RESUMEN
Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4-expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders.
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Colon/fisiología , Motilidad Gastrointestinal , Macrófagos/metabolismo , Miocitos del Músculo Liso/metabolismo , Transducción de Señal , Canales Catiónicos TRPV/metabolismo , Animales , Receptor 1 de Quimiocinas CX3C/metabolismo , Colon/fisiopatología , Ciclooxigenasa 1/deficiencia , Ciclooxigenasa 1/metabolismo , Dinoprostona/análisis , Dinoprostona/metabolismo , Femenino , Mucosa Gástrica/citología , Expresión Génica , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Contracción Muscular , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/deficiencia , Canales Catiónicos TRPV/genéticaRESUMEN
Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.
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Lesión Renal Aguda , Fenotipo , Humanos , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/etiología , Masculino , Persona de Mediana Edad , Metabolómica/métodos , Femenino , Trasplante de Riñón/efectos adversos , Adulto , Citometría de Imagen/métodos , Riñón/patología , Riñón/metabolismo , Fosfolipasas A2/metabolismo , Ácido Araquidónico/metabolismo , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Transcriptoma , Dinoprostona/metabolismo , Dinoprostona/análisis , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Células Epiteliales/metabolismo , Células Epiteliales/patología , Biopsia , MultiómicaRESUMEN
INTRODUCTION: Dry eye disease (DED) is a multifactor-induced disease accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Traditional anti-inflammation agent corticosteroids applied in DED treatment could result in high intraocular pressure, especially in long-term treatment. Therefore, we explored a nano drug that aimed to block the formation pathway of DED which had anti-inflammatory, sustained release, and good biocompatibility characteristics in this study. METHODS: We prepared a novel nanomedicine (Tet-ATS@PLGA) by the thin film dispersion-hydration ultrasonic method and detected its nanostructure, particle size, and zeta potential. Flow cytometry was used to detect the cell survival rate of each group after 24 h of drug treatment on inflammed Statens Seruminstitut Rabbit Corneal (SIRC) cells. Observed and recorded corneal epithelial staining, tear film rupture time, and Schirmer test to detect tear secretion on the ocular surface of rabbits. The corneal epithelial thickness, morphology, and number of bulbar conjunctival goblet cells were recorded by H&E staining. Finally, we detected the expression of VEGF, IL-1ß, PGE2, and TNF-α by cellular immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). RESULTS: The encapsulation efficiency and drug loading of Tet-ATS@PLGA were 79.85% and 32.47%, respectively. At eye surface temperature, Tet can easily release from Tet-ATS@PLGA while that it was difficult to release at storage temperature and room temperature. After 2 weeks medication, Tet-ATS@PLGA can effectively improve the tear film rupture time and tear secretion time in a DED model (p <0.05). Compared with the normal group (62.34 ± 4.86 mm), the thickness of corneal epithelium in ATS (29.47 ± 3.21 mm), Tet-ATS (46.23 ± 2.87 mm), and Tet-ATS@PLGA (55.76 ± 3.95 mm) gradually increased. Furthermore, the flow cytometry indicated that Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory SIRC cells, and the cellular immunofluorescence and ELISA experiments showed that the expression intensity of inflammatory factors such as VEGF, IL-1ß, PGE2, and TNF-α decreased in this process. Interestingly, Tet also had the effect of reducing intraocular pressure. CONCLUSION: Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory corneal epithelial cells, thus inhibiting the expression of inflammatory factors to block the formation of DED and improve the secretion of tear on the ocular surface.
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Síndromes de Ojo Seco , Nanopartículas , Animales , Conejos , Ácido Poliglicólico/análisis , Ácido Poliglicólico/metabolismo , Ácido Poliglicólico/uso terapéutico , Factor de Necrosis Tumoral alfa , Dinoprostona/análisis , Dinoprostona/metabolismo , Dinoprostona/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Síndromes de Ojo Seco/diagnóstico , Lágrimas/metabolismo , Córnea/metabolismo , Antiinflamatorios/uso terapéutico , Nanopartículas/químicaRESUMEN
BACKGROUND: The aim of this study was to investigate the effects of exposure to continuous (CH) and intermittent (IH) hypoxia on biomechanical properties of the mandible and periodontal tissue of animals submitted to experimental periodontitis (EP) when applying loads in a hypoxic environment. METHODS: Adult female Wistar rats were exposed during 90 days to IH or CH (simulated high altitude of 4200 m above sea level). Fourteen days prior to the euthanasia, EP was induced to half of the animals of each group. RESULTS: Only in the rats with EP, IH decreased the maximum capacity of the mandible to withstand load and the limit of elastic load. Indicators of intrinsic properties of the bone material were significantly reduced by both types of hypoxia in rats with EP. Hypoxia enhanced the alveolar bone loss induced by EP in the buccal side of the mandible, without showing additional effects in lingual or interradicular bone. Hypoxia increased prostaglandin E2 content in gingival tissue of healthy animals and further elevated the E2 levels increased by EP. CONCLUSIONS: When periodontitis is present, hypoxic stress induces a decrease in mineral properties that ultimately affects the ability of the mandible to resist load, mainly during intermittent exposure to hypoxia. These effects on bone may be related to the higher levels of prostaglandin E2 reached in the surrounding gingival tissue. The findings of this study may stimulate strategies to prevent unwanted effects of hypoxia on periodontal tissues.
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Hipoxia/complicaciones , Mandíbula/fisiopatología , Periodontitis/complicaciones , Pérdida de Hueso Alveolar/etiología , Animales , Fenómenos Biomecánicos , Dinoprostona/análisis , Femenino , Encía/química , Hipoxia/fisiopatología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Periodontitis/fisiopatología , Periodoncio/fisiopatología , Ratas , Ratas Wistar , Soporte de PesoRESUMEN
The idea of the local drug delivery system is getting popular nowadays to treat gingivitis and periodontitis. The method of delivering the drug locally is quite easy and requires minimal intervention. This delivery system not only treats the periodontal diseases effectively but also prevents the side effects linked with the use of the drugs which are used orally for longer periods to cure these diseases. Chlorhexidine (CHX) is being widely used to treat these conditions because of its broad spectrum anti-bacterial effect and is found to be more effective in lowering plaque formation. The aim of this study was to appraise the effect of the local drug delivery system by using 1% CHX gel in patients with periodontal diseases. 1% CHX gel was prepared and its physicochemical characteristics were then assessed. Clinical parameters and inflammatory salivary biomarkers were evaluated in two groups of patients. Group I: standard treatment group. Group II: gel treatment group. These parameters were evaluated before treatment and after 4 weeks of treatment. 1% CHX gel was highly effective in reducing gingivitis and periodontitis by using the local drug delivery system which allowed the drug to retain into the periodontal pocket for prolong period of time.
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Antiinfecciosos Locales/administración & dosificación , Clorhexidina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Antisépticos Bucales/administración & dosificación , Enfermedades Periodontales/tratamiento farmacológico , Dinoprostona/análisis , Geles , Gingivitis/tratamiento farmacológico , Gingivitis/metabolismo , Humanos , Enfermedades Periodontales/metabolismo , Periodontitis/tratamiento farmacológico , Periodontitis/metabolismo , Saliva/química , Saliva/efectos de los fármacos , Saliva/metabolismo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is becoming a major public health problem worldwide. The study aimed to evaluate the concentration of eicosanoids in serum and liver tissue during steatosis progression and to assess whether eicosanoid change scores may predict liver tissue remodeling. Thirty six eight-week-old male Sprague Dawley rats were enrolled and sacrificed at different stages of NAFLD. Eicosanoid concentrations, namely lipoxin A4, hydroxyeicosatetraenoic acids (HETE), hydroxyloctadecadienoic acids (HODE), protectin DX, Maresine1, leucotriene B4, prostaglandin E2, and resolvin D1 measurement in serum and liver tissue with Agilent Technologies 1260 liquid chromatography were evaluated. For the liver and serum concentrations of 9-HODE and 13-HODE, the correlations were found to be strong and positive (r > 0.7, p < 0.05). Along with NAFLD progression, HODE concentration significantly increased, and change scores were more abundant in the liver. The moderate positive correlation between liver and serum (r = 0.52, p < 0.05) was also observed for resolvin E1. The eicosanoid concentration decreased during NAFLD progression, but mostly in serum. There were significant correlations between HETE concentrations in liver and serum, but their associations were relatively low and changes the most in liver tissue. Eicosanoids profile, predominantly 9-HODE and 13-HODE, may serve as a potential biomarker for NAFLD development.
Asunto(s)
Eicosanoides/sangre , Eicosanoides/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Biomarcadores/análisis , Biomarcadores/sangre , Biomarcadores/metabolismo , Cromatografía Liquida , Dinoprostona/análisis , Dinoprostona/sangre , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/sangre , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/análisis , Ácido Eicosapentaenoico/sangre , Ácido Eicosapentaenoico/metabolismo , Ácidos Hidroxieicosatetraenoicos/análisis , Ácidos Hidroxieicosatetraenoicos/sangre , Ácidos Hidroxieicosatetraenoicos/metabolismo , Ácidos Linoleicos/análisis , Ácidos Linoleicos/sangre , Ácidos Linoleicos/metabolismo , Lipoxinas/análisis , Lipoxinas/sangre , Lipoxinas/metabolismo , Hígado/patología , Masculino , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) intervene in the COX (cyclooxygenase) pathways which generate two important inflammation mediators, prostaglandins (PGs) and leukotriene (LTs). Contradictory claims regarding the effect of NSAIDs in asthmatic patients continues to be an issue. The present study investigated the effects of COX inhibitors on the responsiveness of the tracheal tract and on the levels of LTC4 and PGE2 in cells of the bronchoalveolar lavage fluid in an allergic guinea pig model.Materials and Methods: Adult male Dunkin-Hartley guinea pigs (250 - 300 g) were divided into seven groups of six animals each. Four COX inhibitors, aspirin (200 mg/kg and 20 mg/kg), indomethacin (10 mg/kg), ketoprofen (10 mg/kg), and celecoxib (25 mg/kg), were given orally on day 17 to allergy induced guinea pigs at 0, 12, and 24 h before ovalbumin challenge on day 18. PGF2 and LT4 were measured in the bronchoalveolar lavage fluid as well as inflammatory cell count and total protein. Tracheal responsiveness to acetylcholine (Ach) and histamine (His) also was evaluated.Results: An augment in the response of the trachea to Ach and His, as well as overt allergenic signs including short breath, wheezing and sneezing, was observed. The most significant increase in tracheal hyper-responsiveness was observed in the ketoprofen-treated group with similar but less pronounced changes observed in the indomethacin-treated group. Although some variables increased with the aspirin and celecoxib treatments, overall the tracheal sensitivity was reduced. Inflammatory cells including eosinophils and neutrophils corresponded to the changes observed for each treatment group.Conclusion: Ketoprofen and indomethacin increased the tracheal sensibility to Ach and His; therefore, their administration is not recommended in patients susceptible to allergy.
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Acetilcolina/farmacología , Inhibidores de la Ciclooxigenasa/efectos adversos , Dinoprostona/análisis , Histamina/farmacología , Hipersensibilidad/inmunología , Leucotrieno C4/análisis , Tráquea/efectos de los fármacos , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Modelos Animales de Enfermedad , Cobayas , Hipersensibilidad/tratamiento farmacológico , Masculino , Ovalbúmina/inmunología , Tráquea/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs) are involved in several inflammatory processes including obesity-related vascular diseases and graft failure of coronary artery (CA) bypass grafts [internal mammary artery (IMA), saphenous vein (SV)]. In these inflammatory conditions, the release of prostaglandin E2 (PGE2) is increased via the activity of inducible microsomal PGE synthase-1 (mPGES-1). Our aim was to investigate whether MMPs and their endogenous inhibitor (TIMPs) may be regulated by PGE2 under inflammatory conditions in human vasculature and perivascular adipose tissue (PVAT), as well as in plasma of obese patients. METHODS: MMP-1,-2 and TIMP-1,-2 densities were measured in human plasma (n = 68) as well as in supernatants of human vascular wall (IMA n = 16, SV n = 14, CA n = 13) and their PVAT. The effects of inflammation and mPGES-1 inhibitor (Compound III, 10 µM) on MMPs regulation were evaluated. The correlations between PGE2 and several parameters were calculated in plasma from patients with or without obesity. RESULTS: The vascular wall and PVAT from SV exhibited the greatest MMP-1,-2 release. An increase of MMP-1,-2 and/or a decrease of TIMP-1 quantities have been detected under inflammation only in vascular wall not in PVAT. These changes under inflammation were completely reversed by inhibition of mPGES-1. In obesity, C-reactive protein (CRP), biomarker of inflammation, and PGE2 levels were increased. PGE2 contents were positively correlated with some anthropometric parameters and plasmatic CRP in both genders, while the correlation with the plasmatic MMP-1 density was significant only in women. CONCLUSIONS: The greater MMP activity observed in SV may contribute to the increased prevalence of graft failure. Under inflammation, the greater mPGES-1 and PGE2 levels lead to enhanced MMP activity in human vascular walls. The positive association between PGE2 and MMP-1 or CRP has been observed in plasma of women. We suggest that mPGES-1 inhibitors could prevent graft failure and obesity-related vascular remodeling mostly in women.
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Dinoprostona/metabolismo , Inflamación/metabolismo , Arterias Mamarias/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Obesidad/metabolismo , Anciano , Dinoprostona/análisis , Dinoprostona/sangre , Femenino , Humanos , Masculino , Arterias Mamarias/química , Metaloproteinasas de la Matriz/análisis , Metaloproteinasas de la Matriz/sangre , Persona de Mediana EdadRESUMEN
OBJECTIVES: To elucidate the mechanism of action of the α1 -blocker, naftopidil, in partial bladder outlet obstruction animals, by studying non-voiding contractions, and the levels of mediators were measured with resiniferatoxin treatment. METHODS: A total of 35 female Wistar rats were randomly divided into a sham or bladder outlet obstruction group, and rats in each group were given vehicle or resiniferatoxin. Incomplete urethral ligation was applied to the bladder outlet obstruction group. After cystometry, the intravesical level of prostaglandin E2 and adenosine 5'-triphosphate was measured in the instilled perfusate collected. Naftopidil was given at the time of cystometry. RESULTS: In bladder outlet obstruction rats, non-voiding contractions, bladder capacity, and the intravesical levels of prostaglandin E2 and adenosine 5'-triphosphate were markedly increased compared with sham rats. Naftopidil decreased non-voiding contractions, enlarged the bladder capacity, and decreased the intravesical levels of prostaglandin E2 and adenosine 5'-triphosphate. Resiniferatoxin enhanced non-voiding contractions. The effects of naftopidil on non-voiding contractions and the intravesical level of prostaglandin E2 , but not adenosine 5'-triphosphate, were tolerant to resiniferatoxin. CONCLUSIONS: In bladder outlet obstruction rats, one cause of generation of non-voiding contractions might be bladder wall distension, but not transient receptor potential cation channel V1. The increase in intravesical prostaglandin E2 might also be associated with the generation of non-voiding contractions. Naftopidil inhibits the increase in non-voiding contractions and decreases the intravesical level of prostaglandin E2 , which are independent of transient receptor potential cation channel V1.
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Antagonistas Adrenérgicos alfa/administración & dosificación , Dinoprostona/análisis , Naftalenos/administración & dosificación , Piperazinas/administración & dosificación , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Animales , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Diterpenos/administración & dosificación , Femenino , Humanos , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Hiperplasia Prostática/complicaciones , Ratas , Ratas Wistar , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/análisis , Canales Catiónicos TRPV/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/fisiopatología , Obstrucción del Cuello de la Vejiga Urinaria/etiología , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Micción/efectos de los fármacos , Micción/fisiologíaRESUMEN
BACKGROUND: Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma. METHODS: Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases. RESULTS: Exhaled LTB4 , LTE4 , PGE2, and LXA4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB4 , LXA4 , together with FeNO and FEV1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as "asthma classification ratio" was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively. CONCLUSIONS: In a pediatric study population in Taiwan, the levels of exhaled LTB4 , LTE4 , LXA4, and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4 , together with FeNO and FEV1 , best characterized childhood asthma.
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Asma/clasificación , Asma/diagnóstico , Biomarcadores/análisis , Algoritmos , Área Bajo la Curva , Pruebas Respiratorias , Niño , Preescolar , Dinoprostona/análisis , Eicosanoides/análisis , Femenino , Volumen Espiratorio Forzado , Humanos , Leucotrieno B4/análisis , Leucotrieno E4/análisis , Lipoxinas/análisis , Masculino , Óxido Nítrico/análisis , Curva ROC , Sensibilidad y EspecificidadRESUMEN
It remains an issue to directly quantify trace biologically important carboxyl compounds in body fluids. Herein we propose an innovative method to determine α-lipoic acid, 2-(ß-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman, prostaglandin E2, cholic acid, and chenodeoxycholic acid in saliva. The method consists of two successive steps: fast and direct labeling of the target analytes with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide followed by ultrahigh-performance liquid chromatography-tandem mass spectrometry analysis. The method exhibited a wide linear range from 2.5 to 2500 pg/mL, with linear coefficients greater than 0.9963 and limits of detection and quantification as low as 0.10 and 0.33 pg/mL, respectively. The method precision was evaluated, with relative standard deviations ranging from 2.12% to 10.63% for intraday assays and from 2.98% to 12.88% for interday assays. The recoveries were measured by our spiking saliva samples with standards at three different levels, and ranged from 72.5% to 98.0%. Real applicability was validated by direct quantification of trace target analytes in human saliva, with simple pretreatment, use of a small sample volume, and a short analysis time. Graphical abstract Sequential steps to extract, label, and determine the ultratrace carboxylic acids in saliva. CDCA chenodeoxycholic acid, γ-CEHC 2-(ß-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman, α-LA α-lipoic acid, PGE2 prostaglandin E2, UHPLC-MS/MS ultrahigh-performance liquid chromatography-tandem mass spectrometry.
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Ácidos Carboxílicos/análisis , Cromatografía Líquida de Alta Presión/métodos , Saliva/química , Espectrometría de Masas en Tándem/métodos , Carbodiimidas/química , Ácido Quenodesoxicólico/análisis , Ácido Cólico/análisis , Dinoprostona/análisis , Humanos , Límite de Detección , Metilaminas/química , Reproducibilidad de los Resultados , Ácido Tióctico/análisisRESUMEN
BACKGROUND AND OBJECTIVE: Long-term statin therapy has been shown to protect against several cancers, including esophageal cancer (EC). While the mechanisms underlying this effect are not clear. We investigated the effect of hydrophobic simvastatin and hydrophilic pravastatin on the proliferation of EC cells and sought to explore the underlying mechanisms. METHODS: Esophageal adenocarcinoma OE-19 cells and esophageal squamous cell carcinoma Eca-109 cells were treated with different concentrations of simvastatin or pravastatin for 24 h and 48 h. Cell proliferation was assessed by Cell Counting Kit-8 assay. Malondialdehyde (MDA) levels were measured by thiobarbituric acid (TBA) assay. mRNA and protein expression of COX-2 were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively; The expression of prostaglandin E2 (PGE2) was measured by ELISA. RESULTS: Simvastatin, but not pravastatin, significantly inhibited the proliferation of OE-19 and Eca-109 cells in a dose- and time-dependent manner, accompanying with the increasing of the MDA level. Moreover, simvastatin suppressed the expression of COX-2 and PGE2 in both OE-19 and Eca-109 cells in a dose-dependent manner. CONCLUSIONS: Lipophilic simvastatin, but not hydrophilic pravastatin, had significant inhibitory effects on the proliferation of Eca-109 and OE-19 cells. The reduction of COX-2 and PGE2 by simvastatin suggested that the inhibitory effect of simvastatin on the proliferation of EC cells may be independent of its lipid-lowering effect. Simvastatin may be a promising agent for the prevention and treatment of EC.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Simvastatina/farmacología , Adenocarcinoma/enzimología , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ciclooxigenasa 2/genética , Dinoprostona/análisis , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/fisiopatología , Carcinoma de Células Escamosas de Esófago/enzimología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/fisiopatología , Regulación de la Expresión Génica , Humanos , Pravastatina/farmacología , Pravastatina/uso terapéutico , Simvastatina/uso terapéuticoRESUMEN
In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n = 6; 4.4 mg/kg phenylbutazone PO in 20 ml molasses q 12 hr for 7 days) or placebo (n = 6; 20 ml molasses PO q 12 hr for 7 days) groups. Before treatment and 3 and 7 days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p = .0017), but there was no effect of treatment (p = .49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration.
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Antiinflamatorios no Esteroideos/efectos adversos , Dinoprostona/análisis , Mucosa Gástrica/química , Enfermedades de los Caballos/inducido químicamente , Fenilbutazona/efectos adversos , Gastropatías/veterinaria , Animales , Ensayo de Inmunoadsorción Enzimática/veterinaria , Mucosa Gástrica/patología , Gastroscopía/veterinaria , Enfermedades de los Caballos/patología , Caballos , Gastropatías/inducido químicamente , Gastropatías/metabolismo , Gastropatías/patologíaRESUMEN
The adverse effects of petrodiesel exhaust exposure on the cardiovascular and respiratory systems are well recognized. While biofuels such as rapeseed methyl ester (RME) biodiesel may have ecological advantages, the exhaust generated may cause adverse health effects. In the current study, we investigated the responses of bioactive lipid mediators in human airways after biodiesel exhaust exposure using lipidomic profiling methods. Lipid mediator levels in lung lavage were assessed following 1-h biodiesel exhaust (average particulate matter concentration, 159 µg/m3) or filtered air exposure in 15 healthy individuals in a double-blinded, randomized, controlled, crossover study design. Bronchoscopy was performed 6 h post exposure and lung lavage fluids, i.e., bronchial wash (BW) and bronchoalveolar lavage (BAL), were sequentially collected. Mass spectrometry methods were used to detect a wide array of oxylipins (including eicosanoids), endocannabinoids, N-acylethanolamines, and related lipid metabolites in the collected BW and BAL samples. Six lipids in the human lung lavage samples were altered following biodiesel exhaust exposure, three from BAL samples and three from BW samples. Of these, elevated levels of PGE2, 12,13-DiHOME, and 13-HODE, all of which were found in BAL samples, reached Bonferroni-corrected significance. This is the first study in humans reporting responses of bioactive lipids following biodiesel exhaust exposure and the most pronounced responses were seen in the more peripheral and alveolar lung compartments, reflected by BAL collection. Since the responsiveness and diagnostic value of a subset of the studied lipid metabolites were established in lavage fluids, we conclude that our mass spectrometry profiling method is useful to assess effects of human exposure to vehicle exhaust.
Asunto(s)
Biocombustibles/análisis , Líquido del Lavado Bronquioalveolar/química , Dinoprostona/análisis , Endocannabinoides/análisis , Etanolaminas/análisis , Oxilipinas/análisis , Emisiones de Vehículos/análisis , Adulto , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Masculino , Espectrometría de Masas/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: This cross-sectional study aims to evaluate saliva, serum levels of interleukin-21 (IL-21), IL-33, and prostaglandin E2 (PGE2) in patients with generalised chronic periodontitis or aggressive periodontitis. MATERIALS AND METHODS: Before initiation of any periodontal treatment, saliva and serum samples were collected and clinical periodontal measurements were recorded from 94 participants (25 aggressive periodontitis patients, 25 chronic periodontitis patients, 44 periodontally healthy individuals). IL-21, IL-33 and PGE2 levels in serum and saliva samples were determined by ELISA. Data were tested statistically using Kruskal-Wallis, Mann-Whitney U-, and Spearman-rho rank tests. RESULTS: Saliva IL-33 levels were statistically significantly higher in the chronic than the aggressive group (p < 0.05). Serum IL-33, saliva and serum IL-21 and PGE2 levels were similar in the two periodontitis groups. Saliva IL-33 levels correlated with age in the chronic periodontitis group (p < 0.05). Statistically significant positive correlations were found between serum, saliva PGE2 levels and plaque index (p < 0.05). IL-33 and IL-21 levels in serum samples positively correlated in the periodontitis groups (p < 0.05). CONCLUSION: IL-21 and PGE2 analysis did not exhibit discriminating data between generalised chronic and aggressive periodontitis, but the present findings support the role of these cytokines in periodontitis. Statistically significantly higher saliva IL-33 levels in the chronic periodontitis group warrant further research.
Asunto(s)
Periodontitis Agresiva/metabolismo , Periodontitis Crónica/metabolismo , Dinoprostona/análisis , Interleucina-33/análisis , Interleucinas/análisis , Saliva/química , Adulto , Periodontitis Agresiva/sangre , Periodontitis Crónica/sangre , Estudios Transversales , Dinoprostona/sangre , Femenino , Humanos , Interleucina-33/sangre , Interleucinas/sangre , Masculino , Persona de Mediana EdadRESUMEN
Canine visceral leishmaniasis (CVL) is caused by the intracellular parasite Leishmania infantum. Increased levels of arginase, nitric oxide (NO2 ) and prostaglandin E2 (PGE2 ) can play a regulatory role regarding the immune response in CVL cases. This study aimed to evaluate the arginase activity in adherent macrophages cultured from the lymph nodes of healthy and naturally infected dogs and to examine the NO2 and PGE2 levels in the supernatant of these cultures. In addition, the regulatory effect of PGE2 on the production of tumour necrosis factor (TNF-α) and interleukin-10 (IL-10) in supernatants from the total lymph node was observed in leucocyte cultures. The arginase activity was lower in the adherent macrophages cultured from the lymph nodes of naturally infected dogs and there were higher concentrations of NO2 and PGE2 in the supernatants of these cultures. Higher TNF-α and IL-10 concentrations were observed in supernatants from total lymph node leucocytes cultures, from infected dogs, and the presence of indomethacin only decreased TNF-α in the supernatant of these cultures. We conclude that the low arginase activity in macrophages suggested that M1 polarization and PGE2 were participating in the immune response and were increasing TNF-α in CVL.
Asunto(s)
Dinoprostona/metabolismo , Enfermedades de los Perros/inmunología , Perros/inmunología , Leishmania infantum/fisiología , Leishmaniasis Visceral/veterinaria , Ganglios Linfáticos/inmunología , Macrófagos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Arginasa/análisis , Arginasa/metabolismo , Dinoprostona/análisis , Enfermedades de los Perros/patología , Leishmaniasis Visceral/patología , Ganglios Linfáticos/citología , Ganglios Linfáticos/parasitología , Ganglios Linfáticos/patología , Macrófagos/química , Óxido Nítrico/análisisRESUMEN
BACKGROUND: Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. METHODS: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. RESULTS: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95%CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 ± 129 pg/mL before treatment and 241 ± 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 ± 109 pg/mL before treatment, and 168 ± 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95%CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. CONCLUSION: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02632812 . Registered 14 December 2015.
Asunto(s)
Alanina/análogos & derivados , Antiinflamatorios no Esteroideos/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Naproxeno/efectos adversos , Quinolonas/uso terapéutico , Gastropatías/inducido químicamente , Gastropatías/prevención & control , Adolescente , Adulto , Alanina/uso terapéutico , Dinoprostona/análisis , Método Doble Ciego , Femenino , Mucosa Gástrica/patología , Humanos , Masculino , Persona de Mediana Edad , Gastropatías/patología , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study was to evaluate the effects of non-surgical periodontal therapy on gingival crevicular fluid levels of matrix metalloproteinase-8 (MMP-8), interleukin-6 (IL-6) and prostaglandin E2 (PGE2 ) in patients with rheumatoid arthritis (RA) with periodontal disease. MATERIAL AND METHODS: Twenty-seven patients with gingivitis and periodontitis with RA, 26 patients with gingivitis and periodontitis that were systemically healthy and 13 periodontally and systemically healthy volunteers (control group) were included in this study. RA activity was assessed by disease activity score test. The clinical periodontal parameters, fasting venous blood and gingival crevicular fluid samples were obtained and gingival crevicular fluid MMP-8, IL-6 and PGE2 levels were evaluated at baseline and at 3 mo follow-up after non-surgical periodontal treatment. RESULTS: Gingival crevicular fluid MMP-8, PGE2 and IL-6 levels were higher in all groups than the control group. Following periodontal therapy, there were significant decreases in gingival crevicular fluid MMP-8, PGE2 and IL-6 levels from patients with RA with periodontitis (p < 0.05). Plaque index, gingival index and bleeding on probing were significantly correlated with IL-6 and PGE2 at baseline and at 3 mo follow-up after non-surgical periodontal treatment. CONCLUSION: Non-surgical periodontal therapy of patients with RA with periodontitis may provide beneficial effects on local inflammatory control via decreases in gingival crevicular fluid MMP-8, PGE2 and IL-6 levels.
Asunto(s)
Artritis Reumatoide/complicaciones , Dinoprostona/análisis , Líquido del Surco Gingival/química , Interleucina-6/análisis , Metaloproteinasa 8 de la Matriz/análisis , Enfermedades Periodontales/complicaciones , Enfermedades Periodontales/terapia , Adulto , Artritis Reumatoide/sangre , Biomarcadores/análisis , Índice de Placa Dental , Raspado Dental , Femenino , Gingivitis/complicaciones , Gingivitis/terapia , Humanos , Masculino , Persona de Mediana Edad , Pérdida de la Inserción Periodontal/clasificación , Pérdida de la Inserción Periodontal/complicaciones , Pérdida de la Inserción Periodontal/terapia , Índice Periodontal , Bolsa Periodontal/clasificación , Periodontitis/clasificación , Periodontitis/complicaciones , Periodontitis/terapia , Aplanamiento de la Raíz , TurquíaRESUMEN
BACKGROUND AND OBJECTIVE: This study aimed to assess the effect of multiple sessions of a low-level laser therapy (LLLT) adjuvant to scaling and root planing (SRP) on the treatment of experimental periodontitis (EP) in rats treated with 5-fluorouracil (5-FU). MATERIAL AND METHODS: A total of 120 rats were divided into five groups: no treatment (NT); treatment with 5-FU (60 and 40 mg/kg) and no local periodontal treatment (5FU); treatment with 5-FU and SRP (5FU-SRP); treatment with 5-FU, SRP and one LLLT session (660 nm; 0.035 W; 4.2 J; 120 s) (5FU-SRP-1LLLT); and treatment with 5-FU, SRP and four LLLT sessions (0, 24, 48 and 72 h) (5FU-SRP-4LLLT). EP was induced in the mandibular molars through ligature placement. The alveolar bone loss (ABL) area in the furcation region was analysed histometrically. TRAP, proliferating cell nuclear antigen, RANKL, osteoprotegerin and activated caspase-3 patterns were analysed by immunolabeling. Prostaglandin E2 was quantified using an ELISA, and tumour necrosis factor α and interleukin-6 were assessed using the multiplex method. The prevalence rates of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella nigrescens, Prevotella intermedia and Fusobacterium nucleatum were assessed using the PCR method. The data were subjected to statistical analysis (α = 5%). RESULTS: 5FU, 5FU-SRP and 5FU-SRP-1LLLT treatment groups showed higher ABL compared with the NT group (p < 0.05), whereas the 5FU-SRP-4LLLT group showed lower ABL compared with the 5FU group on day 7 and decreased RANKL immunolabeling (p < 0.05). CONCLUSION: Treatment with 5-FU worsened EP, and multiple LLLT sessions adjuvant to SRP seemed to improve periodontitis in rats subjected to 5-FU chemotherapy.
Asunto(s)
Quimioterapia/métodos , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Terapia por Luz de Baja Intensidad/métodos , Periodontitis/terapia , Pérdida de Hueso Alveolar/patología , Pérdida de Hueso Alveolar/terapia , Animales , Bacterias/aislamiento & purificación , Caspasa 3/análisis , Terapia Combinada , Raspado Dental/métodos , Dinoprostona/análisis , Inflamación/patología , Interleucina-6/análisis , Masculino , Mandíbula , Diente Molar , Osteoprotegerina/análisis , Periodontitis/microbiología , Periodontitis/patología , Ligando RANK/análisis , Ratas , Ratas Wistar , Aplanamiento de la Raíz/métodos , Factor de Necrosis Tumoral alfa/análisisRESUMEN
OBJECTIVES: This study compares peri-implant crevicular fluid (PICF) prostaglandin E2 (PGE2) levels, clinical parameters and implant stability quotient (ISQ) values around implants placed in augmented extraction sockets. MATERIALS AND METHODS: The sockets (24 in total) were randomly augmented using either EMD or Bio-Oss Collagen. Implant placements were performed after three months of healing. ISQ readings were evaluated at three points: at the time of surgery, at the first month and at the third month. PICF was collected for PGE2 evaluation after the first and the third months of implant surgery. RESULTS: After the first month, a higher level of PICF PGE2 was observed in the EMD group than in the Bio-Oss Collagen group, and this increase was of statistical significance; however, at the third month there was no statistically significant difference in PICF PGE2 levels between the two groups. For implants placed in EMD sites, ISQ values were statistically higher at the third month than at the first month, while no significant differences in ISQ value were detected between the first and third months in Bio-Oss Collagen sites. CONCLUSIONS: The results of this research suggest that both EMD and Bio-Oss Collagen are effective treatment modalities for stimulating the formation of new bone at extraction sites prior to implant surgery.