Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21.598
Filtrar
1.
PLoS One ; 16(3): e0248957, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33755708

RESUMEN

The characteristics and evolution of pulmonary fibrosis in patients with coronavirus disease 2019 (COVID-19) have not been adequately studied. AI-assisted chest high-resolution computed tomography (HRCT) was used to investigate the proportion of COVID-19 patients with pulmonary fibrosis, the relationship between the degree of fibrosis and the clinical classification of COVID-19, the characteristics of and risk factors for pulmonary fibrosis, and the evolution of pulmonary fibrosis after discharge. The incidence of pulmonary fibrosis in patients with severe or critical COVID-19 was significantly higher than that in patients with moderate COVID-19. There were significant differences in the degree of pulmonary inflammation and the extent of the affected area among patients with mild, moderate and severe pulmonary fibrosis. The IL-6 level in the acute stage and albumin level were independent risk factors for pulmonary fibrosis. Ground-glass opacities, linear opacities, interlobular septal thickening, reticulation, honeycombing, bronchiectasis and the extent of the affected area were significantly improved 30, 60 and 90 days after discharge compared with at discharge. The more severe the clinical classification of COVID-19, the more severe the residual pulmonary fibrosis was; however, in most patients, pulmonary fibrosis was improved or even resolved within 90 days after discharge.


Asunto(s)
Inteligencia Artificial , Fibrosis Pulmonar/diagnóstico , Tórax/diagnóstico por imagen , /complicaciones , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Alta del Paciente , Fibrosis Pulmonar/etiología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X
2.
J Enzyme Inhib Med Chem ; 36(1): 659-668, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33641565

RESUMEN

Human intestinal epithelial cell line-6 (HIEC-6) cells and primary human hepatocytes (PHHs) were treated with 3-amidinophenylalanine-derived inhibitors of trypsin-like serine proteases for 24 hours. It was proven that treatment with MI-1900 and MI-1907 was tolerated up to 50 µM in HIEC-6. These inhibitors did not cause elevations in extracellular H2O2 levels and in the concentrations of interleukin (IL)-6 and IL-8 and did not alter occludin distribution in HIEC-6. It was also found that MI-1900 and MI-1907 up to 50 µM did not affect cell viability, IL-6 and IL-8 and occludin levels of PHH. Based on our findings, these inhibitors could be safely applicable at 50 µM in HIEC-6 and in PHH; however, redox status was disturbed in case of PHH. Moreover, it has recently been demonstrated that MI-1900 prevents the replication and spread of the new SARS-CoV-2 in infected Calu-3 cells, most-likely via an inhibition of the membrane-bound host protease TMPRSS2.


Asunto(s)
Antivirales/farmacología , Células Epiteliales/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Fenilalanina/farmacología , Inhibidores de Proteasas/farmacología , Serina Endopeptidasas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/enzimología , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/citología , Hepatocitos/enzimología , Humanos , Peróxido de Hidrógeno/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/enzimología , Ocludina/genética , Ocludina/metabolismo , Oxidación-Reducción/efectos de los fármacos , Fenilalanina/análogos & derivados , Cultivo Primario de Células , Serina Endopeptidasas/genética
4.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572938

RESUMEN

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global public health emergency. Periodontitis, the most prevalent disease that leads to tooth loss, is caused by infection by periodontopathic bacteria. Periodontitis is also a risk factor for pneumonia and the exacerbation of chronic obstructive pulmonary disease, presumably because of the aspiration of saliva contaminated with periodontopathic bacteria into the lower respiratory tract. Patients with these diseases have increased rates of COVID-19 aggravation and mortality. Because periodontopathic bacteria have been isolated from the bronchoalveolar lavage fluid of patients with COVID-19, periodontitis may be a risk factor for COVID-19 aggravation. However, the molecular links between periodontitis and COVID-19 have not been clarified. In this study, we found that the culture supernatant of the periodontopathic bacterium Fusobacterium nucleatum (CSF) upregulated the SARS-CoV-2 receptor angiotensin-converting enzyme 2 in A549 alveolar epithelial cells. In addition, CSF induced interleukin (IL)-6 and IL-8 production by both A549 and primary alveolar epithelial cells. CSF also strongly induced IL-6 and IL-8 expression by BEAS-2B bronchial epithelial cells and Detroit 562 pharyngeal epithelial cells. These results suggest that when patients with mild COVID-19 frequently aspirate periodontopathic bacteria, SARS-CoV-2 infection is promoted, and inflammation in the lower respiratory tract may become severe in the presence of viral pneumonia.


Asunto(s)
/metabolismo , Medios de Cultivo Condicionados/química , Citocinas/metabolismo , Fusobacterium nucleatum/metabolismo , /genética , /virología , Línea Celular , Medios de Cultivo Condicionados/farmacología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Regulación hacia Arriba/efectos de los fármacos
5.
J Ovarian Res ; 14(1): 28, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33550983

RESUMEN

Improving early diagnosis along with timely and effective treatment of COVID-19 are urgently needed. However, at present, the mechanisms underlying disease spread and development, defined prognosis, and immune status of patients with COVID-19 remain to be determined. Patients with severe disease state exhibit a hyperinflammatory response associated with cytokine storm syndrome, hypercoagulability, and depressed cell-mediated immunity. These clinical manifestations, sharing similar pathogenesis, have been well-studied in patients with advanced ovarian cancer. The present review suggests treatment approaches for COVID-19 based on strategies used against ovarian cancer, which shares similar immunopathology and associated coagulation disorders.The chronicization of the hyperinflammatory cytokine storm in patients with severe COVID-19 highlights a defective resistance phase that leads to aspecific chronic inflammation, associated with oxidative stress, which impairs specific T-cell response, induces tissue and endothelial damage, and thrombosis associated with systemic effects that lead to severe multi-organ failure and death. These events are similar to those observed in advanced ovarian cancer which share similar pathogenesis mediated primarily by Interleukin-6, which is, as well demonstrated in ovarian cancer, the key cytokine driving the immunopathology, related systemic symptoms, and patient prognosis.Consistent with findings in other disease models with similar immunopathology, such as advanced ovarian cancer, treatment of severe COVID-19 infection should target inflammation, oxidative stress, coagulation disorders, and immunodepression to improve patient outcome. Correctly identifying disease stages, based on available laboratory data, and developing a specific protocol for each phase is essential for effective treatment.


Asunto(s)
/complicaciones , Síndrome de Liberación de Citoquinas/etiología , Interleucina-6/metabolismo , Neoplasias Ováricas/metabolismo , Corticoesteroides/uso terapéutico , Aspirina/uso terapéutico , /metabolismo , /terapia , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Femenino , Humanos , Inmunización Pasiva , Inflamación/tratamiento farmacológico , Inflamación/virología , Interleucina-6/inmunología , Necrosis , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Estrés Oxidativo
6.
Adv Exp Med Biol ; 1290: 1-8, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33559852

RESUMEN

Interleukin-6 (IL-6) is a proinflammatory cytokine, which is involved in pathogenesis of several cancers. Its expression and function in prostate cancer have been extensively studied in cellular models and clinical specimens. High levels of IL-6 were detected in conditioned media from cells which do not respond to androgens. Increased phosphorylation of signal transducer and activator of transcription (STAT)3 factor which is induced in response to IL-6 is one of the typical features of prostate cancer. However, reports in the literature show regulation of neuroendocrine phenotype by IL-6. Effects of IL-6 on stimulation of proliferation, migration, and invasion lead to the establishment of experimental and clinical approaches to target IL-6. In prostate cancer, anti-IL-6 antibodies were demonstrated to inhibit growth in vitro and in vivo. Clinically, application of anti-IL-6 therapies did not improve survival of patients with metastatic prostate cancer. However, clinical trial design in the future may include different treatment schedule and combinations with experimental and clinical therapies. Endogenous inhibitors of IL-6 such as suppressors of cytokine signaling and protein inhibitors of activated STAT have variable effects on prostate cells, depending on presence or absence of the androgen receptor.


Asunto(s)
Interleucina-6 , Neoplasias de la Próstata , Humanos , Interleucina-6/metabolismo , Masculino , Fosforilación , Neoplasias de la Próstata/tratamiento farmacológico , Factor de Transcripción STAT3/genética
7.
Mol Carcinog ; 60(3): 188-200, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33544929

RESUMEN

Interaction between a tumor and its microenvironment is important for tumor initiation and progression. Cancer stem cells (CSCs) within the tumor interact with a microenvironmental niche that controls their maintenance and differentiation. We investigated the CSC-promoting effect of factors released from myofibroblasts into the microenvironment of early colorectal cancer tumors and its molecular mechanism. By messenger RNA microarray analysis, expression of HES1, a Notch signaling target, significantly increased in Caco-2 cells cocultured with 18Co cells (pericryptal myofibroblasts), compared to its expression in Caco-2 cells cultured alone. Caco-2 cells cultured in 18Co-conditioned media (CM) showed a significant increase in CD133+CD44+ cells and HES1 expression compared to that in Caco-2 cells cultured in regular media. Significant amounts of interleukin-6 (IL-6) and IL-8 were detected in 18Co-CM compared to levels in regular media. The 18Co-CM-induced increase in CD133+CD44+ cells was attenuated by IL-6- and IL-8-neutralizing antibodies. Furthermore, these neutralizing antibodies and inhibitors of STAT3 and gamma-secretase reduced the expression of HES1 induced in Caco-2 cells cultured in 18Co-CM. Immunohistochemical analysis of human tissues revealed that IL-6, IL-8, and HES1 expression increased from normal to adenoma, and from adenoma to cancer tissues. In addition, IL-6 and HES1 expression was positively correlated in early colorectal cancer tissues. In conclusion, the increase of CSCs by myofibroblasts could be mediated by IL-6/IL-8-induced HES1 activation in the tumor microenvironment. Based on these data, the IL-6/IL-8-mediated Notch/HES1 and STAT3 pathway, through which CSCs interact with their microenvironment, might be a potential target for the prevention and treatment of colorectal tumors.


Asunto(s)
Neoplasias Colorrectales/patología , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Células Madre Neoplásicas/patología , Factor de Transcripción HES-1/metabolismo , Células CACO-2 , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Medios de Cultivo Condicionados/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Organoides/patología , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción HES-1/genética , Microambiente Tumoral/efectos de los fármacos
8.
Carbohydr Polym ; 256: 117521, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33483042

RESUMEN

In our continuous searching for natural active polysaccharides with immunomodulatory activity, an arabinofuranan (AQP70-3) was isolated and purified from the fruits of Akebia quinata (Houtt.) Decne. by using ion-exchange chromatography and gel permeation chromatography for the first time. AQP70-3 contained both α-l-Araf and ß-l-Araf, and the absolute molecular weight was 1.06 × 104 g/mol. The backbone of AQP70-3 comprised →5)-α-l-Araf-(1→, →3,5)-α-l-Araf-(1→, and →2,5)-α-l-Araf-(1→, with branches of →1)-ß-l-Arafand →3)-α-l-Araf-(1→ residues. Biological assay suggested that AQP70-3 can stimulate phagocytic activity and promote the levels of nitric oxide (NO), interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α) of RAW264.7 cells. Furthermore, AQP70-3 was found to increase the production of reactive oxygen species (ROS) and NO in zebrafish embryo model.


Asunto(s)
Frutas/química , Factores Inmunológicos/química , Polisacáridos/química , Ranunculales/química , Especies Reactivas de Oxígeno/agonistas , Animales , Secuencia de Carbohidratos , Embrión no Mamífero , Factores Inmunológicos/aislamiento & purificación , Factores Inmunológicos/farmacología , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Ratones , Peso Molecular , Óxido Nítrico/inmunología , Óxido Nítrico/metabolismo , Fagocitosis/efectos de los fármacos , Extractos Vegetales/química , Polisacáridos/aislamiento & purificación , Polisacáridos/farmacología , Células RAW 264.7 , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Estereoisomerismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Pez Cebra
9.
Pharmacology ; 106(1-2): 20-28, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33395681

RESUMEN

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder characterized by degeneration of the articular cartilage and joint destruction with an associated risk of mobility disability in elderly people. Although a lot of achievements have been made, OA is still regarded as an incurable disease. Therefore, the pathological mechanisms and novel therapeutic strategies of OA need more investigation. METHODS: MTT assay was conducted to measure the viability of chondrocytes after LPS treatment. Cell apoptosis was analyzed by annexin V/propidium iodide labeling. ELISA was used to determine the concentrations of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in the culture supernatant of chondrocytes. The expression level of miR-155, IL-1ß, FOXO3, TNF-α, IL-6, caspase-3, and caspase-9 in chondrocytes was analyzed by RT-qPCR or Western blot. RESULTS: We found that LPS led to inflammatory responses, cell apoptosis, and increased miR-155 expression in human articular chondrocytes. Tanshinone IIA could inhibit LPS-induced inflammation and cell apoptosis of chondrocytes via regulating the expression of miR-155 and FOXO3. miR-155 directly targeted the 3'-UTR of FOXO3 to regulate its expression. CONCLUSIONS: Taken together, our data suggest tanshinone IIA ameliorates inflammation response in OA via inhibition of the miR-155/FOXO3 axis, and provide some evidences that tanshinone IIA could be designed and developed as a new promising clinical therapeutic drug for OA patients.


Asunto(s)
Abietanos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Proteína Forkhead Box O3/antagonistas & inhibidores , Inflamación/metabolismo , MicroARNs/antagonistas & inhibidores , Osteoartritis/tratamiento farmacológico , Regiones no Traducidas 3' , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Proteína Forkhead Box O3/metabolismo , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , MicroARNs/metabolismo , Osteoartritis/genética , Cultivo Primario de Células , Factor de Necrosis Tumoral alfa/metabolismo
10.
Aging (Albany NY) ; 13(2): 1620-1632, 2021 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-33429366

RESUMEN

Both lung adenocarcinoma and coronavirus disease 2019 would cause pulmonary inflammation. Angiotensin-converting enzyme 2, the functional receptor of SARS-CoV-2, also plays a key role in lung adenocarcinoma. To study the risk of SARS-CoV-2 infection in lung adenocarcinoma patients, mRNA and microRNA profiles were obtained from The Cancer Genome Atlas and Gene Expression Omnibus followed by bioinformatics analysis. A network which regards angiotensin-converting enzyme 2 as the center was structured. In addition, via immunological analysis to explore the essential mechanism of SARS-CoV-2 susceptibility in lung adenocarcinoma. Compared with normal tissue, angiotensin-converting enzyme 2 was increased in lung adenocarcinoma patients. Furthermore, a total of 7 correlated differently expressed mRNAs (ACE2, CXCL9, MMP12, IL6, AZU1, FCN3, HYAL1 and IRAK3) and 5 correlated differently expressed microRNAs (miR-125b-5p, miR-9-5p, miR-130b-5p, miR-381-3p and miR-421) were screened. Interestingly, the most frequent toll-like receptor signaling pathway was enriched by mRNA (interlukin 6) and miRNA (miR-125b-5p) sets simultaneously. In conclusion, it was assumed that miR-125b-5p-ACE2-IL6 axis could alter the risk of SARS-CoV-2 infection in lung adenocarcinoma patients.


Asunto(s)
Adenocarcinoma del Pulmón/virología , /complicaciones , Neoplasias Pulmonares/virología , Transcriptoma , Adenocarcinoma del Pulmón/metabolismo , Biología Computacional , Humanos , Interleucina-6/metabolismo , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Factores de Riesgo
11.
Life Sci ; 270: 119071, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33515562

RESUMEN

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a high incidence and mortality rate, and a rapid course of clinical development. Although miR-125b is closely associated with the pathogenesis of liver fibrosis and hepatocellular carcinoma, the role of miR-125b in NAFLD remains unknown. METHODS: The levels of TNF-α, IL-6, and IL-1ß expression were examined via ELISA assays. Real-time PCR was used to determine the levels of miR-125b and tumor necrosis factor alpha-induced protein 3 (TNFAIP3) expression. The related molecular mechanisms were examined by performing luciferase reporter, western blot, and immunofluorescence assays. Structural changes in the livers of mice with NAFLD were observed via H&E staining. RESULTS: The levels of TNF-α, IL-6, and IL-1ß in NAFLD patients were greatly increased, and miR-125b expression was significantly up-regulated. The phosphorylation of IκBα and p65, and secretion of inflammatory factors were all markedly decreased by miR-125b silencing, but greatly increased by miR-125b overexpression. We also demonstrated that downregulation of TNFAIP3 in NAFLD was negatively correlated with miR-125b. Interestingly, the influence of miR-125b inhibitors on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammatory responses were greatly aggravated by co-treatment with TNFAIP siRNA; however, the opposite results were obtained after treatment with miR-125b mimics and TNFAIP plasmids. Furthermore, the HF-induced liver damage and inflammatory responses were greatly ameliorated by miR-125b inhibitors but further aggravated by co-treatment with TNFAIP3 siRNA. CONCLUSION: MiR-125b promoted the NF-κB-mediated inflammatory response in NAFLD by directly targeting TNFAIP3, and that mechanism might be target for treating NAFLD.


Asunto(s)
MicroARNs/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Animales , Femenino , Células Hep G2 , Humanos , Inflamación/patología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Persona de Mediana Edad , Modelos Animales , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Transducción de Señal/fisiología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
12.
Nat Commun ; 12(1): 66, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397952

RESUMEN

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.


Asunto(s)
Hepatocitos/metabolismo , Interleucina-11/metabolismo , Lípidos/toxicidad , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal , Adulto , Animales , Comunicación Autocrina/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Conducta Alimentaria , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Interleucina-6/metabolismo , Ratones Noqueados , Modelos Biológicos , Comunicación Paracrina/efectos de los fármacos , Fenotipo , Transducción de Señal/efectos de los fármacos
14.
Cell Commun Signal ; 19(1): 7, 2021 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-33441142

RESUMEN

The cytokine release syndrome or cytokine storm, which is the hyper-induction of inflammatory responses has a central role in the mortality rate of COVID-19 and some other viral infections. Interleukin-6 (IL-6) is a key player in the development of cytokine storms. Shedding of interleukin-6 receptor (IL-6Rα) results in the accumulation of soluble interleukin-6 receptors (sIL-6R). Only relatively few cells express membrane-bound IL-6Rα. However, sIL-6R can act on potentially all cells and organs through the ubiquitously expressed gp130, the coreceptor of IL-6Rα. Through this, so-called trans-signaling, IL-6-sIL-6R is a powerful factor in the development of cytokine storms and multiorgan involvement. Some bacteria (e.g., Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes), commonly considered to cause co-infections during viral pneumonia, can directly induce the shedding of membrane receptors, including IL-6Rα, or enhance endogenous shedding mechanisms causing the increase of sIL-6R level. Here we hypothesise that bacteria promoting shedding and increase the sIL-6R level can be an important contributing factor for the development of cytokine storms. Therefore, inhibition of IL-6Rα shedding by drastically reducing the number of relevant bacteria may be a critical element in reducing the chance of a cytokine storm. Validation of this hypothesis can support the consideration of the prophylactic use of antibiotics more widely and at an earlier stage of infection to decrease the mortality rate of COVID-19. Video abstract.


Asunto(s)
Bacterias/enzimología , Proteínas Bacterianas/metabolismo , Síndrome de Liberación de Citoquinas/etiología , Metaloproteasas/metabolismo , /complicaciones , Síndrome de Liberación de Citoquinas/microbiología , Humanos , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Transducción de Señal
15.
Ecotoxicol Environ Saf ; 208: 111609, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396129

RESUMEN

With the wide application of neodymium oxide nanoparticles (NPs-Nd2O3) in various fields, their health hazards have aroused public concern in recent years. However, data regarding the cytotoxicity of NPs-Nd2O3 is limited. In this study, we investigated the function and mechanism of long-chain non-coding RNAs (lncRNAs) in NPs-Nd2O3-induced airway inflammation. Treatment with NPs-Nd2O3 induced an inflammatory response in human bronchial epithelial cells (16HBE) by upregulating the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8). The levels of LDH and intracellular ROS in the cells treated by various doses of NPs-Nd2O3 also increased significantly. After treatment with 10 µg/ml NPs-Nd2O3, RNA microarray and real-time quantitative polymerase chain reaction (qRT-PCR) showed a significant upregulation of lncRNA loc105377478. Functional experiments suggested lncRNA loc105377478 enhanced the expression of IL-6, IL-8 and ROS in NPs-Nd2O3-treated 16HBE cells, and it was further demonstrated that lncRNA loc105377478 promoted the activation of NF-κB by negatively regulating ADIPOR1 expression. Moreover, the expression of IL-6 and IL-8 in NPs-Nd2O3-treated 16HBE cells was regulated by lncRNA loc105377478, which was mediated by the NF-κB signaling pathway. In conclusion, lncRNA loc105377478 promotes NF-κB activation by negatively regulating ADIPOR1 expression, thereby upregulating the expression of IL-6 and IL-8 in 16HBE cells treated with NPs-Nd2O3.


Asunto(s)
Células Epiteliales/efectos de los fármacos , FN-kappa B/metabolismo , Nanopartículas/química , Nanopartículas/toxicidad , Neodimio/toxicidad , Óxidos/toxicidad , ARN Largo no Codificante/genética , Receptores de Adiponectina/metabolismo , Bronquios/efectos de los fármacos , Bronquios/inmunología , Bronquios/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Relación Dosis-Respuesta a Droga , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Inflamación , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neodimio/química , Óxidos/química , Transducción de Señal , Regulación hacia Arriba
16.
Trials ; 22(1): 43, 2021 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-33430891

RESUMEN

OBJECTIVES: The aim of this study is to assess the effectiveness and safety of glucocorticoid infusion pulse therapy to improve the clinical outcomes of patients with COVID-19 pneumonia with elevated inflammatory biomarkers. TRIAL DESIGN: A parallel-group quadruple-blind (participant, intervention provider, outcome assessor and data manager), randomised controlled trial. PARTICIPANTS: All patients admitted to hospital due to COVID-19 pneumonia will be considered eligible. Potential candidates will be identified and consecutively included in the emergency room or in the COVID-19 admission wards of two hospitals in Spain: Complejo Hospitalario de Navarra (Pamplona) and Hospital Moisès Broggi (Sant Joan Despí, Barcelona). Inclusion criteria are: 1) age ≥18 years old; 2) diagnosis of SARS-CoV-2 pneumonia confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal swabs or sputum in accordance with the recommendations of the Spanish Ministry of Health; 3) history of symptoms compatible with COVID-19 ≥7 days; 4) hospital admission; 5) at least one of the following: C-reactive protein (CRP) >60 mg/dL, interleukin-6 (IL-6) >40 pg/mL, and/or ferritin >1000 µg/L; and 6) provision of informed consent. Exclusion criteria are: 1) allergy or contraindication to any of the drugs under study; 2) oxygen saturation (SpO2) <90% (in air ambient) or partial pressure of oxygen in arterial blood (PaO2) <60 mmHg (in ambient air) or PaO2/FiO2 <300 mmHg; 3) ongoing treatment with glucocorticoids, or other immunosuppressants, including biologics for another indication; 4) decompensated diabetes mellitus; 5) uncontrolled hypertension; 6) psychotic or manic disorder; 7) active cancer; 8) pregnancy or breastfeeding; 9) clinical or biochemical suspicion (procalcitonin >0.5 ng/mL) of active infection other than with SARS-CoV-2; 10) management as an outpatient; 11) conservative or palliative management; 12) participation in another clinical trial; or 13) any major uncontrolled medical, psychological, psychiatric, geographic or social problem that contraindicates the patient's participation in the trial or hinders proper follow-up and adherence to the protocol and evaluation of study outcomes. INTERVENTION AND COMPARATOR: Eligible patients will be randomised to receive standard of care plus methylprednisolone (intervention group) or standard of care plus placebo (control group). Intervention group: standard of care at the discretion of the researcher, including lopinavir/ritonavir (200/50 mg, 2 tablets twice daily, per os, for 7 to 14 days) ± remdesivir (a single intravenous loading dose of 200 mg on day 1 followed by once-daily intravenous maintenance doses of 100 mg from day 2 to 5), or no drug treatment, + methylprednisolone (once-daily intravenous infusion of 120 mg on days 1, 2 and 3). CONTROL GROUP: standard of care at the discretion of the researcher, including lopinavir/ritonavir (200/50 mg, 2 tablets every 12 hours, per os, for 7 to 14 days) ± remdesivir (a single intravenous loading dose of 200 mg on day 1 followed by once-daily intravenous maintenance doses of 100 mg from day 2 to 5), or no drug treatment, + placebo (once-daily intravenous infusion of 100 mL of 0.9% saline on days 1, 2 and 3). MAIN OUTCOMES: The primary outcome is the proportion of patients with treatment failure at 14 days after randomisation, defined as: 1) death, 2) need for admission to an intensive care unit (ICU), 3) initiation of mechanical ventilation, 4) SpO2 falling to <90% (in ambient air) or PaO2 <60 mmHg (in ambient air) or PaO2FiO2 <300 mmHg, not explained by a cause other than COVID-19, and/or 5) decrease in PaO2 ≥15% from baseline, together with laboratory and radiological deterioration. RANDOMISATION: Treatment will be allocated by block randomisation stratified by patient age (< or ≥ 75 years of age). For this purpose, we will use the R randomizeR package using two block sizes (4 and 6) with random permutation. The randomisation sequence will be generated by a unit (the Navarrabiomed Clinical Trials Platform) independent from the researchers who will recruit patients and implement the protocol. BLINDING (MASKING): The study will be quadruple-blinded, specifically, with blinding of patients, intervention providers, outcome assessors and data managers. The pharmacy at each participating hospital will prepare indistinguishable bags of methylprednisolone or placebo (0.9% saline) for patients of the experimental and placebo groups, respectively. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The percentage of patients with treatment failure (primary endpoint) is currently unknown. Assuming an absolute difference of 25% in the primary outcome between the two groups (35% in the control group and 10% in the intervention group), we estimate that 60 patients (30 per group) are required to detect this difference with a two-tailed type I error of 0.05 and a type II error of 0.2. Estimating a loss to follow-up of 20%, we should recruit a total sample size of 72 patients (36 per group). TRIAL STATUS: The Spanish Agency of Medicines and Medical Devices (AEMPS) and the Ethics Committee of the University Hospital La Princesa approved version 7.0 of the protocol on 30 April 2020 as a low intervention clinical trial. Subsequently, the protocol has been amended by researchers and re-approved by AEMPS and the same ethics committee on 1 July 2020 (version 8.0) and on 28 August 2020 (version 9.0). Currently, the trial is in the recruitment phase. Recruitment began on 28 May 2020 and is expected to be completed by February 2021. TRIAL REGISTRATION: This study protocol was registered on the eudract.ema.europa.eu on 5 May 2020 (title "Early treatment of COVID-19 pneumonia with glucocorticoids. Randomized controlled clinical trial"; EudraCT Number: 2020-001827-15 ) and on clinicaltrials.gov on 19 June 2020 (title: "Glucocorticoids in COVID-19 (CORTIVID)"; identifier: NCT04438980 ). FULL PROTOCOL: The full protocol (version 9.0) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Metilprednisolona/uso terapéutico , Proteína C-Reactiva/metabolismo , Método Doble Ciego , Ferritinas/metabolismo , Hospitalización , Humanos , Infusiones Intravenosas , Interleucina-6/metabolismo , Quimioterapia por Pulso , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
17.
Nat Commun ; 12(1): 301, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436596

RESUMEN

Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve potentially conflicting cues in the microenvironment via mechanisms that are unclear. Here, we use single-cell RNA sequencing to explore how individual macrophages respond when co-stimulated with inflammatory stimuli LPS and IFN-γ and the resolving cytokine IL-4. These co-stimulated macrophages display a distinct global transcriptional program. However, variable negative cross-regulation between some LPS + IFN-γ-specific and IL-4-specific genes results in cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation leads to mutually exclusive expression of the T-cell-polarizing cytokine genes Il6 and Il12b versus the IL-4-associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion measurements show that these specialized functions are maintained for at least 48 h. This study suggests that increasing functional diversity in the population is one strategy macrophages use to respond to conflicting environmental cues.


Asunto(s)
Polaridad Celular , Macrófagos/citología , Animales , Arginasa/metabolismo , Polaridad Celular/efectos de los fármacos , Polaridad Celular/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Interferón gamma/farmacología , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Aprendizaje Automático , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Redes Neurales de la Computación , Oportunidad Relativa , Análisis de la Célula Individual , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos
18.
Gene ; 775: 145441, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33482280

RESUMEN

Exercise training with anti-inflammatory effects can improve insulin sensitivity in muscle tissue. This study investigated the effects of eight-week swimming exercises on lipid profile, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in gastrocnemius muscle of rats fed with high-fat diet (HFD). Thirty-two healthy male Wistar rats (8 weeks, 200 ± 20 g) were randomly divided into four groups (n = 8 each group): the control (C), aerobic exercise (E), HFD, and HFD + aerobic exercise (HFD & E). The exercise training protocol consisted of swimming 60 min/day, 5 days/week for eight weeks. Serum levels of glucose, insulin, and lipid profile were measured at end of the study. Protein expressions of TLR4, TNF-α, and IL-6 were determined by immunohistochemical method. Gene expression of TLR4/MyD88, TNF-α, IL-6, and PPAR-γ was evaluated by a real-time polymerase chain reaction in gastrocnemius muscle. HFD fed rats showed higher levels of cholesterol and LDL-c that were similar in weight gain. Meanwhile, the HFD group had a higher gene expression of TLR4, MyD88, TNF-α, IL-6, and lower gene expression of PPAR-γ compared to the control group (p < 0.05). Muscle protein expression of TLR4, TNF-α, IL-6 was lower in the E and HFD&E groups (especially when compared to HFD group, P < 0.05). We also showed a decrease in TLR4/MyD88 mRNA and an increase in PPAR-γ mRNA in gastrocnemius of E and HFD&E groups (compared to HFD group, p < 0.05). Insulin resistance in HFD&E groups show a significant decrease compared to the HFD group (p < 0.05). It seems that swimming aerobic exercise for eight weeks controlled the destructive effects of HFD on muscle inflammatory pathways along with the down-regulation of the TLR4/MyD88, inflammatory cytokine, and up-regulation PPAR-γ mRNA. It appears that the down-regulation in the expression of TLR4/MyD88 mRNA reduces the muscle pro-inflammatory cytokines, such as IL-6 and TNF-α, whose action may be caused by the adaptation of swimming aerobic exercise (an increase of PPAR-γ). Therefore, local and systemic inflammatory changes due to HFD and obesity may be affected by metabolic adaptations of aerobic exercise training, which requires further studies.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina/inmunología , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/métodos , Natación/fisiología , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
19.
Medicina (Kaunas) ; 57(1)2021 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-33435405

RESUMEN

Nowadays, humanity faces one of the most serious health crises, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The severity of coronavirus disease 2019 (COVID-19) pandemic is related to the high rate of interhuman transmission of the virus, variability of clinical presentation, and the absence of specific therapeutic methods. COVID-19 can manifest with non-specific symptoms and signs, especially among the elderly. In some cases, the clinical manifestations of hyponatremia may be the first to appear. The pathophysiological mechanisms of hyponatremia among patients with COVID-19 are diverse, including syndrome of inappropriate antidiuretic hormone secretion (SIADH), digestive loss of sodium ions, reduced sodium ion intake or use of diuretic therapy. Hyponatremia may also be considered a negative prognostic factor in patients diagnosed with COVID-19. We need further studies to evaluate the etiology and therapeutic management of hyponatremia in patients with COVID-19.


Asunto(s)
/metabolismo , Hiponatremia/metabolismo , Síndrome de Secreción Inadecuada de ADH/metabolismo , /complicaciones , Diuréticos/efectos adversos , Fluidoterapia/métodos , Humanos , Hiponatremia/epidemiología , Hiponatremia/etiología , Hiponatremia/terapia , Síndrome de Secreción Inadecuada de ADH/etiología , Incidencia , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Pronóstico , Solución Salina Hipertónica/uso terapéutico , Sodio en la Dieta
20.
Int J Nanomedicine ; 16: 471-480, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33500617

RESUMEN

Background: Doxil® (PEGylated liposomal doxorubicin, PLD) has been widely used in cancer treatment due to its excellent therapeutic efficacy, but it can simultaneously cause severe adverse effects such as hand-foot syndrome (HFS). To date, the pathophysiologic mechanism of HFS development induced by PLD administration has not been well understood. Materials and Methods: The histological features of skin lesion in PLD-induced HFS model were characterized by hematoxylin and eosin (H&E) staining and picrosirius red staining, and the induction of inflammation and apoptosis in the epidermal layer was detected by immunohistochemical and TUNEL staining. Moreover, the generation of reactive oxygen species (ROS) was determined to elucidate the potential mechanism of skin lesion in the development of HFS. Results: The administration of PLD has been demonstrated to induce the histological damage of skin tissues including the destruction of collagen fibers and the induction of severe inflammation and apoptosis of epidermal cells. The mechanism was probably attributed to the accumulation of PLD in the skin tissues during the long-term circulation and further the induction of ROS to cause the oxidative damage of keratinocytes owing to the sustained release of doxorubicin from PLD. Conclusion: The ROS generation induced by the administration of PLD has been identified to be a crucial factor in the development of HFS, which could be used as a potential therapeutic target to alleviate the HFS symptom of PLD administration.


Asunto(s)
Apoptosis , Doxorrubicina/análogos & derivados , Síndrome Mano-Pie/etiología , Síndrome Mano-Pie/patología , Inflamación/patología , Polietilenglicoles/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Animales , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Queratinocitos/efectos de los fármacos , Polietilenglicoles/administración & dosificación , Ratas Wistar , Piel/patología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...