Stroke is the second leading cause of death globally, with residual upper limb dysfunction being a major contributor to its high disability rate. Currently, there remains a lack of effective rehabilitation approaches to substantially improve upper limb dysfunction. While transcranial magnetic stimulation (TMS) has shown potential in promoting functional reorganization in stroke patients, more effective treatment protocols are still under exploration. In recent years, numerous clinical evidence has indicated that intermittent theta burst stimulation (iTBS) may offer a more efficient pathway for the upper limb recovery after stroke. A few studies have employed accelerated iTBS protocols, preliminarily confirming its safety and efficacy, yet large-sample comparative studies against the standard protocol are lacking. This ATLAS trial aims to compare the effects of accelerated iTBS versus a standard TMS protocol on upper limb recovery and overall functional outcomes in patients with subacute stroke. This is a prospective, single-blind, multicenter, randomized controlled clinical trial. A total of 240 patients in the subacute phase of stroke will be recruited from 13 hospitals across 11 cities. Participants will be randomly allocated to either an iTBS group or a low-frequency repetitive TMS (LF-rTMS) group. Both groups will receive treatment 5 days per week for three consecutive weeks. In addition, all participants will receive standard conventional rehabilitation therapies, including physical agent modalities, therapeutic exercise, occupational therapy, and other commonly used clinical rehabilitation approaches. The primary outcome is the Fugl-Meyer Assessment for Upper Extremity (FMA-UE) evaluated after 3 weeks of treatment. Secondary outcomes include measures of upper limb function, activities of daily living, clinical disease severity, and neurophysiological indicators assessed by rTMS, evaluated at both post-intervention and after a 3-week follow-up period. ATLAS trial is the first multicenter randomized controlled trial to apply an accelerated iTBS protocol to a large cohort of patients with subacute stroke and compare it directly with a standard stimulation protocol. The findings are expected to address the current gap in high-quality evidence regarding the efficacy of accelerated iTBS on upper limb recovery after stroke, thereby promoting the broader clinical adoption of more efficient iTBS-based therapeutic strategies. Chinese Clinical Trial Registry (ChiCTR2500110766). Registered on Oct 20, 2025.

Intervertebral discs underpin spinal flexibility and stability during locomotion, yet the mechanism guiding their mechanoadaptive development remains inadequately elucidated. Here, we discovered a murine disc type programming spontaneous collagen deposition (collagenesis) within coccygeal regions under heightened mechanical loading, commencing around the 14th day after birth. In contrast to typical discs, these collagen-II-enriched discs (designated as type C) impart resistance to compressive and flexural stresses and lower susceptibility to degeneration. Their development involves a shift featuring emergent chondrogenic cell clusters independent of notochordal lineage and diminished notochord cells. Mechanistically, mechanical unloading inhibited type C disc formation, confirming collagenesis as a mechanoadaptive response. TRPV4 was highly expressed, and its deletion impaired collagenesis, underscoring the critical role of mechanotransduction. Critically, analogous mechanoadaptation programs in developing human lumbar spines demonstrate evolutionary conservation. Our findings reveal a fundamental collagenesis orchestrating mechanoadaptive disc development and lifelong homeostasis, offering insights into spinal function and relevant therapeutic strategies.

Intervertebral disc degeneration (IVDD), a prevalent degenerative disorder, imposes a substantial and growing health burden in aging populations. Recently, ferroptosis-a regulated cell death driven by lipid peroxidation, iron overload, and glutathione peroxidase 4 (GPX4) dysregulation-has been identified as a key pathogenic mechanism of IVDD. Despite these advances, a comprehensive understanding of its regulatory networks remains limited, hindering the development of targeted therapies and leaving clinical management reliant on invasive surgery. To address these challenges, functional biomaterials have now emerged as a promising strategy with combined anti-ferroptotic effects. In this review, we examine the known ferroptotic mechanisms in IVDD and explore emerging functional biomaterials with combined anti-ferroptotic properties, thereby aiming to advance therapeutic strategies for IVDD. The translational potential of this article: Given the critical role of ferroptosis in IVDD pathogenesis, functional biomaterials represent a promising translational strategy by enabling both targeted delivery of anti-ferroptotic therapeutics and biomaterial-intrinsic protection against ferroptotic damage. By systematically summarizing the ferroptosis-targeting mechanisms, and therapeutic advantages of these biomaterials, this review offers theoretical guidance for the development of future, clinically translatable interventions for IVDD.

Although studies have examined vehicle impact on bridge piers and the resulting pier responses, no mature simplified method yet exists for calculating the dynamic response of piers under vehicle impact. This paper establishes an analytical model for pier responses under a half-sine impact load simulating the dominant component of vehicle-impact loading, investigates key parameters including the frequency ratio and offset ratio, and examines the critical section for impact-resistant design, pier modal response characteristics, and the applicability of the equivalent SDOF model. Results show that the impulsive nature of vehicle impact and the asymmetric loading location along the pier height make higher-order modes significantly influence responses, so simplifying the pier as an equivalent SDOF model may cause large errors. Therefore, a modal-superposition-based response spectrum method is proposed to combine higher-order modal responses for rapid and accurate prediction of pier responses, providing a theoretical method for bridge impact-resistant design and safety assessment.

This study develops a machine learning model to predict osteoporosis in Chinese postmenopausal women. The model was trained using the largest nationwide cohort and externally validated. It showed AUCs of 0.744–0.798 and demonstrated prognostic value for 5-year fracture risk, supporting population-level screening where DXA resources are limited. Osteoporosis is highly prevalent among Chinese postmenopausal women, yet underdiagnosis remains due to limited DXA availability. We aimed to develop and validate a machine learning–based model for osteoporosis prediction using easily obtainable variables. The model was trained using data from the largest nationwide cohort (China Osteoporosis Prevalence Study, n = 6,574) and externally validated in two independent cohorts: the China Vertebral and Osteoporosis Study (n = 1,758) and the Peking Vertebral Fracture Study baseline (n = 1,439). Five predictors selected via LASSO regression were used to train the prediction model. Model performance was evaluated by area under the curve (AUC) and calibration plot. To evaluate its ability to predict future fractures, the model was evaluated in a 5-year follow-up cohort (n = 795). A web-based calculator was developed for public use. The model showed strong discrimination (AUC: 0.798 in the training cohort; 0.775 in the internal validation cohort; 0.750 and 0.744 in the external validation cohorts) and good calibration across all cohorts. A rule-out threshold (≥ 0.098) demonstrated high sensitivity (94.7

Background After patients underwent standard postoperative rehabilitation following anterior cruciate ligament reconstruction (ACLR), some still exhibited persistent functional deficits postoperatively, which might be associated with adaptive changes in the excitability of neural pathways. This study investigated corticospinal excitability in patients following ACLR and examined the immediate neuromodulatory effects of transcutaneous spinal direct current stimulation (tsDCS). Methods Twenty ACLR patients and 20 age- and sex-matched healthy controls underwent monopulse transcranial magnetic stimulation of the quadriceps motor cortex to determine motor threshold (MT) and motor evoked potential (MEP) amplitude. ACLR participants subsequently received a single session of tsDCS (2.0 mA, 20 min), with the cathode placed over the T10 spinous process and the anode on the contralateral deltoid muscle. MT and MEP were re-assessed immediately after intervention to evaluate acute neuromodulatory effects. Results All participants were right-leg dominant. Compared with controls, ACLR patients exhibited significantly higher MT values in both the reconstructed and non-reconstructed legs (P < 0.05), indicating bilateral reductions in corticospinal excitability, with more pronounced impairment in the reconstructed leg. Although MEP amplitudes were lower in the reconstructed leg, the differences did not reach statistical significance. Following stimulation, MT significantly decreased in the reconstructed leg (P < 0.05), while MEP amplitudes remained unchanged. No effects were observed in the non-reconstructed leg. Conclusion These findings suggest that ACLR is associated with bilateral corticospinal hypoexcitability and that tsDCS can acutely enhance excitability in the reconstructed leg. The tsDCS may represent a promising adjuvant neuromodulatory strategy to complement conventional rehabilitation in ACLR patients.

Background:The co-occurrence of osteoporosis (OP) and rheumatoid arthritis (RA) has long been observed; their intrinsic link, however, has not been fully understood. Objectives:We aimed to inform the importance of integrated care targeting both diseases by investigating the phenotypic as well as the genetic relationships underlying OP and RA. Design:This is a prospective cohort study and genome-wide cross-trait analysis. Methods:We evaluated phenotypic associations using longitudinal follow-up data from the UK Biobank (N = 472,050). We investigated genetic relationships by leveraging summary statistics from the largest genome-wide association study in European ancestry conducted for RA (N case/control = 22,350/74,823), seropositive RA (N case/control = 17,221/74,823), and a reliable proxy of OP-the heel estimated bone mineral density (eBMD; N = 426,824). Results:Observational analysis suggested a bidirectional relationship (OP → RA: hazard ratio (HR) = 1.59, 95% confidence interval (CI) = 1.28-1.97; RA → OP: HR = 2.94, 95% CI = 2.59-3.35). A negative overall genetic correlation was observed for eBMD with RA ( = -0.06, p = 1.37 × 10-5) and with its seropositive subtype (r g = -0.06, p = 9.15 × 10-6). Cross-trait meta-analysis replicated 96 previously reported trait-associated loci and discovered three novel pleiotropic loci (rs72836346, rs2613812, and rs76458888). Transcriptome-wide association study revealed 23 shared genes. Mendelian randomization analysis suggested a putative causal effect of eBMD on RA (odds ratio (OR) = 0.90, 95% CI = 0.84-0.96), but not of RA on eBMD. Conclusion:Our work demonstrates a significant biological pleiotropy as well as a putative causal relationship between OP and RA, emphasizing an intrinsic link underlying the pronounced phenotypic association. These findings highlight the possibility of preventing and predicting RA development by monitoring and interfering with bone loss in preclinical high-risk individuals.

Dysregulated cholesterol metabolism has been implicated in several aging-associated disorders, including osteoarthritis (OA). 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the key enzyme in cholesterol biosynthesis, but the role of HMGCR in OA and the underlying mechanism remain unclear. In this study, we found that HMGCR+ fibroblasts (FLSs) were significantly increased in the knee synovium of OA patients and OA mice. Elevated expression of HMGCR in synovial FLSs was positively correlated with cellular senescence and OA progression. The inhibition of HMGCR reversed cellular senescence of FLSs induced by TNF-α in vitro. Additionally, the HMGCR-mediated cholesterol biosynthetic pathway contributed to cellular senescence. Targeted inhibition of HMGCR in synovial FLSs via intra-articular adeno-associated virus delivery effectively reversed cellular senescence of FLSs and mitigated synovitis, cartilage degradation, and pain behaviors in OA mice. Mechanistically, the phosphorylation of AKT1 at Ser473 enhanced its binding to Lys140 of Insig1, facilitating AKT1-Insig1 complex formation. The activation of AKT1 induced the phosphorylation of Insig1 at Ser189 and the dissociation of Insig1 from sterol regulatory element‑binding protein cleavage‑activating protein (SCAP), which contributed to HMGCR transcription and cellular senescence of FLSs. Collectively, our study reveals a novel mechanism of HMGCR-driven cellular senescence of FLSs in OA, which highlights HMGCR as a promising therapeutic target for OA.

AIMS:Restoring innervation is essential for functional pulp regeneration. Apelin, an endogenous bioactive peptide widely expressed in the nervous system, has been reported to facilitate neuroprotection and neural differentiation. This study aims to investigate the role of Apelin-13 in promoting neural differentiation of human dental pulp stem cells (hDPSCs) and to elucidate the underlying molecular mechanisms. MATERIALS AND METHODS:The expression pattern of Apelin during dental pulp innervation in mice was examined to explore its potential role in neural regulation. hDPSCs were isolated, characterized, and subjected to neural induction. To investigate the function of Apelin-13, hDPSCs were treated with recombinant Apelin-13 protein and transfected with Apelin-specific siRNA. To determine whether Apelin-13-induced neural differentiation is APJ-dependent and involves Wnt/β-catenin signaling, APJ was silenced by siRNA and the pathway was inhibited with Dickkopf-1. qRT-PCR, Western blot, and immunofluorescence were performed to evaluate the expression of neural markers and key signaling pathway molecules. KEY FINDINGS:During the first molar dental pulp development in mice, endogenous Apelin and Nestin were spatiotemporally co-expressed, suggesting a potential role for Apelin in neural regulation. Apelin-13 significantly promoted the neural differentiation of hDPSCs in vitro, whereas Apelin knockdown suppressed this process. Mechanistically, Apelin-13 induced neural differentiation of hDPSCs in an APJ-dependent manner and concomitantly activated Wnt/β-catenin signaling. SIGNIFICANCE:Apelin-13 promotes the neural differentiation of hDPSCs in an APJ-dependent manner, in part via activation of the Wnt/β-catenin signaling pathway.

Lactate accumulation is a hallmark and contributing factor of intervertebral disc degeneration (IVDD), while the role of protein lactylation caused by lactate accumulation in IVDD remains unclear. Via metabolomics, single-cell RNA-sequencing analysis, and lactylation proteomics, we reveal the lactylome landscape in IVDD and identified superoxide dismutase 1 (SOD1) lactylation at lysine 123 (SOD1K123la) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1K123R mutant male rats, and in silico molecular dynamics simulations, we find that SOD1K123la alters SOD1 conformation and impairs its enzymatic activity, and induces oxidative damage, and activates p53 pathway in nucleus pulposus cells (NPCs). Notably, we identify a small molecule ZL-01 that inhibits SOD1K123la. NPC-targeted delivery of ZL-01 via collagen type II-targeted peptide-modified extracellular vesicles alleviated IVDD in male rats. Together, these findings clarify the mechanism by which SOD1K123la promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.

Genetic manipulation technologies (GMTs) serve as potent instruments for elucidating the molecular and cellular mechanisms that underly both physiological and pathological processes. However, the increasing recognition of the cellular heterogeneity in terms of their spatial distribution, cellular subtypes, and functional states in complex tissues, has posed new challenges to the applicability and precision of these technologies. While current GMTs facilitate precise genetic interventions at the molecular level, their capacity for achieving cell-specific genetic regulation remains constrained. In this context, we utilize research on fibroblast growth factors (FGFs)/FGF receptors (FGFRs) signaling in osteoarthritis (OA) as a case to demonstrate the technical limitations faced by existing GMTs. To address these constraints, we propose a conceptual framework termed Materialogenetics, which integrates advances in biomaterials science with genetic manipulation approaches. Advanced biomaterials with active-targeting and stimuli-responsive properties have been widely explored in disease diagnosis and therapy. When combined with GMTs, these materials can theoretically greatly improve cell-specific and spatiotemporally controlled genetic manipulation at both molecular and cellular levels. Moreover, biomaterial-assisted genetic manipulation offers several practical advantages, including cost-effectiveness, operational simplicity, and a high degree of tunability, rendering the platform highly adaptable to a wide range of research contexts. Collectively, Materialogenetics establishes a conceptual framework that bridges the fields of materials science and genetics, representing a versatile and promising platform for achieving precise genetic manipulation in complex biological systems.

Objective Synovial fibrosis is an important pathological change in osteoarthritis(OA)and is closely associated with disease progression.During the progression of synovial fibrosis in OA,fibroblasts differentiate into myofibroblasts,leading to abnormal deposition of extracellular matrix(ECM)and resulting in clinical symptoms such as joint pain and limited mobility.This study aims to investigate the role and cellular and molecular mechanisms of the fibroblast growth factor 7(FGF7)-fibroblast growth factor receptor 1(FGFR1)signaling axis in OA synovial fibrosis.Methods ① By mining publicly available synovial single-cell sequencing data,combined with differential analysis,enrichment analysis,fibrosis scoring,correlation analysis,and virtual knockout techniques,the relationship between FGF7/FGFR1 and OA synovial fibrosis was explored.② An OA mouse model was established via destabilization of the medial meniscus(DMM),and the mice receiving sham surgery served as the control group.Recombinant FGF7 protein(2 μg/10 μL)or PBS was injected into the joint cavity once weekly for 4 weeks.Functional assessments were performed at 4(n=6)and 8 weeks(n=5)after modeling via behavioral testing,including gait analysis,hindlimb balance test,and knee joint range-of-motion evaluation.Histopathological analyses,including HE,Masson's trichrome,and Sirius Red staining,as well as immunostaining for collagen type Ⅰ alpha 1 chain(COL1A1)and alpha-smooth muscle actin(α-SMA),were conducted to evaluate synovial fibrosis and inflammatory changes.③ EdU,CCK-8 assay,wound-healing assay,qPCR,and Western blotting were applied to investigate the role of FGF7 in fibroblast-to-myofibroblast differentiation.Results ① FGF7 expression was positively correlated with synovial fibrosis scores.② Exogenous FGF7 markedly aggravated OA-related joint dysfunction in DMM mice.At 4 weeks post-DMM,compared with the PBS group,the FGF7 group showed decreased distribution of right hindlimb ground contact time(P<0.01),right hindlimb weight-bearing(P<0.01),and knee joint range-of-motion(P<0.001),with a similar trend observed at 8 weeks post-DMM.③ FGF7 promoted ECM deposition and upregulated fibrosis markers in the synovial tissues.Histological analysis revealed that FGF7 treatment significantly aggravated synovial inflammation at 4 weeks(P<0.000 1)and 8 weeks(P<0.01),and promoted ECM deposition compared with the PBS group.COL1A1 immunohistochemical staining indicated increased type Ⅰ collagen deposition in the FGF7 group at 4(P<0.05)and 8 weeks(P<0.000 1),and immunofluorescence assay showed increased α-SMA expression in the FGF7 group at 4(P<0.001)and 8 weeks(P<0.01).④ In in vitro study,EdU and CCK-8 assays indicated that FGF7 promoted fibroblast proliferation(P<0.05);the scratch assay showed that FGF7 enhanced fibroblast migration(P<0.01);FGF7 upregulated α-SMA(P<0.001)and COL1A1(P<0.001)expression in fibroblasts.⑤Mechanistically,FGF7 exerted pro-fibrotic effects through the FGFR1 pathway.FGF7 activated p-FGFR1(P<0.05)and p-ERK(P<0.01)expression in fibroblasts;BGJ398 inhibited the FGF7-induced upregulation of p-FGFR1(P<0.05),p-ERK(P<0.05),COL1A1(P<0.05),and α-SMA(P<0.01)in fibroblasts.Conclusion Exogenous FGF7 exacerbates synovial fibrosis in OA mice.Our findings revealed that FGF7 promotes fibroblast proliferation,migration,and differentiation into myofibroblasts via activation of the FGFR1 pathway,thereby providing a potential novel target for the treatment of OA synovial fibrosis.

Background The JAK/STAT pathway plays a pivotal role in hepatic ischaemia/reperfusion (I/R) injury, a serious perioperative complication. Although signal transducers and activators of transcription 1 (STAT1) activation is known to drive I/R-induced injury, the specific post-translational modifications (PTMs) governing its activity in hepatic I/R remain poorly understood.Objective This study identifies SMYD2, SET and MYND domain Containing 2 (SMYD2) as a critical regulator of STAT1 and investigates the mechanistic basis of SMYD2-mediated PTMs in modulating STAT1 function during hepatic I/R.Design Using an integrated transcriptomic-proteomic approach and functional screening, we identified SMYD2 as a critical regulator of STAT1 activation in hepatic I/R injury. Clinical correlations linked SMYD2 expression to postoperative liver function, while loss-of-function and gain-of-function studies in vitro and in vivo validated its mechanistic role.Results Our findings demonstrate that SMYD2 modulates hepatic I/R injury through the JAK-STAT1 pathway. Clinically, elevated SMYD2 expression correlated with improved liver function and better surgical outcomes following hepatectomy. Mechanistic studies revealed that SMYD2 physically interacts with STAT1 and mediates its methylation at lysine 175 (K175), thereby inhibiting STAT1 phosphorylation and nuclear translocation. Both in vitro and in vivo studies demonstrated that SMYD2 overexpression alleviated hepatic I/R injury, whereas its genetic depletion or pharmacological inhibition exacerbated the damage.Conclusion This study establishes SMYD2 as a novel negative regulator of STAT1 activity through K175 methylation, providing new insights into the epigenetic control of STAT1 during hepatic I/R injury. Our findings reveal a previously unrecognised mechanism for fine-tuning STAT1 signalling in hepatic I/R injury, and targeting the SMYD2-STAT1 axis may present a promising therapeutic strategy for mitigating I/R-associated liver damage.

Background Skeletal stem/progenitor cells (SSPCs) are pivotal orchestrators of embryonic skeletogenesis, underlying chondrogenesis and osteogenesis, however, the molecular determinants governing SSPC functionality remain elusive. Methods We performed single-cell RNA sequencing (scRNA-seq) to delineate cellular heterogeneity within the developing limb bud and to identify candidate cellular markers. The spatiotemporal distribution of target cell populations was further examined via immunofluorescence staining. Fluorescence-activated cell sorting (FACS) was used to isolate endothelial cells and SSPCs based on surface markers. Functional properties of these cells were assessed using in vitro assays, and direct co-culture experiments were conducted to evaluate intercellular communication and underlying molecular pathways. Results We delineate a CD140a + PDPN + SSPC population characterized by robust self-renewal and multipotency, peaking in abundance at embryonic day 14.5. Concomitantly, we resolved the heterogeneity within endothelial cell (EC) populations during embryonic angiogenesis, identifying a distinct subpopulation exhibiting high Pecam1 and low Emcn expression (recapitulating type E). Critically, SSPCs manifested enhanced chondrogenic differentiation potential and type II collagen synthesis when co-cultured specifically with type E ECs, highlighting an indispensable role in endochondral ossification during long bone formation. Mechanistic intercellular crosstalk analyses demonstrated that BMP signaling plays an essential role in modulating type E endothelial cell-mediated regulation of SSPC potency through the coordinated actions of transcription factors ID1, MSX2, and SOX9. Notably, pharmacological inhibition of BMP signaling abolished the pro-chondrogenic and pro-osteogenic enhancement conferred by type E ECs upon SSPCs. Conclusion These findings uncover a fundamental mechanism of long bone development mediated by CD140a + PDPN + SSPCs and modulated by type E ECs. This reciprocal, bipotent coupling between skeletogenesis and angiogenesis provides a conceptual framework for understanding skeletal development and homeostasis, proffering novel therapeutic avenues for associated pathologies. The translational potential of this article By elucidating the regulatory function of type E endothelial cells in orchestrating chondrogenic priming during embryonic skeletogenesis, this study unveils potential therapeutic strategies for bone regeneration through targeting the vascular network.

Objective Hepatopulmonary syndrome (HPS) is characterized by inflammation, pulmonary vasodiation and angiogenesis. Elevated serum level of fatty acid binding protein 4 (FABP4) in patients with liver cirrhosis is associated with poor prognosis, and FABP4 is involved in the regulation of inflammation and angiogenesis. Using a bile duct ligation (BDL) -induced HPS rat model and the FABP4inhibitor BMS309403 for intervention, this study aims to investigate the role of the FABP4/PPAR-u03B3 signaling axis in the pathogenesis of HPS and to evaluate the protective mechanism of FABP4 inhibition against hepatopulmonary injury. Methods A total of 24 male SPF SD rats (6 to 8 weeks old, weighing 200 to 220 g) were enrolled and randomly divided into (n=6): a sham operation group (Sham group), the BDL postoperative3-week group (BDL3W group), the BDL postoperative 5-week group (BDL5W group), and a BDL+BMS309403treatment group (BDLB group). The BDL3W, BDL5W and BDLB groups underwent BDL to establish an HPS model, while the Sham group underwent only bile duct manipulation without ligation. The BDLB group received intraperitoneal injections of BMS309403 (5 mg/kg, twice per week) from postoperative day 15 for3 weeks. The BDL3W group was sacrificed at week 3 post-surgery, while the Sham, BDL5W, and BDLB groups were sacrificed at week 5 post-surgery. Histopathological changes in the liver and lung tissues were evaluated using HE staining. The severity of hepatic fibrosis was assessed by Masson ' s trichrome staining, while hepatic lipid accumulation was examined using Oil Red O staining. Microarray was performed on lung tissues from the Sham and BDL3W groups, and integrated analysis of differentially expressed genes (DEGs) was conducted, including: heatmap plotting based on specific gene sets, visualization of differential expression with volcano plots, and GO functional enrichment analysis. Immunohistochemistry was used to detect the localization and expression levels of CD31, iNOS, TNF-u03B1, NF-u03BAB p65, and PPAR-u03B3 in lung tissues. Immunofluorescence staining was performed to determine the expression of FABP4. The protein levels of FABP4 and PPAR-u03B3 in lung tissues were quantified by Western blotting. Arterial blood gas analysis was conducted to measure PaO2 and P(A-a)O2 for the evaluation of pulmonary function, and serum levels of ALT and AST were determined to evaluate hepatic function. Results u2460 Compared with the BDL3W group, the BDL5W group exhibited progressively disorganized liver structure, gradually aggravated fibrosis, and a significant increase in relative collagen areas (Pu0026lt;0. 01). Serum ALT levels increased continuously from the Sham group to the BDL3W and BDL5W groups (Pu0026lt;0. 01), with AST levels showing the same trend (Pu0026lt;0. 01). In the lungs, inflammatory cell infiltration aggravated progressively, and PaO2 decreased gradually from the Sham to BDL3W and BDL5W groups (Pu0026lt;0. 05). Compared with the BDL3W group, P(A-a)O2 was markedly elevated in the BDL5W group (Pu0026lt;0. 01), confirming the successful establishment of the HPS model. u2461 In the BDL3W group, FABP4 gene was significantly upregulated in the lung tissues (FCu22651. 5, Pu22640. 05). GO enrichment analysis revealed significant enrichment of lipid metabolism-related genes, suggesting that FABP4and lipid metabolic processes play important roles in the pulmonary pathogenesis during HPS. u2462 Compared with the BDL5W group, the BDLB group showed significantly decreased serum AST and ALT levels (Pu0026lt;0. 01), accompanied by attenuated hepatic fibrosis, as evidenced by a significant reduction in relative collagen area (Pu0026lt;0. 01). Pulmonary inflammatory infiltration, hemorrhage, and atelectasis were alleviated, with a significant increase in PaO2 (Pu0026lt;0. 01) and an obvious decrease in P(A-a)O2 (Pu0026lt;0. 01). u2463 Immunofluorescence and Western blotting revealed that FABP4 expression in the lung tissues of the BDLB group was significantly lower than that in the BDL5W group (Pu0026lt;0. 05). Immunohistochemistry and Western blotting further demonstrated that PPAR-u03B3 expression in the lung tissues was significantly enhanced in the BDLB group compared with the BDL5W group (Pu0026lt;0. 05). u2464 Compared with the BDL5W group, the BDLB group exhibited reduced hepatic lipid droplet accumulation. Immunohistochemical analysis showed a significant decrease in the diameter of pulmonary microvascular lumens (Pu0026lt;0. 01), along with significantly downregulated expression of iNOS (Pu0026lt;0. 01), and remarkably reduced expression levels of the inflammatory factors TNF-u03B1 and NF-u03BAB p65 (Pu0026lt;0. 01). Conclusion The FABP4 inhibitor BMS309403 ameliorates hepatopulmonary pathological injury and improves hypoxemia in HPS rats by modulating the FABP4/PPAR-u03B3 signaling axis, ameliorating hepatic lipid metabolism disorder, inhibiting NF- u03BAB p65/TNF- u03B1 -mediated pulmonary inflammatory response, and suppressing iNOS/NO-driven pulmonary microvascular dilation.

Renal fibrosis is a common outcome of chronic kidney disease (CKD), forming a fibrotic niche characterized by fibroblast activation and vascular rarefaction. Currently, there are no effective treatment strategies targeting fibrotic niche. Here, we show that chimeric antigen receptor-modified M2 macrophages (CAR-M2) targeting FAP and secreting interleukin (IL)-4 are delivered via an injectable HAMA-CS hydrogel beneath the renal subcapsule and attenuate renal fibrosis while promoting renal revascularization. The single-cell RNA sequencing reveals the heterogeneity and interaction of stroma and endothelial cells (ECs). A fibrosis-related Cxcr2+ EC subset is identified, and its specific depletion effectively mitigates renal fibrosis. Further results reveal that CAR-M2 can release matrix metalloproteinase 2 (MMP2) in close proximity to activate retinoid X receptor alpha (Rxra) in the Cxcr2+ ECs and further triggers its mitochondrial autophagy, leading to apoptosis. Our research provides innovative strategies and proof of principle for the immunotherapy of organ fibrosis.

This study estimated FRAX®-based intervention thresholds for initiating osteoporosis treatment in Chinese postmenopausal women, using real-world data from the largest nationally representative osteoporosis survey in China and a validated Markov microsimulation model. Denosumab became cost-effective at a 10-year major osteoporotic fracture probability of 7

Objective Osteoarthritis (OA) is a chronic disease characterized by degeneration of articular cartilage, affecting over half a billion individuals globally. Current treatments such as non-steroidal anti-inflammatory drugs are effective in symptom relief, but lack the ability to modify OA progression. Fibroblast growth factor 8b (FGF8b) plays crucial roles in chondrogenesis and cartilage formation, suggesting its potential application in cartilage homeostasis maintenance. This study aims to investigate the effect of exogenous FGF8b on cartilage protection and OA progression, and explore the underlying mechanisms. Design Therapeutic effects of intra-articular FGF8b injections either once weekly or once every four weeks were evaluated in OA mouse models induced by destabilization of the medial meniscus (DMM) using histological analysis, X-ray imaging, micro-computed tomography (micro-CT), immunohistochemistry (IHC), and RNA sequencing of cartilage. Additionally, the therapeutic effects and underlying mechanisms of FGF8b on human cartilage and chondrocytes were further investigated using ex vivo OA models and in vitro assays. Results Once-weekly administration of FGF8b attenuated cartilage degradation while exacerbating osteophyte formation in a dose-dependent manner. Higher doses of FGF8b resulted in stronger cartilage-protective effects while increased osteophyte formation. Conversely, intermittent administration of FGF8b (once every four weeks) protected cartilage from degeneration without causing significant osteophyte formation. Mechanistically, FGF8b was found to help the maintenance of cartilage homeostasis by promoting anabolic metabolism and inhibiting catabolic metabolism in chondrocytes through activation of the FGFR3-PI3K-AKT signaling pathway. Conclusions Exogenous FGF8b attenuates articular cartilage degeneration by increasing anabolism and inhibiting catabolism, thereby presenting therapeutic potential for OA treatment. The translational potential of this article In this study, we demonstrate that intermittent administration of FGF8b protects articular cartilage from degeneration by increasing anabolic metabolism and inhibiting catabolic metabolism in cartilage, making it a promising disease-modifying agent for OA. Moreover, the findings offer valuable insights into optimizing the exposure regimens of FGFs to achieve safer and more effective OA treatment.

BackgroundMild cognitive impairment (MCI), a condition that falls somewhere between normal aging and severe cognitive dysfunction (e.g., Alzheimer’s disease), is a common manifestation of the neurocognitive function decline that seniors encounter as they age. The fundamental processes causing its beginning are still not well understood yet.MethodsWe employed aged (18-month-old) male C57BL/6J mice, including astrocyte-specific Pantothenate kinases 4 (PANK4) conditional knockout (Pank4f/f;Gfap-Cre, Pank4-CKO) mice. Cognitive function was assessed using the Barnes maze, Y-maze (spatial novelty preference, spontaneous alternation), novel object recognition (NOR) test, and open field test (OFT). Hippocampal PANK4 localization was analyzed via immunofluorescence (IF) and subcellular fractionation/western blotting (WB). Cuproptosis markers (FDX1, LIAS, DLAT), copper transporters (ATP7A, ATP7B, SLC31A1), and copper content (ICP-MS) were quantified in hippocampal tissue. In vitro studies used LPS-stimulated primary astrocytes for RNA-seq and qPCR validation.ResultsAged wild-type (18M+WT) mice exhibited specific deficits in Barnes maze retention and reversal learning, indicative of mild cognitive impairment, while Pank4-CKO mice showed significant rescue. We discovered a novel age-dependent nuclear accumulation of PANK4 in hippocampal cells, which was absent in Pank4-CKO mice. Aged hippocampi displayed upregulated pro-cuproptotic factors (FDX1, LIAS) and reduced DLAT, alongside decreased expression of the copper exporter ATP7A, ATP7B, SLC31A1 and increased copper accumulation. Astrocyte-specific Pank4 knockout reversed these changes: it suppressed FDX1/LIAS upregulation, restored ATP7B expression and DLAT levels, and normalized hippocampal copper content. In vitro, LPS-induced neuroinflammation triggered PANK4 nuclear translocation and selectively downregulated Atp7b expression in astrocytes. Small interfering RNA (siRNA)-mediated knockdown of Pank4 significantly upregulated Atp7b expression.ConclusionThis study identifies a novel pathological mechanism in age-related MCI: the nuclear accumulation of PANK4 in hippocampal exacerbates cuproptosis susceptibility by specifically impairing ATP7B-dependent copper efflux, leading to copper overload. Astrocyte-specific PANK4 ablation mitigates these effects, highlighting PANK4 as a potential therapeutic target for preventing or treating age-associated cognitive decline.

Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical function of the spine. Regenerative medicine strategies, particularly those harnessing endogenous progenitor cells, offer a promising avenue for achieving biological repair and functional homeostasis. The identification of intervertebral disc progenitor cells (IVD-PCs) has unveiled a potential cellular reservoir for self-repair, given their demonstrated stemness attributes, including clonogenicity and multipotent differentiation. However, the clinical translation of IVD-PCs is significantly hampered by an incomplete understanding of their inherent heterogeneity, hierarchical organization, and, most critically, the dynamic interplay with their unique microenvironment, which dictates their fate decisions. This review synthesizes recent advances in deciphering the molecular signatures and functional plasticity of IVD-PCs. We place a particular emphasis on how key physicochemical, mechanical, and cellular cues within the IVD niche orchestrate progenitor cell behavior—ranging from maintenance and activation to aberrant differentiation—during both homeostasis and degeneration. Furthermore, we propose forward-looking insights to bridge critical knowledge gaps, aiming to propel the development of novel progenitor cell-based therapeutics for IVD degeneration.