RESUMEN
The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Receptores de Esteroides , Humanos , Masculino , Acetilación , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Glucosa , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Complejo Piruvato Deshidrogenasa/metabolismoRESUMEN
A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the "short" inverse agonist 6. With the increase in the size of the 6-position substituents, the "short" inverse agonist 6 first reversed its function to agonists and then to "long" inverse agonists. The cocrystal structures of RORγt complexed with the representative "short" inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the "long" inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of "short" inverse agonist 6 and "long" inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that "short" or "long" inverse agonists led to different behaviors of helixes H11, H11', and H12 of RORγt. The "short" inverse agonist 6 destabilizes H11' and dislocates H12, while the "long" inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.
Asunto(s)
Carbazoles/farmacología , Cristalografía , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Receptores de Ácido Retinoico/agonistas , Carbazoles/síntesis química , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
Most existing multi-scale object detectors depend on multi-level feature maps. The Feature Pyramid Networks (FPN) is a significant architecture for object detection that utilizes these multi-level feature maps. However, the use of FPN also increases the detector's complexity. For object detection methods that only use a single-level feature map, the detection performance is limited to some extent because the single-level feature map cannot balance deep semantic information and shallow detail information. We introduce a novel detector - the Spiking Neural P Multiple-in-Single-out (SNPMiSo) detector to address these challenges. The SNPMiSo detector is constructed based on SNP-like neurons. In SNPMiSo, we employ two kinds of Transformers to boost the important features across different-level feature maps separately. After enhancing the features, we use an incremental upsampling module to upsample and merge the two feature maps. This combined feature map is input into the NAF dilated residual module and the NAF dual-branch detection head. This process allows us to extract multi-scale features and carry out detection tasks. Our tests show promising results: On the COCO dataset, SNPMiSo attains an Average Precision (AP) of 38.7, an improvement of 1.0 AP over YOLOF. In addition, SNPMiSo demonstrates a quicker detection speed, outperforming some advanced multi-level and single-level object detectors.
Asunto(s)
Redes Neurales de la Computación , Neuronas , Neuronas/fisiología , Potenciales de Acción/fisiología , Humanos , Modelos NeurológicosRESUMEN
Based on two previously discovered carbazole carboxamide retinoic acid receptor-related orphan receptor-γt (RORγt) agonists 6 and 7 (t1/2 = 8.7 min and 16.4 min in mouse liver microsome, respectively), new carbazole carboxamides were designed and synthesized according to the molecular mechanism of action (MOA) and metabolic site analysis with the aim of identifying novel RORγt agonists with optimal pharmacological and metabolic profiles. By modifying the "agonist lock" touching substitutions on carbazole ring, introducing heteroatoms into different parts of the molecule and attaching a side chain to the sulfonyl benzyl moiety, several potent RORγt agonists were identified with greatly improved metabolic stability. Best overall properties were achieved in compound (R)-10f with high agonistic activities in RORγt dual FRET (EC50 = 15.6 nM) and Gal4 reporter gene (EC50 = 141 nM) assays and greatly improved metabolic stability (t1/2 > 145 min) in mouse liver microsome. Besides, the binding modes of (R)-10f and (S)-10f in RORγt ligand binding domain (LBD) were also studied. Altogether, the optimization of carbazole carboxamides led to the discovery of (R)-10f as a potential small molecule therapeutics for cancer immunotherapy.
Asunto(s)
Carbazoles , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Animales , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Carbazoles/farmacología , Unión Proteica , Relación Estructura-ActividadRESUMEN
BACKGROUND: As an oncogene, long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) can promote tumor metastasis. Hyperexpression of MALAT1 has been observed in many malignant tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of MALAT1 in HCC remain unclear. METHODS: Thirty human HCC and paracancerous tissue specimens were collected, and the human hepatoma cell lines Huh7 and HepG2 were cultured according to standard methods. MALAT1 and Snail family zinc finger (Slug) expression were measured by real-time PCR, immunohistochemistry, and western blotting. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR-124-3p and Slug(SNAI2) or MALAT1. Wound healing and transwell assays were performed to examine invasion and migration, and a subcutaneous tumor model was established to measure tumor progression in vivo. RESULTS: MALAT1 expression was upregulated in HCC tissues and positively correlated with Slug expression. MALAT1 and miR-124-3p bind directly and reversibly to each other. MALAT1 silencing inhibited cell migration and invasion. miR-124-3p inhibited HCC metastasis by targeting Slug. CONCLUSIONS: MALAT1 regulates Slug through miR-124-3p, affecting HCC cell metastasis. Thus, the MALAT1/miR-124-3p/Slug axis plays an important role in HCC.