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Thyroid carcinoma is the most common endocrine malignancy, with a rising global incidence. Simultaneously, the increased life expectancy of patients with transfusion-dependent thalassemia (TDT) has revealed new long-term complications, including an elevated risk of thyroid cancer. This epidemiological convergence raises the possibility of shared molecular mechanisms. In this review, we explore potential mechanistic associations between TDT and thyroid cancer, focusing on the oncogenic consequences of iron overload. Iron excess in TDT promotes a tumor-permissive environment via oxidative stress, chronic inflammation, and modulation of ferroptosis, a process with dual roles in tumor biology. These alterations contribute to DNA damage, genomic instability, and activation of oncogenic signaling cascades such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), while impairing immune surveillance. Iron-induced epigenetic remodeling and non-coding RNA dysregulation further support malignant transformation. Although a causal relationship remains unproven, the convergence of these pathways underscores the need for thyroid surveillance in thalassemia patients and supports targeted strategies addressing iron metabolism and ferroptotic vulnerability.
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Idiopathic membranous nephropathy (IMN) is among the leading causes of primary glomerular kidney disease and nephrotic syndrome in adults. Meanwhile, it significantly contributes to the incidence of end-stage renal disease. The complex and unique pathogenesis of IMN poses significant challenges to clinical treatments. The growing research evidence suggests a correlation between phospholipase A2 receptor (PLA2R) antibody levels and disease activity in IMN, while thrombospondin type 1 domain containing 7A (THSD7A) also plays a key role in its pathogenesis. However, the reciprocal regulatory relationship between these target antigens and IMN is yet to be explored, thereby preventing the implementation of targeted therapies as the definitive treatment. In recent years, advances in understanding IMN immunopathogenesis have facilitated the development of targeted immunotherapies, particularly B cell-directed agents such as rituximab. These therapies have demonstrated promising clinical efficacy, with significant reductions in proteinuria and delayed disease progression in a subset of patients. However, treatment resistance, relapses, and adverse events remain prevalent, limiting the widespread adoption of these therapies. This review aims to provide a comprehensive overview of the current understanding of IMN, including its pathogenic mechanisms, clinical features, differential diagnosis, and therapeutic strategies rooted in disease biology. Particular emphasis is placed on balancing efficacy with safety to inform the development of more precise and individualized treatment approaches.
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Colorectal cancer (CRC) represents a significant cancer type that leads to many worldwide deaths because its occurrence keeps rising in specific demographic groups. Three elements affect CRC development: genetic makeup, in addition to environmental variables and disturbances in the gut microbiome population. Research now demonstrates that dysbiosis, which is an irregularity in gut microbial populations, plays a fundamental role in stimulating colorectal cancer formation and its advancement. Three bacterial types, namely Fusobacterium nucleatum, Escherichia coli, and Bacteroides fragilis, act as carcinogenic agents in the body by generating chronic inflammation conditions, causing DNA damage and impairing immune defenses. The composition of gut microbiota experiencing modifications due to lifestyle elements like diet and obesity, together with smoking habits and alcohol consumption, ultimately impacts CRC development. Scientific discoveries in the field of microbiome research now enable better opportunities for the prevention and early detection of CRC. Scientists identify microbial biomarkers as potential tools for creating non-invasive testing methods that could fulfill upcoming screening needs. Scientists are currently examining microbiota-targeted treatments like probiotics alongside prebiotics and dietary interventions and also consider fecal microbiota transplantation (FMT) for both CRC prevention and management approaches. The specific treatments intend to rebuild correct gut bacterial levels while promoting beneficial microbial activity alongside lowering inflammatory pathways that contribute to tumor development. A detailed analysis of CRC-gut microbiota associations occurs in this review through investigations about carcinogenic bacterial species plus their pathways, along with environmental factor impacts. The review explores diagnostic methods and treatment possibilities based on microbiome research for managing CRC. Progress in gut microbiota allows potential development of personalized prevention and treatment methods, which hold promise to lower global colorectal cancer incidents.
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Out-of-hospital cardiac arrest (OHCA) remains a critical public health challenge with high mortality and poor neurological outcomes. Extracorporeal cardiopulmonary resuscitation (ECPR) has emerged as a promising intervention for refractory OHCA, offering improved survival and neurological recovery compared with conventional cardiopulmonary resuscitation (CCPR). This expert consensus, developed by the Emergency Medicine Branch of the Chinese Medical Association and the Emergency Medicine Branch of the Guangdong Medical Doctor Association, presents evidence-based recommendations for pre-hospital ECPR implementation in China. Key areas include dispatch protocols, team composition and training, equipment logistics, indications and timing, procedural techniques, and patient transport. The consensus emphasizes initiation of ECPR within 20 minutes of CCPR, establishment of extracorporeal membrane oxygenation within 60 minutes of arrest, and maintenance of high-quality resuscitation during cannulation. Special considerations for unique settings, such as large public events, are also discussed. This document aims to standardize pre-hospital ECPR practices, optimize patient outcomes, and guide healthcare providers in delivering effective extracorporeal life support for OHCA.
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Background: Previous studies have shown that sepsis induces systemic inflammation, affecting liver function. Additionally, noise exposure, as an environmental stressor, can exacerbate inflammation and contribute to organ damage. However, the combined effects of noise exposure and sepsis on liver injury have not been extensively studied. This study aimed to investigate the impact of exposure to different noise intensities on lipopolysaccharide (LPS)-induced liver damage in septic rats.
Methods: Healthy 6–8-week-old Wistar rats were randomly assigned to five groups: control, LPS, noise exposure (NE)-45, NE-75, and NE-105, with 20 rats per group. Rats in the experimental groups received intraperitoneal injection of LPS (5 mg/kg) to induce sepsis, followed by exposure to noise at 0, 45, 75, or 105 dB for 1 hour daily over 7 consecutive days. Within 24 hours after the final noise exposure, blood samples were collected for the assessment of liver function-related biochemical parameters. The expression levels of inflammatory factors and related proteins in liver tissue were determined using Enzyme-Linked Immunosorbent Assay (ELISA) and western blot assays. The liver weight/body weight ratio was calculated for each group to evaluate relative changes in liver mass.
Results: Compared to the LPS group, the survival rate of rats in the NE-105 group was significantly reduced to 5–10% (p < 0.01). Serum and liver biochemical tests showed significant increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as in the liver weight/body weight ratio (p < 0.01). Activities of superoxide dismutase (SOD) and glutathione (GSH) were significantly decreased (p < 0.01), while malondialdehyde (MDA) levels were significantly elevated (p < 0.01). ELISA and western blot analyses indicated significant increases in tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) levels in both serum and liver tissue of rats in the NE-105 group (p < 0.01), accompanied by significant upregulation of Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells p65 (p-NF-κB p65) protein levels (p < 0.01).
Conclusions: High-intensity noise may exacerbate inflammatory responses and oxidative stress in septic rats through the activation of the TLR4/MyD88/NF-κB signaling pathway, thereby significantly aggravating liver damage.
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Background: The development of novel targeted therapies for gastric cancer (GC) has been significantly hindered by our limited understanding of the molecular mechanisms underlying its progression. As SIN3 transcription regulator family member A (SIN3A) and synaptopodin-2 (SYNPO2) may influence GC progression, this study aimed to investigate the impact of SIN3A-mediated regulation of SYNPO2 on GC progression.
Methods: The expression levels of SYNPO2 and its binding interaction with SIN3A in GC were analyzed using bioinformatics tools. The binding sites between SIN3A and SYNPO2 were validated through a dual-luciferase reporter assay. Furthermore, the biological function of SIN3A in regulating SYNPO2 was investigated in GC cells using gene silencing and overexpression approaches. Cell proliferation, colony formation, apoptosis, migration, and invasion were assessed using cell counting, colony formation assay, flow cytometry, wound healing, Transwell, and molecular analyses.
Results: GC cells presented significantly reduced SYNPO2 expression (p < 0.01). SYNPO2 overexpression inhibited GC cell viability, colony formation, migration, and invasion, while promoting apoptosis (p < 0.01). SYNPO2 was found to bind to SIN3A and mediate its transcriptional repression. SIN3A overexpression enhanced GC cell viability, colony formation, migration, and invasion, inhibited apoptosis, upregulated B-cell lymphoma 2 (Bcl-2), and downregulated Bcl-2-associated X protein (Bax) and cleaved caspase-3 expression, whereas SIN3A knockdown produced the opposite effects (p < 0.05). The effects of SIN3A knockdown were reversed by SYNPO2 silencing in GC cells (p < 0.05).
Conclusion: SIN3A knockdown-mediated upregulation of SYNPO2 suppresses GC malignancy processes, offering insights into a novel strategy for developing targeted therapies for gastric cancer.
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Background: Respiratory distress syndrome (RDS) is a common clinical condition in preterm infants, complicated by pulmonary inflammation and edema. Early identification remains challenging due to limitations in conventional diagnostics. This study aims to explore the clinical significance of pulse oximetry monitoring in predicting RDS in low birth weight (LBW) neonates.
Methods: This retrospective analysis included 140 LBW neonates admitted to Zhongshan Hospital of Xiamen University between February 2022 and March 2023. The patients were divided into an RDS group (n = 51) and a non-RDS group (n = 89) based on the RDS diagnostic criteria. Furthermore, based on the severity of RDS, they were categorized into mild, moderate, and severe RDS subgroups. Additionally, based on surfactant therapy, patients in the RDS group were divided into the surfactant and non-surfactant subgroups. Baseline clinical characteristics were compared between the two groups. Similarly, pulse oximetry, heart rate, and respiratory rate were analyzed among the patients. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for RDS diagnosis. The clinical significance of combined heart rate, respiratory rate, 1-minute Apgar score, and the ratio of peripheral oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) in predicting RDS was assessed using receiver operating characteristic (ROC) curve analysis.
Results: Compared to the non-RDS group, the RDS group had significantly higher heart rate and respiratory rate at 6 h (p < 0.001) and lower SpO2 and SpO2/FiO2 (p = 0.017, p < 0.001). Additionally, the surfactant group showed a significantly higher SpO2/FiO2 ratio at 6 h, 12 h, and 24 h, compared to the non-surfactant group (p < 0.05). Multivariate logistic regression analysis identified heart rate (p = 0.042) and respiratory rate (p = 0.009), as independent risk factors, while 1-minute Apgar score (p = 0.037) and SpO2/FiO2 (6 h) (p = 0.005) were identified as independent protective factors for predicting RDS in LBW neonates. The ROC curve analysis revealed that the combined prediction model had an area under the curve of 0.995.
Conclusion: In conclusion, heart rate and respiratory rate were identified as independent risk factors, whereas 1-minute Apgar score and SpO2/FiO2 were independent protective factors for RDS in LBW neonates. The combined predictive model shows reliable diagnostic performance, underscoring the clinical significance of pulse oximetry monitoring in early RDS identification.
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Background: Galectin-9 (Gal-9), a crucial immune checkpoint ligand, plays an essential role in human tumors, but its clinical significance in chronic lymphocytic leukemia (CLL) is still unclear. In the current study, we took a closer look at Gal-9 expression as a part of our quest to identify novel prognostic biomarkers of CLL.
Methods: In this study, 126 untreated CLL patients and 40 age and gender-matched controls were analyzed. Plasma Gal-9 levels were quantified using enzyme-linked immunosorbent assay (ELISA), while Gal-9 expression on immune cells was assessed by multicolor flow cytometry. Confocal microscopy was used to visualize Gal-9 localization on B cell membranes. Epstein-Barr virus (EBV)-miR-BamH1 fragment H rightward facing 1-1 (BHRF1-1) expression was detected via reverse transcription quantitative polymerase chain reaction (RT-qPCR), and digital PCR was used to quantify Gal-9 transcripts in purified CD19+ B cells. The presence of CLL-associated cytogenetic abnormalities was determined by fluorescence in situ hybridization (FISH). The study also identified and characterized B regulatory cell (Breg)-like CLL cells and myeloid-derived suppressor cell (MDSC) subsets (monocytic (M-MDSC), polymorphonuclear (PMN-MDSC), and early-stage (eMDSC)) expressing Gal-9. Survival analyses, including Kaplan-Meier and Cox regression models, were performed to evaluate the prognostic significance of Gal-9 expression.
Results: Our results confirmed an increased expression of Gal-9 mRNA (p < 0.0001) as well as an elevated percentage of B-cells with membrane Gal-9 expression (p = 0.04) in CLL patients compared to healthy volunteers. Elevated Gal-9 levels in plasma and increased Gal-9 expression on B cells were associated with poor prognostic markers. Notably, the percentage of Gal-9-positive B-cells was found to be an independent prognostic factor of time to first treatment in CLL patients (p = 0.006). Plasma levels of Gal-9 were closely linked to the percentages of CD19+/Gal-9+ (p < 0.001), eMDSC/Gal-9+ (p < 0.001), and M-MDSC/Gal-9+ (p = 0.001) cells. Moreover, it was noted that Gal-9 expression was significantly higher (p < 0.0001) within the CD19+CD5+CD24highCD38high fraction in comparison to the non-Breg CLL cells. Finally, higher levels of Gal-9 expression were linked to EBV positivity and the expression of EBV-miR-BHRF1-1.
Conclusions: Gal-9 expression in leukemic B cells and plasma may serve as a marker of disease activity in CLL. Moreover, an increase in malignant B cell production, along with a boost in MDSC cells, appears to coincide with a significant increase in Gal-9 concentration. Breg-like CLL cells show distinct Gal-9 expression compared to non-Breg CLL cells. Gal-9 may enhance the immunosuppressive potential of Breg. Moreover, EBV-driven Gal-9 upregulation may worsen prognosis in CLL.
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Background: Deltex E3 ubiquitin ligase 3L (DTX3L) is implicated in the progression of various cancer types; however, its specific contribution to intrahepatic cholangiocarcinoma (ICC) remains unexplored. Therefore, this study sought to investigate the involvement of DTX3L in ICC development and elucidate its regulatory effect on endoplasmic reticulum stress (ERS) and apoptosis via P53 ubiquitination.
Methods: We systematically evaluated DTX3L expression in ICC samples using qRT-PCR and Western blotting. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry, were performed to assess cell proliferation and apoptosis. Co-immunoprecipitation and ubiquitination assays were employed to investigate the interaction between DTX3L and P53. In vivo, tumor xenograft models were used to examine the effects of DTX3L knockdown on tumor growth and ERS pathway activation.
Results: DTX3L was significantly overexpressed in ICC tissues and cells (p < 0.05), and its overexpression promoted proliferation, suppressed apoptosis, and downregulated ERS-associated markers, including phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), and activating transcription factor 4 (ATF4) (p < 0.01). Mechanistically, DTX3L directly interacted with P53 and enhanced its ubiquitination and degradation, attenuating its tumor-suppressive effects. Knockdown of DTX3L significantly activated ERS signaling and induced apoptosis (p < 0.01), the effects were reversed by simultaneous P53 knockdown (p < 0.01).
Conclusion: DTX3L is a critical oncogene in ICC progression by promoting P53 ubiquitination-mediated suppression of ERS and apoptosis. These findings suggest that DTX3L may serve as a promising therapeutic target in ICC.
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Background: Sepsis, a life-threatening condition resulting from a dysregulated host response to infection, frequently progresses to acute lung injury (ALI), a severe complication associated with high mortality due to the lack of reliable early-stage biomarkers. Neutrophil extracellular traps (NETs) and the associated inflammatory cascade aggravate disease progression via positive feedback mechanisms. This study aimed to investigate the heterogeneity of NETs- and inflammation-related genes (NIRGs) in sepsis-induced ALI (siALI), construct a diagnostic model, and characterize the immune microenvironment (IME) and its association with immune cell infiltration (ICI).
Methods: Publicly available transcriptomic datasets from the Gene Expression Omnibus (GEO) (GSE66890, GSE32707, GSE10474), GeneCards and relevant literature were used to identify differentially expressed Neutrophil extracellular traps and Inflammatory-Related Differentially Expressed Genes (NIRDEGs), which were subsequently validated. Perturbed biological processes and immune-cell dynamics were examined via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), as well as immune cell deconvolution using CIBERSORT. Multiple machine learning algorithms were employed to construct a diagnosis model, which was evaluated using receiver operating characteristic (ROC) curve analysis, calibration plots, decision curve analysis (DCA), and external validation. Regulatory networks (mRNA-transcription factor, mRNA-miRNA, and mRNA-drug) were constructed using ChIPBase, StarBase 3.0, and the Comparative Toxicogenomics Database (CTD).
Results: Eight genes, S100 Calcium Binding Protein A12 (S100A12), Proteinase 3 (PRTN3), Toll-like receptor 2 (TLR2), triggering receptors expressed on myeloid cells-1 (TREM1), Serum and glucocorticoid-induced kinanse-1 (SGK1), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), Fibrinogen-like protein 2 (FGL2), and Toll-like receptor 8 (TLR8), were identified as candidate diagnostic biomarkers and therapeutic targets for siALI. High-risk patients showed enrichment in thrombopoietin (TPO), receptor for advanced glycation end-products (RAGE), Toll-like receptor (TLR), and NOD-like receptor (NLR) signaling pathways. Distinct patterns of ICI effectively distinguished sepsis from siALI, and the identified genes were related to immune regulation.
Conclusions: This study elucidates the molecular architecture and immune microenvironment of siALI, offering a robust foundation for early diagnosis and personalized therapeutic strategies.
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Background: The oncogenic gene E2F transcription factor 1 (E2F1) plays a key role in tumors. This study was designed to explore the effect of E2F1 gene expression manipulation and cisplatin on retinoblastoma cells and delineate the underlying mechanism.
Methods: E2F1 expression in retinoblastoma cells was determined using quantitative real-time polymerase chain reaction (qRT-PCR). After E2F1 knockdown, cisplatin-treated cells presenting a malignant phenotype were identified through several methods, such as MTT assay, determination of half-maximal inhibitory concentration (IC50) values, flow cytometry, and comet assay. The effects of E2F1 silencing with/without cisplatin on downstream target genes were explored using qRT-PCR and Western blotting. To elucidate the mechanism involving E2F1 and centromere protein E (CENPE) in retinoblastoma, rescue experiments were conducted using cells overexpressing CENPE.
Results: E2F1 was highly expressed in retinoblastoma cells (p < 0.05). E2F1 silencing improved the effectiveness of cisplatin in suppressing viability, as well as promoting apoptosis, increasing G1 phase and DNA damage of retinoblastoma cells (p < 0.05). Upregulation of CENPE expression partially reversed the effects of E2F1 silencing on cisplatin-treated cells (p < 0.05).
Conclusion: E2F1 silencing enhances the effect of cisplatin in retinoblastoma by inhibiting CENPE.
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Background: Temporomandibular joint (TMJ) disorders are common in adults, leading to cartilage degradation and joint dysfunction. Transforming growth factor-beta (TGF-β) has been found to increase extracellular matrix synthesis and suppress inflammation in osteoarthritis; however, its specific role in TMJ disorders remains uninvestigated. Therefore, this study aims to explore the involvement of TGF-β in TMJ injury repair, particularly examining its effects in aged rats.
Methods: The Sprague-Dawley rats were assigned to young (n = 10) and aged (n = 30) groups, with TMJ injury induced using type II collagenase. TGF-β was injected to activate the TGF-β/Smad signaling pathway, while SB431542 was used as an inhibitor of the pathway. Histological analysis (hematoxylin and eosin [H&E] staining and Safranin O/Fast Green staining) was used to examine cartilage repair, and Western blot analysis was employed to determine changes in TGF-β/Smad pathway and cartilage matrix-related proteins. Furthermore, head withdrawal threshold (HWT) and feeding behavior were evaluated to determine the impact of TGF-β treatment on pain sensitivity and feeding behavior.
Results: TGF-β treatment significantly improved cartilage repair in aged rats following TMJ injury. Histological analysis revealed increased cartilage thickness, improved cell arrangement, and reduced proteoglycan depletion in the TGF-β group. Western blot analysis demonstrated substantially elevated phosphorylated-Smad2/Smad2 (p-Smad2/Smad2) and p-Smad3/Smad3 ratios in the TGF-β group (p < 0.01). Furthermore, TGF-β treatment upregulated the expression of Aggrecan and Collagen II, while downregulating the levels of matrix-degrading enzymes matrix metalloproteinase-13 (MMP-13), matrix metalloproteinase-3 (MMP-3), and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) (p < 0.01). Additionally, the TGF-β group had significantly reduced pain sensitivity and improved feeding behavior compared to the injury group (p < 0.05). In contrast, SB431542 treatment aggravated cartilage degradation, increased proteoglycan loss, elevated matrix-degrading enzymes, and worsened pain sensitivity (p < 0.05).
Conclusion: TGF-β activation promotes cartilage repair in aged rats with TMJ injury by enhancing extracellular matrix synthesis and reducing degradation, offering a novel approach for treating age-related TMJ disorders.
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Background: Early neonatal hypoxic-ischemic encephalopathy (HIE) diagnosis is crucial for prompt neuroprotective intervention. However, current diagnostic methods are restricted by suboptimal sensitivity and delays in prompt identification. Therefore, this study evaluates the impact of combining magnetic resonance imaging (MRI) with color Doppler ultrasound (CDU) on the diagnostic accuracy of early-stage neonatal HIE.
Methods: This retrospective cohort study included 56 neonates with HIE and 47 healthy controls. All study participants underwent both MRI and CDU examinations. MRI provided diffusion-weighted imaging sequences and apparent diffusion coefficient (ADC) values, while CDU assessed cerebral hemodynamics in the middle cerebral artery (MCA) and anterior cerebral artery (ACA). Furthermore, the diagnostic performance of this multimodal approach was evaluated using receiver operating characteristic (ROC) analysis.
Results: MRI showed significantly higher ADC values in the HIE group (14.44 ± 4.43) compared to controls (9.43 ± 3.42, p < 0.001). However, CDU findings revealed significantly lower peak systolic velocity (Vs) and end-diastolic velocity (Vd) values, along with higher resistance index in both MCA and ACA among the HIE group (p < 0.001). The combined MRI and CDU approach demonstrated significantly higher diagnostic accuracy for HIE (area under the curve (AUC): 0.918) compared to MRI alone (AUC: 0.797).
Conclusion: Integrating MRI and CDU significantly enhances early detection of neonatal HIE, enabling the prompt initiation of neuroprotective therapies and improving prognostic assessment. This multimodal strategy may bridge critical gaps in early HIE diagnosis.
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Background: The metabolic and methylation interactions among mutated genes in myelodysplastic syndrome (MDS) represent promising avenues for novel anticancer therapies. This study investigates the mutational and transcriptomic landscapes of MDS to identify hallmark gene mutations, deregulated pathways, and their implications for disease pathogenesis and therapeutic strategies.
Methods: A retrospective, cross-sectional analysis was conducted using mutational data from the cBioPortal for Cancer Genomics (UTokyo, Tokyo, Japan; Nature 2011) and multicenter MDS cohorts (Wellcome Trust Sanger Institute, Hinxton, UK; 2020). Transcriptomic data were sourced from three publicly accessible datasets in the Gene Expression Omnibus database: GSE114922 (Wellcome Trust Centre for Human Genetics, Oxford, UK; 2018), GSE63569 (University of Oxford, Oxford, UK; 2014), and GSE183328 (National Institute for Bioprocessing Research and Training (NIBRT), Dublin, Ireland; 2022). Integrated mutational and transcriptomic data analyses were performed to uncover connections between genetic alterations and metabolic deregulation.
Results: We identified a set of genes harboring mutations that form mutually exclusive modules, potentially driving alterations in cellular metabolism and DNA methylation in patients with MDS. Transcriptomic analyses revealed significant upregulation of these mutated genes, implicating them in disease pathogenesis. Pathway enrichment analysis further elucidated dysregulation in key metabolic processes, including oxidative phosphorylation (OXPHOS), glycolysis, and epigenetic regulation via DNA methylation. These findings highlight the molecular heterogeneity of MDS and its intricate interplay with metabolic and epigenetic networks. Moreover, risk stratification models incorporating DNA methyltransferase 3 alpha (DNMT3A) and tet methylcytosine dioxygenase 2 (TET2) mutations demonstrated robust predictive value for overall survival, reinforcing their clinical relevance and prognostic utility in oncological contexts.
Conclusions: This study offers novel insights into the molecular, metabolic, and DNA methylation mechanisms driving MDS. Integrating mutational signatures with transcriptomic data reveals potential therapeutic targets within key metabolic and DNA methylation pathways. These findings lay the foundation for developing personalized treatment strategies and refining risk stratification models for MDS and related malignancies.
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Background: Cisplatin resistance remains a significant challenge in the treatment of lung cancer, severely limiting its therapeutic efficacy. Solanine has shown potential in sensitizing resistant cancer cells to chemotherapy. The Beclin1-YAP1 signaling axis plays a pivotal role in autophagy regulation and drug resistance. Based on this pathway, the present study aimed to investigate the molecular mechanisms through which solanine overcomes cisplatin resistance in lung cancer.
Methods: A549/cisplatin (DDP) cells were divided into four groups: control, DDP, solanine, and DDP + solanine. Cell invasion and proliferation were evaluated using Transwell assays, scratch wound healing assays, and colony formation assays. The expression levels of Beclin1, Yes-associated protein 1 (YAP1), P-glycoprotein (P-gp), lung resistance-related protein (LRP), transcriptional coactivator with PDZ-binding motif (TAZ), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and mammalian target of rapamycin (mTOR) were analyzed by Western blotting. Additionally, Beclin1 overexpression was employed to validate the impact of solanine.
Results: The DDP, solanine, and DDP + solanine groups demonstrated a significant reduction in the number of invading cells and colonies, as well as a marked decrease in cell migration distance compared to the control group (p < 0.05). Additionally, the expression of proteins associated with DDP resistance was significantly downregulated. The DDP + solanine group showed a substantial decrease in colony formation, invasion, and cell migration distance compared to either the DDP or solanine groups alone. Additionally, overexpression of Beclin1 was found to attenuate the reversal effect of solanine.
Conclusion: Solanine enhances cisplatin sensitivity in A549/DDP cells in vitro, potentially through modulation of the Beclin1-YAP1 signaling pathway.
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Background: The pathological hallmarks of Alzheimer's disease (AD) include microglial polarization toward the pro-inflammatory M1 phenotype and significant neuronal apoptosis. Overactivation of transient receptor potential vanilloid 4 (TRPV4) channels has been identified as a common feature in AD animal models associated with microglial activation and neuronal injury. However, the downstream molecules and signaling pathways regulated by TRPV4 remain incompletely understood. Therefore, this study aimed to elucidate the mechanisms by which TRPV4 promotes microglial M1 polarization and its subsequent effect on hippocampal neuronal apoptosis.
Methods: BV-2 cells were employed as an in vitro model to mimic microglial function, while HT22 cells represented hippocampal neurons. BV-2 cells were treated with the TRPV4 activator GSK1016790A, the TRPV4 antagonist HC-067047, and exogenous recombinant human transforming growth factor-beta 1 (TGF-β1) protein. Following treatment, phagocytic activity was evaluated by co-culturing BV-2 cells with fluorescent microspheres. Enzyme-linked immunosorbent assay was performed to quantify cytokine levels in the supernatant. The proportion of M1 phenotype cells was determined by immunofluorescence staining. Additionally, TGF-β1 protein expression and NF-κB pathway activation were evaluated via Western blot analysis. Subsequently, supernatants from BV-2 cells were collected as a conditioned medium to culture HT22 cells. Cell viability of HT22 cells was assessed using the MTT assay, and apoptosis was measured via Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.
Results: TRPV4 activation significantly enhanced the phagocytic activity and pro-inflammatory cytokine release in BV-2 cells, elevated M1 phenotype marker expression, reduced intracellular TGF-β1 protein levels, and activated the NF-κB signaling pathway (p < 0.05). Additionally, TRPV4 activation impaired HT22 cell viability and significantly promoted apoptosis (p < 0.01). However, treatment with HC-067047 or exogenous TGF-β1 partially reversed the adverse effects of TRPV4 activation on BV-2 and HT22 cells.
Conclusion: In vitro models demonstrated that TRPV4 activation downregulates TGF-β1 expression and activates the NF-κB signaling pathway, thereby enhancing BV-2 microglial polarization toward the M1 phenotype and accelerating neuronal apoptosis. These findings provide a theoretical foundation for developing novel AD therapies targeting TGF-β1, highlighting its potential clinical significance.
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Background: Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, contributes to endothelial dysfunction and the progression of atherosclerosis. Moreover, mitochondrial damage leads to ferroptosis through accumulation of reactive oxygen species (ROS). This study aimed to determine whether bone marrow mesenchymal stem cells (BMSCs) protect endothelial cells from ferroptosis through mitochondrial transfer.
Methods: Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to induce dysfunction. BMSCs were co-cultured with these damaged HUVECs in a direct system without Transwell inserts. Mitochondrial transfer was evaluated using MitoTracker probes. Key indicators, including adenosine triphosphate (ATP) production, mitochondrial membrane potential, ferroptosis markers (Fe2+, ROS, malondialdehyde (MDA), lactate dehydrogenase (LDH)), and ferroptosis-related protein expression (Glutathione Peroxidase 4 (GPX4), Solute Carrier Family 7 Member 11(SLC7A11), Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)) were assessed. Furthermore, rescue experiments were performed using ferroptosis activator Rat Sarcoma Viral Oncogene Homolog (RAS)-selective lethal small molecule 3 (RSL3) to validate the underlying mechanisms.
Results: Dual fluorescence microscopy revealed that BMSCs successfully transferred mitochondria to ox-LDL-injured HUVECs. Mitochondrial transfer significantly increased ATP production (1.9-fold, p < 0.01), restored mitochondrial membrane potential (p < 0.01), and enhanced endothelial viability (p < 0.01). Furthermore, ferroptosis-related markers were significantly altered: Fe2+, MDA, LDH, and ROS levels decreased (p < 0.05), while glutathione (GSH) levels and anti-ferroptosis protein GPX4 and SLC7A11 increased (p < 0.01), and pro-ferroptosis protein ACSL4 decreased (p < 0.01). RSL3 treatment reversed these protective effects, confirming the role of ferroptosis inhibition.
Conclusion: This study demonstrates that BMSCs can inhibit ferroptosis and restore endothelial cell function via mitochondrial transfer. These findings offer novel therapeutic insights into the treatment of atherosclerosis by targeting ferroptosis.
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Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and damage. The aim of this study was to evaluate the therapeutic effects of Loxo-305, a novel treatment, on RA in a mouse model.
Methods: Through intravenous injection of collagen-Complete Freund's Adjuvant (CFA) emulsion (100 μL), Dilute Brown Non-Agouti 1 (DBA/1) mice were induced with RA. Two weeks after immunization, the severity of joint swelling was assessed. Mice in the low-dose and high-dose Loxo-305 groups were treated with 10 mg/kg/day and 20 mg/kg/day of Loxo-305, respectively, for 2 weeks, while animals in the control and model groups were administered saline. The mice were euthanized after the treatment period, and their peripheral blood, spleen, and joint tissues were collected for analysis. Histological analysis of joint tissues was performed using hematoxylin and eosin (HE) staining, and osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase (TRAP) staining. The expression of Cluster of Differentiation 19 (CD19), Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL), and Cluster of Differentiation 11b (CD11b) in tissues was detected by means of immunohistochemistry (IHC). Spleen cells were isolated and stimulated with anti-immunoglobulin M (IgM) antibodies to induce B cell differentiation. Cell proliferation was assessed using 5-ethynyl-2′-deoxyuridine staining (EdU) staining, and B cell activation was analyzed by flow cytometry. Serum immunoglobulin and inflammatory cytokine levels were measured through enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) was used to quantify the expression of osteoclast-related genes in joint tissues.
Results: Loxo-305 effectively inhibited the progression of RA in mice, significantly reducing paw swelling, synovial hyperplasia, inflammatory cell infiltration, cartilage erosion, and bone destruction in a dose-dependent manner (p < 0.05). It attenuated osteoclast formation, inhibited B cell activation, and reduced plasma cell numbers and serum immunoglobulin G (IgG) levels (p < 0.05). Loxo-305 also decreased the expression of TRAP, Dendritic Cell-Specific Transmembrane Protein (DC-STAMP), Cathepsin K (CTSK), and RANKL while increasing Osteoprotegerin (OPG) levels in joint tissues (p < 0.05) and significantly suppressed joint inflammation by reducing interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-1β, and CD11b expression (p < 0.05).
Conclusions: Loxo-305 effectively inhibits the progression of RA by suppressing osteoclastogenesis, B cell and plasma cell activation, and reducing the expression of inflammatory cytokines and RANKL, demonstrating significant therapeutic potential. Loxo-305 effectively controls the progression of RA through a dual mechanism of “immune regulation and bone protection”. Compared to existing Bruton's tyrosine kinase (BTK) inhibitors, it offers superior target specificity, safety, and breadth of action, highlighting its potential and promising clinical translational value in the treatment of RA.
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Background: Atherosclerosis (AS) is a primary driver of cardiovascular disease. This study aimed to investigate the effects of a high-cholesterol diet (HD) on body weight, lipid profile, inflammatory cytokines, plaque stability, and histopathological changes in Apolipoprotein E (ApoE)-/- and wild-type (WT) mice, to clarify the underlying mechanisms of AS.
Methods: ApoE-/- and wild-type mice were fed HD or normal diet (ND) for 4 weeks. Body weight was monitored weekly to assess the development of obesity. The serum levels of blood lipids and inflammatory factors were examined using the corresponding kits. The expression of plaque stability markers was confirmed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot. Besides, the structure and fat deposition of coronary artery tissues were assessed using hematoxylin and eosin (H&E), Masson trichrome, oil red O, Prussian blue, and immunohistochemical staining.
Results: Relative to the ND group, the body weight of mice notably increased in the HD group (p < 0.01). HD feeding elevated serum lipids and pro-inflammatory markers in ApoE-/- and wild-type mice (p < 0.01). Expression of plaque instability markers was significantly upregulated in HD-fed groups (p < 0.05). Histological analysis revealed structural disorganization, increased lipid and iron deposition, and greater collagen accumulation in coronary tissues, particularly in the ApoE-/- mice.
Conclusion: This study demonstrated that HD might accelerate AS by promoting obesity, dyslipidemia, inflammation, plaque instability, and vascular remodeling, especially in genetically susceptible ApoE-/- mice. These results may provide new insights for AS prevention and therapy.
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Bispecific antibodies represent a new weapon in the solid tumor oncology armamentarium. In gastric cancer, where available targeted therapies are restricted to a minority of patients, bispecific antibodies may provide much needed new targeted options. This commentary discusses the main constructs and targets of bispecific antibodies in development for gastric cancer.
