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1.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807880

RESUMEN

Two siblings with CF are homozygous for F508del (referred to as Subject A and Subject B). Despite having the same CFTR genotype and similar environment, these two subjects exhibited different disease phenotypes. We analyzed their medical records and CF Foundation Registry data and measured inflammatory protein mediators in their sputum samples. Then, we examined the longitudinal relationships between inflammatory markers and disease severity for each subject and compared between them. Subject A presented a more severe disease than Subject B. During the study period, Subject A had two pulmonary exacerbations (PEs) whereas Subject B had one mild PE. The forced expiratory volume in 1 s (FEV1, % predicted) values for Subject A were between 34-45% whereas for Subject B varied between 48-90%. Inflammatory protein mediators associated with neutrophils, Th1, Th2, and Th17 responses were elevated in sputum of Subject A compared with Subject B, and also in samples collected prior to and during PEs for both subjects. Neutrophilic elastase (NE) seemed to be the most informative biomarkers. The infectious burden between these two subjects was different.


Asunto(s)
Secuencia de Aminoácidos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística , Homocigoto , Mediadores de Inflamación/metabolismo , Eliminación de Secuencia , Hermanos , Linfocitos T Colaboradores-Inductores/metabolismo , Biomarcadores/metabolismo , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Femenino , Humanos , Elastasa de Leucocito/metabolismo , Masculino , Esputo/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808880

RESUMEN

Peroxisome proliferator activated receptor beta/delta (PPARß/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARß/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARß/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARß/δ-regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL-6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL-6 is not significantly reduced by incubation with PPARß/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS-induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARß/δ agonists leads to a significant increase in Pdk-4 and Angptl-4 mRNA expression, which is significantly decreased in the presence of PPARß/δ antagonists. Docking using computational chemistry methods indicates that PPARß/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARß/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co-incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARß/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARß/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARß/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.


Asunto(s)
PPAR delta/química , PPAR-beta/química , Animales , Benzamidas/química , Benzamidas/farmacología , Sitios de Unión , Biomarcadores , Expresión Génica , Mediadores de Inflamación/metabolismo , Ligandos , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/inmunología , Masculino , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Óxido Nítrico/metabolismo , PPAR delta/agonistas , PPAR delta/antagonistas & inhibidores , PPAR delta/genética , PPAR-beta/agonistas , PPAR-beta/antagonistas & inhibidores , PPAR-beta/genética , Unión Proteica , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Tiazoles/química , Tiazoles/farmacología
3.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803130

RESUMEN

Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.


Asunto(s)
Movimiento Celular , Quimiocinas/metabolismo , Mediadores de Inflamación/metabolismo , Leucocitos/metabolismo , Sistema Linfático/metabolismo , Animales , Enfermedad Crónica , Humanos , Inflamación/metabolismo , Inflamación/patología , Leucocitos/patología , Sistema Linfático/patología
4.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810153

RESUMEN

Currently, retinal pigment epithelium (RPE) transplantation includes sheet and single-cell transplantation, the latter of which includes cell death and may be highly immunogenic, and there are some issues to be improved in single-cell transplantation. Y-27632 is an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of Rho. We herein investigated the effect of Y-27632 in vitro on retinal pigment epithelium derived from induced pluripotent stem cells (iPS-RPE cells), and also its effects in vivo on the transplantation of iPS-RPE cell suspensions. As a result, the addition of Y-27632 in vitro showed suppression of apoptosis, promotion of cell adhesion, and higher proliferation and pigmentation of iPS-RPE cells. Y-27632 also increased the viability of the transplant without showing obvious retinal toxicity in human iPS-RPE transplantation into monkey subretinal space in vivo. Therefore, it is possible that ROCK inhibitors can improve the engraftment of iPS-RPE cell suspensions after transplantation.


Asunto(s)
Supervivencia de Injerto/efectos de los fármacos , Células Madre Pluripotentes Inducidas/citología , Inhibidores de Proteínas Quinasas/farmacología , Trasplante de Células Madre , Quinasas Asociadas a rho/antagonistas & inhibidores , Amidas/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Macaca fascicularis , Piridinas/farmacología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo
5.
mBio ; 12(2)2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879586

RESUMEN

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development.IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit's value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.


Asunto(s)
/genética , /patogenicidad , Animales , /virología , Síndrome de Liberación de Citoquinas/etiología , Modelos Animales de Enfermedad , Femenino , Interacciones Microbiota-Huesped , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Transgénicos , Pandemias , Neumonía Viral/etiología , Neumonía Viral/virología , Genética Inversa/métodos , /fisiología , Tropismo Viral , Replicación Viral
6.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823870

RESUMEN

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Asunto(s)
Antiinflamatorios/farmacología , Reposicionamiento de Medicamentos , Hipoxia/tratamiento farmacológico , Justicia , Pulmón/efectos de los fármacos , Extractos Vegetales/farmacología , Neumonía/prevención & control , Fibrosis Pulmonar/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Bleomicina , /virología , Ciego/microbiología , Ciego/cirugía , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , Justicia/química , Ligadura , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificación , Neumonía/genética , Neumonía/metabolismo , Neumonía/microbiología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Sepsis/genética , Sepsis/metabolismo , Sepsis/microbiología , Transcriptoma
7.
Medicine (Baltimore) ; 100(14): e25355, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832115

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is a kind of chronic non-specific ulcerative colitis, which is characterized by repeated abdominal pain, diarrhea, and mucus purulent stool. The disease is more recurrent, easy to delay, and canceration, seriously affect the quality of life, increase the economic burden of patients and society, treatment is more difficult, the World Health Organization as one of the modern refractory diseases. Shenling Atractylodes Powder in the treatment of ulcerative colitis showed a strong advantage, the effect is accurate. Therefore, this paper will systematically evaluate and meta-analyze the efficacy and safety of heat-sensitive moxibustion in the treatment of ulcerative colitis. METHODS: Eight electronic databases were searched, including the PubMed, Embase, Web of Science, Cochrane Library, China National knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biomedical Literature Database. We will search in the above electronic database from early 2021 to December without any language restrictions. Outcome indicators, including colonic mucosal symptom score Mayo colonoscopy grading, total effective rate, total incidence of adverse reactions, clinical symptom score, recurrence rate, laboratory indicators: IL-6, IL-9, TNF-α, IL-4, IL-10 inflammation-related factor levels. Rev Man5.3 software will be used for statistical analysis. The efficacy and safety results of Shenling Atractylodes Powder in the treatment of ulcerative colitis will be used as the average difference between the risk ratio of dichotomy data and the 95% co-card interval of continuous data. RESULTS: When this research program is completed, the relevant results can be obtained. ETHICS AND DISSEMINATION: This article does not need to pass the ethics committee review, because this article does not involve the ethics question, only collates the related literature research. The results of this study will be disseminated in the form of a paper to help better guide the clinical practice of heat-sensitive moxibustion in the treatment of ulcerative colitis. REGISTRATION NUMBER: INPLASY202120018.


Asunto(s)
Atractylodes , Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Colitis Ulcerosa/patología , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/efectos adversos , Humanos , Mediadores de Inflamación/metabolismo , Polvos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Índice de Severidad de la Enfermedad
8.
Medicine (Baltimore) ; 100(14): e25378, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832124

RESUMEN

INTRODUCTION: Multimodality assessment of coronary artery lesions has demonstrated superior effectiveness compared to the conventional approach, for assessing both anatomical and functional significance of a coronary stenosis. Multiple imaging modalities can be integrated into a fusion imaging tool to better assess myocardial ischemia. MATERIAL AND METHODS: The FUSE-HEART trial is a single center, prospective, cohort study that will assess the impact of a coronary artery stenosis on myocardial function and viability, based on advanced fusion imaging technics derived from Cardiac Computed Tomography Angiography (CCTA). Moreover, the study will investigate the correlation between morphology and composition of the coronary plaques and myocardial ischemia in the territory irrigated by the same coronary artery. At the same time, imaging parameters will be correlated with inflammatory status of the subjects. The trial will include 100 subjects with coronary lesions found on CCTA examination. The study population will be divided into 2 groups: first group will consist of subjects with anatomically significant coronary lesions on native coronary arteries and the second one will include subjects surviving an acute myocardial infarction. The vulnerability score of the subjects will be calculated based on presence of CCTA vulnerability markers of the coronary plaques: napkin ring sign, positive remodeling, spotty calcifications, necrotic core, and low-density plaques. 3D fusion images of the coronary tree will be generated, integrating the images reflecting wall motion with the ones of coronary circulation. The fusion models will establish the correspondence between plaque composition and wall motion in the subtended myocardium of the coronary artery. The study primary outcome will be represented by the rate of major adverse cardiac events related to myocardial ischemia at 1-year post assessment, in correlation with the degree of coronary artery stenosis and myocardial ischemia or viability.The secondary outcomes are represented by the rate of re-hospitalization, rate of survival and rate of major adverse cardiovascular events (including cardiovascular death or stroke), in correlation with the morphology and composition of atheromatous plaques located in a coronary artery, and myocardial ischemia in the territory irrigated by the same coronary artery. CONCLUSION: In conclusion, FUSE-HEART will be a study based on modern imaging tools that will investigate the impact of a coronary artery stenosis on myocardial function and viability, using advanced fusion imaging technics derived from CCTA, sighting to validate plaque composition and morphology, together with inflammatory biomarkers, as predictors to myocardial viability.


Asunto(s)
Vasos Coronarios/diagnóstico por imagen , Imagen Multimodal/métodos , Isquemia Miocárdica/complicaciones , Imagen de Perfusión Miocárdica/métodos , Estudios de Cohortes , Angiografía por Tomografía Computarizada/métodos , Estenosis Coronaria/complicaciones , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/fisiopatología , Vasos Coronarios/patología , Humanos , Mediadores de Inflamación/metabolismo , Ensayos Clínicos Controlados no Aleatorios como Asunto , Evaluación de Resultado en la Atención de Salud , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/fisiopatología , Estudios Prospectivos
9.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802689

RESUMEN

Palmitoylethanolamide (PEA) is an endogenous lipid produced on demand by neurons and glial cells that displays neuroprotective properties. It is well known that inflammation and neuronal damage are strictly related processes and that microglia play a pivotal role in their regulation. The aim of the present work was to assess whether PEA could exert its neuroprotective and anti-inflammatory effects through the modulation of microglia reactive phenotypes. In N9 microglial cells, the pre-incubation with PEA blunted the increase of M1 pro-inflammatory markers induced by lipopolysaccharide (LPS), concomitantly increasing those M2 anti-inflammatory markers. Images of microglial cells were processed to obtain a set of morphological parameters that highlighted the ability of PEA to inhibit the LPS-induced M1 polarization and suggested that PEA might induce the anti-inflammatory M2a phenotype. Functionally, PEA prevented Ca2+ transients in both N9 cells and primary microglia and antagonized the neuronal hyperexcitability induced by LPS, as revealed by multi-electrode array (MEA) measurements on primary cortical cultures of neurons, microglia, and astrocyte. Finally, the investigation of the molecular pathway indicated that PEA effects are not mediated by toll-like receptor 4 (TLR4); on the contrary, a partial involvement of cannabinoid type 2 receptor (CB2R) was shown by using a selective receptor inverse agonist.


Asunto(s)
Amidas/farmacología , Etanolaminas/farmacología , Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Ácidos Palmíticos/farmacología , Adenosina Trifosfato/farmacología , Animales , Calcio/metabolismo , Polaridad Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/farmacología , Ratones , Microglía/efectos de los fármacos , FN-kappa B/metabolismo , Ratas , Receptor Cannabinoide CB2/metabolismo , Células THP-1 , Acetato de Tetradecanoilforbol/farmacología , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
10.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807591

RESUMEN

Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view.


Asunto(s)
Inflamación/patología , Intestinos/patología , Animales , Enfermedad Crónica , Humanos , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología
11.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809795

RESUMEN

We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3ß-actin mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. These protective effects of SRG3 overexpression correlated with the phenotypic conversion of hepatic macrophages from an M1 toward an M2 phenotype. Furthermore, SRG3ß-actin mice had decreased numbers and activation of natural killer (NK) cells but not natural killer T (NKT) cells in the liver during sepsis, indicating that SRG3 overexpression might contribute to cross-talk between NK cells and macrophages in the liver. Finally, we demonstrated that NKT cell-deficient CD1d KO/SRG3ß-actin mice are protected from LPS/d-GalN-induced sepsis, indicating that NKT cells are dispensable for SRG3-mediated sepsis suppression. Taken together, our findings provide strong evidence that SRG3 overexpression may serve as a therapeutic approach to control overwhelming inflammatory diseases such as sepsis.


Asunto(s)
Cromatina/metabolismo , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Hígado/patología , Macrófagos/metabolismo , Células T Asesinas Naturales/metabolismo , Sepsis/inducido químicamente , Sepsis/prevención & control , Factores de Transcripción/metabolismo , Actinas/genética , Animales , Ensamble y Desensamble de Cromatina , Células Dendríticas/metabolismo , Galactosamina , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Sustancias Protectoras/metabolismo , Sepsis/inmunología , Sepsis/patología , Índice de Severidad de la Enfermedad
12.
Life Sci ; 276: 119432, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33794253

RESUMEN

BACKGROUND: Adenoid hypertrophy (AH) can cause harmful effects on untreated children, which include mouth breathing, chronic intermittent hypoxia, sleep disordered breathing (SDB), and even some behavioral problems. However, the molecular mechanisms underlying this pathophysiological process have remained poorly understood. METHODS: In this study, SUMO was induced silencing and overexpression using RNAi and lentiviral-mediated vector. FITC-Dextran and TEER were performed to examine the role of SUMO in cell permeability. Co-immunoprecipitation (Co-IP) assay was performed to examine the interaction between SUMO1 and HIF-1α. Immunohistochemistry staining was used to examine the expressions of ZO-1, Claudin-1 and occluding respectively. RESULTS: We found that a hypoxic condition caused a dramatic upregulation of SUMO-1 expression in a time-dependent manner, a member of the ubiquitin-like protein family. Knockdown of SUMO-1 deeply suppressed the secretions of pro-inflammation cytokines including IL-6, IL-8, and TNF-α, and decreased the permeability of HTECs. Moreover, the HIF-1α inhibitor 2-MeOE2 abolished the function of SUMO-1 in HTECs. Furthermore, results obtained from CO-IP had suggested that SUMO-1 interacted with HIF-1α, and prevented its ubiquitination and degradation in HTECs by sumoylating. Importantly, our data showed that hypoxia-induced inflammation was markedly inhibited by M2 macrophages that possess potent anti-inflammatory function. CONCLUSION: Our results suggest that selectively inhibiting the SUMO-1-HIF-1α signaling pathway leads to anti-inflammatory responses in human tonsil epithelial cells, which might be a novel therapeutic approach for managing hypoxia-induced SDB resulting from AH.


Asunto(s)
Citocinas/metabolismo , Células Epiteliales/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/fisiopatología , Mediadores de Inflamación/metabolismo , Tonsila Palatina/patología , Proteína SUMO-1/metabolismo , Permeabilidad de la Membrana Celular , Células Cultivadas , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Tonsila Palatina/inmunología , Tonsila Palatina/metabolismo , Proteína SUMO-1/genética
13.
Int J Mol Sci ; 22(6)2021 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-33801157

RESUMEN

There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-ß (TGF-ß), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-ß elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren's syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-ß/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-ß family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-ß in pSS that are dictated by orchestrations of SMADs, and describe TGF-ß/SMADs value as both disease markers and/or therapeutic target for pSS.


Asunto(s)
Susceptibilidad a Enfermedades , Síndrome de Sjögren/etiología , Síndrome de Sjögren/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Transición Epitelial-Mesenquimal , Fibrosis , Regulación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Fosforilación , Unión Proteica , Transducción de Señal , Síndrome de Sjögren/patología , Factor de Crecimiento Transformador beta/metabolismo
14.
Sci Rep ; 11(1): 7052, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782412

RESUMEN

SARS-CoV2 is a previously uncharacterized coronavirus and causative agent of the COVID-19 pandemic. The host response to SARS-CoV2 has not yet been fully delineated, hampering a precise approach to therapy. To address this, we carried out a comprehensive analysis of gene expression data from the blood, lung, and airway of COVID-19 patients. Our results indicate that COVID-19 pathogenesis is driven by populations of myeloid-lineage cells with highly inflammatory but distinct transcriptional signatures in each compartment. The relative absence of cytotoxic cells in the lung suggests a model in which delayed clearance of the virus may permit exaggerated myeloid cell activation that contributes to disease pathogenesis by the production of inflammatory mediators. The gene expression profiles also identify potential therapeutic targets that could be modified with available drugs. The data suggest that transcriptomic profiling can provide an understanding of the pathogenesis of COVID-19 in individual patients.


Asunto(s)
Bronquios/metabolismo , Perfilación de la Expresión Génica , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar , /virología , Humanos , Mediadores de Inflamación/metabolismo , Células Mieloides/metabolismo , Unión Proteica , /aislamiento & purificación
15.
Am J Physiol Heart Circ Physiol ; 320(4): H1609-H1624, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33666506

RESUMEN

This study aimed to determine the mechanosensing role of angiotensin II type 1 receptor (AT1R) in flow-induced dilation (FID) and oxidative stress production in middle cerebral arteries (MCA) of Sprague-Dawley rats. Eleven-week old, healthy male Sprague-Dawley rats on a standard diet were given the AT1R blocker losartan (1 mg/mL) in drinking water (losartan group) or tap water (control group) ad libitum for 7 days. Blockade of AT1R attenuated FID and acetylcholine-induced dilation was compared with control group. Nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) and cyclooxygenase inhibitor indomethacin (Indo) significantly reduced FID in control group. The attenuated FID in losartan group was further reduced by Indo only at Δ100 mmHg, whereas l-NAME had no effect. In losartan group, Tempol (a superoxide scavenger) restored dilatation, whereas Tempol + l-NAME together significantly reduced FID compared with restored dilatation with Tempol alone. Direct fluorescence measurements of NO and reactive oxygen species (ROS) production in MCA, in no-flow conditions revealed significantly reduced vascular NO levels with AT1R blockade compared with control group, whereas in flow condition increased the NO and ROS production in losartan group and had no effect in the control group. In losartan group, Tempol decreased ROS production in both no-flow and flow conditions. AT1R blockade elicited increased serum concentrations of ANG II, 8-iso-PGF2α, and TBARS, and decreased antioxidant enzyme activity (SOD and CAT). These results suggest that in small isolated cerebral arteries: 1) AT1 receptor maintains dilations in physiological conditions; 2) AT1R blockade leads to increased vascular and systemic oxidative stress, which underlies impaired FID.NEW & NOTEWORTHY The AT1R blockade impaired the endothelium-dependent, both flow- and acetylcholine-induced dilations of MCA by decreasing vascular NO production and increasing the level of vascular and systemic oxidative stress, whereas it mildly influenced the vascular wall inflammatory phenotype, but had no effect on the systemic inflammatory response. Our data provide functional and molecular evidence for an important role of AT1 receptor activation in physiological conditions, suggesting that AT1 receptors have multiple biological functions.


Asunto(s)
Circulación Cerebrovascular , Endotelio Vascular/metabolismo , Leucocitos/metabolismo , Mecanotransducción Celular , Arteria Cerebral Media/metabolismo , Estrés Oxidativo , Receptor de Angiotensina Tipo 1/metabolismo , Vasodilatación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Antioxidantes/farmacología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Circulación Cerebrovascular/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Endotelio Vascular/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica , Mediadores de Inflamación/metabolismo , Leucocitos/efectos de los fármacos , Masculino , Mecanotransducción Celular/efectos de los fármacos , Arteria Cerebral Media/efectos de los fármacos , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología
16.
Am J Physiol Renal Physiol ; 320(5): F838-F858, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33645317

RESUMEN

Alteration of bladder morphology and function was the most important consequence of bladder outlet obstruction (BOO). Using a rat model of partial BOO (pBOO), we found that rats treated with metformin showed lower baseline pressures with a reduced inflammatory reaction in the early phase (2 wk) after pBOO. The NLR family pyrin domain containing 3 inflammasome pathway was inhibited in pBOO rat bladders with treatment of metformin in the early phase. Metformin reduced the activity of NLR family pyrin domain containing 3 in primary urothelial cells. In the chronic phase (9 wk after pBOO), metformin treatment ameliorated bladder fibrosis and improved the reduced compliance. Treatment with metformin suppressed the activation of Smad3 and compensated the diminished autophagy in 9-wk pBOO rat bladders. Autophagy was inhibited with upregulation of profibrotic proteins in primary fibroblasts from chronic pBOO bladders, which could be restored by administration of metformin. The antifibrotic effects of metformin on fibroblasts were diminished after silencing of AMP-activated protein kinase or light chain 3B. In summary, this study elucidates that oral administration of metformin relieves inflammation in the bladder during the early phase of pBOO. Long-term oral administration of metformin can prevent functional and histological changes in the pBOO rat bladder. The current study suggests that metformin might be used to prevent the development of bladder dysfunction secondary to BOO.NEW & NOTEWORTHY The present study in a rat model showed that oral administration of metformin alleviated inflammation following partial bladder outlet obstruction in the early phase and ameliorated bladder fibrosis as well as bladder dysfunction by long-term treatment. Our study indicated that metformin is a potential drug to inhibit bladder remodeling and alleviate bladder dysfunction. Clinical trials are needed to validate the effect of metformin on the bladder dysfunction and bladder fibrosis in the future.


Asunto(s)
Antiinflamatorios/farmacología , Metformina/farmacología , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Humanos , Mediadores de Inflamación/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Factores de Tiempo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Vejiga Urinaria/fisiopatología , Obstrucción del Cuello de la Vejiga Urinaria/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/patología , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Urodinámica/efectos de los fármacos , Urotelio/efectos de los fármacos , Urotelio/metabolismo , Urotelio/patología
17.
Am J Physiol Heart Circ Physiol ; 320(5): H1851-H1861, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33710927

RESUMEN

High altitude-related excessive erythrocytosis (EE) is associated with increased cardiovascular risk. The experimental aim of this study was to determine the effects of microvesicles isolated from Andean highlanders with EE on endothelial cell inflammation, oxidative stress, apoptosis, and nitric oxide (NO) production. Twenty-six male residents of Cerro de Pasco, Peru (4,340 m), were studied: 12 highlanders without EE (age: 40 ± 4 yr; BMI: 26.4 ± 1.7; Hb: 17.4 ± 0.5 g/dL, Spo2: 86.9 ± 1.0%) and 14 highlanders with EE (43 ± 4 yr; 26.2 ± 0.9; 24.4 ± 0.4 g/dL; 79.7 ± 1.6%). Microvesicles were isolated, enumerated, and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with microvesicles from highlanders without and with EE. Microvesicles from highlanders with EE induced significantly higher release of interleukin (IL)-6 (89.8 ± 2.7 vs. 77.1 ± 1.9 pg/mL) and IL-8 (62.0 ± 2.7 vs. 53.3 ± 2.2 pg/mL) compared with microvesicles from healthy highlanders. Although intracellular expression of total NF-κB p65 (65.3 ± 6.0 vs. 74.9 ± 7.8.9 AU) was not significantly affected in cells treated with microvesicles from highlanders without versus with EE, microvesicles from highlanders with EE resulted in an ∼25% higher (P < 0.05) expression of p-NF-κB p65 (173.6 ± 14.3 vs. 132.8 ± 12.2 AU). Cell reactive oxygen species production was significantly higher (76.4.7 ± 5.4 vs. 56.7 ± 1.7% of control) and endothelial nitric oxide synthase (p-eNOS) activation (231.3 ± 15.5 vs. 286.6 ± 23.0 AU) and NO production (8.3 ± 0.6 vs. 10.7 ± 0.7 µM/L) were significantly lower in cells treated with microvesicles from highlanders with versus without EE. Cell apoptotic susceptibility was not significantly affected by EE-related microvesicles. Circulating microvesicles from Andean highlanders with EE increased endothelial cell inflammation and oxidative stress and reduced NO production.NEW & NOTEWORTHY In this study, we determined the effects of microvesicles isolated from Andean highlanders with excessive erythrocytosis (EE) on endothelial cell inflammation, oxidative stress, apoptosis, and NO production. Microvesicles from highlanders with EE induced a dysfunctional response from endothelial cells characterized by increased cytokine release and expression of active nuclear factor-κB and reduced nitric oxide production. Andean highlanders with EE exhibit dysfunctional circulating extracellular microvesicles that induce a proinflammatory, proatherogenic endothelial phenotype.


Asunto(s)
Aclimatación , Altitud , Micropartículas Derivadas de Células/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Policitemia/sangre , Adulto , Apoptosis , Estudios de Casos y Controles , Micropartículas Derivadas de Células/patología , Células Cultivadas , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo , Perú , Fenotipo , Policitemia/patología , Policitemia/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción ReIA/metabolismo
18.
Pharmacol Res ; 167: 105548, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33722710

RESUMEN

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Asunto(s)
Antiinflamatorios/farmacología , Colon/efectos de los fármacos , Enterotoxinas , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Pulmón/efectos de los fármacos , Resveratrol/farmacología , Superantígenos , Animales , Línea Celular , Colon/inmunología , Colon/metabolismo , Colon/microbiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disbiosis , Femenino , Mediadores de Inflamación/metabolismo , Lactobacillus reuteri/efectos de los fármacos , Lactobacillus reuteri/crecimiento & desarrollo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Ratones Endogámicos C3H , /metabolismo , /microbiología
19.
Int Heart J ; 62(2): 390-395, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33731531

RESUMEN

Perivascular adipose tissue (PVAT) secretes large amounts of inflammatory mediators and plays a certain role in atherosclerosis formation from the exterior of the vessel. In the present study, we examined the expression level of inflammation-related mediators using adipose tissue samples harvested from patients with and without coronary artery disease (CAD). The subjects were 23 patients who underwent elective coronary bypass surgery (CAD group) and 17 patients who underwent elective mitral valve surgery (non-CAD group) between January 2017 and March 2018. The adipose tissue was harvested from three sites: the ascending aorta (AO), subcutaneous fat (SC), and pericoronary artery (CO) for the measurement of the expression levels of interleukin (IL) -1ß, IL-6, IL-10, tumor necrosis factor (TNF) -α, interferon (INF) -γ, and arginase (Arg) -1. In both the non-CAD and CAD groups, the expression levels of all mediators, except Agr-1, which showed a tendency to have higher levels in the SC than in the AO and CO, tended to upregulate in the AO than in the SC and CO. The CAD group had higher values of almost all mediators, except Arg-1. Most importantly, the expression levels of IL-1ß, IL-6, and IL-10 in the coronary artery were significantly higher in the CAD group. The expression levels of inflammatory mediators in the pericoronary adipose tissue were significantly higher in the CAD than in the non-CAD group. The adipose tissue appears to influence atherosclerosis formation from the exterior of the coronary artery.


Asunto(s)
Tejido Adiposo/metabolismo , Aterosclerosis/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Mediadores de Inflamación/metabolismo , Anciano , Aterosclerosis/diagnóstico , Biomarcadores/metabolismo , Vasos Coronarios , Femenino , Humanos , Masculino
20.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669765

RESUMEN

Signaling mediated by cytokines and chemokines is involved in glaucoma-associated neuroinflammation and in the damage of retinal ganglion cells (RGCs). Using multiplexed immunoassay and immunohistochemical techniques in a glaucoma mouse model at different time points after ocular hypertension (OHT), we analyzed (i) the expression of pro-inflammatory cytokines, anti-inflammatory cytokines, BDNF, VEGF, and fractalkine; and (ii) the number of Brn3a+ RGCs. In OHT eyes, there was an upregulation of (i) IFN-γ at days 3, 5, and 15; (ii) IL-4 at days 1, 3, 5, and 7 and IL-10 at days 3 and 5 (coinciding with downregulation of IL1-ß at days 1, 5, and 7); (iii) IL-6 at days 1, 3, and 5; (iv) fractalkine and VEGF at day 1; and (v) BDNF at days 1, 3, 7, and 15. In contralateral eyes, there were (i) an upregulation of IL-1ß at days 1 and 3 and a downregulation at day 7, coinciding with the downregulation of IL4 at days 3 and 5 and the upregulation at day 7; (ii) an upregulation of IL-6 at days 1, 5, and 7 and a downregulation at 15 days; (iii) an upregulation of IL-10 at days 3 and 7; and (iv) an upregulation of IL-17 at day 15. In OHT eyes, there was a reduction in the Brn3a+ RGCs number at days 3, 5, 7, and 15. OHT changes cytokine levels in both OHT and contralateral eyes at different time points after OHT induction, confirming the immune system involvement in glaucomatous neurodegeneration.


Asunto(s)
Encéfalo/patología , Glaucoma/patología , Inflamación/patología , Neuronas/patología , Células Ganglionares de la Retina/patología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Glaucoma/fisiopatología , Mediadores de Inflamación/metabolismo , Presión Intraocular , Masculino , Ratones , Microglía/patología , Hipertensión Ocular/metabolismo , Hipertensión Ocular/fisiopatología , Factores de Tiempo
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