Systematic Pharmacology and Experimental Validation to Reveal the Alleviation of Astragalus membranaceus Regulating Ferroptosis in Osteoarthritis.

Background: Astragalus membranaceus (AM) shows promise as a therapeutic agent for osteoarthritis (OA), a debilitating condition with high disability rates. OA exacerbation is linked to chondrocyte ferroptosis, yet the precise pharmacological mechanisms of AM remain unclear. Methods: We validated AM's protective efficacy in an anterior cruciate ligament transection (ACLT) mouse model of OA. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database was utilized to identify AM's active components and their targets. FerrDb (a database for regulators and markers of ferroptosis and ferroptosis-disease associations) pinpointed ferroptosis-related targets, while GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenomics Knowledgebase (PharmGKB), Therapeutic Target Database (TTD), and DrugBank sourced OA-related genes. Molecular docking analysis further validated these targets. Ultimately, the validation of the results was accomplished through in vitro experiments. Results: AM exhibited anabolic effects and suppressed catabolism in OA chondrocytes. Network pharmacology identified 19 common genes, and molecular docking suggested quercetin, an AM constituent, interacts with key proteins like HO-1 and NRF2 to inhibit chondrocyte ferroptosis. In vitro experiments confirmed AM's ability to modulate the NRF2/HO-1 pathway via quercetin, mitigating chondrocyte ferroptosis. Conclusion: This study elucidates how AM regulates chondrocyte ferroptosis, impacting OA progression, providing a theoretical basis and experimental support for AM's scientific application.

Phosphorus recovery from phosphate tailings through a two-stage leaching-precipitation process: Toward the harmless and reduction treatment of P-bearing wastes.

To achieve highly efficient extraction of phosphorus (P) and comprehensive utilization of phosphate tailings, a two-stage leaching-precipitation method was proposed. Phosphate tailings primarily consisted of dolomite, fluorapatite, and quartz. During the first-stage leaching, the large majority of dolomite was selectively dissolved and the leaching efficiency of Mg reached 93.1 % at pH 2.0 and 60 °C. The subsequent second-stage leaching of fluorapatite was performed and the P leaching efficiency was 98.8 % at pH 1.5 and 20 °C, while the quartz remained in the residue. Through two-stage leaching, a stepwise leaching of dolomite and fluorapatite was achieved. After chemical precipitation, calcium phosphate with a high purity of 97.9 % was obtained; and the total recovery efficiency of P exceeded 98 %. The obtained calcium phosphate can be a raw material in the phosphorus chemical industry, while the Mg-rich leachate and the final quartz-rich residue have the potential for Mg extraction and the production of mortars or geopolymers, respectively. The two-stage leaching-precipitation process could significantly reduce the leaching costs, and enhance the reaction rates. It is expected to realize a volume reduction and efficient resource utilization of the phosphate tailings by using this sustainable and promising solution.

Association of life's essential 8 and risk of fragility fractures: A large cohort study.

Cardiovascular health (CVH) score is not only associated with cardiovascular diseases, but also some disorders in other systems. This study aims to investigate the association between CVH score and the risk of fragility fractures. The analysis enrolled 89,464 participants at baseline in Kailuan study initiated in 2006-2007. All participants were then followed up every 2 years and the incidence of fragility fractures was recorded annually. A total CVH score was classified as low (0-49 points), moderate (50-79 points), and ideal (80-100 points). The primary outcome was incident fragility fractures before December 31, 2021. Kaplan-Meier was used to estimate cumulative incidence. Multivariable adjusted Cox proportional hazards regression models and time-dependent Cox hazards regression models were used to estimate fragility fracture hazard ratios (aHR) and 95% confidence intervals (95% CI). After 13.98 ± 2.84 years of follow-up, a total of 1534 cases of fragility fractures were identified, with an incidence density of 1.23 per 1000 person-years. Compared with the low CVH group, the risk of fragility fractures was significantly lower in moderate (aHR = 0.78, 95% CI: 0.66-0.92) and ideal CVH groups (aHR = 0.65, 95% CI: 0.51-0.83), particularly in the age <60 group (aHR = 0.72, 95% CI: 0.59-0.88; aHR= 0.55, 95% CI: 0.41-0.73, respectively). Time-dependent Cox hazards regression models, sensitivity analysis, and death competition model confirmed the reliability of these findings. The ideal CVH score is associated with a decreased risk of fragility fractures. With the increase of CVH score, the risk of fragility fracture decreases.

Astragalus polysaccharides ameliorate osteoarthritis via inhibiting apoptosis by regulating ROS-mediated ASK1/p38 MAPK signaling pathway targeting on TXN.

This research aims to explore the potential of astragalus polysaccharides (APS) in treating osteoarthritis. The primary component of APS extracted in this study was glucose, and noticeably it had a relatively high content of glucuronic acids. In vitro, APS reduced ROS levels, protected chondrocytes from apoptosis, and promoted collagen II expression by regulating ASK1 (apoptosis-signal-regulating kinase1)/p38 cell apoptosis pathway. Further co-immunoprecipitation and immunofluorescence localization experiments demonstrated that the thioredoxin (TXN) antioxidant system was responsible for its bioactivity. Moreover, TXN silencing remarkably blocked the protective effects of APS, indicating that APS inhibited chondrocyte apoptosis by targeting TXN. In vivo, APS effectively mitigated cartilage loss and chondrocyte apoptosis and decreased expressions of p-ASK1 and p-p38. Collectively, this research first demonstrated that APS could ameliorate osteoarthritis by ASK1/p38 signaling pathway through regulating thioredoxin. In conclusion, APS holds promise as a nutraceutical supplement for osteoarthritis in future drug development.

Leaching of phosphorus from phosphate tailings and extraction of calcium phosphates: Toward comprehensive utilization of tailing resources.

Phosphate tailing is an extremely fine by-product during phosphate ore flotation. Due to the large quantities and relatively higher P2O5 content, the phosphate tailings have been considered as a potential P resource, compared to other P-bearing wastes. Besides, phosphate tailings also contain a large amount of available components, such as Ca, Mg, and Si. To explore a low-cost and efficient process for the utilization of phosphate tailings, the hydrochloric acid leaching-precipitation method was employed to recover phosphorus. The P in phosphate tailings can be selectively dissolved into leaching liquor, followed by the precipitation of calcium phosphates from the leaching liquor through pH adjustment. The results showed that P was predominantly concentrated in fluorapatite and its dissolution ratio increased with the decrease in pH. At pH 1.0, the P dissolution efficiency from phosphate tailings reached 96.3%, along with the majority of Mg and Ca. However, Si was hardly dissolved. It demonstrated that almost all the fluorapatite and dolomite were dissolved while the quartz was difficult to dissolve. Dolomite was more preferentially dissolved than fluorapatite. Increasing temperature contributed to the dissolution of dolomite while suppressing fluorapatite dissolution. The residue containing 87.9% SiO2 (quartz) and only 0.25% P2O5 has the potential as a building material. As the pH increased to 7.0, the collected precipitate consisted of 34.18% P2O5 and 56.10% CaO, which can serve as a source of a slow-released phosphate fertilizer. The highly efficient utilization of phosphate tailings was achieved via this process.

Mitigation role of physical exercise participation in the relationship between blood cadmium and sleep disturbance: a cross-sectional study.

The neurotoxicity of heavy metals received increasingly attention in recent years. Sleeping is regulated and coordinated by nervous system, however, the health hazard of heavy metal like cadmium (Cd) exposure on sleep health remained unknown. Rescue strategies like physical exercise (PE) has emerged to mitigate such influence. An epidemiological design with cross-sectional data from National Health and Nutrition Examination Survey 2007-2010 was applied. The relationship between three blood heavy metals [cadmium (Cd), lead (Pb), mercury (Hg)] and sleep disturbance was analyzed. A total of 8,751 participants were finally included in and the weighted participants were 330,239,463. Weighted quantile sum (WQS) regression indicated that mixed blood metals were positively related to risk of sleep disturbance and the mixture effect of exposure to heavy metals was mainly attributable to Cd (89.1%). Weighted logistic regression showed a significant positive association between the highest quartile of blood Cd and sleep disturbance [(OR (95% CI)): 1.191 (1.014,1.400), p = 0.036] in the fully adjusted model, while no association was found under Pb and Hg exposure. In the association between Q3 and Q4 level of blood Cd and sleep disturbance, moderate-to-vigorous physical exercise group had lower risks than none and low exercise group. In the restricted cubic spline model, it was also verified that higher PE participation was associated with the lowest incidence of sleep disturbance with the increment in Cd concentration. Our study suggested that both policy makers and the public should minimize heavy metal exposure. Moreover, conducting moderate to vigorous physical exercise is a protecting factor to mitigate Cd's influence on sleep health.

A review on the P enrichment and recovery from steelmaking slag: Towards a sustainable P supply and comprehensive utilization of industrial solid wastes.

Phosphorus (P) is one of the desirable nutrient elements for the growing of crops and is a non-renewable resource. The over-exploitation of high-grade phosphate rocks makes finding alternative P sources urgent for a sustainable and stable P supply. Steelmaking slag has been considered a potential P source due to its huge production and the increasing P content in slag with the utilization of low-grade iron ores. If the efficient separation of P from steelmaking slag is achieved, the obtained P can be used as the raw material for phosphate products, and the P-removal steelmaking slag can be reused as a metallurgical flux in steel plants, realizing the comprehensive utilization of steelmaking slag. To better understand the separation method and mechanism of P from steelmaking slag, this paper reviews: (1) the enrichment mechanism of P in steelmaking slag, (2) the methods of the P-rich phase separation from slag and P recovery, and (3) facilitating the enrichment of P in the mineral phase by cooling treatment and modification. Furthermore, some industrial solid wastes were selected as modifiers for steelmaking slag, which not only provided several valuable components but also significantly reduced treatment costs. Hence, a collaborative processing of steelmaking slag and other P-bearing industrial solid wastes is proposed, providing a new solution for P recovery and the comprehensive utilization of industrial solid wastes, achieving the sustainable development of steel and phosphate industries.

New-onset stroke on the risk of hip fracture: the Kailuan cohort study in China.

PURPOSE: Stroke is a documented risk factor for hip fracture(HF). However, no data is currently available on this issue in mainland China, we therefore assessed the risk of hip fracture after new-onset stroke using a cohort study. METHODS: This study included 165,670 participants without a history of stroke at baseline from the Kailuan study. All participants were followed biennially until December 31, 2021. During follow-up, a total of 8,496 new-onset stroke cases were identified. For each case subject, four control subjects was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 42,455 pair-matched cases and controls. A multivariate Cox proportional hazard regression model was used to estimate the effect of new-onset stroke on the risk of hip fracture. RESULTS: During an average follow-up of 8.87 (3.94) years, a total of 231 hip fracture cases occurred, 78 cases in the stroke group and 153 cases in the control group, with incidence rates of 1.12 and 0.50 per 1000 person-years, respectively. The cumulative incidence of the stroke group was higher than that of the controls (P < 0.01). The adjusted hazard ratio (95% confidence interval) of hip fractures in the stroke group was 2.35 (1.77 to 3.12) (P < 0.001) to controls. After stratifying by gender, age, and body mass index, the higher risk was revealed in female (HR 3.10, 95 CI: 2.18 to 6.14, P < 0.001), age < 60 years old (HR 4.12, 95% CI: 2.18 to 7.78, P < 0.001), and non-obesity (BMI<28 kg/m2) (HR 1.74, 95% CI:1.31 to 2.31, P < 0.001) subgroup. CONCLUSIONS: Stroke significantly increases the risk of hip fracture, strategy for protecting stroke patients from falls and hip fractures should be emphasized in poststroke long-term management, particularly the female, age < 60 years old, and non-obese patients.

Pulse Pressure Variability and the Risk of Fragility Fracture: The Kailuan Prospective Cohort Study in China.

OBJECTIVES: To investigate the association of the magnitude and direction of pulse pressure variability (PPV) with the incidence of fragility fracture in the general population. METHODS: This prospective cohort study included current Kailuan Group employees and retirees who attended health checkups continuously from 2006 to 2010 and were followed up until December 31, 2021. A total of 56,129 individuals who completed the health checkups were selected and grouped according to coefficient of variation (CV) quartile for PPV. The standard deviation (SD) and variability independent of the mean were also calculated as measures of PPV. The cumulative incidence of fragility fracture in the four groups was calculated and the impact of PPV on the risk of fragility fracture was analyzed using a multivariate Cox regression model. The direction of the variation was also assessed. RESULTS: There were 671 cases of fragility fracture (1.2%) during a median follow-up of 11 years. In the multivariable-adjusted model, the hazard ratio for fragility fracture was 1.37 (95% confidence interval 1.11-1.70) for the highest CV quartile for PPV versus the lowest CV quartile for PPV. There was a linear association between higher PPV and fragility fracture. Consistent results were noted for higher PPV and the risk of fragility fracture using other indices of variability and in various sensitivity and subgroup analyses. CONCLUSIONS: High PPV was associated with a higher rate of fragility fracture independently of blood pressure. Reduction of PPV may help to prevent fragility fractures in the general population.

Uncemented Tibial Fixation Has Comparable Prognostic Outcomes and Safety Versus Cemented Fixation in Cruciate-Retaining Total Knee Arthroplasty: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Cemented and uncemented fixation are the primary methods of tibial prosthesis fixation in total knee arthroplasty. However, the optimal fixation method remains controversial. This article explored whether uncemented tibial fixation has better clinical and radiological outcomes, fewer complications, and revision rates compared to cemented tibial fixation. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases up to September 2022 to identify randomized controlled trials (RCTs) that compared uncemented total knee arthroplasty (TKA) and cemented TKA. The outcome assessment consisted of clinical and radiological outcomes, complications (aseptic loosening, infection, and thrombosis), and revision rate. Subgroup analysis was used to explore the effects of different fixation methods on knee scores in younger patients. RESULTS: Nine RCTs were finally analyzed with 686 uncemented knees and 678 cemented knees. The mean follow-up time was 12.6 years. The pooled data revealed significant advantages of uncemented fixations over cemented fixations in terms of the Knee Society Knee Score (KSKS) (p = 0.01) and the Knee Society Score-Pain (KSS-Pain) (p = 0.02). Cemented fixations showed significant advantages in maximum total point motion (MTPM) (p < 0.0001). There was no significant difference between uncemented fixation and cemented fixation regarding functional outcomes, range of motion, complications, and revision rates. When comparing among young people (<65 years), the differences in KSKS became statistically insignificant. No significant difference was shown in aseptic loosening and the revision rate among young patients. CONCLUSIONS: The current evidence shows better knee score, less pain, comparable complications and revision rates for uncemented tibial prosthesis fixation, compared to cemented, in cruciate-retaining total knee arthroplasty.

Recent advances in the identification of related factors and preventive strategies of hip fracture.

Hip fracture is the most devastating type of osteoporosis-related fracture, and is a major worldwide public health problem with a high socioeconomic burden, morbidity rate, and mortality rate. Thus, it is crucial to uncover the risk factors and protective factors to create a hip fracture prevention strategy. In addition to a briefly review of some well accepted risk and protective factors of hip fracture, this review mainly summarized the recent advances in the identification of emerging risk or protective factors for hip fracture, in terms of regional differences in medical services, diseases, drugs, mechanical load, neuromuscular mass, genes, blood types, cultural differences. This review provides a comprehensive review of the associated factors and effective prevention measures for hip fracture, and discusses issues that need further investigation. These issues include the determination of the influencing mechanism of risk factors triggering hip fracture and their interlinked correlation with other factors, as well as the confirmation or correction of emerging factors associated with hip fracture, particularly those that are still controversial. These recent findings will aid in optimizing the strategy for preventing hip fracture.

Identification of Immune-Related Risk Genes in Osteoarthritis Based on Bioinformatics Analysis and Machine Learning.

In this research, we aimed to perform a comprehensive bioinformatic analysis of immune cell infiltration in osteoarthritic cartilage and synovium and identify potential risk genes. Datasets were downloaded from the Gene Expression Omnibus database. We integrated the datasets, removed the batch effects and analyzed immune cell infiltration along with differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was used to identify the positively correlated gene modules. LASSO (least absolute shrinkage and selection operator)-cox regression analysis was performed to screen the characteristic genes. The intersection of the DEGs, characteristic genes and module genes was identified as the risk genes. The WGCNA analysis demonstrates that the blue module was highly correlated and statistically significant as well as enriched in immune-related signaling pathways and biological functions in the KEGG and GO enrichment. LASSO-cox regression analysis screened 11 characteristic genes from the hub genes of the blue module. After the DEG, characteristic gene and immune-related gene datasets were intersected, three genes, PTGS1, HLA-DMB and GPR137B, were identified as the risk genes in this research. In this research, we identified three risk genes related to the immune system in osteoarthritis and provide a feasible approach to drug development in the future.

METTL3 promotes SMSCs chondrogenic differentiation by targeting the MMP3, MMP13, and GATA3.

Objective: Synovium-derived mesenchymal stem cells (SMSCs) are multipotential non-hematopoietic progenitor cells that can differentiate into various mesenchymal lineages in adipose and bone tissue, especially in chondrogenesis. Post-transcriptional methylation modifications are relative to the various biological development procedures. N6-methyladenosine (m6A) methylation has been identified as one of the abundant widespread post-transcriptional modifications. However, the connection between the SMSCs differentiation and m6A methylation remains unknown and needs further exploration. Methods: SMSCs were derived from synovial tissues of the knee joint of male Sprague-Dawley (SD) rats. In the chondrogenesis of SMSCs, m6A regulators were detected by quantitative real-time PCR (RT-PCR) and Western blot (WB). We observed the situation that the knockdown of m6A "writer" protein methyltransferase-like (METTL)3 in the chondrogenesis of SMSCs. We also mapped the transcript-wide m6A landscape in chondrogenic differentiation of SMSCs and combined RNA-seq and MeRIP-seq in SMSCs by the interference of METTL3. Results: The expression of m6A regulators were regulated in the chondrogenesis of SMSCs, only METTL3 is the most significant factor. In addition, after the knockdown of METTL3, MeRIP-seq and RNA-seq technology were applied to analyze the transcriptome level in SMSCs. 832 DEGs displayed significant changes, consisting of 438 upregulated genes and 394 downregulated genes. DEGs were enriched in signaling pathways regulating the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and ECM-receptor interaction via Kyoto Encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. The findings of this study indicate a difference in transcripts of MMP3, MMP13, and GATA3 containing consensus m6A motifs required for methylation by METTL3. Further, the reduction of METTL3 decreased the expression of MMP3, MMP13, and GATA3. Conclusion: These findings confirm the molecular mechanisms of METTL3-mediated m6A post-transcriptional change in the modulation of SMSCs differentiating into chondrocytes, thus highlighting the potential therapeutic effect of SMSCs for cartilage regeneration.

A CT-based radiomics nomogram for the differentiation of pulmonary cystic echinococcosis from pulmonary abscess.

The purpose of this study was to establish a clinical prediction model for the differential diagnosis of pulmonary cystic echinococcosis (CE) and pulmonary abscess according to computed tomography (CT)-based radiomics signatures and clinical indicators. This is a retrospective single-centre study. A total of 117 patients, including 53 with pulmonary CE and 64 with pulmonary abscess, were included in our study and were randomly divided into a training set (n = 95) and validation set (n = 22). Radiomics features were extracted from CT images, a radiomics signature was constructed, and clinical indicators were evaluated to establish a clinical prediction model. Finally, a model combining imaging radiomics features and clinical indicators was constructed. The performance of the nomogram, radiomics signature and clinical prediction model was evaluated and validated with the training and test datasets, and then the three models were compared. The radiomics signature of this study was established by 25 features, and the radiomics nomogram was constructed by using clinical factors and the radiomics signature. Finally, the areas under the receiver operating characteristic curve (AUCs) for the training set and test set were 0.970 and 0.983, respectively. Decision curve analysis showed that the radiologic nomogram was better than the clinical prediction model and individual radiologic characteristic model in differentiating pulmonary CE from pulmonary abscess. The radiological nomogram and models based on clinical factors and individual radiomics features can distinguish pulmonary CE from pulmonary abscess and will be of great help to clinical diagnoses in the future.

Exploring the best monochromatic energy level in dual energy spectral imaging for coronary stents after percutaneous coronary intervention.

In this study, the optimal monochromatic energy level in dual-energy spectral CT required for imaging coronary stents after percutaneous coronary intervention (PCI) was explored. Thirty-five consecutive patients after PCI were examined using the dual-energy spectral CT imaging mode. The original images were reconstructed at 40-140 keV (10-keV interval) monochromatic levels. The in-stent and out-stent CT values at each monochromatic level were measured to calculate the signal-to-noise ratio(SNR) and contrast-to-noise ratio (CNR) for the vessel and the CT value difference between the in-stent and out-stent lumen (dCT (in-out)), which reflects the artificial CT number increase due to the beam hardening effect caused by the stents. The subjective image quality of the stent and in-stent vessel was evaluated by two radiologists using a 5-point scale. With the increase in energy level, the CT value, SNR, CNR, and dCT (in-out) all decreased. At 80 keV, the mean CT value in-stent reached (345.24 ± 93.43) HU and dCT (in-out) started plateauing. In addition, the subjective image quality of the stents and vessels peaked at 80 keV. The 80 keV monochromatic images are optimal for imaging cardiac patients with stents after PCI, balancing the enhancement and SNR and CNR in the vessels while minimizing the beam hardening artifacts caused by the stents.