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To investigate the cell linkage between tooth dentin and bones, we studied TGF-ß roles during postnatal dentin development using TGF-ß receptor 2 (Tgfßr2) cKO models and cell lineage tracing approaches. Micro-CT showed that the early Tgfßr2 cKO exhibit short roots and thin root dentin (n = 4; p<0.01), a switch from multilayer pre-odontoblasts/odontoblasts to a single-layer of bone-like cells with a significant loss of ~85% of dentinal tubules (n = 4; p<0.01), and a matrix shift from dentin to bone. Mechanistic studies revealed a statistically significant decrease in odontogenic markers, and a sharp increase in bone markers. The late Tgfßr2 cKO teeth displayed losses of odontoblast polarity, a significant reduction in crown dentin volume, and the onset of massive bone-like structures in the crown pulp with high expression levels of bone markers and low levels of dentin markers. We thus concluded that bones and tooth dentin are in the same evolutionary linkage in which TGF-ß signaling defines the odontogenic fate of dental mesenchymal cells and odontoblasts. This finding also raises the possibility of switching the pulp odontogenic to the osteogenic feature of pulp cells via a local manipulation of gene programs in future treatment of tooth fractures.
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Dentina , Odontoblastos , Receptores de Factores de Crecimiento Transformadores beta , Transducción de Señal , Factor de Crecimiento Transformador beta , Dentina/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Odontoblastos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Ratones , Diente/metabolismo , Huesos/metabolismo , Microtomografía por Rayos X , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ratones NoqueadosRESUMEN
OBJECTIVES: This study aimed to investigate the temporal and spatial changes in the expression of periostin during periodontal inflammation in mice. METHODS: A periodontitis model was constructed using silk thread ligation. Mice were randomly divided into five groups including control group, 4-day ligation group, 7-day ligation group, 14-day ligation group, and self-healing group (thread removal for 14 days after 14-day ligation). Micro-CT and histological staining were performed to characterize the dynamic changes in the mouse periodontal tissue in each group. RNAscope and immunohistochemical staining were used to analyze the pattern of changes in periostin at various stages of periodontitis. The cell experiment was divided into three groups: control group, lipopolysaccharide (LPS) stimulation group (treated with LPS for 12 h), and LPS stimulation removal group (treated with LPS for 3 h followed by incubation with medium for 9 h). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of periostin, transforming growth factor-ß1 (TGF-ß1), and matrix metalloproteinase 2 (MMP2). RESULTS: Significant alveolar bone resorption was observed 7 days after ligation. With increasing duration of ligation, the damage to the mouse periodontal tissue was aggravated, which manifested as increased osteoclasts, widening of the periodontal membrane space, and decreased alveolar bone height. Some degree of periodontal tissue repair was observed in the self-healing group. Periostin expression decreased at 4 and 7 days compared with the control group and increased at 14 days compared with 4 and 7 days. A significant recovery was found in the self-healing group. The qRT-PCR results showed that the expression of periostin and TGF-ß1 in the LPS stimulation group decreased compared with that in the control group but significantly recovered in the LPS removal group. CONCLUSIONS: Periostin expression in the PDL of mice showed a downward and upward trend with inflammation progression. The significant recovery of periostin expression after removing inflammatory stimuli may be related to TGF-ß1, which is crucial to maintain the integrity of the PDL.
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Pérdida de Hueso Alveolar , Moléculas de Adhesión Celular , Modelos Animales de Enfermedad , Lipopolisacáridos , Periodontitis , Factor de Crecimiento Transformador beta1 , Animales , Moléculas de Adhesión Celular/metabolismo , Ratones , Periodontitis/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Pérdida de Hueso Alveolar/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Microtomografía por Rayos X , PeriostinaRESUMEN
BACKGROUND: Percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) has been reported to be safe and effective at midterm follow-up to treat drug-refractory hypertrophic obstructive cardiomyopathy in a single center. However, data from other centers are lacking. This retrospective cohort study aimed to investigate the efficacy and safety of PIMSRA from another independent center. METHODS AND RESULTS: PIMSRA was performed in 76 patients with hypertrophic obstructive cardiomyopathy in our center from April 2020 to June 2023. The primary outcome was the reduction of left ventricular outflow tract gradient after 6 months or more post-PIMSRA. Secondary outcomes were periprocedural major adverse clinical events. Sixty-one patients returned to the hospital for follow-up 6 to 30 (median, 14) months after the procedure. At the last follow-up of the 61 patients, the maximum septal thickness decreased from a median of 23.6 (interquartile range, 20.5-26.4) to 19.1 (interquartile range, 16.0-22.1) mm (P<0.001) and the left ventricular outflow tract peak gradient at rest decreased from a median of 70.0 (interquartile range, 29.1-107.5) to 20.0 (interquartile range, 10.8-48.8) mm Hg (P<0.001). The percentage of patients with symptoms of New York Heart Association functional class III/IV decreased from 51% to 0%. Of all 76 patients, there was no in-hospital or 30-day death, no right or left branch block, and no permanent pacemaker implantation. Six (8%) patients had pericardial effusion, with 1 experiencing cardiac tamponade and ventricular fibrillation, and 1 (1%) patient developed septal branch aneurysm that was treated with coil occlusion. CONCLUSIONS: PIMSRA allows for the reduction in the left ventricular outflow tract gradient and enhances symptomatic improvement, with a limited incidence of adverse events and complications among patients with hypertrophic obstructive cardiomyopathy.
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Cardiomiopatía Hipertrófica , Tabiques Cardíacos , Humanos , Cardiomiopatía Hipertrófica/cirugía , Cardiomiopatía Hipertrófica/fisiopatología , Cardiomiopatía Hipertrófica/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Tabiques Cardíacos/cirugía , Tabiques Cardíacos/diagnóstico por imagen , Anciano , Ablación por Catéter/métodos , Ablación por Catéter/efectos adversos , Factores de Tiempo , Ablación por Radiofrecuencia/métodos , Ablación por Radiofrecuencia/efectos adversos , Adulto , Función Ventricular Izquierda , Estudios de Seguimiento , EcocardiografíaRESUMEN
Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of ß-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.
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Apoptosis , Carbolinas , Nitrilos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/métodos , Humanos , Carbolinas/química , Carbolinas/farmacología , Nitrilos/química , Nitrilos/farmacología , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Autofagia/efectos de los fármacosRESUMEN
Identification of promising seed cells plays a pivotal role in achieving tissue regeneration. This study demonstrated that LepR-expressing cells (LepR+ cells) are required for maintaining periodontal homeostasis at the adult stage. We further investigated how LepR+ cells behave in periodontal healing using a ligature-induced periodontitis (PD) and a self-healing murine model with LepRCre/+; R26RtdTomato/+ mice. Lineage tracing experiments revealed that the largely suppressed osteogenic ability of LepR+ cells results from periodontal inflammation. Periodontal defects were partially recovered when the ligature was removed, in which the osteogenic differentiation of LepR+ cell lineage was promoted and contributed to the newly formed alveolar bone. A cell ablation model established with LepRCre/+; R26RtdTomato/+; R26RDTA/+ mice further proved that LepR+ cells are an important cell source of newly formed alveolar bone. Expressions of ß-catenin and LEF1 in LepR+ cells were upregulated when the inflammatory stimuli were removed, which are consistent with the functional changes observed during periodontal healing. Furthermore, the conditional upregulation of WNT signaling or the application of sclerostin neutralized antibody promoted the osteogenic function of LepR+ cells. In contrast, the specific knockdown of ß-catenin in LepR+ human periodontal ligament cells with small interfering RNA caused arrested osteogenic function. Our findings identified the LepR+ cell lineage as a critical cell population for endogenous periodontal healing post PD, which is regulated by the WNT signaling pathway, making it a promising seed cell population in periodontal tissue regeneration.
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Osteogénesis , Periodontitis , Adulto , Ratones , Humanos , Animales , beta Catenina/metabolismo , Ligamento Periodontal/metabolismo , Inflamación , Vía de Señalización Wnt/fisiología , Diferenciación Celular , Células CultivadasRESUMEN
Barrett's esophagus (BE) belongs to a pathological phenomenon occurring in the esophagus, this paper intended to unveil the underlying function of miR-378a-5p and its target TSPAN8 in BE progression. GEO analysis was conducted to determine differentially expressed genes in BE samples. Non-dysplastic metaplasia BE samples, high-grade dysplastic BE samples and controls were collected from subjects. CP-A and CP-B cells were exposed to bile acids (BA) to mimic gastroesophageal reflux in BE cells. RT-qPCR as well as western blot were applied for verifying expressions of miR-378a-5p, TSPAN8, CDX2 and SOX9. CCK-8, wound scratch together with Transwell assays were exploited for ascertaining cell proliferation, migration as well as invasion. The targeted relationship of miR-378a-5p and TSPAN8 could be verified by correlation analysis, dual-luciferase reporter experiment, and rescue experiments. Through analyzing GSE26886 dataset, we screened the most abundantly expressed gene TSPAN8 in BE samples. miR-378a-5p was reduced whereas TSPAN8 was elevated in CP-A as well as CP-B cells after triggering with BA. Knocking down TSPAN8 could counteract BA-triggered enhancement in BE cell proliferation, migration along with invasion. miR-378a-5p could suppress BE cell proliferation, and migration along with invasion via targeting TSPAN8. In BE, miR-378a-5p targeted TSPAN8 to inhibit BE cell proliferation, and migration along invasion. miR-378a-5p deletion or elevation of TSPAN8 may be key point in regulating CDX2 and SOX9 levels, thereby promoting BE formation.
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Esófago de Barrett , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Esófago de Barrett/genética , Proliferación Celular/genética , Hiperplasia , Movimiento Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMEN
Hypertrophic cardiomyopathy (HCM) is associated with adverse outcomes, such as heart failure, arrhythmia, and mortality. Sudden cardiac death (SCD) is a common cause of death in HCM patients, and identification of patients at a high risk of SCD is crucial in clinical practice. The China Hypertrophic Cardiomyopathy Project is a hospital-based, multicenter, prospective, registry cohort study of HCM patients, covering a total of 3000 participants and with a 5-year follow-up plan. A large number of demographic characteristics and clinical data will be fully collected to identify prognostic factors in Chinese HCM patients. Furthermore, the main purpose of this study is to integrate demographic and clinical characteristics to establish new 5-year SCD risk predictive equations for Chinese HCM patients by the use of machine learning technologies. The project has crucial clinical significance for risk stratification and determination of HCM patients with high risk of adverse outcomes. CLINICAL TRIALS REGISTRATION: ChiCTR2300070909.
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Cardiomiopatía Hipertrófica , Muerte Súbita Cardíaca , Sistema de Registros , Humanos , Cardiomiopatía Hipertrófica/mortalidad , Cardiomiopatía Hipertrófica/epidemiología , Cardiomiopatía Hipertrófica/terapia , Cardiomiopatía Hipertrófica/fisiopatología , Cardiomiopatía Hipertrófica/diagnóstico , Estudios Prospectivos , China/epidemiología , Medición de Riesgo , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/epidemiología , Factores de Riesgo , Pronóstico , Factores de Tiempo , Masculino , Femenino , Proyectos de Investigación , Persona de Mediana Edad , Adulto , Estudios Multicéntricos como Asunto , Aprendizaje Automático , Anciano , Adulto JovenRESUMEN
The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3'-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.
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Vesículas Extracelulares , MicroARNs , Femenino , Humanos , Animales , Ratones , Ácido Valproico/farmacología , Antagomirs , Hibridación Fluorescente in Situ , Vesículas Extracelulares/genética , MicroARNs/genéticaRESUMEN
High temperature is an important abiotic stressor that limits the survival and growth of aquatic organisms. American shad (Alosa sapidissima), a migratory fish suitable for culturing at low temperatures, is known for its delicious taste and thus has high economic value. Studies concerning changes in A. sapidissima under high temperature are limited, especially at the gene expression and protein levels. High-temperature stress significantly reduced the survival rates and increased vacuolar degeneration and inflammatory infiltration in the gills and liver. High temperature increased the activities of SOD, CAT, and cortisol, with a trend of initial increase followed by decreases in MDA, ALP, and LDH, and irregular changes in T-AOC and Na-K-ATPase. Comprehensive analysis of the transcriptome, proteome, and metabolome of gills from fish treated with different culture temperatures (24, 27, and 30 °C) revealed that differentially expressed genes, proteins, and metabolites were highly enriched in pathways involved in protein digestion and absorption, protein processing in endoplasmic reticulum, metabolic pathways, and purine metabolism. Gene expression and protein profiles indicated that genes coding for antioxidants (i.e., cat and alpl) and members of the heat shock protein (i.e., HSP70, HSP90AA1, and HSP5) were significantly upregulated. Additionally, a conjoint analysis revealed that several key enzymes, including nucleoside diphosphate kinase 2, adenosine deaminase, and ectonucleoside triphosphate diphosphohydrolase 5/6 were altered, thereby affecting the metabolism of guanosine, guanine, and inosine. An interaction network further confirmed that levels of the essential amino acids DL-arginine and L-histidine were significantly reduced, and corticosterone levels were significantly increased, suggesting that A. sapidissima may be more dependent on amino acids for energy in vivo. Overall, this work suggests that living in a high-temperature environment leads to differential defense responses in fishes. The results provide novel perspectives for studying the molecular basis of adaptation to climate change in A. sapidissima and for genetic selection.
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Peces , Multiómica , Animales , Temperatura , Peces/fisiología , ATPasa Intercambiadora de Sodio-PotasioRESUMEN
Tumor selective near-infrared (NIR) fluorescent contrast agents has the potential to greatly enhance the efficiency and precision of tumor surgery by enabling real-time tumor margin identification for tumor resection guided by imaging. However, the development of these agents is still challenging. In this study, based on the acidic tumor microenvironment (TME), we designed and synthesized a novel pH-sensitive NIR fluorescent contrast agent OBD from ß-carboline. The fluorescence quantum yield of OBD exhibited a notable increase at pH 3.6, approximately 12-fold higher compared to its value at pH 7.4. After cellular uptake, OBD lighted up the cancer cells with high specificity and accumulated in the mitochondria. Spraying OBD emitted selective fluorescence in xenograft tumor tissues with tumor-to-normal tissue ratios (TNR) as high as 11.18, implying successful image-guided surgery. Furthermore, OBD was also shown to track metastasis in spray mode. After simple topical spray, OBD rapidly and precisely visualized the tumor margins of clinical colon and liver tissues with TNR over 4.2. Therefore, the small-molecule fluorescent contrast agent OBD has promising clinical applications in tumor identification during surgery.
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Medios de Contraste , Neoplasias , Humanos , Microambiente Tumoral , Neoplasias/diagnóstico por imagen , Colorantes Fluorescentes/química , Fluorescencia , Imagen Óptica/métodosRESUMEN
Notopterol, an active component isolated from the traditional Chinese medicine Notopterygium incisum Ting ex H.T. Chang, exerts anti-inflammatory activity in rheumatoid arthritis. However, its roles in suppression of inflammatory insults and halting progression of tissue destruction in periodontitis remain elusive. In this study, we reveal that notopterol can inhibit osteoclastogenesis, thereby limiting alveolar bone loss in vivo. In vitro results demonstrated that notopterol administration inhibited synthesis of inflammatory mediators such as IL-1ß, IL-32, and IL-8 in LPS-stimulated human gingival fibroblasts. Mechanistically, notopterol inhibits activation of the NF-κB signaling pathway, which is considered a prototypical proinflammatory signaling pathway. RNA sequencing data revealed that notopterol activates the PI3K/protein kinase B (Akt)/NF-E2-related factor 2 (Nrf2) signaling pathway in LPS-stimulated human gingival fibroblasts, a phenomenon validated via Western blot assay. Additionally, notopterol treatment suppressed reactive oxygen species levels by upregulating the expression of antioxidant genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), catalase (CAT), and glutathione reductase (GSR), indicating that notopterol confers protection against oxidative stress. Notably, inhibition of Akt activity by the potent inhibitor, MK-2206, partially attenuated both anti-inflammatory and antioxidant effects of notopterol. Collectively, these results raise the possibility that notopterol relieves periodontal inflammation by suppressing and activating the NF-κB and PI3K/AKT/Nrf2 signaling pathways in periodontal tissue, respectively, suggesting its potential as an efficacious treatment therapy for periodontitis.
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FN-kappa B , Periodontitis , Humanos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Antioxidantes , Hemo-Oxigenasa 1/metabolismoRESUMEN
Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids ß-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.
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Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Oxígeno Singlete , Hipoxia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Carbolinas/farmacología , Carbolinas/uso terapéutico , Línea Celular TumoralRESUMEN
OBJECTIVE: The goal of this study was to evaluate the efficacy of machine learning (ML) techniques in predicting survival for chordoma patients in comparison with the standard Cox proportional hazards (CoxPH) model. METHODS: Using a Surveillance, Epidemiology, and End Results database of consecutive newly diagnosed chordoma cases between January 2000 and December 2018, we created and validated three ML survival models as well as a traditional CoxPH model in this population-based cohort study. Randomly, the dataset was divided into training and validation datasets. Tuning hyperparameters on the training dataset involved a 1000-iteration random search with fivefold cross-validation. Concordance index (C-index), Brier score, and integrated Brier score were used to evaluate the performance of the model. The receiver operating characteristic (ROC) curves, calibration curves, and area under the ROC curves (AUC) were used to assess the reliability of the models by predicting 5- and 10-year survival probabilities. RESULTS: A total of 724 chordoma patients were divided into training (n = 508) and validation (n = 216) cohorts. Cox regression identified nine significant prognostic factors (p < 0.05). ML models showed superior performance over CoxPH model, with DeepSurv having the highest C-index (0.795) and the best discrimination for 5- and 10-year survival (AUC 0.84 and 0.88). Calibration curves revealed strong correlation between DeepSurv predictions and actual survival. Risk stratification by DeepSurv model effectively discriminated high- and low-risk groups (p < 0.01). The optimized DeepSurv model was implemented into a web application for clinical use that can be found at https://hust-chengp-ml-chordoma-app-19rjyr.streamlitapp.com/ . CONCLUSION: ML algorithms based on time-to-event results are effective in chordoma prediction, with DeepSurv having the best discrimination performance and calibration.
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Cordoma , Aplicaciones Móviles , Humanos , Cordoma/diagnóstico , Estudios de Cohortes , Reproducibilidad de los Resultados , Aprendizaje AutomáticoRESUMEN
OBJECTIVE: This study investigated the effect of auditory working memory task on situation awareness (SA) and eye-movement patterns in complex dynamic environments. BACKGROUND: Many human errors in aviation are caused by a lack of SA, and distraction from auditory secondary tasks is a serious threat to SA. However, it remains unclear how auditory working memory tasks affect SA and eye-movement patterns. METHOD: Participants (n = 28) were randomly allocated to two groups and received different periods of visual search training (short versus long). They subsequently completed a situation awareness measurement task in three auditory secondary task conditions (without secondary task, auditory calculation task, and auditory 2-back task). Eye-movement data were collected during the situation awareness measurement task. RESULTS: The auditory 2-back task significantly reduced overall SA, Level 1 SA, dwell times, and total percentage of fixation time on task-related areas of interests in the SA measurement task. Overall SA and Level 3 SA were not reduced by the auditory 2-back task in individuals in the longer visual search training time condition. CONCLUSION: Auditory working memory load impairs SA in the perception and projection stage; however, greater experience can overcome impairment of SA in the projection stage. APPLICATION: This study provided possible approaches to preventing loss of SA: (1) improving crew members' communication skills to ensure the accurate and clear transmission of information, reducing the difficulty of processing information, and (2) providing targeted cognitive training tailored to each pilot's level of experience.
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Chemodynamic therapy (CDT) utilizing toxic hydroxyl radicals (·OH) to kill cancer cells exhibits huge potentiality in antitumor treatment. However, inadequate acidity, insufficient hydrogen peroxide (H2O2) amount, and overexpressed reduced glutathione (GSH) inside cancer cells severely restrict the efficacy of CDT. Although numerous efforts have been made, fabricating a versatile CDT material for surmounting these obstacles simultaneously is still a great challenge, especially for supramolecular materials owing to lacking an active metal unit for the Fenton reaction. Here, we intriguingly proposed a powerful supramolecular nanoagent (GOx@GANPs) based on the host-guest interaction between pillar[6]arene and ferrocene for all-sided boosting CDT efficacy via in situ cascade reactions. GOx@GANPs could stimulate intracellular glucose conversion into H+ and H2O2 to optimize the in situ Fenton reaction conditions and continuously produce sufficient â¢OH. Meanwhile, consumption of the original intracellular GSH pool and inhibition of GSH regeneration were synchronously achieved through the GSH-responsive gambogic acid prodrug and cutting off adenosine triphosphate (ATP) supply for GSH resynthesis, respectively. This complete GSH exhausting characteristic of GOx@GANPs effectively suppressed â¢OH elimination, ultimately resulting in a superior CDT effect. Furthermore, GOx@GANPs also produced synergistic effects of starvation therapy, chemotherapy, and CDT, exhibiting low toxicity toward normal tissues. Thus, this work introduces a valuable way for optimizing and elevating CDT efficiency and synergistic treatment of tumors.
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Peróxido de Hidrógeno , Neoplasias , Humanos , Peróxido de Hidrógeno/farmacología , Adenosina Trifosfato , Glucosa , Radical Hidroxilo , Neoplasias/tratamiento farmacológico , Línea Celular TumoralRESUMEN
AIM: Inducing odontogenic differentiation and tubular dentine formation is extremely important in dentine repair and tooth regeneration. Bone morphogenic proteins (BMPs) signalling plays a critical role in dentine development and tertiary dentine formation, whilst how BMPR1A-mediated signalling affects odontoblastic differentiation of Axin2-expressing (Axin2+ ) odontogenic cells and tubular dentine formation remains largely unknown. This study aims to reveal the cellular and molecular mechanisms involved in the formation of secondary dentine. METHODOLOGY: Axin2lacZ/+ mice harvested at post-natal 21 (P21) were used to map Axin2+ mesenchymal cells. Axin2CreERT2/+ ; R26RtdTomato/+ mice and Axin2CreERT2/+ ; R26RDTA/+ ; R26RtdTomato/+ mice were generated to observe the tempo-spatial distribution pattern of Axin2-lineage cells and the effect of ablation of Axin2+ cells on dentinogenesis, respectively. A loss-of-function model was established with Axin2CreERT2/+ ; Bmpr1afl/fl ; R26RtdTomato/+ (cKO) mice to study the role of BMP signalling in regulating Axin2+ cells. Micro-computed tomography, histologic and immunostainings, and other approaches were used to examine biological functions, including dentine formation, mineralization and cell differentiation in cKO mice. RESULTS: The results showed rich expression of Axin2 in odontoblasts at P21. Lineage tracing assay confirmed the wide distribution of Axin2 lineage cells in odontoblast layer and dental pulp during secondary dentine formation (P23 to P56), suggesting that Axin2+ cells are important cell source of primary odontoblasts. Ablation of Axin2+ cells (DTA mice) significantly impaired secondary dentine formation characterized with notably reduced dentine thickness (Mean of control: 54.11 µm, Mean of DTA: 27.79 µm, p = .0101). Furthermore, malformed osteo-dentine replaced the tubular secondary dentine in the absence of Bmpr1a with irregular cell morphology, abnormal cellular process formation and lack of cell-cell tight conjunction. Remarkably increased expression of osteogenic markers like Runx2 and DMP1 was detected, whilst DSP expression was observed in a dispersed manner, indicating an impaired odontogenic cell fate and failure in producing tubular dentine in cKO mice. CONCLUSIONS: Axin2+ cells are a critical population of primary odontoblasts which contribute to tubular secondary dentine formation, and BMP signalling pathway plays a vital role in maintaining the odontogenic fate of Axin2+ cells.
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Dentina Secundaria , Ratones , Animales , Microtomografía por Rayos X , Dentina Secundaria/metabolismo , Odontogénesis , Diferenciación Celular , Odontoblastos , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Pulpa Dental , Dentina/patología , Proteína Axina/metabolismo , Proteína Axina/farmacologíaRESUMEN
A fluorescent diagnostic probe for real-time intraoperative image-guided tumor resection can significantly improve the efficiency and quality of oncological therapy, but their development is challenging. Herein, a novel fluorescent diagnostic probe called HLTC based on ß-carboline was designed and synthesized. HLTC was found to show a â¼10-fold enhancement of fluorescence quantum field with pH from 7.4 to 4.0, indicating its imaging potential in acid environment which is a typical hallmark of the tumor microenvironment (TME). Following fluorescence microscopy imaging showed HLTC could emit specific signals in cancer cells and sections, by both one-photon excitation and two-photon excitation. Importantly, HLTC enabled the precise and rapid delineation of both transplanted tumor and clinical tumor tissues within several minutes of simple topical spray. The tumor-to-background ratio (TBR) was up to 10.2 ± 1.0 at clinical liver cancer tissues and 9.9 ± 0.3 at clinical colon cancer tissues, allowing precise tumor margin identification and the effective guidance of surgical tumor resection. Furthermore, CCK8 assay, pharmacokinetic evaluation, blood analysis and H&E staining were performed, which verified high biocompatibility and biosafety of HLTC at working concentration. These results reveal the exciting potential of this small-molecule fluorescent diagnostic probe for real-time fluorescence-based navigation during surgical tumor resection.
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Técnicas Biosensibles , Neoplasias Hepáticas , Humanos , Colorantes Fluorescentes/química , Microambiente TumoralRESUMEN
Increasing data reveals that gelatin that has been methacrylated is involved in a variety of physiologic processes that are important for therapeutic interventions. Gelatin methacryloyl (GelMA) hydrogel is a highly attractive hydrogels-based bioink because of its good biocompatibility, low cost, and photo-cross-linking structure that is useful for cell survivability and cell monitoring. Methacrylated gelatin (GelMA) has established itself as a typical hydrogel composition with extensive biomedical applications. Recent advances in GelMA have focused on integrating them with bioactive and functional nanomaterials, with the goal of improving GelMA's physical, chemical, and biological properties. GelMA's ability to modify characteristics due to the synthesis technique also makes it a good choice for soft and hard tissues. GelMA has been established to become an independent or supplementary technology for musculoskeletal problems. Here, we systematically review mechanism-of-action, therapeutic uses, and challenges and future direction of GelMA in musculoskeletal disorders. We give an overview of GelMA nanocomposite for different applications in musculoskeletal disorders, such as osteoarthritis, intervertebral disc degeneration, bone regeneration, tendon disorders and so on.
Asunto(s)
Degeneración del Disco Intervertebral , Nanocompuestos , Humanos , Gelatina/química , Hidrogeles/química , Ingeniería de Tejidos/métodosRESUMEN
Lipoxin A4 (LXA4) has been identified as the braking signal of inflammation, but the specific role of LXA4 in regulating the regenerative potential of periodontal ligament stem cells (PDLSCs) remains unclear. The aim of this study was to investigate whether and, if so, how LXA4 improves the osteogenic differentiation of PDLSCs in a lipopolysaccharide (LPS)-induced inflammatory environment. We detected the effects of LXA4 on the osteogenic differentiation of PDLSCs in vitro and explored the bone regenerative potential of LXA4-treated inflammatory PDLSCs in vivo using a calvarial critical sized defect model in male rats. RNA sequencing, real-time PCR and western blot were performed to elucidate the relevant potential mechanisms. Results showed that LXA4 promoted the proliferation, migration and osteogenic differentiation of PDLSCs in vitro, and effectively improved the impaired osteogenic capacity of PDLSCs induced by LPS both in vitro and in vivo. Mechanistically, LXA4 significantly promoted the PI3K/AKT phosphorylation under inflammatory conditions. Additionally, LY294002 (a PI3K inhibitor) blocked the effect of LXA4, suggesting that the PI3K/AKT pathway is a key signaling pathway that mediates the effect of LXA4 on the osteogenesis of inflammatory PDLSCs. These findings indicate LXA4 may be a promising strategy for periodontal regeneration using inflammatory PDLSCs.