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1.
J Environ Sci (China) ; 147: 332-341, 2025 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-39003051

RESUMEN

Growing evidences showed that heavy metals exposure may be associated with metabolic diseases. Nevertheless, the mechanism underlying arsenic (As) exposure and metabolic syndrome (MetS) risk has not been fully elucidated. So we aimed to prospectively investigate the role of serum uric acid (SUA) on the association between blood As exposure and incident MetS. A sample of 1045 older participants in a community in China was analyzed. We determined As at baseline and SUA concentration at follow-up in the Yiwu Elderly Cohort. MetS events were defined according to the criteria of the International Diabetes Federation (IDF). Generalized linear model with log-binominal regression model was applied to estimate the association of As with incident MetS. To investigate the role of SUA in the association between As and MetS, a mediation analysis was conducted. In the fully adjusted log-binominal model, per interquartile range increment of As, the risk of MetS increased 1.25-fold. Compared with the lowest quartile of As, the adjusted relative risk (RR) of MetS in the highest quartile was 1.42 (95% confidence interval, CI: 1.03, 2.00). Additionally, blood As was positively associated with SUA, while SUA had significant association with MetS risk. Further mediation analysis demonstrated that the association of As and MetS risk was mediated by SUA, with the proportion of 15.7%. Our study found higher As was remarkably associated with the elevated risk of MetS in the Chinese older adults population. Mediation analysis indicated that SUA might be a mediator in the association between As exposure and MetS.


Asunto(s)
Arsénico , Exposición a Riesgos Ambientales , Síndrome Metabólico , Ácido Úrico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arsénico/sangre , Arsénico/toxicidad , China/epidemiología , Pueblos del Este de Asia , Exposición a Riesgos Ambientales/efectos adversos , Síndrome Metabólico/epidemiología , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/sangre , Ácido Úrico/sangre
2.
Acad Radiol ; 2024 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-39245597

RESUMEN

RATIONALE AND OBJECTIVE: To compare the performance of large language model (LLM) based Gemini and Generative Pre-trained Transformers (GPTs) in data mining and generating structured reports based on free-text PET/CT reports for breast cancer after user-defined tasks. MATERIALS AND METHODS: Breast cancer patients (mean age, 50 years ± 11 [SD]; all female) who underwent consecutive 18F-FDG PET/CT for follow-up between July 2005 and October 2023 were retrospectively included in the study. A total of twenty reports from 10 patients were used to train user-defined text prompts for Gemini and GPTs, by which structured PET/CT reports were generated. The natural language processing (NLP) generated structured reports and the structured reports annotated by nuclear medicine physicians were compared in terms of data extraction accuracy and capacity of progress decision-making. Statistical methods, including chi-square test, McNemar test and paired samples t-test, were employed in the study. RESULTS: The structured PET/CT reports for 131 patients were generated by using the two NLP techniques, including Gemini and GPTs. In general, GPTs exhibited superiority over Gemini in data mining in terms of primary lesion size (89.6% vs. 53.8%, p < 0.001) and metastatic lesions (96.3% vs 89.6%, p < 0.001). Moreover, GPTs outperformed Gemini in making decision for progress (p < 0.001) and semantic similarity (F1 score 0.930 vs 0.907, p < 0.001) for reports. CONCLUSION: GPTs outperformed Gemini in generating structured reports based on free-text PET/CT reports, which is potentially applied in clinical practice. DATA AVAILABILITY: The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

3.
Discov Oncol ; 15(1): 433, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39264524

RESUMEN

The occurrence and progression of tumors are linked to the process of pyroptosis. However, the precise involvement of pyroptosis-associated genes (PRGs) in endometrial cancer (EC) remains uncertain. 29 PRGs were identified as being either up-regulated or down-regulated in EC. PRGs subgroup analysis demonstrated distinct survival outcomes and diverse responses to chemotherapy and immune checkpoint blockade therapy. A higher expression of GPX4 and NOD2, coupled with lower levels of CASP6, PRKACA, and NLRP2, were found to be significantly associated with higher overall survival (OS) rates (p < 0.05). Conversely, lower expression of NOD2 was linked to lower progression-free survival (p = 0.021) and advanced tumor stage(p = 0.0024). NOD2, NLRP2, and TNM stages were identified as independent prognostic factors (p < 0.001). The LASSO prognostic model exhibited a notable decrease in OS among EC patients in the high-risk score group (ROC-AUC10-years: 0.799, p = 0.00644). Furthermore, NOD2 displayed a positive correlation with the infiltration of immune cells and the expression of immune checkpoints (p < 0.001). GPX4 and CASP6 are significantly associated with TMB and MSI (RTMB = 0.39; RMSI = 0.23). Additionally, a substantial upregulation of NOD2 was confirmed in both EC cells and tissue, indicating a positive relationship between advanced TNM stage (p < 0.0001) and infiltration of M1 phenotype macrophages. Nonetheless, its impact on patient OS did not reach statistical significance (p = 0.141). Our findings have contributed to the advancement of a prognostic model for EC patients. NOD2 receptor-mediated pyroptosis mechanism potentially regulates tumor immunity and promotes the transformation of macrophages from the M2 phenotype to the M1 phenotype, which significantly impacts the progression of EC.

4.
J Pharm Pharmacol ; 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39258498

RESUMEN

OBJECTIVES: Hypoxia conditions promote the adaptation and progression of non-small-cell lung cancer (NSCLC) via hypoxia-inducible factors (HIF). HIF-1α may regulate estrogen receptor ß (ERß) and promote the progression of NSCLC. The phytochemical homoharringtonine (HHT) exerts strong inhibitory potency on NSCLC, with molecular mechanism under hypoxia being elusive. METHODS: The effects of HHT on NSCLC growth were determined by cell viability assay, colony formation, flow cytometry, and H460 xenograft models. Western blotting, molecular docking program, site-directed mutagenesis assay, immunohistochemical assay, and immunofluorescence assay were performed to explore the underlying mechanisms of HHT-induced growth inhibition in NSCLC. KEY FINDINGS: HIF-1α/ERß signaling-related E2F1 is highly expressed and contributes to unfavorable survival and tumor growth. The findings in hypoxic cells, HIF-1α overexpressing cells, as well as ERß- or E2F1-overexpressed and knockdown cells suggest that the HIF-1α/ERß/E2F1 feedforward loop promotes NSCLC cell growth. HHT suppresses HIF-1α/ERß/E2F1 signaling via the ubiquitin-proteasome pathway, which is dependent on the inhibition of the protein expression of HIF-1α and ERß. Molecular docking and site-directed mutagenesis revealed that HHT binds to the GLU305 site of ERß. HHT inhibits cell proliferation and colony formation and promotes apoptosis in both NSCLC cells and xenograft models. CONCLUSION: The formation of the HIF-1α/ERß/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC.

5.
SAGE Open Med ; 12: 20503121241276683, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39257516

RESUMEN

Introduction: The treatment of COVID-19 patients, especially high-risk patients, remains a large challenge. Glucocorticoids have been accepted as effective medicines for severe COVID-19. However, the glucocorticoid usage guidelines do not cover all the indications for high-risk patients. Objective: To identify more effective treatments for high-risk patients with COVID-19, this retrospective study analyzed routine epidemiological, clinical, and laboratory data from 33 high-risk patients with COVID-19 in Beijing Gobroad Boren Hospital, Beijing, China, most of whom responded well to treatment. Methods: Severe acute respiratory syndrome coronavirus-2 infection was confirmed via real-time reverse transcriptase polymerase chain reaction assays. Outcome measures such as duration of mechanical ventilation, intensive care unit length of stay, and 28-day mortality were analyzed. Patients were divided into two groups: mild to moderate COVID-19 (n = 26) and severe COVID-19 (n = 7). Chest computed tomography images were used to guide methylprednisolone administration or withdrawal. Results: Upon intensive care unit admission, 12.1% of patients were mechanically ventilated with an average partial pressure of oxygen/fraction of inspired oxygen(PaO2/FiO2) ratio of 279 ± 146. No coinfections with other endemic viruses were observed. The duration of mechanical ventilation was 16 days (interquartile range: 8-28); the intensive care unit length of stay was 11 (interquartile range: 2-33) days; and the 28-day total mortality was 3.0%. Conclusion: Multivariate regression analysis revealed that low-dose, timely methylprednisolone administration was associated with a lower severe COVID-19 rate and mortality in high-risk patients. For high-risk patients, once there are ground-glass opacities (GGO) in the computed tomography image, continuous and low-dose methylprednisolone administration promotes inflammation remission and protects them from severe COVID-19 or mortality.

6.
PLoS One ; 19(9): e0310310, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39255300

RESUMEN

To improve the informatization and intelligence level of high-speed railway (HSR) bridge construction, a parametric modeling method for continuous beam bridges based on Building Information Modeling (BIM) is proposed in this study. By this method, the parametric families of continuous beam components and key construction machinery are established, and the rapid modeling of overall continuous beam bridge and the simulation of critical construction process are realized as well. Taking the Caoxian-Shangqiu bridge of Xiong'an-Shangqiu HSR as a case study, the parametric modeling method is applied to conduct the engineering application on the prestressed duct layout and rebar clash detection. The results indicate that the modeling efficiencies of HSR continuous beam bridge and construction machinery are significantly increased by the established parametric modeling method. Based on the BIM model of continuous beam bridge, the improvement in the precision of prestressed duct layout and the elimination of rebar clash points can be achieved. The research achievement can guide the visualization of construction disclosure, enhance construction efficiency, and provide reference and technical support for the construction management and control of HSR continuous beam bridges.


Asunto(s)
Modelos Teóricos , Vías Férreas , Ingeniería/métodos
7.
Asia Pac Allergy ; 14(3): 97-102, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39220569

RESUMEN

Background: The importance of IL-37 and downstream signal in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) demanding further investigation. Objective: We sought to address the potential importance of the IL-37-IL-1R8 axis in regulating inflammatory response in patients with CRSwNP. Methods: Nasal polyp (NP) tissues and control sinonasal tissues were obtained from adult CRSwNP, chronic rhinosinusitis without nasal polyps patients and healthy control subjects. The mRNA and protein levels of IL-37 and IL-1R8 in nasal tissues were examined by using quantitative PCR, immunohistochemical staining, and immunoblotting. In addition, the regulation of IL-1R8 expression was evaluated in human nasal epithelial cells (HNECs) in the presence of different stimuli. Results: The mRNA and protein levels of IL-37 and IL-1R8 were significantly elevated in nasal polyps compared with that in control tissues. IL-37 and IL-1R8 were mainly distributed in the epithelial layer and lamina propria of tissues. IL-1R8 mRNA level in nasal polys was negatively associated with eosinophil and neutrophil infiltration, as well as endoscopic score and computed tomography score. Moreover, the mRNA expression of IL-1R8 in HNECs was significantly increased by toll-like receptor agonists, but significantly inhibited by proinflammatory cytokines, which can be rescued by using steroid (DEX). Conclusion: Our findings showed that enhanced IL-37-IL-1R8 axis in NP tissues was negatively associated with inflammatory and clinical severity of CRSwNP patients, which could be considered as a future therapeutic target in CRSwNP patients.

8.
ACS Nano ; 18(36): 24984-24996, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39189387

RESUMEN

Lightweight materials with high strength and long cyclic lifespan are greatly demanded in practical applications, yet these properties are usually mutually exclusive. Here, we present a strong, lightweight, highly deformation-tolerant, and fatigue-resistant carbon nanotube (CNT) composite enabled by an amorphous/crystalline heterophase carbon shell. In particular, we obtain nanocrystallites with CNT-induced crystalline orientation uniformly embedded within an amorphous matrix by controlled thermal annealing. The heterophase carbon shell effectively alleviates the stress concentration and inhibits crack propagation, which renders our composite superior mechanical properties and high fatigue resistance (106 compression cycles at 20% strain with high stress of 144 kPa, or 5 × 105 cycles at 50% strain with stress up to 260 kPa). This study provides a deep understanding of amorphous-crystalline phase transition and insight into utilizing phase engineering to design and develop other high-performance functional materials such as structural materials and catalysis.

9.
Sci Rep ; 14(1): 20265, 2024 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-39217256

RESUMEN

To investigate the relationship between preoperative blood glucose levels and long-term all-cause mortality in patients with osteoporotic vertebral compression fractures (OVCF) who underwent percutaneous vertebroplasty (VP). This single-center retrospective study involved a chart review of patients admitted for VP to treat OVCF between 2013 and 2020. Patients with pathological or multiple fractures or those who did not undergo bone mineral density assessment were excluded. All relevant information was collected from electronic medical records. The survival status of all patients was confirmed at the end of March 2021. Cox proportional hazard models with multivariate adjustments were used to examine the effects of blood glucose levels on all-cause mortality. Overall, 131 patients were retrospectively analyzed (mean age: 75.8 ± 9.3 years, male patients: 26.7%) with a median follow-up period of 2.1 years. Preoperative hyperglycemia (hazard ratio: 2.668, 95% confidence interval [CI] 1.064, 6.689; p = 0.036) and glucose levels (hazard ratio: 1.007, 95% CI 1.002-1.012; p = 0.006) were found to be independently associated with a higher risk of all-cause mortality. This correlation remained significant even after adjusting for age and sex, and other factors and comorbidities that might affect outcomes (hazard ratio: 2.708, 95% CI 1.047, 7.003, p = 0.040 and 1.007; 95% CI 1.001, 1.013, p = 0.016, respectively). Furthermore, a history of diabetes mellitus was not a significant factor influencing long-term all-cause mortality. Preoperative glucose levels were found to be independently associated with survival outcomes in patients with OVCF who underwent VP. Conversely, diabetes mellitus was not associated with long-term all-cause mortality. Our findings highlight that preoperative hyperglycemia is a risk factor for long-term mortality in this aging surgical population.


Asunto(s)
Glucemia , Fracturas por Compresión , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Vertebroplastia , Humanos , Masculino , Anciano , Femenino , Fracturas por Compresión/cirugía , Fracturas por Compresión/mortalidad , Fracturas Osteoporóticas/cirugía , Fracturas Osteoporóticas/mortalidad , Fracturas de la Columna Vertebral/mortalidad , Fracturas de la Columna Vertebral/cirugía , Fracturas de la Columna Vertebral/etiología , Glucemia/análisis , Glucemia/metabolismo , Estudios Retrospectivos , Anciano de 80 o más Años , Periodo Preoperatorio , Factores de Riesgo , Modelos de Riesgos Proporcionales , Hiperglucemia/mortalidad , Hiperglucemia/complicaciones , Hiperglucemia/etiología
10.
Int J Biol Macromol ; 277(Pt 3): 134431, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39147629

RESUMEN

Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (-35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients.


Asunto(s)
Apoptosis , Neoplasias de la Mama , Quitosano , Heparina , Ácido Oleanólico , Quitosano/química , Quitosano/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Femenino , Ratones , Apoptosis/efectos de los fármacos , Heparina/química , Heparina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Portadores de Fármacos/química , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Adv Sci (Weinh) ; : e2404913, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39119888

RESUMEN

Actuators based on shape memory polymers and composites incorporating nanomaterial additives have been extensively studied; achieving both high output stress and precise shape change by low-cost, scalable methods is a long-term-desired yet challenging task. Here, conventional polymers (polyurea) and carbon nanotube (CNT) fillers are combined to fabricate reinforced composite fibers with exceptional actuation performance, by a wet-spinning method amenable for continuous production. It is found that a thermal-induced shrinkage step could obtain densified strong fibers, and the presence of CNTs effectively promotes the tensile orientation of polymer molecular chains, leading to much improved mechanical properties. Consequently, the CNT/ polyurea composite fibers exhibit stresses as high as 33 MPa within 0.36 s during thermal actuation, and stresses up to 22 MPa upon electrical stimulation enabled by the built-in conductive CNT networks. Utilizing the flexible thin fibers, various shape change behavior are also demonstrated including the conversion between different structures/curvatures, and recovery of predefined simple patterns. This high-performance composite fibers, capable of both thermal and electrical actuation and produced by low-cost materials and fabrication process, may find many potential applications in wearable devices, robotics, and biomedical areas.

12.
Cell Res ; 34(9): 648-660, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39103523

RESUMEN

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.


Asunto(s)
Carcinoma Hepatocelular , N-Metiltransferasa de Histona-Lisina , Neoplasias Hepáticas , Lisina , Metiltransferasas , Proteínas Ribosómicas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Lisina/metabolismo , Metilación , Ratones Desnudos , Biosíntesis de Proteínas , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo
13.
J Hazard Mater ; 478: 135548, 2024 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-39154483

RESUMEN

Thimerosal (THI) has become a significant source of organic mercury pollutants in aquatic ecosystems, but there is limited information regarding its adverse effects on fish. In this study, zebrafish embryos were exposed to THI at 0 (control), 5.0, and 50 ng/L from 0-5 days post fertilization (dpf), and variations in their survival, development, behavior, free amino acid contents, and the biochemical responses involved in monoaminergic systems were examined. Although THI exposure did not significantly affect the survival, heart rate, or hatching time of zebrafish embryos, it substantially increased swimming velocity (136-154 % of the control) and reduced exploratory behavior (141-142 % of the control) in zebrafish larvae at 5 dpf. Exposure also significantly altered the amino acid contents (51-209 % of the control) and monoamine levels (70-154 % of the control) in zebrafish larvae, some of which displayed significant correlations with behavioral traits. THI significantly elevated dopamine receptor gene expression and monoamine oxidase activity in zebrafish larvae. Adding extra phenylalanine or tryptophan to the E3 medium facilitates the recovery of zebrafish larvae from the abnormal behaviors induced by THI. These findings reveal for the first time that THI exposure at the level of ng/L is sufficient to induce neurobehavioral toxic effects in the early life stages of zebrafish, and disrupting amino acid homeostasis is a critical underlying mechanism. This study provides valuable insights into the toxicity of THI to fish and highlights the importance of assessing its potential risks to aquatic ecosystems.


Asunto(s)
Aminoácidos , Conducta Animal , Homeostasis , Timerosal , Contaminantes Químicos del Agua , Pez Cebra , Animales , Aminoácidos/metabolismo , Homeostasis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Timerosal/toxicidad , Contaminantes Químicos del Agua/toxicidad , Embrión no Mamífero/efectos de los fármacos , Larva/efectos de los fármacos , Larva/metabolismo , Monoaminooxidasa/metabolismo , Monoaminooxidasa/genética , Monoaminooxidasa/efectos de los fármacos
14.
Commun Biol ; 7(1): 1006, 2024 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-39152200

RESUMEN

Antibiotic-induced dysbiosis in the fish gut causes significant adverse effects. We use fecal microbiota transplantation (FMT) to accelerate the restoration of florfenicol-perturbed intestinal microbiota in koi carp, identifying key bacterial populations and metabolites involved in the recovery process through microbiome and metabolome analyses. We demonstrate that florfenicol disrupts intestinal microbiota, reducing beneficial genera such as Lactobacillus, Bifidobacterium, Bacteroides, Romboutsia, and Faecalibacterium, and causing mucosal injuries. Key metabolites, including aromatic amino acids and glutathione-related compounds, are diminished. We show that FMT effectively restores microbial populations, repairs intestinal damage, and normalizes critical metabolites, while natural recovery is less effective. Spearman correlation analyses reveal strong associations between the identified bacterial genera and the levels of aromatic amino acids and glutathione-related metabolites. This study underscores the potential of FMT to counteract antibiotic-induced dysbiosis and maintain fish intestinal health. The restored microbiota and normalized metabolites provide a basis for developing personalized probiotic therapies for fish.


Asunto(s)
Antibacterianos , Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Tianfenicol , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Tianfenicol/análogos & derivados , Tianfenicol/farmacología , Disbiosis/terapia , Disbiosis/microbiología , Antibacterianos/farmacología , Antibacterianos/efectos adversos , Carpas/microbiología , Bacterias/metabolismo , Bacterias/efectos de los fármacos
15.
Int Immunopharmacol ; 141: 113006, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-39213865

RESUMEN

Pyroptosis, a newly identified form of programmed cell death intertwined with inflammatory responses, is facilitated by the Gasdermin family's pore-forming activity, leading to cell lysis and the release of pro-inflammatory cytokines. This process is a double-edged sword in innate immunity, offering protection against pathogens while risking excessive inflammation and tissue damage when dysregulated. Specifically, pyroptosis operates through two distinct signaling pathways, namely the Caspase-1 pathway and the Caspase-4/5/11 pathway. In the context of chronic liver diseases like fibrosis and cirrhosis, inflammation emerges as a central contributing factor to their pathogenesis. The identification of inflammation is characterized by the activation of innate immune cells and the secretion of pro-inflammatory cytokines such as IL-1α, IL-1ß, and TNF-α. This review explores the interrelationship between pyroptosis and the inflammasome, a protein complex located in liver cells that recognizes danger signals and initiates Caspase-1 activation, resulting in the secretion of IL-1ß and IL-18. The article delves into the influence of the inflammasome and pyroptosis on various liver disorders, with a specific focus on their molecular and pathophysiological mechanisms. Additionally, the potential therapeutic implications of targeting pyroptosis for liver diseases are highlighted for future consideration.


Asunto(s)
Inflamasomas , Hepatopatías , Piroptosis , Humanos , Animales , Hepatopatías/inmunología , Hepatopatías/metabolismo , Inflamasomas/metabolismo , Inflamasomas/inmunología , Enfermedad Crónica , Inflamación/inmunología , Inflamación/metabolismo , Inmunidad Innata , Transducción de Señal , Hígado/inmunología , Hígado/patología , Hígado/metabolismo
16.
Aquat Toxicol ; 275: 107063, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39191072

RESUMEN

Diazepam (DZP) is a universally detected emerging pollutant in aquatic ecosystems. Although the sex-dependent effects of DZP on fish have been properly established, the underlying mechanisms remain unclear. In this study, zebrafish of both sexes were separately exposed to DZP (8 µg/L) for 21 days, and the alteration of the behaviors, brain amino acid neurotransmitter contents, and transcriptomic profiles were investigated. Although DZP exposure showed a sedative effect on both sexes, significantly reduced cumulative duration of high mobility and willingness to encounter the opposite sex were only observed in females. However, DZP significantly enhanced the brain levels of glutamate and glutamine in males but not in females. Transcriptome analysis identified more different expression genes (DEGs) in females (322 up-regulated and 311 down-regulated) than in males (138 up-regulated genes and 38 down-regulated). The DEGs in both sexes were significantly enriched in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway of the synaptic vesicle cycle, indicating a possible pathway for the sedative effects of DZP on zebrafish. DZP exhibited different or even opposing regulatory patterns on gene expression in the brains of females and males, providing some insights into its sex-dependent impacts on the behaviors and brain neurotransmitter contents in zebrafish. Moreover, enrichment analysis also suggested that DZP exposure may affect the oocyte maturation in female zebrafish, which highlights the need to study its reproductive and transgenerational toxicity to fish species.


Asunto(s)
Diazepam , Transcriptoma , Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/genética , Femenino , Masculino , Diazepam/toxicidad , Contaminantes Químicos del Agua/toxicidad , Transcriptoma/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Conducta Animal/efectos de los fármacos , Factores Sexuales , Regulación de la Expresión Génica/efectos de los fármacos
17.
Eur J Med Chem ; 277: 116710, 2024 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-39098133

RESUMEN

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Descubrimiento de Drogas , Indazoles , Enfermedades Inflamatorias del Intestino , Inhibidores de Fosfodiesterasa 4 , Animales , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Relación Estructura-Actividad , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Ratones , Indazoles/farmacología , Indazoles/química , Indazoles/síntesis química , Humanos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Estructura Molecular , Relación Dosis-Respuesta a Droga , Masculino , Ratones Endogámicos C57BL
18.
Front Oncol ; 14: 1425837, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39132503

RESUMEN

Purpose: This study aimed to establish and evaluate the value of integrated models involving 18F-FDG PET/CT-based radiomics and clinicopathological information in the prediction of pathological complete response (pCR) to neoadjuvant therapy (NAT) for non-small cell lung cancer (NSCLC). Methods: A total of 106 eligible NSCLC patients were included in the study. After volume of interest (VOI) segmentation, 2,016 PET-based and 2,016 CT-based radiomic features were extracted. To select an optimal machine learning model, a total of 25 models were constructed based on five sets of machine learning classifiers combined with five sets of predictive feature resources, including PET-based alone radiomics, CT-based alone radiomics, PET/CT-based radiomics, clinicopathological features, and PET/CT-based radiomics integrated with clinicopathological features. Area under the curves (AUCs) of receiver operator characteristic (ROC) curves were used as the main outcome to assess the model performance. Results: The hybrid PET/CT-derived radiomic model outperformed PET-alone and CT-alone radiomic models in the prediction of pCR to NAT. Moreover, addition of clinicopathological information further enhanced the predictive performance of PET/CT-derived radiomic model. Ultimately, the support vector machine (SVM)-based PET/CT radiomics combined clinicopathological information presented an optimal predictive efficacy with an AUC of 0.925 (95% CI 0.869-0.981) in the training cohort and an AUC of 0.863 (95% CI 0.740-0.985) in the test cohort. The developed nomogram involving radiomics and pathological type was suggested as a convenient tool to enable clinical application. Conclusions: The 18F-FDG PET/CT-based SVM radiomics integrated with clinicopathological information was an optimal model to non-invasively predict pCR to NAC for NSCLC.

19.
Medicine (Baltimore) ; 103(35): e39284, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39213215

RESUMEN

RATIONALE: Biliary system anomalies, such as duplicated gallbladders, are rare congenital conditions that present significant diagnostic challenges. Dr. Boyden's classification system, especially the H-type anomaly, offers vital insight into these variations. Failure to detect these anomalies preoperatively can increase the risk of surgical complications, making early identification crucial for surgical planning. PATIENT CONCERN: A 42-year-old male, asymptomatic, was incidentally found to have a gallbladder mass during routine imaging. An upper abdominal magnetic resonance imaging showed gallbladder wall thickening, gallstones, and a liver lesion. Despite the absence of symptoms, a laparoscopic cholecystectomy revealed an atrophied gallbladder with a cystic duct cyst, which was identified as an H-type double gallbladder anomaly. The surgery was completed without complications, and pathology confirmed the presence of gallstones and inflammation. DIAGNOSES: The patient was diagnosed with a duplicated gallbladder, classified as an H-type anomaly, following laparoscopic cholecystectomy. Preoperative imaging identified gallbladder wall thickening and gallstones, and further investigation during surgery confirmed the congenital anomaly. INTERVENTIONS: The patient underwent laparoscopic cholecystectomy for the removal of the gallbladder, and during the procedure, an H-type double gallbladder anomaly was discovered. The surgery proceeded without incident, ensuring the complete excision of the gallbladders. OUTCOMES: The case highlights the diagnostic difficulty of identifying duplicated gallbladders and the importance of advanced imaging techniques in detecting atypical anatomical variations. The successful laparoscopic removal of both gallbladders illustrates the current capabilities of minimally invasive surgery. Postoperative recovery was uneventful, and the pathology confirmed gallstones and inflammation. LESSONS: This case emphasizes the importance of recognizing biliary anomalies such as duplicated gallbladders to avoid complications during surgery. Preoperative identification, aided by imaging, and careful surgical planning are key to managing these rare conditions. The case contributes to the growing body of knowledge about biliary system anomalies and reinforces the need for comprehensive management strategies to ensure optimal patient outcomes.


Asunto(s)
Colecistectomía Laparoscópica , Vesícula Biliar , Humanos , Masculino , Vesícula Biliar/anomalías , Vesícula Biliar/cirugía , Vesícula Biliar/diagnóstico por imagen , Adulto , Colecistectomía Laparoscópica/métodos , Imagen por Resonancia Magnética , Hallazgos Incidentales
20.
Clin Chim Acta ; : 119951, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39216815

RESUMEN

OBJECTIVES: The COVID-19 pandemic poses ongoing challenges to global public health systems, emphasizing the critical necessity for efficient diagnostic and prognostic markers. This study evaluates the MAGLUMI® SARS-CoV-2 Ag N protein chemiluminescent immunoassay (MAG-CLIA) for its analytical performance and its role in predicting disease severity and prognosis among severe COVID-19 patients with comorbidities. METHODS: Analytical validation of plasma MAG-CLIA SARS-CoV-2 Ag N protein encompassed precision, interference, LoQ and linearity. Plasma N protein concentrations and other biomarkers were measured within 48 h of admission, tracked until discharge or death. The Mann-Whitney U test explored the association between plasma N protein and COVID-19 severity or prognosis. Longitudinal monitoring of plasma N protein dynamics was conducted in representative patients. RESULTS: MAG-CLIA demonstrated precise quantification of plasma N protein with a CV below 10 % and minimal interference. The LoQ was 0.88 ng/L, with a broad linear range. Plasma N protein showed high diagnostic accuracy for COVID-19, achieving 95.42 % specificity and 78.32 % sensitivity at 2.388 ng/L. Plasma N protein emerged as a valuable prognostic indicator, correlating with mechanical ventilation need and patient survival. Plasma N protein concentrations ≥ 424.3 ng/L (AUC 0.8102, sensitivity 78.38 %, specificity 85.48 %) were associated with poor prognosis in severe COVID-19 patients with comorbidities. CONCLUSIONS: MAG-CLIA's SARS-CoV-2 N protein detection in plasma demonstrates both analytical reliability and clinical relevance in our inaugural evaluation. As a promising prognostic biomarker for severe COVID-19 patients, it offers crucial insights into disease severity and progression, emphasizing the significance of early monitoring and intervention, especially for patients with comorbidities.

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