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1.
Br J Radiol ; 94(1117): 20200634, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33296222

RESUMEN

OBJECTIVES: To identify the value of radiomics method derived from CT images to predict prognosis in patients with COVID-19. METHODS: A total of 40 patients with COVID-19 were enrolled in the study. Baseline clinical data, CT images, and laboratory testing results were collected from all patients. We defined that ROIs in the absorption group decreased in the density and scope in GGO, and ROIs in the progress group progressed to consolidation. A total of 180 ROIs from absorption group (n = 118) and consolidation group (n = 62) were randomly divided into a training set (n = 145) and a validation set (n = 35) (8:2). Radiomics features were extracted from CT images, and the radiomics-based models were built with three classifiers. A radiomics score (Rad-score) was calculated by a linear combination of selected features. The Rad-score and clinical factors were incorporated into the radiomics nomogram construction. The prediction performance of the clinical factors model and the radiomics nomogram for prognosis was estimated. RESULTS: A total of 15 radiomics features with respective coefficients were calculated. The AUC values of radiomics models (kNN, SVM, and LR) were 0.88, 0.88, and 0.84, respectively, showing a good performance. The C-index of the clinical factors model was 0.82 [95% CI (0.75-0.88)] in the training set and 0.77 [95% CI (0.59-0.90)] in the validation set. The radiomics nomogram showed optimal prediction performance. In the training set, the C-index was 0.91 [95% CI (0.85-0.95)], and in the validation set, the C-index was 0.85 [95% CI (0.69-0.95)]. For the training set, the C-index of the radiomics nomogram was significantly higher than the clinical factors model (p = 0.0021). Decision curve analysis showed that radiomics nomogram outperformed the clinical model in terms of clinical usefulness. CONCLUSIONS: The radiomics nomogram based on CT images showed favorable prediction performance in the prognosis of COVID-19. The radiomics nomogram could be used as a potential biomarker for more accurate categorization of patients into different stages for clinical decision-making process. ADVANCES IN KNOWLEDGE: Radiomics features based on chest CT images help clinicians to categorize the patients of COVID-19 into different stages. Radiomics nomogram based on CT images has favorable predictive performance in the prognosis of COVID-19. Radiomics act as a potential modality to supplement conventional medical examinations.


Asunto(s)
/diagnóstico por imagen , Nomogramas , Tomografía Computarizada por Rayos X , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Distribución Aleatoria , Estudios Retrospectivos
2.
Mol Cell Endocrinol ; 520: 111095, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33253762

RESUMEN

The literature has reported a higher prevalence of negative clinical outcomes due to Coronavirus disease 19 (COVID-19) in obese individuals. This can be explained by the cytokine storm, result from the cytokine production from both obesity and viral infection. Gamma-oryzanol (γOz) is a compound with anti-inflammatory and antioxidant activities. However, little is known about the γOz action as a possible agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of this study was to test the hypothesis that γOz attenuates the cytokine storm by stimulating PPAR-γ in the adipose tissue. METHODS: Male Wistar rats were randomly divided into three experimental groups and fed ad libitum for 30 weeks with control diet (C, n = 6), high sugar-fat diet (HSF, n = 6) or high sugar-fat diet + Î³Oz (HSF + Î³Oz, n = 6). HSF groups also received water + sucrose (25%). The γOz dose was 0.5% in the chow. Evaluation in animals included caloric intake, body weight, adiposity index, plasma triglycerides, and HOMA-IR. In adipose tissue was evaluated: PPAR-γ gene and protein expression, inflammatory and oxidative stress parameters, and histological analysis. RESULTS: Adipose tissue dysfunction was observed in HSF group, which presented remarkable PPAR-γ underexpression and increased levels of cytokines, other inflammatory markers and oxidative stress. The γOz treatment prevented adipose tissue dysfunction and promoted PPAR-γ overexpression. CONCLUSION: Natural compounds as γOz can be considered a coadjutant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions.


Asunto(s)
Tejido Adiposo/metabolismo , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , PPAR gamma/metabolismo , Fenilpropionatos/farmacología , /metabolismo , Tejido Adiposo/patología , Tejido Adiposo/virología , Animales , /patología , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Inflamación/virología , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar
3.
Toxicology ; 447: 152627, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33161053

RESUMEN

PM2.5 exposure elevates the level of reactive oxygen species (ROS) in the lungs and leads to lung injury or other pulmonary conditions. Nrf2 is a key antioxidative regulator that suppresses ROS production. Extracellular vesicles (EVs) secreted by adipose mesenchymal stem cells (ADSCs) have been identified as therapeutic as well as potential drug/gene/protein carriers. In this study, we established rat (PM2.5, 100 µL, 5 mg/mL) or cell (PM2.5, 50 µg/mL) models to conduct in vivo and in vitro studies on the adverse pulmonary effects of PM2.5. Our findings indicated that the initial responses to PM2.5 exposure were robust oxidative stress and inflammation. EVs and antioxidative EVs (Antioxi-EVs, derived from ADSCs that overexpress Nrf2) had been tested as interventions in PM2.5-treated rat or cell models through tracheal instillation or co-incubation. Treatment with EVs or Antioxi-EVs (3 × 1010 particles in vivo and 1 × 109in vitro) was found to have a suppressive effect on the levels of ROS and inflammatory cytokines, with Antioxi-EVs having a superior effect on anti-oxidative stress. In particular, the occurrence of lung injury or cell apoptosis correlated positively with the ROS level, and inhibition of ROS by upregulating Nrf2 alleviated lung injury and cell apoptosis. Furthermore, treatment with EVs or Antioxi-EVs increased the level of M2-like macrophages as compared to treatment with PBS and further reduced IL-6 and TNF-α levels. Our results suggest that Antioxi-EVs can reduce the severity of oxidative stress, inflammation, and lung injury induced by PM2.5via anti-oxidative stress and immunomodulation pathways.


Asunto(s)
Tejido Adiposo/trasplante , Antioxidantes/administración & dosificación , Vesículas Extracelulares/trasplante , Inmunomodulación/fisiología , Trasplante de Células Madre Mesenquimatosas/métodos , Estrés Oxidativo/fisiología , Material Particulado/toxicidad , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/terapia , Tejido Adiposo/citología , Animales , Inmunomodulación/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno
4.
Toxicol Appl Pharmacol ; 410: 115343, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33227293

RESUMEN

Hazard evaluation of graphene-based materials (GBM) is still in its early stage and it is slowed by their large diversity in the physicochemical properties. This study explores transcriptomic differences in the lung and liver after pulmonary exposure to two GBM with similar physical properties, but different surface chemistry. Female C57BL/6 mice were exposed by a single intratracheal instillation of 0, 18, 54 or 162 µg/mouse of graphene oxide (GO) or reduced graphene oxide (rGO). Pulmonary and hepatic changes in the transcriptome were profiled to identify commonly and uniquely perturbed functions and pathways by GO and rGO. These changes were then related to previously analyzed toxicity endpoints. GO exposure induced more differentially expressed genes, affected more functions, and perturbed more pathways compared to rGO, both in lung and liver tissues. The largest differences were observed for the pulmonary innate immune response and acute phase response, and for hepatic lipid homeostasis, which were strongly induced after GO exposure. These changes collective indicate a potential for atherosclerotic changes after GO, but not rGO exposure. As GO and rGO are physically similar, the higher level of hydroxyl groups on the surface of GO is likely the main reason for the observed differences. GO exposure also uniquely induced changes in the transcriptome related to fibrosis, whereas both GBM induced similar changes related to Reactive Oxygen Species production and genotoxicity. The differences in transcriptomic responses between the two GBM types can be used to understand how physicochemical properties influence biological responses and enable hazard evaluation of GBM and hazard ranking of GO and rGO, both in relation to each other and to other nanomaterials.


Asunto(s)
Grafito/toxicidad , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Absorción a través del Sistema Respiratorio/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Animales , Femenino , Grafito/administración & dosificación , Hígado/patología , Hígado/fisiología , Pulmón/patología , Pulmón/fisiología , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Absorción a través del Sistema Respiratorio/fisiología , Transcriptoma/fisiología
5.
Toxicol Appl Pharmacol ; 410: 115340, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33264646

RESUMEN

BACKGROUND AND AIM: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75µg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner. METHODS: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. RESULTS: OCT pretreatment at doses (50 or 75 µg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. CONCLUSION: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.


Asunto(s)
Melatonina/administración & dosificación , FN-kappa B/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Octreótido/administración & dosificación , Piroptosis/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Receptor Toll-Like 4/antagonistas & inhibidores , Animales , Antioxidantes/administración & dosificación , Quimioterapia Combinada , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/fisiología , Distribución Aleatoria , Ratas , Daño por Reperfusión/metabolismo , Receptor Toll-Like 4/metabolismo
6.
Life Sci ; 264: 118605, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33096119

RESUMEN

The purpose of this study was to prepare non-PEGylated (HSPC/DSPG/Chol, LIPF1) and PEGylated (HSPC/DSPG/Chol/mPEG2000-DSPE, LIPF2) liposomal formulations containing Interferon-gamma (IFN-γ) and evaluation their effects on macrophages and their antitumor properties. The results showed that the size of liposomal formulations LIP-F1 and LIP-F2 was 120 and 135 nm, respectively. The encapsulation efficiencies of LIP-F1 and LIP-F2 were 52.79% and 49.2%, respectively. Nitric Oxide Synthase (INOS) and arginase assays showed an increase in nitric oxide (NO) level and a reduction in arginase level after the treatment of M2 phenotype macrophage cell line with IFN-γ liposomes. The biodistribution study illustrated the amplitude of iodinated-IFN-γ liposomal formulations in the tumor site, the circulation time and tumor accumulation of LIP-F2 was significantly more than LIPF1. As a result, PEGylated liposomes containing IFN-γ induced significant antitumor responses due to the increased delivery of the cargo to the immune cells and induction of antitumor immune responses.


Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Modelos Animales de Enfermedad , Inmunoterapia/métodos , Interferón gamma/administración & dosificación , Nanopartículas/administración & dosificación , Animales , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Femenino , Interferón gamma/inmunología , Interferón gamma/farmacocinética , Liposomas , Ratones , Ratones Endogámicos BALB C , Nanopartículas/metabolismo , Distribución Aleatoria , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiología
7.
Biochem Pharmacol ; 183: 114302, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33121927

RESUMEN

Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 µM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form ß of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1ß and TNF-α in serum. In conclusion, oral administration of crystal form ß of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.


Asunto(s)
Antioxidantes/uso terapéutico , /patología , Flavanonas/uso terapéutico , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Antioxidantes/farmacocinética , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Femenino , Flavanonas/farmacocinética , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Células Vero
8.
Life Sci ; 265: 118789, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33220291

RESUMEN

AIMS: The objectives of this study were to explore physiological and pathological changes in the corneas of diabetic rats by intervening in the expression of silent information regulator 1 (Sirt1) and to investigate whether Sirt1 can regulate the activation of endoplasmic reticulum stress (ERS) while influencing corneal epithelial cell apoptosis under high glucose conditions. MATERIALS AND METHODS: Using 8-week old Sprague-Dawley rats, we established a model of type 1 diabetes, with or without Sirt1 intervention. Clinical evaluation was performed once per week. Primary rat corneal epithelial cells (RCECs) were cultured by combining Sirt1 intervention under high glucose conditions. Generation of reactive oxygen species (ROS), apoptosis, and the expression of Sirt1 and ERS-related proteins were evaluated in rat corneal tissues and RCECs. KEY FINDINGS: During the intervention, clinical evaluation of the ocular surface, ROS generation, apoptosis, and protein expression of ERS-related proteins in corneal tissue and cultured RCECs were altered with Sirt1expression levels. SIGNIFICANCE: Sirt1 expression influences the pathological progression of diabetic keratopathy, plays an important role in regulating the ERS pathway, and decreases corneal epithelial cell apoptosis.


Asunto(s)
Enfermedades de la Córnea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Sirtuina 1/biosíntesis , Animales , Células Cultivadas , Enfermedades de la Córnea/genética , Enfermedades de la Córnea/patología , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Células Epiteliales/metabolismo , Femenino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Sirtuina 1/genética
9.
Life Sci ; 265: 118786, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33221346

RESUMEN

AIMS: To assess the effects of three specific exercise training modes, aerobic exercise (A), resistance training (R) and autonomous climbing (AC), aimed at proposing a cross-training method, on improving the physical, molecular and metabolic characteristics of mice without many side effects. MATERIALS AND METHODS: Seven-week-old male mice were randomly divided into four groups: control (C), aerobic exercise (A), resistance training (R), and autonomous climbing (AC) groups. Physical changes in mice were tracked and analysed to explore the similarities and differences of these three exercise modes. Histochemistry, quantitative real-time PCR (RT-PCR), western blot (WB) and metabolomics analysis were performed to identify the underlying relationships among the three training modes. KEY FINDINGS: Mice in the AC group showed better body weight control, glucose and energy homeostasis. Molecular markers of myogenesis, hypertrophy, antidegradation and mitochondrial function were highly expressed in the muscle of mice after autonomous climbing. The serum metabolomics landscape and enriched pathway comparison indicated that the aerobic oxidation pathway (pentose phosphate pathway, galactose metabolism and fatty acid degradation) and amino acid metabolism pathway (tyrosine, arginine and proline metabolism) were significantly enriched in group AC, suggesting an increased muscle mitochondrial function and protein balance ability of mice after autonomous climbing. SIGNIFICANCE: We propose a new exercise mode, autonomous climbing, as a convenient but effective training method that combines the beneficial effects of aerobic exercise and resistance training.


Asunto(s)
Prueba de Esfuerzo/métodos , Fuerza de la Mano/fisiología , Músculo Esquelético/fisiología , Condicionamiento Físico Animal/métodos , Condicionamiento Físico Animal/fisiología , Entrenamiento de Resistencia/métodos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria
10.
Life Sci ; 265: 118788, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33245966

RESUMEN

AIM: This study aimed to investigate the regulatory role of differentially-expressed circular RNAs (circRNAs) in mouse cardiomyocytes during doxorubicin (DOX)-induced cardiotoxicity. MAIN METHODS: Two groups of mice were injected with equal volumes (0.1 mL) of normal saline and DOX. Mouse heart tissue was isolated and digested for total RNA extraction and then subjected to next-generation RNA-sequencing. Expression profiles of circRNAs and circRNA-miRNA-mRNA networks were also constructed. Overall, 48 upregulated and 16 downregulated circRNAs were found to be statistically significant (p < 0.05) in the DOX-injected group. Bioinformatics analysis revealed several potential biological pathways that might be related to apoptosis caused by DOX-induced cardiotoxicity. In addition, using qRT-PCR, we found that a circRNA coded by the Arhgap12 gene, termed circArhgap12, was upregulated in the mouse heart tissue upon DOX intervention. CircArhgap12 enhanced apoptotic cell rate, as assessed using terminal-deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, and increased reactive oxygen species and malondialdehyde release as well as superoxide dismutase and caspase-3 activation. Using a luciferase reporter assay, we found that circArhgap12 could sponge miR-135a-5p. In rat primary cardiomyocytes, we found that si-circArhgap12 promoted apoptosis and oxidative stress by sponging the miR-135a-5p inhibitor. Using bioinformatics analysis and luciferase reporter assay, we found that miR-135a-5p might have a potential target site for ADCY1 mRNA. KEY FINDINGS: Our research demonstrated that the expression profile of circRNAs was modified significantly and that circArhgap12 might play a competitive role among endogenous RNAs in mouse cardiomyocytes during DOX-induced cardiotoxicity. SIGNIFICANCE: Our study may provide a preliminary understanding of DOX-induced cardiotoxicity modulated by circRNA and its competing endogenous RNAs network.


Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Cardiotoxicidad/metabolismo , Doxorrubicina/toxicidad , Proteínas Activadoras de GTPasa/biosíntesis , MicroARNs/biosíntesis , ARN Circular/biosíntesis , Animales , Cardiotoxicidad/genética , Células Cultivadas , Proteínas Activadoras de GTPasa/genética , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , ARN Circular/genética , Distribución Aleatoria , Ratas
11.
J Surg Res ; 257: 468-476, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32896815

RESUMEN

BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Obtención de Tejidos y Órganos , Animales , Muerte , Evaluación Preclínica de Medicamentos , Corazón/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-18/antagonistas & inhibidores , Interleucina-18/genética , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/genética , Masculino , Ratones Noqueados , Daño por Reperfusión Miocárdica/metabolismo , Distribución Aleatoria
12.
Nat Microbiol ; 6(1): 11-18, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33273742

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.


Asunto(s)
Antivirales/farmacología , /transmisión , Citidina/análogos & derivados , Hidroxilaminas/farmacología , /efectos de los fármacos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Animales , Chlorocebus aethiops , Citidina/farmacología , Citocinas/inmunología , Modelos Animales de Enfermedad , Transmisión de Enfermedad Infecciosa/prevención & control , Femenino , Hurones , Distribución Aleatoria , Células Vero
13.
Ann Otol Rhinol Laryngol ; 130(2): 182-187, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32749146

RESUMEN

OBJECTIVE: Iatrogenic injury is a common cause of subglottic stenosis (SGS). We investigated the role of pre-injury dexamethasone as a preventive treatment for iatrogenic subglottic stenosis. METHODS: 16 New Zealand White rabbits were used in an IACUC approved study. Subjects were divided into two groups: intramuscular dexamethasone (DEX) at a dose of 2 mg/kg 15 minutes prior to an endoscopic injury to create SGS, and the same injury creation with a preoperative intramuscular saline (SAL) injection. Three independent, blinded raters evaluated endoscopic images to obtain cross sectional area (CSA) airway measurements. Rabbit airways were measured just prior to injury and at one week post-injury. All subjects were provided as-needed postoperative steroids and buprenorphine for symptoms of respiratory distress. Data analysis was performed using Student t-test. Intraclass correlation coefficients were used to assess inter-rater agreement. RESULTS: All subjects survived to the one-week post-injury airway evaluation. There was no difference in airway size between groups prior to injury (P = .28). Subjects in the DEX group demonstrated an average stenosis of 20.3% (95% CI 10.2-30.5) at one week compared to 60.6% (95% CI 40.3-80.9) in the SAL group (P = .01). Subjects in the control group required significantly more doses of postoperative dexamethasone (P = .02). Inter-rater agreement for between raters was excellent (ICC = .88). CONCLUSION: This is the first study to examine the role of pre-injury glucocorticoids in preventing iatrogenic subglottic stenosis. In our model, a single dose of intramuscular dexamethasone given prior to a subglottic injury resulted in a statistically significant reduction in airway stenosis. This research suggests that administering systemic dexamethasone should be considered prior to any procedure that may injure the subglottis, including traumatic intubation, to prevent iatrogenic subglottic stenosis.


Asunto(s)
Dexametasona/administración & dosificación , Glucocorticoides/administración & dosificación , Enfermedad Iatrogénica , Laringoestenosis/prevención & control , Animales , Modelos Animales de Enfermedad , Inyecciones Intramusculares , Laringoscopía , Conejos , Distribución Aleatoria
14.
Toxicol Appl Pharmacol ; 410: 115336, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33212065

RESUMEN

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. The abnormal activation of glycolytic metabolism and PTEN/AKT signaling in NSCLC cells are highly correlated with their proliferation abilities and viability. Ligustilide is one of the major bioactive components of multiple Chinese traditional medicine including Angelica sinensis and Ligusticum. Ligustilide exposure inhibits the proliferation and viability of multiple cancer cell lines in vitro. However, the impact of ligustilide to the progression of NSCLC and its detailed pharmacological mechanisms remain unclear. In this research, CCK-8 and colony formation assay were performed to demonstrate ligustilide treatment inhibited the viability and proliferation ability of NSCLC cells in vitro. Caspase-3/-7 activity assay and nucleosome ELISA assay were utilized to show ligustilide promoted the apoptosis of NSCLC cells. Metabolic analysis and qRT-PCR assay were used to demonstrated that ligustilide dampened aerobic glycolysis of NSCLC cells. Nude mice were exposed to 5 mg/kg ligustilide and ligustilide inhibited orthotopic NSCLC growth in vivo. qRT-PCR and Western blot analysis were performed to substantiate the regulatory function of ligustilide to PTEN/AKT signaling in NSCLC cells. Overall, this study revealed that ligustilide regulated the proliferation, apoptosis and aerobic glycolysis of NSCLC cells through PTEN/AKT signaling pathway.


Asunto(s)
4-Butirolactona/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular/efectos de los fármacos , Glucólisis/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , 4-Butirolactona/farmacología , 4-Butirolactona/uso terapéutico , Células A549 , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proliferación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Glucólisis/fisiología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Distribución Aleatoria
15.
Acta Psychol (Amst) ; 212: 103215, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33316458

RESUMEN

We explore dance video clip stimuli as a means to test human observers' accuracy in detecting genuine emotional expressivity in full-body movements. Stimuli of every-day-type full-body expressions of emotions usually use culturally very recognizable actions (e.g. fist shaking for anger, etc). However, expressive dance movement stimuli can be created to contain fully abstract movements. The expressivity results from subtle variations in the body movements of the expressor, and emotions cannot be recognised by observers via particular actions (e.g. fist shaking, etc). Forty-one participants watched and rated 24 pairs of short dance videos -from a published normalised dance stimuli library- in randomised order (N = 48). Of each carefully matched pair, one version of the full-body movement sequence had been danced to be emotionally genuinely expressive (clip a), while the other version of the same sequence (clip b) had been danced -while technically correct- without any emotional expressivity. Participants rated (i) expressivity (to test their accuracy; block 1), and (ii) how much they liked each movement (an implicit measure to test their emotional response ("liking"); block 2). Participants rated clips that were intended to be expressive as more expressive (part 1: expressivity ratings), and liked those expressive clips more than the non-expressive clips (part 2: liking ratings). Besides, their galvanic skin response differed, depending on the category of clips they were watching (expressive vs. non-expressive), and this relationship was modulated by interceptive accuracy and arts experience. Results are discussed in relation to the Body Precision Hypothesis and the Hypothesis of Constructed Emotion.


Asunto(s)
Baile , Emociones , Movimiento , Respuesta Galvánica de la Piel , Humanos , Psicofisiología , Distribución Aleatoria
16.
Chemosphere ; 262: 127792, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32805656

RESUMEN

Tebuconazole is a triazole fungicide, used in agriculture to treat phytopathogenic fungi, and as a biocide, has been reported to be related to reproductive and developmental toxicity. The purpose of this study was to investigate the effect of tebuconazole exposure on rat fetal Leydig cells and fetal testis during pregnancy. Pregnant Sprague-Dawley rats were randomly divided into 4 groups, daily gavaged with corn oil (as a control), 25, 50, and 100 mg/kg body weight tebuconazole for 10 days (from the 12th day of pregnancy). Tebuconazole increased fetal serum testosterone and progesterone levels at a dose of 100 mg/kg. Exposure to 100 mg/kg tebuconazole significantly caused an increase in the number of fetal Leydig cells per testis without inducing cell aggregation. Tebuconazole up-regulated the expression of Star, Cyp11a1, Hsd17b3, and Fshr and their proteins. Further investigation found that tebuconazole caused increased phosphorylation of AKT1, ERK1/2, and mTOR, the level of BCL2, as well as the decrease of Beclin1, LC3B, and BAX, which may contribute to the fetal Leydig cell autophagy and proliferation. In conclusion, in utero exposure of tebuconazole causes the proliferation of fetal Leydig cells.


Asunto(s)
Fungicidas Industriales/toxicidad , Células Intersticiales del Testículo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Reproducción/efectos de los fármacos , Triazoles/toxicidad , Animales , Femenino , Células Intersticiales del Testículo/metabolismo , Masculino , Fosfoproteínas/genética , Fosforilación , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testículo/embriología , Testículo/patología , Testosterona/sangre , Regulación hacia Arriba
17.
Exp Parasitol ; 220: 108042, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33207240

RESUMEN

The aim of the current investigation was to assess the impacts of methanolic extract of Allium sativum (MEAS) on IL-4 (a cytokine derived from Th2 cells) and IFN-É£ (a cytokine derived from Th1 cells) levels in mice infected with Echinococcus granulosus. Sixty healthy BALB/c female mice were used in this study. Each animal was intraperitoneally injected with 1500 protoscoleces. The infected animals were randomly divided into six groups: albendazole (100 mg/kg), MEAS 10 (10 mg/kg), MEAS 20 (20 mg/kg), MEAS 40 (40 mg/kg), MEAS 80 (80 mg/kg) and control group with no treatment. The studied animals received albendazole and/or MEAS through drinking water for 30 days. Serum IFN-γ concentration significantly increased in the MEAS 20 and 80 groups in comparison to the control, albendazole and MEAS 10 groups (P < 0.05). The serum IL-4 level showed no significant difference between the trial groups. The findings of this study showed that MEAS at 20 and 80 mg/kg concentrations enhanced Th1 cell response in mice with cystic echinococcosis.


Asunto(s)
Equinococosis/tratamiento farmacológico , Echinococcus granulosus/inmunología , Ajo/química , Interferón gamma/sangre , Interleucina-4/sangre , Extractos Vegetales/farmacología , Administración Oral , Albendazol/administración & dosificación , Albendazol/farmacología , Albendazol/uso terapéutico , Animales , Anticestodos/administración & dosificación , Anticestodos/farmacología , Anticestodos/uso terapéutico , Agua Potable/química , Equinococosis/inmunología , Echinococcus granulosus/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Distribución Aleatoria
18.
PLoS One ; 15(12): e0243007, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33284796

RESUMEN

Because leg injuries produce welfare concerns and impact production for broilers, numerous interventions have been suggested as potential solutions. One mineral which may affect bone quality is silicon. The objective of this study was to determine if supplementing bioavailable silicon could affect bone morphology, mineralization, and strength without negatively influencing welfare and meat quality. Male broilers were raised from d 1 after hatching until 42 d of age and randomly assigned to treatment groups for silicon supplementation in water: Control (no supplement, C; n = 125), Normal (0.011 ml supplement/kg bodyweight, N; n = 125) and High (0.063 ml supplement/kg bodyweight, H; n = 125). Toe damage, footpad dermatitis, hock burn, and keel blisters were assessed on d 42. Blood samples were collected from wing veins for serum osteocalcin, pyridinoline cross-links, and mineral analysis. Clinical QCT scans and analysis were conducted immediately before four-point bending tests of tibias. Texture analysis was performed on cooked fillets. Silicon supplementation tended to increase daily water consumption in N and H as compared to C (P = 0.07). Footpad dermatitis and hock burn scores were higher in H than in N or C (P < 0.05 for both comparisons). Supplementation altered serum minerals (P < 0.001), but bone density, morphology, and strength measures were similar among groups. The highest level of supplementation in the current study on a kg bodyweight basis was above recommended intakes but below previous amounts demonstrating silicon's positive influence on bone, indicating that previously suggested minimum thresholds need to be reevaluated. Factors such as growth rate and mechanical loading likely play a greater role in developing bone quality than trying to supplement on top of good basic nutrition alone.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Huesos/fisiología , Silicio/administración & dosificación , Aminoácidos/sangre , Alimentación Animal/análisis , Animales , Peso Corporal/efectos de los fármacos , Huesos/diagnóstico por imagen , Huesos/efectos de los fármacos , Pollos , Suplementos Dietéticos , Masculino , Osteocalcina/sangre , Distribución Aleatoria , Silicio/farmacología , Tomografía Computarizada por Rayos X
19.
PLoS One ; 15(12): e0233200, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33264283

RESUMEN

The evaluation of cultivars using multi-environment trials (MET) is an important step in plant breeding programs. One of the objectives of these evaluations is to understand the genotype by environment interaction (GEI). A method of determining the effect of GEI on the performance of cultivars is based on studies of adaptability and stability. Initial studies were based on linear regression; however, these methodologies have limitations, mainly in trials with genetic or statistical unbalanced, heterogeneity of residual variances, and genetic covariance. An alternative would be the use of random regression models (RRM), in which the behavior of the genotypes is characterized as a reaction norm using longitudinal data or repeated measurements and information regarding a covariance function. The objective of this work was the application of RRM in the study of the behavior of common bean cultivars using a MET, based on Legendre polynomials and genotype-ideotype distances. We used a set of 13 trials, which were classified as unfavorable or favorable environments. The results revealed that RRM enables the prediction of the genotypic values of cultivars in environments where they were not evaluated with high accuracy values, thereby circumventing the unbalanced of the experiments. From these values, it was possible to measure the genotypic adaptability according to ideotypes, according to their reaction norms. In addition, the stability of the cultivars can be interpreted as variation in the behavior of the ideotype. The use of ideotypes based on real data allowed a better comparison of the performance of cultivars across environments. The use of RRM in plant breeding is a good alternative to understand the behavior of cultivars in a MET, especially when we want to quantify the adaptability and stability of genotypes.


Asunto(s)
Adaptación Fisiológica/genética , Interacción Gen-Ambiente , Modelos Genéticos , Fitomejoramiento/métodos , Plantas/genética , Algoritmos , Altitud , Brasil , Inestabilidad Genómica , Genotipo , Funciones de Verosimilitud , Phaseolus/genética , Phaseolus/fisiología , Probabilidad , Distribución Aleatoria , Análisis de Regresión , Estaciones del Año
20.
PLoS One ; 15(12): e0239888, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33264302

RESUMEN

BACKGROUND: Human challenge models for enterotoxigenic Escherichia coli (ETEC) facilitate vaccine down-selection. The B7A (O148:H28 CS6+LT+ST+) strain is important for vaccine development. We sought to refine the B7A model by identifying a dose and fasting regimen consistently inducing moderate-severe diarrhea. METHODS: An initial cohort of 28 subjects was randomized (1:1:1:1) to receive B7A following an overnight fast at doses of 108 or 109 colony forming units (cfu) or a 90-minute fast at doses of 109 or 1010 cfu. A second cohort included naïve and rechallenged subjects who had moderate-severe diarrhea and were given the target regimen. Immune responses to important ETEC antigens were assessed. RESULTS: Among subjects receiving 108 cfu of B7A, overnight fast, or 109 cfu, 90-minute fast, 42.9% (3/7) had moderate-severe diarrhea. Higher attack rates (71.4%; 5/7) occurred in subjects receiving 109 cfu, overnight fast, or 1010 cfu, 90-minute fast. Upon rechallenge with 109 cfu of B7A, overnight fast, 5/11 (45.5%) had moderate-severe diarrhea; the attack rate among concurrently challenge naïve subjects was 57.9% (11/19). Anti-CS6, O148 LPS and LT responses were modest across all groups. CONCLUSIONS: An overnight fast enabled a reduction in the B7A inoculum dose; however, the attack rate was inconsistent and protection upon rechallenge was minimal.


Asunto(s)
Antígenos Bacterianos/análisis , Diarrea/etiología , Escherichia coli Enterotoxigénica/patogenicidad , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/análisis , Vacunas contra Escherichia coli , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/inmunología , Carga Bacteriana , Toxinas Bacterianas/inmunología , Ciprofloxacino/uso terapéutico , Diarrea/microbiología , Diarrea/terapia , Relación Dosis-Respuesta Inmunológica , Escherichia coli Enterotoxigénica/inmunología , Escherichia coli Enterotoxigénica/aislamiento & purificación , Enterotoxinas/inmunología , Infecciones por Escherichia coli/prevención & control , Proteínas de Escherichia coli/inmunología , Ayuno , Heces/microbiología , Femenino , Fluidoterapia , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lipopolisacáridos/inmunología , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Factores de Tiempo , Adulto Joven
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