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Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.
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Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/genética , N-Metiltransferasa de Histona-Lisina/fisiología , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Animales , Carcinogénesis/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral , Epigénesis Genética/genética , Epigenómica/métodos , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Código de Histonas/efectos de los fármacos , Código de Histonas/genética , N-Metiltransferasa de Histona-Lisina/genética , Histonas/genética , Histonas/fisiología , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiología , Complejo Represivo Polycomb 2/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología , Activación Transcripcional , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Factores de Transcripción p300-CBP/fisiologíaRESUMEN
Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here, we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes ("spermatoproteasomes") contain a spermatid/sperm-specific α subunit α4 s/PSMA8 and/or the catalytic ß subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.
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Reparación del ADN , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Espermatogénesis , Testículo/metabolismo , Acetilación , Secuencia de Aminoácidos , Animales , Roturas del ADN de Doble Cadena , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Proteínas Nucleares/química , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de SecuenciaRESUMEN
An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Interferones/metabolismo , Proteínas de Transporte de Membrana/genética , Inmunidad Innata , Genoma Viral , Proteínas de Transporte de Nucleósidos/genética , Proteínas de Transporte de Nucleósidos/metabolismoRESUMEN
Spermiogenesis is considered to be crucial for the production of haploid spermatozoa with normal morphology, structure and function, but the mechanisms underlying this process remain largely unclear. Here, we demonstrate that SPEM family member 2 (Spem2), as a novel testis-enriched gene, is essential for spermiogenesis and male fertility. Spem2 is predominantly expressed in the haploid male germ cells and is highly conserved across mammals. Mice deficient for Spem2 develop male infertility associated with spermiogenesis impairment. Specifically, the insufficient sperm individualization, failure of excess cytoplasm shedding, and defects in acrosome formation are evident in Spem2-null sperm. Sperm counts and motility are also significantly reduced compared to controls. In vivo fertilization assays have shown that Spem2-null sperm are unable to fertilize oocytes, possibly due to their impaired ability to migrate from the uterus into the oviduct. However, the infertility of Spem2-/- males cannot be rescued by in vitro fertilization, suggesting that defective sperm-egg interaction may also be a contributing factor. Furthermore, SPEM2 is detected to interact with ZPBP, PRSS21, PRSS54, PRSS55, ADAM2 and ADAM3 and is also required for their processing and maturation in epididymal sperm. Our findings establish SPEM2 as an essential regulator of spermiogenesis and fertilization in mice, possibly in mammals including humans. Understanding the molecular role of SPEM2 could provide new insights into future therapeutic treatment of human male infertility and development of non-hormonal male contraceptives.
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Infertilidad Masculina , Espermatogénesis , Testículo , Animales , Masculino , Ratones , Fertilinas , Infertilidad Masculina/genética , Mamíferos , Semen , Interacciones Espermatozoide-Óvulo , Espermatogénesis/genética , Testículo/metabolismoRESUMEN
Major depressive disorder (MDD) is a prevalent and devastating mental illness. To date, the diagnosis of MDD is largely dependent on clinical interviews and questionnaires and still lacks a reliable biomarker. DNA methylation has a stable and reversible nature and is likely associated with the course and therapeutic efficacy of complex diseases, which may play an important role in the etiology of a disease. Here, we identified and validated a DNA methylation biomarker for MDD from four independent cohorts of the Chinese Han population. First, we integrated the analysis of the DNA methylation microarray (n = 80) and RNA expression microarray data (n = 40) and identified BICD2 as the top-ranked gene. In the replication phase, we employed the Sequenom MassARRAY method to confirm the DNA hypermethylation change in a large sample size (n = 1,346) and used the methylation-sensitive restriction enzymes and a quantitative PCR approach (MSE-qPCR) and qPCR method to confirm the correlation between DNA hypermethylation and mRNA down-regulation of BICD2 (n = 60). The results were replicated in the peripheral blood of mice with depressive-like behaviors, while in the hippocampus of mice, Bicd2 showed DNA hypomethylation and mRNA/protein up-regulation. Hippocampal Bicd2 knockdown demonstrates antidepressant action in the chronic unpredictable mild stress (CUMS) mouse model of depression, which may be mediated by increased BDNF expression. Our study identified a potential DNA methylation biomarker and investigated its functional implications, which could be exploited to improve the diagnosis and treatment of MDD.
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Metilación de ADN , Trastorno Depresivo Mayor , Hipocampo , Proteínas Asociadas a Microtúbulos , Animales , ADN/metabolismo , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Marcadores Genéticos , Hipocampo/metabolismo , Humanos , Ratones , Proteínas Asociadas a Microtúbulos/genética , ARN Mensajero/metabolismo , Estrés Psicológico/genéticaRESUMEN
Early-onset preeclampsia, which occurrs before 34 weeks of gestation, is the most dangerous classification of preeclampsia, which is a pregnancy-specific disease that causes 1% of maternal deaths. G protein-coupled receptor 124 (GPR124) is significantly expressed at various stages of the human reproductive process, particularly during embryogenesis and angiogenesis. Our prior investigation demonstrated a notable decrease in GPR124 expression in the placentas of patients with early-onset preeclampsia compared to that in normal pregnancy placentas. However, there is a lack of extensive investigation into the molecular processes that contribute to the role of GPR124 in placenta development. This study aimed to examine the mechanisms by which GPR124 affects the occurrence of early-onset preeclampsia and its function in trophoblast. Proliferative, invasive, migratory, apoptotic, and inflammatory processes were identified in GPR124 knockdown, GPR124 overexpression, and normal HTR8/SVneo cells. The mechanism of GPR124-mediated cell function in GPR124 knockdown HTR8/SVneo cells was examined using inhibitors of the JNK or P38 MAPK pathway. Downregulation of GPR124 was found to significantly inhibit proliferation, invasion and migration, and promote apoptosis of HTR8/SVneo cells when compared to the control and GPR124 overexpression groups. This observation is consistent with the pathological characteristics of preeclampsia. In addition, GPR124 overexpression inhibits the secretion of pro-inflammatory cytokines interleukin (IL)-8 and interferon-γ (IFN-γ) while enhancing the secretion of the anti-inflammatory cytokine interleukin (IL)-4. Furthermore, GPR124 suppresses the activation of P-JNK and P-P38 within the JNK/P38 MAPK pathway. The invasion, apoptosis, and inflammation mediated by GPR124 were partially restored by suppressing the JNK and P38 MAPK pathways in HTR8/SVneo cells. GPR124 plays a crucial role in regulating trophoblast proliferation, invasion, migration, apoptosis, and inflammation via the JNK and P38 MAPK pathways. Furthermore, the effect of GPR124 on trophoblast suggests its involvement in the pathogenesis of early-onset preeclampsia.
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Apoptosis , Movimiento Celular , Proliferación Celular , Inflamación , Preeclampsia , Receptores Acoplados a Proteínas G , Trofoblastos , Proteínas Quinasas p38 Activadas por Mitógenos , Humanos , Trofoblastos/metabolismo , Trofoblastos/patología , Apoptosis/genética , Proliferación Celular/genética , Femenino , Movimiento Celular/genética , Embarazo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Preeclampsia/patología , Preeclampsia/genética , Preeclampsia/metabolismo , Inflamación/patología , Inflamación/genética , Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas , Línea Celular , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Placenta/metabolismo , Placenta/patología , Receptores de EstrógenosRESUMEN
This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.
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Linfocitos Infiltrantes de Tumor , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Cerebral malaria (CM) is the most lethal complication of malaria, and survivors usually endure neurological sequelae. Notably, the cytotoxic effect of infiltrating Plasmodium-activated CD8+ T cells on cerebral microvasculature endothelial cells is a prominent feature of the experimental CM (ECM) model with blood-brain barrier disruption. However, the damage effect of CD8+ T cells infiltrating the brain parenchyma on neurons remains unclear. Based on the immunosuppressive effect of the PD-1/PD-L1 pathway on T cells, our previous study demonstrated that the systemic upregulation of PD-L1 to inhibit CD8+ T cell function could effectively alleviate the symptoms of ECM mice. However, it has not been reported whether neurons can suppress the pathogenic effect of CD8+ T cells through the PD-1/PD-L1 negative immunomodulatory pathway. As the important inflammatory factor of CM, interferons can induce the expression of PD-L1 via different molecular mechanisms according to the neuro-immune microenvironment. Therefore, this study aimed to investigate the direct interaction between CD8+ T cells and neurons, as well as the mechanism of neurons to alleviate the pathogenic effect of CD8+ T cells through up-regulating PD-L1 induced by IFNs. METHODS: Using the ECM model of C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), morphological observations were conducted in vivo by electron microscope and IF staining. The interaction between the ECM CD8+ T cells (immune magnetic bead sorting from spleen of ECM mice) and primary cultured cortical neurons in vitro was observed by IF staining and time-lapse photography. RNA-seq was performed to analyze the signaling pathway of PD-L1 upregulation in neurons induced by IFNß or IFNγ, and verified through q-PCR, WB, IF staining, and flow cytometry both in vitro and in vivo using IFNAR or IFNGR gene knockout mice. The protective effect of adenovirus-mediated PD-L1 IgGFc fusion protein expression was verified in ECM mice with brain stereotaxic injection in vivo and in primary cultured neurons via viral infection in vitro. RESULTS: In vivo, ECM mice showed infiltration of activated CD8+ T cells and neuronal injury in the brain parenchyma. In vitro, ECM CD8+ T cells were in direct contact with neurons and induced axonal damage, as an active behavior. The PD-L1 protein level was elevated in neurons of ECM mice and in primary cultured neurons induced by IFNß, IFNγ, or ECM CD8+ T cells in vitro. Furthermore, the IFNß or IFNγ induced neuronal expression of PD-L1 was mediated by increasing STAT1/IRF1 pathway via IFN receptors. The increase of PD-L1 expression in neurons during PbA infection was weakened after deleting the IFNAR or IFNGR. Increased PD-L1 expression by adenovirus partially protected neurons from CD8+ T cell-mediated damage both in vitro and in vivo. CONCLUSION: Our study demonstrates that both type I and type II IFNs can induce neurons to upregulate PD-L1 via the STAT1/IRF1 pathway mediated by IFN receptors to protect against activated CD8+ T cell-mediated damage, providing a targeted pathway to alleviate neuroinflammation during ECM.
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Antígeno B7-H1 , Linfocitos T CD8-positivos , Malaria Cerebral , Ratones Endogámicos C57BL , Neuronas , Factor de Transcripción STAT1 , Regulación hacia Arriba , Animales , Ratones , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Factor 1 Regulador del Interferón/metabolismo , Interferón gamma/metabolismo , Malaria Cerebral/inmunología , Malaria Cerebral/metabolismo , Malaria Cerebral/patología , Ratones Noqueados , Neuronas/metabolismo , Plasmodium berghei , Transducción de Señal/fisiología , Factor de Transcripción STAT1/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Iodide perovskites have demonstrated their unprecedented high efficiency and commercialization potential, and their superior optoelectronic properties, such as high absorption coefficient, high carrier mobility, and narrow direct bandgap, have attracted much attention, especially in solar cells, photodetectors, and light-emitting diodes (LEDs). However, whether it is organic iodide perovskite, organic-inorganic hybrid iodide perovskite or all-inorganic iodide perovskite the stability of these iodide perovskites is still poor and the contamination is high. In recent years, scholars have studied more iodide perovskites to improve their stability as well as optoelectronic properties from various angles. This paper systematically reviews the strategies (component engineering, additive engineering, dimensionality reduction engineering, and phase mixing engineering) used to improve the stability of iodide perovskites and their applications in recent years.
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Developing efficient and stable halide perovskite-based photocatalysts for highly selectivity reduction CO2 to valuable fuels remains a significant challenge due to their intrinsic instability. Herein, a novel heterostructure featuring 2D Cs3Sb2I9 nanosheets on a 3D flower-like mesoporous NiTiO3 framework using a top-down stepwise membrane fabrication technique is constructed. The unique bilayer heterostructure formed on the 3D mesoporous framework endowed NiTiO3/Cs3Sb2I9 with sufficient and close interface contact, minimizing charge transport distance, and effectively promoting the charge transfer at the interface, thus improving the reaction efficiency of the catalyst surface. As revealed by characterization and calculation, the coupling of Cs3Sb2I9 with NiTiO3 facilitates the hydrogenation process during catalytic, directing reaction intermediates toward highly selective CH4 production. Furthermore, the van der Waals forces inherent in the 3D/2D heterostructure with face-to-face contact provide superior stability, ensuring the efficient realization of photocatalytic CO2 reduction to CH4. Consequently, the optimized 3D/2D NiTiO3/Cs3Sb2I9 heterostructure demonstrates an impressive CH4 yield of 43.4 µmol g-1 h-1 with a selectivity of up to 88.6%, surpassing most reported perovskite-based photocatalysts to date. This investigation contributes to overcoming the challenges of commercializing perovskite-based photocatalysts and paves the way for the development of sustainable and efficient CO2 conversion technologies.
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Sugarcane (Saccharum spp.), a leading sugar and energy crop, is seriously impacted by drought stress. However, the molecular mechanisms underlying sugarcane drought resistance, especially the functions of epigenetic regulators, remain elusive. Here, we show that a S. spontaneum KDM4/JHDM3 group JmjC protein, SsJMJ4, negatively regulates drought-stress responses through its H3K27me3 demethylase activity. Ectopic overexpression of SsJMJ4 in Arabidopsis reduced drought resistance possibly by promoting expression of AtWRKY54 and AtWRKY70, encoding two negative regulators of drought stress. SsJMJ4 directly bound to AtWRKY54 and AtWRKY70, and reduced H3K27me3 levels at these loci to ensure their proper transcription under normal conditions. Drought stress down-regulated both transcription and protein abundance of SsJMJ4, which was correlated with the reduced occupancy of SsJMJ4 at AtWRKY54 and AtWRKY70 chromatin, increased H3K27me3 levels at these loci, as well as reduced transcription levels of these genes. In S. spontaneum, drought stress-repressed transcription of SsWRKY122, an ortholog of AtWRKY54 and AtWRKY70, was associated with increased H3K27me3 levels at these loci. Transient overexpression of SsJMJ4 in S. spontaneum protoplasts raised transcription of SsWRKY122, paralleled with reduced H3K27me3 levels at its loci. These results suggest that the SsJMJ4-mediated dynamic deposition of H3K27me3 is required for an appropriate response to drought stress.
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Sequías , Proteínas de Plantas , Saccharum , Saccharum/genética , Saccharum/fisiología , Saccharum/metabolismo , Saccharum/enzimología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico , Arabidopsis/genética , Arabidopsis/fisiología , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Histonas/metabolismo , Histonas/genéticaRESUMEN
Actin filaments form unique structures with robust actin bundles and cytoskeletal networks affixed to the extracellular matrix and interact with neighboring cells, which are crucial structures for cancer cells to acquire a motile phenotype. This study aims to investigate a novel antitumor mechanism by which Tanshinone IIA (Tan IIA) modulates the morphology and migration of liver cancer cells via actin cytoskeleton regulation. 97H and Huh7 exhibited numerous tentacle-like protrusions that interacted with neighboring cells. Following treatment with Tan IIA, 97H and Huh7 showed a complete absence of cytoplasmic protrusion and adherens junctions, thereby effectively impeding their migration capability. The fluorescence staining of F-actin and microtubules indicated that these tentacle-like protrusions and cell-cell networks were actin-based structures that led to morphological changes after Tan IIA treatment by retracting and reorganizing beneath the membrane. Tan IIA can reverse the actin depolymerization and cell morphology alterations induced by latrunculin A. Tan IIA down-regulated actin and Rho GTPases expression significantly, as opposed to inducing Rho signaling activation. Preventing the activity of proteasomes and lysosomes had no discernible impact on the modifications in cellular structure and protein expression induced by Tan IIA. However, as demonstrated by the puromycin labeling technique, the newly synthesized proteins were significantly inhibited by Tan IIA. In conclusion, Tan IIA can induce dramatic actin cytoskeleton remodeling by inhibiting the protein synthesis of actin and Rho GTPases, resulting in the suppression of tumor growth and migration. Targeting the actin cytoskeleton of Tan IIA is a promising strategy for HCC treatment.
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Abietanos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Actinas , Proteínas de Unión al GTP rho/farmacología , Proliferación Celular , Carcinoma Hepatocelular/tratamiento farmacológico , Citoesqueleto , Citoesqueleto de Actina , Línea Celular Tumoral , ApoptosisRESUMEN
The reparative potential of cardiac Lin-KIT+ (KIT) cells is influenced by their population, but identifying their markers is challenging due to changes in phenotype during in vitro culture. Resolving this issue requires uncovering cell heterogeneity and discovering new subpopulations. Single-cell RNA sequencing (scRNA-seq) can identify KIT cell subpopulations, their markers, and signaling pathways. We used 10× genomic scRNA-seq to analyze cardiac-derived cells from adult mice and found 3 primary KIT cell populations: KIT1, characterized by high-KIT expression (KITHI), represents a population of cardiac endothelial cells; KIT2, which has low-KIT expression (KITLO), expresses transcription factors such as KLF4, MYC, and GATA6, as well as genes involved in the regulation of angiogenic cytokines; KIT3, with moderate KIT expression (KITMOD), expresses the cardiac transcription factor MEF2C and mesenchymal cell markers such as ENG. Cell-cell communication network analysis predicted the presence of the 3 KIT clusters as signal senders and receivers, including VEGF, CXCL, and BMP signaling. Metabolic analysis showed that KIT1 has the low activity of glycolysis and oxidative phosphorylation (OXPHOS), KIT2 has high glycolytic activity, and KIT3 has high OXPHOS and fatty acid degradation activity, indicating distinct metabolic adaptations of the 3 KIT populations. Through the systemic infusion of KIT1 cells in a mouse model of myocardial infarction, we observed their involvement in promoting the formation of new micro-vessels. In addition, in vitro spheroid culture experiments demonstrated the cardiac differentiation capacity of KIT2 cells.
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Células Endoteliales , Análisis de Expresión Génica de una Sola Célula , Ratones , Animales , Células Endoteliales/metabolismo , Diferenciación Celular/genética , Regulación de la Expresión Génica , Corazón , Factores de Transcripción/metabolismoRESUMEN
According to statistics, the incidence of liver cancer is increasing yearly, and effective treatment of liver cancer is imminent. For early liver cancer, resection surgery is currently the most effective treatment. However, resection does not treat the disease in advanced patients, so finding a method with a better prognosis is necessary. In recent years, ferroptosis and cuproptosis have been gradually defined, and related studies have proved that they show excellent results in the therapy of liver cancer. Cuproptosis is a new form of cell death, and the use of cuproptosis combined with ferroptosis to inhibit the production of hepatocellular carcinoma cells has good development prospects and is worthy of in-depth discussion by researchers. In this review, we summarize the research progress on cuproptosis combined with ferroptosis in treating liver cancer, analyze the value of cuproptosis and ferroptosis in the immune of liver cancer, and propose potential pathways in oncotherapy with the combination of cuproptosis and ferroptosis, which can provide background knowledge for subsequent related research.
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Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of HD's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in HD, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to HD progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in HD. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with HD severity. Using the R6/2 ENT3-/- mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens HD progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes.
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Modelos Animales de Enfermedad , Progresión de la Enfermedad , Enfermedad de Huntington , Microglía , Proteínas de Transporte de Nucleósidos , Animales , Humanos , Masculino , Ratones , Encéfalo/metabolismo , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Proteínas de Transporte de Nucleósidos/metabolismo , Proteínas de Transporte de Nucleósidos/genéticaRESUMEN
INTRODUCTION: Adjusting for confounding variables is critical for objective comparison of outcomes. The explanatory power of variables used in adjusted models for injury and their relative utility across age groups has not been well-defined. This study aimed to assess the explanatory power of covariates commonly adjusted in injury research and their relative performance across age groups. METHODS: Inpatients 18-100 y (2017-2022) were selected from 90 hospital trauma registries. Patients were grouped into sequential 5-y age blocks. Mortality was defined as the proportion of patients "expired + hospice". Dominance analysis was used to determine the average contribution (McFadden's R2) for covariates commonly included in multivariable logistic regressions. RESULTS: Three hundred seventeen-thousand one hundred thirty-six patients were included (51.1% male, mean age: 63, mean injury severity score [ISS]: 9.8, mean Glasgow Coma Scale: 14.3, 93.5% blunt). Total explanatory power (McFadden's R2) for mortality was highest in youngest age group (52.7% in 18-24 group) and decreased with age, with the lowest R2 (19.6%) in 95-100 group. Regardless of age, the Glasgow Coma Scale was the most important covariate (R2 ranging from 9.0% to 20.4%). At age 18-24 y, ISS was a more dominant contributor than Elixhauser Score, but beyond 55 y, Elixhauser Score became more dominant than ISS. CONCLUSIONS: The explanatory power of adjustment models including common covariates is limited and varies significantly across age groups, decreasing linearly with age. Adjusting for outcomes using these covariates may limit objective comparisons especially for older adults. Additional research is needed to identify covariates that enhance the explanatory power of adjustment models to allow for more objective comparisons across all ages.
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Drought and nitrogen enrichment could profoundly affect the productivity of semiarid ecosystems. However, how ecosystem productivity will respond to different drought scenarios, especially with a concurrent increase in nitrogen availability, is still poorly understood. Using data from a 4-year field experiment conducted in a semiarid temperate steppe, we explored the responses of aboveground net primary productivity (ANPP) to different drought scenarios and nitrogen addition, and the underlying mechanisms linking soil properties, plant species richness, functional diversity (community-weighted means of plant traits, functional dispersion) and phylogenetic diversity (net relatedness index) to ANPP. Our results showed that completely excluding precipitation in June (1-month intense drought) and reducing half the precipitation amount from June to August (season-long chronic drought) both significantly reduced ANPP, with the latter having a more negative impact on ANPP. However, reducing half of the precipitation frequency from June to August (precipitation redistribution) had no significant effect on ANPP. Nitrogen addition increased ANPP irrespective of drought scenarios. ANPP was primarily determined by soil moisture and nitrogen availability by regulating the community-weighted means of plant height, rather than other aspects of plant diversity. Our findings suggest that precipitation amount is more important than precipitation redistribution in influencing the productivity of temperate steppe, and nitrogen supply could alleviate the adverse impacts of drought on grassland productivity. Our study advances the mechanistic understanding of how the temperate grassland responds to drought stress, and implies that management strategies to protect tall species in the community would be beneficial for maintaining the productivity and carbon sequestration of grassland ecosystems under climate drought.
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Sequías , Pradera , Nitrógeno , Nitrógeno/metabolismo , Plantas/clasificación , Suelo/química , ChinaRESUMEN
PURPOSE: Since May 2022, Mpox has spread extensively outside of Africa, posing a serious threat to the health of people globally, and particularly to the men who have sex with men (MSM) population. Chongqing, a province in Southwest China, has relatively large MSM and people living with HIV (PLWH) populations, presenting conditions conducive to the wide dissemination of Mpox. In this study, we investigated the clinical characteristics of Mpox patients among MSM and PLWH in Chongqing, aiming to inform the development of targeted prevention, control, and treatment strategies for Mpox. METHOD: We evaluated the clinical characteristics, travel history, time of onset, distribution and number of skin lesions of Mpox patients admitted to the Chongqing Public Health Medical Center between September 2022 and October 2023. Meanwhile, a series of clinical samples were collected and the pathogen of interest was identified as Mpox virus using quantitative polymerase chain reaction (qPCR). The results were presented in the form of cycle thresholds (Ct), which help to approximate the quantification of viral load. RESULTS: As of October 11, 2023, the Chongqing Public Health Medical Center reported a total of nine Mpox virus infections. All the patients identified were male and belonged to the MSM population, among whom seven (77.8%) were living with HIV, and maintained a preserved immune system while achieving viral suppression via effective ART. We observed no discernible clinical differences between MSM with Mpox with or without HIV, and no fatalities were recorded. Viral loads were observed to be higher in samples taken from the skin than those from the throat, nasopharynx, blood, or semen. CONCLUSION: In this retrospective study, the clinical manifestations of MPXV infection appeared consistent among MSM patients, regardless of HIV status. Elevated MPXV viral loads in the skin and mucosal tissues, particularly at genital and anal sites, indicate that transmission is more likely to occur via direct physical contact as opposed to respiratory pathways or through exposure to bodily fluids.
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Infecciones por VIH , Homosexualidad Masculina , Carga Viral , Humanos , Masculino , China/epidemiología , Estudios Retrospectivos , Adulto , Homosexualidad Masculina/estadística & datos numéricos , Infecciones por VIH/virología , Infecciones por VIH/epidemiología , Infecciones por VIH/tratamiento farmacológico , Persona de Mediana Edad , Adulto Joven , FemeninoRESUMEN
BACKGROUND: Familial hypercholesterolemia (FH) is a prevalent hereditary disease that can cause aberrant cholesterol metabolism. In this study, we confirmed that c.415G > A in low-density lipoprotein receptor (LDLR), an FH-related gene, is a pathogenic variant in FH by in silico analysis and functional experiments. METHODS: The proband and his family were evaluated using the diagnostic criteria of the Dutch Lipid Clinic Network. Whole-exome and Sanger sequencing were used to explore and validate FH-related variants. In silico analyses were used to evaluate the pathogenicity of the candidate variant and its impact on protein stability. Molecular and biochemical methods were performed to examine the effects of the LDLR c.415G > A variant in vitro. RESULTS: Four of six participants had a diagnosis of FH. It was estimated that the LDLR c.415G > A variant in this family was likely pathogenic. Western blotting and qPCR suggested that LDLR c.415G > A does not affect protein expression. Functional studies showed that this variant may lead to dyslipidemia by impairing the binding and absorption of LDLR to low-density lipoprotein ( LDL). CONCLUSION: LDLR c.415G > A is a pathogenic variant in FH; it causes a significant reduction in LDLR's capacity to bind LDL, resulting in impaired LDL uptake. These findings expand the spectrum of variants associated with FH.
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Hiperlipoproteinemia Tipo II , Humanos , Fenotipo , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Lipoproteínas LDL/genética , Mutación , Proproteína Convertasa 9/genéticaRESUMEN
BACKGROUND: Monkeypox is a zoonotic disease caused by the monkeypox virus and is increasingly recognized as a serious public health concern worldwide. Our aim was to investigate the knowledge and attitudes of Chinese medical students regarding monkeypox. METHODS: A cross-sectional study was conducted among 8,897 college students from China. An e-questionnaire was used to collect data on knowledge (17 items), attitudes (12 items), and baseline criteria. The relationships between a range of factors and knowledge and attitudes were studied using univariate and multivariate analyses. RESULTS: A total of 79.33% of the study participants were female, 89.10% were of Han ethnicity, 72.50% were from rural areas, 50.39% were in their first year, and 80.65% were medical majors. A total of 50.88% had good knowledge of monkeypox, and 57.11% had a positive attitude towards monkeypox knowledge. Univariate analysis revealed that origin and major were the factors affecting the knowledge level of monkeypox among participants. Rural students had more knowledge of monkeypox than urban students, and nonmedical students had greater awareness of monkeypox than did medical students. Moreover, sex and grade were the factors influencing participants' attitudes towards monkeypox; men had more positive attitudes than women did, and senior students had more positive attitudes than junior students did. Multivariate analysis revealed that major and the origin of the students independently influenced the monkeypox knowledge of Chinese medical students, while sex, grade and monkeypox knowledge were significantly related to attitudes towards monkeypox. CONCLUSION: This study revealed that nearly half of the Chinese medical students had good knowledge and a positive attitude towards monkeypox. Student origin and major independently influenced the knowledge of Chinese medical students of monkeypox, while sex, grade and knowledge were independently related to the attitudes of Chinese medical students towards monkeypox.