RESUMEN

Homeodomain-only protein homeobox (HOPX) mainly exerts its transcriptional repression by physically sequestering the serum co-repressor and recruiting histone deacetylase (HDAC), possessing important potential as a prognostic gene in acute myeloid leukemia (AML). HDACs play crucial roles in cell growth, gene regulation, and metabolism, and they are also important factors in promoting AML progression. Therefore, this project attempts to investigate whether HOPX affects AML progression by interacting with HDAC2 protein. Bioinformatics analysis was employed to identify potential prognostic genes in AML. Flow cytometry and MTT assays were performed to analyze the cellular biological functions of the AML prognostic marker HOPX. The interaction network of HOPX was analyzed using the Search Tool for the Retrieval of Interacting Genes database, and the interaction between HOPX and HDAC2 was observed using endogenous and exogenous immunoprecipitation. HOPX is highly expressed in AML cells. Further research uncovered that low expression of HOPX can repress the proliferation activity, anti-apoptotic ability, and differentiation blockage of AML cells. Moreover, mechanistically, HOPX induced AML differentiation blockage and malignant progression through interaction with HDAC. HOPX can serve as a prognostic marker for AML and can interact with HDAC2 to induce AML differentiation blockage and malignant progression.

Asunto(s)

Diferenciación Celular , Histona Desacetilasa 2 , Proteínas de Homeodominio , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Histona Desacetilasa 2/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proliferación Celular , Regulación Leucémica de la Expresión Génica , Apoptosis , Línea Celular Tumoral , Pronóstico , Proteínas Supresoras de Tumor

RESUMEN

Background: This study investigated the genetic characteristics of five Chinese families with keratoconus (KC). Methods: In the five families affected by KC, medical records, clinical observations, and blood samples were collected from all individuals. All KC family members (n = 20) underwent both whole exome sequencing of genomic DNA and Sanger sequencing to confirm the variants. Online software was utilized to analyze all variants, and the online server I-TASSER was employed for in silico predictions of the three-dimensional protein structures of the variants. The newly discovered variants and single nucleotide polymorphisms were further examined in 322 sporadic KC patients. Results: The Pentacam tomographic composite index in those affected first-degree family members of the probands showed a pathological change. Five new variants were detected in the five probands and other affected members in their families: a heterozygous missense variant g.19043832C>T (p.Ser145Asn) in the homer scaffolding protein 3 (HOMER3) gene; a heterozygous missense variant g.99452113G>A (p.Gly483Arg) in the insulin-like growth factor 1 receptor (IGF1R) gene; a heterozygous missense variant g.55118280G>T (p.Trp843Leu) in the echinoderm microtubule-associated protein like 6 (EML6) gene; a heterozygous frameshift variant c. 1226_1227del (p.Gln410Glufs*17) in the DOP1 leucine zipper-like protein B (DOP1B) gene; and a heterozygous splice-site variant c.7776+2T>A in the neurobeachin-like protein 2 (NBEAL2) gene. These variations were predicted to be potentially pathogenic and associated with KC. Conclusion: Five novel variants in HOMER3, IGF1R, EML6, DOP1B, and NBEAL2 genes were identified in this study and may be associated with the pathogenesis of KC. This study provides new information about the gene variants and their protein changes in KC patients. The findings should be explored further and could potentially be applied to the early diagnosis of KC before clinical onset.

Asunto(s)

Pueblo Asiatico , Queratocono , Linaje , Polimorfismo de Nucleótido Simple , Humanos , Queratocono/genética , Masculino , Femenino , Adulto , China , Pueblo Asiatico/genética , Receptor IGF Tipo 1/genética , Proteínas de Homeodominio/genética , Secuenciación del Exoma , Mutación Missense , Persona de Mediana Edad , Adulto Joven , Proteínas Asociadas a Microtúbulos/genética , Predisposición Genética a la Enfermedad/genética , Adolescente , Pueblos del Este de Asia

RESUMEN

In the realm of this study, obtaining a comprehensive understanding of ischemic brain injury and its molecular foundations is of paramount importance. Our study delved into single-cell data analysis, with a specific focus on sub-celltypes and differentially expressed genes in the aftermath of ischemic injury. Notably, we observed a significant enrichment of the "ATP METABOLIC PROCESS" and "ATP HYDROLYSIS ACTIVITY" pathways, featuring pivotal genes such as Pbx3, Dguok, and Kif21b. A remarkable finding was the consistent upregulation of genes like Fabp7 and Bcl11a within the MCAO group, highlighting their crucial roles in regulating the pathway of mitochondrial ATP synthesis coupled proton transport. Furthermore, our network analysis unveiled pathways like "Neuron differentiation" and "T cell differentiation" as central in the regulatory processes of sub-celltypes. These findings provide valuable insights into the intricate molecular responses and regulatory mechanisms that govern brain injury. The shared differentially expressed genes among sub-celltypes emphasize their significance in orchestrating responses post-ischemic injury. Our research, viewed from the perspective of a medical researcher, contributes to the evolving understanding of the molecular landscape underlying ischemic brain injury, potentially paving the way for targeted therapeutic strategies and improved patient outcomes.

Asunto(s)

Adenosina Trifosfato , Infarto de la Arteria Cerebral Media , Cinesinas , Mitocondrias , Células Precursoras de Oligodendrocitos , Transducción de Señal , Animales , Transducción de Señal/genética , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Mitocondrias/metabolismo , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/biosíntesis , Cinesinas/genética , Cinesinas/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Humanos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Masculino , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Ratas , Proteínas Proto-Oncogénicas

RESUMEN

BACKGROUND: Understanding the lineage differentiation of human prostate not only is crucial for basic research on human developmental biology but also significantly contributes to the management of prostate-related disorders. Current knowledge mainly relies on studies on rodent models, lacking human-derived alternatives despite clinical samples may provide a snapshot at certain stage. Human embryonic stem cells can generate all the embryonic lineages including the prostate, and indeed a few studies demonstrate such possibility based on co-culture or co-transplantation with urogenital mesenchyme into mouse renal capsule. METHODS: To establish a stepwise protocol to obtain prostatic organoids in vitro from human embryonic stem cells, we apply chemicals and growth factors by mimicking the regulation network of transcription factors and signal transduction pathways, and construct cell lines carrying an inducible NKX3-1 expressing cassette, together with three-dimensional culture system. Unpaired t test was applied for statistical analyses. RESULTS: We first successfully generate the definitive endoderm, hindgut, and urogenital sinus cells. The embryonic stem cell-derived urogenital sinus cells express prostatic key transcription factors AR and FOXA1, but fail to express NKX3-1. Therefore, we construct NKX3-1-inducible cell line by homologous recombination, which is eventually able to yield AR, FOXA1, and NKX3-1 triple-positive urogenital prostatic lineage cells through stepwise differentiation. Finally, combined with 3D culture we successfully derive prostate-like organoids with certain structures and prostatic cell populations. CONCLUSIONS: This study reveals the crucial role of NKX3-1 in prostatic differentiation and offers the inducible NKX3-1 cell line, as well as provides a stepwise differentiation protocol to generate human prostate-like organoids, which should facilitate the studies on prostate development and disease pathogenesis.

Asunto(s)

Diferenciación Celular , Linaje de la Célula , Proteínas de Homeodominio , Células Madre Embrionarias Humanas , Próstata , Factores de Transcripción , Humanos , Próstata/citología , Próstata/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Células Madre Embrionarias Humanas/citología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Masculino , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Organoides/metabolismo , Organoides/citología , Ratones , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Animales , Línea Celular

RESUMEN

Upregulation of homeoprotein SIX1 in gastric cancer (GC) is related to tumour proliferation and invasion. MicroRNA-7160 (miR-7160) is a homeoprotein SIX1-targeting miRNA that downregulates miR-7160, leading to cancer development. Total gastric cancer samples were collected from six patients, and relative expression levels of SIX1 mRNA and miRNAs were analysed by qRT-PCR. To evaluate the regulation of SIX1 by miR-7160, pGL3-SIX1-mut, pGL3-SIX1, and miR-7160 mimics transfected into cells using lipofectamine 2000. After transfection, proliferation and apoptosis in cultured cells were assessed using the nuclear TUNEL staining and CCK8 reagent, respectively. We demonstrated that the downregulation of miR-7160 in human gastric cancer cells is related to the upregulation of SIX1 mRNA. In gastric cancer cell lines, miR-7160 overexpression could downregulate the expression and inhibit cancer cell proliferation and growth in vitro. However, overexpression of miR-7160 did not increase gastric cancer cell apoptosis. In vitro downregulation of SIX1 decreased vimentin, N-cadherin, and other EMT-related gene expression and increased E-cadherin expression. In brief, miR-7160, by targeting SIX1, inhibits gastric cancer proliferation and cell growth in vitro, which provides an idea for introducing a new treatment option for gastric cancer.

Asunto(s)

Apoptosis , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio , MicroARNs , Neoplasias Gástricas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Proliferación Celular/genética , Línea Celular Tumoral , Apoptosis/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Metástasis de la Neoplasia , Transición Epitelial-Mesenquimal/genética , Silenciador del Gen , Movimiento Celular/genética

Asunto(s)

Mutación , Miopatías Estructurales Congénitas , Humanos , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Mutación/genética , Masculino , Femenino , Músculo Esquelético/patología , Proteínas Musculares/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adulto , Proteínas de Homeodominio/genética

RESUMEN

BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

Asunto(s)

Trastorno del Espectro Autista , Discapacidad Intelectual , Síndrome del Ovario Poliquístico , Riñón Único , Humanos , Femenino , Adolescente , Trastorno del Espectro Autista/genética , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/diagnóstico , Discapacidad Intelectual/genética , Riñón Único/complicaciones , Secuenciación del Exoma , Proteínas del Tejido Nervioso/genética , Proteínas de Homeodominio/genética , Cardiopatías , Facies , Trastornos del Neurodesarrollo

RESUMEN

The precise regulation of stem cells in the shoot apical meristems (SAMs) involves the function of the homeodomain transcription factor (TF)-WUSCHEL (WUS). WUS has been shown to move from the site of production-the rib-meristem (RM), into overlaying cells of the central zone (CZ), where it specifies stem cells and also regulates the transcription of CLAVATA3 (CLV3). The secreted signalling peptide CLV3 activates a receptor kinase signalling that restricts WUS transcription and also regulates the nuclear gradient of WUS by offsetting nuclear export. WUS has been shown to regulate both CLV3 levels and spatial activation, restricting its expression to a few cells in the CZ. The HAIRY MERISTEM (HAM), a GRASS-domain class of TFs expressed in the RM, has been shown to physically interact with WUS and regulate CLV3 expression. However, the mechanisms by which this interaction regulates CLV3 expression non-cell autonomously remain unclear. Here, we show that HAM function is required for regulating the WUS protein stability, and the CLV3 expression responds to altered WUS protein levels in ham mutants. Thus, HAM proteins non-cell autonomously regulates CLV3 expression.

Asunto(s)

Proteínas de Arabidopsis , Arabidopsis , Regulación de la Expresión Génica de las Plantas , Proteínas de Homeodominio , Meristema , Meristema/genética , Meristema/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Mutación/genética

RESUMEN

Arterial endothelial cells (AECs) are the founder cells for intraembryonic haematopoiesis. Here, we report a method for the efficient generation of human haemogenic DLL4+ AECs from pluripotent stem cells (PSC). Time-series single-cell RNA-sequencing reveals the dynamic evolution of haematopoiesis and lymphopoiesis, generating cell types with counterparts present in early human embryos, including stages marked by the pre-haematopoietic stem cell genes MECOM/EVI1, MLLT3 and SPINK2. DLL4+ AECs robustly support lymphoid differentiation, without the requirement for exogenous NOTCH ligands. Using this system, we find IL7 acts as a morphogenic factor determining the fate choice between the T and innate lymphoid lineages and also plays a role in regulating the relative expression level of RAG1. Moreover, we document a developmental pathway by which human RAG1+ lymphoid precursors give rise to the natural killer cell lineage. Our study describes an efficient method for producing lymphoid progenitors, providing insights into their endothelial and haematopoietic ontogeny, and establishing a platform to investigate the development of the human blood system.

Asunto(s)

Hematopoyesis , Linfopoyesis , Humanos , Hematopoyesis/genética , Linfopoyesis/genética , Células Endoteliales/metabolismo , Células Endoteliales/citología , Diferenciación Celular , Linaje de la Célula/genética , Interleucina-7/metabolismo , Interleucina-7/genética , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/citología , Hemangioblastos/metabolismo , Hemangioblastos/citología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Análisis de la Célula Individual/métodos , Receptores Notch/metabolismo , Receptores Notch/genética

RESUMEN

The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.

Asunto(s)

Regulación del Desarrollo de la Expresión Génica , Neocórtex , Células-Madre Neurales , Neurogénesis , Factores del Dominio POU , Animales , Neocórtex/metabolismo , Neocórtex/embriología , Neocórtex/citología , Factores del Dominio POU/metabolismo , Factores del Dominio POU/genética , Neurogénesis/genética , Ratones , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Hurones , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Macaca , Proliferación Celular/genética , Receptores Notch/metabolismo , Receptores Notch/genética , Masculino , Femenino

RESUMEN

Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.

Asunto(s)

Mutación , Proteínas del Tejido Nervioso , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Disruptores Endocrinos/toxicidad , Trastorno del Espectro Autista/genética , Sistemas CRISPR-Cas , Interacción Gen-Ambiente , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/inducido químicamente , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo

RESUMEN

Diabetes mellitus, a chronic and non-transmissible disease, triggers a wide range of micro- and macrovascular complications. The differentiation of pancreatic ß-like cells (PßLCs) from induced pluripotent stem cells (iPSCs) offers a promising avenue for regenerative medicine aimed at treating diabetes. Current differentiation protocols strive to emulate pancreatic embryonic development by utilizing cytokines and small molecules at specific doses to activate and inhibit distinct molecular signaling pathways, directing the differentiation of iPSCs into pancreatic ß cells. Despite significant progress and improved protocols, the full spectrum of molecular signaling pathways governing pancreatic development and the physiological characteristics of the differentiated cells are not yet fully understood. Here, we report a specific combination of cofactors and small molecules that successfully differentiate iPSCs into PßLCs. Our protocol has shown to be effective, with the resulting cells exhibiting key functional properties of pancreatic ß cells, including the expression of crucial molecular markers (pdx1, nkx6.1, ngn3) and the capability to secrete insulin in response to glucose. Furthermore, the addition of vitamin C and retinoic acid in the final stages of differentiation led to the overexpression of specific ß cell genes.

Asunto(s)

Ácido Ascórbico , Diferenciación Celular , Diabetes Mellitus , Células Madre Pluripotentes Inducidas , Células Secretoras de Insulina , Tretinoina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/citología , Ácido Ascórbico/farmacología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Humanos , Diabetes Mellitus/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Transducción de Señal/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Transactivadores/metabolismo , Transactivadores/genética , Insulina/metabolismo , Proteínas del Tejido Nervioso

RESUMEN

BACKGROUND: The development of the human vermiform appendix at the cellular level, as well as its function, is not well understood. Appendicitis in preschool children, although uncommon, is associated with a high perforation rate and increased morbidity. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on the human appendix during fetal and pediatric stages as well as preschool-age inflammatory appendices. Transcriptional features of each cell compartment were discussed in the developing appendix. Cellular interactions and differentiation trajectories were also investigated. We compared scRNA-seq profiles from preschool appendicitis to those of matched healthy controls to reveal disease-associated changes. Bulk transcriptomic data, immunohistochemistry, and real-time quantitative PCR were used to validate the findings. RESULTS: Our analysis identified 76 cell types in total and described the cellular atlas of the developing appendix. We discovered the potential role of the BMP signaling pathway in appendiceal epithelium development and identified HOXC8 and PITX2 as the specific regulons of appendix goblet cells. Higher pericyte coverage, endothelial angiogenesis, and goblet mucus scores together with lower epithelial and endothelial tight junction scores were found in the preschool appendix, which possibly contribute to the clinical features of preschool appendicitis. Preschool appendicitis scRNA-seq profiles revealed that the interleukin-17 signaling pathway may participate in the inflammation process. CONCLUSIONS: Our study provides new insights into the development of the appendix and deepens the understanding of appendicitis in preschool children.

Asunto(s)

Apendicitis , Apéndice , Análisis de la Célula Individual , Humanos , Apendicitis/genética , Apendicitis/patología , Preescolar , Análisis de la Célula Individual/métodos , Femenino , Masculino , Análisis de Secuencia de ARN/métodos , Lactante , Proteínas de Homeodominio/genética

RESUMEN

INTRODUCTION: Mandibular prognathism (MP) patients present with aesthetic concerns and functional issues, including difficulties in mastication and pronunciation. Studies revealed that mandibular prognathism had definitive Mendelian inheritance patterns. This study aimed to ascertain distinct genetic markers associated with mandibular prognathism in individuals of Indian descent, focusing on exploring the prevalent genetic variations associated with certain genes. This study sought to identify the association of the following gene markers with mandibular prognathism: 1) Matrilin-1 (MATN1) (rs1065755), 2) Bone morphogenic protein 3 (BMP-3) (Tyr67Asn), 3) Homeobox protein hox-A2 (HOXA2) (Val327Ile), 4) Rho-GTPase activating protein (ARHGAP 21) (Gly1121Ser), 5) Myosin 1H (MYO1H) (rs10850110).

Asunto(s)

Proteínas de Homeodominio , Prognatismo , Humanos , Masculino , India , Femenino , Prognatismo/genética , Proteínas de Homeodominio/genética , Miosina Tipo I/genética , Adulto , Proteínas Activadoras de GTPasa/genética , Adulto Joven , Adolescente , Proteínas de la Matriz Extracelular/genética , Marcadores Genéticos , Estudios de Casos y Controles

RESUMEN

BACKGROUND: The roles of the transcriptional factor SIX2 have been identified in several tumors. However, its roles in gastric cancer (GC) progression have not yet been revealed. Our objective is to explore the impact and underlying mechanisms of SIX2 on the stemness of GC cells. METHODS: Lentivirus infection was employed to establish stable expression SIX2 or PFN2 in GC cells. Gain- and loss-of-function experiments were conducted to detect changes of stemness markers, flow cytometry profiles, tumor spheroid formation, and tumor-initiating ability. ChIP, RNA-sequencing, tissue microarray, and bioinformatics analysis were performed to reveal the correlation between SIX2 and PFN2. The mechanisms underlying the SIX2/PFN2 loop-mediated effects were elucidated through tissue microarray analysis, RNA stability assay, IP-MS, Co-Immunoprecipitation, and inhibition of the JNK signaling pathway. RESULTS: The stemness of GC cells was enhanced by SIX2. Mechanistically, SIX2 directly bound to PFN2's promoter and promoted PFN2 activity. PFN2, in turn, promoted the mRNA stability of SIX2 by recruiting RNA binding protein YBX-1, subsequently activating the downstream MAPK/JNK pathway. CONCLUSION: This study unveils the roles of SIX2 in governing GC cell stemness, defining a novel SIX2/PFN2 regulatory loop responsible for this regulation. This suggests the potential of targeting the SIX2/PFN2 loop for GC treatment (Graphical Abstracts).

Asunto(s)

Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio , Células Madre Neoplásicas , Profilinas , Neoplasias Gástricas , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Línea Celular Tumoral , Profilinas/metabolismo , Profilinas/genética , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Animales , Regiones Promotoras Genéticas/genética , Estabilidad del ARN/genética , Sistema de Señalización de MAP Quinasas , Unión Proteica

RESUMEN

Cocaine use disorder (CUD) is a chronic neuropsychiatric disorder estimated to effect 1-3% of the population. Activity-dependent neuroprotective protein (ADNP) is essential for brain development and functioning, shown to be protective in fetal alcohol syndrome and to regulate alcohol consumption in adult mice. The goal of this study was to characterize the role of ADNP, and its active peptide NAP (NAPVSIPQ), which is also known as davunetide (investigational drug) in mediating cocaine-induced neuroadaptations. Real time PCR was used to test levels of Adnp and Adnp2 in the nucleus accumbens (NAc), ventral tegmental area (VTA), and dorsal hippocampus (DH) of cocaine-treated mice (15 mg/kg). Adnp heterozygous (Adnp +/-)and wild-type (Adnp +/-) mice were further tagged with excitatory neuronal membrane-expressing green fluorescent protein (GFP) that allowed for in vivo synaptic quantification. The mice were treated with cocaine (5 injections; 15 mg/kg once every other day) with or without NAP daily injections (0.4 µg/0.1 ml) and sacrificed following the last treatment. We analyzed hippocampal CA1 pyramidal cells from 3D confocal images using the Imaris x64.8.1.2 (Oxford Instruments) software to measure changes in dendritic spine density and morphology. In silico ADNP/NAP/cocaine structural modeling was performed as before. Cocaine decreased Adnp and Adnp2 expression 2 h after injection in the NAc and VTA of male mice, with mRNA levels returning to baseline levels after 24 h. Cocaine further reduced hippocampal spine density, particularly synaptically weaker immature thin and stubby spines, in male Adnp+/+) mice while increasing synaptically stronger mature (mushroom) spines in Adnp+/-) male mice and thin and stubby spines in females. Lastly, we showed that cocaine interacts with ADNP on a zinc finger domain identical to ketamine and adjacent to a NAP-zinc finger interaction site. Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD.

Asunto(s)

Cocaína , Hipocampo , Proteínas del Tejido Nervioso , Plasticidad Neuronal , Animales , Masculino , Ratones , Cocaína/farmacología , Femenino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Ratones Endogámicos C57BL , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Oligopéptidos

RESUMEN

Breast cancer is the second primary cause of cancer death among women. Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is a central regulator for X chromosome inactivation, and its abnormal expression is a primary feature of breast cancer. So far, the mechanism of XIST in breast cancer has not been fully elucidated. We attempted to illustrate the mechanism of XIST in breast cancer. The expressions of XIST, microRNA-455-3p (miR-455-3p) in breast cancer were measured using quantitative real-time PCR. The expressions of homeobox C4 (HOXC4) were assessed with immunohistochemical and Western blot. Also, the functions of XIST in breast cancer were assessed by Cell Counting Kit-8 analysis, colony formation assay, flow cytometry, Western blot, Transwell, and cell scratch assays. Meanwhile, the mechanism of XIST in breast cancer was validated using database analysis and dual-luciferase reporter assay. Furthermore, the function of XIST in breast cancer in vivo was estimated by tumor xenograft model, immunohistochemical assay, and hematoxylin-eosin staining. XIST and HOXC4 expressions were increased, but miR-455-3p expressions were decreased in breast cancer tissues and cells. Knocking down XIST restrained breast cancer cell proliferation, invasion, migration, epithelial-mesenchymal transformation (EMT), and induced cell cycle arrest at G0/G1. Meanwhile, XIST interacted with miR-455-3p, while miR-455-3p interacted with HOXC4. XIST knockdown repressed breast cancer cell proliferation, invasion, and EMT, while miR-455-3p inhibitor or HOXC4 overexpression abolished those impacts. HOXC4 overexpression also blocked the impacts of miR-455-3p mimic on breast cancer cell malignant behavior. In vivo experimental data further indicated that XIST knockdown repressed breast cancer cell tumorigenic ability, and decreased HOXC4 and p-SMAD3 (TGF-ß/SMAD-related protein) expressions.XIST/miR-455-3p/HOXC4 facilitated breast cancer development by activating the TGF-ß/SMAD pathway.

Asunto(s)

Neoplasias de la Mama , Proteínas de Homeodominio , MicroARNs , ARN Largo no Codificante , Transducción de Señal , Factor de Crecimiento Transformador beta , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Animales , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Ratones , Proliferación Celular , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas Smad/metabolismo , Proteínas Smad/genética , Ratones Desnudos , Transición Epitelial-Mesenquimal , Células MCF-7

RESUMEN

The current research was designed to investigate the impact of whole-process high-quality nursing on acute pancreatitis (AP) patients' quality of life as well as the mechanism of miR-126-5p/HOXC8 axis promoting AP progression. One hundred AP patients admitted to our hospital were chosen and separated into control group (CG, n=50) and study group (SG, n=50). The CG took the routine nursing, while the SG adopted the whole-process high-quality nursing. Besides, cerulein (CE) was treated in AR42J cells to establish an experimental model of AP. The proliferation, apoptosis along with inflammation of CE-treated AR42J cells were assessed. The outcomes manifested that in contrast to the CG, the recovery time of bowel sound, the improvement time of abdominal distension, the improvement time of abdominal pain, the exhaust time and the defecation time in the SG presented shorter, the anxiety and depression scores in the SG presented lower, the WHOQOL-100 scores of patients in the SG presented higher in the fields of physiology, psychology, environment and social relations, the total incidence of complications of the SG presented lower, and the total nursing satisfaction of the SG was better. Besides, miR-126-5p presented upregulation in CE-stimulated AR42J cells, and miR-126-5p inhibition increased the proliferation along with repressed the apoptosis and inflammation in CE-stimulated AR42J cells. Moreover, HOXC8 could be the target mRNA of miR-126-5p, and HOXC8 elevation promoted the proliferation along with repressed the apoptosis and inflammation in CE-stimulated AR42J cells. In addition, rescue assays further validated that HOXC8 silence offset the protective impact of miR-126-5p repression on AP cell damage. In conclusion, our study indicated that whole-process high-quality nursing could promote the quality of life of AP patients, and revealed that miR-126-5p inhibition relieved CE-stimulated AR42J cells injury caused by AP via targeting HOXC8. Our study might offer novel insights for AP treatment and nursing.

Asunto(s)

Apoptosis , Progresión de la Enfermedad , Proteínas de Homeodominio , MicroARNs , Pancreatitis , Calidad de Vida , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Pancreatitis/patología , Pancreatitis/genética , Masculino , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Apoptosis/genética , Femenino , Proliferación Celular , Persona de Mediana Edad , Enfermedad Aguda , Adulto , Ratas , Animales

RESUMEN

Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45+lineage-CD90.2+NK1.1-NKp46-ST2-KLRG1+IL-17RB+ memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7. ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence.

Asunto(s)

Asma , Factor Nuclear 1-alfa del Hepatocito , Proteínas de Homeodominio , Inmunidad Innata , Memoria Inmunológica , Linfocitos , Animales , Femenino , Humanos , Masculino , Ratones , Traslado Adoptivo , Asma/inmunología , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Interleucina-13/metabolismo , Interleucina-13/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Intestinos/inmunología , Intestinos/patología , Linfocitos/inmunología , Ratones Endogámicos C57BL , Pyroglyphidae/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo

RESUMEN

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e-5) and the CGGA (p = 0.03, p < 1e-3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e-6, p < 0.001, p < 1e-3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.

Asunto(s)

Neoplasias Encefálicas , Proteínas de Homeodominio , Oligodendroglioma , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Edad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Metilación de ADN , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Mutación , Oligodendroglioma/genética , Oligodendroglioma/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo