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1.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33806254

RESUMEN

The global COVID-19 pandemic caused by SARS-CoV-2 has resulted in over 2.2 million deaths. Disease outcomes range from asymptomatic to severe with, so far, minimal genotypic change to the virus so understanding the host response is paramount. Transcriptomics has become incredibly important in understanding host-pathogen interactions; however, post-transcriptional regulation plays an important role in infection and immunity through translation and mRNA stability, allowing tight control over potent host responses by both the host and the invading virus. Here, we apply ribosome profiling to assess post-transcriptional regulation of host genes during SARS-CoV-2 infection of a human lung epithelial cell line (Calu-3). We have identified numerous transcription factors (JUN, ZBTB20, ATF3, HIVEP2 and EGR1) as well as select antiviral cytokine genes, namely IFNB1, IFNL1,2 and 3, IL-6 and CCL5, that are restricted at the post-transcriptional level by SARS-CoV-2 infection and discuss the impact this would have on the host response to infection. This early phase restriction of antiviral transcripts in the lungs may allow high viral load and consequent immune dysregulation typically seen in SARS-CoV-2 infection.


Asunto(s)
Citocinas/genética , Procesamiento Postranscripcional del ARN , Ribosomas/metabolismo , Ribosomas/virología , Factores de Transcripción/genética , Animales , Antivirales/antagonistas & inhibidores , Línea Celular Tumoral , Chlorocebus aethiops , Biología Computacional , Citocinas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/virología , Perfilación de la Expresión Génica , Interacciones Microbiota-Huesped , Humanos , Inmunidad Innata/genética , Pulmón/inmunología , Pulmón/virología , ARN Mensajero/metabolismo , RNA-Seq , Ribosomas/genética , Factores de Transcripción/metabolismo , Transcriptoma , Células Vero
2.
Mediators Inflamm ; 2021: 6635925, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833618

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the "cytokine storm" of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients (n = 10) and healthy donors (n = 4) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group (p < 0.05). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.


Asunto(s)
/sangre , ARN/sangre , ARN/genética , Adulto , Anciano , Estudios de Casos y Controles , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/genética , Citocinas/biosíntesis , Citocinas/genética , Femenino , Expresión Génica , Humanos , Mediadores de Inflamación/sangre , Masculino , MicroARNs/sangre , MicroARNs/genética , Persona de Mediana Edad , Pandemias , Mapas de Interacción de Proteínas/genética , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , ARN Mensajero/sangre , ARN Mensajero/genética , Análisis de Secuencia de ARN , Transducción de Señal , Secuenciación del Exoma Completo , Adulto Joven
3.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809042

RESUMEN

Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.


Asunto(s)
Virus del Dengue/aislamiento & purificación , Dengue/diagnóstico , Interleucina-10/genética , Receptores Tipo II de Interleucina-1/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Citocinas/clasificación , Citocinas/genética , Dengue/genética , Dengue/patología , Dengue/virología , Virus del Dengue/genética , Virus del Dengue/patogenicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Transcriptoma/genética , Adulto Joven
4.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809077

RESUMEN

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14+ monocytes and co-cultures of CD4+ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission.


Asunto(s)
Vesículas Extracelulares/genética , Inmunidad/genética , Esclerosis Múltiple/genética , Proteoma/genética , Comunicación Celular/genética , Técnicas de Cocultivo , Citocinas/genética , Decidua/inmunología , Decidua/metabolismo , Vesículas Extracelulares/inmunología , Femenino , Humanos , Inmunomodulación/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Placenta/inmunología , Placenta/metabolismo , Embarazo , Linfocitos T Reguladores/inmunología , Trofoblastos/inmunología , Trofoblastos/metabolismo
5.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809214

RESUMEN

Extracellular vesicles (EVs) are generated and secreted by cells into the circulatory system. Stem cell-derived EVs have a therapeutic effect similar to that of stem cells and are considered an alternative method for cell therapy. Accordingly, research on the characteristics of EVs is emerging. EVs were isolated from human epidural fat-derived mesenchymal stem cells (MSCs) and human fibroblast culture media by ultracentrifugation. The characterization of EVs involved the typical evaluation of cluster of differentiation (CD antigens) marker expression by fluorescence-activated cell sorting, size analysis with dynamic laser scattering, and morphology analysis with transmission electron microscopy. Lastly, the secreted levels of cytokines and chemokines in EVs were determined by a cytokine assay. The isolated EVs had a typical size of approximately 30-200 nm, and the surface proteins CD9 and CD81 were expressed on human epidural fat MSCs and human fibroblast cells. The secreted levels of cytokines and chemokines were compared between human epidural fat MSC-derived EVs and human fibroblast-derived EVs. Human epidural fat MSC-derived EVs showed anti-inflammatory effects and promoted macrophage polarization. In this study, we demonstrated for the first time that human epidural fat MSC-derived EVs exhibit inflammatory suppressive potency relative to human fibroblast-derived EVs, which may be useful for the treatment of inflammation-related diseases.


Asunto(s)
Diferenciación Celular/genética , Vesículas Extracelulares/genética , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Animales , Polaridad Celular/genética , Tratamiento Basado en Trasplante de Células y Tejidos , Quimiocinas/genética , Citocinas/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Fibroblastos/citología , Fibroblastos/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Inflamación/genética , Inflamación/terapia , Macrófagos/metabolismo , Células Madre Mesenquimatosas/metabolismo
6.
Viruses ; 13(3)2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802569

RESUMEN

The recently emerged SARS-CoV-2 virus is responsible for the ongoing COVID-19 pandemic that has rapidly developed into a global public health threat. Patients severely affected with COVID-19 present distinct clinical features, including acute respiratory disorder, neutrophilia, cytokine storm, and sepsis. In addition, multiple pro-inflammatory cytokines are found in the plasma of such patients. Transcriptome sequencing of different specimens obtained from patients suffering from severe episodes of COVID-19 shows dynamics in terms of their immune responses. However, those host factors required for SARS-CoV-2 propagation and the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive. In the present study, we analyzed the mRNA-long non-coding RNA (lncRNA) co-expression network derived from publicly available SARS-CoV-2-infected transcriptome data of human lung epithelial cell lines and bronchoalveolar lavage fluid (BALF) from COVID-19 patients. Through co-expression network analysis, we identified four differentially expressed lncRNAs strongly correlated with genes involved in various immune-related pathways crucial for cytokine signaling. Our findings suggest that the aberrant expression of these four lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection of the lungs. Thus, the present study uncovers molecular interactions behind the cytokine storm activation potentially responsible for hyper-inflammatory responses in critical COVID-19 patients.


Asunto(s)
/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , /fisiología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/genética , Citocinas/inmunología , Redes Reguladoras de Genes , Humanos , Pulmón/inmunología , Pulmón/virología , ARN Largo no Codificante/inmunología , ARN Mensajero/inmunología , /genética
7.
Biofactors ; 47(2): 232-241, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33847020

RESUMEN

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.


Asunto(s)
/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Fatiga/tratamiento farmacológico , Luteolina/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Encéfalo/virología , /fisiopatología , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/virología , Citocinas/genética , Fatiga/complicaciones , Fatiga/fisiopatología , Fatiga/virología , Humanos , Mastocitos/efectos de los fármacos , Mastocitos/virología , /patogenicidad
8.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805598

RESUMEN

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/prevención & control , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/prevención & control , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/uso terapéutico , Neoplasias Óseas/genética , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Huesos/efectos de los fármacos , Huesos/inmunología , Huesos/patología , Comunicación Celular , Citocinas/genética , Citocinas/metabolismo , Humanos , Metástasis Linfática , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/inmunología , Osteoblastos/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/inmunología , Osteoclastos/patología , Transducción de Señal , Escape del Tumor/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/metabolismo
9.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823870

RESUMEN

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


Asunto(s)
Antiinflamatorios/farmacología , Reposicionamiento de Medicamentos , Hipoxia/tratamiento farmacológico , Justicia , Pulmón/efectos de los fármacos , Extractos Vegetales/farmacología , Neumonía/prevención & control , Fibrosis Pulmonar/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Bleomicina , /virología , Ciego/microbiología , Ciego/cirugía , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , Justicia/química , Ligadura , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificación , Neumonía/genética , Neumonía/metabolismo , Neumonía/microbiología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Sepsis/genética , Sepsis/metabolismo , Sepsis/microbiología , Transcriptoma
10.
Medicine (Baltimore) ; 100(16): e25433, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879674

RESUMEN

ABSTRACT: Discoid lupus erythematosus (DLE) is the most common skin manifestation of lupus; however, the molecular mechanisms underlying DLE remain unknown. Therefore, we aimed to identify key differentially expressed genes (DEGs) in discoid lupus skin and investigate their potential pathways.To identify candidate genes involved in the occurrence and development of the disease, we downloaded the microarray datasets GSE52471 and GSE72535 from the Gene Expression Database (GEO). DEGs between discoid lupus skin and normal controls were selected using the GEO2R tool and Venn diagram software (http://bioinformatics.psb.ugent.be/webtools/Venn/). The Database for Annotation, Visualization, and Integrated Discovery (DAVID), Enrichr, and Cytoscape ClueGo were used to analyze the Kyoto Encyclopedia of Gene and Genome pathways and gene ontology. Protein-protein interactions (PPIs) of these DEGs were further assessed using the Search Tool for the Retrieval Interacting Genes version 10.0.Seventy three DEGs were co-expressed in both datasets. DEGs were predominantly upregulated in receptor signaling pathways of the immune response. In the PPI network, 69 upregulated genes were selected. Furthermore, 4 genes (CXCL10, ISG15, IFIH1, and IRF7) were found to be significantly upregulated in the RIG-I-like receptor signaling pathway, from analysis of Enrichr and Cytoscape ClueGo.The results of this study may provide new insights into the potential molecular mechanisms of DLE. However, further experimentation is required to confirm these findings.


Asunto(s)
Redes Reguladoras de Genes/inmunología , Lupus Eritematoso Discoide/genética , Quimiocina CXCL10/genética , Biología Computacional , Citocinas/genética , Proteína 58 DEAD Box/metabolismo , Conjuntos de Datos como Asunto , Perfilación de la Expresión Génica , Humanos , Factor 7 Regulador del Interferón/genética , Helicasa Inducida por Interferón IFIH1/genética , Lupus Eritematoso Discoide/epidemiología , Lupus Eritematoso Discoide/inmunología , Lupus Eritematoso Discoide/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Piel/inmunología , Piel/patología , Programas Informáticos , Ubiquitinas/genética , Regulación hacia Arriba/inmunología
11.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799477

RESUMEN

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Inmunidad Innata/inmunología , Hígado/inmunología , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/genética , Humanos , Inmunidad Innata/genética , Hígado/efectos de los fármacos , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología
12.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806988

RESUMEN

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 µL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.


Asunto(s)
Asfixia/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Vaina de Mielina/metabolismo , Animales , Animales Recién Nacidos , Puntaje de Apgar , Asfixia/etiología , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patología , Diferenciación Celular , Supervivencia Celular , Citocinas/genética , Citocinas/metabolismo , Expresión Génica , Hipocampo/metabolismo , Hipocampo/patología , Inmunohistoquímica , Mediadores de Inflamación , Células Madre Mesenquimatosas/citología , Vaina de Mielina/patología , Neuroglía/inmunología , Neuroglía/metabolismo , Oligodendroglía/metabolismo , ARN Mensajero , Ratas
13.
J Int Med Res ; 49(4): 3000605211006522, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33823642

RESUMEN

OBJECTIVE: To explore the relationship between the omentin-1 gene rs2274907 A>T polymorphism and colorectal cancer (CRC) in the Chinese Han population. METHODS: rs2274907 A>T was assessed by PCR-restriction fragment length polymorphism analysis. Plasma omentin-1 expression from 358 patients with CRC and 286 healthy controls was analyzed by enzyme-linked immunosorbent assay. CRC and control groups were divided into subgroups according to the body mass index (BMI) threshold of 25 kg/m2. RESULTS: No significant differences were observed between CRC and control groups in terms of genotype or allele frequencies of rs2274907 A>T. Compared with individuals with BMI <25 kg/m2 and the rs2274907 TT genotype, those with AA+AT genotypes and BMI ≥25 kg/m2 had a 3.027-fold increased risk of CRC. A significant tendency toward a higher stage of colorectal adenocarcinomas and depth of invasion was observed in individuals with the rs2274907 AA genotype compared with other genotypes. CONCLUSIONS: The omentin-1 gene rs2274907 A>T polymorphism does not seem to play a critical role in the development of CRC in the Chinese Han population, but an interaction between the rs2274907 A allele and BMI may increase the CRC risk. The rs2274907 AA genotype is a potential biomarker for CRC stage progression.


Asunto(s)
Neoplasias Colorrectales , Citocinas , Lectinas , Polimorfismo de Nucleótido Simple , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , China , Neoplasias Colorrectales/genética , Citocinas/genética , Femenino , Proteínas Ligadas a GPI/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lectinas/genética , Masculino , Polimorfismo de Nucleótido Simple/genética
14.
Anticancer Res ; 41(3): 1213-1218, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788712

RESUMEN

BACKGROUND/AIM: Overexpression of inflammatory cytokines and oxidative stress increase the risk of colorectal cancer (CRC) in obesity and hyperlipidemia. The aim of this study was to investigate whether the monoterpene antioxidant p-cymene would reduce the incidence of CRC in a rat model of hyperlipidemia. MATERIALS AND METHODS: The hyperlipidemic CRC rat model was established by a high-fat diet and dimethyl hydrazine (DMH) induction. All rats received 30 mg/kg DMH to induce CRC, and were then assigned to groups with a normal diet or high-fat diet with/without 30 mg/kg/day p-cymene orally during the entire experimental period. Tumor incidence in each group, and the level of serum inflammatory cytokines and oxidative stress-related markers in intestinal tissues were measured. RESULTS: p-Cymene significantly inhibited CRC occurrence in hyperlipemic rats (p=0.024) by reducing the expression of serum inflammatory cytokines (interleukin-1 by 54.5%; interleukin-6 by 28.3%; adiponectin by 26.3%; cyclo-oxygenase-2 by 48.4%) and intestinal oxidative-stress cytokines (total antioxidant capacity by 30.4%; superoxide dismutase by 30.3%; malondialdehyde by 47.1%). CONCLUSION: p-Cymene has clinical potential to reduce the incidence of CRC in hyperlipemia.


Asunto(s)
Antioxidantes/farmacología , Neoplasias Colorrectales/prevención & control , Cimenos/farmacología , Citocinas/genética , Hiperlipidemias/complicaciones , Estrés Oxidativo/efectos de los fármacos , Animales , Neoplasias Colorrectales/metabolismo , Cimenos/uso terapéutico , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Femenino , Masculino , Ratas , Ratas Wistar
15.
Front Immunol ; 12: 636289, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33763080

RESUMEN

Although widely prevalent, Lyme disease is still under-diagnosed and misunderstood. Here we followed 73 acute Lyme disease patients and uninfected controls over a period of a year. At each visit, RNA-sequencing was applied to profile patients' peripheral blood mononuclear cells in addition to extensive clinical phenotyping. Based on the projection of the RNA-seq data into lower dimensions, we observe that the cases are separated from controls, and almost all cases never return to cluster with the controls over time. Enrichment analysis of the differentially expressed genes between clusters identifies up-regulation of immune response genes. This observation is also supported by deconvolution analysis to identify the changes in cell type composition due to Lyme disease infection. Importantly, we developed several machine learning classifiers that attempt to perform various Lyme disease classifications. We show that Lyme patients can be distinguished from the controls as well as from COVID-19 patients, but classification was not successful in distinguishing those patients with early Lyme disease cases that would advance to develop post-treatment persistent symptoms.


Asunto(s)
Leucocitos Mononucleares/inmunología , Enfermedad de Lyme/genética , Adulto , /inmunología , Citocinas/genética , Citocinas/inmunología , Femenino , Estudios de Seguimiento , Humanos , Leucocitos Mononucleares/química , Enfermedad de Lyme/sangre , Enfermedad de Lyme/inmunología , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Estudios Prospectivos , RNA-Seq
16.
Cardiovasc Ther ; 2021: 6651009, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33680092

RESUMEN

Background: Pulmonary complications of systemic sclerosis (SSc), including pulmonary arterial hypertension (PAH), are the leading causes of patient death. However, the precise molecular mechanisms of its etiology are unclear. This study's objective was to identify the candidate genes involved in the progression of SSc-PAH and investigate the genes' function. Methods: The gene expression profiles of GSE33463 were obtained from the Gene Expression Omnibus (GEO) database. A free-scale gene coexpression network was constructed using the weighted gene coexpression network analysis (WGCNA) to explore the association between gene sets and clinical features and identify candidate biomarkers. Then, gene ontology analysis was performed. A second dataset was used, GSE19617, to validate the hub genes. The verified hub genes' potential function was further explored using gene set enrichment analysis (GSEA). Results: Through average link-level clustering, a total of seven modules were classified. A total of 938 hub genes were identified in the key module, and the key module's function mainly enriched was related to chemokine activities. Subsequently, four candidate genes, BTG3, CCR2, RAB10, and TMEM60, were filtered. The expression levels of these four hub genes were consistent in the GSE19617 and GSE33463 datasets. We plotted the ROC curve of the hub genes (all AUC > 0.70). Furthermore, the results of the GSEA for hub genes were correlated with complement and inflammatory responses. Conclusions: The hub genes (BTG3, CCR2, RAB10, and TMEM60) performed well in distinguishing the SSc-PAH patients from controls, and some biological functions, related to immunity, inflammation, and cytokines, might pave the way for follow-up studies on the diagnosis and treatment of SSc-PAH.


Asunto(s)
Citocinas/genética , Inmunidad , Inflamación/complicaciones , Hipertensión Arterial Pulmonar/etiología , Esclerodermia Sistémica/complicaciones , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Hipertensión Arterial Pulmonar/inmunología , Transcriptoma
17.
Front Immunol ; 12: 618807, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33679760

RESUMEN

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.


Asunto(s)
Alternaria/inmunología , Alternariosis/inmunología , GMP Cíclico/análogos & derivados , Inmunidad Innata , Pulmón/inmunología , Proteínas de la Membrana/inmunología , Neumonía/inmunología , Alternariosis/genética , Alternariosis/patología , Animales , GMP Cíclico/genética , GMP Cíclico/inmunología , Citocinas/genética , Citocinas/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Neumonía/genética , Neumonía/microbiología , Neumonía/patología , Transducción de Señal/genética , Transducción de Señal/inmunología
18.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669022

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. METHODS: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6-/- MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. RESULTS: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. CONCLUSION: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.


Asunto(s)
Endotelio Vascular/metabolismo , Interleucina-6/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Linfocitos T/inmunología , Acetilcolina/farmacología , Animales , Aorta/inmunología , Aorta/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/genética , Riñón/metabolismo , Riñón/patología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
19.
Zhongguo Zhong Yao Za Zhi ; 46(2): 412-419, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33645130

RESUMEN

In this paper, Asarum polysaccharides(AP) were extracted, and its composition was analyzed to study the activity against H1 N1 influenza virus in vitro and its intervention effect on mice with kidney Yang deficiency syndrome. AP was prepared by the strategy of water extraction and alcohol precipitation, the content was determined, and its monosaccharide composition was analyzed. The cell Real-time monitoring system and Reed-Muench model were adopted to evaluate the antiviral activity of AP in vitro. And the mouse model of kidney Yang deficiency syndrome was established in vivo to compare the efficacy of Mahuang Xixin Fuzi Decoction(MXF) and AP. MXF group and AP group were treated with clinical equivalent doses of 1.8 g·kg~(-1)·d~(-1) and 0.077 g·kg~(-1)·d~(-1) respectively, once a day for 6 consecutive days. Real-time PCR was used to detect the relative expression of M gene of H1 N1 influenza virus and cytokines in lung tissue. The content of AP in Asarum was 25.22%, and the protein content was 0.8%. And the monosaccharide composition was identified as L-rhamnose, D-arabinose, D-xylose, D-glucose, D-galactose and D-mannose. TI values of Tamiflu, MXF and AP were 30.00, 8.06 and 10.33, respectively. Three different doses of AP could significantly reduce the concentration of virus in supernatant. Compared with the model mice, lung indexes of MXF group and AP group decreased significantly(P<0.05), and the relative expression of M gene decreased significantly(P<0.05). The relative expressions of IL-10 and IFN-γ were up-regulated to varying degrees, while the relative gene expressions of IL-1ß, IL-6 and MCP-1 were down-regulated to different degrees. In addition, AP could significantly enhance the expression of TNF-α(P<0.01). AP had a good anti-influenza virus activity in vitro, and could protect mice with kidney Yang deficiency syndrome by reducing the viral load in lung tissue, decreasing inflammation damage in lung tissue, and regulating the expression of inflammatory cytokines. Compared with the prescription of MXF, AP had a better antiviral activity.


Asunto(s)
Asarum , Medicamentos Herbarios Chinos , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Animales , Antivirales/uso terapéutico , Citocinas/genética , Gripe Humana/tratamiento farmacológico , Gripe Humana/genética , Pulmón , Ratones , Polisacáridos
20.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673027

RESUMEN

Lactosylceramide (LacCer), also known as CD17/CDw17, is a member of a large family of small molecular weight compounds known as glycosphingolipids. It plays a pivotal role in the biosynthesis of glycosphingolipids, primarily by way of serving as a precursor to the majority of its higher homolog sub-families such as gangliosides, sulfatides, fucosylated-glycosphingolipids and complex neutral glycosphingolipids-some of which confer "second-messenger" and receptor functions. LacCer is an integral component of the "lipid rafts," serving as a conduit to transduce external stimuli into multiple phenotypes, which may contribute to mortality and morbidity in man and in mouse models of human disease. LacCer is synthesized by the action of LacCer synthase (ß-1,4 galactosyltransferase), which transfers galactose from uridine diphosphate galactose (UDP-galactose) to glucosylceramide (GlcCer). The convergence of multiple physiologically relevant external stimuli/agonists-platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), stress, cigarette smoke/nicotine, tumor necrosis factor-α (TNF-α), and in particular, oxidized low-density lipoprotein (ox-LDL)-on ß-1,4 galactosyltransferase results in its phosphorylation or activation, via a "turn-key" reaction, generating LacCer. This newly synthesized LacCer activates NADPH (nicotinamide adenine dihydrogen phosphate) oxidase to generate reactive oxygen species (ROS) and a highly "oxidative stress" environment, which trigger a cascade of signaling molecules and pathways and initiate diverse phenotypes like inflammation and atherosclerosis. For instance, LacCer activates an enzyme, cytosolic phospholipase A2 (cPLA2), which cleaves arachidonic acid from phosphatidylcholine. In turn, arachidonic acid serves as a precursor to eicosanoids and prostaglandin, which transduce a cascade of reactions leading to inflammation-a major phenotype underscoring the initiation and progression of several debilitating diseases such as atherosclerosis and cancer. Our aim here is to present an updated account of studies made in the field of LacCer metabolism and signaling using multiple animal models of human disease, human tissue, and cell-based studies. These advancements have led us to propose that previously unrelated phenotypes converge in a LacCer-centric manner. This LacCer synthase/LacCer-induced "oxidative stress" environment contributes to inflammation, atherosclerosis, skin conditions, hair greying, cardiovascular disease, and diabetes due to mitochondrial dysfunction. Thus, targeting LacCer synthase may well be the answer to remedy these pathologies.


Asunto(s)
Antígenos CD/metabolismo , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Lactosilceramidos/metabolismo , Estrés Oxidativo , Transducción de Señal , Enfermedades de la Piel/metabolismo , Animales , Antígenos CD/genética , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/terapia , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/terapia , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Diabetes Mellitus/terapia , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Inflamación/terapia , Lactosilceramidos/genética , Ratones , Enfermedades de la Piel/genética , Enfermedades de la Piel/patología , Enfermedades de la Piel/terapia
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