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Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo. Pyrosequencing and the demethylating drug 5-Aza-dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland.
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Carcinoma Endometrioide , Hiperplasia Endometrial , Neoplasias Endometriales , Humanos , Femenino , Animales , Ratones , Carcinoma Endometrioide/patología , Neoplasias Endometriales/patología , Progesterona/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Metilación , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Estrógenos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismoRESUMEN
Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.
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Lisina , Neoplasias , Humanos , Lisina/uso terapéutico , Histona Demetilasas/metabolismo , Histona Demetilasas/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Histonas , Neoplasias/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
BACKGROUND: Circular RNAs (circRNAs) are a novel kind of non-coding RNAs proved to play crucial roles in the development of multiple diabetic complications. However, their expression and function in diabetes mellitus (DM)-impaired salivary glands are unknown. RESULTS: By using microarray technology, 663 upregulated and 999 downregulated circRNAs companied with 813 upregulated and 525 downregulated mRNAs were identified in the parotid glands (PGs) of type2 DM mice under a 2-fold change and P < 0.05 cutoff criteria. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis of upregulated mRNAs showed enrichments in immune system process and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Infiltration of inflammatory cells and increased inflammatory cytokines were observed in diabetic PGs. Seven differently expressed circRNAs validated by qRT-PCR were selected for coding-non-coding gene co-expression (CNC) and competing endogenous RNA (ceRNA) networks analysis. PPAR signaling pathway was primarily enriched through analysis of circRNA-mRNA networks. Moreover, the circRNA-miRNA-mRNA networks highlighted an enrichment in the regulation of actin cytoskeleton. CONCLUSION: The inflammatory response is elevated in diabetic PGs. The selected seven distinct circRNAs may attribute to the injury of diabetic PG by modulating inflammatory response through PPAR signaling pathway and actin cytoskeleton in diabetic PGs.
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Diabetes Mellitus Tipo 2 , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Glándula Parótida , ARN Circular , Animales , ARN Circular/genética , Ratones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glándula Parótida/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Transcriptoma , Ontología de Genes , Masculino , Transducción de Señal , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismoRESUMEN
Advanced atomic-level heterointerface engineering provides a promising method for the preparation of next-generation catalysts. Traditional carbon-based heterointerface catalytic performance rely heavily on the undetermined defects in complex and demanding preparation processes, rendering it impossible to control the catalytic performance. Here, we present a general method for the controlled growth of metal atom arrays on graphdiyne (GDY/IrCuOx), and we are surprised to find strong heterointerface strains during the growth. We successfully controlled the thickness of GDY to regulate the heterointerface metal atoms and achieved compressive strain at the interface. Experimental and density functional theory calculation results show that the unique incomplete charge transfer between GDY and metal atoms leads to the formation of strong interactions and significant heterointerface compressive strain between GDY and IrCuOx, which results in high oxidation performances with 1000 mA cm-2 at a low overpotential of 283 mV and long-term stability at large current densities in alkaline simulated seawater. We anticipate that this finding will contribute to construction of high-performance heterogeneous interface structures, leading to the development of new generation of GDY-based heterojunction catalysts in the field of catalysis for future promising performance.
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Murepavadin is a peptidomimetic that specifically targets the lipopolysaccharide transport protein LptD of Pseudomonas aeruginosa. Here, we found that murepavadin enhances the bactericidal efficacies of tobramycin and amikacin. We further demonstrated that murepavadin enhances bacterial respiration activity and subsequent membrane potential, which promotes intracellular uptake of aminoglycoside antibiotics. In addition, the murepavadin-amikacin combination displayed a synergistic bactericidal effect in a murine pneumonia model.
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Amicacina , Péptidos Cíclicos , Infecciones por Pseudomonas , Animales , Ratones , Amicacina/farmacología , Pseudomonas aeruginosa , Potenciales de la Membrana , Antibacterianos/farmacología , Aminoglicósidos/farmacología , Tobramicina/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pruebas de Sensibilidad MicrobianaRESUMEN
A challenge facing the chlor-alkali process is the lack of electrocatalyst with high activity and selectivity for the efficient industrial production of chlorine. Herein the authors report a new electrocatalyst that can generate multi-interface structure by in situ growth of graphdiyne on the surface of cobalt oxides (GDY/Co3O4), which shows great potential in highly selective and efficient chlorine production. This result is due to the strong electron transfer and high density charge transport between GDY and Co3O4 and the interconversion of the mixed valence states of the Co atoms itself. These intrinsic characteristics efficiently enhance the conductivity of the catalyst, facilitate the reaction kinetics, and improve the overall catalytic selectivity and activity. Besides, the protective effect of the formed GDY layer is remarkable endowing the catalyst with excellent stability. The catalyst can selectively produce chlorine in low-concentration of NaCl aqueous solution at room temperature and pressure with the highest Faraday efficiency of 80.67% and an active chlorine yield rate of 184.40 mg h-1 cm-2, as well as superior long-term stability.
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Functionalized nanochannels can convert environmental thermal energy into electrical energy by driving water evaporation. This process involves the interaction between the solid-liquid interface and the natural water evaporation. The evaporation-driven water potential effect is a novel green environmental energy capture technology that has a wide range of applications and does not depend on geographical location or environmental conditions, it can generate power as long as there is water, light, and heat. However, suitable materials and structures are needed to harness this natural process for power generation. MOF materials are an emerging field for water evaporation power generation, but there are still many challenges to overcome. This work uses MOF-801, which has high porosity, charged surface, and hydrophilicity, to enhance the output performance of evaporation-driven power generation. It can produce an open circuit voltage of ≈2.2 V and a short circuit current of ≈1.9 µA. This work has a simple structure, easy preparation, low-cost and readily available materials, and good stability. It can operate stably in natural environments with high practical value.
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Branch angle (BA) is a critical morphological trait that significantly influences planting density, light interception and ultimately yield in plants. Despite its importance, the regulatory mechanism governing BA in rapeseed remains poorly understood. In this study, we generated 109 transcriptome data sets for 37 rapeseed accessions with divergent BA phenotypes. Relative to adaxial branch segments, abaxial segments accumulated higher levels of auxin and exhibited lower expression of six TCP1 homologues and one GA20ox3. A co-expression network analysis identified two modules highly correlated with BA. The modules contained homologues to known BA control genes, such as FUL, YUCCA6, TCP1 and SGR3. Notably, a homoeologous exchange (HE), occurring at the telomeres of A09, was prevalent in large BA accessions, while an A02-C02 HE was common in small BA accessions. In their corresponding regions, these HEs explained the formation of hub gene hotspots in the two modules. QTL-seq analysis confirmed that the presence of a large A07-C06 HE (~8.1 Mb) was also associated with a small BA phenotype, and BnaA07.WRKY40.b within it was predicted as candidate gene. Overexpressing BnaA07.WRKY40.b in rapeseed increased BA by up to 20°, while RNAi- and CRISPR-mediated mutants (BnaA07.WRKY40.b and BnaC06.WRKY40.b) exhibited decreased BA by up to 11.4°. BnaA07.WRKY40.b was exclusively localized to the nucleus and exhibited strong expression correlations with many genes related to gravitropism and plant architecture. Taken together, our study highlights the influence of HEs on rapeseed plant architecture and confirms the role of WRKY40 homologues as novel regulators of BA.
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Sitios de Carácter Cuantitativo , Transcriptoma , Transcriptoma/genética , Sitios de Carácter Cuantitativo/genética , Brassica rapa/genética , Regulación de la Expresión Génica de las Plantas , Brassica napus/genética , Brassica napus/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ácidos Indolacéticos/metabolismo , Fenotipo , Genes de Plantas/genéticaRESUMEN
Interferon-stimulated gene 15 (ISG15) is strongly upregulated during viral infections and exerts pro-viral or antiviral actions. While many viruses combat host antiviral defenses by limiting ISG expression, PRV infection notably increases expression of ISG15. However, studies on the viral strategies to regulate ISG15-mediated antiviral responses are limited. Here, we demonstrate that PRV-induced free ISG15 and conjugated proteins accumulation require viral gene expression. Conjugation inhibition assays showed that ISG15 imposes its antiviral effects via unconjugated (free) ISG15 and restricts the viral release. Knockout of ISG15 in PK15 cells interferes with IFN-ß production by blocking IRF3 activation and promotes PRV replication. Mechanistically, ISG15 facilitates IFNα-mediated antiviral activity against PRV by accelerating the activation and nuclear translocation of STAT1 and STAT2. Furthermore, ISG15 facilitated STAT1/STAT2/IRF9 (ISGF3) formation and ISGF3-induced IFN-stimulated response elements (ISRE) activity for efficient gene transcription by directly interacting with STAT2. Significantly, ISG15 knockout mice displayed enhanced susceptibility to PRV, as evidenced by increased mortality and viral loads, as well as more severe pathology caused by excessive production of the inflammatory cytokines. Our studies establish the importance of free ISG15 in IFNα-induced antiviral immunity and in the control of viral infections.
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Herpesvirus Suido 1 , Virosis , Ratones , Animales , Ratones Noqueados , Antivirales/farmacología , Interferón-alfa/farmacologíaRESUMEN
In plant species, anthocyanin accumulation is specifically regulated by light signaling. Although the CONSTITUTIVELY PHOTOMORPHOGENIC1/SUPPRESSOR OF PHYA-105 (COP1/SPA) complex is known to control anthocyanin biosynthesis in response to light, the precise mechanism underlying this process remains largely unknown. Here, we report that Increase in BONSAI Methylation 1 (IBM1), a JmjC domain-containing histone demethylase, participates in the regulation of light-induced anthocyanin biosynthesis in Arabidopsis. The expression of IBM1 was induced by high light (HL) stress, and loss-of-function mutations in IBM1 led to accelerated anthocyanin accumulation under HL conditions. We further identified that IBM1 is directly associated with SPA1/3/4 chromatin in vivo to establish a hypomethylation status on H3K9 and DNA non-CG at these loci under HL, thereby releasing their expression. Genetic analysis showed that quadruple mutants of IBM1 and SPA1/3/4 resemble spa134 mutants. Overexpression of SPA1 in ibm1 mutants complements the mutant phenotype. Our results elucidate the significance and mechanism of IBM1 histone demethylase in the epigenetic regulation of anthocyanin biosynthesis in Arabidopsis under HL conditions.
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Antocianinas , Proteínas de Arabidopsis , Epigénesis Genética , Regulación de la Expresión Génica de las Plantas , Histona Demetilasas con Dominio de Jumonji , Luz , Antocianinas/biosíntesis , Antocianinas/genética , Arabidopsis/genética , Arabidopsis/efectos de la radiación , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Cromatina/metabolismo , Metilación de ADN/genética , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Mutación/genética , FenotipoRESUMEN
Rice is susceptible to chilling stress. Identifying chilling tolerance genes and their mechanisms are key to improve rice performance. Here, we performed a genome-wide association study to identify regulatory genes for chilling tolerance in rice. One major gene for chilling tolerance variation in Indica rice was identified as a casein kinase gene OsCTK1. Its function and natural variation are investigated at the physiological and molecular level by its mutants and transgenic plants. Potential substrates of OsCTK1 were identified by phosphoproteomic analysis, protein-protein interaction assay, in vitro kinase assay, and mutant characterization. OsCTK1 positively regulates rice chilling tolerance. Three of its putative substrates, acidic ribosomal protein OsP3B, cyclic nucleotide-gated ion channel OsCNGC9, and dual-specific mitogen-activated protein kinase phosphatase OsMKP1, are each involved in chilling tolerance. In addition, a natural OsCTK1 chilling-tolerant (CT) variant exhibited a higher kinase activity and conferred greater chilling tolerance compared with a chilling-sensitive (CS) variant. The CT variant is more prevalent in CT accessions and is distributed more frequently in higher latitude compared with the CS variant. This study thus enables a better understanding of chilling tolerance mechanisms and provides gene variants for genetic improvement of chilling tolerance in rice.
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Frío , Oryza , Proteínas de Plantas , Adaptación Fisiológica/genética , Genes de Plantas , Variación Genética , Estudio de Asociación del Genoma Completo , Mutación/genética , Oryza/genética , Oryza/enzimología , Oryza/fisiología , Fosforilación , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente , Especificidad por SustratoRESUMEN
PURPOSE: To evaluate the prognostic performance of [68Ga]Pentixafor PET/CT at baseline for staging of patients with newly diagnosed multiple myeloma (MM) and to compare it with [18F]FDG PET/CT and the Revised-International Staging System (R-ISS). METHODS: Patients who underwent [68Ga]Pentixafor and [18F]FDG PET/CT imaging were retrospectively included. Patient staging was performed according to the Durie-Salmon PLUS staging system based on [68Ga]Pentixafor PET/CT and [18F]FDG PET/CT images, and the R-ISS. Progression-free survival (PFS) at patient follow-up was estimated using the Kaplan-Meier estimator and compared using the log-rank test. Area under the receiver operating characteristic curve (AUC) was calculated to assess predictive performance. RESULTS: Fifty-five MM patients were evaluated. Compared with [18F]FDG PET, [68Ga]Pentixafor PET detected 25 patients as the same stage, while 26 patients were upstaged and 4 patients were downstaged (P = 0.001). After considering the low-dose CT data, there was no statistically significant difference in the number of patients classified in each stage using [68Ga]Pentixafor PET/CT and [18F]FDG PET/CT (P = 0.091). [68Ga]Pentixafor PET/CT-based staging discriminated PFS outcomes in patients with different disease stages (stage I vs. stage II, stage I vs. stage III, and stage II vs. stage III; all P < 0.05), whereas for [18F]FDG PET/CT, there was only a difference in median PFS between stage I and III (P = 0.021). When staged by R-ISS, the median PFS for stage III was significantly lower than that for stage I and II (P = 0.008 and 0.035, respectively). When predicting 2-year PFS based on staging, the AUC of [68Ga]Pentixafor PET/CT was significantly higher than that of [68Ga]Pentixafor PET (0.923 vs. 0.821, P = 0.002), [18F]FDG PET (0.923 vs. 0.752 P = 0.002), and R-ISS (0.923 vs. 0.776, P = 0.005). CONCLUSIONS: [68Ga]Pentixafor PET/CT-based staging possesses substantial potential to predict disease progression in newly diagnosed MM patients.
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Fluorodesoxiglucosa F18 , Mieloma Múltiple , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Mieloma Múltiple/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Pronóstico , Péptidos Cíclicos , Adulto , Estudios Retrospectivos , Complejos de Coordinación , Anciano de 80 o más AñosRESUMEN
ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for 2 weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum, left ventricle posterior wall diastole, and left ventricular posterior wall systole were significantly increased, and ejection fraction was decreased compared with control mice. Masson and Wheat Germ Agglutinin staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes, we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and neonatal rat cardiomyocytes. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase in dynamin-associated protein 1 (Drp1) phosphorylation at S616 and decrease in Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.
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Compuestos de Bencidrilo , Cardiomegalia , Glucósidos , Dinámicas Mitocondriales , Ratas , Ratones , Masculino , Animales , Isoproterenol/farmacología , Ratones Endogámicos C57BL , Cardiomegalia/metabolismo , Miocitos CardíacosRESUMEN
Polymeric immunoglobulin receptor (pIgR) is an important immune factor in the mucosal immune system of fish, which plays a key role in mediating the secretion and transport of immunoglobulin into mucus. In this study, the full-length cDNA sequence of Megalobrama amblycephala pIgR gene was firstly cloned and the immune response to Aeromonas hydrophila was detected. After being challenged by Aeromonas hydrophila at 3 d, significantly pathological features were observed in intestine, head kidney, spleen, liver and gill of Megalobrama amblycephala. The content of lysozyme (Lys) and the activities of acid phosphatase (ACP) and alkaline phosphatase (AKP) increased significantly at 1 d and reached the peak at 3 d, and the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) in serum reached the peak at 5 d and 7 d after infection, respectively. The expression level of IL-1ß gene reached the peak at 3 d in intestine, 5 d in gill and spleen, 7 d in head kidney and liver of Megalobrama amblycephala after infected by Aeromonas hydrophila, respectively. The TNF-α gene expression reached the peak at 3 d in intestine and gill, 5 d in head kidney and spleen, 7 d in liver after infection, respectively. The experimental results showed that the infection of Aeromonas hydrophila caused the pathological changes of immune-related tissues and triggered the inflammation responses. The full-length cDNA sequence of Megalobrama amblycephala pIgR was 1828 bp, and its open reading frame (ORF) was 1023 bp, encoding 340 amino acids. The pIgR of Megalobrama amblycephala has a signal peptide sequence, followed by extracellular region, transmembrane region and intracellular region. The extracellular region includes two Ig-like domains (ILDs), and its tertiary structure is twisted "L". The phylogenetic tree was constructed using the adjacency method, and the pIgR genes of Megalobrama amblycephala and cyprinidae fish were clustered into a single branch. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of pIgR gene in different tissues of Megalobrama amblycephala. The expression level of pIgR gene was the highest in liver, followed by intestine, head kidney, skin, middle kidney and spleen, lower in heart, gill and brain, and the lowest in muscle. After being infected by Aeromonas hydrophila, the expression level of Megalobrama amblycephala pIgR gene in intestine, head kidney, spleen, liver and gill showed a trend of increasing first and then decreasing within 28 d. The pIgR gene expression reached the peak in mucosal immune-related tissues (gill and intestine) was earlier than that in systemic immune-related tissues (head kidney and spleen), and the relative expression level of pIgR gene at peak in intestine (12.3 fold) was higher than that in head kidney (3.73 fold) and spleen (7.84 fold). These results suggested that Megalobrama amblycephala pIgR might play an important role in the mucosal immune system to against Aeromonas hydrophila infection.
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Reactivating p53 activity to restore its anticancer function is an attractive cancer treatment strategy. In this study, we designed and synthesized a series of novel PROTACs to reactivate p53 via the co-degradation of CK1α and CDK7/9 proteins. Bioactivity studies showed that the selected PROTAC 13i exhibited potency antiproliferative activity in MV4-11 (IC50 = 0.096 ± 0.012 µM) and MOLM-13 (IC50 = 0.072 ± 0.014 µM) cells, and induced apoptosis of MV4-11 cells. Western-blot analysis showed that PROTAC 13i triple CK1α and CDK7/9 protein degradation resulted in the significantly increased expression of p53. At the same time, the transcriptional repression due to the degradation significantly reduced downstream gene expression of MYC, MDM2, BCL-2 and MCL-1, and reduced the inflammatory cytokine levels of TNF-α, IL-1ß and IL-6 in PMBCs. These results indicate the beneficial impact of simultaneous CK1α and CDK7/9 degradation for acute myeloid leukemia therapy.
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Antineoplásicos , Caseína Quinasa Ialfa , Proliferación Celular , Quinasa 9 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes , Ensayos de Selección de Medicamentos Antitumorales , Leucemia Mieloide Aguda , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Caseína Quinasa Ialfa/metabolismo , Caseína Quinasa Ialfa/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Línea Celular Tumoral , Proteolisis/efectos de los fármacos , Células Tumorales Cultivadas , Quimera Dirigida a la Proteólisis , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
BACKGROUND: Postpartum depression (PPD) has received widespread attention. Shenzhen has been running a large-scale program for PPD since 2013. The program requires mothers to self-assess when applying information technology to PPD screening beginning in 2021. The purpose of this study was to conduct a longitudinal analysis of the impact of mHealth apps on the health-seeking behaviors of PPD patients. METHODS: Longitudinal data from districts in the Shenzhen Maternal and Child Health Management Information System (MCHMIS) for ten years was used in this study. Referral success rate (RSR, successful referrals to designated hospitals as a percentage of needed referrals) was used to assess health-seeking behavior. Trend χ2 tests were used to assess the overall trend of change after the implementation of mHealth in ten districts in Shenzhen. Interrupted Time Series Analysis (ITSA) was employed to assess the role of the mHealth app in changing patient health-seeking behaviors. RESULTS: For the results of the trend χ2 tests, the ten districts of Shenzhen showed an upward trend. For the ITSA results, different results were shown between districts. Nanshan district, Longhua district, and Longgang district all demonstrated an upward trend in the first-year application of the mHealth app. Nanshan district and Longgang district both exhibited an upward trend in terms of sustained effects. CONCLUSIONS: There is a difference in the performance of the mHealth app across the ten districts. The results show that the three districts with better health resource allocation, Nanshan, Longgang, and Longhua districts, demonstrated more significant mHealth app improvements. The mHealth app's functions, management systems, and health resource allocation may be potential factors in the results. This suggests that when leveraging mHealth applications, the first step is to focus on macro-level area resource allocation measures. Secondly, there should be effective process design and strict regulatory measures. Finally, there should also be appropriate means of publicity.
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Depresión Posparto , Aplicaciones Móviles , Derivación y Consulta , Telemedicina , Humanos , Femenino , Depresión Posparto/diagnóstico , Depresión Posparto/terapia , Estudios Longitudinales , China , Derivación y Consulta/estadística & datos numéricos , Adulto , Aceptación de la Atención de Salud/estadística & datos numéricos , Análisis de Series de Tiempo Interrumpido , Tamizaje Masivo/métodos , Embarazo , Política de SaludRESUMEN
BACKGROUND: Emerging evidence suggests that alterations in BCAA metabolism may contribute to the pathogenesis of sarcopenia. However, the relationship between branched-chain amino acids (BCAAs) and sarcopenia is incompletely understood, and existing literature presents conflicting results. In this study, we conducted a community-based study involving > 100,000 United Kingdom adults to comprehensively explore the association between BCAAs and sarcopenia, and assess the potential role of muscle mass in mediating the relationship between BCAAs and muscle strength. METHODS: Multivariable linear regression analysis examined the relationship between circulating BCAAs and muscle mass/strength. Logistic regression analysis assessed the impact of circulating BCAAs and quartiles of BCAAs on sarcopenia risk. Subgroup analyses explored the variations in associations across age, and gender. Mediation analysis investigated the potential mediating effect of muscle mass on the BCAA-muscle strength relationship. RESULTS: Among 108,017 participants (mean age: 56.40 ± 8.09 years; 46.23% men), positive associations were observed between total BCAA, isoleucine, leucine, valine, and muscle mass (beta, 0.56-2.53; p < 0.05) and between total BCAA, leucine, valine, and muscle strength (beta, 0.91-3.44; p < 0.05). Logistic regression analysis revealed that increased circulating valine was associated with a 47% reduced sarcopenia risk (odds ratio = 0.53; 95% confidence interval = 0.3-0.94; p = 0.029). Subgroup analyses demonstrated strong associations between circulating BCAAs and muscle mass/strength in men and individuals aged ≥ 60 years. Mediation analysis suggested that muscle mass completely mediated the relationship between total BCAA, and valine levels and muscle strength, partially mediated the relationship between leucine levels and muscle strength, obscuring the true effect of isoleucine on muscle strength. CONCLUSION: This study suggested the potential benefits of BCAAs in preserving muscle mass/strength and highlighted muscle mass might be mediator of BCAA-muscle strength association. Our findings contribute new evidence for the clinical prevention and treatment of sarcopenia and related conditions involving muscle mass/strength loss.
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Aminoácidos de Cadena Ramificada , Fuerza Muscular , Sarcopenia , Humanos , Sarcopenia/sangre , Sarcopenia/epidemiología , Masculino , Femenino , Estudios Transversales , Aminoácidos de Cadena Ramificada/sangre , Persona de Mediana Edad , Fuerza Muscular/fisiología , Anciano , Reino Unido/epidemiología , Músculo Esquelético/metabolismo , AdultoRESUMEN
The yeast-to-hypha transition is tightly associated with pathogenicity in many human pathogenic fungi, such as the model fungal pathogen Cryptococcus neoformans, which is responsible for approximately 180,000 deaths annually. In this pathogen, the yeast-to-hypha transition can be initiated by distinct stimuli: mating stimulation or glucosamine (GlcN), the monomer of cell wall chitosan. However, it remains poorly understood how the signal specificity for Cryptococcus morphological transition by disparate stimuli is ensured. Here, by integrating temporal expression signature analysis and phenome-based clustering evaluation, we demonstrate that GlcN specifically triggers a unique cellular response, which acts as a critical determinant underlying the activation of GlcN-induced filamentation (GIF). This cellular response is defined by an unusually hyperactive cell wall synthesis that is highly ATP-consuming. A novel cell surface protein Gis1 was identified as the indicator molecule for the GlcN-induced cell wall response. The Mpk1-directed cell wall pathway critically bridges global cell wall gene induction and intracellular ATP supply, ensuring the Gis1-dependent cell wall response and the stimulus specificity of GIF. We further reveal that the ability of Mpk1 to coordinate the cell wall response and GIF activation is conserved in different Cryptococcus pathogens. Phosphoproteomics-based profiling together with genetic and phenotypic analysis revealed that the Mpk1 kinase mediates the regulatory specificity of GIF through a coordinated downstream regulatory network centered on Skn7 and Crz1. Overall, our findings discover an unprecedented and conserved cell wall biosynthesis-dependent fungal differentiation commitment mechanism, which enables the signal specificity of pathogenicity-related dimorphism induced by GlcN in Cryptococcus pathogens.
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Pared Celular/genética , Cryptococcus neoformans/genética , Glucosamina/genética , Virulencia/genética , Proteínas Fúngicas/genética , Eliminación de Gen , Regulación Fúngica de la Expresión Génica/genéticaRESUMEN
Ganoderma lucidum spore powder, valued for its nutritional and medicinal properties, contains polysaccharides crucial for its efficacy. However, the complex structural nature of these polysaccharides necessitates further investigation to fully realize their potential. This study aimed to investigate the effects of acid heat treatment on Ganoderma lucidum spore polysaccharides (GLSPs) to enhance their properties and application in antitumor activity. The GLSP was obtained via acid heat treatment, concentration, and centrifugal separation. This process led to a notable reduction in polysaccharide molecular weight, increasing water solubility and bioavailability. Analytical techniques including NMR spectroscopy and methylation analysis revealed a polysaccharide composition comprising four distinct monosaccharides, with molecular weights of 3291 Da (Mw) and 3216 Da (Mn). Six different linkage modes were identified, with a molar ratio of 1:5:2:3:4:3. In vivo experiments demonstrated the GLSP's significant inhibitory effect on the growth of four tumor models (sarcoma S180, Lewis lung cancer, liver cancer H22, and colon cancer C26) in mice, with no observed toxicity. These findings suggest the GLSP's potential as an antitumor therapeutic agent for clinical use.
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Antineoplásicos , Reishi , Esporas Fúngicas , Animales , Reishi/química , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Polisacáridos/química , Polisacáridos/farmacología , Polisacáridos/aislamiento & purificación , Polisacáridos Fúngicos/química , Polisacáridos Fúngicos/farmacología , Línea Celular Tumoral , Peso MolecularRESUMEN
Objective: To explore the application effect of intelligent health education based on the health belief model on patients with postoperative kinesophobia after surgical treatment of cervical spondylosis. Methods: A prospective cohort study was conducted with patients who underwent anterior cervical discectomy, decompression, and fusion surgery with a single central nerve and spine center, and who had postoperative kinesophobia, ie, fear of movement. The patients made voluntary decisions concerning whether they would receive the intervention of intelligent health education. The patients were divided into a control group and an intelligent education group and the intervention started on the second day after the surgery. The intelligent education group received intelligent education starting from the second day after surgery through a WeChat widget that used the health belief model as the theoretical framework. The intelligent health education program was designed according to the concept of patient problems, needs, guidance, practice, and feedbacks. It incorporated four modules, including knowledge, intelligent exercise, overcoming obstacles, and sharing and interaction. It had such functions as reminders, fun exercise, shadowing exercise, monitoring, and documentation. Health education for the control group also started on the second day after surgery and was conducted by a method of brochures of pictures and text and WeChat group reminder messages. The participants were surveyed before discharge and 3 months after their surgery. The primary outcome measure compared between the two groups was the degree of kinesophobia. Secondary outcome measures included differences in adherence to functional exercise (Functional Exercise Adherence Scale), pain level (Visual Analogue Scale score), degree of cervical functional impairment (Cervical Disability Index), and quality of life (primarily assessed by the Quality of Life Short Form 12 [SF-12] scale for psychological and physiological health scores). Results: A total of 112 patients were enrolled and 108 patients completed follow-up. Eventually, there were 53 cases in the intelligent education group and 55 cases in the control group. None of the patients experienced any sports-related injuries. There was no statistically significant difference in the primary and secondary outcome measures between the two groups at the time of discharge. At the 3-month follow-up after the surgery, the level of kinesophobia in the intelligent education group (25.72±3.90) was lower than that in the control group (29.67±6.16), and the difference between the two groups was statistically significant (P<0.05). In the intelligent education group, the degree of pain (expressed in the median [25th percentile, 75th percentile]) was lower than that of the control group (0 [0, 0] vs. 1 [1, 2], P<0.05), the functional exercise adherence was better than that of the control group (63.87±7.26 vs. 57.73±8.07, P<0.05), the psychological health was better than that of the control group (40.78±3.98 vs. 47.78±1.84, P<0.05), and the physical health was better than that of the control group (43.16±4.41 vs. 46.30±3.80, P<0.05), with all the differences being statistically significant. There was no statistically significant difference in the degree of cervical functional impairment between the two groups (1 [1, 2] vs. 3 [2, 7], P>0.05). Conclusion: Intelligent health education based on the health belief model can help reduce the degree of kinesophobia in patients with postoperative kinesophobia after surgical treatment of cervical spondylosis and improve patient prognosis.