Search Results (4,440)

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Cotton Verticillium wilt seriously threatens global cotton production, necessitating the development of resistant cultivars through molecular breeding. Members of the ethylene response factor (ERF) family function as pivotal transcriptional regulators of the ethylene signaling pathway, orchestrating plant defensive responses against pathogen invasion. Here, through comprehensive phenotypic and transcriptional analyses of lignin biosynthesis genes in AtERF49-overexpressing lines, loss-of-function mutants, dominant repressor plants, and GhERF49-silenced cotton plants (TRV-VIGS), we demonstrate that AtERF49 functions as a negative regulator of Verticillium wilt resistance. Overexpression of AtERF49 significantly compromised defense responses in Arabidopsis thaliana, whereas GhERF49 silencing enhanced cotton resistance to Verticillium wilt. Transcription analysis showed that ERF49-mediated susceptibility correlates with suppression of lignin biosynthesis-related genes following pathogen challenge, suggesting that ERF49 interferes with inducible cell wall fortification. These findings elucidate a previously unrecognized negative regulatory node linking ethylene signaling to lignin-mediated disease resistance, providing promising biotechnological targets for engineering durable Verticillium wilt resistance in cotton and related crops. Full article

Although the parental recombinant protein rLj-RGD3 exhibits antitumor activity, it carries immunogenicity risks owing to its large molecular size (13.5 kDa). We generated a genetically truncated mutant, rLj-RGD4 (6.27 kDa, four RGD motifs), which inhibited B16 melanoma cell proliferation, migration, and invasion in vitro. However, the in vivo efficacy and mechanisms of action remain unclear. Here, B16 xenograft mice were treated with rLj-RGD4 (5, 10, and 20 μg/kg i.p. daily for 14 days). Tumor growth was measured, and histopathology/apoptosis was evaluated using hematoxylin and eosin (HE), Masson’s dye, Hoechst, and TUNEL staining. Apoptotic pathways (mitochondrial, death receptor, and MAPK) were analyzed via Western blotting, whereas endocytosis mechanisms were explored using inhibitors (filipin III, NaN₃, cytochalasin D), and EGFR (epidermal growth factor receptor) interactions via fluorescence co-localization and phosphoprotein assays. The results demonstrated dose-dependent tumor growth inhibition (21.60–89.26% volume reduction, 41.03–86.51% weight reduction), with histological evidence of tissue loosening, fibrosis, and apoptosis. rLj-RGD4 induced apoptosis by activating the mitochondrial (Bax/Bcl-2 upregulation), death receptor (caspase-8 activation), and MAPK (JNK/p38 phosphorylation) pathways. Internalization was blocked by NaN₃ and cytochalasin D, indicating actin-dependent macropinocytosis. Direct EGFR binding was confirmed, accompanied by reduced EGFR expression and the inhibition of FAK/AKT/Src signaling. In conclusion, rLj-RGD4 exerts potent in vivo antitumor activity via two mechanisms: induction of multi-pathway apoptosis and EGFR-targeted suppression of pro-survival signaling. RGD4 exerts its antitumor function in vivo by targeting and co-internalizing with EGFR. Full article

Background: This narrative review introduces the “From Plaque to Perfusion” framework, a clinically pragmatic approach that maps multimodality imaging technologies to critical decision points in the acute coronary syndrome (ACS) patient journey. By integrating non-invasive assessment, invasive procedural guidance, and post-event tissue characterisation, this framework provides a structured pathway for deep phenotyping of ACS. Artificial intelligence (AI) is highlighted as an essential enabling layer that enhances diagnostic precision, automates quantification, and supports scalable, data-driven care. Contemporary ACS management pathways, while effective, often leave residual clinical uncertainty. The diagnostic objective has evolved beyond confirming myocardial injury to comprehensively phenotyping the entire ACS cascade: defining the plaque substrate, identifying the culprit mechanism, and quantifying the myocardial consequence. This requires a systematic integration of advanced imaging modalities. Methods: This narrative review is based on a comprehensive literature search of major medical databases (PubMed/MEDLINE, Scopus, Embase, Google Scholar) for high-level evidence, including randomized controlled trials, meta-analyses, and international expert consensus documents published between January 2010 and February 2026. Results: The “From Plaque to Perfusion” framework consists of three core stages. First, non-invasive assessment with coronary computed tomography angiography (CCTA), fractional flow reserve (FFR-CT), and PET-CT defines plaque substrate and vascular inflammation. Second, invasive precision in the catheterization laboratory, guided by optical coherence tomography (OCT) and intravascular ultrasound (IVUS), resolves the culprit mechanism and optimizes percutaneous coronary intervention (PCI). Third, post-event tissue characterization with cardiac magnetic resonance (CMR) quantifies myocardial injury and refines prognosis. AI-driven platforms are shown to enhance each stage by automating analysis, standardizing interpretation, and providing actionable metrics for clinical decisions, including complex scenarios like Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA). Conclusions: The “From Plaque to Perfusion” framework, enabled by AI, reframes ACS imaging as an integrated, mechanism-driven pathway. This approach moves beyond isolated test interpretation toward a scalable model of precision, phenotype-led care that promises to improve diagnostic certainty and personalize patient management. Full article

Background/Objectives: Inflammatory mediators within the tumor microenvironment contribute to lung cancer progression by enhancing cellular motility and invasive capacity through cytokine-dependent signaling networks. Modulation of these inflammation-associated pathways by dietary bioactive compounds may provide complementary strategies for limiting cancer aggressiveness. Our objective was to examine the inhibitory effects of a cyanidin-3-O-glucoside (C3G)-rich fraction from Kum Akha pigmented black rice (CKAB-P1) on inflammation-stimulated A549 cancer cell progression. Methods: CKAB-P1 was obtained through solvent-partition extraction and chemically characterized using the pH differential method and high-performance liquid chromatography. A549 cells were pretreated with CKAB-P1 or C3G, followed by stimulation with conditioned medium predominantly containing IL-6 and IL-1β derived from LPS-exposed THP-1 macrophages (THP-1-CS). Effects on cancer cell migration and invasion were evaluated using wound-healing, Transwell invasion, gelatin zymography, and Western blot analyses. Results: CKAB-P1 contained 106.62 ± 3.54 mg/g extract of total anthocyanins, with C3G representing the major constituent (59.42 ± 2.54 mg/g extract). Exposure of THP-1-CS stimulated migration and invasion of A549 lung cancer, and neutralization of IL-6 and IL-1β reduced these pro-migratory effects, confirming cytokine involvement. Treatment with CKAB-P1 (10–40 μg/mL) or C3G (2.5–20 μg/mL) markedly attenuated inflammation-enhanced migration and invasion (p < 0.05). A reduction in MMP-2 and MMP-9 activity, along with decreased expression of invasion-associated protein expressions (uPA, uPAR, and MT1-MMP), was observed. Furthermore, both CKAB-P1 and C3G attenuated phosphorylation of JAK1 and STAT3. Conclusions: These findings suggest that anthocyanin-enriched black rice fraction may limit inflammation-driven A549 lung cancer cell aggressiveness through modulation of the cytokine-driven JAK1/STAT3 signaling cascade, indicating its potential relevance as a bioactive dietary component targeting tumor-associated inflammatory signaling. Full article

Background: Osteosarcoma (OS) is an aggressive bone tumor. The lack of physiologically relevant three-dimensional models that recapitulate the native tumor microenvironment hampers drug development and mechanistic studies. The study aimed to develop bone-mimetic microspheres for the construction of an OS model. Materials and Methods: We employed droplet microfluidics to fabricate bone-mimetic microspheres (named MSHA) from a composite of gelatin methacryloyl, polyethylene glycol diacrylate, and nano-hydroxyapatite (nHA). MNNG/HOS cells were cultured on MSHA microspheres and subsequently evaluated for their bioactivity and capabilities of stemness, migration, and invasion. Results: The microfluidic platform enabled efficient and scalable production of highly uniform MSHA microspheres with controlled sizes. MNNG/HOS cells cultured on MSHA maintained high viability and spontaneously formed compact tumor spheroids after 7 days. Compared with two-dimensional cultures, cells cultured on these microsphere-based platforms exhibited enhanced migration and invasion capacities, along with increased expression of relevant biomarkers. RNA sequencing further revealed the activation of cancer-related pathways. Notably, the incorporation of nHA into microspheres amplified these malignant phenotypes, potentially through the activation of ECM–receptor interaction and calcium signaling pathways. Conclusions: The microfluidics-fabricated MSHA microspheres, as biomimetic three-dimensional culture scaffolds, offer a promising platform for applications in mechanistic studies of osteosarcoma progression and drug screening. Full article

Brain–machine interfaces (BMIs) aim to decode motor intentions from neural activity to enable direct control of external devices. However, most existing decoders rely on monolithic architectures that fail to capture the distinct neural representations of different joint movement directions, limiting their generalizability. In this work, we propose a Single-Direction CNN-LSTM decoder inspired by motor cortex encoding mechanisms, which separately models extension and flexion dynamics through parallel CNN-LSTM branches. Each branch extracts spatial–temporal features from neural spike data and predicts directional joint variables, which are then combined by subtraction to yield the net angular velocity and torque of upper-limb joints. Using invasive recordings from a macaque during a 2D center-out reaching task, we demonstrate that our decoder achieves comparable performance to a conventional CNN-LSTM when trained on all tasks, while significantly outperforming both CNN-LSTM and linear regression baselines in cross-target generalization scenarios. Moreover, the model can capture physiologically meaningful co-contraction patterns, providing richer insights into motor control. These results suggest that incorporating neuroscience-inspired modular decoding into deep neural architectures enhances robustness and adaptability across tasks, offering a promising pathway for BMI applications in prosthetics and rehabilitation. Full article

Background/Objectives: Cysts are the most common kidney lesions identified in patients undergoing abdominal imaging, with ultrasound (US) typically serving as the initial diagnostic tool. Contrast-enhanced ultrasound (CEUS) has emerged as a highly effective modality for the evaluation of cystic renal lesions, particularly when conventional B-mode ultrasound (US) or CE-CT are inconclusive. While simple renal cysts are readily characterised on US, cystic renal lesions require further assessment. Methods: The Bosniak classification, originally developed for CE-CT, remains the cornerstone for categorising cystic renal lesions, guiding management from surveillance to surgical intervention. Recent efforts to standardise CEUS-specific imaging parameters and adapt the Bosniak criteria aim to improve interobserver agreement, reduce subjectivity, and enhance diagnostic accuracy. Results: CEUS offers superior sensitivity for detecting slow blood flow and minimal vascularity within septa, wall or solid components, often outperforming CE-CT in real-time vascular assessment. However, the high sensitivity of CEUS can reveal additional septa or subtle enhancement, potentially leading to lesion overscoring, if the different sensitivity of CEUS and CT/MRI for detecting enhancement is not taken into account. CEUS also plays a crucial role in the follow-up of non-surgical cystic lesions, providing a radiation-free and cost-effective alternative for long-term monitoring. Certain scenarios, such as post-interventional changes, traumatic cystic rupture, or infected cysts, fall outside the scope of the Bosniak system and require careful clinical correlation. Conclusions: By integrating CEUS into the diagnostic pathway, sonologists can achieve accurate lesion characterisation, optimise patient management, and minimise unnecessary invasive procedures, reinforcing CEUS as an essential tool in the evaluation and follow-up of complex renal cystic masses. Full article

Therapeutic endoscopic ultrasound (t-EUS) has transformed the management of biliopancreatic diseases by enabling minimally invasive access and intervention through the gastrointestinal wall. This narrative review summarizes current indications and evolving roles of t-EUS in benign and malignant biliary disease, with a focus on the different modalities of transmural drainage, EUS-guided gastroenterostomy (EUS-GE), and EUS-guided radiofrequency ablation (EUS-RFA). In benign settings, EUS-gallbladder drainage (EUS-GBD) has emerged as a minimally invasive alternative to percutaneous cholecystostomy for high-risk patients with acute cholecystitis, offering internal drainage with fewer tube-related adverse events. In malignant biliary obstruction, transmural drainages are consolidated alternatives of endoscopic retrograde cholangiopancreatography (ERCP) as first-line or rescue strategies, providing durable internal biliary drainage, avoiding post-ERCP pancreatitis without deteriorating quality of life. In surgically altered anatomy, t-EUS overcomes the limitations of enteroscopy-assisted ERCP by creating direct access routes to the biliary tree or pancreatic duct. EUS-guided pancreatic duct drainage offers a rescue or primary approach in benign strictures, anastomotic stenosis, and disconnected duct syndrome. EUS-GE has rapidly become a preferred modality for palliation of gastric outlet obstruction in pancreatic cancer, while EUS-RFA provides a platform for locoregional therapy in selected cases of pancreatic neuroendocrine tumors, adenocarcinoma, and pancreatic cystic neoplasms. Collectively, these applications position t-EUS as a central tool in the multidisciplinary management of complex biliopancreatic disease, with ongoing innovations expected to further expand its indications and safety and to refine patient selection and training pathways. Full article

Colorectal cancer (CRC) persists as a significant public health burden due to its high morbidity and mortality rates worldwide, yet the molecular events that govern its initiation and progression remain incompletely understood. We recently conducted microRNA (miRNA) profiling and identified multiple dysregulated miRNAs in CRC compared to adjacent normal tissue. Among those, miR-138-5p emerged as a potential tumor suppressor due to its marked downregulation in CRC tissue; however, the stage-specific expression of this miRNA during CRC progression and underlying molecular mechanisms remains to be unraveled. In this study, we performed differential expression profiling of healthy colon, adenomatous polyp (AP), and CRC tissues based on public datasets, revealing significant downregulation of miR-138-5p in CRC compared to controls, but not during the AP stage, suggesting a role in later stages of malignant progression. Forced expression of miR-138-5p in HCT116 and HT-29 CRC models suppressed clonogenic survival, proliferation, and migration while inducing cell death. Additionally, miR-138-5p significantly inhibited tumor formation under three-dimensional culture settings, reinforcing its tumor-suppressive function in a physiologically relevant context. Transcriptomic profiling of miR-138-5p-overexpressing CRC models revealed widespread changes in the pathways related to zinc ion binding, cilium morphogenesis, smoothened signaling, and nuclear transport. Integrated computational and experimental analyses identified 41 potential gene targets, among which TCF3, UBE2C, EIF4EBP1, LYPLA1, and CD44 were validated as potential miR-138-5p-regulated genes. Collectively, these findings establish miR-138-5p as a stage-specific tumor suppressor in CRC, acting through coordinated regulation of oncogenic networks across multiple pathways. Downregulation of miR-138-5p appears to be a late oncogenic event, conferring proliferative, survival, and invasive advantages to tumor cells. Restoration of miR-138-5p or therapeutic targeting of its downstream effectors may represent promising avenues for CRC therapeutic intervention. Full article

Background: Miscarriage is the most common complication of pregnancy. Current trends in medicine point to the increasing importance of evidence-based personalization in diagnostic and therapeutic processes. Purpose: The aim of this study was to develop an innovative prenatal screening panel and treatment strategy for miscarriage prevention. Results: Previous studies have demonstrated an imbalance between oxidative and anti-oxidant mechanisms, resulting in systemic oxidative stress in women with a history of miscarriage. The importance of monitoring toxic metal concentrations as potential risk factors in early pregnancy was confirmed. The involvement of NETs in the pathogenesis of miscarriages was demonstrated, while identifying early biomarkers of this process. The effect of BPA on the activation of NETs and the development of an inflammatory response in the female participants was demonstrated. Furthermore, a mechanism of NO-dependent oxidative–anti-oxidative imbalance and NLRP3 inflammasome activation during pregnancy loss was identified in a pathway independent of NET formation, excluding apoptosis. The participation of certain microRNA molecules in reproductive failure and their value in minimally invasive diagnostics in the early stages of pregnancy have been proven. Conclusions: The proposed screening panel accounts for the above parameters, represents a novel approach in modern prenatal care, and prioritizes miscarriage prevention strategies. Full article

Chronic inflammation contributes to bladder cancer (BC) development and progression through dysregulated cytokine signaling and tumor–immune interactions. This case–control study investigated associations between IL6 rs1800795, TNF rs1800629, CCL2 rs1024611, and VEGFA rs699947 polymorphisms, circulating cytokine levels, clinicopathological characteristics, and autonomic nervous system balance assessed by heart rate variability (HRV) in 73 BC patients and 88 controls. Genotyping was performed using PCR–RFLP, serum cytokine levels were measured by ELISA, and associations were evaluated using logistic, linear regression, and survival analyses. No significant associations with BC risk were observed for IL6, TNF, or VEGFA variants. However, the CCL2 rs1024611 GG genotype was associated with increased BC risk (recessive model: OR = 5.82, p = 0.026). Stratified analyses showed a lower frequency of the IL6 rs1800795 C allele and TNF rs1800629 GA genotype in high-grade and muscle-invasive tumors, suggesting potential associations with reduced tumor aggressiveness. No polymorphism was associated with serum cytokine levels or disease-free survival. In BC patients, the TNF rs1800629 A allele was associated with higher parasympathetic-related HRV indices and lower sympathetic parameters, whereas no such associations were observed in controls. These findings indicate that genetic variation within inflammatory pathways may contribute to BC susceptibility and tumor phenotype and may also modulate neuroimmune interactions. Full article

The Dengying Formation gas reservoir in the Penglai gas field, located in the central Sichuan Basin, exhibits substantial resource potential and promising development prospects. This reservoir is characterized by well-developed fractures and dissolution cavities, strong heterogeneity, complex gas–water relationships, and widespread edge–bottom water. During production, edge–bottom water is prone to channeling and intrusion through high-permeability pathways, which severely constrains well productivity and overall gas recovery. To address these challenges, this study takes a fractured-vuggy carbonate edge–bottom water gas reservoir as an example. By integrating large-scale physical simulation with cross-scale numerical simulation, a rational production allocation method suitable for strongly heterogeneous gas reservoirs has been developed. The research results indicate that: (1) Large-scale physical simulation experiments demonstrate that for fractured-vuggy bottom water gas reservoirs, implementing rate reduction and pressure control after water breakthrough can effectively suppress water invasion and coning, extend the stable production period, and increase the recovery factor by approximately 16%; (2) Based on the dynamic characteristics of water invasion, key similarity criteria including the Bond number, capillary number, gravity–viscous force ratio, and geometric–temporal similarity ratio were selected to establish a scientific parameter design method for cross-scale numerical simulation; (3) By considering factors such as reservoir type and aquifer energy, single-well mechanistic models were used to determine appropriate production rates for individual wells, enabling rapid optimization of production allocation plans. This provides crucial guidance for efficient gas well development and surface facility planning. Full article

Fusarium ear rot (FER), caused by F. verticillioides, is a devastating disease in maize, leading to substantial yield losses and mycotoxin contamination. Therefore, revealing the molecular mechanisms underlying FER resistance is essential for crop breeding. Here, we performed integrated transcriptomic and metabolomic analyses on two maize inbred lines with contrasting FER resistance: the resistant line ZL30-12 (ZL30) and the susceptible line 92C0468U (92C). Following F. verticillioides inoculation, ZL30 exhibited sustained inhibition of fungal colonization and fumonisin accumulation, whereas 92C showed progressive disease development and elevated fumonisin levels. Both transcriptomic and metabolomic analyses converged on the phenylpropanoid pathway, with DEGs enriched in phenylpropanoid metabolism and DAMs enriched in phenylpropanoid biosynthesis, highlighting its central role in resistance. Further integrative analysis revealed that the lignin biosynthetic process, a key branch of phenylpropanoid metabolism, plays an important role in resistance. Several key DEGs (ZmPAL, ZmHCT, peroxidases, and ZmCOMT) and DAMs (sinapic acid, sinapaldehyde, coniferin, cinnamic acid, and caffeic acid) were differentially regulated between the two lines. Correlation analysis revealed a significant correlation between ZmCOMT expression and sinapic acid accumulation. RT-qPCR validation confirmed the expression patterns of key lignin-associated genes. The elevated activation of lignin biosynthesis in ZL30, via time-dependent induction of key genes (ZmPAL, ZmHCT, and peroxidases), suggests an increase in lignin accumulation, which likely reinforces cell wall integrity and restricts fungal invasion, thereby contributing to FER resistance. Collectively, these findings provide insights into the molecular mechanisms of FER resistance and identify key lignin-associated genes as promising targets for maize breeding. Full article

Endoscopic bariatric and metabolic therapies (EBMTs) offer minimally invasive treatment options for obesity and related metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). These therapies are broadly categorized into gastric and small bowel interventions. Gastric EBMTs, including intragastric balloons and endoscopic sleeve gastroplasty, promote weight loss primarily through mechanical restriction and delayed gastric emptying, thereby improving metabolic outcomes. Small bowel therapies target the proximal intestine to modulate nutrient-sensing and hormonal pathways, providing metabolic benefits that may occur independently of weight loss. Techniques such as duodenal mucosal resurfacing, electroporation-based re-cellularization, and duodenal-jejunal bypass liners demonstrate promising effects on glycemic control, insulin sensitivity, and liver health. Emerging technologies utilizing thermal, vapor, and laser ablation further expand therapeutic possibilities. While these interventions show favorable safety profiles and potential as standalone or adjunctive treatments, further long-term studies and randomized trials are necessary to optimize patient selection and procedural protocols. Collectively, EBMTs represent an evolving paradigm in the management of obesity and metabolic diseases, bridging the gap between conservative medical therapies and bariatric surgery. Full article