RESUMEN
PURPOSE OF REVIEW: By providing a concise overview of adipose tissue types, elucidating the regulation of adipose thermogenic capacity in both physiological contexts and chronic wasting diseases (a protracted hypermetabolic state that precipitates sustained catabolism and consequent progressive corporeal atrophy), and most importantly, delving into the ongoing discourse regarding the role of adipose tissue thermogenic activation in chronic wasting diseases, this review aims to provide researchers with a comprehensive understanding of the field. RECENT FINDINGS: Adipose tissue, traditionally classified as white, brown, and beige (brite) based on its thermogenic activity and potential, is intricately regulated by complex mechanisms in response to exercise or cold exposure. This regulation is adipose depot-specific and dependent on the duration of exposure. Excessive thermogenic activation of adipose tissue has been observed in chronic wasting diseases and has been considered a pathological factor that accelerates disease progression. However, this conclusion may be confounded by the detrimental effects of excessive lipolysis. Recent research also suggests that such activation may play a beneficial role in the early stages of chronic wasting disease and provide potential therapeutic effects. A more comprehensive understanding of the changes in adipose tissue thermogenesis under physiological and pathological conditions, as well as the underlying regulatory mechanisms, is essential for the development of novel interventions to improve health and prevent disease.
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Tejido Adiposo Pardo , Termogénesis , Humanos , Termogénesis/fisiología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Beige/metabolismo , Animales , Lipólisis , Ejercicio Físico/fisiología , Metabolismo Energético/fisiología , Tejido Adiposo Blanco/metabolismoRESUMEN
Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.
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Proteínas Quinasas Activadas por AMP , Síndrome de Peutz-Jeghers , Animales , Ratones , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/patología , Proteínas Serina-Treonina Quinasas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Análisis de Secuencia de ARN , Serina , Tamoxifeno/farmacologíaRESUMEN
Obesity is characterized by chronic low-grade inflammation, which is driven by macrophage infiltration in adipose tissue and leads to elevated cytokines such as interleukin-1ß (IL-1ß) in the circulation and tissues. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in the development and progression of cancer and cardiovascular diseases. However, the role of SENP3 in obesity-associated inflammation remains largely unknown. To better understand the effects of SENP3 on adipose tissue macrophage (ATM) activation and function within the context of obesity, we generated mice with myeloid-specific deletion of SENP3 (Senp3flox/flox;Lyz2-Cre mice). We found that the expression of SENP3 is dramatically increased in ATMs during high-fat diet (HFD)-induced obesity in mice. Senp3flox/flox;Lyz2-Cre mice show lower body weight gain and reduced adiposity and adipocyte size after challenged with HFD and during aging. Myeloid-specific SENP3 deletion attenuates macrophage infiltration in adipose tissue and reduces serum levels of inflammatory factors during diet and age-induced obesity. Furthermore, we found that SENP3 knockout markedly inhibits cytokine release from macrophage after lipopolysaccharide and palmitic acid treatment in vitro. Mechanistically, in cultured peritoneal macrophages, SENP3 protein level is enhanced by IL-1ß, in parallel with the upregulation of Yes-associated protein 1 (YAP1). Moreover, we demonstrated that SENP3 modulates de-SUMO modification of YAP1 and SENP3 deletion abolishes the upregulation of YAP1 induced by IL-1ß. Most importantly, SENP3 deficiency reduces YAP1 protein level in adipose tissue during obesity. Our results highlight the important role of SENP3 in ATM inflammation and diet and age-induced obesity.
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Resistencia a la Insulina , Sumoilación , Animales , Ratones , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Inflamación/metabolismo , Dieta Alta en Grasa/efectos adversos , Citocinas/metabolismo , Factores de Transcripción/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismoRESUMEN
SUMMARY: The stomach receives a rich blood supply from five sets of arteries, all of which originate from the celiac trunk. During the dissection of a female cadaver that had been fixed with formalin, an atypical branching pattern was observed. An accessory left gastric artery was found to originate from the left hepatic artery and send small branches to the esophagus, cardia, and fundus of the stomach. However, there was no anastomosis between the lower accessory left gastric artery and the left gastric artery. This is a rare variant of the gastric artery that has not been previously described in detail. It is important to recognize this variation for safe and effective interventional diagnosis and treatment techniques if dealing with the liver or gastric arteries.
El estómago recibe un rico suministro de sangre de cinco conjuntos de arterias, todas las cuales se originan en el tronco celíaco. Durante la disección de un cadáver femenino que había sido fijado con formalina, se observó un patrón de ramificación atípico. Se encontró una arteria gástrica izquierda accesoria que se originaba en la arteria hepática izquierda y enviaba pequeñas ramas al esófago, el cardias y el fondo del estómago. Sin embargo, no hubo anastomosis entre la arteria gástrica izquierda accesoria inferior y la arteria gástrica izquierda. Se trata de una variante rara de la arteria gástrica que no se ha descrito previamente en detalles. Es importante reconocer esta variación para la aplicación de técnicas de diagnóstico y tratamiento intervencionistas seguras y efectivas a nivel del hígado o las arterias gástricas.
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Humanos , Femenino , Anciano , Variación Anatómica , Artería Gástrica/anatomía & histología , CadáverRESUMEN
Perivascular adipose tissue (PVAT) is an adipose tissue depot that surrounds blood vessels and exhibits the phenotypes of white, beige, and brown adipocytes. Recent discoveries have shed light on the central role of PVAT in regulating vascular homeostasis and participating in the pathogenesis of cardiovascular diseases. A comprehensive understanding of PVAT properties and regulation is of great importance for the development of future therapies. Primary cultures of periaortic adipocytes are valuable for studying PVAT function and the crosstalk between periaortic adipocytes and vascular cells. This paper presents an economical and feasible protocol for the isolation, culture, and adipogenic induction of stromal vascular fraction-derived preadipocytes from mouse periaortic adipose tissue, which can be useful for modeling adipogenesis or lipogenesis in vitro. The protocol outlines tissue processing and cell differentiation for culturing periaortic adipocytes from young mice. This protocol will provide the technological cornerstone at the bench side for the investigation of PVAT function.
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Adipogénesis , Fracción Vascular Estromal , Animales , Ratones , Tejido Adiposo , Diferenciación Celular , Adipocitos MarronesRESUMEN
Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching to contribute to the deteriorating aortic wall structure. Recently, the unprecedented heterogeneity and diversity of VSMCs and their complex relationship to aortic aneurysms (AAs) have been revealed by high-resolution research methods, such as lineage tracing and single-cell RNA sequencing. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype. This difference predisposes to hereditary AAs in the aortic root and ascending aorta. Several VSMC phenotypes with different functions, for example, secreting VSMCs, proliferative VSMCs, mesenchymal stem cell-like VSMCs, immune-related VSMCs, proinflammatory VSMCs, senescent VSMCs, and stressed VSMCs are identified in non-hereditary AAs. The transformation of VSMCs into different phenotypes is an adaptive response to deleterious stimuli but can also trigger pathological remodeling that exacerbates the pathogenesis and development of AAs. This review is intended to contribute to the understanding of VSMC diversity in health and aneurysmal diseases. Papers that give an update on VSMC phenotype diversity in health and aneurysmal disease are summarized and recent insights on the role of VSMCs in AAs are discussed.
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Aneurisma de la Aorta , Músculo Liso Vascular , Humanos , Músculo Liso Vascular/metabolismo , Células Cultivadas , Aorta/metabolismo , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/patología , Fenotipo , Miocitos del Músculo Liso/metabolismoRESUMEN
Hepatitis B virus exposure in children usually develops into chronic hepatitis B (CHB). Although hepatitis B surface antigen (HBsAg)-specific CD8+ T cells contribute to resolve HBV infection, they are preferentially undetected in CHB patients. Moreover, the mechanism for this rarely detected HBsAg-specific CD8+ T cells remains unexplored. We herein found that the frequency of HBsAg-specific CD8+ T cells was inversely correlated with expansion of monocytic myeloid-derived suppressor cells (mMDSCs) in young rather than in adult CHB patients, and CCR9 was upregulated by HBsAg on mMDSCs via activation of ERK1/2 and IL-6. Sequentially, the interaction between CCL25 and CCR9 mediated thymic homing of mMDSCs, which caused the cross-presentation, transferring of peripheral HBsAg into the thymic medulla, and then promoted death of HBsAg-specific CD8+ thymocytes. In mice, adoptive transfer of mMDSCs selectively obliterated HBsAg-specific CD8+ T cells and facilitated persistence of HBV in a CCR9-dependent manner. Taken together, our results uncovered a novel mechanism for establishing specific CD8+ tolerance to HBsAg in chronic HBV infection.
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Hepatitis B Crónica , Células Supresoras de Origen Mieloide , Animales , Linfocitos T CD8-positivos , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Humanos , RatonesRESUMEN
In this study, chitosan (CH) coating with different number-average molecular weight (MW, ca. 5, 19 and 61 kDa) was electrostatic sprayed on strawberry. The effects of MW on strawberry quality changes were evaluated during 15 days of storage at 4 °C. The qualities of strawberry included mold growth, weight loss, firmness, total soluble solids (TSS), pH, flavonoids content, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Results showed that CH coating could significantly maintain the strawberry qualities during storage compared to uncoated treatment. CH coating with 61 kDa was more effective in retarding the increases of pH and MDA, and could better maintain flavonoids content. However, MW had no significant impact on mold growth, weight loss, firmness, SOD activity of coated strawberry. According to evaluation criteria, CH coating with 61 kDa had better performance on strawberry preservation with the highest synthetic value (6.93), and could be used to maintain quality and prolong the shelf life of strawberry during cold storage.
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Quitosano/química , Materiales Biocompatibles Revestidos/química , Conservación de Alimentos , Fragaria , Flavonoides/química , Fragaria/microbiología , Concentración de Iones de Hidrógeno , Malondialdehído , Peso Molecular , Solubilidad , Superóxido Dismutasa/metabolismoRESUMEN
Enterovirus 71 (EV71) is a major pathogen that causes hand, foot and mouth disease (HFMD), which is a life threatening disease in certain children. The pathogenesis of EV71-caused HFMD is poorly defined due to the lack of simple and robust animal models with severe phenotypes that recapitulate symptoms observed in humans. Here, we generated the infectious clone of a clinical isolate from a severe HFMD patient. Virus rescued from the cDNA clone was infectious in cell lines. When administrated intraperitoneally to neonatal ICR, BALB/c and C57 immune competent mice at a dosage of1.4 × 104â pfu per mouse, the virus caused weight loss, paralysis and death in the infected mice after 4-5 days of infection. In the infected mice, detectable viral replication was detected in various tissues such as heart, liver, brain, lung, kidney, small intestine, leg skeletal muscle and medulla oblongata. The histology of the infected mice included massive myolysis, glomerular atrophy, villous blunting in small intestine, widened alveolar septum, diminished alveolar spaces and lymphocytes infiltration into the lung. By using the UV-inactivated virus as a control, we elucidated that the virus first amplified in the leg skeletal muscle tissue and the muscle tissue served as a primary viral replication site. In summary, we generated a stable EV71 infectious clone that is capable of infecting neonatal immune competent mice without adaptive mutations and provide a simple, valuable animal model for the studies of EV71pathogenesis and therapy.
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Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidad , Enfermedad de Boca, Mano y Pie/virología , Animales , Animales Recién Nacidos , Línea Celular Tumoral , Chlorocebus aethiops , ADN Complementario , Modelos Animales de Enfermedad , Humanos , Lactante , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Mutación , ARN Viral , Organismos Libres de Patógenos Específicos , Células Vero , Virulencia , Replicación ViralRESUMEN
Based on measles surveillance in Shanghai, People's Republic of China, from 2006 to 2015, we found that measles virus isolates from 40 throat swab samples exhibited atypical cytopathic effects in Vero/hSLAM cells, which was found to be a result of coinfection with measles virus (MeV) and human herpes simplex virus type 1 (HSV-1). Serological and molecular approaches were used to confirm and characterize the coinfections in these patients. Among the 40 measles cases, measles-specific IgM was detected in 37 cases, while measles-specific IgG was detected in 27 cases. HSV-1-specific IgM and IgG were detected in 7 and 34 cases, respectively, suggesting that most of the MeV infections were primary, but that HSV-1 infection was due to the reactivation of latent virus in most cases. The titers of HSV-1 IgG in patients with either measles or measles-HSV-1 coinfection were significantly higher than those in the healthy group (P = 0.0026 and P < 0.0001, respectively); however, there was no significant difference in the titers of HSV-1 IgG in the MeV and MeV-HSV-1 coinfection patients (P = 0.105). Nucleic acids from MeV and HSV-1 were detected in 40 and 39 throat swabs, respectively. Twenty five MeV RNA sequences were genotyped, and all represented genotype H1, which is the endemic genotype in China. Sequences from the glycoprotein G gene of HSV-1 were used to classify the isolates into two distinct phylogenetic groups: 34 belonged to group A and 3 belonged to group B.
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Anticuerpos Antivirales/sangre , Coinfección , Herpes Simple , Herpesvirus Humano 1 , Inmunoglobulina M/sangre , Virus del Sarampión , ARN Viral , Adolescente , Adulto , Niño , Preescolar , China/epidemiología , Coinfección/sangre , Coinfección/genética , Coinfección/virología , Femenino , Herpes Simple/epidemiología , Herpes Simple/genética , Herpes Simple/metabolismo , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Humanos , Lactante , Masculino , Sarampión , Virus del Sarampión/genética , Virus del Sarampión/metabolismo , Persona de Mediana Edad , Filogenia , ARN Viral/genética , ARN Viral/metabolismoRESUMEN
This study used electrostatic spraying (ES) system as an efficient technique for strawberry preservation with chitosan (CH) coating. The effects of CH deacetylation degree (DD, 81.0, 88.1 and 95.2%) on the qualities (weight loss, pH, total soluble solids (TSS), firmness, flavonoids content, malondialdehyde (MDA) content and superoxide dismutase (SOD) activity and mold growth) of strawberry during cold storage were investigated. Results showed that CH coating by ES formed more continuous and uniform protective layer compared with conventional spraying (CS). CH coating effectively enhanced the overall quality and extended shelf life of strawberry at least 2â¯days. CH coating with 81.0% and 88.1% DD were more effective in reducing weight loss of strawberry, and CH coating with 88.1% DD could better maintain TSS content, while CH coating with 95.2% DD delayed the decline in flavonoids more obviously. However, DD had no significant impact on pH, firmness, SOD activity, MDA and mold growth of coated samples. The evaluation criteria indicated CH coating with 88.1% DD had better preservation performance with the highest synthetic value (6.17) during storage. These findings suggest that CH coating especially with 88.1% DD by ES, as a safe, cheap and efficient technique, has great potential for industrial application of fruit preservation.
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Quitosano/farmacología , Conservación de Alimentos/métodos , Fragaria/efectos de los fármacos , Fragaria/metabolismo , Electricidad Estática , Flavonoides/metabolismo , Malondialdehído/metabolismo , Fenómenos Mecánicos , Solubilidad , Superóxido Dismutasa/metabolismo , Propiedades de SuperficieRESUMEN
Virus reprogramming of host cellular function is a critical strategy for viral survival and replication. A better understanding of virus-host interaction may provide new potential avenues for the treatment of viral diseases. It has been reported that hypoxia-inducible factor-1 (HIF-1) pathway is activated by a range of pathogens via different mechanisms, but the impact of Influenza A virus on HIF-1 signaling is still unclear. In this study, we observed H1N1 infection stabilized HIF-1α under normoxic conditions. In detail, H1N1 did not increase HIF-1α mRNA transcription, nor impaired posttranslational prolyl hydroxylation or ubiquitination of HIF-1α, but inhibited the function of proteasome, resulting in HIF-1α accumulation. Furthermore, a decreased expression of factor inhibiting HIF-1 (FIH-1), which hydroxylates asparagine 803 within HIF-1α to repress HIF-1α activity, was seen after H1N1 infection. Taken together, these findings reveal a previously unrecognized mechanism of viral activation of the HIF-1 pathway, resembling a hypoxic response in normoxia.
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Interacciones Huésped-Patógeno , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Complejo de la Endopetidasa Proteasomal/metabolismo , Células A549 , Humanos , Estabilidad Proteica , ProteolisisRESUMEN
BACKGROUND: Enteroviruses cause hand, foot and mouth disease (HFMD). The host B-cells recognize the viral proteins and provoke humoral responses. Deciphering the B-cell responses to the viral epitopes helps diagnosis and vaccine development. OBJECTIVES: The objective of the present study was to investigate for the first time the landscape of genome-wide linear B-cell epitopes of enterovirus 71 in HFMD population. STUDY DESIGN: The peptides encompassing the entire coding region of EV71 were chemically synthesized and displayed on a microarray. The peptide microarray was used to screen serum samples from an HFMD population, including EV71-, CAV10-, CAV16- and CAV6-infected patients. We identified the dominant epitope-containing-peptides (DECPs) that react with the sera of more than 20% of the HFMD population and the common DECPs that cross-react with the sera from other enteroviruses-infected population. RESULTS: Ten DECPs reacting with IgM and 9 DECPs reacting with IgG antibodies were identified, of which, 6 IgM and 5 IgG common DECPs cross-reacted with the sera from other enteroviruses. Some DECPs preferentially reacted with IgG or IgM antibodies and some epitope-antibody interactions correlated with the severity of HFMD. CONCLUSIONS: We uncovered the DECPs and the common DECPs among a group of enteroviruses in HFMD population and found that some epitope-antibody reactions were associated with the outcome of HFMD. These data may guide developing vaccines against the enteroviruses and help the diagnosis and prognosis of HFMD.
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Anticuerpos Antivirales/sangre , Enterovirus Humano A/inmunología , Epítopos de Linfocito B/genética , Enfermedad de Boca, Mano y Pie/inmunología , Antígenos Virales/inmunología , Niño , Preescolar , China/epidemiología , Reacciones Cruzadas , Enterovirus Humano A/genética , Femenino , Enfermedad de Boca, Mano y Pie/sangre , Enfermedad de Boca, Mano y Pie/epidemiología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lactante , Masculino , Tamizaje Masivo , Péptidos/inmunología , Análisis por Matrices de ProteínasRESUMEN
Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barré syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3-9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10-22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.
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Astrocitos/virología , Interferón Tipo I/inmunología , Proteínas Proto-Oncogénicas/inmunología , Proteínas Tirosina Quinasas Receptoras/inmunología , Transducción de Señal , Virus Zika/patogenicidad , Astrocitos/inmunología , Línea Celular , Células Cultivadas , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor de Interferón alfa y beta/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Tirosina Quinasa del Receptor AxlRESUMEN
BACKGROUND: Human enterovirus 71 (EV71) was previously known to enter cells through clathrin or caveolar mediated endocytic pathways. However, we observed chlorpromazine (CPZ) or dynasore (DNS), which inhibit clathrin and dynamin mediated endocytosis, did not suppress EV71 cell entry in particular cell types. So the current knowledge of entry mechanisms by EV71 is not complete. METHODS: Viral infection was examined by flow cytometry or end-point dilution assays. Viral entry was monitored by immunofluorescence or pseudoviral infections. Various inhibitors were utilized for manipulating endocytic pathways. Cellular proteins were knockdown by siRNA. RESULTS: CPZ and DNS did not inhibit but rather enhance viral infection in A549 cells, while they inhibited infections in other cells tested. We further found CPZ did not affect EV71 binding to target cells and failed to affect viral translation and replication, but enhanced viral entry in A549 cells. Immunofluorescence microscopy further confirmed this increased entry. Using siRNA experiment, we found that the enhancement of EV71 infection by CPZ did not require the components of clathrin mediated endocytosis. Finally, CPZ also enhanced infection by Coxackivirus A16 in A549 cells. CONCLUSIONS: CPZ and DNS, previously reported as EV71 entry inhibitors, may rather lead to increased viral infection in particular cell types. CPZ and DNS increased viral entry and not other steps of viral life cycles. Therefore, our study indicated an unknown dynamin-independent entry pathway utilized by enteroviruses that cause Hand-Foot-and-Mouth Diseases.
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Endocitosis/efectos de los fármacos , Enterovirus Humano A/efectos de los fármacos , Enterovirus Humano A/fisiología , Infecciones por Enterovirus/virología , Enfermedad de Boca, Mano y Pie/virología , Internalización del Virus/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular , Clorpromazina/farmacología , Clatrina/metabolismo , Dinaminas/metabolismo , Infecciones por Enterovirus/metabolismo , Regulación Viral de la Expresión Génica/efectos de los fármacos , Enfermedad de Boca, Mano y Pie/metabolismo , Humanos , Hidrazonas/farmacología , Acoplamiento Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate viral infection in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Shanghai, and to analyze the clinical characteristics and biomarkers in viral infection. METHODS: This study included all consecutive patients who were admitted for a diagnosis of AECOPD during June 2013 to May 2015. Thirty-one stable COPD patients and 31 healthy controls were also recruited. Oropharyngeal samples were assessed, PCR for respiratory viruses were performed. Patients were divided into AECOPD virus-positive (+) group and AECOPD virus-negative (-) group according to viral detection. Luminex was used to detect the concentrations of inflammatory cytokines in the serum. RESULTS: A total of 264 patients were included with a mean age of 75 ± 0.5 years. There were 72 patients (27.3%) identified with viral positive, of whom two patients were detected with double viral infections (FluA + FluB and RSVA + HRV, respectively). The rate of viral detection was associated with season, highest in winter. Comparisons of clinical characteristics showed no significant differences between AECOPD virus+ group and AECOPD virus- group. However, serum concentrations of interferon-inducible protein-10 (IP-10) and interferon-gamma (IFN-γ) in virus+ AECOPD patients were significantly higher than those in the virus- AECOPD, stable COPD and healthy control groups (P < .05). CONCLUSION: Viral infection was an important pathogen in AECOPD patients; the most common viruses included FluA, HRV and FluB. It was very difficult to diagnose the viral infection according to clinical characteristics. The increased of serum IP-10 and IFN-γ levels might be value to indicate viral infection in AECOPD.
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Citocinas/sangre , ADN Viral/análisis , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Virosis/epidemiología , Virus/genética , Anciano , Biomarcadores/sangre , China/epidemiología , Comorbilidad/tendencias , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Virosis/sangre , Virosis/virología , Capacidad VitalRESUMEN
Interferon-alpha (IFN-α) therapy of chronic hepatitis B (CHB) patients is constrained by limited response and side effects. We described a panel of circulating microRNAs (miRNAs) which could potentially predict outcome of IFN-α therapy. Here, we report development of a simplified scoring model for personalized treatment of CHB patients. 112 CHB patients receiving IFN-α treatment were randomly divided into a training (n = 75) or a validation group (n = 37). The expression of 15 candidate miRNAs was detected in training group with 5 miRNAs exhibiting significantly different levels (p < 0.0001) between early virological response (EVR) and non-early virological response (N-EVR). These 5 miRNAs were further tested in validation phase. Refinement analyses of results from training phase established a model composed of miR-210, miR-22 and alanine aminotransferase (ALT), with area under ROC curve (AUC) of 0.874 and 0.816 in training and validation groups, respectively. In addition, this model showed prognostic value for sustained virological response (SVR) (AUC = 0.821). Collectively, this simplified scoring model composed of miR-210, miR-22 and ALT can reproducibly predict the EVR and SVR of IFN-α therapy in CHB patients. The model should help to forecast the outcome of IFN-α treatment prior to therapy decision involving nucleoside analogs or IFNs.
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Alanina Transaminasa/sangre , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , MicroARNs/sangre , Adolescente , Adulto , Antivirales/administración & dosificación , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/genética , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión , Pronóstico , Adulto JovenRESUMEN
The avian origin influenza A virus (IAV) H7N9 has caused a considerable number of human infections associated with high rates of death since its emergence in 2013. As a vital component of the host innate immune system, the nucleotide-binding domain leucine-rich repeat containing receptor, pyrin domain containing 3 (NLRP3) inflammasome plays a critical role against H1N1 viral infection. However, the function of NLRP3 inflammasome in host immunological responses to the lethal H7N9 virus is still obscure. Here, we demonstrated that mice deficient for NLRP3 inflammasome components, including NLRP3, caspase-1, and Apoptosis-associated speck-like protein containing a CARD (ASC), were less susceptible to H7N9 viral challenge than wild type (WT) controls. Inflammasome deficiency in these animals led to significantly milder mortality and less pulmonary inflammation compared with WT mice. Furthermore, IL-1 receptor deficient mice also exhibited a higher survival rate than WT controls. Thus, our study reveals that the NLRP3 inflammasome is deleterious for the host during H7N9 infection in mice, which is due to an overwhelming inflammatory response via caspase-1 activation and associated IL-1 signal. Therefore, fine-tuning the activity of NLRP3 inflammasome or IL-1 signaling may be beneficial for the host to control H7N9 associated lethal pathogenesis.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Caspasa 1/genética , Caspasas/genética , Interacciones Huésped-Patógeno , Subtipo H7N9 del Virus de la Influenza A/patogenicidad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Infecciones por Orthomyxoviridae/genética , Receptores Tipo I de Interleucina-1/genética , Animales , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas Adaptadoras de Señalización CARD/inmunología , Caspasa 1/deficiencia , Caspasa 1/inmunología , Caspasas/deficiencia , Caspasas/inmunología , Caspasas Iniciadoras , Células Dendríticas/inmunología , Células Dendríticas/patología , Células Dendríticas/virología , Femenino , Regulación de la Expresión Génica , Inmunidad Innata , Inflamasomas/genética , Inflamasomas/inmunología , Inflamación , Subtipo H7N9 del Virus de la Influenza A/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/mortalidad , Infecciones por Orthomyxoviridae/virología , Receptores Tipo I de Interleucina-1/deficiencia , Receptores Tipo I de Interleucina-1/inmunología , Transducción de Señal , Análisis de SupervivenciaRESUMEN
Zika virus (ZIKV) infection can cause fetal developmental abnormalities and Guillain-Barré syndrome in adults. Although progress has been made in understanding the link between ZIKV infection and microcephaly, the pathology of ZIKV, particularly the viral reservoirs in human, remains poorly understood. Several studies have shown that compared to serum samples, patients' urine samples often have a longer duration of ZIKV persistency and higher viral load. This finding suggests that an independent viral reservoir may exist in the human urinary system. Despite the clinical observations, the host cells of ZIKV in the human urinary system are poorly characterized. In this study, we demonstrate that ZIKV can infect renal proximal tubular epithelial cells (RPTEpiCs) in immunodeficient mice in vivo and in both immortalized and primary human renal proximal tubular epithelial cells (hRPTEpiCs) in vitro. Importantly, ZIKV infection in mouse kidneys caused caspase-3-mediated apoptosis of renal cells. Similarly, in vitro infection of immortalized and primary hRPTEpiCs resulted in notable cytopathic effects. Consistent with the clinical observations, we found that ZIKV infection can persist with prolonged duration in hRPTEpiCs. RNA-Seq analyses of infected hRPTEpiCs revealed a large number of transcriptional changes in response to ZIKV infection, including type I interferon signaling genes and anti-viral response genes. Our results suggest that hRPTEpiCs are a potential reservoir of ZIKV in the human urinary system, providing a possible explanation for the prolonged persistency of ZIKV in patients' urine.
Asunto(s)
Túbulos Renales Proximales/patología , Túbulos Renales Proximales/virología , Urotelio/virología , Infección por el Virus Zika/virología , Virus Zika/fisiología , Animales , Apoptosis , Línea Celular Tumoral , Efecto Citopatogénico Viral , Modelos Animales de Enfermedad , Reservorios de Enfermedades/virología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Riñón/patología , Riñón/virología , Túbulos Renales Proximales/citología , Ratones , Ratones Endogámicos C57BL , Orina/virología , Urotelio/citología , Carga Viral , Replicación Viral , Virus Zika/aislamiento & purificación , Infección por el Virus Zika/patologíaRESUMEN
Analysis of complete capsid sequences of the emerging norovirus GII.17 Kawasaki 308 from 13 countries demonstrated that they originated from a single haplotype since the initial emergence in China in late 2014. Global spread of a sublineage SL2 was identified. A new sublineage SL3 emerged in China in 2016.