Sensitive detection of kanamycin (KAN) is vital for ensuring food safety. In this study, a novel fluorescent aptasensor for KAN detection was developed by synergizing high-affinity split aptamers, a miniaturized DNA nanotetrahedron (mini-NTH) scaffold, and rolling circle amplification (RCA). Contrasting conventional views, the split aptamers exhibited superior affinity to intact ones, a phenomenon elucidated by molecular dynamics (MD) simulations and validated via bio-layer interferometry (BLI). The mini-NTH scaffold ensured precise probe orientation on magnetic beads. Upon KAN binding, a ternary complex formed that consumed RCA primers, triggering a sensitive "signal-off" fluorescence response. The aptasensor achieved a linear range of 100 pM-100 nM with a detection limit of 0.5 nM. It demonstrated excellent stability (96.1% retention after 15 days), high precision (RSD < 5%), and reliable accuracy in milk samples (recoveries: 93.9-105.0%), showing strong agreement with HPLC analysis. This work presents a robust tool for antibiotic monitoring.

Growing evidence indicates that lactate and long non-coding RNAs (lincRNAs) exert a crucial influence on tumor development. This study aimed to investigate lactate-induced histone lactylation promotes the roles of lincRNA in lung cancer progression by enhancing proliferation and PD-L1-mediated inhibition of T cell antitumor function. Results showed that both linc00824 and lactate levels were elevated in NSCLC tissues compared to adjacent controls. Lactate upregulated linc00824 expression by regulating histone H3K18 lactylation. Functioning as an oncogene, linc00824 promoted NSCLC cell proliferation and migration. Furthermore, linc00824 upregulated PD-L1 expression through targeting miR-4483 in H1975 cells, thereby suppressing CD8+ T cell activation. MiR-4483 inhibited lung cancer cell proliferation and exhibited synergistic antitumor effects with envafolimab. In summary, lactate-induced histone lactylation drives linc00824 upregulation, facilitating lung cancer progression by enhancing tumor cell proliferation and suppressing T cell antitumor function via regulating miR-4483/PD-L1. We identified an antitumor strategy for lung cancer by using miR-4483.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related death, underscoring the need for an improved molecular understanding. This study investigated the regulatory mechanism of the long non-coding RNA deoxyguanosine kinase antisense RNA 1 (DGUOK-AS1) in LUAD. DGUOK-AS1 was significantly upregulated in LUAD cells and serum samples, and its elevated expression showed a preliminary association with LUAD. Functional experiments demonstrated that DGUOK-AS1 promoted LUAD proliferation and migration both in vitro and in vivo, partly by acting as a competing endogenous RNA for miR-2467-5p to modulate PRMT5 expression. Mechanistically, RNA-binding motif protein 15 (RBM15) enhanced DGUOK-AS1 stability through m6A modification, which in turn enabled heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) binding in an m6A-dependent manner via its RNA recognition motif 3 (RRM3) domain, promoting degradation. RBM15 knockdown attenuated the malignant phenotype through the miR-2467-5p/PRMT5 axis. These findings reveal an m6A-dependent mechanism governing DGUOK-AS1 stability and provide insights into its contribution to LUAD progression.

Flexible wearable sensors have garnered significant attention in recent years and exhibit promising application potential in the field of healthcare. Conductive hydrogels have emerged as ideal materials for the development of flexible wearable sensors due to their tunable structural properties, mechanical flexibility, and ease of processing. Nevertheless, most hydrogels are primarily engineered for detecting physiological signals, such as movement and electromyography (EMG), yet lack therapeutic functionalities. In addition, Previous reported hydrogels fabricated from synthetic polymers may retain residual small-molecule monomers, posing cytotoxicity risks. Herein, we report a multifunctional conductive hydrogel composed of carboxymethyl cellulose (CMC), polydopamine (PDA), and polypyrrole-polydopamine-MnOx nanoparticles (P-NPs), designed for concurrent motion monitoring, electromyography (EMG) signal detection, and photothermal therapy. The hydrogel was synthesized through a one-step amidation/oxidative polymerization approach, yielding an interpenetrating dual-network architecture with enhanced mechanical strength and tissue adhesion relative to single-network systems. The incorporation of P-NPs imparts high electrical conductivity, enabling real-time monitoring of physiological signals (e.g., joint movement, muscle activity), as well as effective photothermal conversion under near-infrared (NIR) irradiation. Notably, the hydrogel facilitates on-demand photothermal therapy to mitigate muscle fatigue upon detection of abnormal EMG signals, offering a strategy to prevent exercise-induced injury. Owing to its excellent biocompatibility and stability, the CMC/PDA/P-NPs hydrogel represents a promising platform for next-generation wearable devices integrating diagnostic and therapeutic functions.

The ultimate goal of a genome-wide association study (GWAS) is to translate its discoveries into clinical practice. To explore the clinical use of GWAS findings in the bone field, we conducted a GWAS of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 91 unique and independent loci were identified for 11 DXA-derived BMD traits and fractures, including 5 novel loci (harboring the genes ABCA1, CHSY1, CYP24A1, SWAP70, and PAX1) for 6 BMD traits. These loci exhibited evidence of association in both males and females, which could serve as independent replication. We demonstrated that each polygenic risk score (PRS) was independently associated with fracture risk. Although incorporating multiple PRSs (i.e., metaPRS) with clinical risk factors from the Fracture Risk Assessment Tool (FRAX) yielded the highest predictive performance, the improvement was modest in fracture prediction. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm (IA). Finally, by integrating gene expression and GWAS datasets, we prioritized genes (e.g., ESR1 and SREBF1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation reveals a new genetic basis for BMD and its clinical relevance to fracture prediction. More importantly, it suggests that head BMD is genetically correlated with IA. The prioritization of genetically supported targets implies the potential repurposing of drugs [e.g., omega-3 polyunsaturated fatty acid (PUFA) supplements] for the prevention of osteoporosis.

Lung adenocarcinoma (LUAD) is one of the common malignant tumors worldwide, and the 5-year survival rate remains unsatisfactory. Reliable prognostic biomarkers are needed to provide references for personalized treatment of patients. Some studies have shown that disulfidptosis-related genes (DRGs) are closely associated with tumorigenesis and development. This study constructed a prognostic risk model to explore the prognostic value of DRGs in LUAD and provide a reference for formulating personalized treatment plans for LUAD patients. RNA-seq data of LUAD tissues and adjacent or normal lung tissues were downloaded from TCGA database and GEO database. A risk scores model was constructed through univariate Cox analysis, Lasso analysis, and multivariate Cox analysis. ROC curves and nomogram models were drawn to evaluate the risk model. External validation was performed using LUAD data, data in the LUAD single-cell dataset, and other data in the GEO database. In addition, the immune microenvironment and drug sensitivity of the high-risk and low-risk groups were analyzed. The key gene PPP1R14B in the model was further experimentally verified by in vitro cell experiments. In this study, a risk model composed of four genes was constructed, and the overall survival (OS) of the low-risk group was higher than that of the high-risk group (P < 0.001). The area under the curve (AUC) of the ROC curves of the training set risk model at 1-, 3-, and 5-year were 0.767, 0.759, and 0.711, respectively. Drug sensitivity analysis showed that there was a statistical significance between the high-risk and low-risk groups of patients for drugs such as gefitinib, afatinib, lapatinib, and paclitaxel (P < 0.001). The results of in vitro cell experiments showed that the proliferation and migration of knockdown PPP1R14B LUAD cells were significantly inhibited, and the number of apoptosis of LUAD cells was significantly increased (P < 0.05). The risk model constructed based on four DRGs can predict the prognosis of LUAD patients with relative accuracy. There are differences in the immune microenvironment between the high-risk and low-risk groups. Patients in the high-risk group are more sensitive to drugs such as gefitinib, afatinib, lapatinib, and paclitaxel, providing a reference for personalized treatment of LUAD patients. Knockdown PPP1R14B significantly inhibited the proliferation and migration of LUAD cells and promoted the apoptosis of LUAD cells.

EGFR-targeted therapy and anti-PD-1/PD-L1 immunotherapy are crucial in treating advanced or metastatic non-small cell lung cancer (NSCLC). However, therapeutic drug resistance frequently develops, leading to treatment failure. To address this, a novel nanoparticle PFPR (PDA-Fe-PEI-RGD), composed of polydopamine (PDA), iron ions, and Arg-Gly-Asp (RGD) peptides, was designed to deliver siRNA targeting EGFR and PD-L1 into NSCLC cells to investigate the nanoparticle-combined therapy to NSCLC through EGFR and PD-L1 blockade. PFPR nanoparticles can elevate ROS production in PFPR-laser-treated cultures, and significantly induce NSCLC cell death compared to control treatment. PFPR-siEGFR and PFPR-siPD-L1 markedly suppress cell proliferation, colony formation, and migration compared with PFPR-siCon, with further enhancement under laser treatment. The suppressive effects of PFPR-siRNA to NSCLC may be related to upregulation of Bax, Caspase 3, and E-cadherin, alongside downregulation of Cyclin D1 and N-cadherin. H1975 xenograft results further demonstrate significant reductions in tumor weight and volume in PFPR-siRNA-treated groups, with additional decreases upon laser irradiation. PFPR-siPD-L1 increases the proportion of CD3+CD8+ T cells and elevates CD107a and IFN-γ levels, enhancing cytotoxic activity against NSCLC. In summary, the novel PFPR nanoparticle system, synergistically combining the properties of PDA, iron, RGD, and siRNA, effectively suppresses NSCLC progression by activating photodynamic therapy (PDT) and anti-tumor immunity.

Natural conductive hydrogels are regarded as desirable materials for motion monitoring owing to their outstanding biocompatibility and degradability. It has been reported that the occurrence rate of injuries in the final 30 % of the activity is closely associated with fatigue-induced changes in neuromuscular control. However, most hydrogels are designed solely for motion state and electromyography (EMG) detection and do not provide the capability to alleviate muscle fatigue. The development of conductive hydrogels that integrate motion monitoring with fatigue alleviation could enable simultaneous fatigue detection and on-demand fatigue relief, thereby reducing the risk of sports-related injuries. Photothermal therapy has been proven to be an effective method for relieving muscle fatigue. In this study, a double-network hydrogel composed of chitosan and sodium alginate was prepared, which incorporates lignin‑silver nanoparticles (NPs) and melanin NPs to achieve effective motion monitoring and photothermal therapy. A physical cross-linking network formed via electrostatic interactions between chitosan and sodium alginate was reinforced with a Genipin-mediated chemical cross-linking network. The addition of lignin‑silver NPs enhanced the hydrogel's conductivity and mechanical integrity, whereas melanin NPs improved adhesion and conferred photothermal responsiveness. The resulting hydrogel enabled reliable motion monitoring and real-time identification of exercise-induced fatigue through EMG. Upon fatigue detection, the photothermal properties of the hydrogel facilitated rapid fatigue alleviation.

Cancer-related pain is prevalent and severely impairs patients’ quality of life. However, conventional cancer therapies primarily target tumor cell destruction, often overlooking the management of cancer pain. Thus, there is an immediate necessity to develop therapeutic agents that can both suppress tumor growth and alleviate cancer pain. In this study, we report a celastrol (CEL)-based nanocomposites (PDA-BSA-MnO2-CEL) for pain-less cancer immunotherapy. Results from in vitro and in vivo experiments demonstrate the efficacy and mechanism of the nanocomposites in pain-less immunotherapy. MnO2 and CEL induce immunogenic cell death (ICD), mediating immunotherapy. Additionally, CEL significantly reduces the secretion of the immunosuppressive factor Yes-associated protein (YAP) within the tumor microenvironment, thereby enhancing the efficacy of immunotherapy. The downregulation of YAP leads to reduced expression of vascular endothelial growth factor (VEGF), inhibiting tumor growth and decreasing activation of the pain-associated VEGF receptor 1 (VEGFR1), thus providing an analgesic effect. Moreover, CEL reduces inflammatory pain by lowering levels of inflammatory factors in tumors. The design of this nanocomposites system integrates immunotherapy with cancer pain inhibition, offering a novel approach to patient-centered tumor therapy.

Sulfur dioxide (SO2), a pungent toxic gaseous pollutant, excessively exposed to organism would stimulate respiratory system and cause inflammation and other respiratory diseases. Endogenous SO2 mainly generates from sulfur-containing amino acids and also maintains reactive sulfur species metabolic balance as an important signaling molecule. Although great progress of current SO2 detection analysis has been made via fluorescence probe, visualized evidence for the research of inflammation and other diseases in respiratory caused by SO2 is scarce. Developing powerful analysis tools to investigate SO2 function on the respiratory system is still necessary. Herein, we designed a simple fluorescent probe OPD-SO2 for evaluating the effects of SO2 on lung tissue inflammation. OPD-SO2 provides visualized evidences for elevating SO2 in aspartate aminotransferase-1 (AAT1) gene over-expressed common/inflammatory cells, and verifies that inflammation occurrence promoted SO2 generation and AAT1-overexpressed cells might resist inflammation by up-regulating intracellular SO2, exhibits favorable detectability of SO2 in bronchoalveolar lavage fluid of SO2 exposed mice. The inflammation state related to SO2 levels before and after anti-inflammatory treatment has also been investigated. Moreover, the evaluation assisted by PCR, ELISA, and histopathologic analysis reveals the dual effects between SO2 levels and lung tissue inflammatory.

Purpose:This study aims to develop an innovative delivery system, (Q+M/MnOx)@Clip, to enhance the bioavailability and therapeutic efficacy of quercetin both in tumor treatment and pain alleviation. Methods:The (Q+M/MnOx)@Clip system was evaluated to enhance the release of quercetin, investigate its ability to target cancer cells, alleviate tumor hypoxia, and improve the efficacy of chemodynamic therapy (CDT). Tumor hypoxia markers and immune response activation were assessed, along with the impact on pain relief biomarkers. Results:(Q+M/MnOx)@Clip successfully mitigated tumor hypoxia, facilitated controlled Q release, and enhanced CDT in vitro and in vivo. The system demonstrated a dual therapeutic effect: anti-tumor immunity and significant cancer pain relief by reducing HIF-1α and VEGF-A levels. Conclusion:The novel (Q+M/MnOx)@Clip system represents a promising advancement in nanomedicine, improving the bioavailability of quercetin and offering a more effective approach to cancer treatment by downregulation of HIF-1α and VEGF-A. This study demonstrates the potential for combining anti-tumor immunity with pain relief for triple-negative breast cancer therapy.

BackgroundLung adenocarcinoma (LUAD) is one of the common malignant tumors worldwide, and the 5-year survival rate remains unsatisfactory. To investigate the association between disulfidptosis-related ferroptosis genes (DFRGs) and the prognosis of patients with LUAD, establish a risk prognostic model, validate key biomarkers in vitro, and provide references for the prognosis of LUAD patients.MethodsR software was employed to identify DFRGs. Univariate Cox regression and Lasso-Cox regression analyses were combined to construct a risk score prognostic model. The predictive power of the model was evaluated using Kaplan-Meier survival curves, receiver operating characteristic (ROC) curves, and calibration curves. Immune-related functions, tumor mutation burden, and single-cell analyses were performed on the model genes. Finally, in vitro validation of key prognostic markers was conducted via qRT-PCR, wound healing assay, Transwell assay, CCK8 assay, and flow cytometry apoptosis assay.ResultsSix DFRGs were screened through univariate Cox regression and Lasso-Cox regression analyses to construct the prognostic model. The areas under the ROC curve (AUC) for 1, 2, and 3 years in the training set were 0.836, 0.771, and 0.786, respectively. Decision curve analysis (DCA) indicated that the risk score model effectively predicted lung adenocarcinoma prognosis. In vitro validation demonstrated that knockdown of DECR1 significantly suppressed lung adenocarcinoma cell proliferation and migration, and promoted cell apoptosis (P < 0.05).ConclusionThis study established a risk score model based on six DFRGs, which demonstrated favorable prognostic value. DECR1 promotes the progression of LUAD and holds promise as an effective biomarker.

Communication between cancer cells and tumor microenvironment (TME) plays a complicated role in cancer malignancy. Circular RNAs (circRNAs), known for their stability and conservation, contribute to TME remodeling in various cancers. This study aims to investigate the role of N6-methyladenosine (m6A)-modified circZNF548 in the proliferation and migration of non-small cell lung cancer (NSCLC) within the TME. circZNF548 expression is lower in NSCLC tissues than that in adjacent normal controls, and the higher circZNF548 levels correlate with the improved patient survival. circZNF548 overexpression suppresses NSCLC cell proliferation and migration, whereas siRNA-mediated downregulation promotes proliferation and migration. METTL14 overexpression decreases circZNF548 levels through m6A modification, whereas siRNA-mediated METTL14 downregulation increases them. circZNF548 interacts with and regulates the abundance of exosomal miR-7108-3p. CD8A and junction-mediating and regulating Y protein (JMY) are identified as downstream targets of miR-7108-3p. Exosomal miR-7108-3p suppresses the activation of CD3+CD8+ T cells by decreasing CD107a levels and downregulating the production of IFN-γ, perforin 1, and granzyme B in TME. circZNF548 promotes CD3 + CD8 + T cell-mediated cytotoxicity and inhibits NSCLC cell proliferation by modulating exosomal miR-7108-3p and the JMY-p53 pathway. m6A-modified circZNF548 suppresses NSCLC cell proliferation and migration by enhancing anti-tumor immunity via exosomal miR-7108-3p and the JMY-p53 pathway. These findings suggest new therapeutic targets for NSCLC. • circZNF548, affected by METTL14 through m6A, could suppress NSCLC cell proliferation by regulating the activation of CD3+CD8+ T cells through exosomal miR-7108-3p and miR-7108-3p-JMY-p53 pathway. • Exosomal miR-7108-3p treatment suppressed the activation of CD3+CD8+ T cells through decreasing CD107a levels and downregulating IFN-γ, perforin 1, and Granzyme B production. • CD8A was another downstream factor of miR-7108-3p, and CD8A-3ʹ-UTR recovery attenuated miR-7108-3p-promoting cell proliferation and cell migration.

Purpose:To investigate whether Danshensu ethyl ester (DEE) can attenuate acute lung injury (ALI) and explore the detailed mechanism. Methods:The ALI model was induced in mice using LPS. The effects of DEE on lung wet-to-dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein levels, and neutrophil infiltration (neutrophils) were assessed. In addition, molecular docking and molecular dynamics simulations were also carried out to determine the binding situation between DEE and NLRP3. We evaluated in both in vivo and in vitro models the expression of NLRP3-related proteins as well as the release of cytokines. The generation of reactive oxygen species (ROS) and the formation of ASC fluorescent specks in cells were also observed. Results:The results demonstrated that DEE significantly alleviated pulmonary edema and lung injury of mice. Molecular docking and simulations revealed that DEE directly targets and tightly binds to the NLRP3 protein. Furthermore, both in vivo and in vitro experiments showed that DEE suppressed activation of the NF-κB signaling pathway induced by LPS, and decreased the expression of NLRP3, ASC, and cleaved caspase-1, inhibiting the release of cytokines such as IL-1β, IL-6, and TNF-α. Additionally, DEE suppressed ROS generation and ASC specks formation, thereby inhibiting the assembly and activation of the NLRP3 inflammasome. Conclusion:DEE exerts an inhibitory influence on the LPS-induced inflammatory response by suppressing the activation of the NLRP3 inflammasome. This study provides the potential application of DEE in NLRP3-driven ALI therapy.

As a common malignancy symptom, cancer pain significantly affects patients' quality of life. Approximately 60%-90% of patients with advanced cancer experience debilitating pain. Therefore, a comprehensive treatment system that combines cancer pain suppression and tumor treatment could provide significant benefits for these patients. Here, we designed a manganese oxide (MnO2)/Bovine serum albumin (BSA)/polydopamine (PDA) composite nanoplatform internally loaded with capsaicin for cancer pain suppression and immunotherapy. MBD&C nanoparticles (NPs) can ablate tumor-innervated sensory nerve fibers via Transient receptor potential vanilloid 1 (TRPV1) channels, thereby reducing the pain caused by various inflammatory mediators. The ablation of TRPV1+ nerve terminals can also decrease the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP) in sensory nerve fibers, thus reducing the tumor pain and inhibit tumor progression. MBD&C can promote calcium influx by activating overexpressed TRPV1 channels on the tumor membrane surface, thereby achieving cancer immunotherapy induced by endogenous Ca2+ overloading. In addition, MnO2 NPs can alleviate tumor hypoxia and mitigate the immunosuppressive tumor microenvironment (TME). Ultimately, this treatment system with dual capabilities of inhibiting tumor growth and relieving cancer pain makes comfortable tumor therapy feasible and paves the way for the development of patient-centered approaches to cancer treatment in the future.

Lactylation, a post-translational modification process that adds lactate groups to lysine residues, plays a crucial role in cancer biology, especially in drug resistance. However, the specific molecular mechanisms of lactylation in cancer progression and drug resistance are still unclear, and therapeutic strategies targeting the lactylation pathway are expected to overcome metabolic reprogramming and immune evasion. Therefore, this article provides a comprehensive description and summary of lactylation modification and tumor drug resistance. Numerous studies have shown that, due to the Warburg effect, there is an abnormally high level of lactate in tumor cells. Elevated levels of lactate promote metabolic reprogramming and alter key cellular processes, including gene expression, DNA repair, and immune regulation. These cellular processes are precisely the key factors for tumor cells to develop drug resistance. Lactylation also affects the tumor microenvironment, promoting immune evasion and resistance to immunotherapy in tumor cells. This modification affects proteins involved in metabolic pathways, glycolysis, and mitochondrial function, further supporting tumor growth and metastasis. Therefore, this article provides a comprehensive description and summary of lactylation modification and tumor drug resistance to clarify the specific mechanisms between the two and provide references and directions for future research on tumor drug resistance.

Natural polysaccharides with excellent biocompatibility are considered ideal materials for repairing diabetic foot ulcer. However, diabetic foot ulcer is often accompanied by decreased muscle function, even resulting in muscle atrophy. During wound repair, monitoring muscle function at the wound site in real time can identify the decreased muscle strength timely, which is crucial for precise wound rehabilitation. Nevertheless, the majority of hydrogels are primarily utilized for wound healing and lack the capability for electromyography monitoring.Here, we designed a multinetwork hydrogel composed of astragalus polysaccharide, chitosan, and sodium alginate and internally embedded conductive PPy-PDA-MnO2 nanoparticles (P-NPs) loaded with resveratrol (Res) for wound repair and muscle function assessment. The intrinsic hypoglycemic and anti-inflammatory properties of astragalus polysaccharides, combined with the antioxidative and proangiogenic functions of Res, synergistically facilitate wound healing. The multinetwork structure affords the hydrogel excellent mechanical properties. Furthermore, the addition of conductive NPs not only improves the mechanical performance of the hydrogel but also confers electrical conductivity. The conductive hydrogel acts as an epidermal electrode which can be utilized for monitoring of electromyography signals. This novel approach for treating diabetic wounds ultimately achieves improved wound repair and muscle function assessment, carrying out a monitoring-guided safe and accurate wound repair.

Here, we conducted genome-wide association studies (GWAS) of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 92 unique and independent loci were identified for 11 DXA-derived BMD traits and fracture, including 5 novel loci (i.e., ABCA1, CHSY1, CYP24A1, SWAP70 and PAX1) and 2 sex-specific loci (i.e., CYP19A1 and CYP3A7). We demonstrated that polygenic risk scores (PRSs) were independently associated with fracture risk. Although incorporating multiple PRSs (metaPRS) with the clinical risk factors (i.e., the FRAX model) exhibited the highest predictive performance, the improvement was marginal in fracture prediction. The metaPRS were capable of stratifying individuals into different trajectories of fracture risk, but clinical risk factors played a more significant role in the stratification. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm. And the joint associated genes such as PLCE1 might play important roles in the shared genetic basis. Finally, by integrating gene expression, and GWAS datasets, we prioritized genes (e.g. ESR1, SREBF1, CCR1 and NCOR1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation revealed new genetic basis for BMD and its clinical relevance on fracture prediction. More importantly, it was suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implied the potential repurposing drugs (e.g. the n-3 PUFA supplement targeting SREBF1) for the prevention of osteoporosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Natural Science Foundation of China (#82370887), the "Pioneer" and "Leading Goose" R&D Program of Zhejiang (#2023C03164), the Chinese National Key Technology R&D Program, Ministry of Science and Technology (#2021YFC2501702), and the funds from the Westlake Laboratory of Life Sciences and Biomedicine (#202208014). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval for the UK Biobank research was obtained from the North West Multicentre Research Ethical Committee, and all participants provided informed consent (original ethics committee approval number: 21/NW/0157). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The summary statistics of the present GWAS on 11 DXA-BMD traits were deposited on the website (https://wbbc.westlake.edu.cn/downloads.html).

Cancer pain seriously reduces the quality of life of cancer patients. However, most research about cancer focuses solely on inhibiting tumor growth, neglecting the issue of cancer pain. Therefore, the development of therapeutic agents with both tumor suppression and cancer pain relief is crucial to achieve human-centered treatment. Here, the work reports curcumin (CUR) and ropivacaine (Ropi) coincorporating CaCO3/PDA nanoparticles (CaPNMCUR+Ropi) that realized efficient tumor immunotherapy and cancer pain suppression. The therapeutic efficiency and mechanism are revealed in vitro and in vivo. The results indicate that CaPNMCUR+Ropi underwent tumor microenvironment-responsive degradation and realized rapid release of calcium ions, Ropi, and CUR. The excessive intracellular calcium triggered the apoptosis of tumor cells, and the transient pain caused by the tumor injection was relieved by Ropi. Simultaneously, CUR reduced the levels of immunosuppressive factor (TGF-β) and inflammatory factor (IL-6, IL-1β, and TNF-α) in the tumor microenvironment, thereby continuously augmenting the immune response and alleviating inflammatory pain of cancer animals. Meanwhile, the decrease of TGF-β leads to the reduction of transient receptor potential vanilloid 1 (TRPV1) expression, thereby alleviating hyperalgesia and achieving long-lasting analgesic effects. The design of the nanosystem provides a novel idea for human-centered tumor treatment in the future.

Acute Lung Injury (ALI) manifests as an acute exacerbation of pulmonary inflammation with high mortality. The potential application of Danshensu methyl ester (DME, synthesized in our lab) in ameliorating ALI has not been elucidated. Our results demonstrated that DME led to a remarkable reduction in lung injury. DME promoted a marked increase in antioxidant enzymes, like superoxide dismutase (SOD), and glutathione (GSH), accompanied by a substantial decrease in reactive oxygen species (ROS), myeloperoxidase (MPO), and malondialdehyde (MDA). Moreover, DME decreased the production of IL-1β, TNF-α and IL-6, in vitro and in vivo. TLR4 and MyD88 expression is reduced in the DME-treated cells or tissues, which further leading to a decrease of p-p65 and p-IκBα. Meanwhile, DME effectively facilitated an elevation in cytoplasmic p65 expression. In summary, DME could ameliorate ALI by its antioxidant functionality and anti-inflammation effects through TLR4/NF-κB, which implied that DME may be a viable medicine for lung injury.