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As an emerging insulin resistance marker, the relationship between estimated glucose disposal rate (eGDR) and frailty needs further exploration. This study examines the eGDR-frailty link, develops a machine learning predictive model to address this gap, and explores diabetes mellitus (DM) as a mediator, providing new insights for clinical intervention. Using National Health and Nutrition Examination Survey (NHANES) 2005-2010 data, we analyzed glucose disposal and frailty associations. Feature selection used LASSO, and class imbalance was handled by SMOTEN. The resampled data were split 7:3 into a training set (n = 29,309) and a test set (n = 12,561).Ten machine learning models were built, with discrimination, calibration, and clinical utility evaluated to identify the optimal model. Confusion matrices visualized performance. Mediation analysis assessed DM's role in the eGDR-frailty relationship. Among 26,282 participants, eGDR negatively correlated with frailty. Higher eGDR significantly reduced frailty risk in subgroups: women, age ≤ 60, normal/high BMI, never/current smokers, and alcohol users. LASSO selected 12 predictors. Across 10 models, CatBoost performed best on the test set (AUC = 0.970, accuracy = 0.920, F1 = 0.918), with robust calibration and decision-curve net benefit. SHAP interpretation ranked eGDR among the most influential predictors: SHAP summary and dependence plots indicated that higher eGDR decreased the model's predicted probability of frailty. Confusion matrices validated classification accuracy. Mediation analysis showed DM partially mediated the eGDR-frailty relationship: indirect effect β=-0.003 (95% CI -0.003 to -0.002; P < 0.001), mediation proportion = 8.71%. This first NHANES-based study demonstrates a significant negative correlation between eGDR and frailty, confirming DM's partial mediating role. The developed machine learning models effectively support early frailty risk assessment and intervention.

Orthopedic implants have faced challenges in treating bone defects due to various factors, including inadequate osseointegration, oxidative stress, bacterial infection, immunological rejection, and poor individualized treatment. These challenges profoundly affect both the results of treatment and patients' daily lives. There is great promise for the layer-by-layer (LbL) assembly method in tissue engineering. The method primarily relies on electrostatic attraction and entails the consecutive deposition of electrolyte complexes with opposite charges onto a substrate, leading to the formation of homogeneous single layers that can be quickly deposited to produce nanolayer films. LbL has attracted considerable interest as a coating technology because of its ease of production, cost-effectiveness, and capability to apply diverse biomaterial coatings without compromising the primary bio-functional properties of the substrate materials. This review will look into the fundamentals and evolution of LbL in orthopedics, provide an analysis of the chemical strategy used to prepare bone implants with LbL and introduce the application of LbL bone implants in orthopedics over recent years. Among the many potential uses of LbL, such as the implementation of sustained-release and programmed drug delivery, which in turn promotes the osseointegration and the development of new blood vessels, as well as antibacterial, antioxidant, and other similar applications. In addition, we offer a thorough examination of cell behavior and biomaterial interaction to facilitate the advancement of next-generation LbL films for tissue engineering.

To explore the relationship between Frailty Index (FI) and Knee osteoarthritis (KOA) in Chinese people aged 45 and above. Data on symptomatic KOA, FI, and over ten covariates were from the China Health and Retirement Longitudinal Study (CHARLS). Logistic regression and restricted cubic splines (RCS) were used to analyze the correlation. Subgroup and interaction analyses were also conducted, and FI was divided into quartiles to assess result stability. Six machine learning constructs were used to build predictive models, which were then evaluated. Among 29,105 participants, 5,012 had symptomatic KOA. Weighted multivariate logistic results showed a correlation between KOA and frailty (OR 3.63(3.48,3.78)), present across quartiles. Subgroup analyses revealed potential effects of various factors on their association, with significant interactions found for gender, education, place of residence, alcohol consumption, hypertension, and dyslipidemia. RCS results indicated a logarithmic non-linear relationship between symptomatic KOA and frailty. The area under the curve of the Random Forest Machine model is 0.90, and it performs best on the calibration curve and decision curve analysis. This study showed a nonlinear relationship between FI and KOA in middle-aged and older Chinese adults, with higher FI scores linked to higher KOA prevalence and a significant inflection point, informing focused KOA interventions in aging populations.

Bone fracture continues to pose a significant clinical challenge in regenerative medicine due to limited repair capacity and inadequate therapeutic options. Among the various therapeutic strategies, mesenchymal stem cells have shown strong potential due to their ability to promote bone formation, modulate inflammation, and migrate to injury sites. However, clinical outcomes have been limited by issues like low survival rates, poor integration, and non-specific distribution after transplantation. Functionalized mesenchymal cells enhanced through genetic, chemical, or material-based modifications have emerged as an advanced strategy to overcome these limitations and significantly improve bone regeneration. This review explores recent developments in the functionalization of stem cells to increase their bone-forming potential. It covers techniques of gene modification, preconditioning, nanoparticle integration, and scaffold-based delivery. The role of these engineered cells is in activating key pathways involved in bone repair, including bone morphogenetic proteins and Wnt signaling. Furthermore, the study highlights current delivery platforms, including injectable gels, printed scaffolds, and bioactive coatings that support targeted, sustained cell activity. Despite encouraging preclinical outcomes, unresolved challenges in manufacturing, immune compatibility, and regulatory pathways persist, prompting the exploration of emerging solutions like precision-engineered implants and artificial intelligence-driven design to guide the future of advanced bone regeneration therapies.

The clinical management of bone defects presents a significant challenge in regenerative medicine due to the limited self-repair capacity of bone tissue and inadequate vascularization. Nitric oxide, a gaseous signaling molecule, has garnered attention as a potent modulator of bone remodeling, exhibiting pro-osteogenic, pro-angiogenic, and anti-inflammatory properties. However, its therapeutic application is limited by its short half-life, high reactivity, and dose-dependent biphasic effects. Advanced polymer-based nanoformulations have been developed to address these challenges and enable controlled and localized NO delivery to bone tissue. This review explores role of NO in bone repair mechanisms and the limitations of conventional delivery systems. Significant focus is given to innovative polymeric platforms, such as dendrimers, micelles, nanogels, and hybrid composites, which offer precise control over release kinetics, high encapsulation efficiency, and targeted delivery. Additionally, integrating NO delivery within nanoengineered scaffolds and coatings for orthopedic implants is explored as a promising strategy to enhance osteointegration and reduce the risk of post-surgical infections. Preclinical studies demonstrate promising osteogenic effects yet face significant challenges including cytotoxicity at elevated NO concentrations along with non-standardized evaluation protocols and scalability limitations. Future perspectives point to the potential of stimuli-responsive systems, co-delivery approaches, and personalized strategies utilizing additive manufacturing technologies. This review consolidates the latest advancements in the field, underscoring the significant potential of polymer-based NO nanoformulations to revolutionize bone tissue engineering.

Osteosarcoma (OS), chondrosarcoma (CHS), and Ewing sarcoma (EWS) are the main types of bone cancer (BC). OS is the most common BC in this group. It is most common in children and older people, especially in their long bones. Treatments for bone sarcomas and tumors have slowly improved, so researchers began looking into additional and alternative approaches to standard therapies. Therefore, the ability to precisely manipulate metallic nanoparticles (MNPs)' form, size, charge, and surface modification makes them very useful in treating bone cancer. However, due to the biocompatibility and possible toxicity of MNPs, MNP has limits for clinical use in treating BC. Therefore, the green synthesis of MNPs is achieved by bio-reducing metallic ions, which results in the creation of NPs, using living entities or their extracts. Green MNPs derived from natural sources provide a secure and environmentally responsible solution. Benefits of green MNPs include tailored medicine delivery and biocompatibility. Green MNPs reduce damage to healthy cells while improving the targeting of bone cancer cells. In this study, we reviewed how different MNPs synthesized using green methods can help treat various types of BC. This work reviewed the usual way of making MNPs for treating BC, the problems with this standard way of making MNPs, and the benefits and possible future uses of green synthetic MNPs for treating BC. Graphical Abstract

Background Pregnancy induced hypertension (PIH) is characterized by aberrant uterine arterial remodeling, a process tightly associated with an imbalance between placental growth factor (PlGF) and soluble fms like tyrosine kinase 1 (sFlt 1) as well as the down regulation of matrix metalloproteinases 2/9 (MMP 2/9). This study investigated the regulatory effect of PlGF on the two pore domain potassium channel KCNK2 and its downstream targets MMP 2/9, and explored the role of the PlGF KCNK2 MMP 2/9 axis in PIH related uterine arterial dysfunction. Methods In vitro, human aortic endothelial cells (HAECs) were assessed for proliferation and migration using CCK 8 and Transwell assays. Nitric oxide (NO) and endothelin 1 (ET 1) levels were quantified by ELISA, while KCNK2 and MMP 2/9 expression was analyzed by Western blotting. In vivo, a Sprague Dawley rat PIH model was established to monitor blood pressure and 24 h urinary protein. Hematoxylin–eosin staining was used to measure uterine arterial intimal thickness; endothelial nitric oxide synthase (eNOS) and ET 1 localization was determined by immunohistochemistry, and KCNK2 as well as MMP 2/9 expression was quantified by immunohistochemistry and Western blotting. Results 2,2,2 Trichloroethanol and PlGF significantly enhanced endothelial cell proliferation and migration, increased NO, decreased ET 1, and up regulated KCNK2 and MMP 2/9 expression ( P <  0.05); ropivacaine produced opposite effects. PIH rats exhibited markedly elevated blood pressure and urinary protein, intimal thickening, reduced eNOS and elevated ET 1, together with diminished MMP 2/9 expression. Combined treatment with PlGF and 2,2,2 trichloroethanol lowered blood pressure and urinary protein, attenuated intimal thickness, increased eNOS and decreased ET 1, and up regulated KCNK2 and MMP 2/9 ( P <  0.05). Conclusion 2,2,2 Trichloroethanol activates KCNK2, elevates MMP 2/9, and improves uterine arterial endothelial function, while PlGF synergizes with KCNK2 signaling to potentiate these effects. The PlGF KCNK2 MMP 2/9 axis plays a pivotal regulatory role in the vascular pathology of PIH, highlighting its potential as a therapeutic target for PIH related vascular dysfunction.

Background Gastric cancer (GC) is one of the most common malignant tumors in the digestive system. However, the development of its targeted therapies has been slow. Therefore, exploring the mechanisms of malignant behavior of GC is key to developing their treatment methods. Pregnancy-associated plasma protein-A(PAPPA) is thought to play an important role in the occurrence and progression of cancer, yet its significance in the development of GC has not been reported. Methods Bioinformatics analysis elucidated PAPPA's expression in GC and its prognostic significance. The study correlated PAPPA expression with immune infiltration and signaling pathways. Cellular assays, including CCK-8, Western blotting, and flow cytometry, were utilized to examine PAPPA's role in gastric cancer cell apoptosis, migration, and invasion. Results Bioinformatics analysis has demonstrated that the expression of PAPPA is upregulated in GC and correlates with poor prognosis. Correlation and Cox regression analyses have revealed that TNM staging, pathological staging, age, outcome assessment, postoperative tumor residue, and PAPPA expression are prognostic determinants in GC. Further analysis indicates that PAPPA is associated with the infiltration of various immune cells and pathways related to GC. Cellular experiments have shown that PAPPA promotes cell proliferation, and its deficiency can inhibit the proliferation of GC cells, inducing cell cycle arrest at the G1/S phase. Conclusions The findings of this investigation suggest that PAPPA serves as a crucial modulator of GC, underscoring its potential as a GC treatment target.

Our study aimed to establish a prediction model for coronary artery disease (CAD) that integrates immune infiltration and a gene expression signature. 613 differentially expressed genes (DEGs) and 12 hub genes were screened via the GSE113079 dataset. The pathway enrichment analysis indicated that these genes (613 DEGs and 12 hub genes) were closely associated with the inflammatory and immune responses. Based on the differentially expressed miRNA (DEmiRNA)-DEG regulatory network and immune cell infiltration, the Lasso algorithm constructed a CAD risk prediction model containing the risk score and immune score. Then, ROC-AUC and polymerase chain reaction (PCR) were performed for validation. Six hub genes (PTGER1, PIK3R1, ADRA2A, CORT, CXCL12, and S1PR5) had a high distinguishing capability (AUC > 0.90). In addition, the miRNAs targeting 12 hub genes were predicted and intersected with the DEmiRNAs, and the DEmiRNA-DEG regulatory network was then constructed. Two LASSO models and a novel CAD risk prediction model were constructed through LASSO regression analysis, and they both accurately obtained the risk of CAD. The CAD risk prediction model shows good performance (AUC = 0.988). We also constructed a valid nomogram, and PCR results verified three downregulation hub genes and one upregulation gene in the CAD risk model. We demonstrated the molecular mechanism of the hub genes in CAD and provided a valuable tool for predicting the risk of CAD.

To explore the burden and trend of osteoarthritis (OA) at different sites in middle-aged and elderly people (45 years and older) from 1990 to 2021. Age-standardized incidence rates, prevalence rates, disability-adjusted life years (Daly) rates and average annual percent change were used to quantify the disease burden and trend of OA at different sites. Decomposition analysis was conducted to explore the impact of three population-level determinants on the burden of OA and the distribution of OA burden inequality in the Socio-Demographic Index (SDI) across countries. The age-standardized prevalence rate had increased by 8.9%, and the OA cases had increased by 2.41 times compared to 1990. The incidence and prevalence of knee, hip and hand OA decreased sequentially, while high SDI regions tended to have higher age-standardized incidence rates, prevalence rates, and Daly rates. Decomposition analysis revealed that 85.9% of the increase in OA age-standardized Daly rates was attributable to population growth. This increase was most pronounced in high SDI populations for hip OA and middle SDI populations for knee and hand OA. From 1990 to 2021, the inequality in overall OA burden between countries had decreased. The absolute inequality gap for hand OA had narrowed the most significantly (45.3%), which followed by knee OA (11.9%), while the inequality gap for hip OA has slightly increased. In summary, all parts of the OA burden in middle-aged and elderly people had steadily increased from 1990 to 2021, which calls to implement personalized prevention targeting different parts of OA.