Acute cerebral infarction causes irreversible injury in the infarct core and secondary damage in surrounding ischemic tissue, where apoptosis-related signaling may contribute to lesion progression. This study evaluated whether inhibition of microRNA-423-5p is associated with improved early outcomes in a rat model of permanent middle cerebral artery occlusion. Adult male Sprague-Dawley rats were assigned to Sham, permanent middle cerebral artery occlusion, permanent middle cerebral artery occlusion plus negative-control adenovirus, or permanent middle cerebral artery occlusion plus microRNA-423-5p-interfering adenovirus groups. A stereotactic intracerebroventricular injection was performed 72 h before occlusion. Neurological deficits were assessed 24 h after surgery using the Zea Longa score; infarct volume was quantified by 2,3,5-triphenyltetrazolium chloride staining; Bax and Bcl-2 protein expression were evaluated by Western blotting; and microRNA-423-5p expression was measured by quantitative real-time polymerase chain reaction. Bioinformatic prediction was also summarized to contextualize BAX as a potential microRNA-423-5p-associated apoptosis-related gene. microRNA-423-5p inhibition was associated with lower neurological deficit scores, reduced infarct volume, decreased Bax expression, increased Bcl-2 expression, and reduced microRNA-423-5p abundance in ischemic brain tissue. These findings support a preliminary association between inhibition of microRNA-423-5p and reduced injury severity after permanent cerebral ischemia. However, direct target validation and direct apoptosis assays are required to define the underlying mechanism.

Acquired resistance to epidermal growth factor receptor (EGFR)-targeted therapies remain a major challenge in non-small cell lung cancer (NSCLC), particularly in patients with malignant pleural effusion (MPE). The MPE microenvironment, characterized by acidic, cytokine- and metabolite-rich conditions, promotes the emergence of osimertinib-tolerant persister cells (OTPCs), contributing to disease relapse. In this study, we investigated the role of MPE in driving OTPC formation and identified key molecular regulators underlying this adaptive phenotype. MPE samples from advanced EGFR-mutant NSCLC were used to generate OTPCs through coculture with PC9 and H1975 cell lines. In contrast, non-malignant pleural effusions induced only limited tolerance. Transcriptomic profiling revealed extensive reprogramming in OTPCs, with PLCG1 and RAC1 among the most significantly upregulated genes, enriched in pathways related to glycolysis, hypoxia, and epithelial-mesenchymal transition. Functional analyses demonstrated that OTPCs exhibit enhanced macropinocytosis, metabolic flexibility, and invasive capacity. Mechanistically, PLCG1 and RAC1 formed a co-dependent signaling network, as supported by reciprocal knockdown and protein interaction studies. Inhibition of PLCG1 significantly impaired both mitochondrial respiration and glycolytic activity, reduced mesenchymal marker expression, and decreased OTPC viability by >60%, thereby restoring sensitivity to osimertinib. In vivo, combined inhibition of EGFR and PLCG1 resulted in sustained tumor suppression and improved survival without detectable toxicity. Collectively, these findings identify a co-dependent PLCG1-RAC1 signaling network that integrates metabolic adaptation and phenotypic plasticity to sustain drug tolerance in MPE-associated NSCLC. Targeting this pathway represents a promising strategy to overcome resistance to EGFR-directed therapies.

Patients undergoing general anesthesia are susceptible to postoperative complications, among which postoperative pulmonary complications (PPCs) are highly prevalent. Penehyclidine (PHC) is a novel anticholinergic agent; however, its efficacy in preventing PPCs remains uncertain. Therefore, this systematic review and meta-analysis was conducted to evaluate the efficacy of PHC in preventing PPCs in patients undergoing general anesthesia. Randomized controlled trials (RCTs) were searched without language restrictions from database inception to December 31, 2023. Published literature was retrieved from Web of Science, The Cochrane Library, PubMed, EMbase, Sinomed, China National Knowledge Infrastructure (CNKI), and Wanfang Database. The references of the included studies were also manually screened. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A total of 10 randomized controlled trials involving 1,313 patients were included in this study. The forest plot demonstrated that, compared with the control group, PHC was associated with a lower incidence of PPCs (RR = 0.59, 95

Acute myeloid leukaemia (AML) is a common haematological malignancy with an unsatisfactory prognosis despite recent therapeutic advances. Neddylation and ferroptosis have been implicated in the regulation of malignant cell proliferation, survival and therapy response. However, the relationship between neddylation-related dysregulation and ferroptosis-associated pathways in AML remains poorly understood. Transcriptomic data from TCGA-AML and GTEx normal controls were integrated for differential expression and functional enrichment analyses. Prognostic neddylation-related genes were identified using univariate Cox regression, LASSO regression and multivariate Cox regression analyses. The expression and regulatory association of EXOSC4 with NEDD8 and Cullin1 neddylation were validated in clinical samples and AML cell lines using qRT-PCR and Western blotting. CCK-8 assays were performed to evaluate the effects of EXOSC4 overexpression, MLN4924, erastin and Ferrostatin-1 on AML cell viability. A ceRNA regulatory network was constructed based on the key neddylation-related genes. GO and KEGG enrichment analyses showed that differentially expressed neddylation-related genes were mainly enriched in post-translational modification-related biological processes and pathways. Cox regression analyses identified EXOSC4 as a prognostic neddylation-related gene significantly associated with AML prognosis. Validation in clinical samples showed that EXOSC4 and NEDD8 were differentially expressed at both the mRNA and protein levels. In vitro experiments further showed that EXOSC4 expression was positively associated with NEDD8 protein levels and Cullin1 neddylation, suggesting that EXOSC4 may be involved in neddylation-related regulation in AML. Correlation analysis indicated a potential association between neddylation-related dysregulation and ferroptosis-associated pathways. Moreover, CCK-8 assays showed that EXOSC4 overexpression enhanced AML cell viability, whereas MLN4924 suppressed this effect and further enhanced erastin-induced reduction in cell viability, suggesting a potential role of EXOSC4 in ferroptosis-related cellular responses. In conclusion, this study reveals a potential association between neddylation-related dysregulation and ferroptosis-associated pathways in AML. EXOSC4 was identified as a candidate regulatory molecule that may connect neddylation activity with ferroptosis-related cellular responses. These findings provide new insights into the molecular mechanisms of AML and support further investigation of EXOSC4 as a potential therapeutic target.

Heart failure (HF) is frequently accompanied by pleural effusion, yet the biological impact of HF-associated pleural fluid on vascular endothelial function remains unclear. Here, we show that HF pleural fluid impairs endothelial barrier integrity and angiogenic capacity in human umbilical vein endothelial cells. Functional assays revealed increased permeability, reduced migration, and altered tube formation following treatment with patient-derived pleural fluid. Mechanistically, HF pleural fluid increased reactive oxygen species production and inflammatory signaling while downregulating tight junction protein ZO-1. Small RNA profiling identified miR-501-3p as a key mediator of these effects. Gain-and loss-of-function experiments demonstrated that miR-501-3p directly regulates ZO-1 expression and contributes to barrier disruption. These findings establish a microRNA-dependent mechanism linking HF pleural fluid to endothelial dysfunction and suggest a potential molecular pathway contributing to vascular complications in HF.

Objective This study aimed to investigate the molecular mechanism by which cordycepin (Cor) combined with photodynamic therapy (PDT) exerts cytotoxicity against human breast cancer cells in vitro. Methods CCK‑8 assay, colony formation assay and Calcein‑AM/PI staining were used to evaluate cell proliferation. DCFH‑DA and JC‑1 staining combined with flow cytometry were performed to detect intracellular ROS and mitochondrial membrane potential. LDH release assay, ELISA and western blot were adopted to assess cell damage, inflammatory cytokine secretion and pyroptosis‑related protein expression. Results Combined Cor and PDT treatment produced robust anti‑tumour effects and oxidative stress accumulation in breast cancer cell lines. This combinatorial regimen modulated the expression of core pyroptotic molecules and stimulated the secretion of pro‑inflammatory mediators. Pharmacological inhibition of ROS or caspase‑1 attenuated the anti‑tumour effects induced by combined treatment. Conclusions Cor synergistically enhances the anti-proliferative effect of PDT on breast cancer cells. This combinatorial treatment induces GSDMD-dependent pyroptosis via caspase-1 activation. Our findings offer new experimental evidence and research insights for the potential use of active components from traditional Chinese medicine in tumor therapy.

ObjectivesWe aimed to characterize the gut microbiota compositions in individuals with distinct types of chronic rhinosinusitis (CRS) and investigate their association with clinical, hematological, and histopathological changes.MethodsFecal samples were collected from 68 patients with CRS and 33 healthy controls (HCs). The patients with CRS were classified into distinct subtypes based on the presence or absence of nasal polyps and the occurrence of eosinophilic tissue inflammation. The microbiome structures of all samples were analyzed using high-throughput 16S rRNA gene sequencing. Clinical, hematological, and histopathological analyses were conducted.ResultsGut microbiota dysbiosis was found in individuals with distinct types of CRS. The abundances of members from the phylum Proteobacteria and its major genera (Escherichia-Shigella and Klebsiella) decreased significantly in the patients with CRS phenotypes and decreased correspondingly in the patients with CRS endotypes, compared with those in the HCs. The abundances of members from the phylum Bacteroidetes and its major genus (Bacteroides) increased significantly in the patients with CRS with nasal polyps (CRSwNP) and increased correspondingly in the patients with CRSwNP endotypes, compared with those in the HCs and patients with CRS without nasal polyps (CRSsNP) and its endotypes. Most of the bacteria were correlated with the clinical indicators of CRS.ConclusionsGut microbiota dysbiosis is characterized by the presence of unique bacterial flora in distinct types of CRS. The dysbiosis of gut microbiota was correlated with different subtypes and the severity of CRS. Our findings will provide novel insights into the pathogenesis of CRS.Level of EvidenceLevel 3.

The advances in AI-enabled techniques have accelerated the creation and automation of visualizations in the past decade. However, presenting visualizations in a descriptive and generative format remains a challenge. Moreover, current visualization embedding methods focus on standalone visualizations, neglecting the importance of contextual information for multi-view visualizations. To address this issue, we propose a new representation model, Chart2Vec, to learn a universal embedding of visualizations with context-aware information. Chart2Vec aims to support a wide range of downstream visualization tasks such as recommendation and storytelling. Our model considers both structural and semantic information of visualizations in declarative specifications. To enhance the context-aware capability, Chart2Vec employs multi-task learning on both supervised and unsupervised tasks concerning the cooccurrence of visualizations. We evaluate our method through an ablation study, a user study, and a quantitative comparison. The results verified the consistency of our embedding method with human cognition and showed its advantages over existing methods.

Objective:Opioids have constituted an essential element of general anesthesia for a considerable length of time. However, with the increase in opioid misuse and associated postoperative adverse effects, studies related to opioid-free anesthesia (OFA) have emerged, which pose a challenge in identifying key research directions. Accordingly, the objective of this study was to provide a review of the relevant literature in the field of OFA over the past 2 decades, with the goal of identifying the prevailing trends and research Frontiers. Methods:A systematic review of the publications on OFA was conducted using the Web of Science Core Collection database, with the objective of identifying relevant publications between the years 2005 and 2024. The bibliometric analysis was conducted using CiteSpace (version 6.1. R6), VOSviewer (version 1.6.19), and R (version4.4.2). Results:In conclusion, 477 publications were included in this study. The number of annual publications in this field has exhibited a steady increase over the past 2 decades. The United States and its institutions were found to be the most central. Forget, Patrice, and BELOEIL H were identified as the most prolific and highly cited authors, respectively. The journal with the highest number of publications was BMC Anesthesiology. The most frequently cited journal was Anesthesia and Analgesia, followed by Anesthesiology. In addition, keyword burst, keywords co-occurrence, and analysis of cited references indicate that recent studies have focused on: opioid consumption, pain, and postoperative nausea and vomiting (PONV). Meanwhile, analysis of keyword clusters and keywords timeline view showed that the main research frontiers are sevoflurane anesthesia, plane block, multimodal anesthesia, opioid-sparing anesthesia. Conclusion:Our results show that the current trends and directions of research focus on opioid consumption, pain, and PONV. Frontiers for future research are expected to include research areas related to sevoflurane anesthesia, plane block, multimodal anesthesia, opioid-sparing anesthesia.

Bladder cancer, more prevalent in men, has high recurrence rates in non-muscle-invasive forms and is highly lethal upon metastasis in muscle-invasive cases. Transient receptor potential canonical channels (TRPCs), specifically TRPC3, play a role in calcium signaling, influencing cancer cell behavior. This study examines the effects of Pyr3, a TRPC3 inhibitor, and TRPC3 knockdown on both muscle-invasive (T24) and non-muscle-invasive (RT4) bladder cancer cells. Pyr3 treatment reduced cell viability, migration, adhesion, and calcium influx in these cells. Additionally, Pyr3 treatment and siTRPC3 downregulated protein kinase C alpha (PKC alpha), phosphoPKC alpha, and protein phosphatase 2A (PP2A) levels. While PKC activator phorbol 12-myristate 13-acetate (PMA) could not restore Pyr3-induced viability loss, it reversed the migration inhibition. In a xenograft model, Pyr3 suppressed T24 cell viability, Ki67, phospho-PKC alpha, PP2A and TRPC3 expression. These findings suggest that Pyr3 inhibits bladder cancer cell migration through PKC signaling and holds potential as a therapeutic agent for bladder cancer.

Glioblastoma multiforme (GBM) is a brain cancer characterized by low survival and high recurrence rates. Farnesoid X receptor (FXR), a nuclear receptor for bile acids, is expressed at low levels in GBM. This study explores the impact of FXR regulation on GBM cell migration and invasion. Higher FXR expression correlated with increased survival in GBM patients, based on TCGA data. FXR overexpression inhibited cell viability, migration and invasion as well as matrix metalloproteinase 2 (MMP2) activity, while knockdown of FXR exerted the opposite effects. The expression of the tight junction proteins occludin and ZO-1 was enhanced after FXR overexpression. Moreover, a JAK2 activator reversed the migration and invasion of FXR-overexpressing GBM cells. In an animal study, FXR overexpression combined with temozolomide treatment decreased tumor mass, and MMP2 expression and elevated occludin expression in mice. In conclusion, FXR overexpression inhibits the progression of GBM, which may be mediated by inhibiting JAK2 and enhancing tight junction protein expression.

Background The relationships between Ki-67/MKI67 expression, lymph node metastasis (LNM), vascular invasion (VI), and perineural invasion (PI) in esophageal squamous cell cancer (ESCC) remain unclear. This retrospective cohort study was performed to evaluate the prognostic value of Ki-67 expression and its association with LNM in patients with resected ESCC. Methods The analysis included 168 patients with ESCC with available Ki-67 protein expression data. The patients were divided into Ki-67 high-expression group (Ki-67 High, 93 cases) and Ki-67 low-expression (Ki-67 Low, 75 cases) groups. Associations between Ki-67 expression and ESCC pathological features was assessed using chi-square test. Overall survival (OS) was compared between the two groups using Kaplan–Meier survival analysis and Cox proportional hazards model. Results Median follow-up duration was 33.5 months (range 3.0–60.0 months). High Ki-67 expression was significantly associated with poor OS in patients with ESCC compared to that of the low-expression in both univariate (hazard ratios (HR) = 3.42, 95% CI [2.22–5.27], P < 0.001) and multivariate analyses (HR = 1.98, 95% CI [1.33–2.94], P < 0.001). Furthermore, high Ki-67 expression was significantly associated with an increased risk of LNM (χ2 = 11.219, P = 0.011), VI (χ2 = 6.359, P = 0.012), and PI (χ2 = 8.877, P = 0.003). Conclusions High Ki-67 protein expression is associated with poor prognosis in ESCC. Increased Ki-67 expression significantly increases the risk of LNM, VI, and PI in ESCC, and thus may serve as an indication for adjuvant therapy in ESCC management.

Objective:To examine how patients having open heart surgery under cardiopulmonary bypass (CPB) react to surgical stress following bilateral transversus thoracis plane (TTP) block with ropivacaine improved by dexmedetomidine (DEX). Methods:Three groups of sixty patients (26M/34F, ASA II-III, 18-65 years old) slated for elective CPB heart surgery were randomly assigned: general anesthesia alone (Group C), TTP (ropivacaine) combined with general anesthesia group (Group R), or TTP (ropivacaine + DEX) combined with general anesthesia group (Group RD). Primary outcomes measured serum cortisol levels at five perioperative phases, while the secondary outcomes included glucose/C-reactive protein (CRP) levels, Numeric Rating Scale (NRS) pain scores postextubation, 48-hr sufentanil consumption, patient-controlled analgesia (PCA) demand frequency, rescue analgesia rates, mechanical ventilation duration, ICU stay, and complications. Results:At 24 h postoperatively, RD and R groups exhibited statistical lower serum cortisol levels compared to controls (p < 0.05), with parallel glucose reductions. However, the CRP level increased significantly. NRS scores in RD/R groups were significantly lower than controls at 0 h, 6 h, and 12 h postextubation (p < 0.05), and the RD group maintained superior analgesia vs. both groups at 24 h. RD and R groups demonstrated significant reductions for 48-h sufentanil consumption vs. controls, and RD group showed less total sufentanil consumption vs. R group. Besides, both mechanical ventilation duration and ICU stay were shortened by serval hours compared to control. Significant reductions in the count of effective analgesic pump compressions were observed in groups R and RD compared to the control group. Moreover, rescue analgesia rates were 55%, and 15% lower in RD vs. R and Control groups, respectively (p = 0.031). However, no intergroup differences occurred pulmonary complications. Conclusion:DEX-enhanced TTP blockade may contribute to attenuating the stress response, optimizing analgesia, and improving early postoperative recovery parameters in CPB cardiac surgery through opioid-sparing mechanisms and sympatholytic effects, demonstrating clinical viability within Enhanced Recovery After Surgery (ERAS) protocols. Clinical Trial Registration:https://www.chictr.org.cn/index.html, identifier ChiCTR2400085899.

BACKGROUND:Non-small cell lung cancer (NSCLC) frequently develops resistance to EGFR-tyrosine kinase inhibitors (TKIs), particularly in malignant pleural effusion (MPE), where a highly acidic tumor microenvironment promotes the emergence of drug-tolerant persister (DTP) cells. Building upon previous evidence that MPE acidity drives metabolic plasticity, this study investigates how acid-sensing ion channel 3 (ASIC3) coordinates PLCG1-dependent macropinocytosis to maintain osimertinib tolerance. METHODS:Primary MPE-derived NSCLC cultures underwent next-generation sequencing to define mutational heterogeneity. Acidic (pH 6.5-6.8) conditions were used to generate osimertinib-induced DTP (Osi-DTP) models. Functional assays assessed viability, invasion, colony formation, autophagy, and macropinocytosis. ASIC3 was silenced using shRNA, followed by Seahorse metabolic analysis. Transcriptomic profiling identified differentially expressed genes. ASIC3-targeted therapeutic interventions were evaluated in vitro and in xenograft models. RESULTS:MPE-derived NSCLC cultures showed substantial genomic diversity, including EGFR exon 19 deletion and T790M mutations. Acid-adapted Osi-DTP cells exhibited EMT-like phenotypes, reduced proliferation, elevated stemness markers, and strong activation of stress-response pathways. ASIC3 was consistently upregulated under acidic conditions and drove PLCG1-mediated macropinocytosis to support nutrient scavenging and survival. ASIC3 knockdown markedly reduced DTP cell viability, invasiveness, colony formation, autophagy, and glycolysis, while inducing a metabolic shift toward oxidative phosphorylation. In vivo, combining an ASIC3 inhibitor with osimertinib significantly delayed tumor progression and improved survival without added toxicity. Clinically, high ASIC3 expression correlated with poor overall survival and increased autophagy-associated markers. CONCLUSION:ASIC3 is a central regulator of acidosis-driven drug persistence in MPE-associated NSCLC, sustaining osimertinib tolerance through PLCG1-dependent macropinocytosis and metabolic reprogramming. Targeting ASIC3 restores TKI sensitivity by disrupting nutrient acquisition, autophagy, and metabolic adaptation, representing a promising therapeutic strategy to prevent or delay EGFR-TKI resistance.

We report ultra-low-temperature ^23Na NMR measurements on the Ising triangular lattice antiferromagnet Na_2BaCo(PO_4)_2, which precisely resolve the phase diagram under magnetic field applied along the crystalline c axis. With increasing field, the NMR spectra resolve three ordered phases with distinct spin configurations: the Y, up-up-down (UUD), and V phases. The spin-lattice relaxation rate 1/T_1 data demonstrate gapless excitations in the Y and V phases, strongly supporting their supersolid nature. However, the phase transitions from the UUD phase to the two supersolid phases exhibit dramatically different behaviors upon cooling. Prior to entering the Y phase, 1/T_1 identifies a gapless regime within the UUD phase, suggesting a Berezinskii-Kosterlitz-Thouless phase above a second-order phase transition. In contrast, the coexistence of the UUD and V phases observed in our experiments provides direct evidence of a first-order phase transition between these phases.

Aging is a complex biological process characterized by increased inflammation and susceptibility to various age-related diseases, including cognitive decline, osteoporosis, and type 2 diabetes. Exercise has been shown to modulate mitochondrial function, immune responses, and inflammatory pathways, thereby attenuating aging through the regulation of exerkines secreted by diverse tissues and organs. These bioactive molecules, which include hepatokines, myokines, adipokines, osteokines, and neurokines, act both locally and systemically to exert protective effects against the detrimental aspects of aging. This review provides a comprehensive summary of different forms of exercise for older adults and the multifaceted role of exercise in anti-aging, focusing on the biological functions and sources of these exerkines. We further explore how exerkines combat aging-related diseases, such as type 2 diabetes and osteoporosis. By stimulating the secretion of these exerkines, exercise supports healthy longevity by promoting tissue homeostasis and metabolic balance. Additionally, the integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating age-related pathologies at the molecular level. As our understanding deepens, it may pave the way for personalized interventions leveraging physical activity to enhance healthspan and improve quality of life.

Lung cancer (LC) and breast cancer (BC) are two common malignant tumors with the highest incidence rate in men and women worldwide, respectively. As the treatment effect of currently available therapies for LC and BC is unsatisfying, searching for new therapeutic drugs has become an urgent need to be addressed. EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., has been previously documented to exert anti-tumor effects on liver cancer by us. However, the underlying molecular mechanisms of its resistance to LC and BC have not been clearly elucidated. Thus, in the present study, we further investigated the anticancer effect of EM-2 on LC and BC with focusing on the involved molecular mechanisms. Our results suggest that EM-2 induces the impaired autophagy, which subsequently promotes ER stress-mediated apoptosis as well as ROS generation. ROS accumulation induced by EM-2 further simultaneously induces G2/M cell cycle arrest through ATM-Chk2-p53-p21 pathway and augments cell apoptosis via MAPK-mediated signaling pathway in LC and BC cells. These results may provide the experimental basis for future clinical application of EM-2 in the treatment for LC and BC.

Glioblastoma multiforme (GBM) is a deadly type of brain tumor with low patient survival rates. Previous studies have shown that inhibiting the intracellular bile acid transport protein can suppress brain tumor growth, migration, and angiogenesis. This study aims to investigate the effects of the bile acid nuclear receptor (farnesoid X receptor, FXR) agonist GW4064 on the migration, and invasion in GBM cells. GW4064 treatment inhibited the migration and invasion of GBM cells. The protein expression of phosphorylated focal adhesion kinase and protein kinase C alpha (PKC alpha) and activity of matrix metalloproteinase-2 (MMP2) were decreased by GW4064. The PKC activator phorbol 12-myristate 13-acetate (PMA) reversed the GW4064-reduced invasion ability in LN229 cells. Moreover, GW4064 combined with temozolomide (TMZ) treatment inhibited tumor progression in null mice. According to the hematoxylin and eosin stain (HE) and immunostaining, the tumor area and p-PKC alpha were reduced in the GW4064 combined with TMZ group. These results suggested that GW4064 declined the progression of GBM cells, with the inhibition of invasion mediated through PKC signaling. Targeting FXR may contribute to future therapeutic strategies for GBM.