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1.
Nat Commun ; 12(1): 836, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547321

RESUMEN

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3ß inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.


Asunto(s)
Colitis/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Homeostasis/genética , Interleucina-33/genética , Proteínas de la Membrana/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Niño , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Femenino , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patología , Células HT29 , Homeostasis/efectos de los fármacos , Humanos , Interleucina-33/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Dodecil Sulfato de Sodio/administración & dosificación
2.
Adv Exp Med Biol ; 1278: 47-62, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33523442

RESUMEN

Regulatory T (Tregs) cells, required to maintain immune homeostasis, have significant power in disease outcomes. Treg dysfunction, predominantly characterized by the loss of the master transcription factor FoxP3 and the acquisition of Teff-like phenotypes, can promote autoimmunity as well as enhance anti-tumor immunity. As FoxP3 expression and stability are pinnacle for Treg suppressive functions, understanding the pathways that regulate FoxP3 is crucial to ascertain Treg-mediated therapies for autoimmune diseases and cancer. Mechanisms controlling FoxP3 expression and stability range from transcriptional to posttranslational, revealing multiple therapeutic opportunities. While many of the transcriptional pathways have been explored in detail, a recent surge in interest on the posttranslational mechanisms regulating FoxP3 has arisen. Particularly, the role of ubiquitination on Tregs both directly and indirectly involving FoxP3 has gained interest. Here, we summarize the current knowledge on ubiquitin-dependent, FoxP3-mediated control of Treg function as it pertains to human diseases.


Asunto(s)
Factores de Transcripción Forkhead , Linfocitos T Reguladores , Autoinmunidad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Humanos , Linfocitos T Reguladores/metabolismo , Ubiquitina
3.
Adv Exp Med Biol ; 1278: 63-80, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33523443

RESUMEN

As an indispensable part of peripheral tolerance, regulatory T (Treg) cells play an important role in immune homeostasis by suppressing other immune cells. Behind this function is a complex network of transcription factors and signaling cascades that regulates the function and plasticity of regulatory T cells. Among these, Forkhead box P3 (Foxp3) is considered as the master transcription factor, and its stability will influence the function and viability of Treg cells. Because of this, understanding the mechanisms that regulate Foxp3 and its co-regulators will provide more understanding to Treg cells and uncover more targets to manipulate Treg cells in treating autoimmune diseases, organ transplantation, and tumor. Interestingly, several recent studies show that ubiquitin-dependent pathways are important regulators of Foxp3, which suggest both great scientific and therapeutic values. In this chapter, we cover emerging evidence of ubiquitin-dependent, posttranslational regulation of Treg function and plasticity.


Asunto(s)
Factores de Transcripción Forkhead , Linfocitos T Reguladores , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Homeostasis , Linfocitos T Reguladores/metabolismo , Ubiquitina
4.
Adv Exp Med Biol ; 1278: 95-114, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33523445

RESUMEN

The discovery of the epigenetic regulation of Treg cells, a cell population with fundamental immunoregulatory properties, has shed considerable insights into an understanding of the role of these cells in health and disease. Research over the past several years has shown that the interaction of Treg cells with the gut microbiota are critical not only for the development of Treg function in health but also for abnormalities of Treg function that play a critical role in the pathogenesis of human diseases such as the allergic diseases, the autoimmune disorders, and cancer. The equilibrium between phenotypic plasticity and stability of Treg cells is defined by the fine-tuned transcriptional and epigenetic events required to ensure stable expression of Foxp3 in Treg cells. In this chapter, we discuss the molecular events that control Foxp3 gene expression and address the importance of DNA methylation as an important molecular switch that regulates the genetic expression of Treg induction and the possible implications of these findings for the treatment of human diseases characterized by abnormalities of Treg cell function.


Asunto(s)
Enfermedades Autoinmunes , Linfocitos T Reguladores , Enfermedades Autoinmunes/genética , Metilación de ADN , Epigénesis Genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Humanos , Linfocitos T Reguladores/metabolismo
5.
Medicine (Baltimore) ; 100(4): e24484, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530265

RESUMEN

BACKGROUND: Ewing sarcoma (ES), the second most prevalent bone malignant tumor has no widely known prognostic biomarker. Earlier studies have suggested that chaperonin containing TCP1 complex 6A (CCT6A), which encodes a molecular protein chaperone, is involved in the pathogenesis of many cancers. However, there are no known reports providing clear evidence of its role in ES pathogenesis. METHODS: We performed a bioinformatic analysis of 32 ES specimens from the GSE17618 dataset concentrating on the differences in gene expression, OS, event-free survival (EFS) in the different subgroups. Immunohistochemical studies were also performed to identify the expression levels of selected genes in ES and immediate paracancerous tissues. RESULTS: After 3 screenings, CCT6A was identified to be highly correlated with ES prognosis. Our survival analysis revealed a low overall survival (OS) for high CCT6A expression (P-value = .024). Our Cox regression analysis identified CCT6A expression, lEFS, and age were strongly associated with prognosis of ES. Our multivariate Cox regression analysis shows that CCT6A (P-value = .015), age (P-value = .026), and EFS (P-value = .002) were independent poor prognostic biomarkers. Our immunohistochemical analysis showed that the expression levels of CCT6A were significantly higher in ES tissues compared to the paracancerous tissues. CONCLUSION: From the results of our study, we identified the expression levels of CCT6A to be strongly associated with prognosis of ES. Thus, the expression levels of the CCT6A gene could serve as a biomarker for the prediction of ES prognosis.


Asunto(s)
Neoplasias Óseas/genética , Chaperonina con TCP-1/metabolismo , Sarcoma de Ewing/genética , Adolescente , Factores de Edad , Biomarcadores de Tumor/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Bases de Datos Genéticas , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Adulto Joven
6.
Cells ; 10(2)2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540583

RESUMEN

Many viruses disrupt host gene expression by degrading host mRNAs and/or manipulating translation activities to create a cellular environment favorable for viral replication. Often, virus-induced suppression of host gene expression, including those involved in antiviral responses, contributes to viral pathogenicity. Accordingly, clarifying the mechanisms of virus-induced disruption of host gene expression is important for understanding virus-host cell interactions and virus pathogenesis. Three highly pathogenic human coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2, have emerged in the past two decades. All of them encode nonstructural protein 1 (nsp1) in their genomes. Nsp1 of SARS-CoV and MERS-CoV exhibit common biological functions for inducing endonucleolytic cleavage of host mRNAs and inhibition of host translation, while viral mRNAs evade the nsp1-induced mRNA cleavage. SARS-CoV nsp1 is a major pathogenic determinant for this virus, supporting the notion that a viral protein that suppresses host gene expression can be a virulence factor, and further suggesting the possibility that SARS-CoV-2 nsp1, which has high amino acid identity with SARS-CoV nsp1, may serve as a major virulence factor. This review summarizes the gene expression suppression functions of nsp1 of CoVs, with a primary focus on SARS-CoV nsp1 and MERS-CoV nsp1.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/virología , Proteínas no Estructurales Virales/fisiología , Animales , Betacoronavirus/patogenicidad , Betacoronavirus/fisiología , Regulación de la Expresión Génica , Interacciones Microbiota-Huesped , Humanos , Ratones , ARN Mensajero/genética , Replicación Viral
7.
Nat Commun ; 12(1): 892, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563972

RESUMEN

Given their copy number differences and unique modes of inheritance, the evolved gene content and expression of sex chromosomes is unusual. In many organisms the X and Y chromosomes are inactivated in spermatocytes, possibly as a defense mechanism against insertions into unpaired chromatin. In addition to current sex chromosomes, Drosophila has a small gene-poor X-chromosome relic (4th) that re-acquired autosomal status. Here we use single cell RNA-Seq on fly larvae to demonstrate that the single X and pair of 4th chromosomes are specifically inactivated in primary spermatocytes, based on measuring all genes or a set of broadly expressed genes in testis we identified. In contrast, genes on the single Y chromosome become maximally active in primary spermatocytes. Reduced X transcript levels are due to failed activation of RNA-Polymerase-II by phosphorylation of Serine 2 and 5.


Asunto(s)
Drosophila/genética , Cromosomas Sexuales/genética , Espermatocitos/metabolismo , Animales , Drosophila/crecimiento & desarrollo , Regulación de la Expresión Génica , Genes Ligados a X/genética , Genes Ligados a Y/genética , Larva/genética , Larva/crecimiento & desarrollo , Masculino , Especificidad de Órganos , ARN Polimerasa II/metabolismo , Cromosomas Sexuales/metabolismo , Espermatogénesis/genética , Testículo/citología , Testículo/metabolismo , Transcripción Genética
8.
Sci Rep ; 11(1): 3379, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33564039

RESUMEN

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.


Asunto(s)
Sistema del Grupo Sanguíneo ABO/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Panobinostat/farmacología , Ácido Butírico/farmacología , /prevención & control , Línea Celular , Células Epiteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Serina Endopeptidasas
9.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537817

RESUMEN

Inflammation is the most common cause of most acute and chronic debilitating diseases. Towards unveiling novel therapeutic options for patients with such complications, N­bromotaurine (TauNHBr) has emerged as a potential anti­inflammatory agent; however, its therapeutic efficacy is hindered due to its relatively poor stability. To address this challenge, the present study focused on examining the effects of a stable active bromine compound, named bromamine T (BAT). The present study examined the protective properties of BAT against lipopolysaccharide (LPS)­mediated inflammation in vitro, by using LPS­stimulated murine J774.A1 macrophages (Mφs), as well as in vivo, by using a murine LPS­mediated air­pouch model. Additionally, its efficacy was compared with that of taurine, a known potent anti­inflammatory molecule. In LPS­stimulated J774A.1 Mφs, BAT and taurine were very effective in reducing the secretion of pro­inflammatory mediators. The in vitro experiments indicated that LPS­mediated inflammation was attenuated due to the protective properties of BAT and of taurine, probably through the inhibition of phosphorylated p65 NF­κB subunit (Ser 536) nuclear translocation. The in vivo experiments also revealed that BAT and taurine inhibited LPS­mediated inflammation by reducing total cell/polymorphonuclear cell (PMN) infiltration in the air­pouch and by decreasing pouch wall thickness. The analysis of exudates obtained from pouches highlighted that the inhibitory effects of BAT and taurine on the secretion of pro­inflammatory cytokines were similar to those observed in vitro. Notably, the effect of BAT at the highest concentration tested was superior to that of taurine at the highest concentration. Taken together, the findings of the present study indicate that BAT prevents the LPS­induced inflammatory response both in vitro and in vivo.


Asunto(s)
Bromo/uso terapéutico , Inflamación/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Bromo/farmacología , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sulfonamidas/farmacología , Taurina/farmacología , Factor de Transcripción ReIA/metabolismo , Transcripción Genética/efectos de los fármacos
10.
J Vis Exp ; (167)2021 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-33522515

RESUMEN

The global prevalence Type 2 diabetes mellitus (T2DM) is escalating at a rapid rate. Patients with T2DM suffer from a multitude of complications and one of these is impaired wound healing. This can lead to the development of non-healing sores or foot ulcers and ultimately to amputation. In healthy individuals, wound healing follows a controlled and overlapping sequence of events encompassing inflammation, proliferation, and remodelling. In T2DM, one or more of these steps becomes dysfunctional. Current models to study impaired wound healing in T2DM include in vitro scratch wound assays, skin equivalents, or animal models to examine molecular mechanisms underpinning wound healing and/or potential therapeutic options. However, these do not fully recapitulate the complex wound healing process in T2DM patients, and ex vivo human skin tests are problematic due to the ethics of taking punch biopsies from patients where it is known they will heal poorly. Here, a technique is described whereby expression profiles of the specific cells involved in the (dys)functional wound healing response in T2DM patients can be examined using surplus tissue discarded following amputation or elective cosmetic surgery. In this protocol samples of donated skin are collected, wounded, cultured ex vivo in the air liquid interface, fixed at different time points and sectioned. Specific cell types involved in wound healing (e.g., epidermal keratinocytes, dermal fibroblasts (papillary and reticular), the vasculature) are isolated using laser capture microdissection and differences in gene expression analyzed by sequencing or microarray, with genes of interest further validated by qPCR. This protocol can be used to identify inherent differences in gene expression between both poorly healing and intact skin, in patients with or without diabetes, using tissue ordinarily discarded following surgery. It will yield greater understanding of the molecular mechanisms contributing to T2DM chronic wounds and lower limb loss.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Procedimientos Quirúrgicos Electivos , Regulación de la Expresión Génica , Captura por Microdisección con Láser , Cicatrización de Heridas/genética , Animales , Crioultramicrotomía , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Modelos Biológicos , Fijación del Tejido
11.
Int J Nanomedicine ; 16: 579-589, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531802

RESUMEN

Purpose: Breast cancer is one of the most lethal types of cancer in women. Curcumin showed therapeutic potential against breast cancer, but applying that by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. Moreover, poor water solubility of curcumin causes accumulation of a high concentration of curcumin and so decrease its permeability to the cell. Many strategies are employed to reduce curcumin metabolism such as adjuvants and designing novel delivery systems. Therefore, in this study sodium alginate and chitosan were used to synthesize the hydrogels that are known as biocompatible, hydrophilic and low toxic drug delivery systems. Also, folic acid was used to link to chitosan in order to actively targetfolate receptors on the cells. Methods: Chitosan-ß-cyclodextrin-TPP-Folic acid/alginate nanoparticles were synthesized and then curcumin was loaded on them. Interaction between the constituents of the particles was characterized by FTIR spectroscopy. Morphological structures of samples were studied by FE-SEM. Release profile of curcumin was determined by dialysis membrane. The cytotoxic test was done on the Kerman male breast cancer (KMBC-10) cell line by using MTT assay. The viability of cells was detected by fluorescent staining. Gene expression was investigated by real-time PCR. Results: The encapsulation of curcumin into nano-particles showed an almost spherical shape and an average particle size of 155 nm. In vitro cytotoxicity investigation was indicated as dose-respond reaction against cancer breast cells after 24 h incubation. On the other hand, in vitro cell uptake study revealed active targeting of CUR-NPs into spheroids. Besides, CXCR 4 expression was detected about 30-fold less than curcumin alone. The CUR-NPs inhibited proliferation and increased apoptosis in spheroid human breast cancer cells. Conclusion: Our results showed the potential of NPs as an effective candidate for curcumin delivery to the target tumor spheroids that confirmed the creatable role of folate receptors.


Asunto(s)
Alginatos/química , Quitosano/química , Curcumina/farmacología , Nanosferas/química , Esferoides Celulares/patología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Fluorescencia , Ácido Fólico/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Nanosferas/ultraestructura , Tamaño de la Partícula , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Esferoides Celulares/efectos de los fármacos
12.
Am J Hum Genet ; 108(2): 269-283, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33545030

RESUMEN

Topologically associating domains (TADs) are fundamental units of three-dimensional (3D) nuclear organization. The regions bordering TADs-TAD boundaries-contribute to the regulation of gene expression by restricting interactions of cis-regulatory sequences to their target genes. TAD and TAD-boundary disruption have been implicated in rare-disease pathogenesis; however, we have a limited framework for integrating TADs and their variation across cell types into the interpretation of common-trait-associated variants. Here, we investigate an attribute of 3D genome architecture-the stability of TAD boundaries across cell types-and demonstrate its relevance to understanding how genetic variation in TADs contributes to complex disease. By synthesizing TAD maps across 37 diverse cell types with 41 genome-wide association studies (GWASs), we investigate the differences in disease association and evolutionary pressure on variation in TADs versus TAD boundaries. We demonstrate that genetic variation in TAD boundaries contributes more to complex-trait heritability, especially for immunologic, hematologic, and metabolic traits. We also show that TAD boundaries are more evolutionarily constrained than TADs. Next, stratifying boundaries by their stability across cell types, we find substantial variation. Compared to boundaries unique to a specific cell type, boundaries stable across cell types are further enriched for complex-trait heritability, evolutionary constraint, CTCF binding, and housekeeping genes. Thus, considering TAD boundary stability across cell types provides valuable context for understanding the genome's functional landscape and enabling variant interpretation that takes 3D structure into account.


Asunto(s)
Cromatina , Evolución Molecular , Variación Genética , Genoma Humano , Herencia Multifactorial , Células Cultivadas , Células Madre Embrionarias , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos
13.
Nat Commun ; 12(1): 1033, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589615

RESUMEN

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Drogas en Investigación/farmacología , Aprendizaje Automático , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Medicamentos bajo Prescripción/farmacología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Reposicionamiento de Medicamentos , Drogas en Investigación/química , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/química , Nootrópicos/química , Farmacogenética/métodos , Farmacogenética/estadística & datos numéricos , Polifarmacología , Medicamentos bajo Prescripción/química , Cultivo Primario de Células , Índice de Severidad de la Enfermedad
14.
Nat Commun ; 12(1): 1042, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589625

RESUMEN

Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand ("A18") that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Enterocolitis Necrotizante/genética , Indoles/administración & dosificación , Leche Humana/fisiología , Receptores de Hidrocarburo de Aril/genética , Receptor Toll-Like 4/genética , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/inmunología , Dieta/métodos , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/inmunología , Enterocolitis Necrotizante/patología , Enterocolitis Necrotizante/prevención & control , Femenino , Regulación de la Expresión Génica , Humanos , Recién Nacido , Recien Nacido Prematuro , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ligandos , Exposición Materna , Ratones , Embarazo , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/inmunología , Transducción de Señal , Porcinos , Receptor Toll-Like 4/inmunología
15.
Nat Commun ; 12(1): 1041, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589633

RESUMEN

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.


Asunto(s)
Regulación del Apetito/fisiología , Ejercicio Físico/fisiología , Conducta Alimentaria/fisiología , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/genética , Resistencia Física/fisiología , Adulto , Animales , Creatina Quinasa/sangre , Creatina Quinasa/genética , Regulación de la Expresión Génica , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/deficiencia , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Interleucina-10/sangre , Interleucina-10/genética , Interleucina-6/administración & dosificación , Leptina/sangre , Leptina/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Motivación/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Condicionamiento Físico Animal , Factores de Tiempo
16.
BMC Genomics ; 22(1): 125, 2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602138

RESUMEN

BACKGROUND: The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are  now available, effective treatment options are still out of reach. RESULTS: To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < - 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. CONCLUSIONS: Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients' expression profiles of BALF cells.


Asunto(s)
/genética , Sistemas de Liberación de Medicamentos , Perfilación de la Expresión Génica , /fisiología , Células A549 , Regulación de la Expresión Génica , Humanos , Modelos Biológicos , Reproducibilidad de los Resultados , Análisis de la Célula Individual
17.
Nat Commun ; 12(1): 805, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547295

RESUMEN

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17-IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Disbiosis/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interferón gamma/inmunología , Interleucinas/inmunología , Fagocitos/inmunología , Animales , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/inmunología , Modelos Animales de Enfermedad , Disbiosis/genética , Disbiosis/microbiología , Disbiosis/patología , Microbioma Gastrointestinal/inmunología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/microbiología , Enfermedad Injerto contra Huésped/patología , Interferón gamma/deficiencia , Interferón gamma/genética , Interleucina-17/deficiencia , Interleucina-17/genética , Interleucina-17/inmunología , Interleucinas/genética , Intestinos/inmunología , Intestinos/microbiología , Intestinos/patología , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Pancreatitis/genética , Proteínas Asociadas a Pancreatitis/inmunología , Fagocitos/citología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores , Linfocitos T Reguladores , Irradiación Corporal Total
18.
Nat Commun ; 12(1): 816, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547301

RESUMEN

Serum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations.


Asunto(s)
Alanina Transaminasa/genética , Fosfatasa Alcalina/genética , Aspartato Aminotransferasas/genética , Genoma Humano , Hepatopatías/genética , Hígado/enzimología , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Aspartato Aminotransferasas/sangre , Bancos de Muestras Biológicas , Células Endoteliales/enzimología , Células Endoteliales/patología , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Hepatocitos/enzimología , Hepatocitos/patología , Humanos , Japón , Células Asesinas Naturales/enzimología , Células Asesinas Naturales/patología , Macrófagos del Hígado/enzimología , Macrófagos del Hígado/patología , Hígado/patología , Hepatopatías/sangre , Hepatopatías/clasificación , Hepatopatías/patología , Sitios de Carácter Cuantitativo , Carácter Cuantitativo Heredable , Análisis de la Célula Individual , Reino Unido
19.
PLoS Pathog ; 17(2): e1009207, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539484

RESUMEN

The recent Coronavirus Disease 2019 pandemic has once again reminded us the importance of understanding infectious diseases. One important but understudied area in infectious disease research is the role of nuclear architecture or the physical arrangement of the genome in the nucleus in controlling gene regulation and pathogenicity. Recent advances in research methods, such as Genome-wide chromosome conformation capture using high-throughput sequencing (Hi-C), have allowed for easier analysis of nuclear architecture and chromosomal reorganization in both the infectious disease agents themselves as well as in their host cells. This review will discuss broadly on what is known about nuclear architecture in infectious disease, with an emphasis on chromosomal reorganization, and briefly discuss what steps are required next in the field.


Asunto(s)
Núcleo Celular/genética , Cromatina/metabolismo , Enfermedades Transmisibles/genética , Animales , /metabolismo , Núcleo Celular/metabolismo , Cromatina/genética , Cromosomas/genética , Cromosomas/metabolismo , Enfermedades Transmisibles/metabolismo , Regulación de la Expresión Génica , Humanos
20.
Nat Commun ; 12(1): 213, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431899

RESUMEN

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.


Asunto(s)
Dieta Alta en Grasa , Exosomas/metabolismo , Resistencia a la Insulina/genética , Fosfatidilcolinas/metabolismo , Regulación hacia Arriba/genética , Tejido Adiposo/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dislipidemias/complicaciones , Dislipidemias/genética , Dislipidemias/patología , Células Epiteliales/metabolismo , Hígado Graso/complicaciones , Hígado Graso/genética , Hígado Graso/patología , Heces , Regulación de la Expresión Génica , Intolerancia a la Glucosa , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Insulina/metabolismo , Interleucina-6/sangre , Intestinos/citología , Lípidos/química , Hígado/metabolismo , Hígado/patología , Activación de Macrófagos , Ratones Endogámicos C57BL , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Tetraspanina 30/metabolismo , Factor de Necrosis Tumoral alfa/sangre
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