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Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.

Asunto(s)

Biología Computacional , Ferroptosis , Insuficiencia Cardíaca , Saponinas , Triterpenos , Animales , Ferroptosis/efectos de los fármacos , Triterpenos/farmacología , Saponinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Ratas , Biología Computacional/métodos , Masculino , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Simulación de Dinámica Molecular , Miocardio/metabolismo , Miocardio/patología

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Background: Depression represents a pressing global public health concern, impacting the physical and mental well-being of hundreds of millions worldwide. Notwithstanding advances in clinical practice, an alarming number of individuals at risk for depression continue to face significant barriers to timely diagnosis and effective treatment, thereby exacerbating a burgeoning social health crisis. Objective: This study seeks to develop a novel online depression risk detection method using natural language processing technology to identify individuals at risk of depression on the Chinese social media platform Sina Weibo. Methods: First, we collected approximately 527,333 posts publicly shared over 1 year from 1600 individuals with depression and 1600 individuals without depression on the Sina Weibo platform. We then developed a hierarchical transformer network for learning user-level semantic representations, which consists of 3 primary components: a word-level encoder, a post-level encoder, and a semantic aggregation encoder. The word-level encoder learns semantic embeddings from individual posts, while the post-level encoder explores features in user post sequences. The semantic aggregation encoder aggregates post sequence semantics to generate a user-level semantic representation that can be classified as depressed or nondepressed. Next, a classifier is employed to predict the risk of depression. Finally, we conducted statistical and linguistic analyses of the post content from individuals with and without depression using the Chinese Linguistic Inquiry and Word Count. Results: We divided the original data set into training, validation, and test sets. The training set consisted of 1000 individuals with depression and 1000 individuals without depression. Similarly, each validation and test set comprised 600 users, with 300 individuals from both cohorts (depression and nondepression). Our method achieved an accuracy of 84.62%, precision of 84.43%, recall of 84.50%, and F1-score of 84.32% on the test set without employing sampling techniques. However, by applying our proposed retrieval-based sampling strategy, we observed significant improvements in performance: an accuracy of 95.46%, precision of 95.30%, recall of 95.70%, and F1-score of 95.43%. These outstanding results clearly demonstrate the effectiveness and superiority of our proposed depression risk detection model and retrieval-based sampling technique. This breakthrough provides new insights for large-scale depression detection through social media. Through language behavior analysis, we discovered that individuals with depression are more likely to use negation words (the value of "swear" is 0.001253). This may indicate the presence of negative emotions, rejection, doubt, disagreement, or aversion in individuals with depression. Additionally, our analysis revealed that individuals with depression tend to use negative emotional vocabulary in their expressions ("NegEmo": 0.022306; "Anx": 0.003829; "Anger": 0.004327; "Sad": 0.005740), which may reflect their internal negative emotions and psychological state. This frequent use of negative vocabulary could be a way for individuals with depression to express negative feelings toward life, themselves, or their surrounding environment. Conclusions: The research results indicate the feasibility and effectiveness of using deep learning methods to detect the risk of depression. These findings provide insights into the potential for large-scale, automated, and noninvasive prediction of depression among online social media users.

Asunto(s)

Depresión , Procesamiento de Lenguaje Natural , Medios de Comunicación Sociales , Humanos , Depresión/diagnóstico , Depresión/psicología , Depresión/epidemiología , Medios de Comunicación Sociales/estadística & datos numéricos , China/epidemiología , Semántica , Medición de Riesgo/métodos

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Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Despite significant advances in current drug therapies, issues such as poor drug targeting and severe side effects persist. In recent years, nanomedicine has been extensively applied in the research and treatment of CVDs. Among these, biomembrane-modified biomimetic nanodrug delivery systems (BNDSs) have emerged as a research focus due to their unique biocompatibility and efficient drug delivery capabilities. By modifying with biological membranes, BNDSs can effectively reduce recognition and clearance by the immune system, enhance biocompatibility and circulation time in vivo, and improve drug targeting. This review first provides an overview of the classification and pathological mechanisms of CVDs, then systematically summarizes the research progress of BNDSs in the treatment of CVDs, discussing their design principles, functional characteristics, and clinical application potential. Finally, it highlights the issues and challenges faced in the clinical translation of BNDSs.

Asunto(s)

Enfermedades Cardiovasculares , Sistemas de Liberación de Medicamentos , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Materiales Biomiméticos/química , Materiales Biomiméticos/uso terapéutico , Biomimética/métodos , Animales , Nanomedicina/métodos , Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/química

RESUMEN

Purpose: the aim of this study was to improve the stability and bioavailability of paeoniflorin (PF) by using nanoparticle encapsulation technology. Methods: paeoniflorin nanoparticles (PF NPs) were prepared with PLGA as the carrier using the compound emulsion method. The nanoparticles were characterised by using a Malvern laser particle sizer, transmission electron microscope (TEM), X-ray diffraction (XRD) analyser, and Fourier-transform infrared (FT-IR) spectrometry. The PF NPs were subjected to a series of stability investigations (such as for 4 °C storage stability, pH stability, and thermal stability), lyophilisation protection technology investigations, and in vitro release studies. Finally, the intestinal absorption properties of PF and PF NPs were studied by the in situ single-pass intestinal perfusion (SPIP) rat model, using the effective permeability coefficient (P eff) and the absorption rate constant (K a) as relevant indexes. Results: the prepared nanoparticles had a particle size of 105.0 nm with blue opalescent, rounded morphology, uniform size, good stability and slow release. We found that 4% alginate was the best lyoprotectant for the PF NPs. In the intestinal absorption experiments, P eff was higher for the PF NPs group compared with the original PF material drug group in all intestinal segments (P < 0.05), and the absorption rate constant K a increased with the increase in the drug concentration. Conclusion: the nanoparticles produced by this method have good stability and a slow-release effect; they can thus improve the absorption of PF in rat intestines, helping improve the stability and bioavailability of PF and enhancing its pharmacological effects.

RESUMEN

BACKGROUND: This study investigates the value of fluorine 18 ([18F])-labeled fibroblast activation protein inhibitor (FAPI) for lymph node (LN) metastases in patients with stage I-IIIA non-small cell lung cancer (NSCLC). METHODS: From November 2021 to October 2022, 53 patients with stage I-IIIA NSCLC who underwent radical resection were prospectively included. [18F]-fluorodeoxyglucose (FDG) and [18F]FAPI examinations were performed within one week. LN staging was validated using surgical and pathological findings. [18F]FDG and [18F]FAPI uptake was compared using the Wilcoxon signed-ranks test. Furthermore, the diagnostic value of nodal groups was investigated. RESULTS: In 53 patients (median age, 64 years, range: 31-76 years), the specificity of [18F]FAPI for detecting LN metastasis was significantly higher than that of [18F]FDG (P < 0.001). High LN risk category, greater LN short-axis dimension(≥ 1.0 cm), absence of LN calcification or high-attenuation, and higher LN FDG SUVmax (≥ 10.1) were risk factors for LN metastasis(P < 0.05). The concurrence of these four risk factors accurately predicted LN metastases (Positive Predictive Value [PPV] 100%), whereas the presence of one to three risk factors was unable to accurately discriminate the nature of LNs (PPV 21.7%). Adding [18F]FAPI in this circumstance improved the diagnostic value. LNs with an [18F]FAPI SUVmax<6.2 were diagnosed as benign (Negative Predictive Value 93.8%), and LNs with an [18F]FAPI SUVmax≥6.2 without calcification or high-attenuation were diagnosed as LN metastasis (PPV 87.5%). Ultimately, the integration of [18F]FDG and [18F]FAPI PET/CT resulted in the highest accuracy for N stage (83.0%) and clinical decision revisions for 29 patients. CONCLUSION: In patients with stage I-IIIA NSCLC, [18F]FAPI contributed additional valuable information to reduce LN diagnostic uncertainties after [18F]FDG PET/CT. Integrating [18F]FDG and [18F]FAPI PET/CT resulted in more precise clinical decisions. TRIAL REGISTRATION: The Chinese Clinical Trial Registry: ChiCTR2100044944 (Registered: 1 April 2021, https://www.chictr.org.cn/showprojEN.html?proj=123995 ).

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Fluorodesoxiglucosa F18 , Neoplasias Pulmonares , Metástasis Linfática , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Persona de Mediana Edad , Masculino , Femenino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Estudios Prospectivos , Anciano , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adulto , Metástasis Linfática/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología

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Recent research has reevaluated the traditional view of cancer's linear progression and recurrence by introducing cellular reprogramming a process in which cancer cells can their state under certain conditions. This change is driven by a combination of genetic and epigenetic factors, with pivotal roles played by key genes, and pathways, notably Wnt and Notch. The complexity of cancer's behavior is further influenced by factors such as the epithelial-mesenchymal transition (EMT) and therapy-induced stress, both of which are significant contributors to cancer recurrence. In this context bibliometric analysis emerges as a crucial tool for evaluating the impacts and trends within scientific literature. Our study utilized bibliometrics to analysis the role of cellular reprogramming oncology over the past two decades, highlighting its potential to improve cancer treatment outcomes. In conducting this analysis, we searched for literature search on cellular reprogramming (CR) in the Web of Science database, covering the years 2002-2022. We employed visualization tools like Citespace, VOSviewer, and Bibliometrix to analyze the collected data resulting in a dataset of 3102 articles. The United States and China emerged as leading contributors to this field, with the University of Texas MD Anderson Cancer Center being the most prolific institution. Menendez was the most influential scholar in this research domain. Cancers was the journal with the most publications on this subject. The most local-cited document was the article titled "Hallmarks of Cancer: The Next Generation". A comprehensive analysis has been conducted based on keywords and cited references. In recent years, the research emphasis has shifted to "extracellular vesicles," "cancer therapy," and "cellular plasticity". Therefore, this analysis uses bibliometrics to chart cutting-edge progress in cancer's cellular reprogramming, aiding experts to quickly understand and innovate in this crucial area.

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Subconjunctival fibrosis is critical to the outcomes of several ophthalmic conditions or procedures, such as glaucoma filtering surgery. This study aimed to investigate the anti-fibrotic effect of celastrol on subconjunctival fibrosis and to further reveal the underlying mechanisms. We used celastrol-loaded nanomicelles hydrogel hybrid as a sustained-release drug. A rabbit model of subconjunctival fibrosis following silicone implantation was used for in vivo study, and TGF-ß1-induced human pterygium fibroblast (HPF) activation as an in vitro model. The effects of celastrol on inhibiting TGF-ß1-induced migration and proliferation of HPFs were evaluated by scratch wound assay and CCK-8, respectively. Immunofluorescence and western blotting were used to examine the effect of celastrol on the expression of α-SMA, collagen I, fibronectin, and the targets of the Hippo signaling pathway. We found that in vivo celastrol treatment reduced the expression of YAP and TAZ in subconjunctival tissue. Moreover, celastrol alleviated collagen deposition and subconjunctival fibrosis at 8 weeks. No obvious tissue toxicity was observed in the rabbit models. Mechanistically, celastrol significantly inhibited TGF-ß1-induced proliferation and migration of HPFs. Pretreatment of HPFs with celastrol also suppressed the TGF-ß1-induced protein expression of α-SMA, collagen I, fibronectin, TGF-ßRII, phosphorylated Smad2/3, YAP, TAZ, and TEAD1. In conclusion, celastrol effectively prevented subconjunctival fibrosis through inhibiting TGF-ß1/Smad2/3-YAP/TAZ pathway. Celastrol could serve as a promising therapy for subconjunctival fibrosis.

Asunto(s)

Fibrosis , Glaucoma , Triterpenos Pentacíclicos , Animales , Conejos , Fibrosis/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Glaucoma/cirugía , Glaucoma/tratamiento farmacológico , Humanos , Siliconas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Proliferación Celular/efectos de los fármacos , Masculino , Hidrogeles , Triterpenos/farmacología , Triterpenos/administración & dosificación , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Factor de Crecimiento Transformador beta1/metabolismo , Conjuntiva/efectos de los fármacos , Conjuntiva/patología , Conjuntiva/metabolismo , Prótesis e Implantes/efectos adversos , Transducción de Señal/efectos de los fármacos , Preparaciones de Acción Retardada , Enfermedades de la Conjuntiva/prevención & control

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Fruit ripening is manipulated by the plant phytohormone ethylene in climacteric fruits. While the transcription factors (TFs) involved in ethylene biosynthesis and fruit ripening have been extensively studied in tomato, their identification in pear remains limited. In this study, we identified and characterized a HOMEODOMAIN TF, PbHB.G7.2, through transcriptome analysis. PbHB.G7.2 could directly bind to the promoter of the ethylene biosynthetic gene, 1-aminocyclopropane-1-carboxylic acid synthase (PbACS1b), thereby enhancing its activity and resulting in increased ethylene production during pear fruit ripening. Yeast-two-hybrid screening revealed that PbHB.G7.2 interacted with PbHB.G1 and PbHB.G2.1. Notably, these interactions disrupted the transcriptional activation of PbHB.G7.2. Interestingly, PbHB.G1 and PbHB.G2.1 also bind to the PbACS1b promoter, albeit different regions from those bound by PbHB.G7.2. Moreover, the regions of PbHB.G1 and PbHB.G2.1 involved in their interaction with PbHB.G7.2 differ from the regions responsible for binding to the PbACS1b promoter. Nonetheless, these interactions also disrupt the transcriptional activation of PbHB.G1 and PbHB.G2.1. These findings offer a new mechanism of ethylene biosynthesis during climacteric fruit ripening.

RESUMEN

The theories of relational regulation and compensatory Internet use suggest that intolerance of uncertainty influences smartphone addiction (SPA), which in turn is influenced by other aspects. This study used previous results to examine how intolerance of uncertainty affects SPA in PhD and master's degree programs. A convenience sample comprising 1727 master's and PhD students (99.9 %; 50.7 % female; Mage = 27.71; SD = 3.80; range = 21-43) was recruited. Using established questionnaires, we measured SPA, anxiety, positive coping style, perceived social support, and intolerance of uncertainty. The results demonstrated that intolerance of uncertainty positively affects SPA in terms of predictive power. Furthermore, anxiety and positive coping style mediate that link in a cascade fashion. A greater SPA indicates that the individual is less likely to use a positive coping style, has a higher anxiety level, and has a lower tolerance for uncertainty. While thinking about how intolerance of uncertainty affects anxiety and positive coping style, perceived social support mediates the relationship. Intolerance of uncertainty has less impact on anxiety and positive coping style when perceived social support is high. These results indicate the possibility of examining SPA prevention and intervention from several angles. Therefore, emotional regulation, which modifies anxiety and the tendency to use a positive coping style, may reduce the impact of intolerance of uncertainty on SPA. Another successful strategy for reducing smartphone addiction is to provide social support from loved ones and the community at large.

RESUMEN

Objective: This study aims to explore the mechanism of action of Yixintai in treating chronic ischemic heart failure by combining bioinformatics and experimental validation. Materials and Methods: Five potential drugs for treating heart failure were obtained from Yixintai (YXT) through early mass spectrometry detection. The targets of YXT for treating heart failure were obtained by a search of online databases. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted on the common targets using the DAVID database. A rat heart failure model was established by ligating the anterior descending branch of the left coronary artery. A small animal color Doppler ultrasound imaging system detected cardiac function indicators. Hematoxylin-eosin (HE), Masson's, and electron microscopy were used to observe the pathological morphology of the myocardium in rats with heart failure. The network pharmacology analysis results were validated by ELISA, qPCR, and Western blotting. Results: A total of 107 effective targets were obtained by combining compound targets and eliminating duplicate values. PPI analysis showed that inflammation-related proteins (TNF and IL1B) were key targets for treating heart failure, and KEGG enrichment suggested that NF-κB signaling pathway was a key pathway for YXT treatment of heart failure. Animal model validation results indicated the following: YXT can significantly reduce the content of intestinal microbiota metabolites such as trimethylamine oxide (TMAO) and improve heart failure by improving the EF and FS values of heart ultrasound in rats and reducing the levels of serum NT-proBNP, ANP, and BNP to improve heart failure. Together, YXT can inhibit cardiac muscle hypertrophy and fibrosis in rats and improve myocardial ultrastructure and serum IL-1ß, IL-6, and TNF-α levels. These effects are achieved by inhibiting the expressions of NF-κB and PKC. Conclusion: YXT regulates the TMAO/PKC/NF-κB signaling pathway in heart failure.

Asunto(s)

Medicamentos Herbarios Chinos , Insuficiencia Cardíaca , Farmacología en Red , Transducción de Señal , Animales , Masculino , Ratas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Metilaminas/farmacología , FN-kappa B/metabolismo , Proteína Quinasa C/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos

RESUMEN

PURPOSE: A serum medicinal chemistry analysis was performed to investigate the pharmacological basis of Xintongtai granule and to predict the potential mechanism of anti-atherosclerotic action based on the blood components. METHODS: UPLC-Q-TOF-MS/MS was used to analyze the in vitro chemical composition and in vivo blood components of Xintongtai granule, and to detect the blood drug concentration. The PPI network was constructed by collecting blood components and disease targets through the network pharmacology method, and the key targets were subjected to GO and KEGG functional enrichment analyses, so as to construct the topology network of drug-component-target-disease, and to validate the network by molecular docking. RESULTS: The UPLC-Q-TOF-MS/MS analysis identified 69 chemical components in Xintongtai granule, including 19 prototype circulating components and 9 metabolites in the bloodstream. Network pharmacology analysis revealed 115 intersecting targets for the circulating components, from which 10 core targets were selected. GO and KEGG analyses unveiled associated signaling pathways and biological processes. The construction of a topology network and preliminary molecular docking provided insights into its mechanism of action. CONCLUSION: The mechanism underlying the anti- atherosclerosis effect of Xintongtai granule may be associated with the intervention of active components such as Cryptotanshinone, Kaempferitrin, and Puerarin in pathways targeting CXCL8, STAT3, TNF, and other related targets.

Asunto(s)

Aterosclerosis , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Cromatografía Líquida de Alta Presión/métodos , Mapas de Interacción de Proteínas/efectos de los fármacos , Masculino , Farmacología en Red , Humanos , Ratones

RESUMEN

BACKGROUND: Impulsivity increases the risk for depression and anxiety. However, the granular pathways among them remain unknown. A network approach that moves from disorder-level analysis to symptom-level analysis can provide further understanding of psychopathological mechanisms. In this study, we examined the network structure of impulsivity and separate and comorbid symptoms of depression and anxiety. METHODS: Regularized partial-correlation networks were estimated using cross-sectional data from 1047 Chinese participants aged 18-26 years (main dataset, mean age = 21.45 ± 2.01 years) and 325 Chinese participants aged 18-36 years (an independent replication dataset, mean age = 21.49 ± 3.73 years), including impulsivity-depression, impulsivity-anxiety, and impulsivity-depression-anxiety networks. The datasets were collected from 1 June 2023 to 4 August 2023 and from 27 April 2022 to 16 May 2022, respectively. Impulsivity, depression, and anxiety were assessed using Barratt Impulsiveness Scale Version 11, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7, respectively. Bridge centrality was analyzed, and a network comparison test (NCT) was conducted to investigate the differences between the main dataset and replication dataset. RESULTS: The motor impulsivity dimension was revealed to be closely connected with individual symptoms of depression and anxiety regardless of whether they were in separate disorder forms or comorbid forms. In all the networks, motor impulsivity was the most important bridge node. The NCT showed comparable network connectivity and network structure between the main and replication datasets. LIMITATIONS: The use of cross-sectional data limited the inferences about the direction of causality between variables. CONCLUSIONS: These findings elucidate the psychopathological mechanisms underlying how impulsivity functions within depression, anxiety, and comorbidity and support that motor impulsivity is an important risk factor across different mental disorders and is responsible for comorbidity. The implications of these findings are discussed.

Asunto(s)

Ansiedad , Depresión , Conducta Impulsiva , Humanos , Conducta Impulsiva/fisiología , Femenino , Masculino , Adulto , Adulto Joven , Estudios Transversales , Adolescente , Depresión/epidemiología , Depresión/psicología , Ansiedad/epidemiología , Ansiedad/psicología , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/psicología , Trastornos de Ansiedad/fisiopatología , Comorbilidad , China/epidemiología , Escalas de Valoración Psiquiátrica

RESUMEN

BACKGROUND: The prevalence of neoplastic polyps in gallbladder polyps (GPs) increases sharply with age and is associated with gallbladder carcinoma (GBC). This study aims to predict neoplastic polyps and provide appropriate treatment strategies based on preoperative ultrasound features in patients with different age level. METHODS: According to the age classification of WHO, 1523 patients with GPs who underwent cholecystectomy from January 2015 to December 2019 at 11 tertiary hospitals in China were divided into young adults group (n=622), middle-aged group (n=665) and elderly group (n=236). Linear scoring models were established based on independent risk variables screened by the Logistic regression model in different age groups. The area under ROC (AUC) to evaluate the predictive ability of linear scoring models, long- and short- diameter of GPs. RESULTS: Independent risk factors for neoplastic polyps included the number of polyps, polyp size (long diameter), and fundus in the young adults and elderly groups, while the number of polyps, polyp size (long diameter), and polyp size (short diameter) in the middle-aged groups. In different age groups, the AUCs of its linear scoring model were higher than the AUCs of the long- and short- diameter of GPs for differentiating neoplastic and non-neoplastic polyps (all P<0.05), and Hosmer-Lemeshow goodness of fit test showed that the prediction accuracy of the linear scoring models was higher than the long- and short- diameter of GPs (all P>0.05). CONCLUSION: The linear scoring models of the young adults, middle-aged and elderly groups can effectively distinguish neoplastic polyps from non-neoplastic polyps based on preoperative ultrasound features.

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Neoplasias de la Vesícula Biliar , Pólipos , Ultrasonografía , Humanos , Persona de Mediana Edad , Neoplasias de la Vesícula Biliar/diagnóstico por imagen , Neoplasias de la Vesícula Biliar/patología , Femenino , Masculino , Estudios Retrospectivos , Adulto , Pólipos/diagnóstico por imagen , Pólipos/patología , Factores de Edad , Anciano , Factores de Riesgo , Colecistectomía , China/epidemiología , Periodo Preoperatorio , Adulto Joven , Cuidados Preoperatorios

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Corneal stromal fibrosis is a common cause of visual impairment resulting from corneal injury, inflammation and surgery. Therefore, there is an unmet need for inhibiting corneal stromal fibrosis. However, bioavailability of topical eye drops is very low due to the tear and corneal barriers. In situ delivery offers a unique alternative to improve efficacy and minimize systemic toxicity. Herein, a drug delivery platform based on thermoresponsive injectable hydrogel/nano-micelles composite with in situ drug-controlled release and long-acting features is developed to prevent corneal scarring and reduce corneal stromal fibrosis in lamellar keratoplasty. The in-situ gelation hydrogels enabled direct delivery of celastrol to the corneal stroma. In vivo evaluation with a rabbit anterior lamellar keratoplasty model showed that hydrogel/micelles platform could effectively inhibit corneal stromal fibrosis. This strategy achieves controlled and prolonged release of celastrol in the corneal stroma of rabbit. Following a single corneal interlamellar injection, celastrol effectively alleviated fibrosis via mTORC1 signal promoting autophagy and inhibiting TGF-ß1/Smad2/3 signaling pathway. Overall, this strategy demonstrates promise for the clinical application of celastrol in preventing corneal scarring and reducing corneal stromal fibrosis post-lamellar keratoplasty, highlighting the potential benefits of targeted drug delivery systems in ocular therapeutics.

Asunto(s)

Trasplante de Córnea , Hidrogeles , Triterpenos Pentacíclicos , Animales , Conejos , Triterpenos Pentacíclicos/administración & dosificación , Hidrogeles/administración & dosificación , Trasplante de Córnea/métodos , Cicatriz/prevención & control , Cicatriz/tratamiento farmacológico , Preparaciones de Acción Retardada , Fibrosis , Sistemas de Liberación de Medicamentos , Córnea/efectos de los fármacos , Córnea/metabolismo , Triterpenos/administración & dosificación , Liberación de Fármacos , Sustancia Propia/efectos de los fármacos , Humanos

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PURPOSE: This study aims to investigate the protective mechanism of dihydromyricetin PLGA nanoparticles (DMY-PLGA NPs) against myocardial ischemia-reperfusion injury (MIRI) in vitro and the improvement of oral bioavailability in vivo. METHODS: DMY-PLGA NPs was prepared and characterized by emulsifying solvent volatilization, and the oxidative stress model of rat H9c2 cardiomyocyte induced by H2O2 was established. After administration, cell survival rate, lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected, and the expressions of PGC1α and PPARα were detected by western blot (WB). At the same time, the pharmacokinetics in rats were studied to explore the improvement of bioavailability. RESULTS: DMY-PLGA NPs can significantly increase cell survival rate, decrease LDH and MDA content, increase SOD content and PGC1α、PPARα protein expression. Compared with DMY, the peak time of DMY-PLGA NPs was extended (P<0.1), and the bioavailability was increased by 2.04 times. CONCLUSION: DMY-PLGA NPs has a significant protective effect on H9c2 cardiomyocytes, which promotes the absorption of DMY and effectively improves bioavailability.

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Flavonoles , Peróxido de Hidrógeno , PPAR alfa , Ratas , Animales , Peróxido de Hidrógeno/metabolismo , PPAR alfa/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Estrés Oxidativo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Superóxido Dismutasa/metabolismo , Apoptosis

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BACKGROUND: Extensive research has been conducted on fruit development in crops, but the metabolic regulatory networks underlying perennial fruit trees remain poorly understood. To address this knowledge gap, we conduct a comprehensive analysis of the metabolome, proteome, transcriptome, DNA methylome, and small RNAome profiles of pear fruit flesh at 11 developing stages, spanning from fruitlet to ripening. Here, we systematically investigate the metabolic landscape and regulatory network involved. RESULTS: We generate an association database consisting of 439 metabolites and 14,399 genes to elucidate the gene regulatory network of pear flesh metabolism. Interestingly, we detect increased DNA methylation in the promoters of most genes within the database during pear flesh development. Application of a DNA methylation inhibitor to the developing fruit represses chlorophyll degradation in the pericarp and promotes xanthophyll, ß-carotene, and abscisic acid (ABA) accumulation in the flesh. We find the gradual increase in ABA production during pear flesh development is correlated with the expression of several carotenoid pathway genes and multiple transcription factors. Of these transcription factors, the zinc finger protein PbZFP1 is identified as a positive mediator of ABA biosynthesis in pear flesh. Most ABA pathway genes and transcription factors are modified by DNA methylation in the promoters, although some are induced by the DNA methylation inhibitor. These results suggest that DNA methylation inhibits ABA accumulation, which may delay fruit ripening. CONCLUSION: Our findings provide insights into epigenetic regulation of metabolic regulatory networks during pear flesh development, particularly with regard to DNA methylation.

Asunto(s)

Metilación de ADN , Pyrus , Pyrus/genética , Multiómica , Epigénesis Genética , Frutas/genética , Ácido Abscísico , Factores de Transcripción/genética

RESUMEN

BACKGROUND: A temporal network of generalized anxiety disorder (GAD) symptoms could provide valuable understanding of the occurrence and maintenance of GAD. We aim to obtain an exploratory conceptualization of temporal GAD network and identify the central symptom. METHODS: A sample of participants (n = 115) with elevated GAD-7 scores (Generalized Anxiety Disorder 7-Item Questionnaire [GAD-7] ≥ 10) participated in an online daily diary study in which they reported their GAD symptoms based on DSM-5 diagnostic criteria (eight symptoms in total) for 50 consecutive days. We used a multilevel VAR model to obtain the temporal network. RESULTS: In temporal network, a lot of lagged relationships exist among GAD symptoms and these lagged relationships are all positive. All symptoms have autocorrelations and there are also some interesting feedback loops in temporal network. Sleep disturbance has the highest Out-strength centrality. CONCLUSIONS: This study indicates how GAD symptoms interact with each other and strengthen themselves over time, and particularly highlights the relationships between sleep disturbance and other GAD symptoms. Sleep disturbance may play an important role in the dynamic development and maintenance process of GAD. The present study may develop the knowledge of the theoretical model, diagnosis, prevention and intervention of GAD from a temporal symptoms network perspective.

Asunto(s)

Evaluación Ecológica Momentánea , Trastornos del Sueño-Vigilia , Humanos , Trastornos de Ansiedad/complicaciones , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , Ansiedad/diagnóstico , Encuestas y Cuestionarios , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/diagnóstico , Sueño

RESUMEN

Introduction: Epidermal growth factor receptor (EGFR) mutation is common in Chinese patients with lung adenocarcinoma (LUAD). Brain metastases (BMs) is high and associated with poor prognosis. Identification of EGFR-mutant patients at high risk of developing BMs is important to reduce or delay the incidence of BMs. Currently, there is no literature on the prediction and modeling of EGFR brain metastasis at the proteinomics level. Methods: We conducted a retrospective study of BMs in postoperative recurrent LUAD with EGFR mutation in the First Affiliated Hospital of Guangzhou Medical University. Tissue proteomic analysis was applied in the primary tumors of resected LUAD in this study using liquid chromatography-mass spectrometry (LC-MS/MS). To identify potential markers for predicting LUAD BM, comparative analyses were performed on different groups to evaluate proteins associated with high risk of BMs. Results: A combination of three potential marker proteins was found to discriminate well between distal metastasis (DM) and local recurrence (LR) of postoperative LUAD with EGFR mutation. Gene Ontology (GO) analysis of significantly altered proteins between BM and non-BM (NBM) indicated that lipid metabolism and cell cycle-related pathways were involved in BMs of LUAD. And the enriched pathways correlated with BMs were found to be quite different in the comparison groups of postoperative adjuvant therapy, tyrosine kinase inhibitor (TKI), and chemotherapy groups. Finally, we developed a random forest algorithm model with eight proteins (RRS1, CPT1A, DNM1, SRCAP, MLYCD, PCID2, IMPAD1 and FILIP1), which showed excellent predictive value (AUC: 0.9401) of BM in patients with LUAD harboring EGFR mutation. Conclusions: A predictive model based on protein markers was developed to accurately predict postoperative BM in operable LUAD harboring EGFR mutation.

Asunto(s)

Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Proteómica , Estudios Retrospectivos , Cromatografía Liquida , Mutación , Recurrencia Local de Neoplasia/genética , Espectrometría de Masas en Tándem , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/cirugía , Adenocarcinoma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Receptores ErbB/metabolismo , Factores de Riesgo , Proteínas Nucleares/genética

RESUMEN

PURPOSE: To evaluate the role of M2 macrophages in subconjunctival fibrosis after silicone implantation (SI) and investigate the underlying mechanisms. MATERIALS AND METHODS: A model of subconjunctival fibrosis was established by SI surgery in rabbit eyes. M2 distribution and collagen deposition were evaluated by histopathology. The effects of M2 cells on the migration (using wound-scratch assay) and activation (by immunofluorescence and western blotting) of human Tenon's fibroblasts (HTFs) were investigated. RESULTS: There were more M2 macrophages (CD68+/CD206+ cells) occurring in tissue samples around silicone implant at 2 weeks postoperatively. Dense collagen deposition was observed at 8 weeks after SI. In vitro experiment showed M2 expressed high level of CD206 and transforming growth factor-ß1 (TGF-ß1). The M2-conditioned medium promoted HTFs migration and the synthesis of collagen I and fibronectin. Meanwhile, M2-conditioned medium increased the protein levels of TGF-ß1, TGF-ßR II, p-Smad2/3, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ). Verteporfin, a YAP inhibitor, suppressedTGF-ß1/Smad2/3-YAP/TAZ pathway and attenuated M2-induced extracellular matrix deposition by HTFs. CONCLUSIONS: TGF-ß1/Smad2/3-YAP/TAZ signalling may be involved in M2-induced fibrotic activities in HTFs. M2 plays a key role in promoting subconjunctival fibrosis and can serve as an attractive target for anti-fibrotic therapeutics.

Asunto(s)

Macrófagos , Factor de Crecimiento Transformador beta1 , Animales , Humanos , Conejos , Colágeno , Medios de Cultivo Condicionados , Fibrosis , Macrófagos/metabolismo , Siliconas , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo

RESUMEN

Background: The move away from investigating mental disorders as whole using sum scores to the analysis of symptom-level interactions using network analysis has provided new insights into comorbidities. The current study explored the dynamic interactions between depressive and anxiety symptoms in older Chinese adults with diabetes mellitus (DM) and identified central and bridge symptoms in the depression-anxiety network to provide potential targets for prevention and intervention for depression and anxiety. Methods: This study used a cross-sectional design with data from the 2017-2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). A regularized partial correlation network for depressive and anxiety symptoms was estimated based on self-reported scales completed by 1685 older adults with DM aged 65 years or older. Depressive and anxiety symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the Seven-Item Generalized Anxiety Disorder Scale (GAD-7), respectively. Expected influence (EI) and bridge expected influence (BEI) indices were calculated for each symptom. Results: According to cutoff scores indicating the presence of depression and anxiety, the prevalences of depression and anxiety in our sample were 52.9% and 12.8%, respectively. The comorbidity rate of depression and anxiety was 11.5%. The six edges with the strongest regularized partial correlations were between symptoms from the same disorder. "Feeling blue/depressed", "Nervousness or anxiety", "Uncontrollable worry", "Trouble relaxing", and "Worry too much" had the highest EI values. "Nervousness or anxiety" and "Everything was an effort" exhibited the highest BEI values. Conclusion: Central and bridge symptoms were highlighted in this study. Targeting these symptoms may be effective in preventing the comorbidity of depressive and anxiety symptoms and facilitate interventions in older Chinese adults with DM who are at risk for or currently have depressive and anxiety symptoms.