Search Results (58)

Background/Objectives: Liuwei Dihuang (LWDH) is a classical plant-derived herbal formula widely used for cognitive decline. This study aimed to evaluate its efficacy and safety in cognitive disorders and to explore its potential pharmacological mechanisms using network pharmacology. Methods: We searched 11 databases through November 2024 for randomized controlled trials comparing LWDH plus conventional therapy with conventional therapy alone in cognitive disorders. Meta-analysis was performed for clinical outcomes, and herb–compound–target and disease-target datasets were integrated to identify core molecular modules. Results: Twelve randomized controlled trials involving 1137 participants were included. Adjunctive LWDH was associated with improvements in Mini-Mental State Examination scores (MD = 2.34, 95% CI 0.88–3.79), activities of daily living, and quality of life. However, substantial heterogeneity and methodological limitations, including unclear randomization and blinding, were observed across studies, indicating a potential risk of bias. Fewer adverse events were reported in the LWDH plus conventional treatment group, although reporting quality was limited. The overall risk of bias was judged as “some concerns”. Network pharmacology analysis identified a broad set of overlapping genes between LWDH-associated targets and cognitive disorder-related genes, which were further refined through filtering procedures. Subsequent analyses suggested associations with pathways related to neurodegeneration, apoptosis, and central nervous system function; however, these findings are exploratory and based on in silico predictions. Conclusions: LWDH may be associated with potential adjunctive benefits in cognitive disorders. However, given the methodological limitations and clinical heterogeneity of the included studies, the findings should be interpreted with caution. The proposed pharmacological mechanisms are exploratory and require further validation. Well-designed randomized controlled trials are needed to establish more robust evidence. Full article

Background/Objectives: Gallbladder cancer (GBC) is an aggressive biliary tract malignancy with poor prognosis. Lymph node metastasis is a major determinant of adverse outcome in patients with GBC. Gene mutations play an essential role in tumorigenesis; however, it remains uncertain whether genetic mutations play a substantial role in lymph node metastasis in GBC. Methods: In this study, transcriptome and whole-exome sequencing (WES) were used to analyze gene mutations and expression in GBC tissues, focusing on lymph node metastasis. Bioinformatics tools identified differentially expressed genes (DEGs) and significantly mutated genes (SMGs), followed by pathway enrichment and survival analyses. Results: In total, 669 DEGs were identified between metastatic and non-metastatic GBC tissues. Through protein–protein interaction (PPI) network analysis of these DEGs, GPT and NR1I2 were identified as candidate genes associated with metabolic reprogramming in lymph node metastasis. Prognostic analysis revealed 22 DEGs associated with patient survival, and significant differences in overall survival, clinicopathological features (e.g., N-stage and positive lymph node count) were observed between cluster 1 and cluster 2. Mutation analysis identified 55 SMGs, primarily related to immune and inflammatory responses. By integrating DEGs and SMGs, PLCL2 was identified as a candidate gene potentially associated with both lymph node metastasis and prognosis. GSEA enrichment analysis suggested that PLCL2 was potentially linked to immunity, inflammation, and cellular processes, which may imply its possible involvement in GBC metastasis pending experimental validation. Conclusions: Based on integrative transcriptomic and exomic analyses, we identified PLCL2 as a candidate gene potentially associated with lymph node metastasis in GBC. These hypothesis-generating findings provide a preliminary basis for future mechanistic validation and biomarker exploration. Full article

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Myocardial fibrosis is a key pathological process driving the progression of cardiovascular diseases toward heart failure, closely linked to persistent inflammation and immune dysregulation. Among CC chemokines, CCL17 has emerged as an important mediator connecting immune cell dynamics with fibrotic remodeling. This review outlines current understanding of the cellular sources, regulatory mechanisms, and functional roles of CCL17, with particular attention to its impact on regulatory T cell (Treg) recruitment through ligand-biased signaling. Beyond this mechanism, CCL17 likely operates within a broader inflammatory network, with potential interactions involving CCR2⁺ macrophages and IL-17-related pathways. Experimental studies show that disruption of CCL17 signaling attenuates fibrosis and improves cardiac function, while clinical data link elevated circulating CCL17 to cardiac dysfunction and adverse outcomes. However, the absence of clinical trials and the redundancy of chemokine networks remain key challenges for translation. Overall, CCL17 may serve as a biomarker and therapeutic target, although its clinical application will require a more integrated, network-based understanding. Full article

Bioresorbable scaffolds (BRS; also referred to as bioresorbable vascular scaffolds, BVS) represent a promising approach in interventional cardiology, offering theoretical advantages such as temporary mechanical support followed by complete resorption. However, clinical experience has revealed challenges, including late-stage scaffold thrombosis and heterogeneous scaffold discontinuity during degradation, prompting investigation into host immune responses. Neutrophil extracellular traps (NETs), which are network-like structures composed of decondensed chromatin decorated with antimicrobial proteins, have emerged as critical mediators of vascular inflammation and thrombosis. This review explores the intersection between NET biology and BRS performance, investigating how NETosis affects biocompatibility, degradation kinetics, and device-related complications. We discuss the molecular mechanisms that trigger neutrophil activation and NET formation in scaffold materials, the effect of NET components on polymeric and metallic scaffold degradation, and emerging biomarkers to monitor NET-mediated complications. We also evaluate therapeutic strategies targeting NET pathways, including DNase-based therapies, peptidylarginine deiminase 4 (PAD4) inhibitors, and anti-inflammatory coatings that can optimize next-generation BRS outcomes. Understanding the immunological environment surrounding bioresorbable vascular devices is crucial for developing scaffolds that deliver predictable degradation while minimizing adverse inflammatory responses. Full article

The rapid emergence of novel chemical substances escalates the occupational and environmental health risks, posing significant challenges to the traditional toxicological risk assessment framework. While adverse outcome pathways (AOPs) have become a pivotal theoretical framework for alternative toxicity testing and future risk assessments, their development and optimization remain hindered by time-consuming and labor-intensive manual processing. This narrative review systematically elucidates how artificial intelligence (AI) facilitates the development and optimization of AOPs. Specifically, AI automates the extraction of knowledge modules for AOPs via natural language processing, quantifies key relationships through integrating methods like Bayesian networks, and supports continuous AOP refinement using machine learning platforms. Together, these technologies establish a modern, data-driven, and iterative framework. Furthermore, the review discusses the current limitations in applying AI to the AOP domain alongside its substantial potential to enhance chemical risk assessment and regulatory decision-making. Ultimately, this work aims to provide new insights and methodologies for advancing AOP development, thereby strengthening the risk assessment and regulation of chemical exposures in environmental and occupational settings. Full article

Trouble sleeping has become a global public health challenge. However, the relationship between organophosphate flame retardant (OPFR) exposure and trouble sleeping remains unclear. This study integrated epidemiological analysis, network toxicology, molecular docking, molecular dynamics simulations, and adverse outcome pathway (AOP) construction to identify OPFRs linked to trouble sleeping and attempted to elucidate underlying molecular mechanisms. We analyzed cross-sectional data from the U.S. National Health and Nutrition Examination Survey (NHANES 2013–2018) involving 4585 eligible adults. Logistic regression confirmed dibutyl phosphate (DBuP) as significantly correlated with trouble sleeping. Restricted cubic splines (RCSs) revealed a significant non-linear, J-shaped relationship between dibutyl phosphate (DBuP) levels and trouble sleeping. Weighted quantile sum (WQS) analysis determined that DBuP accounted for the majority contribution (58.23%) to the observed effects within exposure mixtures. These findings indicated that DBuP, a metabolite of tributyl phosphate (TnBP), was closely related to trouble sleeping, suggesting that the environmental health risks of TnBP may be jointly contributed to by itself and DBuP. We used network analysis to identify five core target genes (PPARG, MMP9, PTGS2, APP, EGFR) that interact with DBuP and its parent compound TnBP. Molecular docking predicted binding poses of TnBP and DBuP toward these five core targets; all showed moderate binding affinity (ΔG ≤ −5.0 kcal/mol) except MMP9, which exhibited weak binding. Molecular dynamics simulations further supported this putative binding. Enrichment analysis highlighted inflammatory response pathways. Ultimately, we elucidated the process from molecular exposure to trouble sleeping by constructing an AOP framework. In conclusion, we proposed that TnBP and DBuP may contribute to trouble sleeping through multi-target interactions, primarily through PPARG-driven inflammatory dysregulation. These findings suggest a potential link between OPFR exposure and trouble sleeping, providing insights that warrant further mechanistic investigation. Full article

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors demonstrated amyloid-lowering efficacy but failed in phase II/III clinical trials due to adverse effects and limited disease-modifying outcomes. This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer’s disease (AD). Methods: Drug-associated targets were intersected with AD-related genes to construct a protein–protein interaction (PPI) network, followed by topological analysis to identify hub proteins. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using statistically significant thresholds (p < 0.05, FDR-adjusted). Molecular docking was conducted using AutoDock Vina to quantify binding affinities and interaction modes between the selected compounds and the identified hub proteins. Results: Network analysis identified 10 hub proteins (CASP3, STAT3, BCL2, AKT1, MTOR, BCL2L1, HSP90AA1, HSP90AB1, TNF, and MDM2). GO enrichment highlighted key biological processes, including the negative regulation of autophagy, regulation of apoptotic signalling, protein folding, and inflammatory responses. KEGG pathway analysis revealed significant enrichment in the PI3K–AKT–MTOR signalling, apoptosis, and TNF signalling pathways. Molecular docking demonstrated strong multitarget binding, with binding affinities ranging from approximately −6.6 to −11.4 kcal/mol across the hub proteins. Umibecestat exhibited the strongest binding toward AKT1 (−11.4 kcal/mol), HSP90AB1 (−9.5 kcal/mol), STAT3 (−8.9 kcal/mol), HSP90AA1 (−8.5 kcal/mol), and MTOR (−8.3 kcal/mol), while Lanabecestat showed high affinity for AKT1 (−10.6 kcal/mol), HSP90AA1 (−9.9 kcal/mol), BCL2L1 (−9.2 kcal/mol), and CASP3 (−8.5 kcal/mol), respectively. These interactions were stabilized by conserved hydrogen bonding, hydrophobic contacts, and π–alkyl interactions within key regulatory domains of the target proteins, supporting their multitarget engagement beyond BACE1 inhibition. Conclusions: This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand–hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer’s disease, warranting further in silico refinement and experimental validation. Full article

Diffusion tensor imaging (DTI) tractography is routinely employed in neurosurgical planning; however, the prognostic significance of quantitative DTI metrics for postoperative functional outcomes remains unclear. We conducted a PRISMA-informed systematic review of PubMed (January 2005–1 December 2025), supplemented by additional indexed sources, to synthesize the evidence on quantitative DTI measures associated with postoperative motor, language, and cognitive outcomes following intracranial surgery. Thirty-seven studies were included, primarily single-center studies, and predominantly focused on glioma surgery. Motor outcomes exhibited the most consistent associations, with reduced corticospinal tract integrity and adverse postoperative diffusion changes correlating with muscle weakness and poorer recovery. Recovery from supplementary motor area syndrome was associated with interhemispheric callosal connectivity, with greater disconnection predicting a prolonged symptom duration. Language outcomes demonstrated reproducible structure–function relationships: higher preoperative integrity of the dorsal language pathways was associated with milder postoperative aphasia and better recovery, whereas postoperative tract disruption and diffusivity changes predicted persistent naming and fluency deficits, and ventral pathway alterations were specifically linked to lexico-semantic impairment. In epilepsy surgery, language performance correlated with contralateral and distributed network diffusion changes, consistent with reorganization. Evidence for cognition and gait outcomes was limited and mainly involved the association, limbic, and callosal pathways. Overall, quantitative DTI provides clinically relevant markers of tract and network disruption and postoperative remodeling; however, methodological heterogeneity and limited external validation currently preclude universal prognostic thresholds. Full article

Freshwater cladocerans such as Daphnia magna (D. magna) are keystone grazers whose hormone-regulated life history traits make them sensitive sentinels of endocrine-disrupting chemicals (EDCs). The organophosphate flame-retardant tris(2-butoxyethyl) phosphate (TBOEP) and perfluoroethylcyclohexane sulfonate (PFECHS) now co-occur at ng L⁻¹–µg L⁻¹ in surface waters, yet their chronic sub-lethal impacts on invertebrate endocrine networks remain unclear. We analysed two publicly available 21-day microarray datasets (TBOEP: GSE55132; PFECHS: GSE75607) using gene ontology enrichment, STRING protein interaction networks, Drosophila phenotype mapping, and KEGG (Kyoto Encyclopaedia of Genes and Genomes)-anchored frameworks to build putative adverse outcome pathways (AOPs) for D. magna. Differentially expressed genes were clustered into functional modules and hub nodes were ranked by degree and betweenness. TBOEP suppressed moulting and growth, altering 1157 genes enriched for metabolism and membrane processes; hubs VRK1, MIB2, and adenylosuccinate synthetase formed a muscle anatomical development sub-network. PFECHS down-regulated vitellogenin and shifted 879 genes dominated by oxidative-stress and glutathione-metabolism signatures; central nodes UBC9, eIF4A-III, Tra-2α, and HDAC1 linked meiotic-cycle, oogenesis, and cyclic-compound binding. Despite chemical dissimilarity, both compounds converged on Wnt-signalling nodes—TBOEP via presenilin-1, and PFECHS via CK1ε/CK2—thereby reducing TCF/LEF-dependent transcription. Predicted outcomes include impaired oocyte maturation, reduced fecundity, and stunted body size, consistent with observed decreases in length and vitellogenin protein. Our network analysis, based on high-dose, sub-lethal exposures used in the underlying microarray studies, indicates that TBOEP- and PFECHS-induced perturbations can destabilise endocrine, developmental, and metabolic pathways in D. magna without overt lethality, and highlights Wnt-centred key events and hub genes as candidate biomarkers to be evaluated in future low-dose studies that use environmentally realistic exposure scenarios. Hub genes and Wnt-mediated key events emerge as sensitive biomarkers for monitoring mixed EDC exposure. Full article

Transcatheter aortic valve implantation (TAVI) is the default therapy for most elderly patients with severe aortic stenosis, but outcomes in complex anatomy depend on imaging-guided planning and disciplined technique. This article aims to present our institutional approach, supported by the current literature, in managing several challenging anatomical scenarios. We focus on seven high-impact scenarios—bicuspid aortic valve (BAV), hostile transfemoral access, iliofemoral/aortic tortuosity, adverse aortic angulation, heavy annulus/Left Ventricular Outflow Tract (LVOT) calcification, small annulus, and risk of coronary obstruction—and propose a practical approach to minimize the risk of complications. In BAV, current generation transcatheter heart valves (THV) achieve favorable early outcomes when sizing accounts for supra-annular constraints and implantation depth is tailored. Transfemoral access remains dominant in contemporary registries, yet a meaningful minority of cases require adjunctive peripheral vascular intervention to enable THV delivery-system passage. In case of annulus or LVOT calcification, small annuli, complex aortic anatomy, high risk for coronary obstruction, and pre-procedural Computed Tomography (CT) allow for an accurate sizing of THV and tailored procedural planning. A structured, CT-driven pathway that links anatomic findings to specific facilitation and bailout steps can standardize decision-making and improve safety across these challenging scenarios. We strongly highlight the importance to build a network where most complex procedures are carried out in Valve Centers where expert operators are trained to manage high volume, high complexity, and difficult complications. Full article

Endocrine-disrupting chemicals (EDCs) are widespread contaminants that interfere with hormonal signaling and compromise reproductive success in aquatic organisms. Vitellogenin (VTG) is one of the most widely established biomarkers of estrogenic exposure, especially in males and juveniles. However, evidence from multi-omics studies indicates that VTG induction occurs within broader transcriptional and regulatory networks, involving genes such as cyp19a1 (aromatase), cyp1a (cytochrome P4501A), and other stress-responsive genes, underscoring the complexity of endocrine disruption. This review focuses on nuclear receptor isoforms, including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR) variants. We examine the diversification of vtg gene repertoires across teleost genomes and epigenetic mechanisms, such as DNA methylation and microRNAs, that modulate sex-dependent sensitivity. In addition, we discuss integrative approaches that combine VTG with transcriptomic, epigenetic, and histological endpoints. Within the Adverse Outcome Pathway (AOP) and weight-of-evidence (WoE) frameworks, these strategies provide mechanistic links between receptor activation and reproductive impairment. Finally, we outline future directions, focusing on the development of sex-specific biomarker panels, the integration of omics-based data with machine learning, and advances in ecogenomics. Embedding molecular responses into ecological and regulatory contexts will help bridge mechanistic insights with environmental relevance and support sustainability goals such as SDG 14 (Life Below Water). Full article

Background/Objectives: Eating disorders (EDs) frequently emerge during critical stages of childhood and adolescence, when identity development and emotional regulation are still maturing. Disturbances in self-concept clarity and identity integration may transform the body into a symbolic battlefield for autonomy, belonging, and self-worth. This review synthesizes developmental, psychosocial, neurocognitive, and therapeutic perspectives on the role of identity disturbance in EDs. Methods: A narrative review was conducted (2010–2025) using combinations of terms related to identity, self-concept clarity, self-discrepancy, objectification, interoception, and eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). Results: Findings indicate that identity vulnerability (expressed as low self-concept clarity, heightened self-discrepancies, and self-objectification) mediates the association between early adversity, sociocultural pressures, and ED symptoms. Neurocognitive studies reveal altered self-referential processing, default mode network connectivity, and interoceptive signaling. Clinically, comorbid borderline personality features further exacerbate identity disturbance and complicate recovery. Evidence-based treatments such as enhanced cognitive-behavioral therapy (CBT-E) effectively target core maintaining mechanisms, while adjunctive interventions (mentalization-based therapy, schema therapy, narrative approaches, and compassion- or acceptance-based methods) show promise in addressing identity-related processes and improving outcomes. Conclusions: Identity disturbance provides a unifying framework for understanding why ED symptoms become entrenched despite adverse consequences. Integrating identity-focused approaches with nutritional and medical care may enhance recovery and reduce chronicity in youth. Future research should adopt longitudinal and mechanistic designs to clarify pathways linking identity change to clinical improvement and test identity-specific augmentations to standard ED treatments. Full article

Objective: To systematically evaluate the efficacy and explore the mechanisms of Yiqi and blood-activating traditional Chinese medicine (TCM) combined with chemotherapy in treating non-small cell lung cancer (NSCLC). Methods: Randomized controlled trials (RCTs) on chemotherapy combined with Yiqi and blood-activating TCM for NSCLC were retrieved from CNKI, VIP, Wanfang, and PubMed databases. The search period covered from the inception of each database to January 2025. Study quality was assessed via the Cochrane Risk of Bias tool. Meta-analysis evaluated clinical efficacy, data mining identified core herbs and active compounds, and network pharmacology analyzed targets and pathways. Immune infiltration analysis explored immunomodulatory mechanisms. Results: A total of 57 RCTs with 4865 patients were analyzed. Combined therapy significantly improved short-term efficacy, relieved symptoms (e.g., cough, fatigue), reduced adverse effects, and enhanced quality of life versus chemotherapy alone. Data mining identified Astragalus membranaceus, Atractylodes macrocephala, and Poria cocos as core herbs. Network pharmacology revealed 40 active compounds (including quercetin and kaempferol) that targeted 137 key proteins (e.g., TP53, AKT1), with these targets mainly involved in immune regulation. Immune infiltration analysis showed increased CD4+ T cells and balanced T cell subsets, indicating enhanced antitumor immunity. Conclusions: Yiqi and blood-activating TCM combined with chemotherapy improves NSCLC outcomes by modulating the tumor immune microenvironment. This supports the integration of TCM and highlights immune regulation as a key mechanism. Full article

Epithelial ovarian cancer (EOC) remains one of the deadliest gynecologic malignancies, largely due to late diagnosis and treatment resistance. The main objective of this study is to identify and validate CDK1 as a high-confidence therapeutic target in EOC and to assess the dual-target inhibitory potential of the natural compound Naringin against both CDK1 and its regulator WEE1. This study employed an integrative pipeline combining transcriptomic profiling, protein–protein interaction network analysis, machine learning, and molecular simulations to identify key oncogenic regulators in EOC. CDK1 emerged as a central hub gene, exhibiting strong association with poor prognosis and signaling convergence. CDK1 overexpression correlated with adverse survival outcomes and robust involvement in critical oncogenic pathways. Molecular docking and dynamics simulations assessed the binding efficacy of seven compounds with CDK1 and WEE1, with Naringin showing high-affinity binding, stable complex formation, and minimal predicted toxicity. This study underscores the power of computational-experimental integration in accelerating oncology drug discovery, providing visual and quantitative evidence that systematically connect the study’s aim to its findings. Full article