Neonicotinoid pesticides are widely used systemic insecticides with increasing evidence of neurotoxicity. However, their potential contribution to Alzheimer's disease (AD)-related neuroinflammation remains poorly understood. In this study, seven representative neonicotinoid pesticides were systematically evaluated by integrating physicochemical characterization, target prediction, pathway enrichment analysis, human AD snRNA-seq, molecular docking, molecular dynamics simulations, and experimental validation. Among the seven compounds, dinotefuran was prioritized based on its favorable blood-brain barrier permeability and enrichment in inflammation-related pathways. Integration of target prediction with AD transcriptomic analyses identified CHUK and NFKB1 as key candidate targets associated with NF-κB signaling. snRNA-seq analysis further demonstrated preferential enrichment of NF-κB signaling activity in microglia from AD brains. Molecular docking and molecular dynamics simulations supported potential interactions between dinotefuran and IKKα (CHUK) as well as NF-κB1 (p50). In Aβ-treated BV2 microglia, dinotefuran further enhanced activation of the CHUK/NFKB1-mediated NF-κB signaling pathway, accompanied by increased expression of IKKα, phosphorylation of IκBα and p65, enhanced NF-κB1 activation, and elevated secretion of IL-1β, TNF-α, IL-6, IFN-α, and IFN-β. These pro-inflammatory effects were markedly attenuated by the NF-κB inhibitor BAY11-7082. Collectively, our findings suggest that CHUK/NFKB1-associated NF-κB signaling may contribute to dinotefuran-enhanced inflammatory responses in Aβ-treated BV2 microglia, providing preliminary mechanistic insights into the potential involvement of neonicotinoid pesticides in AD-related neuroinflammation.
Objective Impaired alveolar bone regeneration following tooth extraction is a common, clinically difficult complication in patients with type 2 diabetes mellitus (T2DM). Diabetic inflammation and immune dysregulation are known to cause defective bone repair, yet the core molecular mechanisms remain unclear. This study aimed to identify the key molecular mediator connecting hyperglycemia and osteoimmunological dysfunction. Methods We combined National Health and Nutrition Examination Survey (NHANES) epidemiological cohort analysis, transcriptomic weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression, single-cell RNA sequencing, streptozotocin-induced diabetic rat tooth extraction animal experiments, NK-92MI cell functional detection, and molecular docking prediction. Results Glycemic markers were negatively correlated with femoral neck bone mineral density. EF-hand domain-containing protein 2 (EFHD2) was identified as the hub gene shared between T2DM and bone metabolism, and its expression was significantly elevated in NK cells in a diabetic immune microenvironment. In diabetic rats, high EFHD2 expression was associated with fewer activated NKp46⁺ NK cells and impaired alveolar bone healing. High glucose upregulated EFHD2, stromal interaction molecule 1 (STIM1), and nuclear factor of activated T cells 1 (NFATC1) and downregulated NKp46 in NK-92MI cells; genistein, which which was predicted by molecular docking to have high binding affinity to EFHD2, reversed these abnormal changes. Conclusion The EFHD2–STIM1–NFATC1 signaling axis mediates hyperglycemia-triggered NK cell exhaustion and impaired alveolar bone regeneration. Genistein is a promising candidate compound targeting this axis, and EFHD2 can serve as a potential diagnostic biomarker and therapeutic target for diabetic bone complications.
Background Locally delivered periodontal adjuncts are usually compared on isolated clinical endpoints, while local pharmacokinetics and economic uncertainty are assessed separately. We developed an auditable proof-of-concept pipeline linking published local-exposure summaries to structural clinical and economic scenarios. Methods Published gingival crevicular fluid (GCF) summaries for doxycycline gel (Atridox), chlorhexidine chip (PerioChip) and minocycline microspheres (Arestin) were represented in a local mini physiologically based pharmacokinetic (PBPK) model. Fits to the same summaries were treated as calibration, not validation. Published probing pocket depth (PPD) effects entered four alternative structural mappings to pocket closure. A 20-year illustrative Markov model and 5000-draw probabilistic sensitivity analysis (PSA) propagated uncertainty. The base case excluded any separate matrix metalloproteinase-8 (MMP-8) quality-adjusted life-year (QALY) gain. Results Calibration absolute average fold errors were 1.00 for Atridox, 1.59 for PerioChip and 1.36 for Arestin; independent validation was not performed. Multistart and residual-Jacobian diagnostics indicated that the Atridox release parameters were not identifiable and that PerioChip precision remained weak with sparse anchors. Across linear, logistic, probit and Emax closure mappings, the deterministic preferred adjunct was Atridox when the chlorhexidine PPD effect was 0.30 mm and PerioChip when it was 0.75 mm. At US$50,000/QALY, probabilities of being optimal were 0.543 for PerioChip, 0.350 for Atridox and 0.107 for Arestin. Illustrative expected value of perfect information was US$419 per treated site (Monte Carlo standard error US$9). Conclusions The framework is reproducible, but its clinical and economic layers remain proof-of-concept simulations. The product ranking is sensitive to comparative PPD evidence, and the current results do not establish clinical or reimbursement superiority. Independent patient-level pharmacokinetic (PK), closure, recurrence and health-system data are required before decision use.
Objective To evaluate the clinical significance of morular metaplasia (MM) and its temporal patterns in predicting outcomes of fertility-preserving treatment (FST) among young patients with endometrial hyperplasia (EH) and atypical endometrial hyperplasia (AEH). Design Retrospective cohort study. Subjects 193 patients aged <40 years with EH or AEH who received progestin-based FST (2020–2025) at a single tertiary hospital. Exposure MM classified as: MM‑Bef (present only before treatment, n = 9), MM‑Sus (persistent, n = 4), MM‑Aft (emerged after treatment, n = 11), and non‑MM (n = 169). Main outcome measure(s) Complete response (CR) rate, time to response (TTR), and factors associated with CR by Cox regression. Result Overall CR was 62.5% in MM vs. 69.8% in non‑MM (P = 0.485). MM‑Bef achieved 100% CR, MM‑Sus 50%, MM‑Aft 36.4% (MM‑Aft vs. non‑MM, P = 0.009). Median TTR was 5.0 vs. 6.0 months (P = 0.849). Kaplan‑Meier showed no significant difference (log‑rank P = 0.893). In univariable Cox regression, only EH diagnosis was associated with higher CR (HR=1.515, P = 0.031). MM overall or subgroups was not significant (P > 0.10). Conclusion MM is not an independent predictor of FST outcomes in young EH/AEH patients. However, temporal patterns of MM may represent potential clinically useful signals. Persistent or treatment‑emergent MM showed numerical trends toward lower response rates and longer TTR, suggesting these patients may benefit from enhanced surveillance. These hypothesis-generating findings require confirmation in larger studies.
Carcinoembryonic antigen (CEA) is a key tumor biomarker, and its sensitive detection is critical for early diagnosis and treatment monitoring. This work presents a novel “turn-on” fluorescent aptasensor for sensitive and cost-effective detection of CEA, based on a FAM-labeled CEA aptamer (FAM-Aptamer) as the recognition unit, and Ce-UiO-66 nanoparticles as an efficient quenching platform. The Ce-UiO-66 material was synthesized and comprehensively characterized by SEM, TEM, XPS, FT-IR, Raman and XRD, demonstrating a high quenching efficiency (QE) of 99.95
