RESUMEN
Maternal infection during pregnancy is an important cause of autism spectrum disorder (ASD) in offspring, and inflammatory infiltration caused by maternal immune activation (MIA) can cause neurodevelopmental disorders in the fetus. Medicine food homologous (MFH) refers to a traditional Chinese medicine (TCM) concept, which effectively combines food functions and medicinal effects. However, no previous study has screened, predicted, and validated the potential targets of MFH herbs for treating ASD. Therefore, in this study, we used comprehensive bioinformatics methods to screen and analyze MFH herbs and drug targets on a large scale, and identified resveratrol and Thoc5 as the best small molecular ingredient and drug target, respectively, for the treatment of MIA-induced ASD. Additionally, the results of in vitro experiments revealed that resveratrol increased the expression of Thoc5 and effectively inhibited lipopolysaccharide-induced inflammatory factor production by BV2 cells. Moreover, in vivo, resveratrol increased the expression of Thoc5 and effectively inhibited placental and fetal brain inflammation in MIA pregnancy mice, and improved ASD-like behaviors in offspring.
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Trastorno del Espectro Autista , Proteínas Nucleares , Efectos Tardíos de la Exposición Prenatal , Resveratrol , Animales , Femenino , Masculino , Ratones , Embarazo , Trastorno del Espectro Autista/inmunología , Trastorno Autístico/inducido químicamente , Trastorno Autístico/inmunología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Resveratrol/farmacología , Proteínas Nucleares/efectos de los fármacos , Proteínas Nucleares/inmunología , Proteínas Nucleares/metabolismoRESUMEN
BACKGROUND: Luteolin, a common dietary flavonoid found in plants, has been shown to have anti-cancer properties. However, its exact mechanisms of action in non-small cell lung cancer (NSCLC) are still not fully understood, particularly its role in regulating broader genomic networks and specific gene targets. In this study, we aimed to elucidate the role of microRNAs (miRNAs) in NSCLC treated with luteolin, using A549 cells as a model system. MATERIALS AND METHODS: miRNA profiling was conducted on luteolin-treated A549 cells using Exiqon microarrays, with validation of selected miRNAs by qRT-PCR. Bioinformatic analysis identified the regulatory roles of miRNAs in biological processes and pathways following luteolin treatment. Computational algorithms were employed to identify potential target genes. A549 cells were transfected with miR-106a-5p mimic and inhibitor or their corresponding controls. The expression levels of 2 genes, twist basic helix-loop-helix transcription factor 1 (TWIST1) and matrix metallopeptidase 2 (MMP2), and cell migration were assessed. RESULTS: miRNA profiling identified 341 miRNAs, with 18 exhibiting significantly altered expression (P < 0.05). Subsequent qRT-PCR analysis confirmed altered expression of 6 selected miRNAs. KEGG and GO analyses revealed significant alterations in pathways and biological processes crucial for tumor biology. TWIST1 and MMP2, which both contain conserved miR-106a-5p binding sites, exhibited an inverse correlation with the expression levels of miR-106a-5p. Dual-luciferase reporter assays confirmed TWIST1 and MMP2 as direct targets of miR-106a-5p. Luteolin treatment led to a reduction in A549 cell migration, and this reduction was further amplified by the overexpression of miR-106a-5p. CONCLUSION: Luteolin inhibits A549 cell migration by modulating the miRNA landscape, shedding light on its mechanisms and laying the foundation for miRNA-based therapeutic approaches for NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Luteolina , Metaloproteinasa 2 de la Matriz , MicroARNs , Proteínas Nucleares , Proteína 1 Relacionada con Twist , Regulación hacia Arriba , Humanos , Luteolina/farmacología , MicroARNs/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genéticaRESUMEN
Treacle ribosome biogenesis factor 1 (TCOF1) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1 and CNBP (CCHC-type zinc finger nucleic acid binding protein) expression in human mesenchymal cells. Given the established role of CNBP in gene regulation during rostral development, we explored the potential for CNBP to modulate TCOF1 transcription. Computational analysis for CNBP binding sites (CNBP-BSs) in the TCOF1 promoter revealed several putative binding sites, two of which (Hs791 and Hs2160) overlap with putative G-quadruplex (G4) sequences (PQSs). We validated the folding of these PQSs measuring circular dichroism and fluorescence of appropriate synthetic oligonucleotides. In vitro studies confirmed binding of purified CNBP to the target PQSs (both folded as G4 and unfolded) with Kd values in the nM range. ChIP assays conducted in HeLa cells chromatin detected the CNBP binding to TCOF1 promoter. Transient transfections of HEK293 cells revealed that Hs2160 cloned upstream SV40 promoter increased transcription of downstream firefly luciferase reporter gene. We also detected a CNBP-BS and PQS (Dr2393) in the zebrafish TCOF1 orthologue promoter (nolc1). Disrupting this G4 in zebrafish embryos by microinjecting DNA antisense oligonucleotides complementary to Dr2393 reduced the transcription of nolc1 and recapitulated the craniofacial anomalies characteristic of Treacher Collins Syndrome. Both cnbp overexpression and Morpholino-mediated knockdown in zebrafish induced nolc1 transcription. These results suggest that CNBP modulates the transcriptional expression of TCOF1 through a mechanism involving G-quadruplex folding/unfolding, and that this regulation is active in vertebrates as distantly related as bony fish and humans. These findings may have implications for understanding and treating MD.
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G-Cuádruplex , Disostosis Mandibulofacial , Animales , Humanos , ADN/metabolismo , Células HEK293 , Células HeLa , Disostosis Mandibulofacial/genética , Disostosis Mandibulofacial/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
Lung cancer (LC) is the most prevalent cancer type, with a high mortality rate worldwide. The current treatment options for LC have not been particularly successful in improving patient outcomes. Yifei Sanjie (YFSJ), a well-applicated traditional Chinese medicine formula, is widely used to treat pulmonary diseases, especially LC, yet little is known about its molecular mechanisms. This study was conducted to explore the molecular mechanism by which YFSJ ameliorated LC progression. The A549, NCI-H1975, and Calu-3 cells were treated with the YFSJ formula and observed for colony number, apoptosis, migration, and invasion properties recorded via corresponding assays. The PRMT6-YBX1-CDC25A axis was tested and verified through luciferase reporter, RNA immunoprecipitation, and chromatin immunoprecipitation assays and rescue experiments. Our results demonstrated that YFSJ ameliorated LC cell malignant behaviors by increasing apoptosis and suppressing proliferation, migration, and invasion processes. We also noticed that the xenograft mouse model treated with YFSJ significantly reduced tumor growth compared with the control untreated group in vivo. Mechanistically, it was found that YFSJ suppressed the expression of PRMT6, YBX1, and CDC25A, while the knockdown of these proteins significantly inhibited colony growth, migration, and invasion, and boosted apoptosis in LC cells. In summary, our results suggest that YFSJ alleviates LC progression via the PRMT6-YBX1-CDC25A axis, confirming its efficacy in clinical use. The findings of our study provide a new regulatory network for LC growth and metastasis, which could shed new insights into pulmonary medical research.
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Neoplasias Pulmonares , MicroARNs , Humanos , Animales , Ratones , Neoplasias Pulmonares/patología , Proliferación Celular/genética , Movimiento Celular/genética , Pulmón/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Proteína 1 de Unión a la Caja Y/genética , Proteína 1 de Unión a la Caja Y/metabolismo , Proteínas Nucleares/genética , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/uso terapéutico , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismoRESUMEN
The therapeutic outcomes for bladder cancer (BLCA) remain suboptimal. Concurrently, there is a growing appreciation for the role of neoantigens in tumors. In this study, we explored the mechanisms underlying the involvement of neoantigen-associated genes in BLCA and their impact on prognosis. Our analysis incorporated both single-cell sequencing and bulk sequencing data sourced from publicly available databases. By employing a comprehensive set of 10 machine learning algorithms, we generated 101 algorithm combinations. The optimal combination, determined based on consistency indices, was utilized to construct a prognostic model comprising nine genes (CAPG, ACTA2, PDIA6, AKNA, PTMS, SNAP23, ID2, CD3G, SP140). Subsequently, we validated this model in an independent cohort, demonstrating its robust testing efficacy. Moreover, we explored the correlations between various clinical traits, model scores, and genes. Leveraging extensive public data resources, we conducted a drug sensitivity analysis to provide insights for targeted drug screening. Additionally, consensus clustering analysis and immune infiltration analysis were performed on bulk sequencing datasets and immunotherapy cohorts. These analyses yield valuable insights into the role of neoantigens in BLCA, guiding future research endeavors.
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Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Algoritmos , Evaluación Preclínica de Medicamentos , Proteínas de Unión al ADN , Proteínas Nucleares , Factores de TranscripciónRESUMEN
JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8+ T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.
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Adenina , Proteínas que Contienen Bromodominio , Melanoma , Succinatos , Receptor Toll-Like 7 , Animales , Ratones , Adenina/análogos & derivados , Adyuvantes Inmunológicos , Antígeno B7-H1 , Linfocitos T CD8-positivos , Proteínas Nucleares , Receptor Toll-Like 7/agonistas , Factores de Transcripción , Proteínas que Contienen Bromodominio/antagonistas & inhibidoresRESUMEN
To explore the connection between chloroplast and coffee resistance factors, designated as SH1 to SH9, whole genomic DNA of 42 coffee genotypes was sequenced, and entire chloroplast genomes were de novo assembled. The chloroplast phylogenetic haplotype network clustered individuals per species instead of SH factors. However, for the first time, it allowed the molecular validation of Coffea arabica as the maternal parent of the spontaneous hybrid "Híbrido de Timor". Individual reads were also aligned on the C. arabica reference genome to relate SH factors with chloroplast metabolism, and an in-silico analysis of selected nuclear-encoded chloroplast proteins (132 proteins) was performed. The nuclear-encoded thioredoxin-like membrane protein HCF164 enabled the discrimination of individuals with and without the SH9 factor, due to specific DNA variants linked to chromosome 7c (from C. canephora-derived sub-genome). The absence of both the thioredoxin domain and redox-active disulphide center in the HCF164 protein, observed in SH9 individuals, raises the possibility of potential implications on redox regulation. For the first time, the identification of specific DNA variants of chloroplast proteins allows discriminating individuals according to the SH profile. This study introduces an unexplored strategy for identifying protein/genes associated with SH factors and candidate targets of H. vastatrix effectors, thereby creating new perspectives for coffee breeding programs.
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Coffea , Humanos , Coffea/genética , Café , Filogenia , Factores R , Fitomejoramiento , Tiorredoxinas , Proteínas Nucleares , Proteínas de la Membrana , Proteínas de Cloroplastos , Cloroplastos/genética , Factor H de ComplementoRESUMEN
A Kinase Interacting Protein 1 (AKIP1) is found to be overexpressed in a variety of human cancers and associated with patients' worse prognosis. Several studies have established AKIP1's malignant functions in tumor metastasis, angiogenesis, and chemoradiotherapy resistance. However, the mechanism of AKIP1 involved in accelerating glioblastoma (GBM) progression remains unknown. Here, we showed that the expression of AKIP1 was positively correlated with the glioma pathological grades. Down-regulating AKIP1 greatly impaired the proliferation, colony formation, and tumorigenicity of GBM cells. In terms of the mechanism, AKIP1 cooperates with transcriptional factor Yin Yang 1 (YY1)-mediated Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) transcriptional activation, enhancing the stability of Epidermal Growth Factor Receptor (EGFR). YY1 was identified as a potential transcriptional factor of HSP90AA1 and directly interacts with AKIP1. The overexpression of HSP90α significantly reversed AKIP1 depletion incurred EGFR instability and the blocked cell proliferation. Moreover, we further investigated the interacted pattern between EGFR and HSP90α. These findings established that AKIP1 acted as a critical oncogenic factor in GBM and uncovered a novel regulatory mechanism in EGFR aberrant expression.
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Glioblastoma , Glioma , Humanos , Glioblastoma/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
Pathogenic variants in SPART cause Troyer syndrome, characterized by lower extremity spasticity and weakness, short stature and cognitive impairment, and a severe mitochondrial impairment. Herein, we report the identification of a role of Spartin in nuclear-encoded mitochondrial proteins. SPART biallelic missense variants were detected in a 5-year-old boy with short stature, developmental delay and muscle weakness with impaired walking distance. Patient-derived fibroblasts showed an altered mitochondrial network, decreased mitochondrial respiration, increased mitochondrial reactive oxygen species and altered Ca2+ versus control cells. We investigated the mitochondrial import of nuclear-encoded proteins in these fibroblasts and in another cell model carrying a SPART loss-of-function mutation. In both cell models the mitochondrial import was impaired, leading to a significant decrease in different proteins, including two key enzymes involved in CoQ10 (CoQ) synthesis, COQ7 and COQ9, with a severe reduction in CoQ content, versus control cells. CoQ supplementation restored cellular ATP levels to the same extent shown by the re-expression of wild-type SPART, suggesting CoQ treatment as a promising therapeutic approach for patients carrying mutations in SPART.
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Disfunción Cognitiva , Ubiquinona , Masculino , Humanos , Preescolar , Ubiquinona/farmacología , Proteínas Nucleares , Metabolismo Energético , Proteínas Mitocondriales/genéticaRESUMEN
Combining the BRD4 and CDK9 inhibitors can trigger the significant down-regulation of the MYC oncogene as well as anti-apoptotic genes and induce tumor cell apoptosis by synergistically impairing RNA synthesis in cancer cells. However, the lack of tumor-targeting capacity and the different pharmacokinetic curves of these two inhibitors may impair the antitumor activity of simultaneous CDK9 and BRD4 inhibition. Herein, CDK9 inhibitor (CI) and BRD4 inhibitor (BI) were codelivered by macrophage membrane-encapsulated black phosphorus nanosheets (M@BP) for the treatment of gastric cancer (GC) via the high expression of BRD4 and CDK9. BP with prominent biocompatibility exhibited a high drug loading efficiency for both CI and BI and could efficiently decrease the expression of the MYC oncogene. More importantly, BP could also serve as a phototherapy agent collaborating with CDK9 and BRD4 inhibition for GC therapy upon near-infrared (NIR) irradiation. Furthermore, the introduction of a macrophage membrane endowed BP with tumor-targeting ability, which could simultaneously deliver CI and BI to tumor tissues. In a murine orthotopic GC model, M@BP could efficiently target and accumulate in the tumor tissues, exhibiting an excellent photothermal effect. The tumor growth monitoring demonstrated that the combination of CI and BI codelivered by M@BP significantly inhibited the tumor progress than the single inhibitors, and the inhibition effect could be further enhanced upon NIR irradiation. Taken together, M@BP with tumor-targeting capacity and high drug loading efficiency for CI and BI could efficiently block the activation of CDK9 and BRD4, exhibiting excellent antitumor activity under NIR irradiation without systemic toxicity in an orthotopic GC model.
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Neoplasias Gástricas , Factores de Transcripción , Ratones , Animales , Neoplasias Gástricas/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Fósforo , BiomiméticaRESUMEN
BACKGROUND: Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia. METHODS: This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed. FINDINGS: Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections. INTERPRETATION: The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia. FUNDING: Pfizer and Amgen.
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Leucemia Mieloide Aguda , Recurrencia Local de Neoplasia , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Gemtuzumab/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Nucleares/genética , Resultado del Tratamiento , Tretinoina/uso terapéuticoRESUMEN
SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.
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Glutamina , Neoplasias , Humanos , Transportador de Glucosa de Tipo 1 , Adenosina Trifosfatasas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Suplementos Dietéticos , ADN Helicasas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Objective: To investigate the role of miR-362-3p and its target in cardiomyocytes with hypoxia/reoxygenation (H/R) injury. Results: We found that miR-362-3p was decreased in myocardial infarction (MI) samples, and promoted the proliferation and restrained the apoptosis of H/R-injured H9c2 cells. TP53INP2 was recognized as the target of miR-362-3p and negatively modulated by miR-362-3p. Furthermore, the promotive effect of miR-362-3p on the proliferation of H/R-injured H9c2 cells was weakened by pcDNA3.1-TP53INP2, while the suppression on the apoptosis of H/R-injured H9c2 cells triggered by an miR-362-3p mimic was increased by pcDNA3.1-TP53INP2 by regulating apoptosis-associated proteins, as well as SDF-1 and CXCR4. Summary: miR-362-3p/TP53INP2 axis could ameliorate H/R-induced injury to cardiomyocytes by adjusting the SDF-1/CXCR4 signaling pathway.
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MicroARNs , Miocitos Cardíacos , Proteínas Nucleares , Apoptosis , Hipoxia , MicroARNs/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal , Animales , RatasRESUMEN
Male and female gametophyte development processes are essential steps in the life cycles of all land plants. Here, we characterized a gene, FviBAG6-A, screened from the Fragaria viridis (2 n = 2x=14) pollen cDNA library and physically interacted with S-RNase. Ubiquitinated of Sa-RNase might be determined by the interaction of FviBAG6-A in the ubiquitin-proteasome system during fertilization. We found that overexpression of FviBAG6-A in Arabidopsis caused shorter silique length, and decreased silique number. Moreover, overexpression of FviBAG6-A in Fragaria vesca (2 n = 2x=14) led to a greatly reduced seed number, with nearly 80% of the seeds aborted. Analyses of paraffin sections and reactive oxygen species (ROS) content revealed that the majority of severe pollen defects were likely due to the early degradation of the tapetum and middle layer as a result of ROS accumulation and abnormal development of the uninucleate megaspore mother. Moreover, the FviBAG6-A interact with the E3 ligase SIZ1 and contribute to the SUMOylation of FviBAG6-A , which may be induced by the high level of ROS content, further promoting gametophyte abortion in strawberry transgenic lines. This study characterized the FviBAG6-A and reveals its novel function in gametophyte development.
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Proteínas de Arabidopsis , Arabidopsis , Fragaria , Proteínas de Arabidopsis/metabolismo , Fragaria/genética , Fragaria/metabolismo , Células Germinativas de las Plantas/metabolismo , Diploidia , Especies Reactivas de Oxígeno/metabolismo , Arabidopsis/genética , Polen/genética , Polen/metabolismo , Ribonucleasas/metabolismo , Ligasas/genética , Proteínas Nucleares/metabolismo , Chaperonas Moleculares/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is one of the leading causes of death, which deserves further study to reveal the underlying molecular mechanisms. Studies have shown that miR-9 in associated with poor prognosis in HCC patients. However, the mechanisms of transcriptional activation regulation of miR-9 and its role in the malignant progression of HCC have been rarely investigated. Some transcriptional coactivators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1 could form a transcriptional complex with p300, creating local high-concentration phase-separated interaction hubs at the super-enhancers of miR-9 and activate its expression to promote the malignant progression of HCC by stimulating the migration and invasion of hepatocellular carcinoma cells. Twist1-YY1-p300 phase-separated condensates were disrupted by metformin (Met) and thus reduce miR-9 expression, thereby inhibiting the malignant progression of HCC. Our study demonstrates that the Twist1 transcriptional factor complex involved in the malignant progression of HCC can form phase separation condensates at super-enhancers of miR-9 to promote the expression of oncogenes in HCC cells. It provides a potential target for the therapy of HCC and offers insights into the mechanism of Met in HCC inhibition.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Metformina , MicroARNs , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Proliferación Celular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
Context: The persistent use of anticancer medicines can cause multidrug resistance in many tumors and serious cytotoxicity for healthy cells, including adriamycin (ADR), a treatment for breast cancer (BC). Cell resistance to ADR in patients with recurrent advanced BC can occur. Creating effective treatments that can grapple with multidrug resistance is still challenging. Traditional Chinese medicine (TCM) may offer a solution in D Rhamnose beta-hederin (DRß-H), an oleanane type of triterpenoid saponin. Objective: The study intended to assess the ability of DRß-H to inhibit the ADR resistance of two BC-lineage cell lines, MCF-7 and SUM-1315, and to explore the causal link between DRß-H and the reversal of chemoresistance. Design: The research team performed a cell biology study. Setting: The study took place at laboratory in China. Outcome Measures: The research team: (1) assessed cell viability and the migration and invasion the cell lines; (2) investigated the molecular mechanism and identified the downstream targets of DRß-H, and (3) comprehensively examined the expression pattern, underlying functions, and evident prognostic significance of NAP1L5 in BC by gathering the online information available. Results: DRß-H can inhibit the viability of the MCF-7/ADR and SUM-1315/ADR cancer cells in a dosage-dependent manner. NAP1L5 might be the main target of DRß-H in reversing ADR resistance. Its expression decreased in BC cells, and the more advanced the BC was, the lower the NAP1L5 expression was. Conclusion: DRß-H at nontoxic concentrations was related to ADR resistance in BC through its downstream target NAP1L5. NAP1L5 is potentially a preferable prognostic marker for BC.
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Neoplasias de la Mama , Saponinas , Humanos , Femenino , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Saponinas/farmacología , Saponinas/uso terapéutico , Proteínas Nucleares/farmacología , Proteínas Nucleares/uso terapéuticoAsunto(s)
Enfermedad de Crohn , Humanos , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Células de Paneth/metabolismo , Factores Protectores , Autofagia , Transporte Biológico , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
Myocardial fibrosis following acute myocardial infarction (AMI) seriously affects the prognosis and survival rate of patients. This study explores the role and regulation mechanism of storax, a commonly used traditional Chinese medicine for treatment of cardiovascular diseases, on myocardial fibrosis and cardiac function. The AMI rat model was established by subcutaneous injection of Isoproterenol hydrochloride (ISO). Storax (0.1, 0.2, 0.4 g/kg) was administered by gavage once/d for 7 days. Electrocardiogram, echocardiography, hemodynamic and cardiac enzyme in AMI rats were measured. HE, Masson, immunofluorescence and TUNEL staining were used to observe the degree of pathological damage, fibrosis and cardiomyocyte apoptosis in myocardial tissue, respectively. Expression of AT1R, CARP and their downstream related apoptotic proteins were detected by WB. The results demonstrated that storax could significantly improve cardiac electrophysiology and function, decrease serum cardiac enzyme activity, reduce type I and III collagen contents to improve fibrosis and alleviate myocardial pathological damage and cardiomyocyte apoptosis. It also found that storax can significantly down-regulate expression of AT1R, Ankrd1, P53, P-p53 (ser 15), Bax and cleaved Caspase-3 and up-regulate expression of Mdm2 and Bcl-2. Taken together, these findings indicated that storax effectively protected cardiomyocytes against myocardial fibrosis and cardiac dysfunction by inhibiting the AT1R-Ankrd1-P53 signaling pathway.
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Medicamentos Herbarios Chinos , Infarto del Miocardio , Animales , Ratas , Apoptosis , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Fibrosis , Proteínas Musculares/efectos de los fármacos , Proteínas Musculares/metabolismo , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/efectos de los fármacos , Proteínas Nucleares/metabolismo , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Proteínas Represoras/efectos de los fármacos , Proteínas Represoras/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Chronic social stress caused by daily agonistic interactions in male mice leads to a mixed anxiety/depression-like disorder that is accompanied by the development of psychogenic immunodeficiency and stimulation of oncogenic processes concurrently with many neurotranscriptomic changes in brain regions. The aim of the study was to identify carcinogenesis- and apoptosis-associated differentially expressed genes (DEGs) in the hypothalamus of male mice with depression-like symptoms and, for comparison, in aggressive male mice with positive social experience. To obtain two groups of animals with the opposite 20-day social experiences, a model of chronic social conflict was used. Analysis of RNA-Seq data revealed similar expression changes for many DEGs between the aggressive and depressed animals in comparison with the control group; however, the number of DEGs was significantly lower in the aggressive than in the depressed mice. It is likely that the observed unidirectional changes in the expression of carcinogenesis- and apoptosis-associated genes in the two experimental groups may be a result of prolonged social stress (of different severity) caused by the agonistic interactions. In addition, 26 DEGs were found that did not change expression in the aggressive animals and could be considered genes promoting carcinogenesis or inhibiting apoptosis. Akt1, Bag6, Foxp4, Mapk3, Mapk8, Nol3, Pdcd10, and Xiap were identified as genes whose expression most strongly correlated with the expression of other DEGs, suggesting that their protein products play a role in coordination of the neurotranscriptomic changes in the hypothalamus. Further research into functions of these genes may be useful for the development of pharmacotherapies for psychosomatic pathologies.
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Hipotálamo , Derrota Social , Animales , Apoptosis , Carcinogénesis/metabolismo , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/metabolismo , Estrés Psicológico/metabolismoRESUMEN
Aging affects salivary gland function and alters saliva production and excretion. This study aimed to investigate whether ascorbic acid can be used to treat salivary gland dysfunction in an extensive aging mouse model of SAMP1/Klotho-/- mice. In our previous study, we found that ascorbic acid biosynthesis was disrupted in the salivary glands of SAMP1/Klotho (-/-) mice subjected to metabolomic profiling analysis. In SAMP1/Klotho -/- mice, daily supplementation with ascorbic acid (100 mg/kg for 18 days) significantly increased saliva secretion compared with the control. The expression of salivary gland functional markers (α-amylase, ZO-1, and Aqua5) is upregulated. Additionally, acetylcholine and/or beta-adrenergic receptors (M1AchR, M3AchR, and Adrb1) were increased by ascorbic acid in the salivary glands of aging mice, and treatment with ascorbic acid upregulated the expression of acetylcholine receptors through the DNA demethylation protein TET2. These results suggest that ascorbic acid could overcome the lack caused by dysfunction of ascorbic acid biosynthesis and induce the recovery of salivary gland function.