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1.
Gene ; 764: 145083, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-32860902

RESUMEN

BACKGROUND/AIMS: Melamine (ML) is a common food adulterant and contaminant. Moringa oleifera is a well-known medicinal plant with many beneficial biological properties. This study investigated the possible prophylactic and therapeutic activity of an ethanolic extract of M. oleifera (MEE) against ML-induced hepatorenal damage. METHOD: Fifty male Sprague Dawley rats were orally administered distilled water, MEE (800 mg/kg bw), ML (700 mg/kg bw), MEE/ML (prophylactically) or MEE+ML (therapeutically). Hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphate (ALP) in serum were measured. Serum total bilirubin, direct bilirubin, indirect bilirubin, protein, albumin, and globulin contents were also assayed, and urea and creatinine levels were determined. Moreover, antioxidant enzyme activity of glutathione peroxidase (GPx) and catalase (CAT) in serum levels were quantified. Complementary histological and histochemical evaluation of renal and hepatic tissues was conducted, and expression of oxidative stress (GPx and CAT) and apoptosis-related genes, p53 and Bcl-2, in hepatic tissue were assessed. In parallel, transcriptional expression of inflammation and renal injury-related genes, including kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), and tumor necrosis factor alpha (TNF-α) in the kidney tissue were determined. RESULTS: ML caused significant increases in serum levels of ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, urea, and creatinine. Further, ML treated rats showed significant reductions in serum levels of protein, albumin, globulin, GPx, and CAT. Distinct histopathological damage and disturbances in glycogen and DNA content in hepatic and renal tissues of ML treated rats were observed. KIM-1, TIMP-1, and TNF-α gene expression was significantly upregulated in kidney tissue. Also, GPx, CAT, and Bcl-2 genes were significantly downregulated, and p53 was significantly upregulated in liver tissue after ML treatment. MEE significantly counteracted the ML-induced hepatorenal damage primarily for co-exposed rats. CONCLUSION: MEE could be an effective therapeutic supplement for treatment of ML-induced hepato-renal damage, probably via modulating oxidative stress, apoptosis, and inflammation.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Moringa oleifera/química , Extractos Vegetales/administración & dosificación , Insuficiencia Renal/prevención & control , Triazinas/toxicidad , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/inmunología , Moléculas de Adhesión Celular/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Modelos Animales de Enfermedad , Contaminantes Ambientales/toxicidad , Etanol/química , Contaminación de Alimentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Estrés Oxidativo/inmunología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Ratas , Insuficiencia Renal/sangre , Insuficiencia Renal/inducido químicamente , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Triazinas/administración & dosificación
2.
Food Chem ; 337: 127774, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32777570

RESUMEN

Apis cerana honey collected from the Qinling Mountains in China has been widely used for its antimicrobial property in traditional Chinese medicine. However, its antibacterial mechanism against Salmonella Typhimurium LT2 is still uncertain. A total of 52 volatile components were identified using headspace-gas-chromatography-ion-mobility, and Qinling A. cerana honey exhibited more abundant aromas than monofloral honeys. The phenolic extracts of honey sample F exhibited the lowest minimum inhibitory concentration (5 mg/mL), and chlorogenic acid exhibited the highest (155.91 ± 0.79 mg/kg), followed by caffeic acid, and rutin. After being treated with the extract, cell membranes of S. Typhimurium LT2 significantly shrunk and further collapsed. The extract treatment on mice caused a significant decrease in S. Typhimurium LT2, and a dramatic increase in the potential prebiotic Lactobacillus in both the caecum and colon. The results demonstrate that the Qinling A. cerana honey extract could effectively inhibit S. Typhimurium in vitro and in vivo.


Asunto(s)
Antiinfecciosos/farmacología , Miel/análisis , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/patogenicidad , Compuestos Orgánicos Volátiles/química , Animales , Antiinfecciosos/química , Antiinfecciosos/uso terapéutico , Abejas , Modelos Animales de Enfermedad , Cromatografía de Gases y Espectrometría de Masas , Ratones , Pruebas de Sensibilidad Microbiana , Fenoles/química , Infecciones por Salmonella/tratamiento farmacológico , Compuestos Orgánicos Volátiles/farmacología , Compuestos Orgánicos Volátiles/uso terapéutico
3.
In Vivo ; 34(6): 3723-3730, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33144490

RESUMEN

BACKGROUND/AIM: Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by immune cells and cytokines in the host airway. Based on our in vivo experience with digitoxin as an inhibitor of TNFα-driven NFĸB signaling for cytokine expression in prostate cancer in rats and in cystic fibrosis in humans, we hypothesize that this drug will also block a virally-activated cytokine storm. Materials Methods: Digitoxin was administered intraperitoneally to cotton rats, followed by intranasal infection with 107TCID50/100 g of cotton rat with influenza strain A/Wuhan/H3N2/359/95. Daily digitoxin treatment continued until harvest on day 4 of the experiment. RESULTS: The cardiac glycoside digitoxin significantly and differentially suppressed levels of the cytokines TNFα, GRO/KC, MIP2, MCP1, and IFNγ, in the cotton rat lung in the presence of influenza virus. CONCLUSION: Since cytokine storm is a host response, we suggest that digitoxin may have a therapeutic potential not only for influenza and but also for coronavirus infections.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Digitoxina/farmacología , Pulmón/virología , Neumonía Viral/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/metabolismo , Gripe Humana/virología , Pulmón/patología , Masculino , FN-kappa B/genética , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/patología , Neumonía Viral/virología , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/virología , Ratas , Factor de Necrosis Tumoral alfa/genética
4.
Zhongguo Zhong Yao Za Zhi ; 45(17): 4071-4080, 2020 Sep.
Artículo en Chino | MEDLINE | ID: mdl-33164391

RESUMEN

Moxa floss is the main material of moxibustion, which plays a therapeutic role through the thermal effect of combustion. In this paper, TG/DSC thermal analysis method was used to study the characteristic parameters of combustion heat of moxa floss produced in Qichun, and the thermal therapeutic effect and mechanism of moxibustion were studied through moxibustion OA animal model. The results show that the combustion process of moxa floss can be divided into three stages: drying, combustion oxidation and carbonization, and ash burnout. The combustion properties of moxa floss are between herbaceous and woody, and tend to be woody, with flammable, slow and lasting combustion characteristics. Moxibustion can relieve the pathological state of knee joint synovium to a certain extent, reduce knee joint swelling and blood stasis in OA rats, reduce interstitial edema, and improve local inflammation. The mechanism and target point of moxibustion treatment for OA may be up-regulating TRPM3 gene to activate ion channels, affecting calcium metabolism and reducing OA swelling degree; down-regulation of GAPDH affects glucose metabolism of knee synovial cells and mediates anti-inflammatory effect. Down-regulation of pain-related gene MMP24 is helpful to relieve OA pain. Up-regulation of CTNNB1 activates Wnt/ß-catenin signaling pathway and affects differentiation and regeneration of OA chondrocytes. This study reveals the pyrolysis characteristics of moxa floss for the first time and discusses the biological effect and possible mechanism of moxibustion heat, providing new ideas for the quality evaluation of moxa floss and the mechanism of moxibustion therapy.


Asunto(s)
Moxibustión , Osteoartritis , Animales , Modelos Animales de Enfermedad , Calor , Oxidación-Reducción , Ratas
5.
Nihon Yakurigaku Zasshi ; 155(6): 390-394, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-33132256

RESUMEN

The current therapeutic drugs for major depression mainly modulate monoaminergic signaling. Since they are not effective for all patients, the development of novel therapeutic target is required. Recently, it has been reported that inflammation-related molecules are increased in the blood from patients with major depression. Therefore, neuroinflammation is a possible cause of these disorders. However, we still do not know whether neuroinflammation induces depression. Since social and environmental stress is a risk factor for mental illnesses, repeated social defeat stress is employed as an animal model of depression. We found that prostaglandin E2 (PGE2) suppresses mesocortical dopaminergic pathway to induce behavioral changes and cyclooxygenase-1 (COX-1), a key enzyme for PGE2 production, is essential for repeated stress-induced PGE2 production and behavioral changes. Based on the finding that COX-1 is expressed in microglia in the brain, we are wondering if microglia plays an important role in stress-induced behavioral changes. We revealed that Toll-like receptor (TLR) 2 and 4 in prefrontal microglia are crucial for repeated stress-induced behavioral changes. Our results indicate that repeated social defeat stress induces microglial activation through TLR2 and 4, thereby leading to neuronal and behavioral changes through proinflammatory cytokines such as TNFα and IL-1α. These findings revealed the essential role and molecular basis of neuroinflammation. In addition, we developed the drug screening platform which targets neuroinflammation for neurodegenerative disease such as amyotrophic lateral sclerosis. Our findings pave the way for the development of therapeutic drugs for major depression targeting neuroinflammation which causes neurological disorders.


Asunto(s)
Depresión , Evaluación Preclínica de Medicamentos , Inflamación , Enfermedades Neurodegenerativas , Animales , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Microglía , Estrés Psicológico
6.
Nat Commun ; 11(1): 5522, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139698

RESUMEN

Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.


Asunto(s)
Disfunción Cognitiva/patología , Histona Desacetilasa 6/metabolismo , Tauopatías/patología , Proteínas tau/metabolismo , Acetilación , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/patología , Disfunción Cognitiva/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Histona Desacetilasa 6/genética , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Fosforilación , Procesamiento Proteico-Postraduccional , Tauopatías/genética , Proteínas tau/genética
7.
Nat Commun ; 11(1): 5536, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139700

RESUMEN

MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115-/- organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115-/- cells compared to the wild-type counterparts. Consequently, the Rnf115-/- mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Infecciones por Cardiovirus/inmunología , Herpes Simple/inmunología , Inmunidad Innata , Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Infecciones por Cardiovirus/patología , Infecciones por Cardiovirus/virología , Modelos Animales de Enfermedad , Virus de la Encefalomiocarditis/inmunología , Femenino , Células HEK293 , Herpes Simple/patología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Lisina/metabolismo , Macrófagos/inmunología , Macrófagos/virología , Masculino , Ratones , Ratones Noqueados , Cultivo Primario de Células , Agregado de Proteínas/inmunología , ARN Interferente Pequeño/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/fisiología , Ubiquitinación/inmunología
8.
Nat Commun ; 11(1): 5520, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139725

RESUMEN

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45-/- mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.


Asunto(s)
Nucleótidos de Adenina/metabolismo , Astenozoospermia/genética , Proteínas del Citoesqueleto/deficiencia , Situs Inversus/genética , Adolescente , Adulto , Animales , Astenozoospermia/patología , Axonema/ultraestructura , Sistemas CRISPR-Cas/genética , Cilios/metabolismo , Cilios/ultraestructura , Proteínas del Citoesqueleto/genética , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Epidídimo/patología , Femenino , Flagelos/metabolismo , Flagelos/ultraestructura , Humanos , Mutación con Pérdida de Función , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Planarias/citología , Planarias/genética , Planarias/metabolismo , Mucosa Respiratoria/citología , Mucosa Respiratoria/patología , Situs Inversus/diagnóstico por imagen , Situs Inversus/patología , Motilidad Espermática/genética , Tomografía Computarizada por Rayos X , Secuenciación del Exoma Completo
9.
J Toxicol Sci ; 45(11): 661-671, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33132240

RESUMEN

As a toxin of Ageratina adenophora (A. adenophora), euptox A (9-oxo-10, 11-dehydroageraphorone) is known to cause hepatotoxicity in animals. In this study, we examined the effects of euptox A on mouse liver cells and its underlying mechanisms for the first time. We found that euptox A induced liver cell cycle arrest and apoptosis in a dose-dependent manner mainly by mitochondria -related pathways, with the affected cells characterized by the appearance of DNA fragmentation, membrane blebbing, and chromatin condensation. The results showed that euptox A similarly induced hepatocyte G0 /GI arrest and apoptosis mainly by ROS accumulation and mitochondria-mediated and caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome C and AIF, activation of caspase-3/-9, Bax, as well as suppression of Bcl-2. This paper will provide new insights into the mechanisms involved in liver toxicity caused by euptox A in mice.


Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/fisiología , Mitocondrias/fisiología , Sesquiterpenos/toxicidad , Transducción de Señal/efectos de los fármacos , Animales , Caspasas/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Hepatocitos/ultraestructura , Ratones , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismo
10.
J Toxicol Sci ; 45(11): 681-693, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33132242

RESUMEN

Trichloroethylene (TCE) as a common organic solvent in industrial production can cause occupational medicamentosa-like dermatitis (OMDT) in some exposed workers. In addition to systemic skin damage, OMDT is also accompanied by severe kidney injury. Our previous studies show that complement (C) plays an important role in immune kidney injury caused by TCE. Specifically, C3 is mainly deposited on glomeruli. Recent studies have found that intracellular complement can be activated by cathepsin L (CTSL) and exert a series of biological effects. The purpose of this study was to explore where C3 on glomeruli comes from and what role it plays. A BALB/c mouse model of skin sensitization induced by TCE in the presence or absence of CTSL inhibitor (CTSLi,10 mg/kg). In TCE sensitization-positive mice, C3 was mainly expressed on podocytes and the expression of CTSL significantly increased in podocytes. Kidney function test and related indicators showed abnormal glomerular filtration and transmission electron microscopy revealed ultrastructure damage to podocytes. These lesions were alleviated in TCE/CTSLi positive mice. These results provide the first evidence that in TCE-induced immune kidney injury, intracellular complement in podocytes can be over-activated by CTSL and aggravates podocytes injury, thereby damaging glomerular filtration function. Intracellular complement activation and cathepsin L in podocytes may be a potential target for treating immune kidney injury induced by TCE.


Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/inmunología , Activación de Complemento/efectos de los fármacos , Podocitos/inmunología , Solventes/efectos adversos , Tricloroetileno/efectos adversos , Lesión Renal Aguda/fisiopatología , Animales , Catepsina L/efectos adversos , Complemento C3/metabolismo , Modelos Animales de Enfermedad , Femenino , Tasa de Filtración Glomerular , Glomérulos Renales/inmunología , Ratones Endogámicos BALB C , Podocitos/patología , Podocitos/ultraestructura
11.
J Toxicol Sci ; 45(11): 701-711, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33132244

RESUMEN

We aimed to investigate the role of programmed cell death protein 1 (PD-1) and T lymphocytes in the proliferation, apoptosis and secretion of cells from patients and mice with Graves' disease (GD). The levels of serum hormones, related antibodies and inflammatory cytokines in GD patients were determined by electrochemiluminescence immunoassay and ELISA. The percentages of CD4 and CD8 T-lymphocytes and PD-1 expression were examined by flow cytometry. A GD mouse model, a thyroid follicular epithelial cell, and a CD4+PD-1+, CD4+PD-1- and CD8+PD-1+, CD8+PD-1- T lymphocyte co-culture system were constructed. The viability, apoptosis-related markers, serum hormones, related antibodies and inflammatory cytokines in thyroid follicular epithelial cells were determined by CCK-8, Western blot, qTR-PCR, electrochemiluminescence immunoassay and ELISA. Elevated free thyroid hormones (FT3, FT4), thyroid hormone antibodies (TRAb, TPOAb and TGAb), inflammatory cytokines, and inhibited TSH were observed in GD patients. The percentage of CD4+ T cells was increased, while that of CD8+ T cells was reduced in GD patients. PD-1 expression level was lifted in both CD4+ and CD8+ cells from GD patients. In mouse thyroid follicular epithelial cells co-cultured with CD4+PD-1+ and CD8+PD-1+ T lymphocytes, the cell viability, TH and TRAb levels and inflammatory cytokines level were the highest, while the TSH level and apoptosis were the lowest. PD-1 positive T lymphocytes were able to promote viability and inhibit apoptosis of thyroid follicular epithelial cells, which further caused a more accelerated development of GD.


Asunto(s)
Antígeno B7-H1/inmunología , Antígeno B7-H1/fisiología , Proliferación Celular , Citocinas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/fisiología , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Mediadores de Inflamación/metabolismo , Linfocitos/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Glándula Tiroides/citología , Adulto , Animales , Apoptosis , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Enfermedad de Graves/patología , Humanos , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad
12.
Yakugaku Zasshi ; 140(11): 1323-1327, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-33132267

RESUMEN

Intracerebral hemorrhage (ICH) results from blood vessels rupture in the brain, forming a blood clot in the brain parenchyma. Leakage of blood constituents causes detrimental tissue damages, ensuing long-lasting neurological deficits; however, effective therapeutic approaches are not yet developed to date. In this study, leukotriene B4 (LTB4) and its receptor leukotriene B4 receptor 1 (BLT1) are proposed as novel therapeutic targets for ICH therapy. After the onset of ICH, the LTB4 content in the brain transiently elevated. Microglia are considered as the source of LTB4 production. Thrombin, a blood constituent, activated the BV-2 microglia and increased the LTB4 secretion from the BV-2 cells. Microglia-released LTB4 promoted its own microglial activation and neutrophil-like differentiated HL-60 cell migration activity. LTB4 receptors comprised of two types: BLT1 and BLT2, with BLT1 known to be a high-affinity receptor associated with chemotaxis. BLT1 knockout mice showed decreased neutrophil invasion, attenuating sensorimotor dysfunction after ICH. Furthermore, therapeutic administration of ONO-4057, an orally active LTB4 receptor antagonist, attenuated neutrophil invasion, microglial activation, axonal fragmentation, and sensorimotor deficits induced by ICH. These results suggest that LTB4 and its receptor BLT1 can be potential promising therapeutic targets that prevent tissue damages following ICH.


Asunto(s)
Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/genética , Descubrimiento de Drogas , Leucotrieno B4 , Terapia Molecular Dirigida , Fenilpropionatos/administración & dosificación , Fenilpropionatos/farmacología , Receptores de Leucotrieno B4/antagonistas & inhibidores , Administración Oral , Animales , Encéfalo/metabolismo , Movimiento Celular , Hemorragia Cerebral/etiología , Hemorragia Cerebral/patología , Modelos Animales de Enfermedad , Células HL-60 , Humanos , Leucotrieno B4/metabolismo , Ratones , Microglía/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Receptores de Leucotrieno B4/metabolismo , Trombina/fisiología
13.
Yakugaku Zasshi ; 140(11): 1351-1363, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-33132271

RESUMEN

Epidemiological studies have shown that coffee consumption may be associated with a lower risk of developing several chronic disorders. To elucidate the molecular mechanism of the effects of coffee, we analyzed molecular response upon exposure to coffee extract using cellular and animal models of these diseases. As obesity is recognized as a major risk factor for these chronic diseases, we investigated the effect of coffee on adipogenesis using mouse preadipocyte 3T3-L1 cells. We found that coffee induced proteasomal degradation of IRS-1, leading to reduction of PPARγ expression, a master transcription factor for adipogenesis. Reduction in weight as well as in IRS-1 expression was detected in the fat tissues of the high fat-diet-fed mice when reared with 60% coffee for 7 weeks. As for Alzheimer's disease, we analyzed the effect of coffee on amyloid ß (Aß) production in human neuronal SH-SY5Y cells. We found a 20% reduction in Aß production when treated with 2.5% coffee for 2 d. This reduction was due to proteasomal degradation of BACE1 (ß-secretase), which was activated by protein kinase A. In addition, coffee ameliorates LPS-induced inflammatory responses in RAW264.7 macrophages by reducing NFκB activity and Nrf2 activation. Roasted coffee prevents selenite-induced cataractogenesis by ameliorating antioxidant loss. Pyrocatechol, a component of roasted coffee, also reduced Aß production and exhibits anti-inflammatory effects by a similar mechanism as coffee. Our results suggest that roasting coffee beans to generate pyrocatechol is necessary for the preventive effects of coffee intake on the chronic diseases.


Asunto(s)
Enfermedad de Alzheimer/prevención & control , Catarata/prevención & control , Enfermedad Crónica/prevención & control , Café , Ingestión de Líquidos/fisiología , Adipogénesis , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Catecoles , Células Cultivadas , Café/química , Modelos Animales de Enfermedad , Manipulación de Alimentos , Calor , Humanos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Células RAW 264.7
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 865-870, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33148379

RESUMEN

Objective To investigate dynamic changes of type 3 innate lymphoid cells (ILC3) in lungs of mice with bronchopulmonary dysplasia (BPD). Methods Forty newborn C57BL/6 mice were randomized into air group and the hyperoxia group, 20 mice in each group. C57BL/6 newborn mice were delivered by caesarean section on the 19th day of pregnancy and exposed to 850 mL/L O2 for replication of the BPD model. Five mice in each group were sacrificed 1 day, 3, 7, 14 days after they were born for procurement of fresh lung tissues. HE staining was used to observe the pathological changes of lung tissues. ELISA was used to detect the protein content of downstream cytokines interleukin-17 (IL-17), IL-22 and granulocyte-macrophage colony stimulating factor (GM-CSF) in lung homogenate. Flow cytometry was used for measuring the proportion of ILC3 in lymphocytes as well as the proportions of IL-17+ ILC3 and IL-22+ ILC3 in the lung. Results The proportion of ILC3 in lung tissues reached the peak on the 7th day after birth. In contrast with the air group, the proportion of ILC3 in the hyperoxia group was significantly elevated at the same time points. The protein content of IL-17 and IL-22 in the hyperoxia group went up significantly in comparison with those in the air group at the same time points, while the GM-CSF content in the hyperoxia group showed no significant changes. The proportions of IL-17+ILC3 and IL-22+ILC3 in the hyperoxia group significantly increased as compared with those in the air group at the same time points. Conclusion The secretion of IL-17 and IL-22 derived from ILC3 is associated with BPD.


Asunto(s)
Displasia Broncopulmonar/inmunología , Interleucina-17/inmunología , Interleucinas/inmunología , Linfocitos/citología , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Hiperoxia , Inmunidad Innata , Pulmón/citología , Pulmón/inmunología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Embarazo , Distribución Aleatoria
15.
BMC Infect Dis ; 20(1): 823, 2020 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-33176722

RESUMEN

BACKGROUND: The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/H5N1-caused ALI, using a mouse model. METHODS: MSCs were prepared from the bone marrow of 9 to 12 week-old BALB/c mice. An H5N1 virus of A/turkey/East Java/Av154/2013 was intranasally inoculated into BALB/c mice. On days 2, 4, and 6 after virus inoculation, MSCs were intravenously administered into the mice. To evaluate effects of the treatment, we examined for lung alveolar protein as an indicator for lung injury, PaO2/FiO2 ratio for lung functioning, and lung histopathology. Expressions of NF-κB, RAGE (transmembrane receptor for damage associated molecular patterns), TNFα, IL-1ß, Sftpc (alveolar cell type II marker), and Aqp5+ (alveolar cell type I marker) were examined by immunohistochemistry. In addition, body weight, virus growth in lung and brain, and duration of survival were measured. RESULTS: The administration of MSCs lowered the level of lung damage in the virus-infected mice, as shown by measuring lung alveolar protein, PaO2/FiO2 ratio, and histopathological score. In the MSC-treated group, the expressions of NF-κB, RAGE, TNFα, and IL-1ß were significantly suppressed in comparison with a mock-treated group, while those of Sftpc and Aqp5+ were enhanced. Body weight, virus growth, and survival period were not significantly different between the groups. CONCLUSION: The administration of MSCs prevented further lung injury and inflammation, and enhanced alveolar cell type II and I regeneration, while it did not significantly affect viral proliferation and mouse morbidity and mortality. The results suggested that MSC administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, although further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality.


Asunto(s)
Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/cirugía , Subtipo H5N1 del Virus de la Influenza A , Trasplante de Células Madre Mesenquimatosas , Infecciones por Orthomyxoviridae/complicaciones , Neumonía/etiología , Neumonía/cirugía , Lesión Pulmonar Aguda/prevención & control , Lesión Pulmonar Aguda/virología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Pulmón/metabolismo , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/virología , Neumonía/prevención & control , Neumonía/virología , Resultado del Tratamiento
16.
Nat Commun ; 11(1): 5671, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168804

RESUMEN

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions. The mutational signatures of human and mouse OSCC overlap extensively. Mutational burden is higher in moderate dysplasias and invasive SCCs than in hyperplasias and mild dysplasias, although mutations in p53, Notch1 and Fat1 occur in early lesions. Laminin-α3 mutations are associated with tumour invasiveness and Notch1 mutant tumours have an increased immune infiltrate. Computational modelling of clonal dynamics indicates that high genetic heterogeneity may be a feature of those mild dysplasias that are likely to progress to more aggressive tumours. These studies provide a foundation for exploring OSCC evolution, heterogeneity and progression.


Asunto(s)
Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Genómica , Neoplasias de la Boca/genética , 4-Nitroquinolina-1-Óxido/efectos adversos , Animales , Cadherinas/genética , Carcinogénesis/inducido químicamente , Carcinoma de Células Escamosas/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Exoma/genética , Genes Relacionados con las Neoplasias , Genes p53/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias de la Boca/patología , Mutación , Invasividad Neoplásica , Receptor Notch1/genética
17.
Nat Commun ; 11(1): 5666, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168815

RESUMEN

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl4, we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Acuaporina 3/antagonistas & inhibidores , Acuaporina 3/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Animales , Acuaporina 3/genética , Células CHO , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Quimiocina CCL4/efectos adversos , Cricetulus , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Glicerol/metabolismo , Peróxido de Hidrógeno/metabolismo , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Medicina Molecular , FN-kappa B/metabolismo , Estrés Oxidativo , Transducción de Señal , Transcriptoma
18.
Zhonghua Yi Xue Za Zhi ; 100(42): 3332-3337, 2020 Nov 17.
Artículo en Chino | MEDLINE | ID: mdl-33202497

RESUMEN

Objective: Modeling the immune-related adverse events (irAE) colitis in mice, and explore the protective effect and related mechanism of Lactobacillus rhamnosus GG (LGG) on irAE colitis. Methods: C57BL/6 mice were divided into dextran sodium sulfate (DSS) group (n=3), DSS+anti-programmed death receptor 1 (PD-1) group (n=4), DSS+anti-PD-1+anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) Group (n=4), DSS+anti-PD-1+anti-CTLA-4+LGG group (n=4), all were given corresponding drugs and probiotics intervention. The severity of colitis were assessed by weight loss, disease activity index (DAI), colon length, colon histopathological score. The inflammatory cytokines and T cell immunity of CD4+, CD8+, FoxP3+regulatory T cells (Treg), were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining respectively. Results: Compared to DSS group, the Day 9 weight [(87.40±1.79)% vs (94.57±0.53)%, P<0.05], colon length [(5.33±0.27)cm vs (6.63±0.12)cm, P<0.05] were lower, and DAI score(2.66±0.24 vs 0.89±0.48), colon histopathological score (12.50±1.04 vs 5.67±0.33), tumor necrosis factor-α (TNF-α) (6.73±1.68 vs 0.91±0.40) (P<0.05), as well CD8+T cells (156.80±8.84 vs 89.00±6.66) and FoxP3+Treg cells (103.80±2.66 vs 48.33±3.18) (P<0.05) were higher in DSS+anti-PD-1+anti-CTLA-4 group. Compared to DSS+anti-PD-1+anti-CTLA-4 group, the DAI score(1.83±0.17 vs 2.66±0.24), colonic histopathology score (8.75±0.63 vs 12.50±1.04), TNF-α level (1.32±0.18 vs 6.73±1.68) (P<0.05) were lower; and CD8+T cells(97.75±3.75 vs 156.80±8.84, P<0.01) level was lower with higher FoxP3+Treg cells (126.00±8.33 vs 103.80±2.66, P=0.046) in DSS+anti-PD-1+anti-CTLA-4+LGG group. Conclusion: DSS combined with anti-PD-1 and anti-CTLA-4 can successfully modeling the irAE colitis in mice, LGG can reduce irAE colitis severity by regulating Treg cells.


Asunto(s)
Colitis , Lactobacillus rhamnosus , Animales , Colitis/inducido químicamente , Colon , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL
19.
Molecules ; 25(21)2020 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-33147850

RESUMEN

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV-V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1ß induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Sacos Aéreos/efectos de los fármacos , Sacos Aéreos/virología , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/fisiopatología , Modelos Animales de Enfermedad , Fiebre/tratamiento farmacológico , Fiebre/etiología , Hemorragia/prevención & control , Humanos , Interleucina-6/metabolismo , Riñón/efectos de los fármacos , Necrosis/patología , Necrosis/prevención & control , Pandemias , Fitoterapia , Neumonía Viral/patología , Neumonía Viral/fisiopatología , Mucosa Respiratoria/trasplante , Activación Transcripcional/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Pez Cebra
20.
Emerg Microbes Infect ; 9(1): 2278-2288, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33003988

RESUMEN

The emergence of SARS-CoV-2 has resulted in an ongoing global pandemic with significant morbidity, mortality, and economic consequences. The susceptibility of different animal species to SARS-CoV-2 is of concern due to the potential for interspecies transmission, and the requirement for pre-clinical animal models to develop effective countermeasures. In the current study, we determined the ability of SARS-CoV-2 to (i) replicate in porcine cell lines, (ii) establish infection in domestic pigs via experimental oral/intranasal/intratracheal inoculation, and (iii) transmit to co-housed naïve sentinel pigs. SARS-CoV-2 was able to replicate in two different porcine cell lines with cytopathic effects. Interestingly, none of the SARS-CoV-2-inoculated pigs showed evidence of clinical signs, viral replication or SARS-CoV-2-specific antibody responses. Moreover, none of the sentinel pigs displayed markers of SARS-CoV-2 infection. These data indicate that although different porcine cell lines are permissive to SARS-CoV-2, five-week old pigs are not susceptible to infection via oral/intranasal/intratracheal challenge. Pigs are therefore unlikely to be significant carriers of SARS-CoV-2 and are not a suitable pre-clinical animal model to study SARS-CoV-2 pathogenesis or efficacy of respective vaccines or therapeutics.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/veterinaria , Pandemias/veterinaria , Neumonía Viral/veterinaria , Enfermedades de los Porcinos/virología , Animales , Betacoronavirus/genética , Betacoronavirus/inmunología , Línea Celular , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/transmisión , Modelos Animales de Enfermedad , Reservorios de Enfermedades , Susceptibilidad a Enfermedades , Femenino , Masculino , Neumonía Viral/inmunología , Neumonía Viral/patología , Neumonía Viral/transmisión , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Porcinos , Enfermedades de los Porcinos/inmunología , Enfermedades de los Porcinos/patología , Enfermedades de los Porcinos/transmisión , Cultivo de Virus , Replicación Viral , Secuenciación del Exoma Completo
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