Osteoarthritis (OA) is a heterogeneous disorder with a rising global prevalence, largely driven by aging and obesity, and it imposes a significant worldwide health burden. Current therapeutic strategies, limited to transient lubrication or pain relief, are unable to halt disease progression due to their failure to repair cartilage. To address this challenge, we developed an integrated theranostic platform using a modified acupuncture needle with helical microgrooves. These grooves are loaded sequentially with three functional hydrogel segments. The degradation of each segment triggers the controlled release of a corresponding therapeutic agent: Batimastat, Etodolac, and Docetaxel. Each hydrogel is engineered to respond specifically to a key OA pathological pathway: matrix degradation (MMP13-responsive), inflammation (ADAMTS5-responsive), and fibrosis (TGF-β-responsive), and is labeled with a distinct fluorescent marker (Cy5, FITC, or Cy5). The core innovation of this system is its capacity for simultaneous diagnosis and treatment. After implantation, the needle can be retrieved, and the degradation status of each hydrogel segment assessed by fluorescence imaging, providing a post-treatment readout of the dominant OA molecular subtype. Collectively, this multifunctional platform, termed helical-groove acupuncture needle (HGN), represents a promising strategy to curtail OA progression by simultaneously promoting cartilage restoration and inhibiting fibrotic changes.

Subchondral bone marrow lesions (BMLs) constitute a pathognomonic imaging feature of both incipient and progressive osteoarthritis (OA). However, the pathological features and molecular mechanisms underlying BMLs remain poorly characterized. Here, we innovatively established and dynamically characterized a standardized mouse model, simulating human BMLs on magnetic resonance imaging (MRI) that correlates significantly with cartilage degeneration, while revealing substantial aberrant bone matrix accumulation within BML regions. By establishing an osteochondral single-cell atlas of mouse knee joints during BML development, we found that proteasome dysfunction and abnormal secretion of misfolded collagen, driven by dysregulated heat shock protein 70 (HSP70) and deubiquitinase 19 (USP19) expression in osteoarthritic subchondral osteoblasts, constitute a key mechanism of BML formation. Furthermore, cell-cell communication and Col10a1-Cre; R26tdt+ fate-mapping analyses uncovered that osteoblast-secreted WNT5A mediates crosstalk with hypertrophic chondrocytes (HTCs), accelerating their hypertrophy and cell death. Critically, pharmacological HSP70 targeting by TRC051384 inhibited collagen misfolding/secretion, preventing BML formation. Notably, results of Mendelian randomization demonstrated a significant correlation between proteasome gene expression and OA risk in humans, further supporting a potential role of proteasome dysfunction in BML pathogenesis. Collectively, these data reveal mechanisms underlying BML formation and therapeutic targets for early OA intervention.

Articular cartilage, a unique avascular and low-cell-density connective tissue, relies predominantly on chondrocyte responses to mechanical cues for the maintenance of tissue homeostasis and functional repair. Among the diverse mechanical stimuli encountered in the joint microenvironment, compressive stress stands as the most prominent and physiologically relevant physical signal regulating chondrocyte behavior. This review systematically dissects the multi-layered mechanisms underlying compressive stress-mediated chondrocyte regulation and its translational implications in cartilage tissue engineering and osteoarthritis (OA) intervention. At the molecular level, compressive stress initiates a cascade of mechanosensing, intracellular transduction, and functional output through the synergistic crosstalk of integrin-mediated adhesion complexes, calcium signaling networks, MAPK pathways, and downstream transcriptional regulators (e.g., SOX9, Runx2, Sp1), which collectively orchestrate the balance between anabolic and catabolic metabolism. At the cellular level, articular cartilage's inherent regional heterogeneity, coupled with distinct responses of healthy/pathological chondrocytes and stem cells to compressive parameters (frequency, strain magnitude, loading mode, duration), underscores the need for cell-type-specific mechanical intervention strategies. At the translational level, moderate dynamic compression promotes cartilage repair by preserving extracellular matrix integrity, suppressing inflammatory cascades, and modulating epigenetic landscapes, while aberrant loading exacerbates OA progression via chondrocyte apoptosis, matrix degradation, and pain sensitization. The optimization of scaffold materials (natural polymers, synthetic composites, intelligent responsive matrices) and culture systems (3D bioprinting, microfluidic bioreactors, shear-compression synergistic loading) has emerged as a critical enabler to enhance mechanical regulation efficacy. Despite significant advances, current research is constrained by insufficiently physiological in vitro/in vivo models, lack of standardized loading parameters, unclear pathway crosstalk mechanisms, and limited clinical translation of mechanical-based therapies. Future endeavors should prioritize the elucidation of multi-pathway synergistic networks using multi-omics approaches, establishment of personalized mechanical parameter databases integrating patient-specific factors (age, gender, disease severity), construction of bionic models recapitulating the joint's dynamic microenvironment, and development of combined mechanical-biological therapeutic strategies. These efforts will provide more precise molecular targets and clinically feasible schemes for cartilage repair and OA management.

Background:Bacterial infection and biofilm formation synergistically hinder wound healing by perpetuating inflammation and evading conventional treatments. Monotherapeutic strategies often fail to simultaneously eradicate resilient biofilms and rectify the dysregulated wound microenvironment. To overcome these limitations, we developed a multifunctional and targeted nanoplatform for synergistic antibacterial therapy and immunomodulation. Methods:The smart nanoplatform (CCP-DFO(Fe)) was constructed with a triple-component architecture: a photothermal Cu7S4 core pre-loaded with chlorogenic acid (CGA), enveloped by a thermo-responsive poly(N-vinylcaprolactam) (PVCL) shell, and surface-functionalized with deferoxamine-iron (DFO(Fe)) via amide coupling for active bacterial targeting. Results:The nanoplatform exhibits effective bacterial targeting via DFO(Fe)-mediated siderophore mimicry, enabling preferential accumulation at infection sites. Under NIR irradiation, CCP-DFO(Fe) nanoplatform exhibits efficient photothermal conversion, rapidly elevating the temperature to 44.3 °C within 4 min, which induces the sudden collapse of the PVCL shell from a uniform swollen state to a phase-separated state, leading to shell disruption and consequent exposure of the CGA-loaded Cu7S4 nanoparticles (CSC). Under physiological conditions, the CSC nanoplatform gradually releases Cu2+ and CGA, which, together with the photothermal effect, synergistically exert potent antibacterial activity. As a result, the nanoplatform achieves highly effective bacterial eradication, reducing the survival rates of both E. coli and S. aureus to below 5%, along with pronounced anti-biofilm activity. Beyond its antibacterial activity, the released CGA further exerts antioxidant and anti-inflammatory effects by scavenging reactive oxygen species and promoting macrophage polarization toward the pro-healing M2 phenotype, thereby facilitating inflammation resolution. In an infected rat wound model, CCP-DFO(Fe) combined with NIR irradiation achieved 98.56 ± 1.08% wound closure by day 14, with nearly complete bacterial eradication, while simultaneously promoting angiogenesis and collagen deposition. Conclusion:This integrated nanoplatform combines targeted antibacterial activity, biofilm disruption, and inflammation resolution into a single system, demonstrating significant potential for treating infected and chronic wounds.

Articular cartilage homeostasis relies on chondrocytes to maintain extracellular matrix (ECM) integrity, with fluid shear stress (FSS) emerging as a critical regulator of chondrocyte function. Osteoarthritis (OA), a leading cause of global disability, is driven by abnormal mechanical loading, yet the dual role of FSS in joint health and disease remains incompletely defined, and existing reviews have not fully integrated its biphasic dose-effect boundaries, mechanotransduction networks, and translational pathways within a unified framework. To address this gap, we synthesize evidence that FSS exerts biphasic control over chondrocyte biology: physiological FSS, operationally approximated as low-to-moderate laminar shear stress within 0.5-10 Pa in many in vitro models, sustains cartilage homeostasis via anabolic pathways (ERK5, PI3K/Akt, AMPK) that promote ECM synthesis, cell proliferation, and cytoprotection; in contrast, pathological FSS, often exceeding approximately 10-15 Pa or occurring as prolonged continuous/turbulent shear or under inflammatory conditions, triggers catabolic and pro-inflammatory responses (NF-κB, JNK, Hippo/YAP) recapitulating OA phenotypes, including ECM degradation and chondrocyte apoptosis. Mechanotransduction of FSS involves conserved sensors (Ca2+ channels, integrins, cytoskeleton) and extensive crosstalk between signaling networks and additional regulation by non-coding RNAs, thereby providing an integrated mechanosensory-to-transcriptional framework for interpreting FSS-dependent chondrocyte responses. Translating this duality, FSS-based strategies, from tissue engineering bioreactors to targeted inhibition of pathological pathways and mechanical interventions, hold promise for OA therapy, providing an integrated framework for clinical translation. However, context dependency of FSS effects, microenvironmental heterogeneity, and signaling redundancy remain barriers to clinical translation. Resolving these challenges via biomimetic models and multidisciplinary approaches will advance precision medicine for OA by harnessing FSS's therapeutic potential while mitigating its pathological contributions.

Neuroinflammation represents a central pathogenic driver in a spectrum of central nervous system disorders, predominantly mediated by microglial activation and the ensuing release of inflammatory cytokines. While the E3 ubiquitin ligase TRIM31 is implicated in peripheral immunity, its precise function within neuroinflammation defies precise delineation. In this study, we define the role of TRIM31 in microglia-driven neuroinflammation and clarify its molecular mechanism. Utilizing both cellular and murine models of lipopolysaccharide-induced neuroinflammation, we detected a marked induction of TRIM31 expression with LPS stimulation. Genetic knockdown of TRIM31 exacerbated the LPS-triggered upregulation of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β. Conversely, TRIM31 overexpression potently suppressed cytokines release and attenuated neuroinflammatory responses in vitro and in vivo. Mechanistic investigations combining transcriptomic profiling and immunoblotting manifested that TRIM31 directly interacts with TAK1, catalyzing its K48-linked polyubiquitination and subsequent proteasomal degradation. This action provokes the downregulation of the NF-κB activation cascade. Collectively, our findings identify TRIM31 as a critical negative regulator of neuroinflammation and underscore its therapeutic potential for treating neuroinflammatory diseases via targeted degradation of TAK1.

Physical activity (PA) is recommended for managing postmenopausal osteoporosis, yet evidence-based prescriptions for optimizing bone mineral density (BMD) remain undefined. To identify beneficial PA thresholds, this study examined the relationship between PA and total lumbar BMD in a cross-sectional analysis of 9339 postmenopausal women from the National Health and Nutrition Examination Survey 2011 to 2018. PA was quantified as Physical Activity Metabolic Equivalent of Task (PA-MET)-hours/week. The association between PA-MET-hours/week and total lumbar BMD was assessed using weighted multivariable linear regression. Nonlinear relationships were explored with smooth curve fitting and two-piecewise linear models. Subgroup analyses were stratified by age and body mass index (BMI). A significant positive association was observed between PA-MET-hours/week and total lumbar BMD (β = 0.0000, 95% CI [0.0000, 0.0001], P = .023), which was more pronounced among younger individuals (<45 years) and those with lower BMI (<25 kg/m²). The relationship exhibited a nonlinear pattern, with an inflection point at 32 metabolic equivalent of task (MET)-h/week. Subgroup analyses further identified specific beneficial thresholds, 54 MET-hours/week for younger adults (<45 years; β = 0.0004, 95% CI [0.0002, 0.0005], P < .0001) and 128 MET-hours/week for those with normal BMI (<25 kg/m²; β = 0.0003, 95% CI [0.0001, 0.0004], P < .0001). PA is positively associated with total lumbar BMD in postmenopausal women. Moderate-intensity PA of approximately 13.5 hours/week for younger individuals (corresponding to the inflection point of 54 MET-hours/week) or 32 hours/week (corresponding to the inflection point of 32 MET-hours/week) for those with normal BMI may be beneficial for lumbar spine bone health in postmenopausal women.

The accumulation of senescent chondrocytes contributes significantly to osteoarthritis (OA) progression, establishing a self-perpetuating cycle of cartilage deterioration. Current therapeutic strategies remain limited by inadequate precision to target senescent populations and the inability to simultaneously trigger endogenous regenerative processes. Herein, we developed a hydrogel microsphere system to locally eliminate senescent chondrocytes, thereby creating a permissive microenvironment and facilitating endogenous stem cell recruitment to accelerate cartilage repair. Specifically, chondrocyte membranes (CM) overexpressing natural killer group 2 member D (NKG2D) receptors (NCM) were fabricated via plasmid transfection and extrusion to target upregulated NKG2D ligands on senescent cells. The fusion of ABT263-loaded liposomes (A-lipo) with NCM produced the senolytic ANCM nanoparticles. Subsequently, ANCM and SDF-1α were co-encapsulated into methacrylic anhydride (MA)-modified hyaluronic acid (HA) hydrogel microspheres (SHM) using microfluidics. The resulting ANCM@SHM exhibited remarkable biocompatibility and a dual-phase functionality: hydrogel-enhanced articular retention followed by ANCM-mediated active targeting of senescent chondrocytes. Functional assessments validated the effective clearance of senescent chondrocytes, achieved by inducing mitochondrial outer membrane permeabilization (MOMP), was accompanied by metabolic reprogramming of surviving chondrocytes toward an anabolic phenotype. Simultaneously, sustained SDF-1α release induced robust mesenchymal stromal cells (MSCs) homing and chondrogenic differentiation, resulting in synergistic cartilage remodeling. In vivo evaluations demonstrated a pronounced attenuation of OA progression, attributable to synergistic remodeling of the joint microenvironment. This multidimensional engineering strategy disrupts the vicious cycle of senescence-associated cartilage degeneration by integrating targeted senolysis with stem cell-mediated regeneration, providing a promising therapeutic approach for OA management.

Exosomes (exos) as potent acellular therapeutic agents have been widely investigated to modify the surfaces of biomaterials to promote bone formation in recent decade. However, effective immobilization of exos is challenging on the surface of metal-based implants. In this study, we developed a simple yet versatile approach for the immobilization of bone marrow stem cell (BMSC)-derived exos onto titanium (Ti) implants, featuring high exos loading capacity and prolonged retention. First, a micro-/nano-structured scholzite (CaZn2(PO4)2 & sdot;2H2O) coating was fabricated on Ti using a phosphate chemical conversion method. Next, an FDA-approved phospholipid-polymer conjugate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol (DSPE-PEG), was used to link the exos and coated Ti together by in situ anchoring. The anchored exos on the coated Ti presented a unique "on-demand" delivery pattern and could be phagocytosed by adherent cells, effectively enhancing BMSC adhesion, spreading, and osteogenic differentiation on Ti. Additionally, the scholzite coating in cooperation with exos exerted a robust immunomodulatory effect by suppressing M1 macrophages while promoting M2 macrophages. The resulting favorable osteoimmune microenvironment accelerated osteogenesis both in vitro and in vivo, possibly via the crosstalk of integrin/FAK signaling pathways. This study suggests a novel route for integrating bioactive exos with clinical metal implants and demonstrates a promising perspective for designing biomaterials with osteoimmunomodulatory functions.

Acupuncture is an ancient form of therapy, which has long been part of traditional Chinese medicine (TCM); however, its use has spread globally, to the point where it is currently practiced worldwide. Although metal needles continue to be used most commonly, through multidisciplinary research, novel technologies, including nanotechnology, have allowed acupuncture to evolve to the point of achieving greater efficiency and more sophisticated functions in clinical practice. We summarized recent advancements in the literature using nano-enabled strategies to create novel needles that enhance and expand their therapeutic effects and found that nanotechnology may help provide new evidence to verify acupuncture theory, improve the features of acupuncture needles and their clinical effects by combining with drug delivery, and even enable new therapeutic methods when combined with acupuncture needles. The use of nano-technology with acupuncture delivery looks very promising for potential clinical applications. We also envisage that with nanotechnology, innovations in acupuncture needles could generate a multi-functional toolbox for use in both diagnostic and therapeutic medicine. Such new types of acupuncture needles could be used at acupoints and data collected to guide the planning of clinical trials may be more consistent with acupuncture theory and traditional clinical applications of this therapeutic modality. Nanotechnology may help provide new evidence to verify acupuncture theory, improve the features of acupuncture needles and their clinical effects by combining with drug delivery, and even enable new therapeutic methods.

Osteoarthritis (OA) is the most common degenerative joint disease worldwide, with the main pathological manifestation of articular cartilage degeneration. It have been investigated that pharmacological activation of transient receptor potential vanilloid 1 (TRPV1) significantly alleviated cartilage degeneration by abolishing chondrocyte ferroptosis. In this work, in view of the thermal activated feature of TRPV1, Citrate-stabilized gold nanorods (Cit-AuNRs) is conjugated to TRPV1 monoclonal antibody (Cit-AuNRs@Anti-TRPV1) as a photothermal switch for TRPV1 activation in chondrocytes under near infrared (NIR) irradiation. The conjugation of TRPV1 monoclonal antibody barely affect the morphology and physicochemical properties of Cit-AuNRs. Under NIR irradiation, Cit-AuNRs@Anti-TRPV1 exhibited good biocompatibility and flexible photothermal responsiveness. Intra-articular injection of Cit-AuNRs@Anti-TRPV1 followed by NIR irradiation significantly activated TRPV1 and attenuated cartilage degradation by suppressing chondrocytes ferroptosis. The osteophyte formation and subchondral bone sclerosis are remarkably alleviated by NIR-inspired Cit-AuNRs@Anti-TRPV1. Furthermore, the activation of TRPV1 by Cit-AuNRs@Anti-TRPV1 evidently improved physical activities and alleviated pain of destabilization of the medial meniscus (DMM)-induced OA mice. The study reveals Cit-AuNRs@Anti-TRPV1 under NIR irradiation protects chondrocytes from ferroptosis and attenuates OA progression, providing a potential therapeutic strategy for the treatment of OA.

Periprosthetic osteolysis induced by the ultrahigh-molecular-weight polyethylene (UHMWPE) wear particles is a major complication associated with the sustained service of artificial joint prostheses and often necessitates revision surgery. Therefore, a smart implant with direct prevention and repair abilities is urgently developed to avoid painful revision surgery. Herein, we fabricate a phosphatidylserine- and polyethylenimine-engineered niobium carbide (Nb2C) MXenzyme-coated micro/nanostructured titanium implant (PPN@MNTi) that inhibits UHMWPE particle-induced periprosthetic osteolysis. The specific mechanism by which PPN@MNTi operates involves the bioresponsive release of nanosheets from the MNTi substrate within an osteolysis microenvironment, initiated by the cleavage of a thioketal-dopamine molecule sensitive to reactive oxygen species (ROS). Subsequently, functionalized Nb2C MXenzyme could target macrophages and escape from lysosomes, effectively scavenging intracellular ROS through its antioxidant nanozyme-mimicking activities. This further achieves the suppression of osteoclastogenesis by inhibiting NF-kappa B/MAPK and autophagy signaling pathways. Simultaneously, based on the synergistic effect of MXenzyme-integrated coatings and micro/nanostructured topography, the designed implant promotes the osteogenic differentiation of bone mesenchymal stem cells to regulate bone homeostasis, further achieving advanced osseointegration and alleviable periprosthetic osteolysis in vivo. This study provides a precise prevention and repair strategy of periprosthetic osteolysis, offering a paradigm for the development of smart orthopedic implants.

Glioma is an aggressive brain tumor with a poor prognosis. Establishing an in vitro culture model that closely replicates the cellular composition and microenvironment of the original tumor has been challenging, limiting its clinical applications. Here, we present a novel approach to generate glioma organoids with a microenvironment (GlioME) from patient-derived glioma tissue. These organoids maintain the genetic and epigenetic characteristics of the pri-mary tumor and preserve cell-to-cell interactions within the tumor microenvironment, including resident immune cells. Bulk RNA sequencing, whole exome sequencing, and DNA methylation analysis were used to confirm the molecular similarities between the organoids and primary glioma tissues. Immunofluorescence and flow cytometry were used to assess immune cell viability, comparing GlioME with floating glioma organoids. GlioME exhibited high responsiveness to chemotherapy and targeted therapy, demonstrating its potential for therapeutic screening applications. Notably, GlioME accurately predicted patient response to the recently approved MET inhibitor, vebreltinib. Thus, this organoid model provides a reliable in vitro platform for glioma microenvironment-related research and clinical drug screening. ### Competing Interest Statement The authors have declared no competing interest.

Abstract Background Osteoarthritis (OA) is an aging-related degenerative joint disorder marked by joint discomfort and rigidity. Senescent chondrocytes release pro-inflammatory cytokines and extracellular matrix-degrading proteins, creating an inflammatory microenvironment that hinders chondrogenesis and accelerates matrix degradation. Targeting of senescent chondrocytes may be a promising approach for the treatment of OA. Herein, we describe the engineering of an injectable peptide-hydrogel conjugating a stem cell–homing peptide PFSSTKT for carrying plasmid DNA-laden nanoparticles and Tanshinon IIA (pPNP + TIIA@PFS) that was designed to attenuate OA progression by improving the senescent microenvironment and fostering cartilage regeneration. Results Specifically, pPNP + TIIA@PFS elevates the concentration of the anti-aging protein Klotho and blocks the transmission of senescence signals to adjacent healthy chondrocytes, significantly mitigating chondrocyte senescence and enhancing cartilage integrity. Additionally, pPNP + TIIA@PFS recruit bone mesenchymal stem cells and directs their subsequent differentiation into chondrocytes, achieving satisfactory chondrogenesis. In surgically induced OA model rats, the application of pPNP + TIIA@PFS results in reduced osteophyte formation and attenuation of articular cartilage degeneration. Conclusions Overall, this study introduces a novel approach for the alleviation of OA progression, offering a foundation for potential clinical translation in OA therapy.

INTRODUCTION:Besides the comorbid risk factors shared by older and younger patients, older individuals may also experience malnutrition, as well as cognitive or functional impairments. The accumulation of frailty and various geriatric syndromes in older individuals results in decreased physiological reserves, which makes the recovery process after spine surgery particularly challenging. Theoretically, combining the presurgery optimisation provided by a multimodal prehabilitation programme with the reduction of surgical stress provided by an enhanced recovery after surgery (ERAS) programme could improve postoperative recovery of older patients. METHODS AND ANALYSIS:This is a prospective, multicentre, assessor-blinded, randomised controlled study. Patients who are 75 years of age or older and are scheduled for spinal fusion surgery will be enrolled on three academic medical centres. Regular preadmission education and perioperative ERAS care will be given to participants who were randomised to the control group. Participants randomised to the intervention group will receive multimodal prehabilitation combined with ERAS (PREERAS) management. We will include 164 patients with spinal fusion in three hospitals in China. All included patients will be followed for 90 days after surgery or until death. The primary outcome is the Comprehensive Complication Index (CCI), which ranges from 0 to 100, where a score of 100 indicates death due to complications. Secondary outcomes include length of stay and non-home discharge, rates of postoperative complications and unplanned readmission, North American Spine Society satisfaction, and Oswestry Disability Index/Neck disability index. Ninety-day CCI will be compared between groups using linear regression. Other continuous or categorical outcomes will be compared using linear or logistic regression. ETHICS AND DISSEMINATION:This study has received ethical approval from the Xuanwu Hospital of Capital Medical University Ethics Committees (2024-088-001). The findings will be submitted to a peer-reviewed journal for publication. TRIAL REGISTRATION NUMBER:NCT06140797.

BACKGROUND:Recent research highlights the importance of muscular strength as a key factor in physical fitness, a strong indicator of overall mortality risk, and a vital target for preventing chronic diseases. This study used a proteome-wide Mendelian randomization analysis plus colocalization analysis for low hand grip strength to explore potential therapeutic targets for muscle weakness. METHODS:We conducted two two-sample Mendelian randomization analyses from four cohorts to identify and validate the causal relationship between plasma proteins and low grip strength. We also employed bidirectional Mendelian randomization analysis with Steiger filtering, Bayesian co-localization, and phenotype scanning to detect reverse causality, thereby consolidating our Mendelian randomization findings. Downstream analyses were also undertaken of identified proteins, including knockout models, enrichment analyses, and protein-protein interaction networks. Finally, we assessed the druggability of the identified proteins. RESULTS:At Bonferroni significance (P < 6.82 × 10-5), Mendelian randomization analysis revealed that three proteins were causally associated with low grip strength. Increased MGP (OR = 0.85) and HP (OR = 0.96) decreased the risk of low grip strength, whereas elevated ART4 (OR = 1.06) increased the risk of low grip strength. None of the three proteins had reverse causality with low grip strength. Bayesian co-localization suggested that MGP shared the same variant with low grip strength (coloc.abf-PPH4 = 0.826). Further downstream analyses showed that MGP, which is highly expressed in musculoskeletal system, is a potential novel target for muscle weakness. CONCLUSIONS:The proteome-wide Mendelian randomization investigation identified three proteins associated with the risk of muscle weakness. MGP, HP, and ART4 deserve further investigation as potential therapeutic targets for muscle weakness.

Grooming, as an evolutionarily conserved repetitive behavior, is common in various animals, including humans, and serves essential functions including, but not limited to, hygiene maintenance, thermoregulation, de-arousal, stress reduction, and social behaviors. In rodents, grooming involves a patterned and sequenced structure, known as the syntactic chain with four phases that comprise repeated stereotyped movements happening in a cephalocaudal progression style, beginning from the nose to the face, to the head, and finally ending with body licking. The context-dependent occurrence of grooming behavior indicates its adaptive significance. This review briefly summarizes the neural substrates responsible for rodent grooming behavior and explores its relevance in rodent models of neuropsychiatric disorders and neurodegenerative diseases with aberrant grooming phenotypes. We further emphasize the utility of rodent grooming as a reliable measure of repetitive behavior in neuropsychiatric models, holding promise for translational psychiatry. Herein, we mainly focus on rodent self-grooming. Allogrooming (grooming being applied on one animal by its conspecifics via licking or carefully nibbling) and heterogrooming (a form of grooming behavior directing towards another animal, which occurs in other contexts, such as maternal, sexual, aggressive, or social behaviors) are not covered due to space constraints.

Osteoarthritis (OA) is the most common disease in aging joints and has characteristics of cartilage destruction and inflammation. It is currently considered a metabolic disease, and the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes plays a crucial catabolic regulatory role in its pathogenesis. Targeting of this axis in chondrocytes may provide a therapeutic approach for OA treatment. Here, in this study, we propose to use a combination of stem cell-recruiting hydrogels and lipid nanoparticles (LNPs) that modulate cholesterol metabolism to jointly promote a regenerative microenvironment. Specifically, we first developed an injectable, bioactive hydrogel composed of self-assembling peptide nanofibers that recruits endogenous synovial stem cells (SMSCs) and promotes their chondrogenic differentiation. At the same time, LNPs that regulate cholesterol metabolism are incorporated into the hydrogel and slowly released, thereby improving the inflammatory environment of OA. Enhancements were noted in the inflammatory conditions associated with OA, alongside the successful attraction of mesenchymal stem cells (MSCs) from the synovial membrane. These cells were then observed to differentiate into chondrocytes, contributing to effective cartilage restoration and chondrocyte regeneration, thereby offering a promising approach for OA treatment. In summary, this approach provides a feasible siRNA-based therapeutic option, offering a potential nonsurgical solution for treatment of OA.

A nano-enabled drug delivery acupuncture technology (nd-Acu) is developed that is based on traditional acupuncture needles where the stainless-steel surface is designed to deliver various payload molecules. To create the nd-Acu platform, an electrochemistry procedure is used to attach methyl salicylate-modified cyclodextrin in which the sugar rings allow the encapsulation of structurally defined single or multiple payload molecules via an inclusion complexation process. Drug loading and release profile are first studied using fluorescent dyes abiotically and at intact animal level. nd-Acu allows more efficient dye loading and time-dependent release compared to pristine needles without cyclodextrin modification. Subsequently, a proof-of-principle efficacy study is conducted using the platform to load a local anesthetic, lidocaine, for the treatment of knee osteoarthritis (KOA) in mice. It is demonstrated that lidocaine-laden nd-Acu can effectively alleviate pain, reduce inflammation, and slow down KOA development biochemically and histologically. Hypothesis-driven and proteomic approaches are utilized to investigate the working mechanisms of lidocaine nd-Acu, indicating that the therapeutic outcome is attributed to the in vivo modulation of the HMGB1/TLR4 signaling pathway. The study also obtained preliminary evidence suggesting the involvement of mitochondria as well as small GTPase such as cdc42 during the treatment by lidocaine nd-Acu.