Search Results (1,461)

Background: Ionizing radiation (IR) induces profound bone marrow (BM) injury by disrupting hematopoietic stem cell (HSC) homeostasis, leading to acute myelosuppression and long-term hematopoietic dysfunction. Although transcriptome-wide analyses have advanced our understanding of radiation responses, the key molecular networks and hub genes governing post-irradiation BM injury remain incompletely defined. Methods: This study aimed to systematically identify radiation-responsive pathways and central genes in BM after irradiation through an integrative bioinformatics approach based on RNA sequencing (RNA-seq). Public RNA-seq data from mouse BM HSCs collected 3 days after whole-body irradiation were analyzed. Differentially expressed genes (DEGs) were identified using two independent statistical frameworks to improve the robustness of the results. Functional analysis was performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Protein–protein interaction (PPI) networks were constructed using STRING, and hub genes were identified using network topology parameters. Results: Both analysis pathways consistently demonstrated extensive transcriptome reprogramming after irradiation. DEGs were primarily enriched in processes related to cytokine signaling, hematopoietic lineage regulation, immune response, and extracellular matrix remodeling. KEGG analysis highlighted cytokine–cytokine receptor interaction, hematopoietic cell lineage, JAK-STAT signaling, and PI3K-Akt signaling as key molecular axes. GSEA further supported coordinated changes in pathways related to inflammatory response, stress response, and metabolic reprogramming. PPI network analysis identified four consensus hub genes, namely Il6, Cd34, Gypa, and Pdgfrb, which are related to inflammatory signaling, hematopoietic regulation, erythroid dynamics, and microenvironmental remodeling, respectively. Conclusion: This integrative bioinformatics study demonstrates that radiation-induced BM injury is associated with coordinated activation of inflammatory cytokine networks, alterations in the hematopoietic program, and microenvironmental restructuring. The hub genes identified in this study may represent candidate regulatory genes or molecular indicators potentially involved in the response to radiation-induced hematopoietic damage. Full article

Background: Infections caused by multidrug-resistant bacteria and inadequate vaccine coverage against opportunistic pathogens highlight the need for interventions that broadly and durably enhance host defense beyond antigen-specific adaptive immunity. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, has been predominantly characterized using Bacille Calmette–Guérin and β-glucan, whereas its induction by Gram-negative bacteria remains poorly defined. To address this gap, we aimed to determine whether heat-killed Klebsiella pneumoniae (HK Kp) induces trained immunity through metabolic and hematopoietic reprogramming to confer heterologous antibacterial protection. Methods: HK Kp-trained murine bone marrow-derived macrophages and HK Kp-immunized C57BL/6 mice were employed to interrogate functional, metabolic, and transcriptomic reprogramming in vitro, hematopoietic progenitor remodeling in vivo, and protective efficacy against systemic Salmonella Typhimurium and Staphylococcus aureus infection. Results: HK Kp-trained macrophages showed markedly enhanced IL-1β secretion across all restimulation conditions, stimulus-dependent amplification of TNF-α responses, increased phagocytosis, and improved intracellular control of S. typhimurium, together with sustained upregulation of the glycolytic enzymes-encoding genes Hk2 and Pfkfb3. Transcriptomic profiling revealed extensive reprogramming enriched in glycolysis/gluconeogenesis and hematopoietic cell lineage pathways. In vivo, HK Kp immunization shifted bone marrow stem/progenitor compartments toward a myeloid-biased state. HK Kp-trained mice challenged with lethal S. typhimurium or S. aureus exhibited less weight loss, improved survival rates, and reduced bacterial burdens. Conclusions: Inactivated K. pneumoniae orchestrates metabolic and hematopoietic reprogramming to establish enhanced innate immune responsiveness and confer heterologous protection in murine S. typhimurium and S. aureus sepsis models, supporting its potential as a potent inducer of trained immunity. These findings establish HK Kp-based trained immunity as a promising strategy for combating multidrug-resistant and vaccine-evading pathogens. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

Chronic alcohol consumption increases the risk of osteoporosis and fracture by disrupting bone remodeling, in part by enhancing osteoclastogenesis. However, the cellular mechanisms underlying this process remain incompletely defined. We analyzed scRNA-seq data from osteoclasts differentiated in vitro from bone marrow mononuclear cells obtained from macaques following 12 months of chronic ethanol or isocaloric control solution consumption. Module scoring, trajectory inference with generalized additive modeling (tradeSeq), and CellChat-based analyses of intercellular communication were applied to uncover ethanol-induced changes in metabolic reprogramming, lineage progression, and signaling network dynamics. Module scoring indicated metabolic reprogramming toward oxidative phosphorylation, with reduced glycolytic, migratory, and phagocytic activities. Pseudotime analysis revealed accelerated osteoclast lineage commitment, broader intermediate differentiation states, and stabilization of mature osteoclasts. CellChat analysis showed globally amplified intercellular signaling, with mature osteoclasts functioning as dominant communication hubs sustained by autocrine feedback. Together, chronic alcohol consumption rewired osteoclastogenesis through early fate priming, metabolic adaptation, and hierarchical remodeling of intercellular communication, promoting enhanced osteoclastogenesis. These findings provide mechanistic insight into alcohol-induced bone pathology and highlight potential targets for therapeutic intervention. Full article

Osteocalcin (OCN) is increasingly recognized as a multifunctional hormone whose actions extend far beyond its traditional role as a marker of bone turnover. This review provides an integrated examination of the molecular, endocrine, and translational dimensions of osteocalcin biology, with emphasis on its bioactive undercarboxylated form (ucOCN), which links skeletal remodeling to systemic physiological processes. The structural determinants, biosynthetic pathways, and vitamin K-dependent carboxylation mechanisms underlying OCN isoform diversity are summarized, together with analytical limitations arising from assay variability and differences between N-MID and ucOCN-specific measurements. Mechanistic evidence demonstrates that ucOCN signals through GPRC6A and GPR158 to modulate insulin secretion, muscle glucose uptake, adipokine production, testosterone synthesis, neurocognitive function, hepatic lipid metabolism, and acute stress response. These receptor-level pathways position osteocalcin as a central regulator at the intersection of bone metabolism and whole-body homeostasis. The review synthesizes data across major clinical contexts, including metabolic syndrome, type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease–mineral and bone disorder (CKD-MBD), cardiovascular dysfunction, and neurodegeneration, highlighting the modifying influence of vitamin K status, circadian rhythms, renal clearance, and local tissue microenvironments. The need for biomarker standardization, methodological harmonization, and receptor-targeted translational strategies is emphasized, alongside emerging therapeutic concepts involving vitamin K supplementation and exercise-induced activation of OCN. Collectively, the evidence reframes osteocalcin as a versatile endocrine mediator at the interface of bone physiology, systemic metabolic regulation, and disease mechanisms. Full article

Quercetin (QE) is a widely distributed dietary flavonol with antioxidant and anti-inflammatory properties that has attracted interest as a modulator of bone remodeling and osteoporosis-related bone loss. In vitro data on osteoblasts, osteoclasts, and mesenchymal stem cells indicate that QE attenuates oxidative stress, suppresses pro-inflammatory signaling, and promotes osteogenic differentiation through modulation of pathways such as Nrf2/ARE, NF-κB, Wnt/β-catenin, and ER stress-related cascades. In vivo findings from animal models of estrogen deficiency, diabetes, and glucocorticoid-induced osteoporosis demonstrate that QE improves bone mineral density, trabecular microarchitecture, and biomechanical strength while reducing osteoclast number and activity, thereby attenuating osteoporotic bone deterioration. Collectively, preclinical evidence positions QE as a pleiotropic agent promoting osteoblastogenesis, inhibiting osteoclastogenesis, and balancing redox/inflammatory homeostasis in bone, despite bioavailability challenges. Future research should prioritize clinical trials with optimized formulations (e.g., nanoparticles) to validate efficacy, safety, and fracture outcomes in humans. The present review critically evaluates the chemical characteristics, pharmacokinetics, safety profile, and bone-targeted biological activity of QE, emphasizing effects on bone cells and skeletal metabolism. Full article

Snakebite envenoming remains a major global health challenge. Naja atra (N. atra) envenomation induces severe acute kidney injury (AKI), largely driven by snake venom phospholipase A₂ (SVPLA₂). Increasing evidence suggests that immune dysregulation, in addition to direct cytotoxicity, contributes to delayed renal injury. Here, we investigated whether N. atra SVPLA₂ exposure is associated with macrophage immunometabolic remodeling and functional changes relevant to AKI progression. In vivo, AKI was induced in C57BL/6J mice by intraperitoneal administration of N. atra venom, followed by treatment with the SVPLA₂ inhibitor varespladib. In vitro, bone marrow–derived macrophages were exposed to venom with or without varespladib. N. atra venom exposure was associated with extensive tubular apoptosis, increased renal macrophage abundance, and elevated kidney injury biomarkers. Macrophages exhibited a shift toward a pro-inflammatory polarization signature accompanied by reduced efferocytic capacity. Targeted metabolomics revealed coordinated increases in glycolytic intermediates together with upregulation of key glycolytic enzymes. Pharmacological inhibition of SVPLA₂ partially restored macrophage metabolic features and efferocytic capacity and was accompanied by attenuation of renal injury. Together, these findings support a model in which SVPLA₂ exposure is associated with macrophage immunometabolic remodeling and impaired apoptotic cell clearance during venom-induced AKI. Full article

Background: Orthodontic tooth movement is traditionally explained through mechanical deformation of the periodontal ligament (PDL); however, increasing evidence indicates that immune mechanisms critically shape bone remodeling outcomes. Mechanical stimuli influence immune cell recruitment, cytokine release, and phenotypic polarization, but these components are rarely integrated into a unified framework. Conceptual framework: We propose the Osteoimmune Axis Model, a conceptual framework describing how mechanical loading may bias immune polarity and thereby gate periodontal remodeling. Compressive loading appears to favor an M1 macrophage/Th17-dominant program associated with pro-inflammatory cytokines and enhanced RANKL-mediated osteoclastogenesis. In contrast, tensile or physiological strains may favor M2 macrophages and regulatory T cells (Treg), supporting IL-10, TGF-β, angiogenesis, extracellular-matrix repair, and osteoblastic activity. Stromal cells are proposed to act as mechanosensors and immune amplifiers that shape cytokine gradients and feedback loops. Predictions: The model predicts that identical forces may produce divergent outcomes depending on immune baseline; load duration may be more destructive than peak magnitude; tensile strain may stabilize M2/Treg pathways; thin periodontal phenotypes may shift toward the catabolic pole at lower mechanical loads; ROS may amplify immune-mediated bone loss; and immunomodulation may raise the threshold for pathological remodeling. Conclusion: The Osteoimmune Axis integrates mechanobiology and immunology into a testable framework for explaining variability in orthodontic periodontal remodeling and for generating hypothesis-driven, immune-aware risk assessment. Full article

Osteosarcoma (OS), the most common primary malignant bone tumor in children and young adults, is characterized by aggressive behavior, frequent metastasis, and resistance to chemotherapy, resulting in poor clinical outcomes. Increasing evidence indicates that OS progression is not solely driven by tumor-intrinsic factors but is strongly influenced by dynamic interactions within the tumor microenvironment (TME). This literature review synthesizes current research on the roles of endothelial cells, fibroblasts, mesenchymal stromal cells, immune populations, and osteoclasts in OS pathogenesis, with emphasis on cell–cell interactions mediated by direct contact, soluble factors, and extracellular vesicles. The studies demonstrate that these interactions promote tumor proliferation, immune evasion, extracellular matrix remodeling, metastatic dissemination, and therapeutic resistance. Adaptive responses of both tumor and stromal cells to environmental stressors contribute to chemoresistance and disease progression. Collectively, our findings highlight the multifactorial nature of OS driven by complex cellular crosstalk within the TME. Understanding these mechanisms highlights the limitations of conventional chemotherapy and encourages the development of combined therapeutic approaches, including targeted therapies, immunomodulation, and microenvironmental interventions. Continued investigation into tumor–microenvironment interactions may facilitate the identification of actionable targets and improve personalized treatment approaches for OS. Full article

Osteoarthritis (OA) represents a degenerative joint disease which advances through cartilage breakdown, synovial inflammation, and subchondral bone transformation until it causes persistent pain and mobility loss. The scientific community lacks complete knowledge about OA disease mechanisms and post-operative healing processes despite arthroplasty surgery providing effective symptom relief. This study investigated plasma proteomic changes in OA patients before and after arthroplasty. The cohort included eight OA patients undergoing knee or hip arthroplasty and ten age-, sex-, and body mass index-matched healthy controls. Plasma proteins were analyzed using liquid chromatography–tandem mass spectrometry following enzymatic digestion and depletion of high-abundance components. The bioinformatic analysis together with quantitative methods showed that OA patients experienced changes in inflammatory pathways, extracellular matrix remodeling, immune system regulation and coagulation processes. A total of 93 proteins were differentially abundant in the pre-operative comparison. Among these, 63 proteins were consistently up-regulated and 23 were consistently down-regulated across both pre- and post-operative time points. In addition, 20 proteins exhibited post-operative-specific changes. These findings highlight both persistent disease-associated alterations and transient proteomic shifts linked to post-operative recovery. Overall, this study identifies candidate plasma proteomic signatures associated with OA and surgical intervention, providing exploratory insights into disease monitoring and potential personalized therapeutic strategies. Full article

This study presents an optimization tool inspired by bone remodeling principles to address the high computational costs of truss topology optimization. Additionally, a new structural analysis method based on primary forces is proposed to overcome the kinematic stability problem. The strategy developed to obtain the optimal topology optimizes the initial dense ground structure in two stages. In Phase I, unnecessary members in the system are filtered to determine the “primary candidate members”; in Phase II, the final topology is reached through this refined subset. The algorithm performs an effective search in the design space by simulating biological processes that link the rate of mass change in the bone matrix to mechanical stimuli. Numerical results demonstrate high accuracy, as shown by the analytical solution of the 2D Michell truss, with a difference of 1.02%. The results show high consistency with reference studies, providing, in some cases, alternative topologies with the same weight and stiffness as given in the benchmarks. The proposed method achieves significant improvements in computational efficiency, reducing processing times for larger systems by 10 to over 250 times compared to literature benchmarks. Full article

7-ketocholesterol (7-KC) is a bioactive oxysterol generated under oxidative stress and may contribute to bone marrow niche reprogramming in acute myeloid leukemia (AML), thereby promoting stress tolerance and therapeutic resistance Bone marrow mesenchymal stromal cells (MSCs) from healthy donors and AML patients were exposed to subtoxic 7-KC concentrations for 24 h. We evaluated the ABC transporters involved in lipid transport, multidrug resistance and membrane microdomain remodeling; Hedgehog pathway proteins; stress–survival signaling; redox balance by glutathione measurements, and mitochondrial function and dynamics, including membrane potential and gene expression of mitochondrial fission and fusion regulators. Results were integrated using principal component analysis (PCA), heatmaps, and correlation-based networks. Multivariate analyses revealed an integrated, lineage-dependent response. Healthy donor MSCs showed greater plasticity of the efflux and microdomain axis and higher oxidative and mitochondrial vulnerability at high 7-KC doses. AML-MSCs exhibited a basal preconditioned state phenotype and preferentially routed the response toward Hedgehog and stress–survival modules, accompanied by glutathione expansion and adaptive mitochondrial remodeling. 7-KC acts as a broad modulator of several MSC functions, linking sterol homeostasis to Hedgehog signaling, stress–survival pathways, redox balance, and mitochondrial remodeling, potentially supporting a pro-survival, more therapy-tolerant leukemic niche. Full article

Bone is a dynamic and multifunctional tissue that provides mechanical support, regulates mineral homeostasis, supports hematopoiesis, and relies on complex interactions among multiple cell types. The increasing incidence of bone-related diseases, such as osteoporosis, osteoarthritis, fracture non-union, and bone cancer, highlights the need for in vitro models that better reflect human bone physiology. Bone-on-a-chip technology, developed through advances in microfluidics, biomaterials, and tissue engineering, offers a promising approach to recreate key features of the bone microenvironment in vitro. By incorporating bone-mimicking materials, relevant bone cells, vascular components, fluid perfusion, and mechanical stimulation, these platforms allow more realistic investigation of bone remodeling, regeneration, disease mechanisms, and drug responses. In parallel, bone organoids and their integration with microfluidic chips have further expanded the capabilities of in vitro bone models by enabling the formation of self-organized, human-relevant bone tissues with increased cellular complexity. This review summarizes recent progress in bone-on-a-chip systems, including models for osteogenesis and bone regeneration, vascularized bone, bone marrow and hematopoietic niches, cancer bone metastasis, and mechanobiological studies. Key design principles, materials, cellular components, and applications in disease modeling, drug screening, toxicity assessment, and personalized medicine are discussed. Current challenges and future directions are also discussed to support the continued development of more physiologically relevant in vitro bone models. Full article

Purpose: Osteotoxicity is a well-recognized adverse effect of Methotrexate (MTX) therapy, primarily driven by oxidative stress and impaired bone remodeling. This study aimed to investigate the protective effects of Tempol, a membrane-permeable nitroxide antioxidant, against MTX-induced osteotoxicity, and to assess how these effects are influenced by ML210, a glutathione peroxidase 4 (GPX4) inhibitor. Methods: Murine osteocyte-like MLO-Y4 cells were treated with MTX alone, Tempol alone, or a combination of MTX with Tempol and ML210. Apoptotic markers (caspase-3, Bax, Bcl-2), MAPK signaling proteins (p-JNK, p-ERK), and oxidative stress parameters (TAS, TOS, SOD, GPx) were measured via ELISA to evaluate the redox and apoptotic responses. Results: MTX significantly induced apoptosis, as evidenced by increased caspase-3 activity and Bax expression, along with decreased Bcl-2 levels. MTX also activated the MAPK pathway by upregulating p-JNK and p-ERK. Furthermore, MTX decreased TAS, SOD, and GPx levels, while increasing TOS. Tempol treatment successfully reversed these effects, restoring apoptotic balance, inhibiting MAPK activation, and enhancing antioxidant capacity. However, co-treatment with ML210 markedly attenuated Tempol’s protective effects, resulting in sustained oxidative stress, elevated apoptotic markers, and persistent MAPK pathway activation. This suggests that Tempol’s cytoprotective actions are dependent on functional GPX4 activity. Conclusion: Tempol exhibits strong potential as an adjunctive antioxidant therapy to counteract MTX-induced osteotoxicity. Nevertheless, its efficacy is significantly influenced by the status of the endogenous antioxidant enzyme GPX4. These findings underscore the need for further investigation into Tempol’s mechanism of action in redox-dependent pathways and its suitability in clinical settings, especially where GPX4 function may be compromised. Full article

Background: The management of bone defects in pediatric oncology represents a major challenge in orthopedics, as it requires preserving both joint function and skeletal growth. Traditional reconstructive approaches, such as autografts and allografts, are limited by availability, complications, and incomplete biological integration. In this context, xeno-hybrid bone substitutes have emerged as a promising alternative. The aim of this study was to evaluate the safety and effectiveness of SmartBone^® ORTHO in the reconstruction of post-oncological bone defects in children. Methods: Twelve pediatric patients treated at the Centro Traumatologico Ortopedico (CTO) and OIRM Hospital, AOU Città della Salute e della Scienza of Turin (Italy), between 2016 and 2019 were retrospectively analyzed. Lesions included simple and aneurysmal bone cysts, non-ossifying fibroma, chondroblastoma, and other benign conditions. All patients underwent curettage followed by defect filling with SmartBone^® ORTHO. Results: At clinical and radiological follow-up, nine patients (75%) showed stable graft integration and complete functional recovery. Three patients (25%) developed local recurrence, which was managed with revision surgery and re-implantation of SmartBone^®, with all achieving stable outcomes. Radiographs demonstrated progressive increases in bone density and trabecular thickness, reaching values comparable to those of native bone within 6–12 months. Conclusions: SmartBone^® ORTHO proved to be a safe and effective biomaterial for pediatric post-oncological bone reconstruction, promoting rapid osteointegration and physiological bone remodeling without infection or intolerance. Full article