Intervertebral disc degeneration (IVDD) is a major contributor to low back pain, yet its cellular and molecular mechanisms remain incompletely understood. In this study, we integrated single-cell and bulk transcriptomic data to uncover the role of senescence-associated secretory phenotype (SASP) signaling in IVDD progression. Single-cell RNA sequencing delineated the heterogeneity of nucleus pulposus cells (NPCs) subtypes and revealed significant differences in senescence levels and SASP activity. Bulk RNA-seq integration across multiple datasets further confirmed widespread SASP activation and defined a core regulatory network centered on Bone Morphogenetic Protein 2 (BMP2) and Matrix Metalloproteinase 3 (MMP3), identified via WGCNA and machine learning algorithms (LASSO, Random Forest, Boruta). A SASP scoring model based on these two genes showed strong diagnostic performance. Drug screening identified Simvastatin as a high-affinity dual inhibitor of BMP2/MMP3, with molecular docking supporting its therapeutic potential. In vitro, Simvastatin treatment reduced NPCs senescence and apoptosis, while in vivo studies demonstrated that Simvastatin preserved disc structure, decreased pro-inflammatory cytokine levels, and mitigated degenerative changes in a murine IVDD model. Collectively, this study establishes a regulatory framework of SASP in IVDD and proposes BMP2/MMP3 as promising targets for intervention. Our findings offer insights and a potential translational path for slowing disc degeneration.

Spinal cord injury (SCI), particularly the traumatic type, is characterized by the loss of nerve cells and leads to neurological deficits that often impair lower limb function. Although endogenous neural stem cells (NSCs) possess innate regenerative potential, their therapeutic utility is hindered by poor differentiation efficiency and slow maturation within the hostile lesion microenvironment. Zinc ions regulate NSC differentiation; however, their therapeutic potential is restricted by the difficulty in achieving precise accumulation within NSCs. This study proposes a novel approach using ZIF-8 nanoparticles, which are degraded in lysosomes under acidic conditions, generating zinc ion influx through endocytosis. Additionally, ZIF-8 nanoparticles are coated with stem cell membranes to enhance targeted binding and improve endocytosis. In vitro results show that membrane-coated ZIF-8 accelerates neuronal differentiation by over 5 d, increasing the proportion of neurons by 10 times compared to spontaneous differentiation. RNA sequencing analysis reveals that the highly efficient regulation was mainly related to the calcium and the mitogen-activated protein kinase signaling pathways. In vivo, membrane-coated ZIF-8 nanoparticles promote the motor, sensory, and autonomic function recovery of limbs in SCI mice, preventing glial scar formation. This innovative strategy of wrapping ZIF-8 with cell membranes offers significant potential for advancing nerve injury repair.

Spinal cord injury (SCI) has traditionally been viewed as a focal trauma to the central nervous system, with research focusing primarily on the disruption of motor and sensory pathways. However, emerging evidence reveals that SCI rapidly induces systemic changes that extend far beyond the spinal cord. This review synthesizes current evidence to conceptualize SCI as a comprehensive systemic disorder, utilizing the "neuro-immune-metabolic network" as a central explanatory framework. Following the initial injury, the disruption of descending autonomic pathways contributes to widespread physiological dysregulation, driving peripheral organ dysfunction such as cardiovascular aberrations and splenic atrophy. Concurrently, systemic inflammation and metabolic disturbances, characterized by the release of pro-inflammatory cytokines, hepatic steatosis, and gut microbiota dysbiosis, generate circulating mediators that subsequently exacerbate central neuroinflammation. This bidirectional crosstalk establishes a self-perpetuating pathogenic cycle in which peripheral deterioration may further impede intrinsic neural repair. By mapping these multi-organ pathological interactions, this review underscores the limitations of isolated spinal interventions. Ultimately, future therapeutics should extend beyond localized spinal repair to target the restoration of systemic physiological networks, thereby advancing clinical management toward comprehensive, multi-targeted interventions.

Programmed cell death pathways exacerbate secondary damage after spinal cord injury, yet their shared regulators and tractable therapeutic points remain elusive. We aimed to identify cross-pathway regulators that integrate pyroptosis and necroptosis after spinal cord injury and to evaluate a repurposable therapeutic capable of modulating these regulators in vivo. Bulk RNA-sequencing datasets (GSE47681, GSE5296, and a Figshare cohort) were integrated with single-cell RNA-sequencing data (GSE162610). Differential expression analysis, immune-infiltration deconvolution, weighted gene co-expression network analysis, and three machine-learning algorithms (least absolute shrinkage and selection operator, random forest, and support vector machine-recursive feature elimination) were combined to pinpoint key genes that modulate key types of programmed cell death. A two-gene ridge regression score was derived to quantify pathway activity across cohorts. Single-cell mapping and spatial profiling localized the candidate regulators to myeloid lineages within the injury core. Drug-gene interaction screening and molecular docking with AutoDock4 were used to prioritize a clinically available compound, which was then tested in a thoracic level 8 contusion mouse model with electrophysiological, behavioral, and molecular assessments. The integrated analysis converged on Pycard and Casp8 as central co-regulators linking pyroptosis and necroptosis. The two-gene ridge regression score robustly stratified samples in training and independent validation datasets. The score also tracked a temporal surge in the activity of programmed cell death that coincides with peak inflammatory cell infiltration. Drug-gene interaction screening prioritized decitabine, and molecular docking showed binding energies of < -5.0 kcal/mol for Pycard and Casp8. In vivo, mice received intraperitoneal decitabine (1.5 mg/kg daily for 7 days) after injury with blinded assessments. Decitabine reduced activation of NOD-like receptor family pyrin domain containing 3 and phosphorylated mixed lineage kinase domain-like protein. Macrophage polarization was shifted away from an inflammatory phenotype. Motor-evoked potential amplitudes increased, and Basso Mouse Scale locomotor scores improved, indicating mitigation of pyroptosis and necroptosis with functional benefit after spinal cord injury. This work addresses the need for unifying regulators bridging multiple programmed cell death programs after spinal cord injury and a multitarget intervention dampening convergent inflammatory pathways. A reproducible pipeline linking multi-omics integration and ensemble machine learning to therapeutic nomination and in vivo testing was established. The key contributions include the identification of a Pycard-Casp8 inflammatory hub that integrates pyroptosis and necroptosis, the development of a two-gene scoring paradigm that generalizes across datasets and time points, and the demonstration that decitabine functions as a multitarget neuroprotective strategy, resulting in measurable improvements in electrophysiological, behavioral, and molecular outcomes in a mouse model of spinal cord injury.

This study investigates the systemic consequences of spinal cord injury (SCI), with a particular focus on alterations in the gut microbiome and multi-organ transcriptomic responses. We identify a rapid and severe disruption of the gut microbiota-termed "microbiome shock"-that emerges within 12 h post-SCI and persists before gradually resolving by 5 days post-injury. To support further research in this field, we established an open-access resource, the Spinal Cord Injury Gut Microbiome and Multi-Organ Gene Expression Atlas (SCIGAMA).

Stem cell spheroids represent a promising strategy for neural tissue construction and spinal cord injury repair (SCI). However, the stem cell-assembled spheroids lack the extracellular matrix (ECM) as well as the ECM-cell interactions naturally present in tissues, making it difficult to actively tune the stem cell fate and tissue development. Here, we develop a simple and efficient method for the fabrication of collagen micro-fibrils with intact periodic banding and triple-helical structure to serve as the ECM of stem cell spheroids. These uniform-sized and well-dispersed collagen micro-fibrils can be self-assembled with neural stem cells (NSCs) to form engineered spheroids. Similar to the native tissue, the collagen micro-fibrils form a fibrillar network and are distributed uniformly in the engineered spheroids, which led to the alleviation of hypoxia, enhancement of ECM-cell interactions, and improvement in the viability of NSCs. More importantly, these fibrils can serve as reservoirs for differentiation-modulators to precisely guide the neuronal differentiation of NSCs, yielding functional neural microtissues. The collagen micro-fibril-engineered spheroids exhibit superior survival and neuronal differentiation after implantation, accelerating motor and tissue recovery of SCI mice. These collagen micro-fibrils with intact micro-nano structure and collagen micro-fibrils-engineered spheroids hold great potential for the construction of microtissues and SCI repair.

Despite the persistence of spared spinal circuits capable of relaying commands after spinal cord injury (SCI), their contribution to recovery remains constrained by functional dormancy of spared neurons and impaired reconnection across the lesion. Serotonergic neuromodulation is pivotal for reactivating dormant neurons, however, achieving precise targeting and modulation of the serotonergic system poses translational challenges. Here, a DNA/RNA heteroduplex hydrogel is reported that integrates 5-hydroxytryptamine (5-HT)-mediated neuronal excitability restoration with phosphatase and tensin homolog (PTEN)-targeted spinal circuit reconstruction for SCI therapy. The 5-hydroxytryptophan (5-HTP)-derived motif, serving both as a targeting ligand and as a neuromodulator, is site-specifically grafted onto three phosphorothioate-bearing single-stranded DNA (ssDNA) strands, which self-assemble into Y-shaped motifs and are subsequently crosslinked by sticky-ended PTEN small interfering RNA (siRNA) to form the hydrogel network. After lesion-site administration, the hydrogel undergoes DNase-mediated network disassembly into nanogels that exert two complementary therapeutic actions by targeting serotonergic system: restoring excitability to reactivate dormant interneurons and reconstructing descending connectivity to reintegrate spared circuits with the host spinal cord, thereby restoring sensory and locomotor functions in paralyzed mice. This strategy coordinately reinstates functional excitability and structural rebuilding by engaging multiple interlocking mechanisms, advancing a versatile paradigm for integrative therapy of central nervous system (CNS) disorders.

Traumatic spinal cord injury (SCI) is a debilitating condition characterized by the impairment of neural circuits, leading to the loss of motor and sensory functions and accompanied by severe complications. Substantial research has reported the therapeutic potential of Omega-3 fatty acids for the central nervous system, particularly after traumatic SCI. Omega-3 fatty acids may contribute to improving SCI recovery through their anti-inflammatory, anti-oxidative, neurotrophic, and membrane integrity-preserving properties. These functions of Omega-3 fatty acids are primarily mediated via the activation of G protein-coupled receptor 120 (GPR120), commonly known as the fish oil-specific receptor. Advancements in understanding of the molecular mechanisms of GPR120’s recognition of Omega-3 fatty acids and its downstream signaling mechanisms has significantly promoted research on the pharmacological potential of Omega-3 fatty acids and the development of highly selective and high-affinity alternatives. This review aims to provide in-depth analysis of the comprehensive therapeutic potential of Omega-3 fatty acids for SCI and its accompanying complications, and the prospects for developing novel drugs based on the recognition of Omega-3 fatty acids by GPR120.

Neurological injury is often accompanied by extensive infiltration of macrophages along with activation of fibroblasts and endothelial cells. The activity of these cells is associated with elevated levels of various proteases, which contribute to the hydrolysis of multiple proteins, disrupt the extracellular matrix, and further promote the migration of immune cells into uninjured neural tissue. In this study, we combined single-cell sequencing with bulk RNA sequencing data from spinal cord injury to identify up-regulated protease-related differentially expressed genes post-injury. Using gene set variation analysis, least absolute shrinkage and selection operator regression, and random forest methods, we identified adamalysins, serine proteases, and matrix metalloproteinases as key protease types. Weighted gene co-expression network analysis combined with machine learning algorithms helped predict critical protease genes involved in spinal cord injury. Immune infiltration and single-cell analyses were applied to identify cell types enriched in proteases and their spatial localization. Molecular docking and in vivo and in vitro assays using a mouse model of spinal cord injury were used to validate potential drug interactions. We identified Mmp12 and Adam17 as key effectors regulating injury progression, and determined that macrophages, fibroblasts, and monocytes are the primary cells mediating the functions of core proteinases after injury. Subsequent in vivo and in vitro experiments demonstrated that selective inhibition of key protease activity with marimastat reduced axonal demyelination and fibrous scar formation after spinal cord injury, thereby promoting the recovery of neurological function. Our study identified the key proteases that regulate spinal cord injury repair along with their mechanisms of action, and verified that inhibiting these proteases effectively alleviates scar formation and inflammatory cell infiltration, providing novel therapeutic targets for the treatment of spinal cord injury.

Background In vitro models of the blood-spinal cord barrier (BSCB) are widely utilized for developing therapeutics against neurological diseases such as spinal cord injury (SCI). However, high variability among existing in vitro BSCB models severely limits their predictive power for preclinical research, highlighting the need for a comprehensive synthesis of current model characteristics and performance. Methods We first reviewed in vitro BSCB models under SCI conditions and conducted a comprehensive meta-analysis of mainstream Transwell-based models. The synthesis systematically analyzed critical factors influencing model performance, including cell types, disease modeling strategies ( e.g., hypoxic culture, inflammatory stimuli, oxidative stress), and the inclusion of biomaterial matrices. The meta-analysis quantified differences in key BSCB properties, including permeability, transendothelial electrical resistance (TEER), and junctional/inflammatory protein expression, across healthy, diseased, and treatment contexts. Results The synthesis identified cell composition, disease induction methods, and biomaterial matrix inclusion as core factors determining the ability of in vitro BSCB models to replicate physiological and pathological characteristics. Meta-analysis results revealed significant quantitative differences among three types of BSCB models. Specifically, disease models exhibited consistently higher permeability (measured via FITC-dextran) and lower mean TEER values (97.94 Ω·cm 2 ) compared to healthy models (183.73 Ω·cm 2 ) and treatment groups (146.28 Ω·cm 2 ). Additionally, co-culturing BSCB endothelial cells with glial cells or pericytes was demonstrated to significantly enhance the physiological relevance of the models. Conclusions This review consolidates critical insights into in vitro BSCB model design and performance, providing a clear framework for developing more accurate and reliable models. These findings will facilitate the development of effective therapeutic interventions capable of crossing the BSCB, addressing a key bottleneck in mechanistic research and therapeutic development for treating SCI and other neurological diseases.

The combination of neural stem cells (NSCs) and biomaterials holds significant promise for promoting spinal cord injury repair. However, the low neuronal differentiation efficiency of NSCs limits their practical application. In this work, biodegradable piezoelectric/conductive composite silk nanofibers were proposed for regulating the neural differentiation of NSCs through ultrasound-driven piezoelectric stimulation. The core-shell nanofibers were produced via electrospinning using silk fibroin, followed by coating with a layer of reduced graphene oxide (rGO), where ultrasound-driven piezoelectric silk fibers generate electric signals and the conductive rGO layer facilitates transfer of charges to the stem cells. The synergistic effect of the piezoelectricity and conductivity of the core-shell nanofibers prompted increased neuronal NSC differentiation from 18.10% (spontaneous differentiation) to 51.64%. Gene sequencing results showed that synergistic activation of PI3K-AKT and MAPK pathways under SF/rGO and ultrasound stimulation is the primary reason for the efficient neuronal differentiation of NSCs. The living material composed of a core-shell nanofiber membrane coated with NSCs was implanted as a patch onto the site of spinal cord injury in a mouse model. Under in vivo ultrasound induction, the spinal cord injury was repaired within 6 weeks and behavioral performance of model mice was almost fully restored. These silk-rGO core-shell nanofibers, endowed with both piezoelectric and conductive properties, provide a promising strategy for spinal cord repair.

m1A (N1-methyladenosine) is an important epigenetic mechanism that regulates the onset and progression of many diseases, including spinal cord injury (SCI). To investigate the overall changes in m1A following SCI, we analyzed transcriptomic sequencing data from SCI samples and assigned m1A scores based on the levels of m1A regulatory factors. In this study, the m1A score is an inferred proxy calculated from the expression of m1A regulator genes (writers/erasers/readers). It does not directly measure RNA m1A modification levels. Our results show that the m1A score increased within the first day after SCI and then decreased, falling below baseline by day 3 and day 7. Further analysis revealed that microglia and neurons are the two cell types with the most significant changes in the m1A score. In microglia, m1A score decreased at all time points, whereas in neurons, m1A score increased at all time points. Additionally, pseudotime and functional enrichment analyses suggested that the m1A score is associated with microglial phenotypic transition and neuronal energy metabolism, which was further validated by both in vivo and in vitro experiments. In summary, our study unveils the characteristic changes of m1A at both the bulk and single-cell levels following SCI, and suggests potential links to neuronal function and supports the rationale for further studies exploring m1A-related regulators as therapeutic targets in SCI.

Mesenchymal stem cells (MSCs) have been proposed as treatments for degenerative diseases, but clinical outcomes have been inconsistent. Here, we reviewed the ClinicalTrials.gov database and identified ~1,600 trials associated with MSC-based therapies; osteoarthritis (OA) and spinal cord injury (SCI) were most frequently investigated, but the reporting of results was consistently low (<7%). We next searched the PubMed database and identified 26 OA and 16 SCI published trials, which included studies from one or both databases. Our analysis identified a common set of factors that influenced therapeutic efficacy in both diseases, including MSC source, donor type, dose/route & frequency of administration, and patient variation. Of these, three factors were significant for improving efficacy. MSC quality is affected by age of the donor, and this is especially important when treating older OA patients with autologous MSCs. Phase of the disease is important, and both OA and SCI may benefit from early treatment, since MSCs can ameliorate inflammation and initiate tissue repair. MSC source is critical as allogenic MSCs are no longer considered "immune privileged", and autologous cells can differentiate and repair damaged tissue without immune interference. The results of this narrative literature review suggest that establishing a personal autologous MSC bank may be an essential component for achieving success with MSC-based therapies, since MSCs from this repository could be deployed early, ameliorate inflammation, and initiate repair of damaged tissues.

Cell therapy shows great promise for healing neurodegenerative disorders and spinal cord injuries, using approaches for example neural stem cells (NSCs), bone marrow mesenchymal stem cells (BMSCs), and the secretions of cells. However, ethical limitations associated with NSCs and the difficulty of inducing BMSCs differentiation into neurons restrict apply cell-based therapies and tissue engineering to clinical practice. Exosomes-cell-derived vesicles involved in processes such as intercellular communication-offer a potential alternative. This study reports a facile strategy for promoting differentiation through exosomes use piezoelectric nanomaterials combine with ultrasonic to provoke wireless electrical stimulation. A beta-phase poly (vinylidene fluoride) (beta-PVDF) membrane with favorable piezoelectric properties released electrons upon mechanical deformation, producing self-powered electrical signals. These signals significantly enhanced exosome production by BMSCs. The resulting exosomes were then used to promote differentiation of NSCs. This efficient and simple strategy not only promotes NSCs differentiation but also overcomes ethical and sustainability challenges associated with traditional stem-cell therapies, which is essential for their clinical application.

Spinal cord injury (SCI) repair has been a great challenge worldwide because of its complex regeneration mechanisms and limited self-healing. The biomimetic construction of a bioactive scaffold represents a promising direction for SCI repair. Inspired by the efficient self-healing properties of the neonatal spinal cord, this study developed a neonatal spinal-cord-like scaffold (NSLS) aimed at regulating SCI repair at different stages. The NSLS features a neonatal spinal cord matrix, multilevel biomimetic structures, and matching mechanical strength via personalized laser processing and dual-network cross-linking. The microenvironments of the NSLS activate energy metabolism, synaptic formation, and the gliogenesis of neural stem cells (NSCs). Notably, the NSLS could achieve rapid hemostasis and integration with the host spinal cord, facilitating nutrient infiltration and establishing a stable connection in the early stage. Furthermore, NSCs loaded with NSLS (NSLT) promoted nerve repair by promoting microglial M2 polarization to decrease local inflammatory responses in the intermediate stage. Finally, axons grow directionally within the channels and form new connections to enhance neural repair and functional recovery in the late stage. Therefore, NSLT could significantly enhance nerve regeneration and functional recovery after SCI via stage-specific regulation.

While extracellular electrical stimulation for neural repair is established, intracellular electrostimulation remains underexplored. This study proposes an intracellular wireless nanodischarge (IWND) system that leverages electromagnetic induction, with endocytosed multishell gold nanoparticles (MS-Au NPs) serving as electromagnetic dischargers inside neural stem cells (NSCs). An external rotating magnetic field (RMF) above the NSCs is employed as a transmitter to trigger an induced electric charge. In vitro, the IWND system accelerates neuronal differentiation, achieving a 5-day advancement and enhancing the mature neuron yield from 15.9% to 49.8%, mainly cholinergic and dopaminergic phenotypes, which are pivotal neuronal populations governing motor coordination and cognitive function. Mechanistically, a moderate concentration of reactive oxygen species (ROS), originating from the electrocatalytic reactions based on wireless nanodischarge-mediated electrogenesis, activates the extracellular signal-related kinase (ERK) signaling cascade, forming a key signaling axis in IWND-driven neural differentiation through controlled oxidative signaling. In vivo experiments demonstrate that transplantation of MS-Au NP-internalized NSCs in combination with external magnetic stimulation significantly restores motor function in mice with spinal cord injury, primarily through differentiation into functional neurons. This study establishes a platform for developing spatiotemporally precise stem cell therapies through intracellular bioelectrical modulation, offering new possibilities for neural circuit reconstruction in neurological disorders.

Three-dimensional (3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair, with gelatin methacrylate being particularly favored owing to its excellent biocompatibility. However, traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment. Therefore, there is a need to develop smart scaffolds with drug delivery and immune regulation functions. In this study, a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner. The scaffold showed good mechanical properties, biocompatibility, and sustained interferon regulatory factor 4 release. The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5, and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization, thereby facilitating neural regeneration and recovery of spinal cord function. This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis, improve the inflammatory microenvironment after spinal cord injury, and thus provide a new target for promoting neural regeneration.

BACKGROUND:Chronic post-surgical pain (CPSP) brings health and financial burdens to patients and impairs quality of life after surgery. Smoking as a lifestyle factor plays an important role in management of chronic pain and its subtypes (e.g., CPSP). However, the impact of smoking on CPSP has not been fully elucidated due to limitations in smoking classification and the lack of secondhand smoke (SHS) exposure in previous studies. Therefore, this study aimed to comprehensively evaluate the association of current smoking and SHS exposure with the risk of CPSP. MATERIALS AND METHODS:We conducted a cohort study using UK Biobank participants who underwent surgery between 2006-2010 and 2019-2020. Participants were categorized into non-current smokers without SHS exposure, non-current smokers with SHS exposure, and current smokers. We used logistic regression models to assess the association of current smoking and SHS exposure with the risk of CPSP reporting odds ratios with 95% confidence intervals. Subgroup analyses stratified by sociodemographic variables (sex, ethnicity, education, and deprivation) were conducted. RESULTS:Of 97,821 participants, with a mean ± SD age of 56.5 ± 7.6 years, 3,509 (3.6%) reported CPSP. The risk of CPSP was significantly increased in non-current smokers with SHS exposure (4.6%, 1.30 [1.19-1.41]) and current smokers (4.8%, 1.37 [1.22-1.55]), compared with non-current smokers without SHS exposure (3.2%). The tendency for smoking to increase the risk of CPSP existed across all sociodemographic subgroups (e.g., males: 1.18 [1.04-1.35] in non-current smokers with SHS exposure and 1.35 [1.13 to 1.60] in current smokers; females: 1.39 [1.24-1.56] in non-current smokers with SHS exposure and 1.38 [1.16-1.64] in current smokers). CONCLUSION:SHS exposure may be as detrimental to the development of CPSP as being a current smoker.

BACKGROUND:Osteoporosis is a widespread metabolic bone disorder characterized by reduced bone mass and increased fracture risk, particularly in postmenopausal women due to estrogen deficiency. This hormonal decline enhances osteoclast activity, leading to excessive bone resorption. Current therapies are limited by long-term safety concerns, necessitating alternative treatments. Methylnissolin (Astrapterocarpan), a bioactive flavonoid from Astragalus membranaceus, has known anti-inflammatory and antioxidant properties, but its role in bone metabolism remains poorly defined. PURPOSE:This study aimed to elucidate the molecular mechanisms by which Methylnissolin regulates osteoclastogenesis and bone resorption, and to evaluate its therapeutic potential in osteoporosis. METHODS:Network pharmacology identified MAPK1 and AKT1 as potential molecular targets of Methylnissolin in osteoporosis. In vitro assays were performed to assess osteoclast formation and bone resorption in response to Methylnissolin. PCR and Western blotting were used to evaluate its effects on signaling pathways and gene expression. ROS levels and antioxidant enzyme expression were also measured. An ovariectomized (OVX) mouse model was used to assess in vivo efficacy and safety. RESULTS:Methylnissolin inhibited osteoclast differentiation and resorptive activity in a dose- and time-dependent manner. It suppressed MAPK1 and AKT1 phosphorylation, reduced ROS levels, and upregulated antioxidant enzymes. These effects led to downregulation of key osteoclastogenic markers at both gene and protein levels. In OVX mice, Methylnissolin significantly improved trabecular bone parameters without detectable toxicity. CONCLUSION:Methylnissolin is a novel osteoclast inhibitor that acts via coordinated suppression of MAPK/AKT signaling and oxidative stress. These findings support its potential as a safe and effective therapeutic candidate for postmenopausal osteoporosis.

The advancement of transient electronics for biomedical applications has created an urgent demand for bioimplantable and bioresorbable power supplies that can safely operate in biological environments. Conventional battery technologies face significant limitations, including a non-degradable nature, rigid structure, and potential toxicity, which hinder their integration with bioresorbable electronic devices or systems. In this study, we demonstrate a bioimplantable and bioresorbable zinc-ion battery (BZIB) using a guar gum/gelatin/Zn2+ (GG-Zn)based biomacromolecule hydrogel as a quasi-solid electrolyte. Owing to the pure biological source and ion crosslinking strategy of the GG-Zn electrolyte, the battery exhibits good biocompatibility, mechanical properties, and energy storage performance and can harmlessly resorb in animal models within 12 weeks. Moreover, in vivo assessments conducted in rodent models demonstrate that the degradation of BZIB does not induce histopathological alterations in vital organs (including cardiac, hepatic, splenic, pulmonary, and renal tissues) or significant deviations of hematological parameters, validating its favorable biocompatibility. To explore the potential applications of BZIBs, the effect of the direct current electrical stimulation on the differentiation of neural stem cells (NSCs) is investigated by combining the BZIB with a biodegradable electroactive region comprising dual electrodes and a silk fibroin substrate. The promoted differentiation of NSCs into functional neurons capable of transmitting neural impulses is realized by electrical stimulation with the developed BZIBs, suggesting their broad application prospects in the treatment of neurodegenerative diseases.