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Osteoarthritis (OA) progresses due to the excessive generation of reactive oxygen and nitrogen species (ROS/RNS) and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria. Highly active single-atom nanozymes (SAzymes) can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases. In this study, we innovatively utilised ligand-mediated strategies to chelate Pt4+ with modified g-C3N4 by π–π interaction to prepare g–C3N4–loaded Pt single-atom (Pt SA/C3N4) nanozymes that serve as superoxide dismutase (SOD)/catalase (CAT) mimics to scavenge ROS/RNS and regulate mitochondrial ATP production, ultimately delaying the progression of OA. Pt SA/C3N4 exhibited a high loading of Pt single atoms (2.45 wt%), with an excellent photothermal conversion efficiency (54.71%), resulting in tunable catalytic activities under near-infrared light (NIR) irradiation. Interestingly, the Pt–N6 active centres in Pt SA/C3N4 formed electron capture sites for electron holes, in which g-C3N4 regulated the d-band centre of Pt, and the N-rich sites transferred electrons to Pt, leading to the enhanced adsorption of free radicals and thus higher SOD- and CAT-like activities compared with pure g-C3N4 and g–C3N4–loaded Pt nanoparticles (Pt NPs/C3N4). Based on the use of H2O2-induced chondrocytes to simulate ROS-injured cartilage invitro and an OA joint model invivo, the results showed that Pt SA/C3N4 could reduce oxidative stress-induced damage, protect mitochondrial function, inhibit inflammation progression, and rebuild the OA microenvironment, thereby delaying the progression of OA. In particular, under NIR light irradiation, Pt SA/C3N4 could help reverse the oxidative stress-induced joint cartilage damage, bringing it closer to the state of the normal cartilage. Mechanistically, Pt SA/C3N4 regulated the expression of mitochondrial respiratory chain complexes, mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase, to reduce ROS/RNS and promote ATP production. This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases. •Design of a ligand-mediated strategy for nanozyme preparation.•Tunable enzymatic activity under NIR light irradiation to scavenge ROS/RNS.•Density Functional Theory study on the SOD/CAT-like catalytic mechanism of Pt SA/C3N4 nanozymes.•Regulation of the expression of mitochondrial respiratory chain complexes.

Background Mesenchymal stem cells (MSCs)-based therapy offers an effective strategy for bone regeneration to solve the clinical orthopedic problems. However, the transcriptional regulation of multiple transitional stages of continuous osteogenesis from MSCs has not been fully characterized. Methods Bone marrow mesenchymal stem cells (BMSCs) stimulated with osteogenic induction media were utilized to construct the in vitro osteogenic differentiation model. BMSCs were harvested after induction for 0, 7, 14 and 21 days, respectively, to perform the mRNA-sequencing (mRNA-Seq). The transcription factor networks and common molecules during the osteogenesis were revealed by using the temporal transcriptome. Further verification was performed by the quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence and Western blotting. Results It showed that BMSCs could differentiate into osteogenic, and crucial regulator in the MAPK signaling pathway, the PPAR signaling pathway, the Toll-like receptor signaling and the Cytokine/JAK/STAT signaling pathway. PPI protein interaction analysis also suggested that three cytokines are involved in osteogenic differentiation as core genes, including leukemia inhibitory factor (LIF), interleukin-6 (IL6) and colony-stimulating factor 3 (CSF3). The osteogenic process was negatively affected by the inhibition of JAK/STAT3 signaling pathway. Conclusions This work might provide new insights in the crucial features of the transcriptional regulation during the osteogenesis, as well as offer important clues about the activity and regulation of the relatively long-activated Cytokine/JAK/STAT3 signaling pathway in osteoinduction of BMSCs.

To study the pharmacological effects and mechanisms of phlorizin in the treatment of osteoarthritis (OA) through network pharmacological analysis, molecular docking, and experimental validation. First, we screened out the relevant targets related to phlorizin and OA from the public database. The key targets, biological processes, and signaling pathways of phlorizin against OA were identified by protein–protein interaction (PPI) network, Gene Ontology (GO), and Encyclopedia of Kyoto Genes and Genomes (KEGG) pathway enrichment analysis. Subsequently, molecular docking was performed to predict the binding activity between phlorizin and key targets. Finally, we evaluated the effects of phlorizin on hydrogen peroxide-induced OA in rats and validated its possible mechanism of action based on the findings of the network pharmacology analysis. Network pharmacology revealed a total of 235 cross-targets involved in the treatment of OA. Phlorizin’s anti-OA effect was found to be primarily mediated through oxidoreductase activity, with JAK-STAT and NF-κB signaling pathways playing a regulating role, according to pathway enrichment analysis. Phlorizin demonstrated a strong affinity for NF-κB1 targets through molecular docking. Moreover, in vitro experiments demonstrated that phlorizin could enhance intracellular antioxidant enzyme activities with good ROS scavenging ability and significantly reduce the expression of NF-κB1 and inflammatory cytokines. Phlorizin can inhibit the progression of OA. The potential underlying mechanism involves inhibiting the NF-κB pathway to reduce inflammation and promote intracellular antioxidant action.

Abstract Cartilage defects may lead to severe degenerative joint diseases. Tissue engineering based on type I collagen hydrogel that has chondrogenic potential is ideal for cartilage repair. However, the underlying mechanisms of chondrogenic differentiation driven by type I collagen hydrogel have not been fully clarified. Herein, we explored potential collagen receptors and chondrogenic signaling pathways through bioinformatical analysis to investigate the mechanism of collagen-induced chondrogenesis. Results showed that the super enhancer-related genes induced by collagen hydrogel were significantly enriched in the TGF-β signaling pathway, and integrin-β1 (ITGB1), a receptor of collagen, was highly expressed in bone marrow mesenchymal stem cells (BMSCs). Further analysis showed genes such as COL2A1 and Tenascin C (TNC) that interacted with ITGB1 were significantly enriched in extracellular matrix (ECM) structural constituents in the chondrogenic induction group. Knockdown of ITGB1 led to the downregulation of cartilage-specific genes (SOX9, ACAN, COL2A1), SMAD2 and TNC, as well as the downregulation of phosphorylation of SMAD2/3. Knockdown of TNC also resulted in the decrease of cartilage markers, ITGB1 and the SMAD2/3 phosphorylation but overexpression of TNC showed the opposite trend. Finally, in vitro and in vivo experiments confirmed the involvement of ITGB1 and TNC in collagen-mediated chondrogenic differentiation and cartilage regeneration. In summary, we demonstrated that ITGB1 was a crucial receptor for chondrogenic differentiation of BMSCs induced by collagen hydrogel. It can activate TGF-SMAD2/3 signaling, followed by impacting TNC expression, which in turn promotes the interaction of ITGB1 and TGF-SMAD2/3 signaling to enhance chondrogenesis. These may provide concernful support for cartilage tissue engineering and biomaterials development. Graphical Abstract

Osteosarcoma (OS) is the most widespread bone tumour among childhood cancers, and distant metastasis is the dominant factor in poor prognosis for patients with OS. Therefore, it is necessary to identify new prognostic biomarkers for identifying patients with aggressive disease. Two OS datasets (GSE21257 and GSE33383) were downloaded from the Gene Expression Omnibus (GEO) and subsequently subjected to weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (DGE) to screen candidate genes. A prognostic model was constructed using OS data derived from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program to further screen key genes and perform gene ontology (GO) analysis. The prognostic values of key genes were assessed using the Kaplan-Meier (KM) plotter. The GEO dataset was used for immune infiltration analysis and association analysis of key genes. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the expression levels of potentially crucial genes in OS cell lines. In the present study, we found 114 genes with a highly significant correlation in the module and 44 downregulated genes; 25 candidate genes overlapped in the two parts of the genes. Among these, three key genes, , , and , were the most significant hub genes, which had the highest node degrees, were clustered into one group, and implicated in most significant biological processes (regulation of immune effector process). Moreover, these three key genes were negatively associated with the prognosis of OS and positively associated with three immune cells (follicular helper T cells, memory B cells, and CD8 T cells). Additionally, compared to non-metastatic OS cell lines, the expression of three key genes was significantly downregulated in metastatic OS cell lines. Our results revealed that three key genes ( , , and were implicated in tumour immune infiltration and may be promising biomarkers for predicting metastasis and prognosis of patients with OS.

Osteoarthritis (OA) progresses due to the excessive generation of reactive oxygen and nitrogen species (ROS/RNS) and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria. Highly active single-atom nanozymes (SAzymes) can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases. In this study, we innovatively utilised ligand-mediated strategies to chelate Pt with modified g-C N by π-π interaction to prepare g-C N -loaded Pt single-atom (Pt SA/C N ) nanozymes that serve as superoxide dismutase (SOD)/catalase (CAT) mimics to scavenge ROS/RNS and regulate mitochondrial ATP production, ultimately delaying the progression of OA. Pt SA/C N exhibited a high loading of Pt single atoms (2.45 wt%), with an excellent photothermal conversion efficiency (54.71%), resulting in tunable catalytic activities under near-infrared light (NIR) irradiation. Interestingly, the Pt-N active centres in Pt SA/C N formed electron capture sites for electron holes, in which g-C N regulated the d-band centre of Pt, and the N-rich sites transferred electrons to Pt, leading to the enhanced adsorption of free radicals and thus higher SOD- and CAT-like activities compared with pure g-C N and g-C N -loaded Pt nanoparticles (Pt NPs/C N ). Based on the use of H O -induced chondrocytes to simulate ROS-injured cartilage and an OA joint model , the results showed that Pt SA/C N could reduce oxidative stress-induced damage, protect mitochondrial function, inhibit inflammation progression, and rebuild the OA microenvironment, thereby delaying the progression of OA. In particular, under NIR light irradiation, Pt SA/C N could help reverse the oxidative stress-induced joint cartilage damage, bringing it closer to the state of the normal cartilage. Mechanistically, Pt SA/C N regulated the expression of mitochondrial respiratory chain complexes, mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase, to reduce ROS/RNS and promote ATP production. This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases.

Laminaria （Saccharina） is one of the economic important seaweeds. Through sequence analysis of 4 099 ESTs from Laminaria （971 were generated from our own cDNA laboratories and 3 128 were downloaded from updated EST databases） with SSRIT software, two hundred and fifty-four SSRs in 206 ESTs were found. From the 254 SSRs, sixty-three SSR primer-pairs were designed. In order to test their practicability, the 63 primer-pairs were tested in commonly used SSR reaction conditions using 12 Laminara DNA samples as templates. The results show that 23 SSR primer-pairs gave good amplification patterns on most （more than 80%） of the 12 Laminara DNA templates. Genetic diversity study of 12 Laminaria lines, which were widely used in breeding and economic cultivation in China, was performed based on the obtained SSR data.

To synthesise and map the evidence of a theory- and evidence-based nursing intervention for the prevention of ICU-acquired weakness and evaluate its effectiveness in terms of the incidence of ICU-acquired weakness, incidence of delirium, and length of hospital stay. We searched PubMed, CINAHL, MEDLINE, Academic Search Complete, Embase, Scopus, Web of Science and the Cochrane Library from database inception to November 2023. The eligible studies focused on critically ill patients in the intensive care unit, used a theory- and evidence-based nursing intervention, and reported the incidence of ICU-acquired weakness and/or used the Medical Research Council Scale. The methodological quality of the included studies was critically appraised by two authors using the appropriate Joanna Briggs Institute appraisal tool for randomised controlled trials, quasi-experimental studies, and cohort studies. Additionally, the weighted kappa coefficient was used to assess inter-rater agreement of the quality assessment. Data were reported using a narrative synthesis. This systematic review was registered by the International Prospective Register of Systematic Review (PROSPERO; CRD42023477011). A total of 5162 studies were initially retrieved, and 9 studies were eventually included after screening. This systematic review revealed that preventive nursing interventions for ICU-acquired weakness mainly include (a) physiotherapy, including neuromuscular electrical stimulation and early rehabilitation, and (b) nutritional support. In addition, (c) airway management, (d) sedation and analgesia management, (e) complication prevention (delirium, stress injury and deep vein thrombosis prevention), and (f) psychological care were also provided. The theories are dominated by goal-oriented theories, and the evidence is mainly the ABCDE bundle in the included studies. The results show that theory- or evidence-based nursing interventions are effective in reducing the incidence of ICU-acquired weakness (or improving the Medical Research Council Scale scores), decreasing the incidence of delirium, shortening the length of hospital stay, and improving patients' self-care and quality of life. Theory- and evidence-based nursing interventions have good results in preventing ICU-acquired weakness in critically ill patients. Current nursing interventions favour a combination of multiple interventions rather than just a single intervention. Therefore, preventive measures for ICU-acquired weakness should be viewed as complex interventions and should be based on theory or evidence. This systematic review is based on a small number of trials. Thus, more high-quality randomised controlled trials are needed to draw definitive conclusions about the impact of theory- and evidence-based nursing interventions on the prevention of ICU-acquired weakness.

Against the backdrop of stricter global carbon emission policies, corporate green transition performance has become a key driver for advancing sustainable development. Based on data from A-share listed companies in China from 2015 to 2022, this study empirically examines the mechanisms by which digital transformation impacts corporate green transformation performance. The findings reveal that (1) Digital transformation significantly promotes corporate green transformation, with supply chain innovation serving as a critical mediating factor; (2) The environmental awareness of senior executives and the strategic proactiveness of enterprises exert a significant moderating effect on this relationship. Enhanced environmental awareness among executives drives enterprises to leverage digital tools for green transformation; conversely, excessive strategic proactiveness exerts a constraining influenc; (3) Heterogeneity analysis indicates that firm-specific characteristics, industry attributes, and regional disparities produce differentiated effects. State-owned enterprises, benefiting from their policy support and resource advantages, are more likely to advance green innovation through enterprise digital transformation. Non-high-tech industries tend to optimize production processes, control pollution, and improve operational efficiency through digitalization. Moreover, in regions with stringent environmental regulations, the positive impact of digitalization on both innovation performance and environmental outcomes becomes particularly pronounced. This study enriches theoretical understanding of the integration between digitalization and greening, and by uncovering the pivotal role of supply chain innovation provides practical guidance and policy insights for enterprises advancing sustainable development.

There are unmet clinical needs for novel therapeutic targets and drugs for bladder cancer. Majority of previous work relied on limited bladder cancer cell lines, which could not well represent the tumor heterogeneity and pathology of this disease. Recently, it has been shown that cancer organoids can recapitulate pathological and molecular properties of bladder cancer. Here, we report, by our knowledge, the first bladder cancer organoid-based small molecule screening for epigenetic drugs. We found that SRT1720, a Sirtuin 1 (SIRT1) activator, significantly inhibits the growth of both mouse and human bladder cancer organoids. And it also restrains the development of mouse in situ bladder cancer and human PDX bladder cancer. Mutation of Sirt1 promotes the growth of cancer organoids and decreases their sensitivity to SRT1720, which validate Sirt1 as the target of SRT1720 in bladder cancer. Mechanistically, SRT1720 treatment represses the hypoxia pathway through deacetylating HIF1α by activating Sirt1. Genetic or pharmaceutic inhibitions of HIF mimic the anti-tumor effect of SRT1720. Furthermore, the SIRT1-repressed gene signature is associated with the hypoxia target gene signature and poor prognosis in human bladder cancers. Thus, our study demonstrates the power of cancer organoid-based drug discovery and, in principle, identifies SRT1720 as a new treatment for bladder cancer.