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Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.
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Proteínas de Transporte de Monosacáridos/ultraestructura , Plasmodium falciparum/metabolismo , Plasmodium falciparum/ultraestructura , Proteínas Protozoarias/ultraestructura , Secuencia de Aminoácidos , Animales , Antimaláricos , Transporte Biológico , Glucosa/metabolismo , Humanos , Malaria , Malaria Falciparum/parasitología , Proteínas de Transporte de Monosacáridos/química , Proteínas de Transporte de Monosacáridos/metabolismo , Parásitos , Plasmodium falciparum/genética , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Azúcares/metabolismoRESUMEN
Cholesterol is highly enriched at the plasma membrane (PM), and lipid transfer proteins may deliver cholesterol to the PM in a nonvesicular manner. Here, through a mini-screen, we identified the oxysterol binding protein (OSBP)-related protein 2 (ORP2) as a novel mediator of selective cholesterol delivery to the PM. Interestingly, ORP2-mediated enrichment of PM cholesterol was coupled with the removal of phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2) from the PM. ORP2 overexpression or deficiency impacted the levels of PM cholesterol and PI(4,5)P2, and ORP2 efficiently transferred both cholesterol and PI(4,5)P2in vitro. We determined the structure of ORP2 in complex with PI(4,5)P2 at 2.7 Å resolution. ORP2 formed a stable tetramer in the presence of PI(4,5)P2, and tetramerization was required for ORP2 to transfer PI(4,5)P2. Our results identify a novel pathway for cholesterol delivery to the PM and establish ORP2 as a key regulator of both cholesterol and PI(4,5)P2 of the PM.
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Membrana Celular/metabolismo , Colesterol/metabolismo , Hepatocitos/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Receptores de Esteroides/metabolismo , Transporte Biológico , Línea Celular Tumoral , Células HEK293 , Humanos , Modelos Moleculares , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Receptores de Esteroides/química , Receptores de Esteroides/genética , Relación Estructura-ActividadRESUMEN
Transcription regulation underlies stem cell function and development. Here, we elucidate an unexpected role of an essential ribogenesis factor, WDR43, as a chromatin-associated RNA-binding protein (RBP) and release factor in modulating the polymerase (Pol) II activity for pluripotency regulation. WDR43 binds prominently to promoter-associated noncoding/nascent RNAs, occupies thousands of gene promoters and enhancers, and interacts with the Pol II machinery in embryonic stem cells (ESCs). Nascent transcripts and transcription recruit WDR43 to active promoters, where WDR43 facilitates releases of the elongation factor P-TEFb and paused Pol II. Knockdown of WDR43 causes genome-wide defects in Pol II release and pluripotency-associated gene expression. Importantly, auxin-mediated rapid degradation of WDR43 drastically reduces Pol II activity, precluding indirect consequences. These results reveal an RNA-mediated recruitment and feedforward regulation on transcription and demonstrate an unforeseen role of an RBP in promoting Pol II elongation and coordinating high-level transcription and translation in ESC pluripotency.
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Proteínas de Transporte de Catión/genética , Cromatina/química , Regulación del Desarrollo de la Expresión Génica , Células Madre Embrionarias de Ratones/metabolismo , ARN Polimerasa II/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Transcripción Genética , Proteínas de Pez Cebra/genética , Animales , Sitios de Unión , Proteínas de Transporte de Catión/metabolismo , Diferenciación Celular , Línea Celular , Cromatina/metabolismo , Embrión de Mamíferos , Elementos de Facilitación Genéticos , Eliminación de Gen , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Células Madre Embrionarias de Ratones/citología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Factor B de Elongación Transcripcional Positiva/genética , Factor B de Elongación Transcripcional Positiva/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Biosíntesis de Proteínas , Proteolisis , ARN Polimerasa II/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Proteínas de Pez Cebra/metabolismoRESUMEN
Lipids establish the specialized thylakoid membrane of chloroplast in eukaryotic photosynthetic organisms, while the molecular basis of lipid transfer from other organelles to chloroplast remains further elucidation. Here we revealed the structural basis of Arabidopsis Sec14 homology proteins AtSFH5 and AtSFH7 in transferring phosphatidic acid (PA) from endoplasmic reticulum (ER) to chloroplast, and whose function in regulating the lipid composition of chloroplast and thylakoid development. AtSFH5 and AtSFH7 localize at both ER and chloroplast, whose deficiency resulted in an abnormal chloroplast structure and a decreased thickness of stacked thylakoid membranes. We demonstrated that AtSFH5, but not yeast and human Sec14 proteins, could specifically recognize and transfer PA in vitro. Crystal structures of the AtSFH5-Sec14 domain in complex with L-α-phosphatidic acid (L-α-PA) and 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA) revealed that two PA ligands nestled in the central cavity with different configurations, elucidating the specific binding mode of PA to AtSFH5, different from the reported phosphatidylethanolamine (PE)/phosphatidylcholine (PC)/phosphatidylinositol (PI) binding modes. Quantitative lipidomic analysis of chloroplast lipids showed that PA and monogalactosyldiacylglycerol (MGDG), particularly the C18 fatty acids at sn-2 position in MGDG were significantly decreased, indicating a disrupted ER-to-plastid (chloroplast) lipid transfer, under deficiency of AtSFH5 and AtSFH7. Our studies identified the role and elucidated the structural basis of plant SFH proteins in transferring PA between organelles, and suggested a model for ER-chloroplast interorganelle phospholipid transport from inherent ER to chloroplast derived from endosymbiosis of a cyanobacteriumproviding a mechanism involved in the adaptive evolution of cellular plastids.
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Proteínas de Arabidopsis , Arabidopsis , Cloroplastos , Ácidos Fosfatidicos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cloroplastos/metabolismo , Ácidos Fosfatidicos/metabolismo , Tilacoides/metabolismoRESUMEN
Coronary artery calcification (CAC) is a hallmark event in the pathogenesis of cardiovascular disease, involving the phenotypic transformation of vascular smooth muscle cells (VSMC) towards an osteogenic state. Despite this understanding, the molecular mechanisms governing the VSMC osteogenic switch remain incompletely elucidated. Here, we sought to examine the potential role of circular RNA (circRNA) in the context of CAC. Through transcriptome analysis of circRNA-seq, we identified circTOP1 as a potential candidate circRNA in individuals with CAC. Furthermore, we observed that overexpression of circTOP1 exacerbated vascular calcification in a CAC model. Subsequent pull-down assays revealed an interaction between circTOP1 and PTBP1, a putative target gene of circTOP1 in the context of CAC. In both in vivo and in vitro experiments, we observed heightened expression of circTOP1 and PTBP1 in the CAC model, and noted that reducing circTOP1 expression effectively reduced calcium salt deposits and mineralized nodules in model mice. Additionally, in vitro experiments demonstrated that overexpression of PTBP1 reversed the weakening of signaling caused by silencing circTOP1, thereby exacerbating the osteogenic transition and calcification of VSMC. Collectively, our findings suggested that circTOP1 promotes CAC by modulating PTBP1 expression to mediate VSMC transdifferentiation.
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Ribonucleoproteínas Nucleares Heterogéneas , Músculo Liso Vascular , Miocitos del Músculo Liso , Proteína de Unión al Tracto de Polipirimidina , ARN Circular , Calcificación Vascular , Animales , Humanos , Masculino , Ratones , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/metabolismo , Vasos Coronarios/patología , Vasos Coronarios/metabolismo , Progresión de la Enfermedad , Regulación de la Expresión Génica/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Osteogénesis/genética , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Calcificación Vascular/genética , Calcificación Vascular/patología , Calcificación Vascular/metabolismoRESUMEN
Biofilm is a spatially organized community formed by the accumulation of both microorganisms and their secretions, leading to persistent and chronic infections because of high resistance toward conventional antibiotics. In view of the tunable physicochemical properties and the related unique biological behavior (e.g., size-, shape-, and surface charge-dependent penetration, protein corona endowed targeting, catalytic- and electronic-related oxidative stress, optical- and magnetic-associated hyperthermia, etc.), nanomaterials-based therapeutics are widely used for the treatment of biofilm-associated infections. In this review, the biological characteristics of biofilm are introduced. And the nanomaterials-based antibacterial strategies are further discussed via biofilm targeting, including preventing biofilm formation, enhancing biofilm penetration, disrupting the mature biofilm, and acting as drug delivery systems. In which, the interactions between biofilm and nanomaterials include mechanical disruption, electron transfer, enzymatic degradation, oxidative stress, and hyperthermia. Additionally, the current advances of nanomaterials for antibacterial nanomaterials by biofilm targeting are summarized. This review aims to present a complete vision of antibacterial nanomaterials-biofilm (nano-bio) interactions, paving the way for the future development and clinical translation of effective antibacterial nanomedicines.
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Nanoestructuras , Nanoestructuras/química , Antibacterianos/química , Biopelículas , Nanomedicina , Sistemas de Liberación de MedicamentosRESUMEN
As a highly promising nanomaterial, exploring the impact of the liver, a vital organ, stands out as a crucial focus in the examination of its biological effects. Kupffer cells (KCs) are one of the first immune cells to contact with exotic-substances in liver. Therefore, this study investigates the immunomodulatory effects and mechanisms of polyethylene glycol-modified graphene oxide (GO-PEG) on KCs. Initial RNA-seq and KEGG pathway analyses reveal the inhibition of the TOLL-like receptor, TNF-α and NOD-like receptor pathways in continually stimulated KCs exposed to GO-PEG. Subsequent biological experiments validate that a 48-hour exposure to GO-PEG alleviates LPS-induced KCs immune activation, characterized by a shift in polarization from M1 to M2. The underlying mechanism involves the absorption of double-stranded RNA/single-stranded RNA, inhibiting the activation of TLR3 and TLR7 in KCs. Employing a Kupffer/AML12 cell co-culture model and animal studies, it is observed that GO-PEG indirectly inhibit oxidative stress, mitochondrial dysfunction, and apoptosis in AML12 cells, partially mitigating systemic inflammation and preserving liver tissue/function. This effect is attributed to the paracrine interaction between KCs and hepatocytes. These findings suggest a meaningful and effective strategy for treating liver inflammation, particularly when combined with anti-inflammatory drugs.
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Grafito , Macrófagos del Hígado , Polietilenglicoles , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Animales , Grafito/química , Grafito/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacología , Ratones , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Inflamación/patología , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Masculino , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Progresión de la Enfermedad , Polaridad Celular/efectos de los fármacos , Línea CelularRESUMEN
MOTIVATION: Phage genome annotation plays a key role in the design of phage therapy. To date, there have been various genome annotation tools for phages, but most of these tools focus on mono-functional annotation and have complex operational processes. Accordingly, comprehensive and user-friendly platforms for phage genome annotation are needed. RESULTS: Here, we propose PhaGAA, an online integrated platform for phage genome annotation and analysis. By incorporating several annotation tools, PhaGAA is constructed to annotate the prophage genome at DNA and protein levels and provide the analytical results. Furthermore, PhaGAA could mine and annotate phage genomes from bacterial genome or metagenome. In summary, PhaGAA will be a useful resource for experimental biologists and help advance the phage synthetic biology in basic and application research. AVAILABILITY AND IMPLEMENTATION: PhaGAA is freely available at http://phage.xialab.info/.
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Bacteriófagos , Bacteriófagos/genética , Programas Informáticos , Computadores , Metagenoma , Genoma Bacteriano , Anotación de Secuencia MolecularRESUMEN
While the distribution of extracellular ARGs (eARGs) in the environment has been widely reported, the factors governing their release remain poorly understood. Here, we combined multi-omics and direct experimentation to test whether the release and transmission of eARGs are associated with viral lysis and heat during cow manure composting. Our results reveal that the proportion of eARGs increased 2.7-fold during composting, despite a significant and concomitant reduction in intracellular ARG abundances. This relative increase of eARGs was driven by composting temperature and viral lysis of ARG-carrying bacteria based on metagenome-assembled genome (MAG) analysis. Notably, thermal lysis of mesophilic bacteria carrying ARGs was a key factor in releasing eARGs at the thermophilic phase, while viral lysis played a relatively stronger role during the non-thermal phase of composting. Furthermore, MAG-based tracking of ARGs in combination with direct transformation experiments demonstrated that eARGs released during composting pose a potential transmission risk. Our study provides bioinformatic and experimental evidence of the undiscovered role of temperature and viral lysis in co-driving the spread of ARGs in compost microbiomes via the horizontal transfer of environmentally released DNA. IMPORTANCE: The spread of antibiotic resistance genes (ARGs) is a critical global health concern. Understanding the factors influencing the release of extracellular ARGs (eARGs) is essential for developing effective strategies. In this study, we investigated the association between viral lysis, heat, and eARG release during composting. Our findings revealed a substantial increase in eARGs despite reduced intracellular ARG abundance. Composting temperature and viral lysis were identified as key drivers, with thermal lysis predominant during the thermophilic phase and viral lysis during non-thermal phases. Moreover, eARGs released during composting posed a transmission risk through horizontal gene transfer. This study highlights the significance of temperature and phage lysis in ARG spread, providing valuable insights for mitigating antibiotic resistance threats.
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Compostaje , Transferencia de Gen Horizontal , Estiércol/microbiología , Estiércol/virología , Microbiología del Suelo , Bacterias/genética , Bacterias/efectos de los fármacos , Animales , Metagenoma , Bovinos , Calor , Genes Bacterianos , Farmacorresistencia Microbiana/genética , Farmacorresistencia Bacteriana/genética , Microbiota , Bacteriófagos/genética , Bacteriófagos/fisiologíaRESUMEN
Emerging studies have demonstrated spinal microglia play a critical role in central sensitization and contribute to chronic pain. Although several mediators that contribute to microglia activation have been identified, the mechanism of microglia activation and its functionally diversified mechanisms in pathological pain are still unclear. Here we report that injured sensory neurons-derived Galectin-3 (Gal3) activates and reprograms microglia in the spinal dorsal horn (SDH) and contributes to neuropathic pain. Firstly, Gal3 is predominantly expressed in the isolectin B4 (IB4)-positive non-peptidergic sensory neurons and significantly up-regulated in dorsal root ganglion (DRG) neurons and primary afferent terminals in SDH in the partial sciatic nerve ligation (pSNL)-induced neuropathic pain model. Gal3 knockout (Gal3 KO) mice showed a significant decrease in mechanical allodynia and Gal3 inhibitor TD-139 produced a significant anti-allodynia effect in the pSNL model. Furthermore, pSNL-induced microgliosis was compromised in Gal3 KO mice. Additionally, intrathecal injection of Gal3 produces remarkable mechanical allodynia by direct activation of microglia, which have enhanced inflammatory responses with TNF-α and IL-1ß up-regulation. Thirdly, using single-nuclear RNA sequencing (snRNA-seq), we identified that Gal3 targets microglia and induces reprogramming of microglia, which may contribute to neuropathic pain establishment. Finally, Gal3 enhances excitatory synaptic transmission in excitatory neurons in the SDH via microglia activation. Our findings reveal that injured sensory neurons-derived Gal3 programs microglia in the SDH and contribute to neuropathic pain.
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Galectina 3 , Neuralgia , Animales , Ratones , Galectina 3/genética , Hiperalgesia , Microglía , Células Receptoras SensorialesRESUMEN
As a widespread environmental pollutant, microplastics pose a great threat to the tissues and organs of aquatic animals. The carp's muscles are necessary for movement and survival. However, the mechanism of injury of polyethylene microplastics (PE-MPs) to carp muscle remains unclear. Therefore, in this study, PE-MPs with the diameter of 8 µm and the concentration of 1000 ng/L were used to feed carp for 21 days, and polyethylene microplastic treatment groups was established. The results showed that PE-MPs could cause structural abnormalities and disarrangement of muscle fibers, and aggravate oxidative stress in muscles. Exposure to PE-MPs reduced microRNA (miR-21) in muscle tissue, negatively regulated Interleukin-1 Receptor Associated Kinase 4 (IRAK4), activated Nuclear Factor Kappa-B (NF-κB) pathway, induced inflammation, and led to endoplasmic reticulum stress and apoptosis. The present study provides different targets for the prevention of muscle injury induced by polyethylene microplastics.
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Carpas , MicroARNs , Contaminantes Químicos del Agua , Animales , Polietileno , Microplásticos , Plásticos , Quinasas Asociadas a Receptores de Interleucina-1 , FN-kappa B , Músculos , Apoptosis , Estrés del Retículo Endoplásmico , Inflamación , Estrés OxidativoRESUMEN
Cubic nanoparticles of CeO2 were partly covered on the tetrahedron surface of γ-Bi2O3 through a hydrothermal reaction and then a calcination process to construct a novel S-type γ-Bi2O3/CeO2 heterojunction. The optimized sample removed 96% of lomefloxacin and 81% of tetracycline. During the cycling test, the photocatalytic efficiency of lomefloxacin and tetracycline was maintained above 87% and 80%, respectively, for five consecutive cycles. According to XRD and Raman spectra characterization, the sample after cycling held a stable crystal structure. Holes, OH-Ë, O2Ë, and electrons participated in the degradation of lomefloxacin, while tetracycline was removed via the effect of the former three active substances. Based on theoretical calculation and experimental tests, the excellent photocatalytic activity of γ-Bi2O3/CeO2 came from the fast transfer of charge carriers along the S-type path. Moreover, the CB electrons of γ-Bi2O3 and VB holes of CeO2 were preserved to generate free radicals for antibiotic degradation. The colony numbers of Escherichia coli were 1.50 × 10-6 CFU mL-1 and 1.39 × 10-6 CFU mL-1 in solutions after the degradation of the two pollutants, which represents the non-toxicity of the final products. The γ-Bi2O3/CeO2 sample has a potential application for antibiotic removal from modern sewage.
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Antibacterianos , Contaminantes Ambientales , Tetraciclina , Electrones , Escherichia coliRESUMEN
OBJECTIVE: To investigate the effectiveness of Baduanjin exercise on executive function in community-dwelling older adults with cognitive frailty. DESIGN: Randomized controlled trial. SETTING: Community residential centers. SUBJECTS: 120 eligible older adults. INTERVENTIONS: Baduanjin training group received supervised Baduanjin training, 60â min sessions three times per week for 24 weeks. The control group did not receive any exercise intervention. MAIN MEASURES: Primary outcome was executive function, assessed using Clock Drawing Test. Secondary outcomes included the subcomponents of executive function (working memory, inhibitory control and cognitive flexibility), attention and cognitive frailty (global cognitive function, physical frailty) assessed using Verbal Fluency Test, Trail Making Test-A/B, Stroop Test, Montreal Cognitive Assessment and Edmonton Frailty Scale, respectively, at baseline and 24 weeks after intervention. RESULTS: After the 24-week intervention, the scores of Clock Drawing Test and Verbal Fluency Test, the Trail Making Test-B time and the Card correct numbers of Stroop Test in Baduanjin training group showed significant improvement compared with control group (all P < 0.05) with small to moderate effect sizes and the significant interaction effect of group by time in the Clock Drawing Test and Trail Making Test-B test (P = 0.003 and P = 0.043); cognitive frailty variables, including Montreal Cognitive Assessment and Edmonton Frail Scale scores, also showed significant improvement (P = 0.002 and P = 0.004) with a moderate effect sizes and a significant interaction effect (P < 0.001, P = 0.013). No adverse events were reported. CONCLUSION: Regular Baduanjin training may be an effective and safe intervention to improve cognitive frailty and executive function in community-dwelling older adults with cognitive frailty. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100050857. Data of registration: 8/5/2020, https://www.chictr.org.cn/showproj.html?proj = 133037.
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Función Ejecutiva , Fragilidad , Humanos , Anciano , Terapia por Ejercicio , Ejercicio Físico , CogniciónRESUMEN
In recent years, semiconductor nanomaterials, as one of the most promising and applied classes of engineered nanomaterials, have been widely used in industries such as photovoltaics, electronic devices, and biomedicine. However, occupational exposure is unavoidable during the production, use, and disposal stages of products containing these materials, thus posing potential health risks to workers. The intricacies of the work environment present challenges in obtaining comprehensive data on such exposure. Consequently, there remains a significant gap in understanding the exposure risks and toxic effects associated with semiconductor nanomaterials. This paper provides an overview of the current classification and applications of typical semiconductor nanomaterials. It also delves into the existing state of occupational exposure, methodologies for exposure assessment, and prevailing occupational exposure limits. Furthermore, relevant epidemiological studies are examined. Subsequently, the review scrutinizes the toxicity of semiconductor nanomaterials concerning target organ toxicity, toxicity mechanisms, and influencing factors. The aim of this review is to lay the groundwork for enhancing the assessment of occupational exposure to semiconductor nanomaterials, optimizing occupational exposure limits, and promoting environmentally sustainable development practices in this domain.
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Extraction of coastline from optical remote sensing images is of paramount importance for coastal zone management, erosion monitoring, and intelligent ocean construction. However, nearshore marine environment complexity presents a challenge when capturing small-scale and detailed information regarding coastlines. Furthermore, the presence of numerous tidal flats, suspended sediments, and coastal biological communities exacerbates the reduction in segmentation accuracy, which is particularly noticeable in medium-high-resolution remote sensing image segmentation tasks. Most previous related studies, based primarily on convolutional neural networks (CNNs) or traditional feature extraction methods, faced challenges in detailed pixel-level refinement and lacked comprehensive understanding of the studied images. Therefore, we proposed a new U-shaped deep learning model (STIRUnet) that combines the excellent global modeling ability of SwinTransformer with an improved CNN using an inverted residual module. The proposed method has the capability of global supervised feature learning and layer-by-layer feature extraction, and we conducted sea-land segmentation experiments using GF-HNCD and BSD remote sensing image datasets to validate the performance of the proposed model. The results indicate the following: 1) suspended sediments and coastal biological communities are major contributors to coastline blurring, and 2) the recovery of minute features (e.g., narrow watercourses and microscale artificial structures) effectively enhances edge details and leads to more realistic segmentation outcomes. The findings of this study are highly important in relation of accurate extraction of sea-land information in complex marine environments, and they offer novel insights regarding mixed-pixel identification.
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Biota , Redes Neurales de la Computación , Telemetría , Procesamiento de Imagen Asistido por ComputadorRESUMEN
This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.
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Ferroptosis , Hemo-Oxigenasa 1 , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2 , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Xantófilas , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Ferroptosis/efectos de los fármacos , Xantófilas/farmacología , Xantófilas/química , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Línea Celular Tumoral , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , Receptores de Transferrina/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Superóxido Dismutasa/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Antígenos CDRESUMEN
Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical manifestations. The primary pathological features include a reduction in the number of dopaminergic neurons in the substantia nigra and decrease in dopamine levels in the nigrostriatal pathway. Existing treatments only alleviate clinical symptoms and do not stop disease progression; slowing down the loss of dopaminergic neurons and stimulating their regeneration are emerging therapies. Preclinical studies have demonstrated that transplantation of dopamine cells generated from human embryonic or induced pluripotent stem cells can restore the loss of dopamine. However, the application of cell transplantation is limited owing to ethical controversies and the restricted source of cells. Until recently, the reprogramming of astrocytes to replenish lost dopaminergic neurons has provided a promising alternative therapy for PD. In addition, repair of mitochondrial perturbations, clearance of damaged mitochondria in astrocytes, and control of astrocyte inflammation may be extensively neuroprotective and beneficial against chronic neuroinflammation in PD. Therefore, this review primarily focuses on the progress and remaining issues in astrocyte reprogramming using transcription factors (TFs) and miRNAs, as well as exploring possible new targets for treating PD by repairing astrocytic mitochondria and reducing astrocytic inflammation.
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Astrocitos , Enfermedad de Parkinson , Humanos , Astrocitos/metabolismo , Dopamina/metabolismo , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas/metabolismo , Inflamación/metabolismoRESUMEN
BACKGROUND: Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. METHODS: RNA-seq analysis was applied to five paired progressive disease (PD) and complete response (CR) NPC tissues. Loss-and gain-of-function assays were used for oncogenic function of FLI1 both in vitro and in vivo. RNA-seq analysis, ChIP assays and dual luciferase reporter assays were performed to explore the interaction between FLI1 and TIE1. Gene expression with clinical information from tissue microarray of NPC were analyzed for associations between FLI1/TIE1 expression and NPC prognosis. RESULTS: FLI1 is a potential radiosensitivity regulator which was dramatically overexpressed in the patients with PD to radiotherapy compared to those with CR. FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in vitro, and promoted radiotherapy resistance in vivo. Mechanistic investigations showed that FLI1 upregulated the transcription of TIE1 by binding to its promoter, thus activated the PI3K/AKT signaling pathway. A decrease in TIE1 expression restored radiosensitivity of NPC cells. Furthermore, NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. CONCLUSION: Our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC.
Asunto(s)
Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Proteína Proto-Oncogénica c-fli-1 , Tolerancia a Radiación , Receptor TIE-1 , Humanos , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Proteína Proto-Oncogénica c-fli-1/genética , Tolerancia a Radiación/genética , Receptor TIE-1/genéticaRESUMEN
Background: The aim of the present study was to investigate whether intra-aortic balloon pump (IABP) support was associated with better outcomes after rotational atherectomy (RA) in patients with multivessel disease and low left ventricular ejection fraction (LVEF). Methods: Between January 2015 and December 2021, 596 consecutive patients with severely calcified coronary lesions who underwent elective RA were retrospectively enrolled. Of these, a total of 156 patients were included in this study based on the propensity score matching and divided into two groups according to elective IABP insertion (IABP group, n = 80) or no insertion (non-IABP group, n = 76) before the RA procedure. The primary endpoints were procedural success and major adverse cardiovascular events (MACE) before discharge. The secondary endpoints were mortality and readmission due to heart failure (HF) during 90-day and 180-day follow-up. Results: 77 of patients (96.3%) in the IABP group and 72 of patients (94.7%) in the non-IABP group got procedural success (p = 0.714), separately. We had not observed significant differences in periprocedural complications except for less frequent hypotension in the IABP group (p < 0.001). In-hospital MACE occurred in 7.5% of patients who received IABP support, which was significantly lower compared to the non-IABP group (p = 0.002). In addition, the cumulative incidence of readmission due to HF was also significantly lower in the IABP group during the 90-day (p < 0.001) and 180-day (p = 0.004) follow-up. However, there were no significant differences between groups regarding the incidence of all-cause mortality. Conclusions: The present study suggests the important role of IABP support in improving the outcomes of patients after RA if multivessel disease and low LVEF are anticipated. Prophylactic IABP implantation was related to a lower incidence of in-hospital MACE, and readmission due to HF within 90-day and 180-day follow-up without significant impact on the procedural success and all-cause mortality.
RESUMEN
Background: Rotational atherectomy (RA) is an important technique for the management of severe coronary calcification. However, optimal rotational speed is yet to be defined. Methods: A total of 372 coronary heart disease (CHD) patients were retrospectively analyzed between February 2017 and January 2022. The patients were divided into four groups based on the maximum RA speed: group 1 ( < 150,000 rpm, 76 cases), group 2 (150,000 rpm, 156 cases), group 3 (160,000 rpm, 90 cases) and group 4 ( ≥ 170,000 rpm, 50 cases). The outcomes analyzed were procedural complications, six-months major cardiovascular and cerebrovascular events (MACCE) and chronic heart failure. Results: Patients in group 4 had a higher incidence of slow flow during the RA operation (p = 0.025). There was no significant difference in other complications among the four groups, as well as six-month MACCE. After adjusting for confounding factors, increase in rotational speed led to a higher probability of slow flow (p for non-linearity = 0.131; adjusted model) and MACCE (p for non-linearity = 0.183; adjusted model). Logistic regression analysis showed that rotational speed was a predictor of slow flow during RA operation (OR = 1.25, 95% CI: 1.05~1.49, p = 0.01). Moreover, the analysis demonstrated that individuals with lower rotational speed ( < 150,000 rpm) were at 230% higher risk of vasospasm compared with a higher rotational speed (160,000 rpm) (OR = 3.3, 95% CI: 1.08~10.09, p = 0.036). Conclusions: CHD patients treated with a rotational speed of ≥ 170,000 rpm had a higher risk of slow flow after RA. Rotational speed is an independent risk factor for slow flow in CHD patients. Moreover, a rotational speed of < 150,000 rpm was associated with a higher risk of vasospasm compared with rotational speed of 160,000 rpm. There was no significant difference in six-month outcomes in comparison to elective CHD patients with different rotational speeds, and the probability of MACCE was intensified with increase in rotational speed.