTHigh-Effort compared to BIVENTLow-Effort and PSV [16.1 ± 1.9cmH2O vs 12.8 ± 1.5cmH2O and 12.5 ± 1.6cmH2O, p = 0.015, and p = 0.010; median (interquartile range) 11 (9-13) vs 7 (6-9) and 7 (6-9), p = 0.021, and p = 0.029, respectively]. BIVENTHigh-Effort increased interleukin-6 expression compared to BIVENTLow-Effort (p = 0.035) as well as expressions of cytokine-induced neutrophil chemoattractant-1, amphiregulin, and type III procollagen compared to PSV (p = 0.001, p = 0.001, p = 0.004, respectively). Tumour necrosis factor-α expression in diaphragm tissue and blood bacteria were higher in BIVENTHigh-Effort than BIVENTLow-Effort (p = 0.002, p = 0.009, respectively). CONCLUSION: BIVENT requires careful control of inspiratory effort to avoid lung and diaphragm damage, as well as blood bacteria. P0.1 might be considered a helpful parameter to optimize inspiratory effort.


Asunto(s)
Presión de las Vías Aéreas Positiva Contínua/efectos adversos , Pulmón/patología , Neumonía Bacteriana/terapia , Infecciones por Pseudomonas/terapia , Pseudomonas aeruginosa/aislamiento & purificación , Lesión Pulmonar Inducida por Ventilación Mecánica/etiología , Animales , Diafragma/patología , Modelos Animales de Enfermedad , Masculino , Neumonía Bacteriana/patología , Infecciones por Pseudomonas/patología , Ratas Wistar , Volumen de Ventilación Pulmonar , Lesión Pulmonar Inducida por Ventilación Mecánica/patología
9.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33467433

RESUMEN

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate the expression of genes related to lipid and glucose metabolism and inflammation. There are three members: PPARα, PPARß or PPARγ. PPARγ have several ligands. The natural agonists are omega 9, curcumin, eicosanoids and others. Among the synthetic ligands, we highlight the thiazolidinediones, clinically used as an antidiabetic. Many of these studies involve natural or synthetic products in different pathologies. The mechanisms that regulate PPARγ involve post-translational modifications, such as phosphorylation, sumoylation and ubiquitination, among others. It is known that anti-inflammatory mechanisms involve the inhibition of other transcription factors, such as nuclear factor kB(NFκB), signal transducer and activator of transcription (STAT) or activator protein 1 (AP-1), or intracellular signaling proteins such as mitogen-activated protein (MAP) kinases. PPARγ transrepresses other transcription factors and consequently inhibits gene expression of inflammatory mediators, known as biomarkers for morbidity and mortality, leading to control of the exacerbated inflammation that occurs, for instance, in lung injury/acute respiratory distress. Many studies have shown the therapeutic potentials of PPARγ on pulmonary diseases. Herein, we describe activities of the PPARγ as a modulator of inflammation, focusing on lung injury and including definition and mechanisms of regulation, biological effects and molecular targets, and its role in lung diseases caused by inflammatory stimuli, bacteria and virus, and molecular-based therapy.


Asunto(s)
Inflamación/metabolismo , Enfermedades Pulmonares/metabolismo , PPAR gamma/metabolismo , Transducción de Señal/fisiología , Animales , Curcumina/metabolismo , Curcumina/farmacología , Eicosanoides/metabolismo , Eicosanoides/farmacología , Humanos , Ligandos , Enfermedades Pulmonares/tratamiento farmacológico , PPAR gamma/agonistas , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
10.
Crit Care Med ; 49(1): 140-150, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33060501

RESUMEN

OBJECTIVES: We hypothesized that a time-controlled adaptive ventilation strategy would open and stabilize alveoli by controlling inspiratory and expiratory duration. Time-controlled adaptive ventilation was compared with volume-controlled ventilation at the same levels of mean airway pressure and positive end-release pressure (time-controlled adaptive ventilation)/positive end-expiratory pressure (volume-controlled ventilation) in a Pseudomonas aeruginosa-induced pneumonia model. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Twenty-one Wistar rats. INTERVENTIONS: Twenty-four hours after pneumonia induction, Wistar rats (n = 7) were ventilated with time-controlled adaptive ventilation (tidal volume = 8 mL/kg, airway pressure release ventilation for a Thigh = 0.75-0.85 s, release pressure (Plow) set at 0 cm H2O, and generating a positive end-release pressure = 1.6 cm H2O applied for Tlow = 0.11-0.14 s). The expiratory flow was terminated at 75% of the expiratory flow peak. An additional 14 animals were ventilated using volume-controlled ventilation, maintaining similar time-controlled adaptive ventilation levels of positive end-release pressure (positive end-expiratory pressure=1.6 cm H2O) and mean airway pressure = 10 cm H2O. Additional nonventilated animals (n = 7) were used for analysis of molecular biology markers. MEASUREMENTS AND MAIN RESULTS: After 1 hour of mechanical ventilation, the heterogeneity score, the expression of pro-inflammatory biomarkers interleukin-6 and cytokine-induced neutrophil chemoattractant-1 in lung tissue were significantly lower in the time-controlled adaptive ventilation than volume-controlled ventilation with similar mean airway pressure groups (p = 0.008, p = 0.011, and p = 0.011, respectively). Epithelial cell integrity, measured by E-cadherin tissue expression, was higher in time-controlled adaptive ventilation than volume-controlled ventilation with similar mean airway pressure (p = 0.004). Time-controlled adaptive ventilation animals had bacteremia counts lower than volume-controlled ventilation with similar mean airway pressure animals, while time-controlled adaptive ventilation and volume-controlled ventilation with similar positive end-release pressure animals had similar colony-forming unit counts. In addition, lung edema and cytokine-induced neutrophil chemoattractant-1 gene expression were more reduced in time-controlled adaptive ventilation than volume-controlled ventilation with similar positive end-release pressure groups. CONCLUSIONS: In the model of pneumonia used herein, at the same tidal volume and mean airway pressure, time-controlled adaptive ventilation, compared with volume-controlled ventilation, was associated with less lung damage and bacteremia and reduced gene expression of mediators associated with inflammation.


Asunto(s)
Neumonía Bacteriana/terapia , Respiración Artificial/métodos , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Resultado del Tratamiento
11.
Int J Mol Sci ; 21(12)2020 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-32599864

RESUMEN

The Mediterranean diet (MedDiet) consists of consumption of vegetables and healthy oils and have beneficial effects on metabolic and inflammatory diseases. Our goal here is to discuss the role of fatty acid content in MedDiet, mostly omega-3, omega-6, and omega-9 on malaria. Malaria affects millions of people around the globe. The parasite Plasmodium causes the disease. The metabolic and inflammatory alterations in the severe forms have damaging consequences to the host. The lipid content in the MedDiet holds anti-inflammatory and pro-resolutive features in the host and have detrimental effects on the Plasmodium. The lipids from the diet impact the balance of pro- and anti-inflammation, thus, lipids intake from the diet is critical to parasite elimination and host tissue damage caused by an immune response. Herein, we go into the cellular and molecular mechanisms and targets of the MedDiet fatty acids in the host and the parasite, reviewing potential benefits of the MedDiet, on inflammation, malaria infection progression, and clinical outcome.


Asunto(s)
Antiinflamatorios/administración & dosificación , Dieta Mediterránea , Inflamación/dietoterapia , Lípidos/análisis , Malaria Falciparum/prevención & control , Plasmodium falciparum/aislamiento & purificación , Humanos , Inflamación/patología , Malaria Falciparum/parasitología
12.
Respir Res ; 17(1): 158, 2016 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-27887604

RESUMEN

BACKGROUND: Variable ventilation has been shown to improve pulmonary function and reduce lung damage in different models of acute respiratory distress syndrome. Nevertheless, variable ventilation has not been tested during pneumonia. Theoretically, periodic increases in tidal volume (VT) and airway pressures might worsen the impairment of alveolar barrier function usually seen in pneumonia and could increase bacterial translocation into the bloodstream. We investigated the impact of variable ventilation on lung function and histologic damage, as well as markers of lung inflammation, epithelial and endothelial cell damage, and alveolar stress, and bacterial translocation in experimental pneumonia. METHODS: Thirty-two Wistar rats were randomly assigned to receive intratracheal of Pseudomonas aeruginosa (PA) or saline (SAL) (n = 16/group). After 24-h, animals were anesthetized and ventilated for 2 h with either conventional volume-controlled (VCV) or variable volume-controlled ventilation (VV), with mean VT = 6 mL/kg, PEEP = 5cmH2O, and FiO2 = 0.4. During VV, tidal volume varied randomly with a coefficient of variation of 30% and a Gaussian distribution. Additional animals assigned to receive either PA or SAL (n = 8/group) were not ventilated (NV) to serve as controls. RESULTS: In both SAL and PA, VV improved oxygenation and lung elastance compared to VCV. In SAL, VV decreased interleukin (IL)-6 expression compared to VCV (median [interquartile range]: 1.3 [0.3-2.3] vs. 5.3 [3.6-7.0]; p = 0.02) and increased surfactant protein-D expression compared to NV (2.5 [1.9-3.5] vs. 1.2 [0.8-1.2]; p = 0.0005). In PA, compared to VCV, VV reduced perivascular edema (2.5 [2.0-3.75] vs. 6.0 [4.5-6.0]; p < 0.0001), septum neutrophils (2.0 [1.0-4.0] vs. 5.0 [3.3-6.0]; p = 0.0008), necrotizing vasculitis (3.0 [2.0-5.5] vs. 6.0 [6.0-6.0]; p = 0.0003), and ultrastructural lung damage scores (16 [14-17] vs. 24 [14-27], p < 0.0001). Blood colony-forming-unit (CFU) counts were comparable (7 [0-28] vs. 6 [0-26], p = 0.77). Compared to NV, VCV, but not VV, increased expression amphiregulin, IL-6, and cytokine-induced neutrophil chemoattractant (CINC)-1 (2.1 [1.6-2.5] vs. 0.9 [0.7-1.2], p = 0.025; 12.3 [7.9-22.0] vs. 0.8 [0.6-1.9], p = 0.006; and 4.4 [2.9-5.6] vs. 0.9 [0.8-1.4], p = 0.003, respectively). Angiopoietin-2 expression was lower in VV compared to NV animals (0.5 [0.3-0.8] vs. 1.3 [1.0-1.5], p = 0.01). CONCLUSION: In this rat model of pneumonia, VV improved pulmonary function and reduced lung damage as compared to VCV, without increasing bacterial translocation.


Asunto(s)
Traslocación Bacteriana , Pulmón/fisiopatología , Neumonía Bacteriana/terapia , Infecciones por Pseudomonas/terapia , Respiración Artificial/métodos , Algoritmos , Animales , Células Endoteliales/patología , Células Epiteliales/patología , Inflamación/patología , Pulmón/ultraestructura , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/fisiopatología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/fisiopatología , Alveolos Pulmonares/patología , Ratas , Ratas Wistar , Pruebas de Función Respiratoria , Volumen de Ventilación Pulmonar
13.
Sci Rep ; 6: 34666, 2016 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-27698491

RESUMEN

The endotoxin lipopolysaccharide (LPS) promotes sepsis, but bacterial peptides also promote inflammation leading to sepsis. We found, intraperitoneal administration of live or heat inactivated E. coli JE5505 lacking the abundant outer membrane protein, Braun lipoprotein (BLP), was less toxic than E. coli DH5α possessing BLP in Swiss albino mice. Injection of BLP free of LPS purified from E. coli DH5α induced massive infiltration of leukocytes in lungs and liver. BLP activated human polymorphonuclear cells (PMNs) ex vivo to adhere to denatured collagen in serum and polymyxin B independent fashion, a property distinct from LPS. Both LPS and BLP stimulated the synthesis of platelet activating factor (PAF), a potent lipid mediator, in human PMNs. In mouse macrophage cell line, RAW264.7, while both BLP and LPS similarly upregulated TNF-α and IL-1ß mRNA; BLP was more potent in inducing cyclooxygenase-2 (COX-2) mRNA and protein expression. Peritoneal macrophages from TLR2-/- mice significantly reduced the production of TNF-α in response to BLP in contrast to macrophages from wild type mice. We conclude, BLP acting through TLR2, is a potent inducer of inflammation with a response profile both common and distinct from LPS. Hence, BLP mediated pathway may also be considered as an effective target against sepsis.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa/toxicidad , Endotoxemia/genética , Proteínas de Escherichia coli/toxicidad , Lipopolisacáridos/toxicidad , Lipoproteínas/toxicidad , Animales , Adhesión Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Endotoxemia/inducido químicamente , Endotoxemia/inmunología , Endotoxemia/mortalidad , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/patología , Peroxidasa/genética , Peroxidasa/inmunología , Factor de Activación Plaquetaria/genética , Factor de Activación Plaquetaria/inmunología , Cultivo Primario de Células , Células RAW 264.7 , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
14.
Shock ; 45(4): 393-403, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26618986

RESUMEN

Dysregulation of the inflammatory response against infection contributes to mortality in sepsis. Inflammation provides critical host defense, but it can cause tissue damage, multiple organ failure, and death. Because the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) exhibits therapeutic potential, we characterized the role of PPARγ in sepsis. We analyzed severity of clinical signs, survival rates, cytokine production, leukocyte influx, and bacterial clearance in a cecal ligation and puncture (CLP) model of sepsis in Swiss mice. The PPARγ agonist rosiglitazone treatment improved clinical status and mortality, while increasing IL-10 production and decreasing TNF-α and IL-6 levels, and peritoneal neutrophil accumulation 24 h after CLP. We noted increased bacterial killing in rosiglitazone treated mice, correlated with increased generation of reactive oxygen species. Polymorphonuclear leukocytes (PMN) incubated with LPS or Escherichia coli and rosiglitazone increased peritoneal neutrophil extracellular trap (NET)-mediated bacterial killing, an effect reversed by the PPARγ antagonist (GW 9662) treatment. Rosiglitazone also enhanced the release of histones by PMN, a surrogate marker of NET formation, effect abolished by GW 9662. Rosiglitazone modulated the inflammatory response and increased bacterial clearance through PPARγ activation and NET formation, combining immunomodulatory and host-dependent anti-bacterial effects and, therefore, warrants further study as a potential therapeutic agent in sepsis.


Asunto(s)
Escherichia coli/inmunología , Trampas Extracelulares/inmunología , Neutrófilos/inmunología , PPAR gamma/agonistas , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Tiazolidinedionas/farmacología , Anilidas/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , PPAR gamma/inmunología , Rosiglitazona , Sepsis/inmunología , Sepsis/microbiología , Sepsis/patología , Transducción de Señal/inmunología
15.
J Endocrinol ; 225(3): 205-17, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26021821

RESUMEN

Glucagon is a hyperglycemic pancreatic hormone that has been shown to provide a beneficial effect against asthmatic bronchospasm. We investigated the role of this hormone on airway smooth muscle contraction and lung inflammation using both in vitro and in vivo approaches. The action of glucagon on mouse cholinergic tracheal contraction was studied in a conventional organ bath system, and its effect on airway obstruction was also investigated using the whole-body pletysmographic technique in mice. We also tested the effect of glucagon on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and inflammation. The expression of glucagon receptor (GcgR), CREB, phospho-CREB, nitric oxide synthase (NOS)-3, pNOS-3 and cyclooxygenase (COX)-1 was evaluated by western blot, while prostaglandin E2 (PGE2) and tumour necrosis factor-α were quantified by enzyme-linked immunoassay and ELISA respectively. Glucagon partially inhibited carbachol-induced tracheal contraction in a mechanism clearly sensitive to des-His1-[Glu9]-glucagon amide, a GcgR antagonist. Remarkably, GcgR was more expressed in the lung and trachea with intact epithelium than in the epithelium-denuded trachea. In addition, the glucagon-mediated impairment of carbachol-induced contraction was prevented by either removing epithelial cells or blocking NOS (L-NAME), COX (indomethacin) or COX-1 (SC-560). In contrast, inhibitors of either heme oxygenase or COX-2 were inactive. Intranasal instillation of glucagon inhibited methacholine-induced airway obstruction by a mechanism sensitive to pretreatment with L-NAME, indomethacin and SC-560. Glucagon induced CREB and NOS-3 phosphorylation and increased PGE2 levels in the lung tissue without altering COX-1 expression. Glucagon also inhibited LPS-induced AHR and bronchoalveolar inflammation. These findings suggest that glucagon possesses airway-relaxing properties that are mediated by epithelium-NOS-3-NO- and COX-1-PGE2-dependent mechanisms.


Asunto(s)
Broncodilatadores/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Dinoprostona/metabolismo , Glucagón/farmacología , Músculo Liso/efectos de los fármacos , Óxido Nítrico/metabolismo , Tráquea/efectos de los fármacos , Administración Intranasal , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Broncodilatadores/administración & dosificación , Broncodilatadores/uso terapéutico , Neuronas Colinérgicas/inmunología , Neuronas Colinérgicas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Glucagón/administración & dosificación , Glucagón/uso terapéutico , Técnicas In Vitro , Masculino , Ratones Endogámicos A , Relajación Muscular/efectos de los fármacos , Músculo Liso/inmunología , Músculo Liso/inervación , Músculo Liso/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Tráquea/inmunología , Tráquea/inervación , Tráquea/metabolismo
16.
PPAR Res ; 2012: 383829, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22851964

RESUMEN

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control. Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγ during mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγ expression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγ expression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγ expression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγ expression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγ enhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγ in favoring the establishment of chronic infection. Collectively, PPARγ is emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

17.
Eur J Pharmacol ; 691(1-3): 261-7, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22713549

RESUMEN

Mast cell function and survival have been shown to be down-regulated under diabetic conditions. This study investigates the role of the peroxisome proliferator-activated receptor (PPAR)-γ in reducing mast cell number and reactivity in diabetic rats. The effect of rosiglitazone on mast cell apoptosis was also evaluated. Diabetes was induced by intravenous injection of alloxan into fasted rats and PPARγ agonist rosiglitazone and/or specific antagonist 2-chloro-5-nitrobenzanilide (GW9662) were administered 3 day after diabetes induction, once daily for 18 consecutive days. Mast cell apoptosis and plasma corticosterone levels were evaluated by TUNEL and radioimmunoassay, respectively. Treatment with rosiglitazone restored mast cell numbers in the pleural cavity and mesenteric tissue of diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced reduction of histamine release by mast cells, as measured by fluorescence, following activation with the antigen in vitro. Increased apoptosis in mast cells from diabetic rats were inhibited by rosiglitazone. Moreover, we noted that the increase in plasma corticosterone levels in diabetic rats was inhibited by rosiglitazone. In addition, GW9662 blocked the ability of rosiglitazone to restore baseline numbers of mast cells and plasma corticosterone in diabetic rats. In conclusion, our findings showed that rosiglitazone restored the number and reactivity of mast cells in diabetic rats, accompanied with a suppression of apoptosis, in parallel with impairment of diabetes hypercorticolism, indicating that PPARγ has an important role in these phenomena.


Asunto(s)
Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/metabolismo , Glucocorticoides/metabolismo , Mastocitos/citología , Mastocitos/efectos de los fármacos , PPAR gamma/metabolismo , Animales , Apoptosis/efectos de los fármacos , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Síndrome de Cushing/complicaciones , Síndrome de Cushing/tratamiento farmacológico , Síndrome de Cushing/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratas , Ratas Wistar , Rosiglitazona , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico
18.
Epigenetics ; 7(5): 440-6, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22419129

RESUMEN

Alterations to DNA methylation have been attributed to in vitro culture and may affect normal embryo development. We chose to analyze DNA methylation reprogramming in the rabbit which, of the species with delayed transcriptional activation of the embryonic genome, allows easy comparisons between in vivo-developed (IVD) and in vitro-cultured (IVC) embryos. In this species, variations in DNA methylation had not previously been quantified, even in IVD embryos. IVD and IVC embryos were recovered at the 2, 4, 8 and 16-cell, morula and blastocyst stages. Immunostaining for 5-methyl-cytidine and normalization of the quantity of methylated DNA vs. the total DNA content were then performed. Our quantitative results evidenced DNA demethylation during pre-implantation development in both IVD and IVC embryos, but with different kinetics. Demethylation occurred earlier in vitro than in vivo between the 2 and 8-cell stages in IVC embryos, reaching its lowest level, while it only started at the 4-cell stage and ended at the 16-cell stage in IVD embryos. We also showed that an absence of serum from the culture medium significantly altered the degree of DNA demethylation. Finally, at the blastocyst stage, ICM was more methylated than the trophectoderm in all cases. Despite a morphological delay observed in in vitro cultured blastocysts, the difference in DNA methylation between ICM and trophectoderm cells appeared at the same time post-fertilization in IVD and IVC embryos, which may reflect another difference in the dynamics of DNA methylation during blastocyst formation. Our data thus clearly establish an effect of embryonic environment on DNA methylation reprogramming during pre-implantation development in a non-rodent species.


Asunto(s)
Blastocisto/citología , Metilación de ADN , Embrión de Mamíferos/metabolismo , Animales , Blastocisto/metabolismo , Medios de Cultivo/metabolismo , Citidina/análogos & derivados , Citidina/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Ectodermo/citología , Ectodermo/metabolismo , Embrión de Mamíferos/citología , Embrión de Mamíferos/embriología , Desarrollo Embrionario , Femenino , Inmunohistoquímica/métodos , Técnicas In Vitro , Conejos , Especificidad de la Especie , Factores de Tiempo , Activación Transcripcional
19.
J Infect Dis ; 204(6): 951-61, 2011 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-21849292

RESUMEN

Lipid bodies (lipid droplets) are lipid-rich organelles with functions in cell metabolism and signaling. Here, we investigate the mechanisms of Trypanosoma cruzi-induced lipid body formation and their contributions to host-parasite interplay. We demonstrate that T. cruzi-induced lipid body formation in macrophages occurs in a Toll-like receptor 2-dependent mechanism and is potentiated by apoptotic cell uptake. Lipid body biogenesis and prostaglandin E2 (PGE2) production triggered by apoptotic cell uptake was largely dependent of α(v)ß3 and transforming growth factor-ß signaling. T. cruzi-induced lipid bodies act as sites of increased PGE synthesis. Inhibition of lipid body biogenesis by the fatty acid synthase inhibitor C75 reversed the effects of apoptotic cells on lipid body formation, eicosanoid synthesis, and parasite replication. Our findings indicate that lipid bodies are highly regulated organelles during T. cruzi infection with roles in lipid mediator generation by macrophages and are potentially involved in T. cruzi-triggered escape mechanisms.


Asunto(s)
Enfermedad de Chagas/patología , Dinoprostona/metabolismo , Interacciones Huésped-Parásitos , Metabolismo de los Lípidos , Macrófagos/metabolismo , Macrófagos/parasitología , Trypanosoma cruzi/patogenicidad , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Receptor Toll-Like 2/metabolismo , Trypanosoma cruzi/crecimiento & desarrollo
20.
Epigenetics ; 6(8): 987-93, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21725201

RESUMEN

The reprogramming of DNA methylation in early embryos has been considered to be essential for the reprogramming of differentiated parental genomes to totipotency, the transcription of embryonic genome activation (EGA) and subsequent development. However, its degree appears to differ as a function of species and it may be altered by the in vitro environment. While the rabbit is a pertinent model for species with a delayed EGA because both in vivo and in vitro developed embryos are easily available, the status of DNA methylation levels in both parental genomes after fertilization remains controversial. In order to generate precise data on the DNA methylation status in rabbit zygotes, we first of all defined five pronuclear (PN) stages during the first cell cycle and then classified in vivo and in vitro developed rabbit zygotes according to these PN stages. Using this classification we precisely quantified both methylated DNA and the total DNA content during the one cell stage. The quantification of methylated DNA, normalized for the total DNA content, showed that both pronuclei displayed distinct patterns of DNA methylation reprogramming. In the maternal pronucleus (MP) the methylation level remained constant throughout the one cell stage, thanks to maintenance methylation during the S phase. Conversely, in the paternal pronucleus (PP) partial demethylation occurred before replication, probably as a result of active DNA demethylation, while maintenance methylation subsequently occurred during the S phase. Interestingly, we showed that PP DNA methylation reprogramming was partially altered by the in vitro environment. Taken together, our approach evidenced that rabbit is one of the species displaying partial DNA demethylation in the PP, and for the first time demonstrated maintenance methylation activity in both pronuclei during the first S phase.


Asunto(s)
Núcleo Celular/genética , Metilación de ADN/genética , Desarrollo Embrionario/genética , Fertilización/genética , Cigoto/metabolismo , Animales , Núcleo Celular/metabolismo , Epigénesis Genética , Femenino , Genoma , Histonas/metabolismo , Mitosis , Conejos , Fase S/genética , Cigoto/crecimiento & desarrollo
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